Podcast appearances and mentions of David Liu

In this episode, I sit down with David Liu, founder of Brittle Fluid, to discuss his fascinating journey from mechanical engineering student to software entrepreneur. David shares his evolution from Harbor Freight mini-mill hobbyist to professional machine shop owner, and his experiences at Neuralink and Atomic Machines. We explore his current ventures creating software tools like Tool Trace and Rocket Brackets that reduce friction in manufacturing workflows, the importance of relationships in the industry, and his vision for the future of US manufacturing. David also offers insights on the value of "sending it" - trying new things without fear - and his philosophy on supporting the machinist community through technology.Check out Dave's IG @davidliuxyzAnd his X at https://x.com/davidliuxyzGo make some foam at https://www.tooltrace.com/and some brackets at https://www.rocketbrackets.com/-----------------------------------------Help support the podcast at the link in bio#instamachinist #withintolerancepodcast

What if we could rewrite the code of life—just like editing a Word doc?Gene-editing pioneer David Liu takes us behind the scenes of the revolutionary tools transforming medicine. He's the Harvard scientist who invented base editing—a breakthrough that lets scientists fix a single DNA letter to correct genetic disease at its root.This is science fiction come to life—and it's happening now. He edits DNA like we edit text. Come meet the man who's changing lives, one letter at a time. 

Doctors in the US have become the first to treat a baby with a customised gene-editing therapy after diagnosing the child with a severe genetic disorder that kills about half of those affected in early infancy. Ian Sample explains to Madeleine Finlay how this new therapy works and how it paves the way for even more complex gene editing techniques. David Liu, a professor at the Broad Institute of MIT and Harvard and the inventor of these therapies, also describes the barriers that could prevent them reaching patients, and how he thinks they can be overcome. Help support our independent journalism at theguardian.com/sciencepod

Sandra Cho and David Liu give their thoughts on auto tariffs. They discuss the uncertainty around the exact rate or the amount that car prices will rise. David sees short-term increases especially. Sandra says history could repeat itself, citing the 1930s where tariffs drove the economy deeper into recession. She also talks about how many manufacturers make the parts for a single car in multiple countries, meaning that a percentage of the car would be subject to tariffs.======== Schwab Network ========Empowering every investor and trader, every market day.Subscribe to the Market Minute newsletter - https://schwabnetwork.com/subscribeDownload the iOS app - https://apps.apple.com/us/app/schwab-network/id1460719185Download the Amazon Fire Tv App - https://www.amazon.com/TD-Ameritrade-Network/dp/B07KRD76C7Watch on Sling - https://watch.sling.com/1/asset/191928615bd8d47686f94682aefaa007/watchWatch on Vizio - https://www.vizio.com/en/watchfreeplus-exploreWatch on DistroTV - https://www.distro.tv/live/schwab-network/Follow us on X – https://twitter.com/schwabnetworkFollow us on Facebook – https://www.facebook.com/schwabnetworkFollow us on LinkedIn - https://www.linkedin.com/company/schwab-network/About Schwab Network - https://schwabnetwork.com/about

David Liu, CEO & Co-Founder, Plus joined Grayson Brulte on The Road to Autonomy podcast to discuss Plus' global vision for autonomous trucking.Plus is taking a global approach to autonomous trucking as a technology enabler rather than a fleet operator with three global OEM partnerships with Traton Group, Hyundai Commercial Vehicle, and IVECO. These partnerships are enabling Plus to focus solely on building a virtual driver, while the partners develop and build the physical truck. Currently Plus is testing their autonomous driving software in the United States, Sweden, and Japan as they prepare for commercial operations in 2027 with their OEM partners. Recorded on Wednesday, December 18, 2024Episode Chapters0:00 Founding of Plus2:55 Is 2025 The Year Autonomy Goes Mainstream?5:24 Plus / Traton Partnership 7:06 Plus / Hyundai Commercial Vehicle Partnership8:38 Partnership Development 12:09 Global Testing, Development and Operations14:54 Data Models17:06 Low Power / Small On-Board Hardware23:53 Vision Only27:28 Redundancy 29:53 Developing and Maintaining Trust 32:49 Plus Business Model36:17 Advancements in AI 41:09 Future of Plus--------About The Road to AutonomyThe Road to Autonomy® is a leading source of data, insight and commentary on autonomous vehicles/trucks and the emerging autonomy economy™.Sign up for This Week in The Autonomy Economy newsletter: https://www.roadtoautonomy.com/autonomy-economy/See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

With new health-related trackers and devices coming to consumers in droves (led by Apple and other Big Tech companies), will we be heading down the path where every waking (and sleeping) moment is being tracked for health data? Will the future be better (being able to become healthier through data monitoring) or worse (tracking data sold off to companies for advertising or stolen by hackers)? David Liu, CEO of Sonde Health, joins the show to discuss the pros and cons of this new era of health data tracking, and how consumers and companies should brave these waters.

When I think of digital biology, I think of Patrick Hsu—he's the prototype, a rarified talent in both life and computer science, who recently led the team that discovered bridge RNAs, what may be considered CRISPR 3.0 for genome editing, and is building new generative A.I. models for life science. You might call them LLLMs-large language of life models. He is Co-Founder and a Core Investigator of the Arc Institute and Assistant Professor of Bioengineering and Deb Faculty Fellow at the University of California, Berkeley.Above is a brief snippet of our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Here's the transcript with links to the audio and external links to relevant papers and things we discussed.Eric Topol (00:06):Well hello, it's Eric Topol with Ground Truths and I'm really delighted to have with me today Patrick Hsu. Patrick is a co-founder and core investigator at the Arc Institute and he is also on the faculty at the University of California Berkeley. And he has been lighting things up in the world of genome editing and AI and we have a lot to talk about. So welcome, Patrick.Patrick Hsu (00:29):Thanks so much. I'm looking forward to it. Appreciate you having me on, Eric.The Arc InstituteEric Topol (00:33):Well, the first thing I'd like to get into, because you're into so many important things, but one that stands out of course is this Arc Institute with Patrick Collison who I guess if you can tell us a bit about how you two young guys got to meet and developed something that's really quite unique that I think brings together investigators at Stanford, UCSF, and Berkeley. Is that right? So maybe you can give us the skinny about you and Patrick and how all this got going.Patrick Hsu (01:05):Yeah, sure. That sounds great. So we started Arc with Patrick C and with Silvana Konermann, a longtime colleague and chemistry faculty at Stanford about three years ago now, though we've been physically operational just over two years and we're an independent research institute working at the interface of biomedical science and machine learning. And we have a few different aspects of our model, but our overall mission is to understand and treat complex human diseases. And we have three pillars to our model. We have this PI driven side of the house where we centrally fund our investigators so that they don't have to write grants and work on their very best ideas. We have a technical staff side of the house more like you'd see in a frontier AI lab or in biotech industry where we have professional teams of R&D scientists working cross-functionally on higher level organizational wide goals that we call our institute initiatives.(02:05):One focused on Alzheimer's disease experimentally and one that we call a virtual cell initiative to simulate human biology with AI foundation models. And our third pillar over time is to have things not just end up as academic papers, but really get things out into the real world as products or as medicines that can actually help patients on the translational side. And so, we thought that some really important scientific programs could be unlocked by enabling new organizational models and we are experimenting at the institutional scale with how we can better organize and incentivize and support scientists to reach these long-term capability breakthroughs.Patrick, Patrick and SilvanaEric Topol (02:52):So the two Patrick's. How did you, one Patrick I guess is a multi-billionaire from Stripe and then there's you who I suspect maybe not quite as wealthy as the other Patrick, how did you guys come together to do this extraordinary thing?Patrick Hsu (03:08):Yeah, no, science is certainly expensive. I met Patrick originally through Silvana actually. They actually met, so funny trivia, all three Arc founders did high school science together. Patrick and Silvana originally met in the European version of the European Young Scientist competition in high school. And Silvana and I met during our PhDs in her case at MIT and I was at Harvard, but we met at the Broad Institute sort of also a collaborative Harvard, MIT and Harvard hospitals Institute based in Kendall Square. And so, we sort of in various pairwise combinations known each other for decades and worked together for decades and have all collectively been really excited about science and technology and its potential to accelerate societal progress. Yet we also felt in our own ways that despite a lot of the tremendous progress, the structures in which we do this work, fund it, incentivize it and roll it out into the real world, seems like it's really possible that we'll undershoot that potential. And if you take 15 years ago, we didn't have the modern transformer that launched the current AI revolution, CRISPR technology, single-cell, mRNA technology or broadly addressable LNPs. That's a tremendous amount of technologies have developed in the next 15 years. We think there's a real unique opportunity for new institutes in the 2020s to take advantage of all of these breakthroughs and the new ones that are coming to continue to accelerate biological progress but do so in a way that's fast and flexible and really focused.Eric Topol (04:58):Yeah, I did want to talk with you a bit. First of all before I get to the next related topic, I get a kick out of you saying you've worked or known each other for decades because I think you're only in your early thirties. Is that right?Patrick Hsu (05:14):I was lucky to get an early start. I first started doing research at the local university when I was 14 actually, and I was homeschooled actually until college. And so, one of the funny things that you got to do when you're homeschooled is well, you could do whatever you want. And in my case that was work in the lab. And so, I actually worked basically full time as an intern volunteer, cut my teeth in single cell patch clamp, molecular biology, protein biochemistry, two photon and focal imaging and kind of spiraled from there. I loved the lab, I loved doing bench work. It was much more exciting to me than programming computers, which was what I was doing at the time. And I think these sort of two loves have kind of brought me and us to where we are today.Eric Topol (06:07):Before you got to Berkeley and Arc, I know you were at Broad Institute, but did you also pick up formal training in computer science and AI or is that something that was just part of the flow?Patrick Hsu (06:24):So I grew up coding. I used to work through problems sets before dinner growing up. And so, it's just something that you kind of learn natively just like learning French or Mandarin.New Models of Funding Life ScienceEric Topol (06:42):That's what I figured. Okay. Now this model of Arc Institute came along in a kind of similar timeframe as the Arena BioWorks in Boston, where some of the faculty left to go to Arena like my friend Stuart Schreiber and many others. And then of course Priscilla and Mark formed the Chan Zuckerberg Institute and its biohub and its support. So can you contrast for one, these three different models because they're both very different than of course the traditional NIH pathway, how Arc is similar or different to the others, and obviously the goal here is accelerating things that are going to really make a difference.Patrick Hsu (07:26):Yeah, the first thing I would say is zooming out. There have been lots of efforts to experiment with how we do science, the practice of science itself. And in fact, I've recently been reading this book, the Demon Under the Microscope about the history of infectious disease, and it talks about how in the 1910s through the 1930s, these German industrial dye manufacturing companies like Bayer and BASF actually launched what became essentially an early model for industrial scale science, where they were trying to develop Prontosil, Salvarsan and some of these early anti-infectives that targeted streptococcus. And these were some of the major breakthroughs that led to huge medical advances on tackling infectious disease compared to the more academic university bound model. So these trends of industrial versus academic labs and different structures to optimize breakthroughs and applications has been a through current throughout international science for the last century.(08:38):And so, the way that we do research today, and that's some of our core tenets at Arc is basically it hasn't always been this way. It doesn't need to necessarily be this way. And so, I think organizational experiments should really matter. And so, there's CZI, Altos, Arena, Calico, a variety of other organizational experiments and similarly we had MRC and Bell Labs and Xerox PARCS, NIBRT, GNF, Google Research, and so on. And so, I think there are lots of different ways that you can organize folks. I think at a high level you can think about ways that you can play with for-profit versus nonprofit structures. Whether you want to be a completely independent organization or if you want to be partnered with universities. If you want to be doing application driven science or really blue sky curiosity driven work. And I think also thinking through internally the types of expertise that you bring together.(09:42):You can think of it like a cancer institute maybe as a very vertically integrated model. You have folks working on all kinds of different areas surrounding oncology or immunotherapy and you might call that the Tower of Babel model. The other way that folks have built institutes, you might call the lily pad model where you have coverage of as many areas of biomedical research as possible. Places like the Whitehead or Salk, it will be very broad. You'll have planned epigenetics, folks looking at RNA structural biology, people studying yeast cell cycle, folks doing in vivo melanoma models. It's very broad and I think what we try to do at Arc is think about a model that you might liken more to overlapping Viking shields where there's sort of five core areas that we're deeply investing in, in genetics and genomics, computation, neuroscience, immunology and chemical biology. Now we really think of these as five areas that are maybe the minimal critical mass that you would need to make a dent on something as complicated as complex human diseases. It's certainly not the only thing that you need, but we needed a critical mass of investigators working at least in these areas.Eric Topol (11:05):Well, yeah, and they really converge on where the hottest advances are being made these days. Now can you work at Arc Institute without being one of these three universities or is it really that you maintain your faculty and your part of this other entity?Patrick Hsu (11:24):So we have a few elements to even just the academic side of the house. We have our core investigators. I'm one of them, where we have dually appointed faculty who retain their latter rank or tenured appointment in their home department, but their labs are physically cited at the Arc headquarters where we built out a lab in Stanford Research Park in Palo Alto. And so, folks move their labs there. They continue to train graduate students based on whatever graduate programs they're formally affiliated with through their university affiliation. And so, we have nearly 40 PhD students across our labs that are training on site every day.(12:03):So in addition to our core investigators, we also have what we call our innovation investigators, which is more of a grant program to faculty at our partner universities. They receive unrestricted funding from us to seed a new project or accelerate an existing area in their group and their labs stay at their home campus and they just get that funding to augment their work. The third way is our technical staff model where folks basically just come work at Arc and many of them also are establishing their own research groups focusing on technology R&D areas. And so, we have five of those technology centers working in molecular engineering, multi-omics, complex cellular models, in vivo models, and in machine learning.Discovery of Bridge RNAsEric Topol (12:54):Yeah, that's a great structure. In fact, just a few months ago, Patrick Collison, the other Patrick came to Stanford HAI where I'm on the board and you've summarized it really well and it's very different than the other models and other entities, companies included that you mentioned. It's really very impressive. Now speaking of impressive on June 26, this past few months ago, which incidentally is coincident with the draft genome in the year 2000, the human sequence. You and your colleagues, perhaps the most impressive jump in terms of an Arc Institute contribution published two papers back-to-back in Nature about bridge RNA: [Bridge RNAs direct programmable recombination of target and donor DNA] and [Structural mechanism of bridge RNA-guided recombination.] And before I get you to describe this breakthrough in genome editing, some would call it genome editing 3.0 or CRISPR 3.0, whatever. But what we have today in the clinic with the approval of CRISPR 1.0 for sickle cell and thalassemia is actually quite crude. I think most people will know it's just a double stranded DNA cleavage with all sorts of issues about repair and it's not very precise. And so, CRISPR 2.0 is supposed to be represented by David Liu's contributions and his efforts at Broad like prime and base editing and then comes yours. So maybe you can tell us about it and how it is has to be viewed as quite an important advance.Patrick Hsu (14:39):The first thing I would say before CRISPR, is that we had RNA interference. And so, even before this modern genome editing revolution with programmable CRISPRs, we had this technology that had a lot of the core selling points as well. Any target will now become druggable to us. We simply need to reprogram a guide RNA and we can get genetic access to things that are intracellular. And I think both the discovery of RNA interference by Craig Mello and Andy Fire or the invention or discovery of programmable CRISPR technologies, both depend on the same fundamental biological mechanism. These non-coding guide RNAs that are essentially a short RNA search string that you can easily reprogram to retarget a desired enzyme function, and natively both RNAi and CRISPR are molecular scissors. Their RNA or DNA nucleases that can be reprogrammed to different regions of the genome or the transcriptome to make a cut.(15:48):And as bioengineers, we have come up with all kinds of creative ways to leverage the ability to make site specific cuts to do all kinds of incredible things including genome editing or beyond transcriptional up or down regulation, molecular imaging and so on and so forth. And so, the first thing that we started thinking about in our lab was, why would mother nature have stopped only RNAi and CRISPR? There probably are lots of other non-coding RNAs out there that might be able to be programmable and if they did exist, they probably also do more complicated and interesting things than just guide a molecular scissors. So that was sort of the first core kind of intuition that we had. The second intuition that we had on the technology side, I was just wearing my biology hat, I'll put on my technology hat, is the thing that we call genome editing today hardly involves the genome.(16:50):It's really you're making a cut to change an individual base or an individual gene or locus. So really you're doing small scale single locus editing, so you might call it gene level or locus level cuts. And what you really want to be able to do is do things at the genome scale at 100 kb, a megabase at the chromosome scale. And I think that's where I think the field will inevitably go if you follow the technology curves of longer and longer range gene sequencing, longer and longer range gene synthesis, and then longer and longer range gene editing. And so, what would that look like? And we started thinking, could there be essentially recombination technologies that allow you to do cut and paste in a single step. Now, the reason for that is the way that we do gene editing today involves a cut and then a multi-step process of cellular DNA repair that resolves the cut to make the exertion or the error prone deletion or the modification that ends up happening.(17:59):And so, it's very complicated and whether that's nucleases or base or prime editing, you're all generally limited to the small-scale single locus changes. However, there are natural mechanisms that have solved this cut and paste problem, right? There are these viruses or bacterial versions of viruses known as phage that have generally been trying to exert their multi kilobase genomes into bacterial hosts and specialize throughout billions of years. So our core thought was, well, if there are these new non-coding RNAs, what kind of functions would we be excited about? Can we look in these mobile genetic elements, these so-called jumping genes for new mechanisms? They're incredibly widespread. Transposons are thought to be some of the most diverse enzyme mechanisms found in nature. And so, we started computationally by asking ourselves a very simple question. If a mobile element inserts itself into foreign DNA and it's able to somehow be programmable, presumably the inside or something encoded in the inside of the element is predictive of some sequence on the outside of the element.(19:15):And so, that was the core insight we took, and we thought let's look across the boundaries of many different mobile genetic elements and we zoomed in on a particular sub family of these MGE known as insertion sequence (IS) elements which are the most autonomous minimal transposons. Normally transposons have all kinds of genes that they use to hitchhike around the genomic galaxy and endow the bacterial host with some fitness advantage like some ability to metabolize some copper and some host or some metal. And these IS elements have only the enzymes that they need to jump around. And if you identify the boundaries of these using modern computational methods, this is actually a really non-trivial problem. But if you solve that problem to figure out with nucleotide resolution where the element boundaries end and then you look for the open reading frame of the transposases enzyme inside of this element, you'll find that it's not just that coding sequence.(20:19):There are also these non-coding flanks inside of the element boundaries. And when we looked across the non-coding, the entire IS family tree, there are hundreds of these different types of elements. We found that this particular family IS110, had the longest non-coding ends of all IS elements. And we started doing experiments in the lab to try to figure out how these work. And what we found was that these elements are cut and paste elements, so they excise themselves into a circular form and paste themselves back in into a target site linearly. But the circularization of this element brings together two distal ends together, which brings together a -35 and a -10 box that create and reconstitute a canonical bacterial transcriptional promoter. This essentially is like plugging a plug into an electrical socket in the wall and it jacks up transcription. Now you would think this transcription would turn on the transposase enzyme so it can jump around more but it transcribes a non-coding RNA out of this non-coding end.(21:30):We're like, holy crap, are these RNAs actually involved in regulating the transposon? Now the boring answer would be, oh, it regulates the expression. It's like an antisense regulate or something. The exciting answer would be, oh, it's a new type of guide RNA and you found an RNA guided integrase. So we started zooming in bound dramatically on this and we undertook a covariation analysis where we were able to show that this cryptic non-coding RNA has a totally novel guide RNA structure, totally distinct from RNAi or CRISPR guide RNAs. And it had a target site that covaried with the target site of the element. And so we're like, oh wow, this could be a programmable transposase. The second thing that we found was even more surprising, there was a second region of complementarity in that same RNA that recognized the donor sequence, which is the circularized element itself. And so, this was the first example of a bispecific guide RNA, and also the first example of RNA guided self-recognition by a mobile genetic element.Eric Topol (22:39):It's pretty extraordinary because basically you did a systematic assessment of jumping genes or transposons and you found that they contain things that previously were not at all recognized. And then you have a way to program these to edit, change the genome without having to do any cuts or nicks, right?Patrick Hsu (23:05):Yeah. So what we showed in a test tube is when we took this, so-called bridge RNA, which we named because it bridges the target and donor together along with the recombinase enzyme. So the two component system, those are the only two things that you need. They're able to cut and paste DNA and recombine them in a test tube without any DNA repair, meaning that it's independent of cellular DNA repair and it does strand nicking, exchange, junction resolution and religation all in a single mechanism. So that's when we got super excited about its potential applications as bioengineering tool.Eric Topol (23:46):Yeah, it's pretty extraordinary. And have you already gone into in vivo assessment?Patrick Hsu (23:54):Yes, in our initial set of papers, what we showed is that these are programmable and functional or recombinases in a test tube and in bacterial cells. And by reprogramming the target and donor the right way, you can use these enzymes not just for insertion, but also for flipping and cutting out DNA. And so, we actually have in a single mechanism the ability to do bridge editing, if you will, for universal DNA recombination, insertion, excision or inversion, similar to what folks have been doing for decades with Cre recombinase, but with fully programmable recognition sequences. The work that we're doing now in the lab as you can imagine is to adapt these into robust tools for mammalian genome editing, including of course, human genomes. We're excited about this, we're making good progress. The CRISPR has had thousands of labs over the last 10, 15 years working on it to make these therapeutic level potency and selectivity. We're going to work and follow that same blueprint for getting bridge systems to get to that level of performance, but we're on the path and we're very optimistic for the future.Exemplar of Digital BiologyEric Topol (25:13):Yeah, I think it's quite extraordinary and it's a whole different look to what we've been seeing in the CRISPR era for over the past decade and how that's been advancing and getting more specific and less need for repair and being able to be more versatile. But this takes it to yet another dimension. Now, this brings me to the field that when I think of this term digital biology, I think of you and now our mutual acquaintance, Jensen Huang, who everybody knows now. Back some months ago, he wrote and said at a conference, “Where do I think the next amazing revolution is going to come? And this is going to be flat out one of the biggest ones ever. There's no question that digital biology is going to be it. For the first time in human history, biology has the opportunity to be engineering, not science.” So can you critique Jensen? Is he right? And tell us how you conceive the field of digital biology.Patrick Hsu (26:20):If you look at gene therapy today, the core concepts are actually remarkably simple. They're elegant. Of course, you're missing a broken gene, you need to put it back. And that can be curative. Very simple, powerful concept. However, for complex diseases where you don't have just a single gene that goes wrong, in many cases we actually have no idea what to do. And in fact, when you're trying to put in DNA, that's over more than a gene scale. We kind of very quickly run out of ideas. Is it a CAR and a cytokine, a CAR and a cytokine and another thing? And then we're kind of out of ideas. And so, we started thinking in the lab, how can we actually design genomes where it's not just let's reduce the genome into individual Lego blocks, iGem style with promoters and different genes that we just sort of shuffle the Lego blocks around, but actually use AI to design genome sequences.(27:29):So to do that, we thought we would have to first of all, train a model that can learn and decode the foreign language of biology and use that in order to design sequences. And so, we sort of have been training DNA foundation models and virtual cell models at Arc, sort of a major effort of ours where the first thing that we tried was to take a variance of transformer architecture that's used to train ChatGPT from OpenAI, but instead apply this to study the next DNA token, right? Now, the interesting thing about next token prediction in English is that you can actually learn a surprising amount of information by just predicting the next word. You can learn world knowledge is the capital of Azerbaijan, is it Baku or is it London, right? Or if you're walking around in the kitchen, then the next text is, I then left the kitchen or the bathroom, right?(28:33):Now you're learning about spatial reasoning, and so you can also learn translation obviously. And so similarly, I think predicting the next token or the next base and DNA can lead you to learn about molecular biochemistry, is the next amino acid residue, hydrophobic or hydrophilic. And it can teach you about the mechanics of some catalytic binding pocket or something. You can learn about a disease mutation. Is the next base, the sick linked base or the wild type base and so on and so forth. And what we found was that at massive scale, DNA foundation models learn about molecular function, not just at the DNA level, but also at the RNA and the protein. And indeed, we could use these to design molecular systems like CRISPR-Cas systems, where you have a protein and the guide RNA. It could also design new DNA transposons, and we could design sequences that look plausibly like real genomes, where we generate a megabase a million bases of continuous genome sequence. And it really looks and feels like it could be a blurry picture of something that you would actually sequence. This has been a wonderful collaboration with Brian Hie, a PI at Stanford and an Arc investigator, and we're really excited about what we've seen in this work because it promises the better performance with even more scale. And so, simply by scaling up these models, by adding in more compute, more training data or more powerful models, they're going to get sharper and sharper.New A.I. Models in Life ScienceEric Topol (30:25):Yeah. Well, this whole use of large language models for the language of life, whether it's the genome proteins and on and on, actually RNA and even cells has really taken root. And of course, this is really one of the foundations of that field of digital biology, which brings together generative AI, AI tools and trying to push forward our understanding in biology. And also, obviously what's been emphasized in drug discovery, perhaps it's been emphasized even too much because we still have a lot to learn about biology, but that gets me to these models. Like today, AlphaProteo was announced by DeepMind, as we all know, AlphaFold 1, 2, now 3. They were kind of precursors of being able to predict proteins from amino acid 3D structure. And that kind of took the field by a little bit like ChatGPT for life science, but now it's a new model all the time. So you've been working on various models and Arc Institute, how do you see this unfolding? Are we just going to have every aspect of the language of life being approached in all the different interactions? And this is going to help us get to a much more deep level of understanding.Patrick Hsu (31:56):I'll say two things. The first is a lot of models that you just described are what I would call task specific models. A model for de novo design of a binder, a model for protein structure prediction. And there are other models for protein fitness or for RNA structure prediction, et cetera, et cetera. And I think what we're going to move towards are more unifying models where there's different classes of models at different levels of scale. So we will have these atomic level models for looking at generative chemistry or ligand docking. We have models that can unify genomes and their molecules, and then we have models that can unify cells and tissues. And so, for example, if you took an H&E stain of some liver, there are folks building models where you can then predict what the single cell spatial transcriptome will look like of that model. And that's obviously operating at a very different level of abstraction than a de novo protein binder. But in the long run, all of these are going to get, I think unified. I think the reason why this is possible is that biology, unlike physics, actually has this unifying theory of evolution that runs across all of its length scales from atomic, molecular, cellular, organismal to entire ecosystem. And the promise of these models is no short then to make biology a predictive discipline.Patrick Hsu (33:37):In physics, the experimentalists win the big prizes for the theorists when they measure gravitational waves or whatever. But in biology, we're very practical people. You do something three times and do a T-test. And I think my prediction is we can actually gauge the success of these LLMs or whatever in biology by how much we respect theory in this field.The A.I. ScientistEric Topol (34:05):Yeah. Well, that's a really interesting perspective, an important perspective because the proliferation of models, which we're going to get into not just doing the things that you described, but also being able to be “pseudo” scientists, the so-called AI scientist. Maybe you could comment about that concept because that's been the idea that everything from the question that could be asked to the hypothesis and the experiment design and the analysis of data and then the feedback. So what is the role of the scientists, that seems to have been overplayed? And maybe you can put that in context.Patrick Hsu (34:48):So yeah, right now there's a lot of excitement that we can use AI agents not just to do software enterprise workflows, but to be a research assistant. And then over time, itself an autonomous research scientist that can read the literature, come up with an idea, maybe run a bunch of robots in the lab or do a bunch of computational analyses and then potentially even analyze data, conclude what is going on and actually write an entire paper. Now, I think the vision of this is compelling in the long term. I think the question is really about timescale. If you break down the scientific method into its constituent parts, like hypothesis generation, doing an experiment, analyzing experiment and iterating, we're clearly going to use AI of some kind at every single step of this cycle. I think different steps will require different levels of maturity. The way that I would liken this is just wet lab automation, folks have dreamed about having pipetting robots that just do their western blots and do their cell culture for them for generations.(36:01):But of course, today they don't actually really feel fundamentally different from the same ones that we had in the 90s, let's say. Right? And so, obviously they're getting better, but it seems to me one of the trends I'm very bullish about is the explosion of humanoid robots and robot foundation models that have a world model and a sense of physics and proportionate space loaded onto them. Within five years, we're going to have home robots that can fold your clothes, that can organize your kitchen and do all of this while you're sleeping, so you wake up to a clean home every day.Eric Topol (36:40):It's not going to be just Roomba anymore. There's going to be a lot more, but it isn't just the hardware, it's also the agents playing in software, right?Patrick Hsu (36:50):It's the integrated loop of the hardware and the software where the ability to make the same machine generally intelligent will make it adaptable to a broad array of tasks. Now, what I'm excited about is those generally intelligent humanoid robots coming into the lab, where instead of creating a centrifuge or a new type of pipetter that's optimized for your Beckman or Hamilton device, instead you just have robot arms that you snap onto the edge of the bench and then they just work alongside you. And I do think that's coming, although it'll take a lot of hardware and software and computer vision engineering to make that possible.A Sense of HumorEric Topol (37:32):Yeah, and I think also going back to originating the question, there still is quite a debate about the creativity and the lack of any simulation of AGI, whatever that means anymore. And so, the human in the loop part of this is obviously I think it's still of critical nature. Now, the other thing I learned about you is you have a great sense of humor, which is really important by the way. And recently, which is great that you're active on X or Twitter because that's one way we get to see what you're thinking on a day-to-day basis. But I think you put out a poll which was really quite provocative , and it was about, here's what it said, “do more people in the world *truly* understand transformers or health insurance?” And interestingly, you got 49% for transformers at 51% for health insurance. Can you tell us what you're thinking when you put that poll together? Because obviously a lot of people don't understand either of these.Patrick Hsu (38:44):I think the core question is, there are different ways of looking at the world, some of which are very bottom up and some of which are very top down. And one of the very surprising things about transformers is they're taking something that is in principle, an incredibly simple task, which is if you have a string of text, what is the next letter? And somehow at massive, massive scale, you can unlock something that looks an awful lot like reasoning, and you've got these emergent behaviors. Now the bottoms up theory of just the linear algebra that's going on in these models couldn't possibly really help us predict that we have these emerging capabilities. And I think similarly in healthcare, there's a literal set of parts that are operating in some complex way that at massive scale becomes this incredibly confusing and dynamic system for how we can actually incentivize how we make medicines, how we actually take care of people, and how we actually pay for any of this from an economic point of view. And so, I think it was, in some sense if transformers can actually be an explainable by just linear algebra equations, maybe there will be a way to decompose the seemingly incredibly confusing world of healthcare in order to actually build a better way forward.Computing Power and the GPU Arms RaceEric Topol (40:12):Yeah. Well that's great. Now the other thing I wanted to ask you about, we open source and the arms race of GPUs and this whole kind of idea is you touched on the need for coalescing a lot of these tools to exploit the synergy. But we have an issue because many academic labs like here at Scripps Research and so many others, including as I learned even at Stanford, have limited access to GPUs. So computing power of large language models is a problem. And then the models that exist today that can be adopted like Llama or others, and they're somewhat limited. And then we also have a movement towards trying to make things more open source, like for example, recently OpenCRISPR with Profluent Bio that is basically trying to use AI for CRISPR guides. And so, how do you deal with this arms race, computing power, open source, proprietary models that are not easily accessible without a lot of resources?Patrick Hsu (41:30):So the first thing I would say is, we are in the academic science sphere really unprepared for the level of resources that are required for doing this type of cutting edge computational work. There are top Stanford computer science professors or computational researchers who have a single GPU in their office, and that's actually what their whole lab runs off of.(41:58):The UC Berkeley campus, the grid runs on something like 12 megawatts of power and how are they going to build an on-premises GPU clusters, like a central question that can scale across the entire needs? And these are two of the top computer science universities in the world. And so, I think one of our kind of core beliefs at Arc is, as science both experimentally and computationally has gotten incredibly complex, not just in terms of conceptually, but also just the actual infrastructure and machines and know-how that you need to do things. We actually need to essentially support this. So we have a private GPU cloud that we use to train our models, and we have access to significantly large clusters for large burst kind of train outs as necessary. And I think infrastructurally for running genomics experiments or doing scalable brain organoid screens, right, we're also building out the infrastructure to support that experimentally.Eric Topol (43:01):Yeah, no, I think this is one of the advantages of the new model like the Arc Institute because not many centers have that type of plasticity with access to computing power when needed. So that's where a brilliant mind you and the Arc Institute together makes for a formidable recipe for future advances and of course building on the ones you've already accomplished.The Primacy of Human TalentPatrick Hsu (43:35):I would just say, my main skill, if I have one, is to recruit really, really smart people. And so, everything that you're seeing and hearing about is the work of unbelievable colleagues who are curious, passionate, and incredible scientists.Eric Topol (43:53):But it also takes the person who can judge those who are in that category set as a role model. And you're certainly doing that. I guess just in closing, I mean, it's just such a delight to get to meet you here and kind of get your thoughts on what is the hottest thing in life science without question, which brings together the fields of AI and what's going on, not just obviously in genome editing, but this digital biology era that we're still in the early phases of, I mean, I think you could say that it's just going to continue to accelerate the exponential curve. We're still kind of on the bottom of that, I would imagine where we're headed. Any other things that you want to bring up that I haven't touched on that will round out this conversation?Patrick Hsu (44:50):I mean, I think it's very early days here at Arc.Patrick Hsu (44:53):When we founded Arc, we asked ourselves, how do we measure success? We don't have customers or revenue in the way that a typical startup does. And we felt sort of three things. The first was research institutes live and die by their talent. Can we actually hire incredible people when we make offers to people we want to come, do they come? The second was, when those folks do come to Arc, do they feel like they're able to work on important research programs that they couldn't do sort of at their prior university or company? And then longer term, the third thing was, and there's just no shortcut around this, you need to do important work. And I think we've been really excited that there are early signs that we're able to do all three of these things, and we're still, again, just following the same scaling laws that we're seeing in natural language and vision, but for the domain of biology. And so, we're excited about what's ahead and think if there are folks who are interested in learning more about Arc, just shoot me an email or DM.Eric Topol (46:07):Yeah, well I would just say, congratulations on what you've already achieved. I know you're going to keep rocking it because you already have in a short time. And for anybody who doesn't know about Arc Institute and your work and your team, I hope this is going to be putting them on notice actually what can be accomplished outside of the usual NIH funded model, which is kind of a risk-free zone where you basically have to have your results nailed down before you send in your proposal frequently, and it doesn't do great things for young people. Really, I think you actually qualify in that demographic where it's hard for them to break in for getting NIH grants and also for this type of work that you're doing. So we'll look for the next bridge beyond bridge RNAs of your just fantastic efforts. So Patrick, thanks so much for joining us today, and we'll be checking back with you and following all the great work that you'll be doing in the times ahead.Patrick Hsu (47:14):Thanks so much, Eric. It was such a pleasure to be here today. Appreciate the opportunity.*******************Thanks for listening, reading or watching!The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informative!Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly help fund our summer internship programs.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

In the first four months of this presidential election year, nearly 5.5 million legal firearms were purchased in the US, according to FBI data, while the candidates from both major parties have starkly different positions on gun control.根据联邦调查局的数据，2024年上半年，美国购买了近550万支合法枪支，而民主党和共和党的两方候选人在枪支管制方面的立场截然不同。Vice-President Kamala Harris, the Democratic candidate, advocates stricter regulations, while Republican candidate and former president Donald Trump is pro-gun rights. These contrasting stances are already resonating differently with likely voters.民主党候选人副总统卡玛拉·哈里斯（Kamala Harris）主张制定更严格的规定，而共和党候选人、前总统唐纳德·特朗普则支持枪支权利。双方立场在选民中引发了不同反应。David Liu, owner of Arcadia Firearm & Safety in Arcadia, California, serves a predominantly Asian community 30 minutes from Monterey Park, where a tragic mass shooting during a Chinese New Year Festival left 11 dead and nine injured last year.大卫·刘（David·Liu）是位于加利福尼亚州阿卡迪亚枪械与安全公司的所有者，该公司为其附近的亚裔社区提供服务。而在2023年中国新年期间发生的悲剧性大规模枪击事件造成11人死亡，9人受伤。"I'm a Trump supporter. And it's not because (Republicans) support guns that I vote for them. Because I look overall on the candidates. I prefer Trump's overall policy," Liu said. "I will not vote for a guy just because he said he supports guns. That's not the point of voting for the president."大卫·刘表示：“我是特朗普的支持者。我投票给他并不是因为（共和党人）支持枪支，而是因为我更喜欢特朗普的整体政策。我不会仅仅因为一个人说他支持枪支就投票给他，这并不是总统大选的意义所在。”Liu said that over the past two months, his sales have been slow, attributing it to a new 11 percent tax on gun sales and ammunition imposed in July by California's Democrat-controlled legislature to fund violence prevention. This is in addition to the existing federal tax of 10 or 11 percent on firearms.在过去的两个月里，大卫·刘的枪支销售趋于平缓，这是由于加州由民主党控制的立法机构于7月对枪支销售和弹药征收了11%的新税，以此预防暴力行为，这也是对现有枪支10%-11%联邦税的补充。About 16.7 million firearms were sold in the United States last year, a 4 percent decline from 2022, according to SafeHome.org, which analyzed the FBI's national instant background-check data.根据SafeHome.org的数据，去年美国售出约1670万支枪支，较2022年下降了 4%，该数据分析了FBI在全美背景下的调查数据。The National Shooting Sports Foundation found that firearm sales to Asian Americans rose by 43 percent in 2020 compared with 2019, a response to a rise in hate crimes against the community during the pandemic.美国国家射击运动基金会（National Shooting Sports Foundation）表示，与2019年相比，2020年向亚裔美国人出售的枪支增长了43%，这是针对疫情期间社区仇恨犯罪增加所给予的回应。The US has more guns than people, with estimates ranging from 425 million to 475 million in a country of 333 million people as of 2022.美国的枪支数量已超过其人口，截至2022年，美国人口近3.33亿，枪支数量在 4.25亿至4.75亿之间。A Quinnipiac University poll conducted in June found that only 4 percent of likely voters considered gun violence the most important issue in choosing a president, with the economy taking precedence.昆尼皮亚克大学（Quinnipiac University）6月进行的一项民意调查发现，只有 4%的潜在选民认为枪支暴力是选择总统时最重要的问题，大部分选民认为经济优先。Nearly half of Republicans and Republican-leaning independents own a gun, compared with 20 percent of Democrats and those who lean liberal, Pew Research Center found.皮尤研究中心（Pew Research Center）发现，近半数共和党和倾向共和党的独立人士拥有枪支，而民主党人和倾向于枪支自由的人仅占20%。Carl Bogus, a law professor at Roger Williams University in Rhode Island, told China Daily that the Republican Party considers the gun lobby to be an "essential" part of its political coalition.罗杰·威廉姆斯大学（Roger Williams University）的法学教授卡尔·博格斯（Carl Bogus）在接受《中国日报》采访时表示，共和党认为枪支游说是其政治联盟的“必不可少”的一部分。Trump has called himself "the best friend gun owners have ever had in the White House". He told an audience in February at the National Rifle Association's Great American Outdoor Show in Harrisburg, Pennsylvania, that "no one will lay a finger on your firearms" if he wins.特朗普称共和党是“枪支拥有者在白宫有史以来最好的朋友”。今年2月，他在宾夕法尼亚州哈里斯堡举行的全国步枪协会（National Rifle Association）美国户外展上对观众说，如果他赢得本次总统选举，“没有人会对你的枪支动手脚”。In his administration, Trump reversed a law that restricted people with mental illness to purchase a gun, and banned bump stocks that can convert semiautomatic weapons into a machine gun-like weapon. In June, the Supreme Court lifted the ban, citing the Second Amendment of the Constitution.在其共和党政府中，特朗普推翻了限制精神疾病患者购买枪支的法律，并禁止将半自动武器转化为类似机枪武器的撞枪托。6月，最高法院援引宪法第二修正案解除了禁令。Harris, head of the first White House Office of Gun Violence Prevention, has repeatedly discussed more gun control on the campaign trail and held a summit against gun violence in Atlanta in June.哈里斯是第一届白宫枪支暴力预防办公室的负责人，她在竞选过程中多次讨论加强枪支管制，并于6月在亚特兰大举行了反对枪支暴力的峰会。On Wednesday, after four people were killed in a school shooting in Georgia, Harris addressed gun violence at schools.在佐治亚州发生校园枪击事件造成4人死亡后，哈里斯谈到了校园枪支暴力问题。"It's just outrageous that every day in our country ... that parents have to send their children to school worried about whether or not their child will come home alive," she said. "It doesn't have to be this way."“在我们国家，父母需要每天送孩子上学，担心他们的孩子是否能活着回家。”哈里斯表示，“事情本不该是这样的。”This year, there have been at least 384 mass shootings — defined as a shooting involving at least four victims, dead or wounded — across the US, and at least 11,557 people have been killed in firearms violence this year in the country, according to the Gun Violence Archive.根据枪支暴力档案（Gun Violence Archive）的数据，今年美国至少发生了384 起大规模枪击事件（涉及至少4名受害者、死亡或受伤的枪击事件）。2024年该国至少有11557人死于枪支暴力。

In this podcast episode Dave Anderson is joined by David Lowe, the CEO of Sonde Health, a company that has developed an AI technology to detect early indications of mental health disorders through analyzing the sound of a person's voice. The conversation explores the potential benefits of using voice AI to identify symptoms of depression, anxiety, and cognitive impairment. They discuss the importance of early detection and intervention, the privacy concerns surrounding voice data, and the goal of improving mental health and productivity in the workplace. The episode highlights the need for increased awareness and understanding of mental health and the potential of AI technology in this field.TakeawaysVoice AI technology can analyze the sound of a person's voice to detect early indications of mental health disorders.Early detection and intervention can lead to better outcomes and improved mental health.Privacy concerns surrounding voice data need to be addressed and transparency is crucial.Improving mental health can have a positive impact on workplace productivity.Sound Bites"What if a voice technology could work out whether or not someone had early indication of anxiety, depression, or some form of mental stress? Would you want to know?""We are able to measure the biomarkers, these signals that are coming from a specific data source. And in this case, it's your voice.""No machine can tell you that. You need clinicians. In fact, you need several clinicians to be able to make that determination over time."

In this podcast, Thomas Czech, Distinguished Professor at the University of Colorado, Boulder, with a lineage of remarkable contributions on RNA, ribozyme, and telomeres, discuss why RNA is so incredibly versatile.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with links to the audio and external linksEric Topol (00:07):Well, hello, this is Eric Topol from Ground Truths, and it's really a delight for me to welcome Tom Cech who just wrote a book, the Catalyst, and who is a Nobel laureate for his work in RNA. And is at the University of Colorado Boulder as an extraordinary chemist and welcome Tom.Tom Cech (00:32):Eric, I'm really pleased to be here.The RNA GuyEric Topol (00:35):Well, I just thoroughly enjoyed your book, and I wanted to start out, if I could, with a quote, which gets us right off the story here, and let me just get to it here. You say, “the DNA guy would need to become an RNA guy. Though I didn't realize it at the time, jumping ship would turn out to be the most momentous decision in my life.” Can you elaborate a bit on that?Tom Cech (01:09):As a graduate student at Berkeley, I was studying DNA and chromosomes. I thought that DNA was king and really somewhat belittled the people in the lab next door who were working on RNA, I thought it was real sort of second fiddle material. Of course, when RNA is acting just as a message, which is an important function, a critical function in all life on earth, but still, it's a function that's subservient to DNA. It's just copying the message that's already written in the playbook of DNA. But little did I know that the wonders of RNA were going to excite me and really the whole world in unimaginable ways.Eric Topol (02:00):Well, they sure have, and you've lit up the world well before you had your Nobel Prize in 1989 was Sid Altman with ribozyme. And I think one of the things that struck me, which are so compelling in the book as I think people might know, it's divided in two sections. The first is much more on the biology, and the second is much more on the applications and how it's changing the world. We'll get into it particularly in medicine, but the interesting differentiation from DNA, which is the one trick pony, as you said, all it does is store stuff. And then the incredible versatility of RNA as you discovered as a catalyst, that challenging dogma, that proteins are supposed to be the only enzymes. And here you found RNA was one, but also so much more with respect to genome editing and what we're going to get into here. So I thought what we might get into is the fact that you kind of went into the scum of the pond with this organism, which by the way, you make a great case for the importance of basic science towards the end of the book. But can you tell us about how you, and then of course, many others got into the Tetrahymena thermophila, which I don't know that much about that organism.Tom Cech (03:34):Yeah, it's related to Tetrahymena is related to paramecium, which is probably more commonly known because it's an even larger single celled animal. And therefore, in an inexpensive grade school microscope, kids can look through and see these ciliated protozoa swimming around on a glass slide. But I first learned about them when I was a postdoc at MIT and I would drive down to Joe Gall's lab at Yale University where Liz Blackburn was a postdoc at the time, and they were all studying Tetrahymena. It has the remarkable feature that it has 10,000 identical copies of a particular gene and for a higher organism, one that has its DNA in the nucleus and does its protein synthesis in the cytoplasm. Typically, each gene's present in two copies, one from mom, one from dad. And if you're a biochemist, which I am having lots of stuff is a real advantage. So 10,000 copies of a particular gene pumping out RNA copies all the time was a huge experimental advantage. And that's what I started working on when I started my own lab at Boulder.Eric Topol (04:59):Well, and that's where, I guess the title of the book, the Catalyst ultimately, that grew into your discovery, right?Tom Cech (05:08):Well, at one level, yes, but I also think that the catalyst in a more general conversational sense means just facilitating life in this case. So RNA does much more than just serve as a biocatalyst or a message, and we'll get into that with genome editing and with telomerase as well.The Big Bang and 11 Nobel Prizes on RNA since 2000Eric Topol (05:32):Yes, and I should note that as you did early in the book, that there's been an 11 Nobel prize awardees since 2000 for RNA work. And in fact, we just had Venki who I know you know very well as our last podcast. And prior to that, Kati Karikó, Jennifer Doudna who worked in your lab, and the long list of people working RNA in the younger crowd like David Liu and Fyodor Urnov and just so many others, we need to have an RNA series because it's just exploding. And that one makes me take you back for a moment to 2007. And when I was reading the book, it came back to me about the Economist cover. You may recall almost exactly 17 years ago. It was called the Biology's Big Bang – Unravelling the secrets of RNA. And in that, there was a notable quote from that article. Let me just get to that. And it says, “it is probably no exaggeration to say that biology is now undergoing its neutron moment.”(06:52):This is 17 years ago. “For more than half a century the fundamental story of living things has been a tale of the interplay between genes, in the form of DNA, and proteins, which is genes encode and which do the donkey work of keeping living organisms living. The past couple of years, 17 years ago, however, has seen the rise and rise of a third type of molecule, called RNA.” Okay, so that was 2007. It's pretty extraordinary. And now of course we're talking about the century of biology. So can you kind of put these last 17 years in perspective and where we're headed?Tom Cech (07:34):Well, Eric, of course, this didn't all happen in one moment. It wasn't just one big bang. And the scientific community has been really entranced with the wonders of RNA since the 1960s when everyone was trying to figure out how messenger RNA stored the genetic code. But the general public has been really kept in the dark about this, I think. And as scientists, were partially to blame for not reaching out and sharing what we have found with them in a way that's more understandable. The DNA, the general public's very comfortable with, it's the stuff of our heredity. We know about genetic diseases, about tracing our ancestry, about solving crimes with DNA evidence. We even say things like it's in my DNA to mean that it's really fundamental to us. But I think that RNA has been sort of kept in the closet, and now with the mRNA vaccines against Covid-19, at least everyone's heard of RNA. And I think that that sort of allowed me to put my foot in the door and say, hey, if you were curious about the mRNA vaccines, I have some more stories for you that you might be really interested in.RNA vs RNAEric Topol (09:02):Yeah, well, we'll get to that. Maybe we should get to that now because it is so striking the RNA versus RNA chapter in your book, and basically the story of how this RNA virus SARS-CoV-2 led to a pandemic and it was fought largely through the first at scale mRNA nanoparticle vaccine package. Now, that takes us back to some seminal work of being able to find, giving an mRNA to a person without inciting massive amount of inflammation and the substitution of pseudouridine or uridine in order to do that. Does that really get rid of all the inflammation? Because obviously, as you know, there's been some negativism about mRNA vaccines for that and also for the potential of not having as much immune cell long term activation. Maybe you could speak to that.Tom Cech (10:03):Sure. So the discovery by Kati Karikó and Drew Weissman of the pseudouridine substitution certainly went a long way towards damping down the immune response, the inflammatory response that one naturally gets with an RNA injection. And the reason for that is that our bodies are tuned to be on the lookout for foreign RNA because so many viruses don't even mess with DNA at all. They just have a genome made of RNA. And so, RNA replicating itself is a danger sign. It means that our immune system should be on the lookout for this. And so, in the case of the vaccination, it's really very useful to dampen this down. A lot of people thought that this might make the mRNA vaccines strange or foreign or sort of a drug rather than a natural substance. But in fact, modified nucleotides, nucleotides being the building blocks of RNA, so these modified building blocks such as pseudoU, are in fact found in natural RNAs more in some than in others. And there are about 200 modified versions of the RNA building blocks found in cells. So it's really not an unusual modification or something that's all that foreign, but it was very useful for the vaccines. Now your other question Eric had to do with the, what was your other question, Eric?Eric Topol (11:51):No, when you use mRNA, which is such an extraordinary way to get the spike protein in a controlled way, exposed without the virus to people, and it saved millions of lives throughout the pandemic. But the other question is compared to other vaccine constructs, there's a question of does it give us long term protective immunity, particularly with T cells, both CD8 cytotoxic, maybe also CD4, as I know immunology is not your main area of interest, but that's been a rub that's been put out there, that it isn't just a weaning of immunity from the virus, but also perhaps that the vaccines themselves are not as good for that purpose. Any thoughts on that?Tom Cech (12:43):Well, so my main thought on that is that this is a property of the virus more than of the vaccine. And respiratory viruses are notoriously hard to get long-term immunity. I mean, look at the flu virus. We have to have annual flu shots. If this were like measles, which is a very different kind of virus, one flu shot would protect you against at least that strain of flu for the rest of your life. So I think the bad rap here is not the vaccine's fault nearly as much as it's the nature of respiratory viruses.RNA And Aging Eric Topol (13:27):No, that's extremely helpful. Now, let me switch to an area that's really fascinating, and you've worked quite a bit on the telomerase story because this is, as you know, being pursued quite a bit, has thought, not just because telomeres might indicate something about biologic aging, but maybe they could help us get to an anti-aging remedy or whatever you want to call it. I'm not sure if you call it a treatment, but tell us about this important enzyme, the role of the RNA building telomeres. And maybe you could also connect that with what a lot of people might not be familiar with, at least from years ago when they learned about it, the Hayflick limit.Tom Cech (14:22):Yes. Well, Liz Blackburn and Carol Greider got the Nobel Prize for the discovery of telomerase along with Jack Szostak who did important initial work on that system. And what it does is, is it uses an RNA as a template to extend the ends of human chromosomes, and this allows the cell to keep dividing without end. It gives the cell immortality. Now, when I say immortality, people get very excited, but I'm talking about immortality at the cellular level, not for the whole organism. And in the absence of a mechanism to build out the ends of our chromosomes, the telomeres being the end of the chromosome are incompletely replicated with each cell division. And so, they shrink over time, and when they get critically short, they signal the cell to stop dividing. This is what is called the Hayflick limit, first discovered by Leonard Hayflick in Philadelphia.(15:43):And he, through his careful observations on cells, growing human cells growing in Petri dishes, saw that they could divide about 50 times and then they wouldn't die. They would just enter a state called senescence. They would change shape, they would change their metabolism, but they would importantly quit dividing. And so, we now see this as a useful feature of human biology that this protects us from getting cancer because one of the hallmarks of cancer is immortality of the tumor cells. And so, if you're wishing for your telomeres to be long and your cells to keep dividing, you have to a little bit be careful what you wish for because this is one foot in the door for cancer formation.Eric Topol (16:45):Yeah, I mean, the point is that it seems like the body and the cell is smart to put these cells into the senescent state so they can't divide anymore. And one of the points you made in the book that I think is worth noting is that 90% of cancers have the telomerase, how do you say it?Tom Cech (17:07):Telomerase.Eric Topol (17:08):Yeah, reactivate.Tom Cech (17:09):Right.Eric Topol (17:10):That's not a good sign.Tom Cech (17:12):Right. And there are efforts to try to target telomerase enzyme for therapeutic purposes, although again, it's tricky because we do have stem cells in our bodies, which are the exception to the Hayflick limit rule. They do still have telomerase, they still have to keep dividing, maybe not as rapidly as a cancer cell, but they still keep dividing. And this is critical for the replenishment of certain worn out tissues in our such as skin cells, such as many of our blood cells, which may live only 30 days before they poop out. That's a scientific term for needing to be replenished, right?Eric Topol (18:07):Yeah. Well, that gets me to the everybody's, now I got the buzz about anti-aging, and whether it's senolytics to get rid of these senescent cells or whether it's to rejuvenate the stem cells that are exhausted or work on telomeres, all of these seem to connect with a potential or higher risk of cancer. I wonder what your thoughts are as we go forward using these various biologic constructs to be able to influence the whole organism, the whole human body aging process.Tom Cech (18:47):Yes. My view, and others may disagree is that aging is not an affliction. It's not a disease. It's not something that we should try to cure, but what we should work on is having a healthy life into our senior years. And perhaps you and I are two examples of people who are at that stage of our life. And what we would really like is to achieve, is to be able to be active and useful to society and to our families for a long period of time. So using the information about telomerase, for example, to help our stem cells stay healthy until we are, until we're ready to cash it in. And for that matter on the other side of the coin, to try to inhibit the telomerase in cancer because cancer, as we all know, is a disease of aging, right? There are young people who get cancer, but if you look at the statistics, it's really heavily weighted towards people who've been around a long time because mutations accumulate and other damage to cells that would normally protect against cancer accumulates. And so, we have to target both the degradation of our stem cells, but also the occurrence of cancer, particularly in the more senior population. And knowing more about RNA is really helpful in that regard.RNA DrugsEric Topol (20:29):Yeah. Well, one of the things that comes across throughout the book is versatility of RNA. In fact, you only I think, mentioned somewhere around 12 or 14 of these different RNAs that have a million different shapes, and there's so many other names of different types of RNAs. It's really quite extraordinary. But one of the big classes of RNAs has really hit it. In fact, this week there are two new interfering RNAs that are having extraordinary effects reported in the New England Journal on all the lipids, abnormal triglycerides and LDL cholesterol, APOC3. And can you talk to us about this interfering the small interfering RNAs and how they become, you've mentioned in the book over 400 RNAs are in the clinic now.Tom Cech (21:21):Yeah, so the 400 of course is beyond just the siRNAs, but these, again, a wonderful story about how fundamental science done just to understand how nature works without any particular expectation of a medical spinoff, often can have the most phenomenal and transformative effects on medicine. And this is one of those examples. It came from a roundworm, which is about the size of an eyelash, which a scientist named Sydney Brenner in England had suggested would be a great experimental organism because the entire animal has only about a thousand cells, and it's transparent so we can look at, see where the cells are, we can watch the worm develop. And what Andy Fire and Craig Mello found in this experimental worm was that double-stranded RNA, you think about DNA is being double-stranded and RNA as being single stranded. But in this case, it was an unusual case where the RNA was forming a double helix, and these little pieces of double helical RNA could turn off the expression of genes in the worm.(22:54):And that seemed remarkable and powerful. But as often happens in biology, at least for those of us who believe in evolution, what goes for the worm goes for the human as well. So a number of scientists quickly found that the same process was going on in the human body as a natural way of regulating the expression of our genes, which means how much of a particular gene product is actually going to be made in a particular cell. But not only was it a natural process, but you could introduce chemically synthesized double helical RNAs. There are only 23 base pairs, 23 units of RNA long, so they're pretty easy to chemically synthesize. And that once these are introduced into a human, the machinery that's already there grabs hold of them and can be used to turn off the expression of a disease causing RNA or the gene makes a messenger RNA, and then this double-stranded RNA can suppress its action. So this has become the main company that is known for doing this is Alnylam in Boston, Cambridge. And they have made quite a few successful products based on this technology.Eric Topol (24:33):Oh, absolutely. Not just for amyloidosis, but as I mentioned these, they even have a drug that's being tested now, as you know that you could take once or twice a year to manage your blood pressure. Wouldn't that be something instead of a pill every day? And then of course, all these others that are not just from Alnylam, but other companies I wasn't even familiar with for managing lipids, which is taking us well beyond statins and these, so-called PCSK9 monoclonal antibodies, so it's really blossoming. Now, the other group of RNA drugs are antisense drugs, and it seemed like they took forever to warm up, and then finally they hit. And can you distinguish the antisense versus the siRNA therapeutics?Tom Cech (25:21):Yes, in a real general sense, there's some similarity as well as some differences, but the antisense, what are called oligonucleotides, whoa, that's a big word, but oligo just means a few, right? And nucleotides is just the building blocks of nucleic acid. So you have a string of a few of these. And again, it's the power of RNA that it is so good at specifically base pairing only with matching sequences. So if you want to match with a G in a target messenger RNA, you put a C in the antisense because G pairs with C, if you want to put an A, if want to match with an A, you put a U in the antisense because A and U form a base pair U is the RNA equivalent of T and DNA, but they have the same coding capacity. So any school kid can write out on a notepad or on their laptop what the sequence would have to be of an antisense RNA to specifically pair with a particular mRNA.(26:43):And this has been, there's a company in your neck of the woods in the San Diego area. It started out with the name Isis that turned out to be the wrong Egyptian God to name your company after, so they're now known as Ionis. Hopefully that name will be around for a while. But they've been very successful in modifying these antisense RNAs or nucleic acids so that they are stable in the body long enough so that they can pair with and thereby inhibit the expression of particular target RNAs. So it has both similarities and differences from the siRNAs, but the common denominator is RNA is great stuff.RNA and Genome EditingEric Topol (27:39):Well, you have taken that to in catalyst, the catalyst, you've proven that without a doubt and you and so many other extraordinary scientists over the years, cumulatively. Now, another way to interfere with genes is editing. And of course, you have a whole chapter devoted to not just well CRISPR, but the whole genome editing field. And by the way, I should note that I forgot because I had read the Codebreaker and we recently spoke Jennifer Doudna and I, that she was in your lab as a postdoc and you made some wonderful comments about her. I don't know if you want to reflect about having Jennifer, did you know that she was going to do some great things in her career?Tom Cech (28:24):Oh, there was no question about it, Eric. She had been a star graduate student at Harvard, had published a series of breathtaking papers in magazines such as Science and Nature already as a graduate student. She won a Markey fellowship to come to Colorado. She chose a very ambitious project trying to determine the molecular structures of folded RNA molecules. We only had one example at the time, and that was the transfer RNA, which is involved in protein synthesis. And here she was trying these catalytic RNAs, which we had discovered, which were much larger than tRNA and was making great progress, which she finished off as an assistant professor at Yale. So what the general public may not know was that in scientific, in the scientific realm, she was already highly appreciated and much awarded before she even heard anything about CRISPR.Eric Topol (29:38):Right. No, it was a great line you have describing her, “she had an uncanny talent for designing just the right experiment to test any hypothesis, and she possessed more energy and drive than any scientist I'd ever met.” That's pretty powerful. Now getting into CRISPR, the one thing, it's amazing in just a decade to see basically the discovery of this natural system to then be approved by FDA for sickle cell disease and beta thalassemia. However, the way it exists today, it's very primitive. It's not actually fixing the gene that's responsible, it's doing a workaround plan. It's got double strand breaks in the DNA. And obviously there's better ways of editing, which are going to obviously involve RNA epigenetic editing, if you will as well. What is your sense about the future of genome editing?Tom Cech (30:36):Yeah, absolutely, Eric. It is primitive right now. These initial therapies are way too expensive as well to make them broadly applicable to the entire, even in a relatively wealthy country like the United States, we need to drive the cost down. We need to get them to work, we need to get the process of introducing them into the CRISPR machinery into the human body to be less tedious and less time consuming. But you've got to start somewhere. And considering that the Charpentier and Doudna Nobel Prize winning discovery was in 2012, which is only a dozen years ago, this is remarkable progress. More typically, it takes 30 years from a basic science discovery to get a medical product with about a 1% chance of it ever happening. And so, this is clearly a robust RNA driven machine. And so, I think the future is bright. We can talk about that some more, but I don't want to leave RNA out of this conversation, Eric. So what's cool about CRISPR is its incredible specificity. Think of the human genome as a million pages of text file on your computer, a million page PDF, and now CRISPR can find one sentence out of that million pages that matches, and that's because it's using RNA, again, the power of RNA to form AU and GC base pairs to locate just one site in our whole DNA, sit down there and direct this Cas9 enzyme to cut the DNA at that site and start the repair process that actually does the gene editing.Eric Topol (32:41):Yeah, it's pretty remarkable. And the fact that it can be so precise and it's going to get even more precise over time in terms of the repair efforts that are needed to get it back to an ideal state. Now, the other thing I wanted to get into with you a bit is on the ribosome, because that applies to antibiotics and as you call it, the mothership. And I love this metaphor that you had about the ribosome, and in the book, “the ribosome is your turntable, the mRNA is the vinyl LP record, and the protein is the music you hear when you lower the needle.” Tell us more about the ribosome and the role of antibiotics.Tom Cech (33:35):So do you think today's young people will understand that metaphor?Eric Topol (33:40):Oh, they probably will. They're making a comeback. These records are making a comeback.Tom Cech (33:44):Okay. Yes, so this is a good analogy in that the ribosome is so versatile it's able to play any music that you feed at the right messenger RNA to make the music being the protein. So you can have in the human body, we have tens of thousands of different messenger RNAs. Each one threads through the same ribosome and spills out the production of whatever protein matches that mRNA. And so that's pretty remarkable. And what Harry Noller at UC Santa Cruz and later the crystallographers Venki Ramakrishnan, Tom Steitz, Ada Yonath proved really through their studies was that this is an RNA machine. It was hard to figure that out because the ribosome has three RNAs and it has dozens of proteins as well. So for a long time people thought it must be one of those proteins that was the heart and soul of the record player, so to speak.RNA and Antibiotics(34:57):And it turned out that it was the RNA. And so, when therefore these scientists, including Venki who you just talked to, looked at where these antibiotics docked on the ribosome, they found that they were blocking the key functional parts of the RNA. So it was really, the antibiotics knew what they were doing long before we knew what they were doing. They were talking to and obstructing the action of the ribosomal RNA. Why is this a good thing for us? Because bacterial ribosomes are just enough different from human ribosomes that there are drugs that will dock to the bacterial ribosomal RNA, throw a monkey wrench into the machine, prevent it from working, but the human ribosomes go on pretty much unfazed.Eric Topol (36:00):Yeah, no, the backbone of our antibiotics relies on this. So I think people need to understand about the two subunits, the large and the small and this mothership, and you illuminate that so really well in the book. That also brings me to phage bacteria phage, and we haven't seen that really enter the clinic in a significant way, but there seems to be a great opportunity. What's your view about that?Tom Cech (36:30):This is an idea that goes way back because since bacteria have their own viruses which do not infect human cells, why not repurpose those into little therapeutic entities that could kill, for example, what would we want to kill? Well, maybe tuberculosis has been very resistant to drugs, right? There are drug resistant strains of TB, yes, of TB, tuberculosis, and especially in immunocompromised individuals, this bug runs rampant. And so, I don't know the status of that. It's been challenging, and this is the way that biomedicine works, is that for every 10 good ideas, and I would say phage therapy for bacterial disease is a good idea. For every 10 such ideas, one of them ends up being practical. And the other nine, maybe somebody else will come along and find a way to make it work, but it hasn't been a big breakthrough yet.RNA, Aptamers and ProteinsEric Topol (37:54):Yeah, no, it's really interesting. And we'll see. It may still be in store. What about aptamers? Tell us a little bit more about those, because they have been getting used a lot in sorting out the important plasma proteins as therapies. What are aptamers and what do you see as the future in that regard?Tom Cech (38:17):Right. Well, in fact, aptamers are a big deal in Boulder because Larry Gold in town was one of the discoverers has a company making aptamers to recognize proteins. Jack Szostak now at University of Chicago has played a big role. And also at your own institution, Jerry Joyce, your president is a big aptamer guy. And you can evolution, normally we think about it as happening out in the environment, but it turns out you can also make it work in the laboratory. You can make it work much faster in the laboratory because you can set up test tube experiments where molecules are being challenged to perform a particular task, like for example, binding to a protein to inactivate it. And if you make a large community of RNA molecules randomly, 99.999% of them aren't going to know how to do this. What are the odds? Very low.(39:30):But just by luck, there will be an occasional molecule of RNA that folds up into a shape that actually fits into the proteins active sighting throws a monkey wrench into the works. Okay, so now that's one in a billion. How are you going to find that guy? Well, this is where the polymerase chain reaction, the same one we use for the COVID-19 tests for infection comes into play. Because if you can now isolate this needle in a haystack and use PCR to amplify it and make a whole handful of it, now you've got a whole handful of molecules which are much better at binding this protein than the starting molecule. And now you can go through this cycle several times to enrich for these, maybe mutagen it a little bit more to give it a little more diversity. We all know diversity is good, so you put a little more diversity into the population and now you find some guy that's really good at recognizing some disease causing protein. So this is the, so-called aptamer story, and they have been used therapeutically with some success, but diagnostically certainly they are extremely useful. And it's another area where we've had success and the future could hold even more success.Eric Topol (41:06):I think what you're bringing up is so important because the ability to screen that tens of thousands of plasma proteins in a person and coming up with as Tony Wyss-Coray did with the organ clocks, and this is using the SomaLogic technology, and so much is going on now to get us not just the polygenic risk scores, but also these proteomic scores to compliment that at our orthogonal, if you will, to understand risk of people for diseases so we can prevent them, which is fulfilling a dream we've never actually achieved so far.Tom Cech (41:44):Eric, just for full disclosure, I'm on the scientific advisory board of SomaLogic in Boulder. I should disclose that.Eric Topol (41:50):Well, that was smart. They needed to have you, so thank you for mentioning that. Now, before I wrap up, well, another area that is a favorite of mine is citizen science. And you mentioned in the book a project because the million shapes of RNA and how it can fold with all hairpin terms turns and double stranded and whatever you name it, that there was this project eteRNA that was using citizen scientists to characterize and understand folding of RNA. Can you tell us about that?RNA Folding and Citizen ScienceTom Cech (42:27):So my friend Rhiju Das, who's a professor at Stanford University, sort of adopted what had been done with protein folding by one of his former mentors, David Baker in Seattle, and had repurposed this for RNA folding. So the idea is to come up with a goal, a target for the community. Can you design an RNA that will fold up to look like a four pointed cross or a five pointed star? And it turned out that, so they made it into a contest and they had tens of thousands of people playing these games and coming up with some remarkable solutions. But then they got a little bit more practical, said, okay, that was fun, but can we have the community design something like a mRNA for the SARS-CoV-2 spike protein to make maybe a more stable vaccine? And quite remarkably, the community of many of whom are just gamers who really don't know much about what RNA does, were able to find some solutions. They weren't enormous breakthroughs, but they got a several fold, several hundred percent increase in stability of the RNA by making it fold more tightly. So I just find it to be a fascinating approach to science. Somebody of my generation would never think of this, but I think for today's generation, it's great when citizens can become involved in research at that level.Eric Topol (44:19):Oh, I think it's extraordinary. And of course, there are other projects folded and others that have exemplified this ability for people with no background in science to contribute in a meaningful way, and they really enjoy, it's like solving a puzzle. The last point is kind of the beginning, the origin of life, and you make a pretty strong case, Tom, that it was RNA. You don't say it definitively, but maybe you can say it here.RNA and the Origin of LifeTom Cech (44:50):Well, Eric, the origin of life happening almost 4 billion years ago on our primitive planet is sort of a historical question. I mean, if you really want to know what happened then, well, we don't have any video surveillance of those moments. So scientists hate to ever say never, but it's hard to sort of believe how we would ever know for sure. So what Leslie Orgel at the Salk Institute next to you taught me when I was a starting assistant professor is even though we'll never know for sure, if we can recapitulate in the laboratory plausible events that could have happened, and if they make sense chemically and biologically, then that's pretty satisfying, even if we can never be absolutely sure. That's what a number of scientists have done in this field is to show that RNA is sort of a, that all the chemistry sort of points to RNA as being something that could have been made under prebiotic conditions and could have folded up into a way that could solve the greatest of all chicken and egg problems, which came first, the informational molecule to pass down to the next generation or the active molecule that could copy that information.(46:32):So now that we know that RNA has both of those abilities, maybe at the beginning there was just this RNA world RNA copying itself, and then proteins came along later, and then DNA probably much more recently as a useful but a little bit boring of genetic information, right?Eric Topol (46:59):Yeah. Well, that goes back to that cover of the Economist 17 years ago, the Big Bang, and you got me convinced that this is a pretty strong story and candidate. Now what a fun chance to discuss all this with you in an extraordinary book, Tom. Did I miss anything that you want to bring up?Tom Cech (47:21):Eric, I just wanted to say that I not only appreciate our conversation, but I also appreciate all you are doing to bring science to the non-scientist public. I think people like me who have taught a lot of freshmen in chemistry, general chemistry, sort of think that that's the level that we need to aim at. But I think that those kids have had science in high school year after year. We need to aim at the parents of those college freshmen who are intelligent, who are intellectually curious, but have not had science courses in a long time. And so, I'm really joining with you in trying to avoid jargon as much as possible. Use simple language, use analogies and metaphors, and try to share the excitement of what we're doing in the laboratory with the populace.Eric Topol (48:25):Well, you sure did that it was palpable. And I thought about it when I read the book about how lucky it would be to be a freshman at the University of Boulder and be having you as the professor. My goodness. Well, thank you so much. This has been so much fun, Tom, and I hope everybody's going to get out there and read the Catalyst to get all the things that we didn't even get a chance to dive into. But this has been great and look forward to future interactions with you.Tom Cech (48:53):Take care, Eric.*********************Thanks for listening or reading this edition of Ground Truths.Please share this podcast with your friends and network. That tells me you found it informative and makes the effort in doing these worthwhile.All Ground Truths newsletters and podcast are free. Voluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff for audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

David Liu, professor of chemistry at Harvard University and co-founder of multiple biotech companies, including Beam Therapeutics and Prime Medicine.

Episode 17 (April 12, 2024): This week, the GEN editors discuss the launch of Nvelop Therapeutics, a new start-up leveraging approaches developed by gene editing pioneers David Liu, PhD, and J. Keith Joung, MD, PhD, to advance delivery of genetic cargo. The GEN editors also recap highlights from the American Association for Cancer Research (AACR) annual meeting held in San Diego, California. Featuring Uduak Thomas (Senior Editor, GEN), Alex Philippidis (Senior Business Editor, GEN), Julianna LeMieux, PhD (Deputy Editor-in-Chief, GEN), and Jonathan Grinstein, PhD (Senior Editor, GEN), and moderated by Fay Lin, PhD (Senior Editor, GEN Biotechnology) Listed below are key references to the GEN stories, media, and other items discussed in this episode of Touching Base: The State of Omics 2024 Registration GEN Summit Cloaking Device: Liu, Joung Launch $100M Nvelop Therapeutics to Advance Delivery of Genetic Cargo By Alex Philippidis, GEN Edge, April 9, 2024 Bertozzi, Regev, and More Inspire During the Opening Plenary Session of AACR By Julianna LeMieux, PhD, GEN, April 8, 2024 AACR 2024: Aviv Regev Shows How Single-Cell Atlases Foster New Axis to Genentech's Drug Discovery By Jonathan Grinstein, PhD, GEN, April 8, 2024 AACR 2024: A Video Update from San Diego By Julianna LeMieux, PhD, and Jonathan Grinstein, PhD, GEN, April 8, 2024 A Video Update from Day Two of the AACR Meeting By Julianna LeMieux, PhD, and Jonathan Grinstein, PhD, GEN, April 9, 2024 AACR 2024: EpiBiologics Advances Degraders of Membrane-Bound Proteins By Jonathan Grinstein, PhD, GEN, April 8, 2024 Celebrating National Robotics WeekBy Uduak Thomas, GEN, April 12, 2024 Hosted on Acast. See acast.com/privacy for more information.

Brain health researchers are exploring new ways to leverage AI in the diagnosis of diseases like Alzheimer's. One emerging field of study is that of vocal biomarkers: the way our voices sound. Some companies are even developing personal smart devices to identify vocal biomarkers — and, perhaps one day in the future, to aid in early diagnosis or even disease prevention. We asked David Liu, the CEO of Sonde Health, to join Live Talks to explain this emerging field, and tell us a bit more about the science behind voice biomarkers and their potential for early-identification of cognitive impairment. Listen to the full live talk to learn more about vocal biomarkers and their potential for early detection of cognitive decline.

“A few years ago, I might have chuckled at the naiveté of this question, but now it's not so crazy to think that we will be able to take some sort of medicine to extend our healthy lifespans in the foreseeable future.”—Coleen MurphyTranscript with external linksEric Topol (00:06):Hello, this is Eric Topol from Ground Truths, and I'm just so delighted to have with me Professor Coleen Murphy, who has written this exceptional book, How We Age: The Science of Longevity. It is a phenomenal book and I'm very eager to discuss it with you, Coleen.Coleen Murphy (00:25):Thanks for having me on.Eric Topol (00:27):Oh yeah. Well, just so everyone who doesn't know Professor Murphy, she's at Princeton. She's the Richard Fisher Preceptor in Integrative Genomics, the Lewis-Sigler Institute for Integrative Genomics at Princeton, and director of the Paul Glenn Laboratories for Aging Research. Well, obviously you've been in this field for decades now, even though you're still very young. The classic paper that I can go back to would be in Nature 2003 with the DAF-16 and doubling the lifespan of C. elegans or better known as a roundworm. Would that be the first major entry you had?Coleen Murphy (01:17):Yeah, that was my postdoctoral work with Cynthia Kenyon.Eric Topol (01:20):Right, and you haven't stopped since you've been on a tear and you've put together a book which has a hundred pages of references in a small font. I don't know what the total number is, but it must be a thousand or something.Coleen Murphy (01:35):Actually, it's just under a thousand. That's right.Eric Topol (01:37):That's a good guess.Coleen Murphy (01:38):Good guess. Yeah.Eric Topol (01:39):So, because I too have a great interest in this area, I found just the resource that you've put together as extraordinary in terms of the science and all the work you've put together. What I was hoping to do today is to kind of take us through some of the real exciting pathways because there's a sentence in your book, which I thought was really kind of nailed it, and it actually is aligned with my sense. Obviously don't have the expertise by any means that you do here but it says, “A few years ago, I might have chuckled at the naivety of this question, but now it's not so crazy to think that we will be able to take some sort of medicine to extend our healthy lifespans in the foreseeable future.” That's a pretty strong statement for a person who's deep into the science. First I thought we'd explore healthy aging health span versus lifespan. Can you differentiate that as to your expectations?Coleen Murphy (02:54):So, I think most people would agree that they don't want to live necessary super long. What they really want to do is live a healthy life as long as they can. I think that a lot of people also have this fear that when we talk about extending lifespan, that we're ignoring that part. And I do want to assure everyone that the people in the researchers in the aging field are very much aware of this issue and have, especially in the past decade, I think put a real emphasis on this idea of quality of life and health span. What's reassuring is actually that many of the mechanisms that extend lifespan in all these model organisms also extend health span as well and so I don't think we're going to, they're not diametrically opposed, like we'll get to a healthier quality of life, I think in these efforts to extend lifespan as well.Eric Topol (03:50):Yeah, I think that's important that you're bringing that up, which is there's this overlap, like a Venn diagram where things that do help with longevity should help with health span, and we don't necessarily have to follow as you call them the immoralists, as far as living to 190 or whatever year. Now, one of the pathways that's been of course a big one for years and studied in multiple species has been caloric restriction. I wonder if you could talk to that and obviously there's now mimetics that could simulate that so you wouldn't have to go through some major dietary starvation, if you will. What are your thoughts on that pathway?Coleen Murphy (04:41):Yeah, actually I'm really glad you brought up mimetics because often the conversation starts and ends with you should eat less. I think that is a really hard thing for a lot of people to do. So just for the background, so dietary restriction or caloric restriction, the idea is that you would have to take in up to 30% less than your normal intake in order to start seeing results. When we've done this with laboratory animals of all kinds, this works from yeast all the way up through mice, actually primates, in fact, it does extend lifespan and in most metrics of health span the quality of life, it does improve that as well. On the other hand, I think psychologically it's really tough to not eat enough and I think that's a part that we kind of blindly ignore when we talk about this pathway.Coleen Murphy (05:30):And of course, if we gave any of those animals the choice of whether they want to start eating more, they would. So, it's like that's not the experiment we ever hear about. And so, the idea for studying this pathway isn't just to say, okay, this works and now we know how it works, but as you pointed out, mimetics, so can we target the molecules in the pathway so that we can help people achieve the benefits of caloric restriction without necessarily having to do the kind of awful part of restriction? I think that's really cool, and especially it might be very good for people who are undergoing certain, have certain diseases or have certain impairments that it might make it difficult ever to do dietary restrictions, so I think that's a really great thing that the field is kind of getting towards now.Eric Topol (06:15):And I think in fact, just today, it's every day there's something published now. Just today there was a University of Southern California study, a randomized study report comparing plant-based fasting-mimicking diet versus controlled diet, and showed that many metabolic features were improved quite substantially and projected that if you stayed on that diet, you'd gain two and a half years of healthy aging or that you would have, that's a bit of an extrapolation, but quite a bit of benefit. Now, what candidates would simulate caloric restriction? I mean, what kind of molecules would help us do that? And by the way, in the book you mentioned that the price to pay is that the brain slows down with caloric restrictions.Coleen Murphy (07:10):There's at least one study that shows that.Coleen Murphy (07:13):Yeah, so it's good to keep in mind. One of the big things that is being looked at as rapamycin, looking at that TOR pathway. So that's being explored as one of these really good mimetics. And of course, you have things that are analogs of that, so rapalogs, and so people are trying to develop drugs that mimic that, do the same kind of thing without probably some of the side effects that you might see with rapamycin. Metformin is another one, although it's interesting when you talk to people about metformin who work on it, it's argued about what is exactly the target of metformin. There's thought maybe also acts in the TOR pathway could affect complex one of mitochondria. Some of the things we know that they work, and we don't necessarily know how they work. And then of course there's new drugs all the time where people are trying to develop to other target, other molecules. So, we'll see, but I think that the idea of mimetics is actually really good, and that part of the field is moving forward pretty quickly. This diet that you did just mention, it is really encouraging that they don't have to take a drug if you don't want to. If you eat the right kind of diet, it could be very beneficial.Eric Topol (08:20):Yeah, no, it was interesting. I was looking at the methods in that USC paper and they sent them a box of stuff that they would eat for three cycles, multiple weeks per cycle. It was a very interesting report, we'll link to that. Before we leave the caloric restriction and these mTOR pathway, you noted in the book that there some ongoing trials like PEARL, I looked that up and they finished the trial, but they haven't reported it and it's not that large. And then there's the FAME trial with metformin. I guess we'll get a readout on these trials in the not-too-distant future. Right?Coleen Murphy (08:57):Yeah, that's the hope that especially with the Metformin trial, which I think is going to be really large the FAME trial, that just to give the listeners a little background, one of the efforts in the field is not just to show that something works, but also to convince the FDA that aging could be a pharmaceutical, a disease that we might want to have interventions for. And to do that, we need to figure out the right way to do it. We can't do 30-year studies of safety and things to make sure that something's good, but maybe there are reasonable biomarkers that would tell us whether people are going to live a long time. And so, if we can use some of those things or targeting age-related diseases where we can get a faster readout as well. Those are reasonable things that companies could do that would help us to really confirm or maybe rule out some of these pharmaceuticals as effective interventions. I think that would be really great for consumers to know, is this thing really going to do good or not? And we just don't have that right now in the field. We have a lot of people saying something will work and it might and the studies in the lab, but when we get to humans, we really need more clinical studies to really tell us that things are going to be effective.Eric Topol (10:12):Right, I'm going to get to that in a bit too because I think you're bringing up a critical topic since there's an explosion of biopharma companies in this space, billions of dollars that have been put up for in capital and the question is what's going to be the ground rules to get these potential candidate drugs to final commercial approval. But before I leave, caloric restriction and insulin signaling and the homolog and the human to what your discovery of DAF-16, FOXO and all this, I just want you to comment, it wasn't necessarily developed in the book, but as you know, the GLP-1 drugs have become just the biggest drug class in medical history, and they do have some effects here that are very interesting. They are being tested as in Alzheimer's disease. Do you see that this is a candidate too that might promote healthy aging?Coleen Murphy (11:12):Yeah, I'm so glad you brought that up because my book, I finished writing it right before all this stuff came out, and it's looking really very compelling. People are on these drugs, they lose a ton of weight, but their blood biomarkers really become very good and on top of just the changes in weight and those kinds of effects. Let me just say, I think the biggest thing, the biggest risk actually for aging people right now are cardiovascular problems, cardiovascular disease, and these drugs, no doubt, it's going to basically make a huge dent in that. I'm absolutely sure of that. What I also find really interesting with those drugs is that the users report that they have fewer cravings for other things. So, this is not being looked at to treat alcoholism and drug addiction, other things, so it really opens up a whole new world of things that are bad for us that maybe we could avoid this with these peptides. It's almost staggering. I really think this going to be a huge, and as far as an aging drug, if you reduce your weight, you improve all your cardiovascular function, you don't feel like drinking all the time, all these things might be really great and I do think that people will live longer.Eric Topol (12:32):Yeah, no, it does have that look and you just have to wonder if as these will go on to oral drugs with triple receptors and very potent, maybe even avoiding peptides in the future too, that this could wind up being something that's exceedingly common to take for reasons far removed from the initial indication of type two diabetes and more recently of course, obesity. Now the next topic I wanted to get into with you were senolytics, these agents that basically are thought to reverse aging or slow aging. And again, since everything's coming out in a daily basis, there was a trial in diabetes macular edema where giving senolytic after people had failed their usual VEGF treatment was highly successful. So, we're starting to see, at least in the eye results. I wonder if you could describe how you conceive this field of senolytics?Coleen Murphy (13:41):Actually, I think they've made great progress in the past couple of years because there were some initial failures, like some of the things for osteoarthritis that went through I think phase two, but I think that one of the great things about the longevity biotech field is that they're starting to identify not just longevity, these age-related disorders that they could actually use. And so, it's kind of doubly beneficial. It tells us that the drugs actually do something and so maybe it'll be used for something else in the future and you get through, you can test safety, but also helping people actually have a very real problem that's acute that they really need to take care of. And so that's really exciting. Then in addition to the example you just mentioned, I was at a conference last summer where it was being explored whether some of these senolytics could be helpful for middle aged survivors of childhood cancers who do show various health effects from having gone through chemotherapies at a young age. So that's really exciting. Could you help people who are not aging, but they actually are showing having problems that we kind of associate with aging. And senolytics were at least the first thing I'd heard about that are actually being used for that, so there may be other approaches that help as well, but I think that's really great.Eric Topol (15:05):Well, and just to be clear the senolytics, I guess could be categorized at least one function might be to help clear dead cells. These senescent cells are bad actors and either they're taken out or they're somehow neutralized in their impact of secreting evil humors, if you will. Are there other forms of senolytics besides that way of dealing with these senescent cells?Coleen Murphy (15:33):I know that some people are exploring senomorphs, so things that make those cells just arrest but I do want to mention, of course, we lost a great Judith Campisi recently, and she was the one who discovered and described the senescent associated secretory phenotype, and she did amazing work in that field really opening that up. So, this idea that bad cells aren't just bad because they don't function, but they're actually toxic to other cells.Coleen Murphy (16:04):That's important for listeners to know. Yeah, so I don't know. I think that one of the things I'm excited about in the aging field is that it doesn't seem like there's one magic bullet. A lot of researchers will spend their time working on that one thing so if you only talk to that one person, you might get that impression, but there's a whole host of things that for bad or good, that things go wrong when we age, but those all end up being maybe targets that could help us live longer or at least in a healthier way. And so, we've already talked about a couple of them, but readers will see as we learn more, there might be more ways to help cells survive or to help us replace ourselves, for example.Eric Topol (16:45):I mean, I think what you're bringing up here is central because there's all these different, as I can see it, shots on goal that of course could be even used as combinations, no less senolytic interventions so we're getting closer as we started this conversation to fulfilling what you, I think is in store in the years ahead, which is extraordinary. Along with the senolytics, I wonder if you could just talk a little bit about these autophagy enhancers as a class of agents, maybe first explaining autophagy and then is this a realistic goal that we should be taking autophagy enhancers, or is this something that's too generalized that might have onward mTOR effects?Coleen Murphy (17:39):Well, it's interesting. Autophagy, so just for the listeners, autophagy literally means self-eating. So this is a pathway whereby proteins basically get degraded within the cell and those parts get recycled. And the idea is that if you have a cell or protein that's damaged in some way, or it can be renewed if you induce autophagy. I think I could be wrong here, but my sense is that the cancer field is really excited about autophagy enhancers. And so, I think that's probably where we'll see the biggest breakthroughs but along the way, of course we'll know because we'll know if they're safe and if there's other off-target effects. I think that that's largely being driven by the cancer field and the longevity field is kind of a little bit behind that, so we'll learn from them. It seems like a really exciting approach as well.Eric Topol (18:34):Yeah, it does. And then as you know, the idea of giving young blood, young plasma, which there already are places that do this, that it can help people who are cognitively impaired and have basically immediate effects, and sometimes at least with some durability. It's very anecdotal, but this idea, we don't know what's in the young blood or young plasma to some extent. How do you process that?Coleen Murphy (19:10):Okay. Well, so what we do know, and this is really work that a lot of people like Saul Villeda and Tony Wyss-Coray have done where they really have, they've taken that blood or plasma and then found the parts in the plasma that actually do specific jobs. And so, we actually are starting to learn a lot about that and that's exciting because of course, we don't really want to give people young blood. What we really would like to do is find out is there a particular factor in the blood? And there seems to be many that could be beneficial. And so, we really are getting close. We as a field, and specifically like the research I just mentioned and that's exciting because you can imagine, for example, if there's one factor that's in blood, that's in young blood, that's very helpful, manufacturing, a lot of that particular thing.Coleen Murphy (20:01):The other exciting thing, again, this is Saul Villeda's lab that found that exercise mice. So even if they're the same age mice, if one of them is exercised, it makes factors that actually from the liver of the mouse upon exercise, that then gets secreted and then affect, improve cognitive function as well. So it seems like even within the blood, there's multiple different ways to get blood factors that are beneficial, whether they're from young blood or from exercise blood. And so, there's a lot of things we don't yet know, but I do think that field is moving very fast and they're identifying a lot of things. In fact, so I'm the director of Simons Collaboration Plasticity in the Aging Brain, and on that website we're developing basically a page that can tell you what are the factors and what has it been shown to be associated with, because we're very interested in slowing normal cognitive aging and blood factors seem to be one of the really powerful ways that might be available to us very soon to be able to improve that.Eric Topol (21:03):Yeah, no, I'm glad you mentioned that, Coleen. I think the point that you made regarding exercise, I certainly was struck by that because in the book, because we've known about this association with exercise and cognition, and this I think is certainly one potential link. An area that is also fascinating is epigenetics, so a colleague of mine here in the Mesa, Juan Carlos Belmonte, who was at Salk and left to go to Altos, one of these many companies that are trying to change the world in health span and lifespan. Anyway, he had published back several years ago.Coleen Murphy (21:53):Yeah, 2016.Eric Topol (21:54):Yeah, CRISPR basically modulation of the epigenome through editing and showed a number of through specific pathways, a number of pretty remarkable effects. I wonder if you could comment about epigenetics, and then I also want to get into this fascinating topic of transgenerational inheritance, which may be tied of course to that. So, what about this pathway? Is there something to it?Coleen Murphy (22:29):Well, absolutely. I just think we need to learn a lot more about it. So just for the listener, so epigenetics, we think about genetics that's basically based on DNA and chromosomes. And so, when we think about epigenetics, that could be either, we could be talking about modulation of the histone marks on the chromosomes that allow the genes to be expressed or be silenced. And then on the DNA itself, there are methylation marks. And so, people have used, of course, Steve developed a, sorry, I'm sorry. Steve Horvath developed a very nice, he was first to develop a DNA methylation clock. So this idea that you could, and that was really interesting because he based it on, he used this machine learning method to narrow down to the 353 marks that were actually predictive or correlated with age, but we don't understand how it biologically what that manifests in. I think that's not well understood. At the chromatin level, there's a lot of work on the specific histone marks that may change, for example, how genes are transcribed and so understanding that better will maybe help us understand what those changes. There's things called epigenetic drift, so genes stop being carefully regulated with age, and then how can we make that maintain better with age? It's one of the goals of the field in addition to basically understanding what's going on at the epigenetic level.Eric Topol (24:01):So now of course, could we alter that? Oh, it is fascinating as you say, that you could have the Horvath clock to so accurately predict a person's biological age. And by the way, just a few days ago, there was a review by all these clock aging folks in nature medicine about the lack of standards. There's so many clocks to basically determine biological age versus chronological age. Before we get into the transgenerational inheritance, what is your sense? Obviously, these are getting marketed now, and this field is got ahead of its skis, if you will, but what about these biologic age markers?Coleen Murphy (25:02):Yeah, I'm glad to hear that. I haven't seen that review. I should look it up. It's good to know that the players in the field are addressing those points. So just for the listeners, so these DNA methylation clocks so when Steve Horvath developed the first one, it was based on the controls from a very large number of cancer controls for other reasons, so he used a huge amount of information. It really depended on the, he was trying to develop a clock that was independent of which tissue, but it turned out there's more and more clocks that are tissue specific and really organism specific, species specific. It really depends on what you're looking at to make these, and whether you're looking at chronological age or trying to predict biological age. I think it's a little frustrating because what you'd really like to know as a consumer, if you send off for one of these clock kits, is it right?Coleen Murphy (25:57):What's the margin of error? If I took it every week, would I get the same number? And so, I think my sense is that people take it until they get a low number then, but you'd really like to know if they work, because if you want to take it, do a control and they start, get your clock number and then start taking some intervention and ask whether it works, right? Yeah. So, I think because the players in the field recognize these issues, they're going to straighten it out, but I think one part that drives a little bit of the problem is that we don't understand what that DNA methylation mark change translates into biologically. If we understood that better, I think we'd have a better feeling about it. Anne Brunet and Tony Wyss-Coray maybe a year and a half ago, they had a nice paper where two years ago where they looked at, they use a different type of clock, a transcriptional clock, and that worked really well. So they were looking at transcriptional clock in the subventricular zone, and they were able to actually see changes not just with age, but also when there was an intervention. I can't remember if they look at dietary restriction and then maybe an exercise in the mice. And so that's important for us to know how well those clocks work.Coleen Murphy (27:13):I think it'll get there. It'll get there.Eric Topol (27:15):You don't want to pay a few hundred dollars and then be told that you're 10 years older biologically than your chronologic age, especially if it's wrong. Right?Coleen Murphy (27:25):Yes. It'll get there. I think it may not be quite there yet.Eric Topol (27:30):And by the way, while we're on that, the organ clocks paper, in fact, just a recent weeks, I did interview Tony Wyss-Coray from Stanford, and we talked about what I consider really a seminal paper because using plasma proteins, they're able to basically clock each organ. And that seems like a promising approach, which could also help prove the case that you're changing something favorably with one of these various intervention classes or categories. Do you think that's true?Coleen Murphy (28:05):That feels more real directly looking at the proteins then.Eric Topol (28:08):Yeah, exactly. I thought that was really exciting work, and I'm actually going to visit with Tony in a few weeks to discuss it further. So excited about it.Coleen Murphy (28:18):That's great. He's doing great work, so it'll be a fascinating conversation.Eric Topol (28:21):Yeah, well this is also fascinating. Now, transgenerational inheritance is a very controversial topic in humans, which it is not so much in every other species. Can you explain why that is?Coleen Murphy (28:38):Well, there's a lot of, I would say emotional baggage attached here, right? Because that's what people are talking about, like transgenerational trauma. There's no doubt that traumatic experiences in childhood actually do seem to change the genome and change have very real biological effects. And that's been shown. So that's within the first generation. It's also no doubt that in other organisms, like in plants like DNA methylation, that's exactly how they regulate things, and that's multiple generations. So that's kind of the norm. And so, the question for humans is whether something like this, like a traumatic experience or starvation or thing, has an effect, not just on the person who's experiencing it, but also on their progeny, even on their grand progeny. And so, it's tough, right? Because the data that are out there are from pretty terrible experiences like the Dutch hunger winter. And so, there's a limited set of data, and some of those data look good, and some of them look weaker. Yeah, I think that we still need to figure out what's going on there, and if it's real, it'd be interesting to know. Are there ways, for example, with these epigenetic modulators, are there ways that you could help people be healthier by erasing some of those marks of trauma, generational trauma?Eric Topol (30:03):Yeah. So, I mean, the theory as you're getting to would be you could change the epigenome, whether it's through chromatin, acetylation, methylation, somehow through these experiences and it would be going through down through multiple generations. The reason I know it's controversial is when I reviewed Sid Mukherjee's book, the Gene, he had put in that it was real in humans, and the attack dogs came out all over the place. Now, we've covered a lot of these pathways. One that we haven't yet touched on is the gut microbiome, and the idea here, of course, it could be somewhat linked to the caloric restriction story, but it seems to be independent of that as well. That is there, our immunity is very much influenced by our gut microbiome. There's the gut brain axis and all sorts of interactions going on there, but what about the idea of using probiotics and particular bacterial species as a introducing the people as an idea in the future to promote health span?Coleen Murphy (31:18):Yeah, it's a great idea. So, I just want to back up and say the microbiome, the reason it's so fraught is because for a long time, people had confused correlation and causation. So, they would see that a person who has X disease has a difference in the microbiome from people who don't have that disease. And so, the question was always, do they have that disease because of a difference in the microbiome or the disease influence in the microbiome? And of course, even things that's eating different food. For example, if a child with autism doesn't want to eat certain range of food, it's going to have an effect on the microbiome. That does not mean the microbiome cause their autism. And so that's something where, and the same thing with Alzheimer's disease patients. I think that's often the source of some of this confusion. I think people wish that they could cure a lot of diseases by taking a probiotic.Coleen Murphy (32:09):On the other hand, now there's actually some really compelling data. Dario Valenzano's lab did a really nice experiment in killifish, which is my second favorite aging model research organism. So killifish, turquoise killifish, only live a few months. And so, you can do aging studies really quickly and what Dario's group did was they took the microbiome at middle aged fish, they wiped out their microbiome with antibiotics, and they added back either young or same age, and they saw a really nice extension of lifespan with the young microbiome. So that suggests, in that case where everything else is the same, it really does have a nice effect. John Cryan's group in Ireland did something similar with mice, and they showed that there was a beneficial effect on cognitive function in older mice. So those are two examples of studies where it really does seem like there is an effect, so it could be beneficial. And then there's of course things like microbiome transfer for people who are in the hospital who have had other things, because your microbiome also helps you prevent other diseases. Those being there, if you wipe out all of your microbiome, you can actually get infected with other things. It's actually a protective barrier. There's a lot of benefits, I think in order to, we don't know a ton about how to control it. We know there are these, it's gross, but fecal microbiome transplantation.Eric Topol (33:42):FMT. Yeah, yeah.Coleen Murphy (33:44):Exactly. And so, I think that is kind of the extreme, but it can be done. I think in appropriate cases it could be a very good strategy.Eric Topol (33:53):It's interesting. There was a study about resilience of the immune system, which showed that women have a significant advantage in that they have just the right balance of not having a hyper inflammatory reaction to whether it's a pathogen or other stimulus. And they also have, of course, an immunocompetent system to respond, so unlike men overall, that although the problem of course with more prone to autoimmunity because of having two x chromosomes and exist or whatever other factors. But also, there's a balance that there's an advantage, in the immune system as a target for health span and lifespan, a lot of things that we've talked about have some interaction with the immune system. Is there anything direct that we can do to promote a healthier immune system and avoid immunosenescence and inflammaging or immuno aging or whatever you want to call it?Coleen Murphy (35:04):Sure, I will admit that immunology is a field that I want to learn more about, but I do not know enough about it to give a really great answer. I think it's one of the things I kind of shied away from when I wrote the book that if I were to rewrite it, I would add a whole new section on it. I think that's a really booming field, this interaction between immunology and aging. Obviously, there's immune aging, but what does that really mean?Coleen Murphy (35:28):I feel like I can't give you a really intelligent answer about that. Even though I'd like to, and I don't know how much of it's because there's just sort of this general idea that the immune system stops functioning well, but I do feel like the immune system is actually so mysterious. I have a peanut allergy, for example. We don't even really, I mean, we can prime ourselves against that now. We can give kids little bits of peanuts, but all the things that I feel like immunology is the one that's probably taking off the most, and we'll probably in a decade know way more about it than we do now, but I can't give you a very smart answer right now.Eric Topol (36:09):Yeah, no, I do think it's really provocative and the fact that if you have these exhausting T cells that are basically your backup system of your immune system, if they're not working, that's not good. And maybe they can be revved up without being problematic. We'll see.Coleen Murphy (36:27):And I guess the real question is do we need to do something independent or is that folded into everything else? If you were giving someone a drug that seemed very good systemically or some of these blood factors, would you have to do something special just for the immune system or is that something that would also be effective? I feel like that would be good to know.Eric Topol (36:44):Now the other area that I want to bring up, which is a little more futuristic is genome editing. So recently when I spoke to David Liu, he mentioned, well, actually it was Jennifer Doudna who first put it out there, but we discussed the idea of changing the people like me who are APOE4 carriers to APOE2, which is associated with longer life and all these other good things. Why don't we just edit ourselves to do that? Is that a prospect that you think ever could be actualized?Coleen Murphy (37:20):Well, I was just at a talk by Britt Adamson just moments ago, and that field is moving really fast, right? All the work that David Liu has done, and it's really exciting, this idea that you can now cure sickle cell anemia.Coleen Murphy (37:35):Fascinating. And I think Jennifer Doudna rightly proposed early on that what we should really be hitting first are like blood. Blood's really good because it's not hitting the germline. It's really something where we can help people at that stage. I was thinking about that while Britt was talking, what are the things we'd really want to address with CRISPR? I'm not sure how high up in the list aging related factors would be compared to a lot of childhood diseases, things that are really debilitating, but certainly is true since when we're looking at APOE4. I think that's the one exception because that is so strongly correlated with healthy lifespan and Alzheimer's and things, so we really want to do something about that. The question is how would we do that? That's not a blood factor. I think we'd have to think hard about that, but it is on the list of looming on the horizon.Eric Topol (38:35):I wouldn't be surprised if someday, and David, of course thought it's realistic, but it's not, obviously in the short term. Well, this has been enthralling to go through all these possibilities. I guess when you put it all together, there's just so many ways that we might be able to, and one of the things that you also pointed out in your book, which something that should not be forgotten, is the fact that all these things could even worsen the inequities that we face today. That is you have any one of these click, if not multiple, it isn't like they're going to be available to all. And the problem we have now, especially in this country without universal health and access issues, could be markedly exacerbated as we're seeing with the GLP-1 drugs too, by the way.Coleen Murphy (39:27):Absolutely.Eric Topol (39:28):So, I just want to give you a chance to reinforce what you wrote in the book, because I think this is where a lot of times science leads and doesn't realize the practical implications of who would benefit.Coleen Murphy (39:42):Yeah, I think actually for aging research often, even when I first started doing this work back in 2000, the first thing people would ask me if they're below a certain age was, don't you think that's terrible? Make the rich people just live the longest? And they're not wrong about that. I think what it can, we should raise awareness about the fact that even these things that we consider simple, like doing caloric restriction or getting exercise, even those things are not that straightforward if you're working two jobs or if you don't have access to excellent foods in your neighborhood, right? Fruits and vegetables. If we really want to not just extend longevity but raise life expectancy, then we should be doing a lot more that's for improving the quality of life of many people. And so there is that idea. On the other hand, I do want to point out that as we discover more and more of these things, like metformin is off patent, it's like it's really old. And so, it's more of these things get discovered and more broadly used. I do think that that may be a case where we could end up having more people might have access to things more easily. So that's my hope.Coleen Murphy (40:57):I don't want to discourage anyone from developing a longevity dry. I think eventually that could help a lot of people if it's not too absurdly expensive.Eric Topol (41:04):Yeah, no, I certainly agree. And one last footnote is that we did a study called The Wellderly here, about 1,400 people over age 85 who'd never been sick, so our goal here wasn't lifespan. It was to understand if there was genomics, which we did whole genome sequencing of this group. We didn't find much like the study that you cited in the book by the Calico group. And so just to give hope that people, if they don't have what they think are family genetics of short life or short health span, that may not be as much to that as a lot of people think. Any final thoughts about that point? Because it's one that's out there and data goes in different directions.Coleen Murphy (41:55):Yeah. The Calico study you mentioned, I think that's the one where they found that your health or lifespan mostly went with almost like your in-laws, which actually points again to your socioeconomic group probably you marry people, most people marry people are in a similar socioeconomic group. That's probably what that mostly had to do with. I do think if I'm going to say one thing because a lot of these drugs are on the horizon, they're not yet available, or there's nothing I can hang onto for an FDA approved drug to extend that. I do think the one thing that I would encourage people to do even more than the dietary restriction stuff, it is exercise because that's just generally beneficial in so many different ways. And so, if we can get people doing a little more exercise, I think that would be the one thing that probably could help a lot of people.Eric Topol (42:40):Well, I'm glad we are winding up with that because I think the data from lifestyle, which is exercise as you're pointing out, as well as nutrition and sleep.Coleen Murphy (42:54):All the boring things we already thought, right.Eric Topol (42:55):That we know about, but we don't necessarily put in our daily lives. There's a lot there. There's no question that studies, I think, really have reinforced that even recent one. Well, what a pleasure to talk to you about this and do this tour of the various exciting prospects. I hope I haven't missed anything. I know we can't go over all the pathways, and obviously there've been some bust in the past, which we don't need to review like the famous Resveratrol Sirtuin story, which you addressed in the book. I do want to encourage people that this book is extraordinary. Your work that you put into it had to be consumptive for I don't know how many years of work.Coleen Murphy (43:37):There was many years of work. My editor, we sat down to lunch right after it finished. She was like, so what are you going to work on for your next book?Eric Topol (43:50):Well, it's a scholarly approach to a very important field. If you can influence the aging process, you influence every part of our body function. The impact here is profound, and the contribution that you've made in your science as well as in your writing here is just so terrific. So thank you, Coleen. Thanks so much for joining us today.Coleen Murphy (44:17):Thank you so much. It's been a pleasure.Thanks for listening and/or reading this edition of Ground Truths, aimed at bringing you cutting-edge biomedical advances via analyses and podcasts.All content is free. Voluntary paid subscriptions go to support Scripps Research and have funded our summer intern program. 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David Liu is an gifted molecular biologist and chemist who has pioneered major refinements in how we are and will be doing genome editing in the future, validating the methods in multiple experimental models, and establishing multiple companies to accelerate their progress.The interview that follows here highlights why those refinements beyond the CRISPR Cas9 nuclease (used for sickle cell disease) are vital, how we can achieve better delivery of editing packages into cells, ethical dilemmas, and a future of somatic (body) cell genome editing that is in some ways is up to our imagination, because of its breadth, over the many years ahead. Recorded 29 November 2023 (knowing the FDA approval for sickle cell disease was imminent)Annotated with figures, external links to promote understanding, highlights in bold or italics, along with audio links (underlined)Eric Topol (00:11):Hello, this is Eric Topol with Ground Truths and I'm so thrilled to have David Liu with me today from the Broad Institute, Harvard, and an HHMI Investigator. David was here visiting at Scripps Research in the spring, gave an incredible talk which I'll put a link to. We're not going to try to go over all that stuff today, but what a time to be able to get to talk with you about what's happening, David. So welcome.David Liu (00:36):Thank you, and I'm honored to be here.Eric Topol (00:39):Well, the recent UK approval (November 16, 2023) of the first genome editing after all the years that you put into this, along with many other colleagues around the world, is pretty extraordinary. Maybe you can just give us a sense of that threshold that's crossed with the sickle cell and beta thalassemia also imminently [FDA approval granted for sickle-cell on 8 December 2023] likely to be getting that same approval here in the U.S.David Liu (01:05):Right? I mean, it is a huge moment for the field, for science, for medicine. And just to be clear and to give credit where credit is due, I had nothing to do with the discovery or development of CRISPR Cas9 as a therapeutic, which is what this initial gene editing CRISPR drug is. But of course, the field has built on the work of many scientists with respect to CRISPR Cas9, including Emmanuel Charpentier and Jennifer Doudna and George Church and Feng Zhang and many, many others. But it is, I think surprisingly rapid milestone in a long decade's old effort to begin to take some control over our genetic features by changing DNA sequences of our choosing into sequences that we believe will offer some therapeutic benefit. So this initial drug is the CRISPR Therapeutics /Vertex drug. Now we can say it's actually a drug approved drug, which is a Crispr Cas9 nuclease programmed to cut a DNA sequence that is involved in silencing fetal hemoglobin genes. And as you know, when you cut DNA, you primarily disrupt the sequence that you cut. And so if you disrupt the DNA sequence that is required for silencing your backup fetal hemoglobin genes, then they can reawaken and serve as a way to compensate for adult hemoglobin genes like the defective sickle cell alleles that sickle cell anemia patients have. And so that's the scientific basis of this initial drug.Eric Topol (03:12):So as you aptly put— frame this—this is an outgrowth of about a decade's work and it was using a somewhat constrained, rudimentary form of editing. And your work has taken this field considerably further with base and prime editing whereby you're not just making a double strand cut, you're doing nicks, and maybe you can help us understand this next phase where you have more ways you can intervene in the genome than was possible through the original Cas9 nucleases.David Liu (03:53):Right? So gene editing is actually a several decades old field. It just didn't quite become as popular as it is now until the discovery of CRISPR nucleases, which are just much easier to reprogram than the previous programmable zinc finger or tail nucleases, for example. So the first class of gene editing agents are all nuclease enzymes, meaning enzymes that take a piece of DNA chromosome and literally cut it breaking the DNA double helix and cutting the chromosome into two pieces. So when the cell sees that double strand DNA break, it responds by trying to get the broken ends of the chromosome back together. And we think that most of the time, maybe 90% of the time that end joining is perfect, it just regenerates the starting sequence. But if it regenerates the starting sequence perfectly and the nuclease is still around, then it can just cut the rejoin sequence again.(04:56):So this cycle of cutting and rejoining and cutting and rejoining continues over and over until the rejoining makes the mistake that changes the DNA sequence at the cut site because when those mistakes accumulate to a point that the nuclease no longer recognizes the altered sequence, then it's a dead end product. That's how you end up with these disrupted genes that result from cutting a target DNA sequence with a nuclease like Crispr Cas9. So Crispr Cas9 and other nucleases are very useful for disrupting genes, but one of their biggest downsides is in the cells that are most relevant to medicine, to human therapy like the cells that are in your body right now, you can't really control the sequence of DNA that comes out of this process when you cut a DNA double helix inside of a human cell and allow this cutting and rejoining process to take place over and over again until you get these mistakes.(06:03):Those mistakes are generally mixtures of insertions and deletions that we can't control. They are usually disruptive to a gene. So that can be very useful when you're trying to disrupt the function of a gene like the genes that are involved in silencing fetal hemoglobin. But if you want to precisely fix a mutation that causes a genetic disease and convert it, for example, back into a healthy DNA sequence, that's very hard to do in a patient using DNA cutting scissors because the scissors themselves of course don't include any information that allows you to control what sequence comes out of that repair process. You can add a DNA template to this cutting process in a process called HDR or Homology Directed Repair (figure below from the Wang and Doudna 10-year Science review), and sometimes that template will end up replacing the DNA sequence around the cut site. But unfortunately, we now know that that HDR process is very inefficient in most of the types of cells that are relevant for human therapy.(07:12):And that explains why if you look at the 50 plus nuclease gene editing clinical trials that are underway or have taken place, all but one use nucleases for gene disruption rather than for gene correction. And so that's really what inspired us to develop base editing in 2016 and then prime editing in 2019. These are methods that allow you to change a DNA sequence of your choosing into a different sequence of your choosing, where you get to specify the sequence that comes out of the editing process. And that means you can, for the first time in a general way, programmable change a DNA sequence, a mutation that causes a genetic disease, for example, into a healthy sequence back into the normal, the so-called wild type sequence, for example. So base editors work by actually performing chemistry on an individual DNA base, rearranging the atoms of that base to become a different base.(08:22):So base editors can efficiently and robustly change A's into G's G's, into A's T's into C's or C's into T's. Those four changes. And those four changes for interesting biochemical reasons turn out to be four of the most common ways that our DNA mutates to cause disease. So base editors can be used and have been used in animals and now in six clinical trials to treat a wide variety of diseases, high cholesterol and sickle cell disease, and T-cell leukemia for example. And then in prime editors we developed a few years later to try to address the types of changes in our genomes that caused genetic disease that can't be fixed with a base editor, for example. You can't use a base editor to efficiently and selectively change an A into a T. You can't use a base editor to perform an insertion of missing DNA letters like the three missing letters, CTT, that's the most common cause of cystic fibrosis accounting for maybe 70% of cystic fibrosis patients.(09:42):You can't use a base editor to insert missing DNA letters like the missing TATC. That is the most common cause of Tay-Sachs disease. So we develop prime editors as a third gene editing technology to complement nucleases and base editors. And prime editors work by yet another mechanism. They don't, again, they don't cut the DNA double helix, at least they don't cause that as the required mechanism of editing. They don't perform chemistry on an individual base. Instead, prime editors take a target DNA sequence and then write a new DNA sequence onto the end of one of the DNA strands and then sort of help the cell navigate the DNA repair processes to have that newly written DNA sequence replace the original DNA sequence. And in the process it's sort of true search and replace gene editing. So you can basically take any DNA sequence of up to now hundreds of base pairs and replace it with any other sequence of your choosing of up to hundreds of base pairs. And if you integrate prime editing with other enzymes like recombinase, you can actually perform whole gene integration of five or 10,000 base pairs, for example, this way. So prime editing's hallmark is really its versatility. And even though it's the newest of the three ways that have been robustly used to edit mammalian cells and rescue animal models of genetic disease, it is arguably the most versatile by far,Eric Topol (11:24):Right? Well, in fact, if you just go back to the sickle cell story as you laid out the Cas9 nuclease, that's now going into commercial approval in the UK and the US, it's more of a blunt instrument of disruption. It's indirect. It's not getting to the actual genomic defect, whereas you can do that now with these more refined tools, these new, and I think that's a very important step forward. And that is one part of some major contributions you've made. Of course, there are many. One of the things, of course, that's been a challenge in the field is delivery whereby we'd like to get this editing done in many parts of the body. And of course it's easy, perhaps I put that in quotes, easy when you're taking blood out and you're going to edit those cells and them put it back in. But when you want to edit the liver or the heart or the brain, it gets more challenging. Now, you did touch on one recent report, and this is of course the people with severe familial hypercholesterolemia. The carriers that have LDL cholesterol several hundred and often don't respond to even everything we have on the shelf today. And there were 10 people with this condition that was reported just a few weeks ago. So that's a big step forward.David Liu (13:09):That was also a very exciting milestone. So that clinical trial was led by scientists at Verve Therapeutics and Beam Therapeutics, and it was the first clinical readout of an in vivo base editing clinical trial. There was previously at the end of 2022, the first clinical readout of an ex vivo base editing clinical trial using CAR T cells, ex vivo  base edited to treat T-cell leukemia in pediatric patients in the UK. Ffigure from that NEJM paper below). But as you point out, there are only a small fraction of the full range of diseases that we'd like to treat with gene editing and the types of cells we'd like to edit that can be edited outside of the body and then transplanted back into the body. So-called ex vivo editing. Basically, you can do this with cells of some kind of blood lineage, hematopoietic stem cells, T-cells, and really not much else in terms of editing outside the body and then putting back into the body as you point out.(14:17):No one's going to do that with the brain or the heart anytime soon. So what was very exciting about the Verve Beam clinical trial is that Verve sought to disrupt the function of PCSK9 storied, gene validated by human genetics, because there are humans that naturally have mutations in PCSK9, and they tend to have much lower incidences of heart disease because their LDL, so-called bad cholesterol, is much lower than it would otherwise be without those mutations. So Verve set out to simply disrupt PCSK9 through gene editing. They didn't care whether they used a nuclease or a base editor. So they compared side-by-side the results of disrupting PCSK9 with Cas9 nuclease versus disrupting it by installing a precise single letter base edit using an adenine base editor. And they actually concluded that the base editor gave them higher efficacy and fewer unwanted consequences.(15:28):And so they went with the base editor. So the clinical trial that just read out were patients treated in New Zealand, in which they were given a lipid nanoparticle mRNA complex of an adenine base editor programmed with a guide RNA to install a specific A to G mutation in a splice site in PCSK9 that inactivates the gene so that it can no longer make functional PCSK9 protein. And the exciting result that read out was that in patients that receive this base editor, a single intravenous injection of the base editor lipid nanoparticle complex, as you know, lipid nanoparticles very efficiently go to the liver. In most cases, PCSK9 was edited in the liver and the result was substantial reduction in LDL cholesterol levels in these patients. And the hope and the anticipation is that that one-time treatment should be durable, should be more or less permanent in these patients. And I think while the patients who are at highest risk of coronary artery disease because of their genetics that give them absurdly high LDL cholesterol levels, that makes the most sense to go after those patients first because they are at extremely high risk of heart attacks and strokes. If the treatment proves to be efficacious and safe, then I think it's tempting to speculate that a larger and larger population of people who would benefit from having lower LDL cholesterol levels, which is probably most people, that they would also be candidates for this kind of therapy.Eric Topol (17:22):Yeah, no, it's actually pretty striking how that could be achieved. And I know in the primates that were done prior to the people in New Zealand, there was a very durable effect that went on well over I think a year or even two years. So yeah, that's right. Really promising. So now that gets us to a couple of things. One of them is the potential for off-target effects. As you've gotten more and more with these tools to be so precise, is the concern that you could have off-target effects just completely, of course inadvertent, but potential for other downstream in time known unknowns, if you will. What are your thoughts about that?David Liu (18:15):Yeah, I have many thoughts on this issue. It's very important the FDA and regulatory bodies are right to be very conservative about off-target editing because we anticipate those off targets will be permanent, those off-target edits will be permanent. And so we definitely have a responsibility to minimize adding to the mutational burden that all humans have as a function of existing on this planet, eating what we eat, being bombarded by cosmic rays and sunlight and everything else. But I think it's also important to put off-target editing into some context. One context is I think virtually every substance we've ever put into a person, including just about every medicine we've ever put into a person, has off-target effects, meaning modulates the function of biological molecules other than the intended target. Of course, the stakes are higher when those are gene editing agents because those modifications can be permanent.(19:18):I think most off-target edits are very likely to have no consequence because most of our genome, if you mutate in the kinds of small ways like making an individual base pair change for a base editor are likely to have no consequence. We sort of already know this because we can measure the mutational burden that we all face as a function of living and it's measurable, it's low, but measurable. I've read some papers that estimate that of the roughly 27 trillion [should be ~37] cells in an adult person, that there are billions and possibly hundreds of billions of mutations that accumulate every day in those 27 [37] trillion cells. So our genomes are not quite the static vaults that we'd like to think that they are. And of course, we have already purposefully given life extending medicines to patients that work primarily by randomly mutating their genomes. These are chemotherapeutic agents that we give to cancer patients.(20:24):So I think that history of giving chemotherapeutic agents, even though we know those agents will mess up the genomes of these patients and potentially cause cancer far later down the road, demonstrates that there are risk benefit situations where the calculus favors treatment, even if you know you are causing mutations in the genome, if the condition that the patient faces and their prognosis is sufficiently grave. All that said, as I mentioned, we don't want to add to the mutational burden of these patients in any clinically relevant way. So I think it is appropriate that the early gene editing clinical candidates that are in trials or approved now are undergoing lots and lots of scrutiny. Of course, doing an off-target analysis in an animal is of limited value because the animal's genome is quite different than the human genome. So the off targets won't align, but doing off-target analysis in human cells and then following up these patients for a long time to confirm hopefully that there isn't clinical evidence of quality of life or lifespan deterioration caused by off-target editing, that's all very, very important.(21:55):I also think that people may not fully appreciate that on target editing consequences also need to be examined and arguably examined with even more urgency than off-target edits. Because when you are cutting a chromosome at a target site with a nucleus, for example, you generate a complex mixture of different products of different DNA sequences that come out, and the more sequences you sequence, the more different products you realize are generated. And I don't think it's become routine to try to force the companies, the clinical groups that are running these trials to characterize the top 1000 on target products for their biological consequence. That would be sort of impractical to do and would probably slow down greatly the benefit of these early nuclease clinical trials for patients. But those are actually the products that are generated with much higher frequency typically than the off-target edits. And that's part of why I think it makes more sense from a clinical safety perspective to use more precise gene editing methods like base editing and prime editing where we know the products that are generated are mostly the products that we want are not uncontrolled mixtures of different deletion and insertion products.(23:27):So I think paying special attention to the on-target products, which are generated typically 70 to 100% of the time as opposed to the off targets which may be generated at a 0.1 to 1% level and usually not that many at that level once it reaches a clinical candidate. I think that's all important to do.Eric Topol (23:51):You've made a lot of great points there and thanks for putting that in perspective. Well, let's go on to the delivery issue. You mentioned nanoparticles, viral vectors, and then you've come up with small virus-like neutered viruses if you will. I think a company Nvelop that you've created to push on that potential. What are your thoughts about where we stand since you've become a force for coming up with much better editing, how about much better and more diverse delivery throughout the body? What are your thoughts about that?David Liu (24:37):Yeah, great. Great question. I think one of the legacies of gene editing is and will be that it inspired many more scientists to work hard on macromolecular delivery technologies. All of these gene editing agents are macromolecules, meaning they're proteins and or nucleic acids. None of them are small molecules that you can just pop a pill and swallow. So they all require special technologies to transfer the gene editing agent from outside of the cell into the cell. And the fact that taking control of our genetic features has become such a popular aspiration of medicine means that there's a lot of scientists as measured, most importantly by the young scientists, by the graduate students and the postdocs and the young professors of which I'm no longer one sadly, who have decided that they're going to devote a big part of their program to delivery. So you summarized many of the clinically relevant, clinically validated delivery technologies already, somewhat sadly, because if there were a hundred of these technologies, you probably wouldn't need to ask this question. But we have lipid nanoparticles that are particularly good at delivering messenger RNA, that was used to deliver the covid vaccine into billions of people. Now also used to deliver, for example, the adenine base editor mRNA into the livers of those hypercholesterolemia patients in the Verve/Beam clinical trial.(26:20):So those lipid nanoparticles are very well matched for gene editing delivery as long as it's liver. And they also are particularly well matched because their effect is transient. They cause a burst of gene editing agents to be produced in the liver and then they go away. The gene editing agents can't persist, they can't integrate into the genome despite what some conspiracy theorists might worry about. Not that you've had any encounter with any of those people. I'm sure that's actually what you want for a gene editing agent. You ideally want a delivery method that exposes the cell only for the shortest amount of time needed to make the on-target edit at the desired level. And then you want the gene editing agent to disappear and never come back because it shouldn't need to. DNA edits to our genome for durable cells should be permanent. So that's one method.(27:25):And then there are a variety of other methods that researchers have used to deliver to other cells, but they each carry some trade-offs. So if you're trying to edit hematopoietic stem cells, you can take them out of the body. Once they're out of the body, you have many more methods you can use to deliver efficiently into them. You can electroporated messenger, RNA or even ribonuclear proteins. You can treat with lipids or viruses, you can edit and then put them back into the body. But as you already mentioned, that's sort of a unique feature of blood cells that isn't applicable to the heart or the brain, for example, or the eyes. So then that brings us to viral vectors. There are a variety of clinically validated viral methods for delivery. AAV— adeno associated virus— is probably the most diverse, most relevant, and one of the best tolerated viral delivery methods. The beauty of AAV is that it can deliver to a variety of tissues. AAV can deliver into spinal cord neurons, for example, into retinal cells, into the heart, into the liver, into a few other tissues as well.(28:48):And that diversity of being able to choose AAV capsids that are known to get into the types of tissues that you're trying to target is a great strength of that approach. One of the downsides of AAV for gene editing agents is that their delivery tends to be fairly durable. You can engineer AAVs into next generation capsids that sort of get rid of themselves or the gene editing agents get rid of themselves. But classic AAV tends to stay around in patients for a long time, at least months, for example, and possibly years. And we also don't yet have a good way, clinically validated way of re-dosing AAV. And once you administer high doses of AAV in a patient that tends to provoke high-titer, neutralizing antibodies against those AAVs making it difficult to then come back six months or a year later and dose again with an AAV.(29:57):So researchers are on the bright side, have become very good at engineering and evolving in the laboratory next generation AAVs that can go to greater diversity issues that can be more potent. Potency is important because if you can back off the dose, maybe you can get around some of these immunogenicity issues. And I think we will see a renaissance with AAV that will further broaden its clinical scope. Even though I appreciate that the decisions by a couple large pharma companies to sort of pull out of using AAV for gene therapy seemed to cause people to, I think prematurely conclude that AAV has fallen out of favor. I think for gene therapy, it's quite different than gene editing. Gene therapy, meaning you are delivering a healthy copy of the gene, and you need to keep that healthy copy of the gene in the patient for the rest of the patient's life.(30:59):That's quite different than gene editing where you just need the edit to take place over days to weeks, and then you want the editing agent to actually go away and you never want to come back. I think AAV will used to deliver gene editing agents will avoid some of the clinical challenges like how do we redose? Because you shouldn't need to redose if the gene editing clinical trial proceeds as you hope. And then you mentioned these virus-like particles. So we became interested in virus-like particles as other labs have because they offer some of the best strengths of non-viral and viral approaches like non-viral approaches such as LMPs. They deliver the transient form of a gene editing agent. In fact, they can deliver the fully assembled protein RNA complex of a base editor or a prime editor or a CRISPR nuclease. So in its final form, and that means the exposure of the cell to the editing agent is minimized.(32:15):You can treat with these virus-like particles, deliver the protein form of these gene editing agents, allow the on-target site to get edited. And then since the half-life of these proteins tends to be very small, roughly 24 hours for example, by a week later, there should be very little of the material left in the animal or prospectively in the patient virus-like particles, as you call them, neutered viruses, they lack viral DNA or RNA. They don't have the ability to integrate a virus's genome into the human genome, which can cause some undesired consequences. They don't randomly introduce DNA into our genomes, therefore, and they disappear more transiently than viruses like AAV or adenoviruses or other kinds of lentiviruses that have been used in the clinic. So these virus-like particles or VLP offer really some of the best strengths on paper at least of both viral and non-viral delivery.(33:30):Their limitation thus far has been that there really haven't been examples of potent in vivo delivery of cargoes like gene editing agents using virus-like particles. And so we recently set out to figure out why, and we identified several bottlenecks, molecular bottlenecks that seemed to be standing in the way of virus-like particles, doing a much more efficient job at delivering inside of an animal. (Figure from that paper below.) And we engineered solutions to each of these first three molecular bottlenecks, and we've identified a couple more since. And that resulted in what we call VLPs engineered virus-like particles. And as you pointed out, Keith Joung and myself, co-founded a company called Nvelop to try to bring these technologies and other kinds of molecular delivery technologies, next generation delivery technologies to patients.Eric Topol (34:28):Well, that gets me to the near wrapping up, and that is the almost imagination you could use about where all this can go in the future. Recently, I spoke to a mutual friend Fyodor Urnov, who talked about wouldn't it be amazing if for people with chronic pain you could just genome edit neurons their spinal cord? As you already touched on recently, Jennifer Doudna, who we both know talked about editing to prevent Alzheimer's disease. Well, that may be a little far off in time, but at least people are talking about these things that is not, we're not talking about germline editing, we're just talking about somatic cell and being able to approach conditions that have previously been either unapproachable or of limited success and potential of curing. So this field continues to evolve and you and all your colleagues are a big part of how this has evolved as quickly as it has. What are your thoughts about, are there any bounds to the potential in the longer term for genome editing? Right.David Liu (35:42):It's a great question because all of the early uses of gene editing in people are appropriately focused on people who are at dire risk of having shorter lives or very poor quality of life as it should be for a new kind of therapeutic because the risks are high until we continue to validate the clinical benefit of these gene editing treatments. And therefore we want to choose patients the highest that face the poorest prognosis where the risk benefit ratio favors treatment as strongly as possible. But your question, I think very accurately highlights that our genome and changes to it determine far more than whether you have a serious genetic disorder like Sickle Cell Disease or Progeria or Cystic Fibrosis or Familial Hypercholesterolemia or Tay-Sachs disease. And being able to not just correct mutations that are associated with devastating genetic disorders, but perhaps take control of our genomes in more sophisticated way that you pointed out two examples that I think are very thought provoking to treat chronic pain permanently to lower the risk of horrible diseases that affect so many families devastating to economies worldwide as well, like Alzheimer's disease, Parkinson's disease, the genetic risk factors that are the strongest genetic determinants of diseases like Alzheimer's disease are actually, there are several that are known already.(37:36):And an interesting possibility for the future, it isn't going to happen in the next few years, but it might happen within the next 10 or 20 years, might be to use gene editing to precisely change some of those most grievous alleles that are risk factors for Alzheimer's disease like a apoE4, to change them to the genetic forms that have normal or even reduced risk for Alzheimer's disease. That's a very tough clinical trial to run, but I'd say not any tougher than the dozens of most predominantly failed Alzheimer's clinical trials that have probably collectively accounted for hundreds of billions of dollars of investmentEric Topol (38:28):Easily.David Liu (38:31):And all of that speaks to the fact that Alzheimer's disease, for example, is enormous burden on society by every measure. So it's worth investing and major resources and taking major risks to try to create perhaps preventative treatments that just lower our risk globally. Getting there will require that these pioneering early clinical trials for gene editing are smashing successes. I'm optimistic that they will be, there will be bumps in the road because there always are bumps in the road. There will be patients who have downturns in their health and everyone will wonder whether those patients had a downturn because of a gene editing treatment they received. And ascertaining whether that's the case will be very important. But as these trials continue to progress, and as they continue hopefully on this quite positive trajectory to date, it's tempting to imagine a future where we can use precise gene editing methods. For example, you can install a variety using prime editing, a variety of alleles that naturally occur in people that reduce the risk of Alzheimer's disease or Parkinson's disease like the mutation that 0.1% of Icelandic people and almost nobody else has in amyloid precursor protein changing alanine 673 to threonine (A673T).(40:09):It is very thought provoking, and I don't think society is ready now to take that step, but I think if things continue to proceed on this promising trajectory, it's inevitable because arguably, the defining trait of our species is that we use every ounce of our talents and our gifts and our resources and our creativity to try to improve our lives and those of our children. And I don't think if we have ways of treating genetic diseases or even of reducing grievous genetic disease risk, that we will be able to sit on our hands and not take steps towards that kind of future solon as those technologies continue to be validated in the clinic as being safe and efficacious. It's, I teach a gene editing class and I walk them through a slippery slope at the end of five ethics cases, starting with progeria, where most people would say having a single C of T mutation in one gene that you, by definition didn't inherit from mom or dad.(41:17):It just happened spontaneously. That gives you an average lifespan of 14 and a half years and strongly affects other aspects of the quality of your life and your family's life that if you can change as we did in animals that T back into a C and correct the disease and rescue many of the phenotypes and extend lifespan, that that's an ethical use of gene editing. Treating genetic deafness is the second case. It's a little bit more complicated because many people in the deaf community don't view deafness as a disability. It's at least a more subjective situation than progeria. But then there are other cases like changing apoE4 to apoE3 or even apoE2 with the lower than normal risk of Alzheimer's disease, or installing that Icelandic mutation and amyloid precursor protein that substantially lowers risk of Alzheimer's disease. And then finally, you can, I always provoke a healthy debate in the class at the end by pointing out that in the 1960s, one of the long distance cross country alpine skiing records was set by a man who had a naturally occurring mutation in his EPO receptor, his erythropoietin receptor, so that his body always thought he was on EPO as if he were dosing on EPO, although that was of course before the era of EPO dosing was really possible, but it was just a naturally occurring mutation in this case, in his family.(42:48):And when I first started teaching this class, most students could accept using gene editing to treat progeria, but very few were willing to go even past that, even to genetic deafness, certainly not to changing a ApoE risk factors for Alzheimer's. Nowadays, I'd say the 50% vote point is somewhere between case three and case four, most people are actually say, yeah, especially since they have family members who've been through Alzheimer's disease. If they are a apoE4, some of them are a apoE4/apoE4 [homozygotes], why not change that to a apoE3 or even an ApoE2 or as one student challenged the class this year, if you were born with a apoE2, would you want to change it to a ApoE3 so you could be more normal? Most people would say, no, there's no way I would do that.(43:49):And for the first time this year, there were one or two students who actually even defended the idea of putting in a mutation in erythropoietin receptor to increased increase their endurance under low oxygen conditions. Of course, it's also presumably useful if you ever, God forbid, are treated with a cancer chemotherapeutic. Normally you get erythropoietin to try to restore some, treat some of the anemia that can result, and this student was making a case, well, why wouldn't we? If this is a naturally occurring mutation that's been shown to benefit certain people doing certain things. I don't think that's a general societal view. And I am a little bit skeptical we'll ever get widespread acceptance of case number five. But I think all of it is healthy stimulates a healthy discussion around the surprisingly gentle continuum between disease treatment, disease prevention, and what some would call human improvement.And it used to be that even the word human improvement was sort of an anathema. I think now at least the students in my class are starting to rethink what does that really mean? We improving ourselves a number of ways genetically and otherwise by virtue of our lifestyles, by virtue of who we choose to procreate with. So it's a really interesting debate, and I think the rapid development and now clinical progression and now approval, regulatory approval of gene editing drugs will play a central role in this discussion.Eric Topol (45:38):No question. I mean, also just to touch on the switch from a apoE4 to apoE2, you would get a potential 2-fer of lesser risk for Alzheimer's and a longer lifespan. So I mean, there's a lot of things here. The thing that got me years ago, I mean, this is many years ago at a meeting with George Church and he says, we're going to just edit 60 genes and then we can do all sorts of xeno-pig transplants and forget the problem of donors. And it's happening now.David Liu (46:11):Yeah, I mean, he used a base editor to edit hundreds of genes at once, if not thousands ofEric Topol (46:16):That's why it's just, yeah, no, it's just extraordinary. And I think people need to be aware that opportunities here, as you say, with potential bumps along the way, unquestionably, is almost limitless. So this has been a masterclass thanks to you, David, in where we are, where we're headed in genome editing at a very extraordinary time where we've really seeing things click. And I just want to also add that you're going to be here with a conference in La Jolla in January, I think, on base and prime editing. Is that right? So for those who are listeners who are into this topic, maybe they can also hear the latest, I'm sure there'll be more between now and next. Well, several weeks from now at your, it's aDavid Liu (47:12):Conference on, it's the fifth international conference on base and prime editing and associated enzymes, the somewhat baroque name. And I will at least be giving a virtual talk there. It actually overlaps with the talk I'm giving at Rockefeller that time. Ah, okay, cool. But I'm speaking at the conference either in person or virtually.Eric Topol (47:34):Yeah. Well, anytime we get to hear from you and the field, of course it's enlightening. So thanks so much for joining. Thank youDavid Liu (47:42):For having me. And thank you also for all of your, I think, really important public service in connecting appropriately the ground truths about science and vaccines and other things to people. I think that's very much appreciated by scientists like myself.Eric Topol (48:00):Oh, thanks David.Thanks for listening, reading, and subscribing to Ground Truths. To be clear, this is a hybrid format, roughly alternating between analytical newsletters/essays and podcasts with exceptional people, attempting to achieve about 2 posts per week. It's all related to cutting-edge advances in life science, medicine, and information tech (A.I.)All content is free. If you wish to become a paid subscriber know that all proceeds go to Scripps Research. Get full access to Ground Truths at erictopol.substack.com/subscribe

Nov. 14, 2023 | Stellantis offers buyouts to thousands of workers; Plus CEO David Liu by Automotive News

The CEO and founder of Plus describes his company's evolutionary approach toward developing automated-driving technology. Further, he provides updates on work with partners like Amazon, Bosch, Cummings and more, and what's ahead for Plus in 2024.

In this special 2 hour season finale of The Unofficial Unreal Engine Podcast with hosts Alex, Jacob and special guest David Liu talks Galactic Starcruiser Pt 2.Special thank you to the Halcyon Rebels by way of Kathryn Yu for helping to secure tickets Join the community archive of Galactic Starcruiser: https://github.com/AgileLens/ProjectCantina

The Unofficial Unreal Engine Podcast with hosts Alex and Jacob and special guest David Liu talks Galactic Starcruiser Pt 1. Special thank you to the Halcyon Rebels by way of Kathryn Yu for helping to secure tickets Join the community archive of Galactic Starcruiser: https://github.com/AgileLens/ProjectCantina

Dr. David R. Liu is the Richard Merkin Professor and Director of the Merkin Institute of Transformative Technologies in Healthcare, vice-chair of the faculty at the Broad Institute of MIT and Harvard, the Thomas Dudley Cabot Professor of the Natural Sciences at Harvard University, and a Howard Hughes Medical Institute (HHMI) investigator. In addition, he is the founder or co-founder of several biotechnology and therapeutics companies, including Beam Therapeutics, Prime Medicine, Editas Medicine, Pairwise Plants, Exo Therapeutics, Chroma Medicine, Resonance Medicine, and Nvelop Therapeutics. David's research integrates components of biological evolution with chemistry to enable the development of new types of therapeutics and to better study biology. Through chemistry, they can change the structure of a molecule in order to change its function in anticipated ways. They also harness the power of cycles of natural selection to evolve molecules with desired tailor-made properties. Outside of science, David's hobbies include photography, making wooden vessels using a wood lathe, growing bonsai trees, and exploring electronic art and other homemade art projects. He enjoys blending creativity and intellectual pursuits to create something surprising and beautiful. He completed his undergraduate education at Harvard College, majoring in chemistry. He was awarded his PhD in organic chemistry from UC Berkeley, and he joined the faculty at Harvard University afterwards. He has been an HHMI investigator since 2005. Over the course of his career, David has received numerous awards and accolades, including being named the 2022 King Faisal Prize Laureate in Medicine and receipt of the Ronald Breslow Award for Biomimetic Chemistry, the American Chemical Society David Perlman Award, ACS Chemical Biology Award, the American Chemical Society Pure Chemistry Award, the Arthur Cope Young Scholar Award, and other prestigious awards for his research and teaching. In 2016 and 2020, he was named one of the Top 20 Translational Researchers in the world by Nature Biotechnology, and he was named one of Nature's 10 researchers in 2022. In addition, he is an elected Member of the U.S. National Academy of Sciences, the U.S. National Academy of Medicine, and the American Association for the Advancement of Science. In this interview, David shares more about his life and science.

David Liu is a professor in the Department of Chemistry and Chemical Biology at Harvard University. Liu's lab has introduced breakthrough technologies to the field of genome editing, including base editing and prime editing, with the aim of treating genetic diseases. In their latest work, his research team took a “no stone unturned” approach to determine a one-time base editing strategy to treat the motor neuron disease, spinal muscular atrophy (SMA). In this episode, Deanna MacNeil from The Scientist's Creative Services Team spoke with Liu to learn more about his philosophy of science, which involves an appreciation of fundamental principles in chemistry and evolution. Science Philosophy in a Flash is a series of mini podcasts produced by The Scientist's Creative Services Team. With a focus on the people behind the science, this podcast highlights researchers' unique outlook on what motivates their pursuit of science and what it means to be a scientist.

John fixes California with David LieSee omnystudio.com/listener for privacy information.

David Liu is the Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare, vice-chair of the faculty at the Broad Institute of MIT and Harvard, the Thomas Dudley Cabot Professor of the Natural Sciences at Harvard University, and a Howard Hughes Medical Institute (HHMI) investigator. Liu's research integrates chemistry and evolution to illuminate biology and enable next-generation therapeutics. His major research interests include the engineering, evolution, and in vivo delivery of genome editing proteins such as base editors and prime editors to study and treat genetic diseases; the evolution of proteins with novel therapeutic potential using phage-assisted continuous evolution (PACE); and the discovery of bioactive synthetic small molecules and synthetic polymers using DNA-templated organic synthesis and DNA-encoded libraries. Base editing—the first general method to perform precision gene editing without double-stranded breaks, and a Science 2017 Breakthrough of the Year finalist—as well as prime editing, PACE, and DNA-templated synthesis are four examples of technologies pioneered in his laboratory. These technologies are used by thousands of labs around the world and have enabled the study and potential treatment of many genetic diseases. Four base editing clinical trials are already underway to treat leukemia, hypercholesterolemia, beta-thalassemia, and sickle-cell disease, with the first base editing clinical readout occuring last December, when it was announced that Alyssa, a 13-year-old girl in the UK, was cleared of T-cell leukemia by receiving triply base-edited CAR-T cells.Liu graduated first in his class at Harvard College in 1994. During his doctoral research at UC Berkeley, Liu initiated the first general effort to expand the genetic code in living cells. He earned his PhD in 1999 and became assistant professor of chemistry and chemical biology at Harvard University in the same year. He was promoted to associate professor in 2003 and to full professor in 2005.Liu became a Howard Hughes Medical Institute investigator in 2005 and joined the JASONs, academic science advisors to the U.S. government, in 2009. In 2016 he became a Core Institute Member and Vice-Chair of the Faculty at the Broad Institute of MIT and Harvard, and Director of the Chemical Biology and Therapeutics Science Program. Liu has been elected to the U.S. National Academy of Sciences, the U.S. National Academy of Medicine, and the American Association for the Advancement of Science. He is the 2022 King Faisal Prize Laureate in Medicine.He is the founder or co-founder of several biotechnology and therapeutics companies, including Prime Medicine, Beam Therapeutics, Editas Medicine, Pairwise Plants, Exo Therapeutics, Chroma Medicine, Resonance Medicine, and Nvelop Therapeutics.Alix Ventures, by way of BIOS Community, is providing this content for general information purposes only. Reference to any specific product or entity does not constitute an endorsement nor recommendation by Alix Ventures, BIOS Community, or its affiliates. The views & opinions expressed by guests are their own & their appearance on the program does not imply an endorsement of them nor any entity they represent. Views & opinions expressed by Alix Ventures employees are those of the employees & do not necessarily reflect the view of Alix Ventures, BIOS Community, affiliates, nor its content sponsors.Thank you for listening!BIOS (@BIOS_Community) unites a community of Life Science innovators dedicated to driving patient impact. Alix Ventures (@AlixVentures) is a San Francisco based venture capital firm supporting early stage Life Science startups engineering biology to create radical advances in human health.Music: Danger Storm by Kevin MacLeod (link & license)

On today's show, Steven tries something new, Brent gets lost & we both catch up on pop culture! Stuff discussed: David Liu's Scream VI anime short*, Waking Life (2001), Boyhood (2014), Rick Beato's interview with Butch Vig**, Gone Girl (2014), Minions: The Rise of Gru (2022), That Was Pretty Scary (podcast), The Sleeping Negro (2021), Actual People (2021 Mubi film), MMPR: Once & Always (upcoming Netflix), The Terror Table ft. NüDis Colony episode, Dracula 2000 (2000), 101 Places to Party Before You Die (TV series), Linkin Park - Minutes to Midnight (2007 album), Rocky (1976), Rocky II (1979), Rocky III (1982), Rocky IV (1985), Rocky V (1990), & Rocky Balboa (2006)! *Check out the Scream VI anime short by David Liu here: https://www.youtube.com/watch?v=jX9DTa75WpU&t=3s **Check out Rick Beato's interview with Butch Big here: https://www.youtube.com/watch?v=5U9XJdd4FlM&t=51s Outtakes - 2:17:13 —————————————————————— Go here to get some LTAS Merch: http://tee.pub/lic/huI4z_dwRsI Email: LetsTalkAboutStuffPodcast@gmail.com Follow LTAS on social media: Twitter: https://twitter.com/LTASpod Instagram: https://www.instagram.com/ltaspod/?hl=en Follow Steven on Letterboxd: https://letterboxd.com/stevenfisher22/ Follow Brent on social media: Twitter - https://twitter.com/BrentHibbard Instagram - https://www.instagram.com/brenthibbard/?hl=en A 5-Star rating on your podcast app is appreciated! And if you like our show, share it with your friends! IT *IS* A FORM OF PAINTING.

In this episode, host Tom Loarie talks with today's guest mentor Dave Liu, former Jefferies Managing Director of Digital Media and Internet Banking. Dave Liu shares his insights and the secrets he learned while becoming the first Asian-American to become a managing director at an investment bank…at the age of 32! Dave raised $16 billion for hundreds of companies—from start-ups to established corporations. He has worked with more than a thousand different individuals, including CEOs and entrepreneurs. David Liu's top-selling book, The Way of the Wall Steet Warrior, is a MUST-READ (or listen, if you prefer audible!). Listen to the show live in San Francisco or via live-streaming on iHeart Radio worldwide… You can also listen on ANY podcast platform, including Apple podcast, iTunes, Spotify, TuneIN, Stitcher, Google Play and all the others. Sign up for the podcast here. SHOW NOTES: DAVID LIU: BIO: https://amzn.to/3fUHY3q WEBSITE: Liucrative.co BOOK: The Way of the Wall Street Warrior: Conquer the Corporate Game Using Tips, Tricks, and Smartcuts, by Dave Liu “Dave learned how to win in investment banking the hard way. Now he is able to share tools that make it easier for budding bankers and other professionals to succeed.” —Frank Baxter, Former CEO of Jefferies and U.S. Ambassador to Uruguay “A must-read for anyone starting their career in Corporate America. Dave's book shares witty and valuable insights that would take a lifetime to learn otherwise. I highly recommend that anyone interested in advancing their career read this book.”—Harry Nelis, Partner of Accel and former Goldman Sachs banker

UC Today's Ryan Smith hosts David Liu, Founder and CEO, Deltapath.In this session, we discuss the following:What push-to-talk isThe key features of Deltapath's push-to-talk solutionThe environments that push-to-talk can be deployed in

On this episode of The Six Five – On The Road, hosts Daniel Newman and Patrick Moorhead sit down with David Liu, CEO of Plus. Their conversation covers: Plus' efforts toward safety, sustainability, satisfaction, and scalability The competitive landscape in the autonomous transportation industry Plus' approach to addressing the challenges hindering adoption in the transportation industry Plus' partnership strategy in an industry that is highly regulated Opportunities for market growth in the automated trucking industry Be sure to subscribe to The Six Five Webcast so you never miss an episode.

UC Today's Tom Wright hosts David Liu, CEO at Deltapath.In this session, we discuss the following:Why demand for business SMS is increasingWho can benefit from itDeltapath's plans for its new business SMS service

In our conversation, Bryan discusses everything from directed evolution and drugging RNA to what it takes to start a lab. The Dickinson Lab at the University of Chicago is a unique group composed of biochemists & synthetic chemists to cell biologists & synthetic biologists. The lab set up shop in 2014 to use chemistry to control biology with both evolutionary and rational methods. Bryan's research is heavily influenced by his career starting as an undergrad at Maryland with mentorship from David Fushman to graduate research with Chris Chang at UC Berkeley and a postdoc with David Liu at Harvard. At each point, picking up new tools to work with and models to follow. Bryan "works with people he is inspired by." And that has been a key driver of his group's success. To run such an interdisciplinary lab, Bryan focuses on important problems rather than a particular technique or tool. This not only cultivates openness to new solutions but aligns everyone around a shared passion & purpose. Bryan's lab has 3 main areas of research - (1) Chemical biology for protein lipidation, (2) Biosensors to control PPIs, and the (3) Epitranscriptome. We touch upon several examples here, but the key theme is inventing new, functional molecules, whether they are small molecules, proteins, or engineered organisms, to make breakthroughs in biology. This molecule-agnostic approach requires the ability to synthesize small molecules, screen large libraries of molecules, and use directed evolution to reprogram cells and design proteins. Finally, we discuss how to determine what is a valuable problem to work on. A skill that is nurtured with support from mentors and a team. A common thread across the conversation is the power of evolution, nature's way of designing things, to not only optimize but uncover new forms of biology. Similar to using a guide to solve a puzzle. As the conversation goes on, it becomes clear chemical biologists will play a central role in breaking down existing barriers to study things like RNA modifications, PPIs, and more. Near the end, we discuss the relationship between academic science and industry especially as early-career scientists join and start their own companies. Bryan's lab has done incredibly creative research and I would recommend everyone to read his papers. Ultimately, Bryan's work is making an impact in therapeutics with a purview on energy/climate and serves as a template for other inventors looking to build interdisciplinary teams.

End users who are not schooled in hardware can often default to, “just give me something that works.” David Liu, Staff AI Engineer, Strategy & Vision for Data Science and AI Products at Intel, understands this thinking but also believes that end users can be educated on the advantages of configuring their computer hardware to suit their specific needs.   David advocates for using the right hardware for a given task—and that may mean different configurations and/or different machines for different tasks, rather than a one-size-fits-all solution.     David and host Peter Wang also discuss:   - The need for more education and resources around hardware performance - Intel's Optane technology and the possibilities it creates   Resources:   Peter Wang LinkedIn - https://www.linkedin.com/in/pzwang/   David Liu LinkedIn - https://www.linkedin.com/in/david-liu-71004723/   Intel LinkedIn - https://www.linkedin.com/company/intel-corporation/   Click https://www.youtube.com/triskadecaepyon to visit David's YouTube channel.   You can find a human-verified transcript of this episode here -  https://know.anaconda.com/rs/387-XNW-688/images/ANACON_David%20Liu_V1%20%281%29.docx.pdf.   If you enjoyed today's show, please leave a 5-star review. For more information, visit https://www.anaconda.com/podcast.

David Liu is CEO of Sonde Health, a company using vocal biomarkers to assess patient health, wellness, and fitness. The company is white labeling its solution for app developers with initial products for respiratory and mental health problems.  In the interview, Liu discusses the product, technology, and key markets serving as the first adopters. These include healthcare providers and payers along with one industry I wasn't expecting.  Liu has been CEO of Sonde Health since 2019. He previously was chief operating officer at Quartet Health and education technology company Knewton and was a senior vice president at AOL. He earned an engineering degree from Purdue and an MBA from Columbia.

David Liu is a retired tech investment banker who now advises CEOs and makes strategic investments to support Asian content creators. A mutual friend introduced us and I was surprised to have met someone else with so many shared interests and passions, while never crossing paths!His personal journey includes moving from China to the US and having to pay for everything on his own, including a college degree from an Ivy League university.After seeing the long list of job openings for investment banks, he applied and made it through the rigorous hiring process to land his first Wall St. internship.Dave learned a LOT about cultural differences and became an astute observer of people, learning what nuanced behaviors made for great success in high-powered environments.And he continued to study and learn… At the pinnacle of his career as the youngest person to have made Managing Director, Dave made a seemingly crazy decision; he left after 25 years and decided to write his observations and notes as a way to share his learnings with his sons. Anyone interested in working on Wall Street will find tremendous value reading The Way of the Wall Street Warrior. 

David Liu is a retired tech investment banker who now advises CEOs and makes strategic investments to support Asian content creators. A mutual friend introduced us and I was surprised to have met someone else with so many shared interests and passions, while never crossing paths!His personal journey includes moving from China to the US and having to pay for everything on his own, including a college degree from an Ivy League university.After seeing the long list of job openings for investment banks, he applied and made it through the rigorous hiring process to land his first Wall St. internship.Dave learned a LOT about cultural differences and became an astute observer of people, learning what nuanced behaviors made for great success in high-powered environments.And he continued to study and learn… At the pinnacle of his career as the youngest person to have made Managing Director, Dave made a seemingly crazy decision; he left after 25 years and decided to write his observations and notes as a way to share his learnings with his sons. Anyone interested in working on Wall Street will find tremendous value reading The Way of the Wall Street Warrior. Amor Boutique Hotel is a beautiful and secret spot in Sayulita Mexico. Our family and friends love it and you will, too! This spot is a safe and family-friendly spot 30 minutes from Puerto Vallarta airport. Amor Boutique Hotel - Sayulita Mexico

In this edition, Nick Luscombe discusses music apps with Musify Founder and CEO, David Liu and learns more about his journey as an entrepreneur. 

Evan Solomon speaks with David Coletto, CEO of Abacus Data, on his final survey of the 2022 Ontario provincial election. Which party appears to have the most support? He breaks it down.  On today's show:  David Coletto, a founding partner and CEO of Abacus Data, on the Ontario election.  Mental Health and Addictions Minister Carolyn Bennett on decriminalizing small possession of illicit drugs in B.C. The War Room political panel with Tim Powers, Sharan Kaur and David Moscrop. Dr. David Liu, director of the Merkin Institute at the Broad Institute and professor at Harvard University, on the future of gene editing and changing our DNA.

Gene editing is the process by which alterations are made to DNA. There are three major challenges: make precise edits at a chosen site, make edits that do not result in subsequent mutations, and have an editing process flexible enough to address the mutations which cause human disease. This week we talk to Professor David Liu of Harvard University's Department of Chemistry and Chemical Biology. They discuss the progress that has been made to overcome these challenges, following the development of the base editing and prime editing methods in his lab.Theory and Practice is a presentation of GV and Google AI.This season we'll dive deep into the languages of life through explorations of the "dark genome", genome editing, protein folding, the future of aging, and more.Hosted by Anthony Philippakis (Venture Partner at GV) and Alex Wiltschko (Staff Research Scientist with Google AI), Theory and Practice opens the doors to the cutting edge of biology and computer science through conversations with leaders in the field.

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As the year comes to an end, we would like to thank everyone who listened to the FYI — For Your Innovation podcast. 2021 was another up and down year, as the world continues to battle the COVID-19 pandemic. In this final episode of 2021, we compiled some of our most interesting podcast episodes for you. Please enjoy this summary and tune back in when we return in 2022 with a new and improved version of FYI. Check out the FYI – For Your Innovation Podcast ‘Best of 2021'. Because investing in innovation starts with understanding it. #FYIpodcast 1. Understanding mRNA. Conversations with Moderna and Arcturus Therapeutics (EP 89) Alexandra Urman, interviews Stéphane Bancel and Joseph Payne, CEOs of Moderna and Arcturus Therapeutics respectively about mRNA technology and its possibilities for the future. We discuss how mRNA can be used as a vaccine to combat SARS-CoV-2, its benefits, challenges, intellectual property landscape, and how it can be used for oncology and rare diseases. (Listen to the Full Episode) 2. Autonomous Vehicles Powered By End-To-End Deep Learning with Alex Kendall, Wayve.ai (EP 90) Tasha Keeney invited Alex Kendall, Co-Founder and CEO at Wayve.ai onto the show to speak about how the company is differentiating itself and solving some of the problems to wide adoption of self-driving cars. The private company Wayve.ai aims to build scalable, adaptable robotics for learning algorithms for self-driving cars. (Listen to the Full Episode) 3. The Terra Blockchain with Do Kwon (EP 98) Frank Downing spoke with Do Kwon, the founder and CEO of Terraform Labs and the Terra blockchain, as well as former ARK analyst James Wang. Terra is in the top 30 of the thousands of different blockchains that currently exist, and as Do explains in the conversation, it has some interesting features that set it apart from its so-called peers. (Listen to the Full Episode) 4. Competitive Mobile Gaming with Andrew Paradise, CEO and Founder of Skillz (EP 100) ARK analysts, Nick Grous and Andrew Kim sat down with Andrew Paradise, CEO and Founder of Skillz Inc., a publicly traded company[1] and mobile games platform that connects players and developers, enabling competitive social games. They discussed his thoughts on the mobile gaming market, the technology stack necessary for mobile gaming platforms, monetization of mobile gamers, the importance of social experiences within and outside of games, and the rise of casual and professional esports. (Listen to the Full Episode) 5. Therapeutic Human Gene Editing with Dr. David Liu (EP 106) Alexandra Urman interviewed Dr. David Liu to discuss exciting developments in therapeutic gene editing. Dr. Liu is a Richard Merkin Professor, Director of the Merkin Institute of Transformative Technologies and Healthcare, Vice-Chair of the Faculty at the Broad Institute of Harvard and MIT, and the Co-founder or Founder of nine biotech or therapeutics companies. He's published over 195 scientific papers and is the inventor of over 75 issued patents. (Listen to the Full Episode)

What motivates a creative scientific mind? How does an accomplished scientist pinpoint new subjects to explore? How is the field of chemical biology evolving? In this episode of Stereo Chemistry, we probe those questions with scientists and serial entrepreneurs David Liu and Stuart Schreiber, both pioneers in developing tools that use chemistry to explore biology. A transcript of this episode and links to past C&EN coverage of David Liu and Stuart Schreiber will be available soon at cen.acs.org. Read Stuart Schreiber's Harvard Magazine article about discovering his family's secrets at https://www.harvardmagazine.com/2019/07/dna-testing-schreiber Sign up for C&EN's weekly newsletter at bit.ly/chemnewsletter. Image credit: Will Ludwig/C&EN/Beam Therapeutics/Stuart Schreiber

For all its supposed genetic editing finesse, CRISPR's a brute. The Swiss Army knife of gene editing tools chops up DNA strands to insert genetic changes. What's called “editing” is actually genetic vandalism—pick a malfunctioning gene, chop it up, and wait for the cell to patch and repair the rest. It's a hasty, clunky process, prone to errors and other unintended and unpredictable effects. Back in 2019, researchers led by Dr. David Liu at Harvard decided to rework CRISPR from a butcher to a surgeon, one that lives up to its search-and-replace potential. The result is prime editing, an alternative version of CRISPR with the ability to “make virtually any targeted change in the genome of any living cell or organism.” It's the nip-tuck of DNA editing: with just a small snip on one DNA chain, we have a whole menu of potential genetic changes at our fingertips. Prime editing was hailed as a fantastic “yay, science!” moment that could conceivably repair nearly 90 percent of over 75,000 diseases caused by genetic mutations. But even at its birth, Liu warned that CRISPR prime was only taking its first toddler steps into the big, wild world of changing a life form's base code. “This first study is just the beginning—rather than the end—of a long-standing aspiration in the life sciences to be able to make any DNA change at any position in an organism,” he told Nature at the time. Flash forward two years. Liu's gene editing ingénue took some stumbles. Despite its precise and effective nature, prime editing could only edit genes in certain types of cells, while being less effective and introducing errors in others. It also failed when trying to make large genetic edits, particularly those that require hundreds of DNA letters to be replaced to fix a disease-causing genetic mistake. But the good news? Toddlers grow up. This week, three separate studies advanced prime editing, helping the CRISPR tool grow into a more sophisticated DNA-editing genius. Two teams, based at the University of Massachusetts Medical School and the University of Washington, reworked the tool's molecular makeup to precisely cut out up to 10,000 DNA letters in one go—a challenge for prime editing 1.0. A third study from the tool's original inventor probed its inner molecular workings, identifying protein friends and foes inside the cell that control the tool's genetic editing abilities. By promoting friendly interactions, the team increased prime editing's efficiency in seven different cell types nearly eight-fold. Even better, the “foes” that block prime's editing potential were identified using CRISPR—in other words, we're witnessing a full circle of innovation whereby gene editing tools help build better gene editing tools. A Primer for CRISPR Prime Prime editing burst onto the gene editing scene for its dexterity and precision. If the original CRISPR-Cas9 is a dancer with two left feet, prime editing is a highly-trained ballerina. The two processes start similarly. Both rely on a molecular “zip code” to target the tool to a specific gene. In CRISPR, it's called a guide RNA. For prime editing, it's a slightly modified version dubbed pegRNA. Once the guides tether their respective dance partners to the gene, their routines differ. For CRISPR, the second component, Cas9, acts as a pair of scissors to snip both DNA strands. From here, cells can either throw out parts of a gene, or—when given a template—insert a healthy version of a gene to replace the original one. The cost is molecular surgery. Just as an incision might not fully heal, a double-stranded break to the DNA can introduce errors into the genetic code, leading to unexpected effects that vary between cells. Prime editing was the sophisticated upgrade set to fix that. Rather than cutting both DNA strands, it lightly nips one chain. From there, it can delete or insert genetic code based on a template without relying on the cell's DNA repair mechanism. In other words, prime editing opened a new universe o...

Scott and Amy Malin have turned trueheart.com into a search engine that does good in the world. Their goal? To raise 1 billion dollars for charities by having people do what they already do everyday online, search. They donate 80% of net profits to charities like SmileTrain, Action Against Hunger, Global Green, A Paws for Ability, PFLAG and the Variety Boys & Girls Club. Celebrities like Brian Austin Green and Sharna Burgess have also lent their names to support the trueheart.com cause. Plus we spoke with SmileTrain ambassador David Liu who is living proof that these life-saving and changing surgeries are needed. Watch his interview here: https://beond.tv/video/carlos-lisa/business/philanthropist-and-successful-businessman-david-liu/ Go to trueheart.com to do some good while you search! More stories, celebrity interviews and talk with your favorite BEONDTV hosts on beond.tv, Roku and Amazon FireTV. --- Support this podcast: https://anchor.fm/beondtv/support

Episode Summary: Enzymes that break down other proteins, or proteases, could be used as a powerful therapeutic if they could specifically chew-up disease causing entities. However many proteases are non-specific, breaking any protein in their path, while the specific ones target proteins that would provide no therapeutic benefit. Travis and his colleagues developed a riff on the method known as PANCE that utilizes bacteria and bacterial viruses known as phages to evolve proteins toward a specific goal. With it, he retrains the sequence-specific protease, botulinum neurotoxin, toward new targets and away from its original ones. The novel enzymes Travis generates have the potential to not only stimulate nerve regeneration but also deliver itself to the correct cell types for a whole new type of therapy. Episode Notes:About the AuthorTravis is a postdoc who performed this work in the lab of Professor David Liu at Harvard University. The Liu lab is famous for engineering and evolving proteins that can be utilized as massively impactful tools for overcoming diverse diseases.  Travis's teachers fostered a curiosity that created a passion for chemistry and ultimately led him to engineer new biochemistries. Key TakeawaysProteases are enzymes that cut up other proteins.Proteases can either be non-specific, a nuke obliterating any protein in their path,  or sequence-specific, a heat seeking missile only cutting very specific protein motifs.Sequence-specific proteases that target disease causing proteins would make great drugs but therapeutically useful proteases rarely exist in nature.Travis focuses on re-engineering the sequence-specific protease known as botulinum neurotoxin so that it cuts an entirely new, therapeutically relevant protein sequence.Using a method called PANCE that utilizes bacteria and bacterial viruses (phages), Travis trains botulinum neurotoxin toward cutting a new target and leaving its original target alone.TranslationBotulinum neurotoxin has a cutting domain that Travis engineered toward a therapeutically relevant target, and a targeting domain that delivers the protein toward neurons.The enzymes generated could be used to cure neural pathologies but the PANCE could also be applied to change which cell type the protease targets, creating a highly programmable therapeutic protease platform.The platform has a ton of interest from industry and Travis is continuing to work on it outside of academia so that these proteases make it to the clinic and impact patient lives.First Author: Travis BlumPaper: Phage-assisted evolution of botulinum neurotoxin proteases with reprogrammed specificity

Therapeutic Human Gene Editing with Dr. David Liu

This week Harry is joined by Kevin Davies, author of the 2020 book Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing. CRISPR—an acronym for Clustered Regularly Interspaced Short Palindromic Repeats—consists of DNA sequences that evolved to help bacteria recognize and defend against viral invaders, as a kind of primitive immune system. Thanks to its ability to precisely detect and cut other DNA sequences, CRISPR has spread to labs across the world in the nine years since Jennifer Doudna and Emmanuel Charpentier published a groundbreaking 2012 Science paper describing how the process works. The Nobel Prize committee recognized the two scientists for the achievement in 2020, one day after Davies' book came out. The book explains how CRISPR was discovered, how it was turned into an easily programmable tool for cutting and pasting stretches of DNA, how most of the early pioneers in the field have now formed competing biotech companies, and how the technology is being used to help patients today—and in at least one famous case, misused. Today's interview covers all of that ground and more.Davies is a PhD geneticist who has spent most of his career in life sciences publishing. After his postdoc with Harvey Lodish at the Whitehead Institute, Davies worked as an assistant editor at Nature, the founding editor of Nature Genetics (Nature's first spinoff journal), editor-in-chief at Cell Press, founding editor-in-chief of the Boston-based publication Bio-IT World, and publisher of Chemical & Engineering News. In 2018 he helped to launch The CRISPR Journal, where he is the executive editor. Davies' previous books include Breakthrough (1995) about the race to understand the BRCA1 breast cancer gene, Cracking the Genome (2001) about the Human Genome Project, The $1,000 Genome (2010) about next-generation sequencing companies, and DNA (2017), an updated version of James Watson's 2004 book, co-authored with Watson and Andrew Berry.Please rate and review MoneyBall Medicine on Apple Podcasts! Here's how to do that from an iPhone, iPad, or iPod touch:1. Open the Podcasts app on your iPhone, iPad, or Mac. 2. Navigate to the page of the MoneyBall Medicine podcast. You can find it by searching for it or selecting it from your library. 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Your review may not be immediately visible.Full TranscriptHarry Glorikian: I'm Harry Glorikian, and this is MoneyBall Medicine, the interview podcast where we meet researchers, entrepreneurs, and physicians who are using the power of data to improve patient health and make healthcare delivery more efficient. You can think of each episode as a new chapter in the never-ending audio version of my 2017 book, “MoneyBall Medicine: Thriving in the New Data-Driven Healthcare Market.” If you like the show, please do us a favor and leave a rating and review at Apple Podcasts.Harry Glorikian: We talk a lot on the show about how computation and data are changing the way we develop new medicines and the way we deliver healthcare. Some executives in the drug discovery business speak of the computing and software side of the business as the “dry lab” —to set it apart from the “wet labs” where scientists get their hands dirty working with actual cells, tissues, and reagents.But the thing is, recent progress on the wet lab side of biotech has been just as amazing as progress in areas like machine learning. And this week, my friend Kevin Davies is here to talk about the most powerful tool to come along in the last decade, namely, precise gene editing using CRISPR.Of course, CRISPR-based gene editing has been all over the news since Jennifer Doudna and Emmanuel Charpentier published a groundbreaking Science paper in 2012 describing how the process works in the lab. That work earned them a Nobel Prize in medicine just eight years later, in 2020.But what's not as well-known is the story of how CRISPR was discovered, how it was turned into an easily programmable tool for cutting and pasting stretches of DNA, how most of the early pioneers in the field have now formed competing biotech companies, and how the technology is being used to help patients today—and in at least one famous case, misused.Kevin put that whole fascinating story together in his 2020 book Editing Humanity. And as the executive editor of The CRISPR Journal, the former editor-in-chief of Bio-IT World, the founding editor at Nature Genetics, and the author of several other important books about genomics, Kevin is one of the best-placed people in the world to tell that story. Here's our conversation.Harry Glorikian: Kevin, welcome to the show. Kevin Davies: Great to see you again, Harry. Thanks for having me on.Harry Glorikian: Yeah, no, I mean, I seem to be saying this a lot lately, it's been such a long time since, because of this whole pandemic, nobody's really seeing anybody on a regular basis. I want to give everybody a chance to hear about, you had written this book called Editing Humanity, which is, you know, beautifully placed behind you for, for product placement here. But I want to hear, can you give everybody sort of an overview of the book and why you feel that this fairly technical laboratory tool called CRISPR is so important that you needed to write a book about it?Kevin Davies: Thank you. Yes. As you may know, from some of my previous “bestsellers” or not, I've written about big stories in genetics because that's the only thing I'm remotely qualified to write about. I trained as a human geneticist in London and came over to do actually a pair of post-docs in the Boston area before realizing my talents, whatever they might be, certainly weren't as a bench researcher. So I had to find another way to stay in science but get away from the bench and hang up the lab coats.So moving into science publishing and getting a job with Nature and then launching Nature Genetics was the route for me. And over the last 30 years, I've written four or five books that have all been about, a) something big happening in genomics, b) something really big that will have both medical and societal significance, like the mapping and discovery of the BRCA1 breast cancer gene in the mid-90s, the Human Genome Project at the turn of the century, and then the birth and the dawn of consumer genetics and personalized medicine with The $1,000 Genome. And the third ingredient I really look for if I'm trying to reach a moderately, significantly large audience is for the human elements. Who are they, the heroes and the anti heroes to propel the story? Where is the human drama? Because, you know, we all love a good juicy, gossipy piece of story and rating the good guys and the bad guys. And CRISPR, when it first really took off in 2012, 2013 as a gene editing tool a lot of scientists knew about this. I mean, these papers are being published in Science in particular, not exactly a specialized journal, but I was off doing other things and really missed the initial excitement, I'm embarrassed to say. It was only a couple of years later, working on a sequel to Jim Watson's DNA, where I was tasked with trying to find and summarize the big advances in genomic technology over the previous decade or whatever, that I thought, well, this CRISPR thing seems to be taking off and the Doudnas and the Charpentiers are, you know, winning Breakthrough Prizes and being feted by celebrities. And it's going on 60 Minutes. They're going to make a film with the Rock, Dwayne Johnson. What the heck is going on. And it took very little time after that, for me to think, you know, this is such an exciting, game-changing disruptive technology that I've got to do two things. I've gotta, a) write a book and b) launch a journal, and that's what I did. And started planning at any rate in sort of 2016 and 17. We launched the CRISPR Journal at the beginning of 2018. And the book Editing Humanity came out towards the end of 2020. So 2020, literally one day before the Nobel Prize—how about that for timing?—for Doudna and Charpentier for chemistry last year. Harry Glorikian: When I think about it, I remember working with different companies that had different types of gene editing technology you know, working with some particularly in the sort of agriculture space, cause it a little bit easier to run faster than in the human space. And you could see what was happening, but CRISPR now is still very new. But from the news and different advances that are happening, especially here in the Boston area, you know, it's having some real world impacts. If you had to point to the best or the most exciting example of CRISPR technology helping an actual patient, would you say, and I've heard you say it, Victoria Gray, I think, would be the person that comes to mind. I've even, I think in one of your last interviews, you said something about her being, you know, her name will go down in history. Can you explain the technology that is helping her and what some of the similar uses of CRISPR might be?Kevin Davies: So the first half of Editing Humanity is about the heroes of CRISPR, how we, how scientists turned it from this bizarre under-appreciated bacterial antiviral defense system and leveraged it and got to grips with it, and then figured out ways to turn it into a programmable gene editing technology. And within a year or two of that happening that the classic Doudna-Charpentier paper came out in the summer of 2012. Of course the first wave of biotech companies were launched by some of the big names, indeed most of the big names in CRISPR gene editing hierarchies. So Emmanuel Charpentier, Nobel Laureate, launched CRISPR Therapeutics, Jennifer Doudna co-founded Editas Medicine with several other luminaries. That didn't go well for, for reasons of intellectual property. So she withdrew from Editas and became a co-founder of Intellia Therapeutics as well as her own company, Caribou, which just went public, and Feng Zhang and others launched Editas Medicine. So we had this sort of three-way race, if you will, by three CRISPR empowered gene editing companies who all went public within the next two or three years and all set their sights on various different genetic Mendelian disorders with a view to trying to produce clinical success for this very powerful gene editing tool. And so, yes, Victoria Gray is the first patient, the first American patient with sickle cell anemia in a trial that is being run by CRISPR Therapeutics in close association with Vertex Pharmaceuticals. And that breakthrough paper, as I think many of your listeners will know, came out right at the end of 2020 published in the New England Journal of Medicine. Doesn't get much more prestigious than that. And in the first handful of patients that CRISPR Therapeutics have edited with a view to raising the levels of fetal hemoglobin, fetal globin, to compensate for the defective beta globin that these patients have inherited, the results were truly spectacular.And if we fast forward now to about two years after the initial administration, the initial procedures for Victoria Gray and some of her other volunteer patients, the results still look as spectacular. Earlier this year CRISPR Therapeutics put out of sort of an update where they are saying that the first 20 or 24 patients that they have dosed with sickle cell and beta thallasemia are all doing well. There've been little or no adverse events. And the idea of this being a once and done therapy appears very well founded. Now it's not a trivial therapy. This is ex-vivo gene editing as obviously rounds of chemotherapy to provide the room for the gene edited stem cells to be reimplanted into the patient. So this is not an easily scalable or affordable or ideal system, but when did we, when will we ever able to say we've pretty much got a cure for sickle cell disease? This is an absolutely spectacular moment, not just for CRISPR, but for medicine, I think, overall. And Victoria Gray, who's been brilliantly profiled in a long running series on National Public Radio, led by the science broadcaster Rob Stein, she is, you know, we, we can call her Queen Victoria, we can call it many things, but I really hope that ,it's not just my idea, that she will be one of those names like Louise Brown and other heroes of modern medicine, that we look and celebrate for decades to come.So the sickle cell results have been great, and then much more recently, also in the New England Journal, we have work led by Intellia Therapeutics, one of the other three companies that I named, where they've been also using CRISPR gene editing, but they've been looking at a rare liver disease, a form of amyloidosis where a toxic protein builds up and looking to find ways to knock out the production of that abnormal gene.And so they've been doing in vivo gene editing, really using CRISPR for the first time. It's been attempted using other gene editing platforms like zinc fingers, but this is the first time that I think we can really say and the New England Journal results prove it. In the first six patients that have been reported remarkable reductions in the level of this toxic protein far, not far better, but certainly better than any approved drugs that are currently on the market. So again, this is a very, very exciting proof of principle for in vivo gene editing, which is important, not just for patients with this rare liver disorder, but it really gives I think the whole field and the whole industry enormous confidence that CRISPR is safe and can be used for a growing list of Mendelian disorders, it's 6,000 or 7,000 diseases about which we know the root genetic cause, and we're not going to tackle all of them anytime soon, but there's a list of ones that now are within reach. And more and more companies are being launched all the time to try and get at some of these diseases.So as we stand here in the summer of 2021, it's a really exciting time. The future looks very bright, but there's so much more to be done. Harry Glorikian: No, we're just at the beginning. I mean, I remember when I first saw this, my first question was off target effects, right? How are we going to manage that? How are they going to get it to that place that they need to get it to, to have it to that cell at that time, in the right way to get it to do what it needs to do. And you know, all these sorts of technical questions, but at the same time, I remember I'm going to, trying to explain this to my friends. I'm like, “You don't understand, this can change everything.” And now a high school student, I say this to people and they look at me strangely, a high school student can order it and it shows up at your house.Kevin Davies: Yeah, well, this is why I think, and this is why one reason why CRISPR has become such an exciting story and receives the Nobel Prize eight years after the sort of launch publication or the first demonstration of it as a gene editing tool. It is so relatively easy to get to work. It's truly become a democratized or democratizing technology. You don't need a million-dollar Illumina sequencer or anything. And so labs literally all around the world can do basic CRISPR experiments. Not everyone is going to be able to launch a clinical trial. But the technology is so universally used, and that means that advances in our understanding of the mechanisms, new tools for the CRISPR toolbox new pathways, new targets, new oftware, new programs, they're all coming from all corners of the globe to help not just medicine, but many other applications of CRISPR as well.Harry Glorikian: Yeah. I always joke about like, there, there are things going on in high school biology classes now that weren't, available, when I was in college and even when we were in industry and now what used to take an entire room, you can do on a corner of a lab bench.Kevin Davies: Yeah. Yeah. As far as the industry goes we mentioned three companies. But you know, today there's probably a dozen or more CRISPR based or gene editing based biotech companies. More undoubtedly are going to be launched before the end of this year. I'm sure we'll spend a bit of time talking about CRISPR 2.0, it seems too soon to be even thinking about a new and improved version of CRISPR, but I think there's a lot of excitement around also two other Boston-based companies, Beam Therapeutics in Cambridge and Verve Therapeutics both of which are launching or commercializing base editing. So base editing is a tool developed from the lab of David Lu of the Broad Institute [of MIT and Harvard]. And the early signs, again, this technology is only five or six years old, but the early signs of this are incredibly promising. David's team, academic team, had a paper in Nature earlier this year, really reporting successful base editing treatment of sickle cell disease in an animal model, not by raising the fetal globin levels, which was sort of a more indirect method that is working very well in the clinic, but by going right at the point mutation that results in sickle cell disease and using given the chemical repertoire of base editing.Base editing is able to make specific single base changes. It can't do the full repertoire of single base changes. So there are some limitations on researchers' flexibility. So they were unable to flip the sickle cell variant back to the quote unquote wild type variants, but the change they were able to make is one that they can live with, we can live with because it's a known benign variant, a very rare variant that has been observed in other, in rare people around the world. So that's completely fine. It's the next best thing. And so that looks very promising. Beam Therapeutics, which is the company that David founded or co-founded is trying a related approach, also going right at the sickle cell mutation. And there are other companies, including one that Matthew Porteus has recently founded and has gone public called Graphite Bio.So this is an exciting time for a disease sickle cell disease that has been woefully neglected, I think you would agree, both in terms of basic research, funding, medical prioritization, and medical education. Now we have many, many shots on goal and it doesn't really, it's not a matter of one's going to win and the others are going to fall by the wayside. Just like we have many COVID vaccines. We'll hopefully have many strategies for tackling sickle cell disease, but they are going to be expensive. And I think you know the economics better than I do. But I think that is the worry, that by analogy with gene therapies that have been recently approved, it's all, it's really exciting that we can now see the first quote, unquote cures in the clinic. That's amazingly exciting. But if the price tag is going to be $1 million or $2 million when these things are finally approved, if and when, that's going to be a rather deflating moment. But given the extraordinary research resources that the CRISPRs and Intellias and Beams and Graphites are pouring into this research, obviously they've got to get some return back on their investment so that they can plow it back into the company to develop the next wave of of gene editing therapies. So you know, it's a predicament Harry Glorikian: One of these days maybe I have to have a show based on the financial parts of it. Because there's a number of different ways to look at it. But just for the benefit of the listeners, right, who may not be experts, how would you explain CRISPR is different from say traditional gene therapies. And is CRISPR going to replace older methods of, of gene therapy or, or will they both have their place? Kevin Davies: No, I think they'll both have their place. CRISPR and, and these newer gene editing tools, base editing and another one called prime editing, which has a company behind it now called Prime Medicine, are able to affect specific DNA changes in the human genome.So if you can target CRISPR, which is an enzyme that cuts DNA together with a little program, the GPS signal is provided in the form of a short RNA molecule that tells the enzyme where to go, where to go in the genome. And then you have a couple of strategies. You can either cut the DNA at the appropriate target site, because you want to inactivate that gene, or you just want to scramble the sequence because you want to completely squash the expression of that gene. Or particularly using the newer forms of gene editing, like base editing, you can make a specific, a more nuanced, specific precision edit without, with one big potential advantage in the safety profile, which is, you're not completely cutting the DNA, you're just making a nick and then coaxing the cell's natural repair systems to make the change that you sort of you're able to prime.So there are many diseases where this is the way you want to go, but that does not in any way invalidate the great progress that we're making in traditional gene therapy. So for example today earlier today I was recording an interview or for one of my own programs with Laurence Reid, the CEO of Decibel Therapeutics, which is looking at therapies for hearing loss both genetic and other, other types of hearing disorders.And I pushed him on this. Aren't you actually joinomg with the gene editing wave? And he was very circumspect and said, no, we're very pleased, very happy with the results that we're getting using old fashioned gene replacement therapy. These are recessive loss of function disorders. And all we need to do is get the expression of some of the gene back. So you don't necessarily need the fancy gene editing tools. If you can just use a an AAV vector and put the healthy gene back into the key cells in the inner ear. So they're complimentary approaches which is great.Harry Glorikian: So, you know, in, in this podcast, I try to have a central theme when I'm talking to people. The relationships of big data, computation, advances in new drugs, and other ways to keep people healthy. So, you know, like question-wise, there's no question in my mind that the whole genomics revolution that started in the ‘90s, and I was happy to be at Applied Biosystems when we were doing that, would have been impossible in the absence of the advances in computing speed and storage in the last three decades. I think computing was the thing that held up the whole human genome, which gave us the book of life that CRISPR is now allowing us to really edit. But I wonder if you could bring us sort of up-to-date and talk about the way CRISPR and computation are intertwined. What happens when you combine precision of an editing tool like CRISPR with the power of machine learning and AI tools to find meaning and patterns in that huge genetic ball? Kevin Davies: Yeah. Well, yeah. I'm got to tread carefully here, but I think we are seeing papers from some really brilliant labs that are using some of the tools that you mentioned. AI and machine learning with a view to better understanding and characterizing some of the properties and selection criteria of some of these gene editing tools. So you mentioned earlier Harry, the need to look out for safety and minimize the concern of off-target effects. So I think by using some of these some algorithms and AI tools, researchers have made enormous strides in being able to design the programmable parts of the gene editing constructs in such a way that you increase the chances that they're going to go to the site that you want them to go to, and nnot get hung up latching onto a very similar sequence that's just randomly cropped up on the dark side of the genome, across the nucleus over there. You don't want that to happen. And I don't know that anybody would claim that they have a failsafe way to guarantee that that could never happen. But the you know, the clinical results that we've seen and all the preclinical results are showing in more and more diseases that we've got the tools and learned enough now to almost completely minimize these safety concerns. But I think everyone, I think while they're excited and they're moving as fast as they can, they're also doing this responsibly. I mean, they, they have to because no field, gene therapy or gene editing really wants to revisit the Jesse Gelsinger tragedy in 1999, when a teenage volunteer died in volunteering for a gene therapy trial at Penn of, with somebody with a rare liver disease. And of course that, that setback set back the, entire field of gene therapy for a decade. And it's really remarkable that you know, many of the sort of pioneers in the field refuse to throw in the towel, they realized that they had to kind of go back to the drawing board, look at the vectors again, and throw it out. Not completely but most, a lot of the work with adenoviruses has now gone by the wayside. AAV is the new virus that we hear about. It's got a much better safety profile. It's got a smaller cargo hold, so that's one drawback, but there are ways around that. And the, the explosion of gene therapy trials that we're seeing now largely on the back of AAV and now increasingly with, with non-viral delivery systems as well is, is very, very gratifying. And it's really delivery. I think that is now the pain point. Digressing from your question a little bit, but delivery, I think is now the big challenge. It's one thing to contemplate a gene therapy for the eye for rare hereditary form of blindness or the ear. Indeed those are very attractive sites and targets for some of these early trials because of the quantities that you need to produce. And the localization, the, the physical localization, those are good things. Those help you hit the target that you want to. But if you're contemplating trying something for Duchenne muscular dystrophy or spinal muscular atrophy, or some of the diseases of the brain, then you're going to need much higher quantities particularly for muscular disorders where, you run into now other challenges, including, production and manufacturing, challenges, and potentially safeguarding and making sure that there isn't an immune response as well. That's another, another issue that is always percolating in the background.But given where we were a few years ago and the clinical progress that we've talked about earlier on in the show it, I think you can safely assume that we've collectively made enormous progress in, in negating most, if not all of these potential safety issues.Harry Glorikian: No, you know, it's funny, I know that people will say like, you know, there was a problem in this and that. And I look at like, we're going into uncharted territories and it has to be expected that you just…you've got people that knew what they were doing. All of these people are new at what they are doing. And so you have to expect that along the way everything's not going to go perfectly. But I don't look at it as a negative. I look at it as, they're the new graduating class that's going to go on and understand what they did right. Or wrong, and then be able to modify it and make an improvement. And, you know, that's what we do in science. Kevin Davies: Well, and forget gene editing—in any area of drug development and, and pharmaceutical delivery, things don't always go according to plan. I'm sure many guests on Moneyball Medicine who have had to deal with clinical trial failures and withdrawing drugs that they had all kinds of high hopes for because we didn't understand the biology or there was some other reaction within, we didn't understand the dosing. You can't just extrapolate from an animal model to humans and on and on and on. And so gene editing, I don't think, necessarily, should be held to any higher standard. I think the CRISPR field has already in terms of the sort of market performance, some of the companies that we've mentioned, oh my God, it's been a real roller coaster surprisingly, because every time there's been a paper published in a prominent journal that says, oh my God, there's, there's a deletion pattern that we're seeing that we didn't anticipate, or we're seeing some immune responses or we're seeing unusual off target effects, or we're seeing P53 activation and you know, those are at least four off the top of my head. I'm sure there've been others. And all had big transient impact on the financial health of these companies. But I think that was to be expected. And the companies knew that this was just an overreaction. They've worked and demonstrated through peer review publications and preclinical and other reports that these challenges have been identified, when known about, pretty much completely have been overcome or are in the process of being overcome.So, you know, and we're still seeing in just traditional gene therapy technologies that have been around for 15, 20 years. We're still seeing reports of adverse events on some of those trials. So for gene editing to have come as far as it's common, to be able to look at these two big New England Journal success stories in sickle cell and ATTR amyloidosis, I don't think any very few, except the most ardent evangelists would have predicted we'd be where we are just a few years ago. [musical transition]Harry Glorikian: I want to pause the conversation for a minute to make a quick request. If you're a fan of MoneyBall Medicine, you know that we've published dozens of interviews with leading scientists and entrepreneurs exploring the boundaries of data-driven healthcare and research. And you can listen to all of those episodes for free at Apple Podcasts, or at my website glorikian.com, or wherever you get your podcasts.There's one small thing you can do in return, and that's to leave a rating and a review of the show on Apple Podcasts. It's one of the best ways to help other listeners find and follow the show.If you've never posted a review or a rating, it's easy. All you have to do is open the Apple Podcasts app on your smartphone, search for MoneyBall Medicine, and scroll down to the Ratings & Reviews section. Tap the stars to rate the show, and then tap the link that says Write a Review to leave your comments. It'll only take a minute, but it'll help us out immensely. Thank you! And now back to the show.[musical transition]Harry Glorikian:One of your previous books was called The $1,000 Genome. And when you published that back in 2010, it was still pretty much science fiction that it might be possible to sequence someone's entire genome for $1,000. But companies like Illumina blew past that barrier pretty quickly, and now people are talking about sequencing individual genome for just a few hundred dollars or less. My question is, how did computing contribute to the exponential trends here. And do you wish you'd called your book The $100 Genome?Kevin Davies: I've thought about putting out a sequel to the book, scratching out the 0's and hoping nobody would notice. Computing was yes, of course, a massive [deal] for the very first human genome. Remember the struggle to put that first assembly together. It's not just about the wet lab and pulling the DNA sequences off the machines, but then you know, the rapid growth of the data exposure and the ability to store and share and send across to collaborators and put the assemblies together has been critical, absolutely critical to the development of genomics.I remember people were expressing shock at the $1,000 genome. I called the book that because I heard Craig Venter use that phrase in public for the first time in 2002. And I had just recently published Cracking the Genome. And we were all still recoiling at the billions of dollars it took to put that first reference genome sequence together. And then here's Craig Venter, chairing a scientific conference in Boston saying what we need is the $1,000 genome. And I almost fell off my chair. “what are you? What are you must you're in, you're on Fantasy Island. This is, there's no way we're going to get, we're still doing automated Sanger sequencing. God bless Fred Sanger. But how on earth are you going to take that technology and go from billions of dollars to a couple of thousand dollars. This is insanity.” And that session we had in 2002 in Boston. He had a local, a little episode of America's Got Talent and he invited half a dozen scientists to come up and show what they had. And George Church was one of them. I think Applied Biosystems may have given some sort of talk during that session. And then a guy, a young British guy from a company we'd never heard of called Celexa showed up and showed a couple of pretty PowerPoint slides with colored beads, representing the budding DNA sequence on some sort of chip. I don't know that he showed any data. It was all very pretty and all very fanciful. Well guess what? They had the last laugh. Illumina bought that company in 2006. And as you said, Harry you know, I think when, when they first professed to have cracked the $1,000 dollar genome barrier, a few people felt they needed a pinch of salt to go along with that. But I think now, yeah, we're, we're, we're well past that. And there are definitely outfits like BGI, the Beijing Genomics Institute being one of them, that are touting new technologies that can get us down to a couple of hundred. And those were such fun times because for a while there Illumina had enormous competition from companies like 454 and Helicose and PacBio. And those were fun heady times with lots and lots of competition. And in a way, Illumina's had it a little easy, I think over the last few years, but with PacBio and Oxford Nanopore gaining maturity both, both in terms of the technology platforms and their business strategy and growth, I think Illumina' gonna start to feel a little bit more competition in the long read sequence space. And one is always hearing whispers of new companies that may potentially disrupt next-gen sequencing. And that would be exciting because then we'd have an excuse to write another book. Harry Glorikian: Well, Kevin, start writing because I actually think we're there. I think there are a number of things there and you're right, I think Illumina has not had to bring the price down as quickly because there hasn't been competition. And you know, when I think about the space is, if you could do a $60 genome, right, it starts to become a rounding error. Like what other business models and opportunities now come alive? And those are the things that excite me. All right. But so, but you have a unique position as editor of the journal of CRISPR and the former editor of a lot of prominent, you know, publications, Nature Genetics, Bio-IT World, Chemical & Engineering News. Do you think that there's adequate coverage of the biological versus the computing side of it? Because I, I have this feeling that the computing side still gets a little overlooked and underappreciated. Kevin Davies: I think you're right. I mean I think at my own company Genetic Engineering News, we still have such deep roots in the wet lab vision and version of biotechnology that it takes a conscious effort to look and say, you know, that's not where all the innovation is happening. Bio-IT World, which you mentioned is interesting because we launched that in 2002. It was launched by the publisher IDG, best-known from MacWorld and ComputerWorld and this, this whole family of high-tech publications.And we launched in 2002 was a very thick glossy print magazine. And ironically, you know, we just couldn't find the advertising to sustain that effort, at least in the way that we'd envisioned it. And in 2006 and 2007, your friend and mine Phillips Kuhl, the proprietor of Cambridge Healthtech Institute, kind of put us out of our misery and said, you know what I'll, take the franchise because IDG just didn't know what to do with it anymore. But what he really wanted was the trade show, the production. And even though at the magazine eventually we fell on our sword and eventually put it out of its misery, the trade show went from strength to strength and it'll be back in Boston very soon because he had the vision to realize there is a big need here as sort of supercomputing for life sciences.And it's not just about the raw high-performance computing, but it's about the software, the software tools and data sharing and management. And it's great to go back to that show and see the, you know, the Googles and Amazons and yeah, all the big household names. They're all looking at this because genome technology, as we've discussed earlier has been one of the big growth boom areas for, for their services and their products.Harry Glorikian: Right. I mean, well, if you look at companies like Tempus, right. When I talked to Joel Dudley over there on the show it's, they want to be the Amazon AWS piping for all things genomic analysis. Right. So instead of creating it on your own and building a, just use their platform, basically, so it's definitely a growth area. And at some point, if you have certain disease states, I don't see how you don't get you know, genomic sequencing done, how a physician even today in oncology, how anybody can truly prescribe with all the drugs that are being approved that have, you know, genomic biomarkers associated with them and not use that data.Kevin Davies: On a much lower, lo-fi scale, as I've been doing a lot of reading about sickle cell disease lately, it's clear that a lot of patients who are, of course, as you, as you know, as your listeners know, are mostly African-American because the disease arose in Africa and the carrier status gives carriers a huge health advantage in warding off malaria. So the gene continues to stay, stay high in in frequency. Many African-American patients would benefit from some generic drugs that are available in this country that provide some relief, but aren't aware of it and maybe their physicians aren't completely aware of it either. Which is very sad. And we've neglected the funding of this disease over many decades, whereas a disease like cystic fibrosis, which affects primarily white people of Northern European descent that receives far more funding per capita, per head, than than a disease like sickle cell does. But hopefully that will begin to change as we see the, the potential of some of these more advanced therapies.I think as far as your previous comment. I think one of the big challenges now is how we tackle common diseases. I think we're making so much progress in treating rare Mendelian diseases and we know thousands of them. But it's mental illness and asthma and diabetes you know, diseases that affect millions of people, which have a much more complicated genetic and in part environmental basis.And what can we learn, to your point about having a full genome sequence, what can we glean from that that will help the medical establishment diagnose and treat much more common diseases, not quite as simple as just treating a rare Mendelian version of those diseases? So that's, I think going to be an important frontier over the next decade.Harry Glorikian: Yeah. It's complicated. I think you're going to see as we get more real-world data that's organized and managed well, along with genomic data, I think you'll be able to make more sense of it. But some of these diseases are quite complicated. It's not going to be find one gene, and it's going to give you that answer.But I want to go back to, you can't really talk about CRISPR without talking about this specter of germline editing. And a big part of your book is about this firestorm of criticism and condemnation around, you know, the 2018 when the Chinese researcher He Jankui, I think I said it correctly.Yep.Kevin Davies: He Jankui is how I say it. Close. Harry Glorikian: He announced that he had created twin baby girls with edits to their genomes that were intended to make them immune to HIV, which sort of like—that already made me go, what? But the experiment was, it seems, unauthorized. It seems that, from what I remember, the edits were sloppy and the case spurred a huge global discussion about the ethics of using CRISPR to make edits that would be inherited by future generations. Now, where are we in that debate now? I mean, I know the National Academy of Sciences published a list of criteria, which said, don't do that. Kevin Davies: It was a little more nuanced than that. It wasn't don't do that. It was, there is a very small window through which we could move through if a whole raft of criteria are met. So they, they refuse to say hereditary genome editing should be banned or there should be a moratorium. But they said it should not proceed until we do many things. One was to make sure it is safe. We can't run before we can walk. And by that, I mean, we've got to first demonstrate—because shockingly, this hasn't been done yet—that genome editing can be done safely in human embryos. And in the last 18 months there've been at least three groups, arguably the three leading groups in terms of looking at genetic changes in early human embryos, Kathy Niakan in London, Shoukhrat Mitalipov in Oregon, and Dieter Egli in New York, who all at roughly the same time published and reports that said, or posted preprints at least that said, when we attempt to do CRISPR editing experiments in very early human embryos, we're seeing a mess. We're seeing a slew of off-target and even on-target undesirable edits.And I think that says to me, we don't completely understand the molecular biology of DNA repair in the early human embryo. It may be that there are other factors that are used in embryogenesis that are not used after we're born. That's speculation on my part. I may be wrong. But the point is we still have a lot to do to understand, even if we wanted to.And even if everybody said, “Here's a good case where we should pursue germline editing,” we've gotta be convinced that we can do it safely. And at the moment, I don't think anybody can say that. So that's a huge red flag.But let's assume, because I believe in the power of research, let's assume that we're going to figure out ways to do this safely, or maybe we say CRISPR isn't the right tool for human embryos, but other tools such as those that we've touched on earlier in the show base editing or prime editing, or maybe CRISPR 3.0 or whatever that is right now to be published somewhere. [Let's say ] those are more safe, more precise tools. Then we've got to figure out well, under what circumstances would we even want to go down this road? And the pushback was quite rightly that, well, we already have technologies that can safeguard against families having children with genetic diseases. It's called IVF and pre-implantation genetic diagnosis. So we can select from a pool of IVF embryos. The embryos that we can see by biopsy are safe and can therefore be transplanted back into the mother, taken to term and you know, a healthy baby will emerge.So why talk about gene editing when we have that proven technology? And I think that's a very strong case, but there are a small number of circumstances in which pre-implantation genetic diagnosis will simply not work. And those are those rare instances where a couple who want to have a biological child, but have both of them have a serious recessive genetic disease. Sickle cell would be an obvious case in point. So two sickle cell patients who by definition carry two copies of the sickle cell gene, once I have a healthy biological child preimplantation genetic diagnosis, it's not going to help them because there are no healthy embryos from whatever pool that they produce that they can select. So gene editing would be their only hope in that circumstance. Now the National Academy's report that you cited, Harry, did say for serious diseases, such as sickle cell and maybe a few others they could down the road potentially see and condone the use of germline gene editing in those rare cases.But they're going to be very rare, I think. It's not impossible that in an authorized approved setting that we will see the return of genome editing, but that's okay. Of course you can can issue no end of blue ribbon reports from all the world's experts, and that's not going to necessarily prevent some entrepreneur whose ethical values don't align with yours or mine to say, “You know what, there's big money to be made here. I'm going offshore and I'm going to launch a CRISPR clinic and you know, who's going to stop me because I'll be out of the clutches of the authorities.” And I think a lot of people are potentially worried that that scenario might happen. Although if anyone did try to do that, the scientific establishment would come down on them like a ton of bricks. And there'll be a lot of pressure brought to bear, I think, to make sure that they didn't cause any harm.Harry Glorikian: Yeah. It's funny. I would like to not call them entrepreneurs. I like entrepreneurs. I'd like to call them a rogue scientist. Kevin Davies: So as you say, there's the third section of four in Editing Humanity was all about the He Jankui debacle or saga. I had flown to Hong Kong. It's a funny story. I had a little bit of money left in my travel budget and there were two conferences, one in Hong Kong and one in China coming up in the last quarter of 2018. So I thought, well, okay, I'll go to one of them. And I just narrowed, almost a flip of a coin, I think. Okay, let's go to the Hong Kong meeting.It's a bioethics conference since I don't expect it to be wildly exciting, but there are some big speakers and this is an important field for the CRISPR Journal to monitor. So I flew there literally, you know, trying to get some sleep on the long flights from New York and then on landing, turn on the phone, wait for the new wireless signal provider to kick in. And then Twitter just explode on my feed as this very, very astute journalists at MIT Technology Review, Antonio Regalado, had really got the scoop of the century by identifying a registration on a Chinese clinical trial website that he and only he had the foresight and intelligence to sort of see. He had met He Jankui in an off the record meeting, as I described in the book, about a month earlier. A spider sense was tingling. He knew something was up and this was the final clue. He didn't know at that time that the Lulu and Nana, the CRISPR babies that you mentioned, had actually been born, but he knew that there was a pregnancy, at least one pregnancy, from some of the records that he'd seen attached to this registration document. So it was a brilliant piece of sleuthing. And what he didn't know is that the Asociated Press chief medical writer Marilynm Marchion had confidentially been alerted to the potential upcoming birth of these twins by an American PR professional who was working with He Jankui in Shenzhen. So she had been working on an embargoed big feature story that He Jankui and his associates hoped would be the definitive story that would tell the world, we did this quote unquote, “responsibly and accurately, and this is the story that you can believe.” So that story was posted within hours.And of course the famous YouTube videos that He Jankui had recorded announcing with some paternal pride that he had ushered into the world these two gene edited, children, screaming and crying into the world as beautiful babies I think was [the phrase]. And he thought that he was going to become famous and celebrated and lauded by not just the Chinese scientific community, but by the world community for having the ability and the bravery to go ahead and do this work after Chinese researchers spent the previous few years editing human embryos. And he was persuaded that he had to present his work in Hong Kong, because he'd set off such a such an extraordinary firestorm. And I think you've all seen now you're the clips of the videos of him nervously walking onto stage the muffled, the silence, or the only sound in the front row, the only sound in the big auditorium at Hong Kong university—[which] was absolutely packed to the rim, one side of the auditorium was packed with press photographers, hundreds of journalists and cameras clicking—and the shutters clattering was the only, that was the applause that he got as he walked on stage.And to his credit, he tried to answer the questions directly in the face of great skepticism from the audience. The first question, which was posed by David Liu, who had traveled all the way there, who just asked him simply, “What was the unmet medical need that you are trying to solve with this reckless experiment? There are medical steps that you can do, even if the couple that you're trying to help has HIV and you're trying to prevent this from being passed on. There are techniques that you can use sperm washing being one of them. That is a key element of the IVF process to ensure that the no HIV is transmitted.”But he was unable to answer the question in terms of I'm trying to help a family. He'd already moved out and was thinking far, far bigger. Right? And his naiveté was shown in the manuscript that he'd written up and by that point submitted to Nature, excerpts of which were leaked out sometime later.So he went back to Shenzhen and he was put under house arrest after he gave that talk in Hong Kong. And about a year later was sentenced to three years in jail. And so he's, to the best of my knowledge that's where he is. But I often get asked what about the children? As far as we know, there was a third child born about six months later, also gene-edited. We don't even know a name for that child, let alone anything about their health. So one hopes that somebody in the Chinese medical establishment is looking after these kids and monitoring them and doing appropriate tests. The editing, as you said, was very shoddily performed. He knocked out the gene in question, but he did not mimic the natural 32-base deletion in this gene CCR5 that exists in many members of the population that confers, essentially, HIV resistance. So Lulu and Nana on the third child are walking human experiments, sad to say. This should never have been done. Never should have been attempted. And so we hope that he hasn't condemned them to a life of, you know, cancer checkups and that there were no off-target effects. They'll be able to live, hopefully, with this inactivated CCR5 gene, but it's been inactivated in a way that I don't think any, no other humans have ever been recorded with such modifications. So we, we really hope and pray that no other damage has been done. Harry Glorikian: So before we end, I'd love to give you the chance to speculate on the future of medicine in light of CRISPR. Easy, fast, inexpensive genome sequencing, give us access to everybody's genetic code, if they so choose. Machine learning and other forms of AI are helping understand the code and trace interactions between our 20,000 genes. And now CRISPR gives us a way to modify it. So, you know, it feels like [we have] almost everything we need to create, you know, precise, targeted, custom cures for people with genetic conditions. What might be possible soon, in your view? What remaining problems need to be solved to get to this new area of medicine? Kevin Davies: If you know the sequence that has been mutated to give rise to a particular disease then in principle, we can devise a, some sort of gene edit to repair that sequence. It may be flipping the actual base or bases directly, or maybe as we saw with the first sickle cell trial, it's because we understand the bigger genetic pathway. We don't have to necessarily go after the gene mutation directly, but there may be other ways that we can compensate boost the level of a compensating gene.But I think we, we should be careful not to get too carried away. As excited as I am—and hopefully my excitement comes through in Editing Humanity—but for every company that we've just mentioned, you know, you can go on their website and look at their pipeline. And so Editas might have maybe 10 diseases in its cross hairs. And CRISPR [Therapeutics] might have 12 diseases. And Intellia might have 14 diseases and Graphite has got maybe a couple. And Beam Therapeutics has got maybe 10 or 12. And Prime Medicine will hasn't listed any yet, but we'll hopefully have a few announced soon. And so I just reeled off 50, 60, less than a hundred. And some of these are gonna work really, really well. And some are going to be either proven, ineffective or unviable economically because the patient pool is too small. And we've got, how many did we say, 6,000 known genetic diseases. So one of the companies that is particularly interesting, although they would admit they're in very early days yet, is Verve Therapeutics. I touched on them earlier because they're looking at to modify a gene called PCSK9 that is relevant to heart disease and could be a gene modification that many people might undergo because the PCSK9 gene may be perfectly fine and the sequence could be perfectly normal, but we know that if we re remove this gene, levels of the bad cholesterol plummet, and that's usually a good thing as far as heart management goes. So that's an interesting, very interesting study case study, I think, to monitor over the coming years, because there's a company looking at a much larger patient pool potentially than just some of these rare syndromes with unpronounceable names. So the future of CRISPR and gene editing is very bright. I think one of the lessons I took away from CRISPR in Editing Humanity is, looking at the full story, is how this technology, this game-changing gene-editing technology, developed because 25 years ago, a handful of European microbiologists got really interested in why certain microbes were thriving in a salt lake in Southeastern Spain. This is not exactly high-profile, NIH-must-fund-this research. There was a biological question that they wanted to answer. And the CRISPR repeats and the function of those repeats fell out of that pure curiosity, just science for science's sake. And so it's the value of basic investigator-driven, hypothesis-driven research that led to CRISPR being described and then the function of the repeats.And then the story shifted to a yogurt company in Europe that was able to experimentally show how having the right sequence within the CRISPR array could safeguard their cultures against viral infection. And then five years of work people in various groups started to see, were drawn to this like moths to a flame. Jennifer Doudna was intrigued by this from a tip-off from a coffee morning discussion with a Berkeley faculty colleagues, Jill Banfield, a brilliant microbiologist in her own. And then she met meets Emmanuelle Charpentier in Puerto Rico at a conference, and they struck up a friendship and collaboration over the course of an afternoon. And that, why should that have worked? Well, it did, because a year later they're publishing in Science. So it's serendipity and basic research. And if that can work for CRISPR, then I know that there's another technology beginning to emerge from somewhere that may, yet trump CRISPR.And I think the beauty of CRISPR is its universal appeal. And the fact is, it's drawn in so many people, it could be in Japan or China or South Korea or parts of Europe or Canada or the U.S. or South America. Somebody is taking the elements of CRISPR and thinking well, how can we improve it? How can we tweak it?And so this CRISPR toolbox is being expanded and modified and updated all the time. So there's a hugely exciting future for genome medicine. And you know, whether it's a new form of sequencing or a new form of synthetic biology, you know, hopefully your show is going to be filled for many years to come with cool, talented, young energetic entrepreneurs who've developed more cool gadgets to work with our genome and other genomes as well. We haven't even had time to talk about what this could do for rescuing the wooly mammoth from extinction. So fun things, but maybe, maybe another time. Harry Glorikian: Excellent. Well, great to have you on the show. Really appreciate the time. I hope everybody got a flavor for the enormous impact this technology can have. Like you said, we talked about human genome, but there's so many other genomic applications of CRISPR that we didn't even touch. Kevin Davies: Yup. Yup. So you have to read the book. Harry Glorikian: Yeah. I will look forward to the next book. So, great. Thank you so much. Kevin Davies: Thanks for having me on the show, Harry. All the best.Harry Glorikian: Take care.Harry Glorikian: That's it for this week's show. You can find past episodes of MoneyBall Medicine at my website, glorikian.com, under the tab “Podcast.” And you can follow me on Twitter at hglorikian.  Thanks for listening, and we'll be back soon with our next interview.

Ep. 151 Innovation MD: An Interview with Dr. David Liu by BackTable

David Liu is a successful businessman having spent decades on Wall Street and Silicon Valley. He's raised over $15 billion for hundreds of companies, created multiple start-ups, and had multiple billion dollar exits. But in this interview with Carlos Amezcua, he talks about something more personal. David shares his experience being born with a bilateral cleft lip and palate. He overcame speech and hearing impediments to become a massive success and now he dedicates his life to helping others. He shares with Carlos Amezcua what it means to support these children as the Chairman of Fundraising Advisory Council for Smile Train. For more information about Smile Train go to SmileTrain.org. More interviews and stories go to beond.tv, or our BEONDTV Roku and Amazon FireTV apps. --- Support this podcast: https://anchor.fm/beondtv/support

The founding CEO of Beam Therapeutics, John Evans explains the new world of precision genome editing (Base Editing). Beam Therapeutics is the base editing company co-founded by David Liu, Feng Zhang and Keith JoungClose to the Edge | Ep. 5 | John Evans, CEO Beam Therapeuticshttps://www.youtube.com/watch?v=ydU-l...Welcome back, tribe members! Today I'm discussing "My Next 4X Stock - Buy Now". If you enjoy this video feel free to SUBSCRIBE! Make sure to follow me on social media for even more coverage of the stock market.The Power of a Tribe: https://www.amazon.com/dp/B096TWBDM3/...Get Surfshark VPN at  https://surfshark.deals/INVESTORS and enter promo code INVESTORS for 83% off and 3 extra months for free!  Facebook: https://www.facebook.com/BestofUSLLC/Instagram: https://www.instagram.com/bestofusinv...Twitter: https://twitter.com/BestOfUsInvestHelp Kerry and Nita win the race against Childhood Cancer and keep their daughter Shay's memory alive. Your support makes a direct impact in the fight against Pediatric Cancer at Children's of Alabama by helping advance research in finding a cure for cancer http://give.childrensal.org/bestofusWe have Up-Graded Our Discord: Kerry's Portfolio, Trades and InsightsThis is the new link: https://discord.io/bestofus. It is now organized by topics and will be easier to navigate and communicate

today after I made a couple videos in the morning I went out to starbucks I wanted to go for a walk and sit in the park when I got to the park the whole playground I've been ripped up and there was some kind of big machine digging so I thought oh man now I can't sit in the park so i sat in starbucks and i was editing my videos and I was definitely experiencing some body pain that sometimes happens when I get into those other states of consciousness I had a bunch of strange perceptions as well then I ended up sitting outside and talking to a friend of mine same friend that talked me through my last psych ward experience and talked with me almost every day it was super helpful who talked for over an hour and it was really helpful as well seems we're both a little bit fearful of going down the path of pathology again and so we're both very aware of becoming too stressed out to the point where then we might be perceived as needing to be pathologized and then I finish watching the interview of Katie motormen dr. David Liu cough and he was saying that a lot of his work is around helping people to avoid being pathologized and he was saying how a mystical experience has an overlap with psychotic features and how if a person ends up in the psych ward they're going to be moved towards the psychotic features whereas if somebody manages to avoid the psych ward and and is able to get support in a different way that isn't pathologizing then it might be more of a mystical experience so it seems that whatever paradigm a person is viewed by is sort of what collapses the wave function of what it is that the person ends up being interpreted as so in that way I feel it's important to do everything I can to avoid being pathologized I want to go home I thought to put this on on my wrist and it's a zap strap and sort of reminding me that I can anchor myself somewhere and I won't keep it on all the time but I feel that right now just in the state that I'm in this is almost a reminder that I can keep myself safe and I also thought of it today where it's handy to have that one around like this so then when I find a place I want to keep myself then I just go like this with the actual item and then put in and then I'm stuck to the item whereas if I just have this part like this I might be able to slip my hand out when I actually fasten myself to something so this really keeps me stuck somewhere and this is almost like my version of the semicolon tattoo this is like I want to live I don't want to die and I don't want to be pathologized either so if I can keep myself safe where I am maybe I won't be led to the psych ward I also have my little DNA tangler which gives my hand something to do a little bit and I also found a bunch of crystals that I might carry around so I'm feeling like I need to protect myself as what the theme seems to be and I also have this hat that sometimes I wear it's not very attractive but it has the material the blocks EMF sometimes when I'm feeling super sensitive I feel like I need to protect my brain signals maybe be better to protect my heart and I remember reading one time that what goes wrong with our car is sort of congruent to our life and I remember one time that I left my lights on for like two hours and I came back and my car started I thought I can leave my lights on like I can leave my lights on i can I can light things up in a way and my energy is not going to die and then yesterday my car started and it started really rough and it was shaking when it was idling at the lights and I'm thinking to myself my car is trembling too just like my nervous system is sort of trembling and fearful my car is trembling too at the same time so i need to get my brother to look at my car and I made some more notes when I was editing videos and walking around and I was thinking about what we've been programmed to make salient which is fear and the ego and whatever our dopamine circuits ask for and I'd really like to make laughter more salient and to go with that i found this that i haven't and I really could talk to myself this way if I wanted to but I don't know if I'm going to go there quite yet but dunce I'm talking to flies and coconuts and things like that and it could be enough for now I think part of crisis is to do with breaking off from the relational mind so a person feels isolated and not able to relate to people and I feel like having self dialogue with myself it's good and that it creates this greater context for myself but if I don't start making some of it relational with other people than it also could be isolating that I'm making this meaning for myself by myself with myself which could actually be a bit isolating and if a person breaks off from the relational mind and is isolated it needs to be repaired there through connection and relationship and unconditional love and we're usually reconnected through the paradigm through the lens through the collapsing of the wave function around mental illness and then we're sort of trapped in that paradigm I think we need to fast from dopamine which is what dr. David Hawkins says when he says we need to surrender the juice and dopamine is tied in to have it and anything that makes us less habit will actually make us fast from dopamine because we have to pay attention when we're fully engaged when we're paying attention we don't need dopamine as a reward attention is innately rewarding without thinking this is rewarding and it seems we run more on these molecules of emotion dopamine and its subsidiaries because we're not paying attention an attention is rewarding an attention is energy and we need energy to pay attention and we're wasting the energy by not paying attention and by engaging in these dopamine circuit activities and these other emotions which I feel like they're created by the energy of the nervous system being electricity getting transformed that electricity being used to create the molecules of emotion because we're not paying attention and then those are sort of pleasurable and things but it's sort of like us drugging ourselves to feel like we are really living when we're not we're not fully alive these molecules of emotion are almost maybe supposed to be like temporary coping mechanisms to get us through a tough time to get back to paying attention because we're actually really engaged it's almost like saying it's okay soon you'll be engaged but we never end up getting engaged and we end up living on these molecules of emotion and these molecules of emotion are the different temporary feelings and by having these temporary feelings were not actually existing in these more permanent state of joy happiness and love and I feel like the energy of the nervous system is transformed into words and those words have a mirror of molecules of emotion in the physical body so in the nervous system in the brain in a way on our mind screen we have words and images and then we create the complement to that in our body in the molecules of emotion if we don't have any words and images we don't have any molecules of emotion in the body and if we don't have any words and images we're actually fully paying attention to the moment which doesn't require any molecules of emotion the molecules of emotion are actually what happens in the gap in the mine screen in the gap between our presence our awareness of the present moment and when we move away from the present moment by thinking of something else and oftentimes we do that because we're not liking the present moment so these molecules of emotion are actually a way for us to sort of cope with the fact that we're not liking the present moment and we sort of pacify ourselves until we can get to that place where we like the present moment but most of time we don't move towards that even if we're having to think something pleasurable in order to get through that's showing us even though we're experience pleasure that's showing us we're using our energy in order to cope with the fact we can't pay attention to the moment we can't focus on the moment we can't be engaged with it because it's not right for us so the nervous impulses instead of being utilized for full perception attention in the moment which would be more bits of information that energy is transformed into words in terms of thoughts it's diverted to words instead of continuing to flow to meet the present moment as it is and then because this energy isn't fully meeting the present moment and we're creating these words which are creating these molecules of emotions dopamine and everything in the physical body that's using up our nutrients to make those molecules of emotion not only that what the bleep do we know talks about how when we up regulate our receptors on our cells for emotional molecules we actually are not able to absorb nutrition because we have way more receptors for the molecules of emotion that were addicted to so because we're addicted to these emotions were not actually absorbing proper nutrition and then it would make sense that our health sort of declines from there and that could even be you know a certain emotion is what causes a certain medical problem and just pops into my mind that that's probably what Louise Hay figured out when she developed affirmations to heal certain pathologies and it's interesting that I'm extrapolating this now because I talked about who knows when but I talked about videos and videos ago about how I feel like maybe we don't really need as much nutrition as we think we do and we think we need more nutrition because we think because we have this voice in our head that's creating these molecules of emotion that's making ourselves addicted to these emotion and and and wanting these images it starts to create those images in our mind to get that emotional fix so it creates those images on our mind makes that salient or makes things salient out in reality so will perceive it in order to get our emotional fix of that particular emotion and then that overrides the nutrition uptake in the cell so we need nutrition to make the molecules of motion the nutrition is blocked from getting in the cells because we're creating more receptors for the molecules of emotion which would also take nutrition and we also need to break down and recycle these molecules of emotion which takes nutrition and I feel like if we're able to have new perceptions it's going to be creating new receptors and new molecules of emotion and that's going to require different nutrition or takeaway Nutrition and different way so we could get depleted and dr. Abram Hoffer talked about how a lot of supposed mental illness as a perceptual disorder and it could be that we're not getting the right nutrients for these other perceptions I'm not sure how that works but I'm sure something will come to me how that works this there's some kind of new nutrition that's needed and it could be something to do with the gaps diet could be something to do with ketogenic diet it could be something to do with i'm not sure what kind of diet it could be that these new perceptions these new meanings and new things people see that are maybe out of the ordinary it could be almost deemed hallucination or delusion that perception is the selective pressure to create epigenetic changes or maybe even genetic engineering gene changes to create genes to help a person to be able to perceive that without utilizing all ones nutrients so it could happen for a short period of time and the nutrients get used up but then eventually what might happen is a new gene or something gets created there's another enzyme that maybe recycles some of the nutrition related to that process or or combine some of the nutrition to make those perceptions more stable more mirrored within the physiology of the human being so if something is seen and it's there's no real compliment for it in the body then it could be seen as scary and something other than something we're meant to perceive so I think there could be some that we're needing to create perceiving differently would produce different biomolecules would produce different metabolites and maybe the liver doesn't have an enzyme for those metabolites so maybe an enzyme needs to be sort of created through this perception of the need for it to be created it could also be trying to write over the dopamine circuits so so much of our our nutrition could be going towards the dopamine circuit and all of a sudden that's being withdrawn and it could be sort of a freak out like a withdrawal reaction to the dopamine as well and then we go back to needing that again because all societies design that way so where it's designed to perceive these dopamine reflex things as opposed to perceive these otherworldly things if we could always be having new and mysterious experiences and not get freaked out by them that would actually be quite rewarding it would be like the best video game ever and if we weren't wasting the energy and the molecules of emotion we would have more energy in our nervous system that neural electricity wouldn't be wasted as neuro chemistry when we're not emoting based on the dopamine gauge we are engaged and then our whole body heart mind seeing is the gauge we're not thinking in terms of good bad based on past program thoughts that aren't even our own we're actually perceiving based on how we're sensing our body is reacting in the moment and I think that's part of the thing when we decouple from the ego dopamine programming all of a sudden our body is so sensitive that we could almost turn and run from something that we find fearful and that's sort of not really considered a proper behavior in our society it would be like talk your way out of the situation politely if we had that sense but it would be felt so strongly like get me out of here now and so one would just kind of run and everyone's sort of going about their day doing something that's not quite right for them and so it makes sense that over time a certain number of people will just sort of run away and feel like oh my gosh get me out of this now and the dopamine ego thought voice is abstracting about reality when we're abstracting about reality with creating molecules of emotion because we're abstracting and comparing it to the false me relative to the me relative to the me this makes me feel good relative to the me this makes me feel bad and so we're just always vacillating like that back and forth and we are using our whole nervous system for nervous words four words of fear when the system is supposed to be powerful it's about power it's about our power thinking we are this me this internal structure this feeling inside is like thinking our body is our shadow our bodily shadow is a phenomena of the Sun hitting our body and not going through it and it produces a shadow and our inner sensation of our ego is like the light of consciousness hitting our thoughts and creating this inner shadow that we think is an ego the light of consciousness is always hitting the stream of thoughts and it's creating this this shadow like structure inside that we take to be real perceiving differently creates a different reality and is trying to create the genetic changes for one to hold ecstasy Krishnamurti often says when you see the danger of thought or when you see a danger you pull away like it's a poisonous snake you don't argue you don't sit and think about it it's just a reflex and I feel like that's what's happening lately is that certain things make my body react inside like perhaps I just saw a snake we make ourselves into habits so we can live up in our head creating dopamine rewards while living mediocre lives it's easy to delay action when one is getting micro rewards in terms of dopamine moment to moment instead of living in the moment and responding to the moment instead of reacting to dopamine we want to make habits so we don't have to be present so we can get the presence of dopamine and this is the gap I feel like this is the gap between being in the moment and and not is these emotional rewards and living in the present is a kaleidoscope of sensitivity and the chrysalis of mount consciousness is trying to break the dopamine prison and it feels confusing all these sensations and all this newness which is really what it is to be alive not just sensing a few different emotions the same ones every day the ego perceptual apparatus is myopic otherwise we have a vast expanse of worldcentric consciousness which can take many different perspectives I was thinking about dissociation because I have dissociated a number of times and I'm wondering if i dissociate from the ego or if I'm just associating or trying to associate with something else with with empathy and I want to focus more on the ability shun aspects the empathy the understanding I feel like this transformation is like an inner earthquake an inner storm and even when I'm feeling these sensations that aren't super comfortable I notice that my heart is beating differently it's being stronger it's it's shaking everything inside whereas if I'm in a calm state I don't really feel my heartbeat at all so what kind of is an inner earthquake in a way it's almost like a a sonar in a way to because as I get closer to something that I could run into or that could maybe hurt me in some way it beats faster and stronger just like a sonar the closer you get to it it beeps faster because the sound is bouncing back to you quicker so in that same way i think the heart be like that is a bit of a sonar it's a sensor for sure i wrote that our free will gifted by God has been hijacked do unto others as you would do unto yourself but you have free will and that pretty much means what we do unto others we will do unto ourselves but we generally don't feel it because of this dopamine emotion pleasure reflex so that's blocking our perception of what we're actually doing and that it's also being done to us and when we become sensitive we sense that and so it makes it a little bit more difficult to navigate and it takes a while to find a way to be heart centered because we sense things that we've done or other people have done and things like that it's like experiencing Karma and it might be better to experience karma in this life now versus waiting to next life it's kind of painful to feel oneness in this life because we're one with whatever arises not having all these pleasure and pain responses inside conceptualising about what's arising and completely missing meeting what is actually arising and that delay just adds up over time and that's what probably creates the allostatic load is not being in the moment to meet the moment and then we've when we finally are in the moment to meet the moment all of this stuff comes flying into the moment that we've been dragging around for so long like oh you're in the moment now well let's process all these moments that you missed and all the moments that we master represented in those emotions and in the body and those molecules of emotions and those molecules of emotions imprint probably on our cellular memory with the molecule plus the sound of our voice in her head imprinted on ourselves and then that starts to come out of cellular memory and a rise in consciousness and it's not just our lifetime but previous lifetimes as well as our our relations and her grandparents and everything when i did my talk somebody told me to patent this app strap idea and i was thinking it could have like a panic button it could have like positive affirmations it could have a little baggie for once p RN to take to stay conwell zap strapped it could I could have a GPS locator and a picture of one's favorite person and like fluff or on the inside so one doesn't hurt one's wrist probably pulling on it once one starts to freak out once zap strapped and it's sort of like how not to kill yourself and somebody also suggested having a medical alert bracelet saying no long-term antipsychotics it gives me an a cast reaction since that's what has happened to me being on antipsychotics for greater than a few weeks and I haven't really talked about eye contact but I think I contact is something that's important I read once something about in the light of a loving I so somebody can be looking with like as a mean I and evil eye or looking with a loving I and I think I might have talked about how I've seen people change into their most beautiful light body self right in front of my eyes like one moment they're just like no it's going to take a long time barely make eye contact and then and then all of a sudden they just transform into this like fabulous version of themselves and even though they're working as a cashier in 7-eleven they're just the most flamboyant and beautiful and magnificent lovely energetic being and then elves and proof their back to their tired old self and it was really strange and that's why I think there's like this adjacent reality that we can step into it's like though it's like the reality of light and miracles and magic but none of us believed in magic so we we abide in this material linear logical society because that's the prevailing consciousness but our consciousness can touch into that and it starts to compute in that way but then if our brain is transformed into computing in that way into computing quantumly and holographically and magically and then we come back here it's sort of short circuits because it's like it's like putting an iphone in water it's not the right medium it's too dense and I was talking about how I was talking to an acquaintance friend of mine and we talked for about an hour and then I felt a lot better that anxious energy went away so dose of that person for an hour made it go away and there are studies that positive people without medication is more powerful than negative people with medication and then positive people with some medication is the most powerful in that study so the effects of medication then around negative people would be negated there'd be no point there needs to be positive people and so in a way if I'm on medication but I'm isolating myself and I'm not really around people so much I'm not being relational it's going to make the medication not really very effective because it's not a replacement for people and being relational and and I was thinking how about in the psych ward when I was feeling terrible on that medication and somebody I knew came and visited me for 10 minutes and all of a sudden that I felt way better that was more powerful than the medication the medication wasn't working that person visiting me for 10 minutes worked and then I was in the process of being tapered off that medication it wasn't helping me and it actually made it so I was able to complete that taper off that medication because it wasn't helping me at all but that person gave me that jumpstart jump-started my brain cells and got me connected relationally in order to be able to journey off that medication and I had a good connection with this person so strong connections are more powerful especially when a person comes in has just unconditionally loving and supportive and just there to visit and say hi if somebody comes in and there's a strong connection they come in worried and with that sort of I it's not going to help it's going to be detrimental and the relational meshwork of a person is like an invisible spider web and it's strengthens the person that helps with the reconnecting as well Get bonus content on PatreonSupport this show http://supporter.acast.com/bipolar_inquiry. See acast.com/privacy for privacy and opt-out information.

The Future of Genome Editing with Professor David Liu

The architect of base editing and prime editing, Harvard University chemist David R. Liu, recalls the genesis of the technology and discusses exciting preclinical results and potential future applications. {Sponsored by Pegasus Books}

CRISPR is a powerful editing tool, but it works best as a way to knock out genes rather than correct them. New approaches to gene editing, though, are providing the promise of more effective tools for addressing the underlying drivers of monogenic diseases. A recent study in Nature of an approach known as base editing in a mouse model of the ultra-rare genetic condition progeria, a disease that causes premature aging, demonstrated the powerful potential of the approach. While CRISPR has been likened to scissors, base editing has been compared to the find-and-replace function of a word processor. We spoke to study leader David Liu, director of the Merkin Institute for Transformative Technologies at the Broad Institute, about base editing, how it works, and why it may offer the potential to treat a wide range of rare diseases. This episode is part of an occasional series on innovations in gene editing and gene therapy.

When we’re coming down with a cold or are feeling a bit stressed, or perhaps even exhibiting the first symptoms of COVID-19: minute changes to our voice are often one of the first indicators that something is wrong. These vocal biomarkers are often beyond what a human can detect: but what if an app on your phone could? Health reporter Michelle Fay Cortez recently spoke to David Liu, CEO of Sonde Health, which has released an app that uses a person’s voice to detect early symptoms of respiratory illnesses, including COVID-19. She explores what vocal biomarkers can tell us. 

David Liu is an award-winning virtual and augmented creative director and executive. Sarah and Kathleen kick off their exploration of art + technology by chatting with David about his creative work, virtual music experiences, holograms and more.  Links David's website: https://www.davidshiyang.com/ David's twitter: https://twitter.com/thedak Podcast website: https://www.amplifiedpod.com/

Quick links falados na News: Evento Comunidade: Pergunte ao David Liu: https://trailblazercommunitygroups.com/salesforce-women-in-tech-developers-group-virtual/ Matéria: 7sherpas trilha novos caminhos e encanta os clientes com a Salesforce: https://www.salesforce.com/br/customer-success-stories/7sherpas/?utm_source=linkedin&utm_medium=organic_social&utm_campaign=latam_cbaw&utm_content=101+Explainer+Content%2CCustomer+Engagement%2CDigital+Transformation%2CImage%2CIT%2CLATAM%2CLink%2CPortuguese+%28Brazilian%29 Aplicativo Heroku: LWC Generator: https://lwc-generator.herokuapp.com/ https://drive.google.com/file/d/1yJ9wHL9MCfBzhhkM2HsftqXhbbGjMf_V/view Matéria: 4 formas para aumenta produtividade em um time de vendas remoto: https://www.salesforce.com/in/blog/2020/06/4-ways-to-improve-productivity-in-a-remote-sales-team.html?utm_source=linkedin&utm_medium=organic_social&utm_campaign=amer_cbaw&utm_content=360%2CAMER%2CBlog%2CEnglish%2CHow-to+Subject%2CLink%2CSales Matéria: FlowRepublic - Cenário Prático CTA: https://flowrepublic.com/robo-santa Matéria: 12 livros para ler em 2021, de acordo com CEOs brasileiros: https://administradores.com.br/noticias/12-livros-para-ler-em-2021-de-acordo-com-ceos-brasileiros Grupo Telegram: https://t.me/joinchat/PcLKnBgy7hK0Jn8LVAU_3w --- Send in a voice message: https://anchor.fm/podcastsalescast/message

David Liu, Founder and CEO of Deltapath, the leading unified communications company joins Enterprise Radio to break down the best phone systems and technology for managing a global or remote workforce.  The post Demystifying Business Communications appeared first on Enterprise Podcast Network - EPN.

pomeさんをゲストに迎え、ボストン界隈を中心としたCRISPR関連のバイオスタートアップについて話を伺いました。Show notes Top CRISPR Startup Companies Changing the Future of Biotech and Medicine … CRISPR関連スタートアップまとめ Researchat.fm, ep76 … ゲノム編集特集回 Researchat.fm, ep77 … ゲノム編集特集回 Researchat.fm, ep2 … CRISPR特集回 Researchat.fm, ep77 Researchat.fm, ep47 … SHERLOCKについて話しました。 Boston MIT … マサチューセッツ工科大学。Kendall Station近くに位置する。厳密にはボストン市ではなく、ケンブリッジ市である。 Harvard University … ハーバード大学。こちらもメインキャンパスはケンブリッジ市。Oxford Stに位置する建物もあるため、Oxford St., Cambridgeと住所的には何が何だかわからないところもある。 Boston University … BU University of Massachusetts … UMass Tufts University Berklee College of Music … いつもバークリーなのかバークレーなのかわからなくなる。有名な音楽学校。 NOVARTIS Takeda Biogen Bayer Cell Press … いわゆるCell誌。MIT,ハーバードの目と鼻の先にある。 カリフォルニア州 マサチューセッツ州 ニューヨーク州 ニュージャージー州 Akamai Feng Zhang David Liu Researchat.fm, Ep60 … 培養肉などについて話しました。 GMO …Genetically modified organism Plantedit FAD2 Solive … by Plantedit spCas9 Cas12 Cas13 Inscripta mad7 nuclease Unreal Engine Unity C4U BioPallete Cas3 モダリス Beam Therapeutics Researchat.fm, ep22 … Base editorやTarget AIDについて話しました。 in vivo ex vivo 鎌状赤血球 CRISPR Therapeutics 造血幹細胞 CD34+ ヘモグロビン BCL11A eGenesis Bio George Church 胚盤胞置換法 Living cell technologies (LCT) Diatranz Otsuka CAR-T レンチウイルス AAV HIV ゾルゲンスマ TLO … Technology License Organizationの略 Wyss Institute Wyss Instituteのポッドキャスト … めちゃくちゃ良い。tadasuはリピートしまくって聞いている時期が度々ある。 Peng Yin Researchat.fm, ep74 … DNA Origamiについて話しました。 Cambridge Innovation Center (CiC) Venture Cafe Venture Cafe Tokyo … 虎ノ門ヒルズ内にある。木曜日にイベントをやっているようです。 CiC Tokyo … 虎ノ門ヒルズ内にある。 Cambridge City, MA … ケンブリッジ市 スタンフォード大学のパテントに関する資料 … Stanford UniversityのOTLによる資料。 lab central Johnson & Johnson Roche Job Description 四行教授 … とあるブログ様を引用させていただきました。当時修士のtadasuに四行教授や「履歴書を汚せ」と説いた人物は黒川清先生です。 Researchat.fm, ep75 … I’m not sure though. Editorial notes とっても楽しいおしゃべりでした。仕事と関係ないマニアックな話をできる場はあんまりないので貴重です。またやりましょう。(pome) 後編もお楽しみに〜 (soh) 同じ地区に住んでいるのに何にも活かせていません…(tadasu) (coela)

dessanをゲストに迎え、CRISPRの仕組みを利用した様々な技術や遺伝子回路、これからの発展について話しました。Show notes The Nobel Prize in Chemistry 2020…The Nobel Prize in Chemistry 2020 was awarded jointly to Emmanuelle Charpentier and Jennifer A. Doudna “for the development of a method for genome editing.” Scientifc Background on the Nobel Prize in Chemistry 2020 A TOOL FOR GENOME EDITING…ノーベル財団による詳細なCRISPR研究のレビュー、そしてなぜDoudnaとCharpentierの二人が受賞に値するのかについて説明している。 76. The Chimeric RNA, Researchat.fm…ゲノム編集についてdessanをゲストに迎えて話しました。 A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity. Science 2012…CharpentierとDoudnaによるノーベル賞につながる論文の一つ。CRISPR–Cas9システムがこの論文によってその大枠が明らかにされた。 Multiplex Genome Engineering Using CRISPR/Cas Systems. Science 2013…Feng Zhang labによるヒト細胞におけるゲノム編集技術の報告。 RNA-Guided Human Genome Engineering via Cas9. Science 2012…George Church labによるヒト細胞におけるゲノム編集技術の報告も同時に掲載された。 First rounders: Feng Zhang (Podcast)…Feng Zhangが出演したNatute Biotechnologyのポッドキャスト。おすすめです。 26. Cool tech googlability, Researchat.fm…RNAを標的にできるCas13bについては、エピソード26で紹介しました。 Cas14 (crisp_bio)…“Cas14は、PAMに依存しないssDNA切断活性に加えて、PAMに依存するdsDNA切断活性も帯びている” CasX enzymes comprise a distinct family of RNA-guided genome editors. Nature 2019…CasX Transposon-encoded CRISPR–Cas systems direct RNA-guided DNA integration. Nature 2019…トランスポゾン型のCasシステムの報告。 RNA-programmed genome editing in human cells. eLife 2013…Doudna labによるヒト細胞におけるゲノム編集技術の報告。FengやChurchらよりも少しだけ遅かった。 Microhomology-mediated end-joining-dependent integration of donor DNA in cells and animals using TALENs and CRISPR/Cas9. Nature Communications 2014 Ep52. Split into a row Double Nicking by RNA-Guided CRISPR Cas9 for Enhanced Genome Editing Specificity. Cell 2013…Double nicking (2つのgRNAとCas9 nickase)によるより正確なゲノム編集方法が示された。 Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex. Nature 2015…Cas9を用いた転写の活性化手法。 Live visualization of chromatin dynamics with fluorescent TALEs. Nature Structural & Molecular Biology 2013 … TALENを用いた染色体の特定領域のイメージング方法 Dynamic Imaging of Genomic Loci in Living Human Cells by an Optimized CRISPR/Cas System. Cell 2013…dCas9-EGFPによる生細胞のイメージング技術。SpCas9の場合は、D10AとH840Aの２つの変異を入れることで、DNAに結合するが切断しないdead Cas9 (dCas9)として利用することができる。 Live cell imaging of low- and non-repetitive chromosome loci using CRISPR-Cas9. Nature Communications 2017…ガイドRNAにMS2 loopをたくさんつなげることで (14個!)、明るい輝点を得ることができる。 CRISPR-mediated live imaging of genome editing and transcription. Science 2019…こちらは蛍光標識したガイドRNAを利用した生細胞イメージング方法。 A protein tagging system for signal amplification in gene expression and fluorescence imaging. Cell 2014…Sun tagとCas9を用いたイメージング方法。 Split Green Fluorescent Proteins: Scope, Limitations, and Outlook…Split GFP Programmable RNA tracking in Live Cells with CRISPR/Cas9. Cell 2016…PAMmerによるSpCas9のmRNAイメージング CRISPR-Mediated Programmable 3D Genome Positioning and Nuclear Organization. Cell 2018 … CRISPR-GO：CRISPR技術、核内でのゲノム空間構造、ポッドキャスト内ではゲノム同士を寄せるという説明をしていましたが、今調べてみると特定のゲノム領域と核膜やカハール体への再配置ということでした。 Manipulation of nuclear architecture through CRISPR-mediated chromosomal looping. Nature Communications 2017 … こちらがCRISPRの仕組みを用いることで人工的に染色体内部にループを作成した論文。 Transcriptional repression mediated by repositioning of genes to the nuclear lamina. Nature 2008 … LacO-LacIの仕組みを用いることでゲノムの特定領域にLacO arrayを差し込み、核膜に局在させたLacIに結合させることである遺伝子領域を核膜側に誘導しようとした論文。最初にこの論文を読んだ時はそのアイデアにたまげました。 9. One-shot beautiful experiment (Researchat.fm)…人工的なDNA領域へ細胞内の情報（細胞系譜）を書き込む技術についてエピソード9で話しました。 CRISPR–Cas encoding of a digital movie into the genomes of a population of living bacteria. Nature 2017…George Churchらは、Cas1-Cas2システムによって馬の動画をバクテリアゲノム書き込み、それを読み出すことに成功した。 Multiplex recording of cellular events over time on CRISPR biological tape. Science 2017…コピー数の異なる2つのプラスミドをCas1-Cas2で取り込ませて、細胞内で人工的な時計のような仕組みを実現した。 Single-Nucleotide-Resolution Computing and Memory in Living Cells. Molecular Cell 2019…Tim Liu Labによる複雑な遺伝子回路の実現。DOMINOについては、プロモーター配列を標的にしているのではなくオペレーター配列でした。 Rewritable multi-event analog recording in bacterial and mammalian cells. Science 2018…David Liu labから報告されたガイドRNAによって連鎖する遺伝子回路（カスケード）の実現。 Terminal Deoxynucleotidyl Transferase, TdT…テンプレートに依存しないDNA合成を可能にする酵素。 Tandem fluorescent protein timers for in vivo analysis of protein dynamics. Nature Biotechnology 2012…GFP Timer Permanent genetic memory with >1-byte capacity. Nature Methods 2014 Continuous genetic recording with self-targeting CRISPR-Cas in human cells. Science 2016…自分で自分のガイドRNAを編集することで、理論的には無限に情報を書き込む方法が提案されたが、領域が壊れてしまう問題もある。 Ten Simple Rules to Win a Nobel Prize. ヘンリー・ブラッグ (Wikipedia) iPS細胞 (Wikipedia) 国境なき医師団 Human Genome Project Xiaowei Zhuang Expansion microscopy (Wikipedia) Renato Dulbecco (Wikipedia) Programmable RNA editing by recruiting endogenous ADAR using engineered RNAs. Nature Biotechnology 2019…LEAPER crisp_bio … 世界広しといえでも、これだけCRISPRの最新情報がまとまっているサイトはCRISP_BIOさんの他に世の中には存在しません。日本語でCRISPRの最先端情報を追える喜び。CRISP_BIOさん、いつもありがとうございます。 Editorial notes 1分でわかるとか無理なのですが、一方で言葉を尽くせばわかる可能性についても同時に信じておりますので…(soh) 思い出しながらどんどん話しているので、後から聞き返すと細部が間違っていたりしています。気になった方はshow notesをご参照ください。(dessan) いい感じのグルーヴがみられてよかったです。ポッドキャストやってきてよかったです。(tadasu) 最初に喋らんと出番が無くなる！と思ってこれまでの流れをまとめてみたんですが細かく色々ミスってました…(coela)

Todas as terças-feiras, um episódio cápsula de até 30 minutos. No quadro De Carona no Jatinho, Thaís contará histórias de celebridades e executivos famosos que têm sucesso nas mais diversas áreas do mundo dos negócios. Nesse episódio Thais conta a história do casal Carley Roney e David Liu que, de sua festa de casamento desastrosa, viram uma oportunidade de negócio e acabaram fundando a The Knot, para ajudar noivos a organizarem seus casamentos. Uma história sobre querer inovar, dar um olhar moderno à um mercado ultra tradicional, e como construíram uma sociedade e casamento de sucesso. Delicia de história, para começar bem a semana. O mapa do sucesso do casal contado aqui. Dá o play! Toda semana tem novo episódio no ar, pra não perder nenhum, siga: https://www.linkedin.com/in/thaisroque/ ||| www.instagram.com/thaisroque Tema do episódio: https://www.instagram.com/theknot/

David Liu is a Salesforce technical architect at Google. He began his career as a Salesforce developer and ended up at Google in his dream job. Throughout his career, he’s learned a lot about success and what it actually looks like. He’s also helped many others through the interview process. In this episode, David shares his story with us. He reveals his failures and how they brought him to where he is today. He also gives a peek behind the curtain into Salesforce careers. Listen in to hear his unique insights.   Show Highlights: How to frame questions to discover how people are thinking about their job. The things he looks for in the people he interviews. What his website, Salesforce for the 99%, means. The importance of targeting a really small niche in marketing. How to frame technical content for non-technical people. His encounters with imposter syndrome. The role of failure in coming through a career.   Links David on Twitter: https://twitter.com/dvdkliu David on LinkedIn: https://www.linkedin.com/in/dvdkliu/ sfdc99: https://www.sfdc99.com/   *** EPISODE CREDITS: If you like this podcast and are thinking of creating your own, consider talking to my producer, Danny Ozment. He helps thought leaders, influencers, executives, HR professionals, recruiters, lawyers, realtors, bloggers, coaches, and authors create, launch, and produce podcasts that grow their business and impact the world. Find out more at https://emeraldcitypro.com 

Jennifer Doudna and David Liu talk with our Senior Editor Markus Elsner about the state of the genome editing field and what challenges remain, especially as various therapies are now entering the clinic. This episode is part of Nature Biotechnology's Focus issue on CRISPR tools and therapies. See acast.com/privacy for privacy and opt-out information.

Peter Wang, CEO and Co-Founder of Anaconda, explains the series of happy accidents that have led to organic adoption of Python as the number one language among developers in data science and machine learning in this episode of Code Together. He and David Liu, an AI Solutions Engineer at Intel, talk about the latest advancements […]

Peter Wang, CEO and Co-Founder of Anaconda, explains the series of happy accidents that have led to organic adoption of Python as the number one language among developers in data science and machine learning in this episode of Code Together. He and David Liu, an AI Solutions Engineer at Intel, talk about the latest advancements […]

Peter Wang, CEO and Co-Founder of Anaconda, explains the series of happy accidents that have led to organic adoption of Python as the number one language among developers in data science and machine learning in this episode of Code Together. He and David Liu, an AI Solutions Engineer at Intel, talk about the latest advancements […]

David Liu is the founder and CEO of Deltapath, a leading  communications company whose innovative technology helps businesses  collaborate internally and with customers in a work culture that  increasingly revolves around smartphones and other personal devices.  Under David’s leadership, Deltapath’s solutions have been adopted by  brands such as Campbell’s, Volkswagen and Nokia in 94 countries. At 14, David began  exploring telecom technology with his home telephone and hi-fi radio. He  connected the two to mimic enterprise system features such as  music-on-hold, call recording and radio broadcast over the telephone  line. As the internet grew in significance, he was determined to bridge  traditional telephone technology with the new network. He founded Deltapath in 2001. In this episode, Jamie talks with David about the challenges of being an entrepreneur, some words of advice he received from ZOOM founder Eric Yuan, his predictions on a post-COVID economy and how his international experience has helped his business.  Please consider leaving a rating and review on your favorite podcast platform. Tell David and Jamie what you think about this  episode.   www.bigideabigmoves.com   Need Help Getting Back to Work? Visit:  https://mailchi.mp/f53826f39bca/careercoaching  JazzHR - awarded the most UserFriendly ATS  https://www.jazzhr.com/?utm_source=partner-epitomehr.

A few weeks back David Liu -- Creative Director at AFVR.co, a virtual reality consulting firm,  and formerly the Creative Director of Viacom Next and recently with the volumetric capture company The Lightframe Co. in NYC -- who tweets under the handle TheDak posted an interesting thread-- which David now refers to as “that thread” about the state of hiring practices in XR. David and I are Twitter friends. I like the cut of his jib. He's got a ton of experience, and he champions the multi-disciplinary approach to team building in XR, the most tech-heavy part of the overall immersive entertainment industry.  We start out on the thread, but this is No Proscenium, so we go all over the place. Especially because David and I have never really chatted before. I love it when these kidneys of episodes work out. I do, however, talk too much. Shock. Plus: a few words about the current cultural moment(s) we find ourselves in at the top of the show from yours truly. -Noah J. Nelson

Today, we are joined by a panel of leading medical professionals who recently formed the group Scientists to Stop Covid 19:Doctors David Liu, Michael Rosbash,Stuart Schreiber, Ramnik Xavier and Edward Skolnick  come from different disciplines and research areas, but have united behind this effort to help policymakers develop a comprehensive and science based approach to stop this virus.  Today, they will discuss promising treatments for COVID-19, including Remdesivir and various Monoclonal antibodies, as well as the timeline for a possible vaccine. The Scientists to Stop COVID-19 discuss both the promise and the pitfalls of various treatment options. Remdesivir, originally developed to treat Ebola, has been used with some success to combat COVID-19, but requires 5-10 days of IV administration, making it inaccessible for those at home. That’s partly why these scientists see more promise in monoclonal antibodies, which use the body’s own immune system to block the virus’s ability to regenerate in the body. Finally, of course, there is the vaccine route and these scientists see potential for a vaccine to be available by the end of the year.Go to NoLabels.org to learn more about how we are bringing together a bipartisan group of public and private leaders working to stop the virus, save lives and get Americans back to work.

Tonya Hall sits down with Dr. David Liu, vice chair of the faculty at the Broad Institute of Harvard and MIT, to learn more about the latest developments from MIT researchers in gene-editing technology, which offers word processor-like precision with search and replace. FOLLOW US  - Subscribe to ZDNet on YouTube: http://bit.ly/2HzQmyf - Watch more ZDNet videos: http://zd.net/2Hzw9Zy - Follow ZDNet on Twitter: https://twitter.com/ZDNet - Follow ZDNet on Facebook: https://www.facebook.com/ZDNet - Follow ZDNet on Instagram: https://www.instagram.com/ZDNet_CBSi - Follow ZDNet on LinkedIn: https://www.linkedin.com/company/ZDNe... - Follow ZDNet on Snapchat: https://www.snapchat.com/add/zdnet_cbsi Learn more about your ad choices. Visit megaphone.fm/adchoices

On this episode, we are pleased to welcome Jessica Murphy to the show. We talk about Jessica's journey into discovering developing with Salesforce and the influence others have had on that experiences - as well as sharing those experiences with Salesforce Saturdays. She is a co-conspirator of Salesforce Saturdays in Phoenix since 2015 with two other women with the goal of helping other developers find success. Salesforce Saturdays occur around the country to various coffee shops and sometimes office locations, as a casual environment to educate and empower people. Their success stories are amazing, as some people have attended Salesforce Saturdays and then gone on to accomplish their goals. They also encourage people to give back. For example, they had a Salesforce Saturday attendee come back to hire others at a Salesforce Saturday when he was looking for employees. There are always new people who want to learn Salesforce, so it is an exciting environment, and all are welcome. Just come - you don’t need any special qualifications! The door is open for you to join a Salesforce Saturday near you. Show Highlights: Jessica’s journey to becoming a woman in technology The profound influence education has had on her life and the confidence it has given her Introduction to Trailhead, and how it ties into your commitment to making yourself better The opportunities present through Salesforce that have had an amazing impact on Jessica People learn things different ways, so there are various hurdles to learning Salesforce The evolution, impact and growth of Trailhead and all the options available that it is supporting Ways you can participate in Salesforce Saturday. Your help is valuable! Everyone is a leader in this group setting and we support each other Resources: Jessica Murphy on LinkedIn:https://www.linkedin.com/in/jessicarmurphy/ Jessica on Twitter: https://twitter.com/jessicarmurphy Salesforce Saturday HomePage: https://www.salesforcesaturday.com/ Salesforce Saturday on LinkedIn:https://www.linkedin.com/company/salesforce-saturday The many shout outs for this episode: Sheena Smith: https://twitter.com/sheenapsmith Rachel Watson: https://twitter.com/TheRachelWatson Paula Nelson: https://twitter.com/ThatDarnWoman Bonny Hinners: https://twitter.com/snugsfbay Steph Herrera: https://twitter.com/steph_herrera_ Shonnah Hughes: https://twitter.com/saasy_sistah Nadine Lisbon: https://twitter.com/nadina_codes Tami Lau: https://twitter.com/tami_ell Brian Kwong: https://twitter.com/Kwongerific Jen W Lee: https://twitter.com/jenwlee Chris Duarte: https://twitter.com/thechrisduarte David Liu: https://twitter.com/dvdkliu   *** EPISODE CREDITS: If you like this podcast and are thinking of creating your own, consider talking to my producer, Danny Ozment. He helps thought leaders, influencers, executives, HR professionals, recruiters, lawyers, realtors, bloggers, coaches, and authors create, launch, and produce podcasts that grow their business and impact the world. Find out more at https://emeraldcitypro.com 

When you think of Salesforce development, for a lot of people, one name springs to mind. David Liu. Based in San Francisco, he was speaking at Down Under Dreaming in Brisbane recently, and so we took the opportunity to record this chat with him, live from the event. David famously taught himself to code, and is now a Technical Architect at Google, with the CTA held firmly in his sights. As a result of his own experiences, David founded a very successful and renowned blog and resources hub, SFDC99, which has visitors daily from all over the globe, benefitting from his easy to follow tutorials. He explained to us, and the audience at Down Under Dreaming, that absolutely anybody can teach themselves to code, and more importantly perhaps, why he thinks that they should. Since his first steps of teaching himself Apex, David has been awarded Salesforce MVP status six times, as well as the inaugural Salesforce Developer Golden Hoodie at the 2018 Dreamforce, and has 17 Salesforce certifications under his belt to date. In this podcast, we discuss his views on Salesforce development, the Admin/Dev hybrid role, what he looks for when he's interviewing talent, and his top pieces of advice for those considering a move into the Salesforce industry. You can follow David on LinkedIn at https://www.linkedin.com/in/dvdkliu/and Twitter at @dvdkliu, and of course, check out his website, SFDC99.

In this episode of the China Tech Investor Podcast powered by TechNode, the guys welcome David Liu, VP of Strategy for Pinduoduo. David talks about PDD’s success in breaking into the ultra-competitive e-commerce market in China, and how they have defied expectations in both their ability to raise capital and grow their user base.Since this is the first time that the guys have had on a representative from a company on their watch list, they’d love to hear from listeners about what they think about this approach. Feedback is welcome, as always! Please note, the hosts may have interest in some of the stocks discussed. The discussion should not be construed as investment advice or a solicitation of services.Get the PDF of the China Consumer Index.Watchlist:TencentAlibabaBaiduiQiyiXiaomiJDPinduoduoMeituan-DianpingGuestDavid Liu, VP of Strategy, PinduoduoHosts:Elliott Zaagman– @elliottzaagmanJames Hull– @jameshullxEditorPeter IsachenkoPodcast information:iTunesSpotifyRSS FeedMusic: “Hey Ho” by Steve Jackson, Royalty Free Music 

When Carley Roney and David Liu got married, they had a seat-of-the-pants celebration on a sweltering Washington rooftop. They never planned to go into the wedding business, but soon saw an opportunity in the market for a fresh approach to wedding planning. In 1996, they founded The Knot, a website with an irreverent attitude about "the big day." The Knot weathered the dot.com bust, a stock market meltdown, and eventually grew into the lifestyle brand XO Group, valued at $500 million. PLUS in our postscript "How You Built That," we check back with Tyson Walters who got so tired of his St. Bernard shedding everywhere that he created a zip-up body suit for dogs: the Shed Defender.

David Liu joins to talk about the personal branding. He is a six-time Salesforce MVP, the inaugural Salesforce Developer “Golden Hoodie” award winner, 20x Dreamforce, Salesforce webinar, and Salesforce user group speaker, 16x Salesforce certified Main Points Intro to David and SFDC99 01:20 – About Me02:31 – Why did you start SFDC99?03:20 – What are the most popular pages on SFDC99?04:32 – Why do you not like your two most popular pages?05:52 – Looking back at SFDC99’s success06:07 – What is David Liu’s brand?07:24 – What do you NOT like about some blogs?07:55 – Are certifications being abused in the industry?09:54 – The post 21. Personal Branding | David Liu appeared first on SalesforceWay.

This week’s Ask the Expert is with David Liu, who is Founder and CEO at Deltapath. Deltapath is a leading unified communications technology company driving business collaboration. In his role, David oversees the company’s vision, strategy, and growth. As well as this, David is responsible for spearheading their technical strategy. What’s more, David led the development of the company’s SIP-based telephone system. In this podcast, David lends his expertise to outline trends in the workforce. Specifically, he explores the different generations, their skill sets, and their different needs. Further to this, David delves into the specifics of attracting and retaining millennials. Finally, David discusses whether saving time actually means saving money. For information regarding your data privacy, visit acast.com/privacy (https://www.acast.com/privacy)

Host Jonathan Blackwood speaks with David Liu, CEO of Deltapath, about how technology is transforming to help organizations and employees – from baby boomers to millennials -- work smarter while staying protected.

While postdocs in David Liu's lab at Harvard University, Alexis Komor (UCSD) and Nicole Gaudelli (Beam Therapeutics) developed a pair of CRISPR-based molecular machines known as base editors, capable of engineering precise single-base substitutions with enormous basic research and therapeutic implications.

David Liu's office on the eighth floor of the Broad Institute in Cambridge, Massachusetts is designed to quiet the mind. A museum-grade gemstone collection lines the walls, interspersed with blue-tinged photos Liu has taken of inspiring science-on-location scenes—the concrete corners of the Salk Institute, a sunset through the Scripps pier, the lights of Durango, Colorado where Darpa often meets.

Many small businesses in the US are exporting to China today. David Liu, a Chinese who has lived and worked in the US for 30 years, and was a technical consultant in the IT industry, is exporting wine to China. He is one of the businesses that are planning to exhibit at the China International Import Expo in November 2018 in Shanghai. Why did David transit from his technology field to the wine business? How is he doing with his export business? What is the impact of the US/China trade war to his business? What is his plan? Please join me with David Liu to hear his thoughts about the trade and his small exporting business between US and China.

Many small businesses in the US are exporting to China today. David Liu, a Chinese who has lived and worked in the US for 30 years, and was a technical consultant in the IT industry, is exporting wine to China. He is one of the businesses that are planning to exhibit at the China International Import Expo in November 2018 in Shanghai. Why did David transit from his technology field to the wine business? How is he doing with his export business? What is the impact of the US/China trade war to his business? What is his plan? Please join me with David Liu to hear his thoughts about the trade and his small exporting business between US and China.

When Carley Roney and David Liu got married, they had a seat-of-the-pants celebration on a sweltering Washington rooftop. They never planned to go into the wedding business, but soon saw an opportunity in the market for a fresh approach to wedding planning. In 1996, they founded The Knot, a website with an irreverent attitude about "the big day." The Knot weathered the dot.com bust, a stock market meltdown, and eventually grew into the lifestyle brand XO Group, valued at $500 million. PLUS for our postscript "How You Built That," how Michael Dixon's business, Mobile Vinyl Recorders, uses portable record lathes to cut vinyl at parties, weddings, and music festivals.

Dr. David Liu, a Sociologist from HACC. We are going to discuss how the American Family has changed over the last 100 years and especially how politics has families divided.

Pilgrim Church first ever Q & A Session!

This week, the Inc. crew discusses how satellite company Spire is sending dozens of satellites into lower Earth orbit to collect data to sell to companies, examines how credit card "charge backs" are hurting small businesses, and interviews David Liu about how he and his wife Carley Roney founded the wedding website The Knot and took it public. Learn more about your ad choices. Visit megaphone.fm/adchoices

The UK science community draws vital benefits from EU membership and could lose influence in the event of an exit, says a House of Lords report out this week. UK researchers placed a high value on collaboration opportunities afforded by EU membership. A number also believe the UK would lose its ability to influence EU science policy in the event of leaving - something that's disputed by pro-Brexit campaigners. To debate the ins and outs of being in or out of the EU, Adam is joined by Viscount Matt Ridley, a member of the committee, and Professor Paul Boyle, the Vice Chancellor of Leicester University and former president of Science Europe. Scientists at Aarhus University in Denmark are developing a quantum computer. To help them solve a particular problem, they have turned to human brain power, harnessing our ability to play computer games. The team have designed video games, such as Quantum Moves - that are helping them to understand the problem of 'slosh'- that atoms move about, when moved, like water sloshing in a cup. Many diseases are caused by a particular type of DNA error called a 'point mutation'. In our genomes, the substitution of a single letter of genetic code can be the root cause of diseases such as Alzheimer's, sickle cell anaemia, and a whole range of cancers. Recently, a new technique for editing DNA, called CRISPR, a precise genetic engineering tool, was developed, which might help combat these diseases. The problem is that the cell often reacts to this editing; trying to mend what it perceives as damage to its DNA. This week, David Liu, from Harvard University, published new research showing how his team have managed to switch out a single letter, a base pair, whilst tricking the cell into not correcting this edit.

One of our Dreamforce episodes.  A wide ranging conversation with David Liu about sfdc99, architecture, software development and working at Google.

Continuation of our conversation from Part 2, including 'Bring your Parents to work' day and Google's free food :)

Interview with Dr. David Liu, Clinical Associate Professor in the Department of Radiology at the University of British Columbia in Vancouver. In their clinical practice guideline, Dr. Liu and colleagues provide recommendations on the diagnosis and management of deep vein thrombosis (DVT), including anticoagulation, thrombus removal strategies and inferior vena cava filters. The poor outcomes seen in patients with iliofemoral DVT treated with standard anticoagulant therapy have led to exploration of other treatment options. The prevention and treatment of post-thrombotic syndrome are also addressed. Full guideline (open access): www.cmaj.ca/lookup/doi/10.1503/cmaj.141614