Podcast appearances and mentions of Jennifer Doudna

Dana Foss and Ross Wilson are the cofounders of Editpep, a biotech startup focused on developing CRISPR-based therapeutics. They are using a proprietary peptide-based delivery platform that enables targeted delivery to specific cell types, particularly for hard-to-reach areas like the brain. While Dana Foss is the CEO, Ross Wilson is also an Assistant Adjunct Professor of Molecular and Cell Biology and also the Director of Therapeutic Delivery at the Innovative Genomics Institute at the University of California, Berkeley. He is one of those very few academics that co-founded a startup and is very active in building Editpep. Ross explains how he does it all so well! Dana was  previously a postdoc in Ross Wilson's lab, where she developed the technology. Ross was a postdoc in Nobel Laureate Jennifer Doudna's lab. Now he has his own lab and collaborates with Jennifer Doudna at the Innovative Genomics Institute.  In this episode of lab to startup, we will explore their initial decisions that lead to launching the startup; existing CRISPR delivery technologies, their challenges, and then do a deep dive into their delivery technology. opportunities,; fundraising efforts, and their future goals. Shownotes https://www.editpep.bio/ CRISPR Delivery problem and current solutions Existing solutions like AV, LNPs are mostly limited to mice Ribonucleoprotein, a complex of RNA and protein (RNP): Technology deep dive Outsiders bringing in fresh perspective Dana transitioning out of academia: working on a shared goal Hard to shepard the technology towards the patient by depending on a third party Self motivation and gumption: Ways to move technologies out of the lab Early stage co-founder chemistry Ross's innovative role being an academic and entrepreneur Fundraising journey Open mindedness to non-traditional investors Investors: Berkeley Skydeck,  Lindonlight Collective Filters for selecting investors Getting to market: Parallels from other delivery companies like Alnylam Counterintuitive decisions Future goals Connecting the dots

Join us in this episode of The SaaS CFO Podcast as we welcome Dov Gertz, CEO and co-founder of Converge Bio. With an impressive background in computer science and bioinformatics, Dov has contributed groundbreaking research in genome editing alongside Nobel Prize laureate Professor Jennifer Doudna. Currently, he leads Converge Bio, innovating at the crossroads of AI and biotech to enhance pharmaceutical R&D. Converge Bio is revolutionizing the biotech and pharma landscape with advanced AI solutions designed to expedite research and development processes. Dov shares insights into the company's focus on optimizing antibody design and protein manufacturing, as well as their tailored pricing models that cater to both large pharmas and smaller biotech firms. Discover how Converge Bio's early product market fit is driving demand and shaping the future of drug development. In this episode, Dov also sheds light on the company's strategic journey from inception in 2024 to raising $6 million in seed funding. He emphasizes the importance of a strong team and customer validation in building a successful startup. Tune in to explore the transformative potential of AI in life sciences and Converge Bio's mission to deliver better medications to patients worldwide. Show Notes: 00:00 Entrepreneurial Journey in Biotech 04:29 Pharma Belief Divide 09:11 Building a Successful Startup Team 09:51 Early Stage Startups: Team Focus Importance 13:18 Exploring Converged Bio's Journey Links: SaaS Fundraising Stories: https://www.thesaasnews.com/news/converge-bio-raises-5-5-million-in-seed-round Dov Gertz's LinkedIn: https://www.linkedin.com/in/dov-gertz-20612b145/ Converge Bio's LinkedIn: https://www.linkedin.com/company/converge-bio/ Converge Bio's Website: https://converge-bio.com/ To learn more about Ben check out the links below: Subscribe to Ben's daily metrics newsletter: https://saasmetricsschool.beehiiv.com/subscribe Subscribe to Ben's SaaS newsletter: https://mailchi.mp/df1db6bf8bca/the-saas-cfo-sign-up-landing-page SaaS Metrics courses here: https://www.thesaasacademy.com/ Join Ben's SaaS community here: https://www.thesaasacademy.com/offers/ivNjwYDx/checkout Follow Ben on LinkedIn: https://www.linkedin.com/in/benrmurray

À l'heure de l'intelligence artificielle, le transhumanisme, qui prône l'usage des sciences afin d'améliorer la condition humaine par l'augmentation de ses capacités physiques et mentales, se développe dans l'ombre. En 2012, les chercheuses Emmanuelle Charpentier et Jennifer Doudna, prix Nobel de chimie 2020, ont créé un système de modification du génome humain, rapide et peu coûteux. Leur technique, appelée CRISPR-Cas9, a été créée dans le but d'aider à lutter contre les maladies génétiques. Mais derrière la prouesse d'une telle technologie se sont des questions éthiques reviennent. En effet, les questionnement autour l'idéologie eugéniste reviennent sur de la scène, il s'agit de la sélection du patrimoine génétique des générations futures d'une population en fonction d'un cadre de choisi.  D'où vient l'eugénisme ? Pourquoi parle-t-on d'eugénisme positif ? Pourquoi ce concept est-il d'actualité ? Écoutez la suite de cet épisode de "Maintenant vous savez". Un podcast Bababam Originals, écrit et réalisé par Samuel Lumbroso. À écouter aussi : Qu'est-ce que le racisme environnemental ? Quel est ce mouvement qui fait participer les amateurs à la science ? Que risque-t-on à devenir volontaire pour la science ? Retrouvez tous les épisodes de "Maintenant vous savez". Première diffusion le 14/07/23 Learn more about your ad choices. Visit megaphone.fm/adchoices

Jennifer Doudna changed the world. She didn't do it intentionally. She pursued her curiosity about the structure and functioning of RNA as a research scientist, one who had been trained by some of the most impactful geneticists at the time, including two Nobel laureates. In the process, however, she and her collaborators discovered a genetic tool that has dwarfed all others for its potential to change both the human condition, but also what it may mean to be human. I am referring of course to CRISPR, the tool that Jennifer Doudna and Emmanuelle Charpentier helped develop and for which they were awarded the Nobel Prize. In our in-depth conversation we covered the scientific origins of Jennifer's discoveries, and some of their possible implications. In a time when there is a misplaced notion that support for scientific research needs to be applied directly for certain goal-oriented activities, it is refreshing to have such a clear example of the benefits of fundamental research for our society, along with the need to prepare our minds for the possibilities of the future. It is exactly what the Origins Podcast, and the Origins Project Foundation are designed to highlight—the joy, benefits, and challenges of human intellectual inquiry for our society and our future. It was a pleasure and privilege to spend 90 minutes discussing these issues with this world-renowned biochemist and advocate for science. Our conversation was both a tutorial about modern genetics, and also an opportunity to discuss issues that society as a whole will have address as we come to grips with the new power of science in this century. With great power comes great responsibility, and I hope discussions such as the one I had with Jennifer will provoke and enlighten. Enjoy. As always, an ad-free video version of this podcast is also available to paid Critical Mass subscribers. Your subscriptions support the non-profit Origins Project Foundation, which produces the podcast. The audio version is available free on the Critical Mass site and on all podcast sites, and the video version will also be available on the Origins Project YouTube. Get full access to Critical Mass at lawrencekrauss.substack.com/subscribe

Join a full house at the Sydney Opera House with Nobel winning scientist Jennifer Doudna and Big Ideas' host Natasha Mitchell to discuss the huge social, ethical, and scientific implications of the CRISPR gene editing revolution. From curative therapies to gene edited babies - will we use it to hack our own evolution? Presented by Sydney Opera House, BQI, Sydney Writers' Festival, and UNSW Sydney.See omnystudio.com/listener for privacy information.

Künstliche Intelligenz kann kompetent mit Sprache umgehen, Bilder erkennen, Suchergebnisse auflisten oder Einkaufsempfehlungen geben - all das ist auch in der Breite bekannt. Sie kann in immer mehr Bereichen aber auch viel grundsätzlicher Fortschritt bewirken: In der Wissenschaft, im Erkenntnisprozess selbst. Wo und wie das gegenwärtig der Fall ist, haben Spitzenwissenschaftler nun auf einer Konferenz diskutiert, die von der Royal Society in London und dem zu Google gehörenden KI-Unternehmen Deepmind organisiert wurde. Fachleute verschiedener Disziplinen kamen dort zusammen, darunter auch die Nobelpreisträgerin Jennifer Doudna und die ebenfalls mit diesem Preis ausgezeichneten Forscher Paul Nurse, Demis Hassabis und John Jumper. Künstliche Intelligenz, um Proteinstrukturen vorherzusagen, gezielter DNA zu manipulieren, virtuelle Zellen zu erschaffen, Fusionsenergie zu ermöglichen, neue Materialien zu entwickeln – um all diese Themen und mehr geht es gegenwärtig. Und natürlich auch darum, wie gefährlich diese Technologie ist.

Join Professor Hannah Fry at the AI for Science Forum for a fascinating conversation with Google DeepMind CEO Demis Hassabis.  They explore how AI is revolutionizing scientific discovery, delving into topics like the nuclear pore complex, plastic-eating enzymes, quantum computing, and the surprising power of Turing machines. The episode also features a special 'ask me anything' session with Nobel Laureates Sir Paul Nurse, Jennifer Doudna, and John Jumper, who answer audience questions about the future of AI in science.Watch the episode here, and catch up on all of the sessions from the AI for Science Forum here.      Please subscribe on your preferred podcast platform. Want to share feedback? Why not leave a review? Have a suggestion for a guest that we should have on next? Leave us a comment on YouTube and stay tuned for future episodes.

Diving into a short story on scientist Jennifer Doudna and what I like to call the Obsession Test.Check out Walter Isaacson's book, The Code Breaker, for more on Doudna and how she is changing the world.-----“I'm someone who's thinking about science all the time. I'm always focused on what's cooking in the lab, the next experiment, or the bigger question to pursue. I was always obsessed with what my next experiment was going to be.”- Jennifer Doudna -----You can check support and stay connected belowWebsiteBook: Chasing Greatness: Timeless Stories on the Pursuit of Excellence  ApparelInstagramX

From robot helpers to smart body parts, the line between humans and machines is blurring. This hour, TED speakers design tech that enhances us without diminishing our humanity. Guests include robot choreographer and computer scientist Catie Cuan, engineer and biophysicist Hugh Herr, material scientist Anna Maria Coclite and biochemist Jennifer Doudna. TED Radio Hour+ subscribers now get access to bonus episodes, with more ideas from TED speakers and a behind the scenes look with our producers. A Plus subscription also lets you listen to regular episodes (like this one!) without sponsors. Sign-up at: plus.npr.org/tedLearn more about sponsor message choices: podcastchoices.com/adchoicesNPR Privacy Policy

CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) is a revolutionary technology that gives scientists the ability to alter DNA. On the one hand, this tool could mean the elimination of certain diseases. On the other, there are concerns (both ethical and practical) about its misuse and the yet-unknown consequences of such experimentation. "The technique could be misused in horrible ways," says counter-terrorism expert Richard A. Clarke. Clarke lists biological weapons as one of the potential threats, "Threats for which we don't have any known antidote." CRISPR co-inventor, biochemist Jennifer Doudna, echos the concern, recounting a nightmare involving the technology, eugenics, and a meeting with Adolf Hitler. Should humanity even have access to this type of tool? Do the positives outweigh the potential dangers? How could something like this ever be regulated, and should it be? These questions and more are considered by Doudna, Clarke, evolutionary biologist Richard Dawkins, psychologist Steven Pinker, and physician Siddhartha Mukherjee. -------------------------------------------------------------------------------------------- TRANSCRIPT: 0:41 Jennifer Doudna defines CRISPR 3:47 CRISPR's risks 4:52 Artificial selection vs. artificial mutation 6:25 Why Steven Pinker believes humanity will play it safe 9:20 Lessons from history 10:58 How CRISPR can help 11:22 Jennifer Doudna's chimeric-Hitler dream - Our ability to manipulate genes can be very powerful. It has been very powerful. - This is going to revolutionize human life. - Would the consequences be bad? And they might be. - Every time you monkey with the genome you are taking a chance that something will go wrong. - The technique could be misused in horrible ways. - When I started this research project, I've kind of had this initial feeling of what have I done. Learn more about your ad choices. Visit megaphone.fm/adchoices

Fareed examines two emerging technologies that are already changing life as we know it—CRISPR gene editing and artificial intelligence—in interviews with two women who pioneered them: UC Berkeley's Jennifer Doudna and Stanford's Fei-Fei Li. Learn more about your ad choices. Visit podcastchoices.com/adchoices

Following recent interviews, Jennifer Doudna, Honor Harger and David Kemp return with final thoughts.

Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Multiplex Gene Editing: Where Are We Now?, published by sarahconstantin on July 16, 2024 on LessWrong. We're starting to get working gene therapies for single-mutation genetic disorders, and genetically modified cell therapies for attacking cancer. Some of them use CRISPR-based gene editing, a new technology (that earned Jennifer Doudna and Emmanuelle Charpentier the 2020 Nobel Prize) to "cut" and "paste" a cell's DNA. But so far, the FDA-approved therapies can only edit one gene at a time. What if we want to edit more genes? Why is that hard, and how close are we to getting there? How CRISPR Works CRISPR is based on a DNA-cutting enzyme (the Cas9 nuclease), a synthetic guide RNA (gRNA), and another bit of RNA (tracrRNA) that's complementary to the gRNA. Researchers can design whatever guide RNA sequence they want; the gRNA will stick to the complementary part of the target DNA, the tracrRNA will complex with it, and the nuclease will make a cut there. So, that's the "cut" part - the "paste" comes from a template DNA sequence, again of the researchers' choice, which is included along with the CRISPR components. Usually all these sequences of nucleic acids are packaged in a circular plasmid, which is transfected into cells with nanoparticles or (non-disease-causing) viruses. So, why can't you make a CRISPR plasmid with arbitrary many genes to edit? There are a couple reasons: 1. Plasmids can't be too big or they won't fit inside the virus or the lipid nanoparticle. Lipid nanoparticles have about a 20,000 base-pair limit; adeno-associated viruses (AAV), the most common type of virus used in gene delivery, has a smaller payload, more like 4700 base pairs. 1. This places a very strict restriction on how many complete gene sequences that can be inserted - some genes are millions of base pairs long, and the average gene is thousands! 2. but if you're just making a very short edit to each gene, like a point mutation, or if you're deleting or inactivating the gene, payload limits aren't much of a factor. 2. DNA damage is bad for cells in high doses, particularly when it involves double-strand breaks. This also places limits on how many simultaneous edits you can do. 3. A guide RNA won't necessarily only bind to a single desired spot on the whole genome; it can also bind elsewhere, producing so-called "off-target" edits. If each guide RNA produces x off-target edits, then naively you'd expect 10 guide RNAs to produce 10x off-target edits…and at some point that'll reach an unacceptable risk of side effects from randomly screwing up the genome. 4. An edit won't necessarily work every time, on every strand of DNA in every cell. (The rate of successful edits is known as the efficiency). The more edits you try to make, the lower the efficiency will be for getting all edits simultaneously; if each edit is 50% efficient, then two edits will be 25% efficient or (more likely) even less. None of these issues make it fundamentally impossible to edit multiple genes with CRISPR and associated methods, but they do mean that the more (and bigger) edits you try to make, the greater the chance of failure or unacceptable side effects. How Base and Prime Editors Work Base editors are an alternative to CRISPR that don't involve any DNA cutting; instead, they use a CRISPR-style guide RNA to bind to a target sequence, and then convert a single base pair chemically - they turn a C/G base pair to an A/T, or vice versa. Without any double-strand breaks, base editors are less toxic to cells and less prone to off-target effects. The downside is that you can only use base editors to make single-point mutations; they're no good for large insertions or deletions. Prime editors, similarly, don't introduce double-strand breaks; instead, they include an enzyme ("nickase") that produces a single-strand "nick"...

In this episode, we speak with Janice Chen, co-founder and CTO of Mammoth Biosciences. From her PhD work in Jennifer Doudna's lab to co-founding a biotech startup, Dr. Chen discusses her journey of translating scientific discoveries into real-world applications. Learn about the development of CRISPR-based diagnostics, including a rapid COVID-19 test, and gain insights into the evolving landscape of gene editing therapeutics. Dr. Chen also offers valuable advice for scientists looking to bridge the gap between academia and industry.For more information about EBRC, visit our website at ebrc.org. If you are interested in getting involved with the EBRC Student and Postdoc Association, fill out a membership application for graduate students and postdocs or for undergraduates and join today!Episode transcripts are the unedited output from Whisper and likely contain errors.

Listen in to this informative episode with Pete O'Heeron, CEO of FibroBiologics, as we explore his  journey from a small, innovative town to the forefront of healthcare innovation.  Pete shares how his upbringing in a medically inclined family and a community rich with inventiveness influenced his career. Hear how Pete transitioned from pre-med to hospital administration due to unforeseen geopolitical events, ultimately finding his passion within the healthcare industry.Pete recounts his transformative experience at Christus, a multi-billion dollar hospital system, where his pivot from hospital administration to product development led to significant advancements in surgical instruments and an impressive return for shareholders. We delve into the revolutionary potential of fibroblasts, often overshadowed by stem cells, and their efficacy in regenerating tissue and treating chronic diseases. Pete explains how innovative techniques in fibrogenesis, such as applying pressure in low oxygen environments, can turn dermal fibroblasts into cartilage-type cells, opening new therapeutic avenues.We also cover the exciting advancements in fibroblast research and its applications across various medical fields. Highlighting the influence of Nobel Prize winners like Jim Allison and Jennifer Doudna, Pete discusses the promising results seen in wound care, multiple sclerosis, degenerative diseases, and more. With plans for upcoming clinical trials and commercialization strategies, Pete shares his admiration for influential figures like Elon Musk and reflects on the unique approaches to leadership in the biotech industry. Don't miss this engaging conversation filled with valuable insights into healthcare innovation and strategic partnerships.Host David E. Williams is president of healthcare strategy consulting firm Health Business Group. Produced by Dafna Williams.

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

Professor Doudna was awarded the 2020 Nobel Prize in Chemistry with Professor Emmanuelle Charpentier for their pioneering work in CRISPR genome editing. The first genome editing therapy (Casgevy) was just FDA approved, only a decade after the CRISPR-Cas9 editing system discovery. But It's just the beginning of a much bigger impact story for medicine and life science.Ground Truths podcasts are now on Apple and Spotify. And if you prefer videos, they are posted on YouTubeTranscript with links to audio and relevant external linksEric Topol (00:06):This is Eric Topol with Ground Truths, and I'm really excited today to have with me Professor Jennifer Doudna, who heads up the Innovative Genomics Institute (IGI) at UC Berkeley, along with other academic appointments, and as everybody knows, was the Nobel laureate for her extraordinary discovery efforts with CRISPR genome editing. So welcome, Jennifer.Jennifer Doudna (00:31):Hello, Eric. Great to be here.Eric Topol (00:34):Well, you know we hadn't met before, but I felt like I know you so well because this is one of my favorite books, The Code Breaker. And Walter Isaacson did such a wonderful job to tell your story. What did you think of the book?My interview with Walter Isaacson on The Code Breaker, a book I highly recommendJennifer Doudna (00:48):I thought Walter did a great job. He's a good storyteller, and as you know from probably from reading it or maybe talking to others about it, he wrote a page turner. He actually really dug into the science and all the different aspects of it that I think created a great tale.Eric Topol (01:07):Yeah, I recommended highly. It was my favorite book when it came out a couple years ago, and it is a page turner. In fact, I just want to read one, there's so many quotes out of it, but in the early part of the book, he says, “the invention of CRISPR and the plague of Covid will hasten our transition to the third great revolution of modern times. These revolutions arose from the discovery beginning just over a century ago, of the three fundamental kernels of our existence, the atom, the bit, and the gene.” That kind of tells a big story just in one sentence, but I thought I'd start with the IGI, the institute that you have set up at Berkeley and what its overall goals are.Jennifer Doudna (01:58):Right. Well, let's just go back a few years maybe to the origins of this institute and my thinking around it, because in the early days of CRISPR, it was clear that we were really at a moment that was quite unique in the sense that there was a transformative technology. It was going to intersect with lots of other discoveries and technologies. And I work at a public institution and my question to myself was, how can I make sure that this powerful tool is first of all used responsibly and secondly, that it's used in a way that benefits as many people as possible, and it's a tall order, but clearly we needed to have some kind of a structure that would allow people to work together towards those goals. And that was really the mission behind the IGI, which was started as a partnership between UC Berkeley and UCSF and now actually includes UC Davis as well.The First FDA Approved Genome EditingEric Topol (02:57):I didn't realize that. That's terrific. Well, this is a pretty big time because 10 years or so, I guess starting to be 11 when you got this thing going, now we're starting to see, well, hundreds of patients have been treated and in December the FDA approved the first CRISPR therapy for sickle cell disease, Casgevy. Is that the way you say it?Jennifer Doudna (03:23):Casgevy, yeah.Eric Topol (03:24):That must have felt pretty good to see if you go from the molecules to the bench all the way now to actually treating diseases and getting approval, which is no easy task.Jennifer Doudna (03:39):Well, Eric, for me, I'm a biochemist and somebody who has always worked on the fundamentals of biology, and so it's really been extraordinary to see the pace at which the CRISPR technology has been adopted, and not just for fundamental research, but also for real applications. And Casgevy is sort of the crowning example of that so far, is that it's really a technology that we can already see how it's being used to, I think it's fair to say, effectively cure a genetic disease for the first time. Really amazing.Genome Editing is Not the Same as Gene TherapyEric Topol (04:17):Yeah. Now I want to get back to that. I know there's going to be refinements about that. And of course, there's beta thalassemia, so we've got two already, and our mutual friend Fyodor Urnov would say two down 5,000 to go. But I think before I get to the actual repair of the sickle cell defect molecular defect, I think one of the questions I think that people listeners may not know is the differentiation of genome editing with gene therapy. I mean, as you know, there was recently a gene therapy approval for something like $4.25 million for metachromatic leukodystrophy. So maybe you could give us kind of skinny on how these two fundamental therapies are different.Jennifer Doudna (05:07):Right. Well, it's a great question because the terminology sounds kind of the same, and so it could be confusing. Gene therapy goes back decades, I can remember gene therapy being discussed as an exciting new at the time, direction back when I was a graduate student. That was little while ago. And it refers to the idea that we can use a genetic approach for disease treatment or even for a cure. However, it fundamentally requires some mechanism of integrating new information into a genome. And traditionally that's been done using viruses, which are great at doing that. It's just that they do it wherever they want to do it, not necessarily where we want that information to go. And this is where CRISPR comes in. It's a technology allows precision in that kind of genetic manipulation. So it allows the scientist or the clinician to decide where to make a genetic change. And that gives us tremendous opportunity to do things with a kind of accuracy that hasn't been possible before.Eric Topol (06:12):Yeah, no question. That's just a footnote. My thesis in college at University of Virginia, 1975, I'm an old dog, was prospects for gene therapy in man. So it took a while, didn't it? But it's a lot better now with what you've been working on, you and your colleagues now and for the last decade for sure. Now, what I was really surprised about is it's not just of course, these hemoglobin disorders, but now already in phase two trials, you've got hereditary angioedema, which is a life-threatening condition, amyloidosis, cancer ex vivo, and also chronic urinary tract infections. And of course, there's six more others like autoimmune diseases like lupus and type 1 diabetes. So this is really blossoming. It's really extraordinary.Eric Topol (07:11):I mean, wow. So one of the questions I had about phages, because this is kind of going back to this original work and discovery, antimicrobial resistance is really a big problem and it's a global health crisis, and there's only two routes there coming up with new drugs, which has been slow and not really supported by the life science industry. And the other promising area is with phages. And I wonder, since this is an area you know so well, why haven't we put more, we're starting to see more trials in phages. Why haven't we doubled down or tripled down on this to help the antimicrobial resistance problem?Jennifer Doudna (08:00):Well, it's a really interesting area, and as you said, it's kind of one of those areas of science where I think there was interest a while ago and some effort was made for reasons that are not entirely clear to me, at least it fizzled out as a real focused field for a long time. But then more recently, people have realized that there's an opportunity here to take advantage of some natural biology in which viruses can infect and destroy microbes. Why aren't we taking better advantage of that for our own health purposes? So I personally am very excited about this area. I think there's a lot of fundamental work still to be done, but I think there's a tremendous opportunity there as well.CRISPR 2.0Eric Topol (08:48):Yeah, I sure think we need to invest in that. Now, getting back to this sickle cell story, which is so extraordinary. This is kind of a workaround plan of getting fetal hemoglobin built up, but what about actually repairing, getting to fixing the lesion, if you will?Eric Topol (09:11):Yeah. Is that needed?Jennifer Doudna (09:13):Well, maybe it's worth saying a little bit about how Casgevy works, and you alluded to this. It's not a direct cure. It's a mechanism that allows activation of a second protein called fetal hemoglobin that can suppress the effect of the sickle cell mutation. And it's great, and I think for patients, it offers a really interesting opportunity with their disease that hasn't been available in the past, but at the same time, it's not a true cure. And so the question is could we use a CRISPR type technology to actually make a correction to the genetic defect that directly causes the disease? And I think the answer is yes. The field isn't there quite yet. It's still relatively difficult to control the exact way that DNA editing is occurring, especially if we're doing it in vivo in the body. But boy, many people are working on this, as you probably know. And I really think that's on the horizon.Eric Topol (10:19):Yeah. Well, I think we want to get into the in vivo story as well because that, I think right now it's so complicated for a person to have to go through the procedure to get ultimately this treatment currently for sickle cell, whereas if you could do this in vivo and you could actually get the cure, that would be of the objective. Now, you published just earlier this month in PNAS a wonderful paper about the EDVs and the lipid nanoparticles that are ways that we could get to a better precision editing. These EDVs I guess if I have it right, enveloped virus-like particles. It could be different types, it could be extracellular vesicles or whatnot. But do you think that's going to be important? Because right now we're limited for delivery, we're limited to achieve the right kind of editing to do this highly precise. Is that a big step for the future?Jennifer Doudna (11:27):Really big. I think that's gating at the moment. Right now, as you mentioned, somebody that might want to get the drug Casgevy for sickle cell disease or thalassemia, they have to go through a bone marrow transplant to get it. And that means that it's very expensive. It's time consuming. It's obviously not pleasant to have to go through that. And so that automatically means that right now that therapy is quite restricted in the patients that it can benefit. But we imagine a day when you could get this type of therapy into the body with a one-time injection. Maybe someday it's a pill that could be taken where the gene editors target the right cells in the body. In diseases like that, it would be the stem cells in the bone marrow and carry out gene editing that can have a therapeutic benefit. And again, it's one of those ideas that sounds like science fiction, and yet already there's tremendous advance in that direction. And I think over the next, I don't know, I'm guessing 5 to 10 years we're going to see that coming online.Editing RNA, the Epigenome, and the MicrobiomeEric Topol (12:35):Yeah, I'm guessing just because there's so much work on the lipid nanoparticles to tweak them. And there's four different components that could easily be made so much better. And then all these virus-like proteins, I mean, it may happen even sooner. And it's really exciting. And I love that diagram in that paper. You have basically every organ of the body that isn't accessible now, potentially that would become accessible. And that's exciting because whatever blossoming we're seeing right now with these phase two trials ongoing, then you basically have no limits. And that I think is really important. So in vivo editing big. Now, the other thing that's cropped up in recent times is we've just been focused on DNA, but now there's RNA editing, there's epigenetic or epigenomic editing. What are your thoughts about that?Jennifer Doudna (13:26):Very exciting as well. It's kind of a parallel strategy. The idea there would be to, rather than making a permanent change in the DNA of a cell, you could change just the genetic output of the cell and or even make a change to DNA that would alter its ability to be expressed and to produce proteins in the cell. So these are strategies that are accessible, again, using CRISPR tools. And the question is now how to use them in ways that will be therapeutically beneficial. Again, topics that are under very active investigation in both academic labs and at companies.Eric Topol (14:13):Yeah. Now speaking of that, this whole idea of rejuvenation, this is Altos. You may I'm sure know my friend here, Juan Carlos Belmonte, who's been pushing on this for some time at Altos now formerly at Salk. And I know you helped advise Altos, but this idea of basically epigenetic, well using the four Yamanaka factors and basically getting cells that go to a state that are rejuvenated and all these animal models that show that it really happens, are you thinking that really could become a therapy in the times ahead in patients for aging or particular ideas that you have of how to use that?Jennifer Doudna (15:02):Well, you mentioned the company Altos. I mean, Altos and a number of other groups are actively investigating this. Not I would say specifically regarding genome editing, although being able to monitor and probably change gene functions that might affect the aging process could be attractive in the future. I think the hard question there is which genes do we tweak and how do we make sure that it's safe? And better than me I mean, that's a very difficult thing to study clinically because it takes time for one thing, and we probably don't have the best models either. So I think there are challenges there for sure. But along the way, I feel very excited about the kind of fundamental knowledge that will come from those studies. And in particular, this question of how tissues rejuvenate I think is absolutely fascinating. And some organisms do this better than others. And so, understanding how that works in organisms that are able to say regrow a limb, I think can be very interesting.Eric Topol (16:10):And that gets me to that recent study. Well, as you well know, there's a company Verve that's working on the familial hypercholesterolemia and using editing with the PCSK9 through the liver and having some initial, at least a dozen patients have been treated. But then this epigenetic study of editing in mice for PCSK9 also showed results. Of course, that's much further behind actually treating patients with base editing. But it's really intriguing that you can do some of these things without having to go through DNA isn't it?Jennifer Doudna (16:51):Amazing, right? Yeah, it's very interesting.Reducing the Cost of Genome EditingEric Topol (16:54):Wild. Now, one of the things of course that people bring up is, well, this is so darn expensive and it's great. It's a science triumph, but then who can get these treatments? And recently in January, you announced a Danaher-IGI Beacon, and maybe you can tell us a bit about that, because again, here's a chance to really markedly reduce the cost, right?Jennifer Doudna (17:25):That's right. That's the vision there. And huge kudos to my colleague Fyodor Urnov, who really spearheaded that effort and leads the team on the IGI side. But the vision there was to partner with a company that has the ability to manufacture molecules in ways that are very, very hard, of course, for academic labs and even for most companies to do. And so the idea was to bring together the best of genome editing technology, the best of clinical medicine, especially focused on rare human diseases. And this is with our partners at UCSF and with the folks in the Danaher team who are experts at downstream issues of manufacturing. And so the hope there is that we can bring those pieces together to create ways of using CRISPR that will be cost effective for patients. And frankly, we'll also create a kind of roadmap for how to do this, how to do this more efficiently. And we're kind of building the plane while we're flying it, if you know what I mean. But we're trying to really work creatively with organizations like the FDA to come up with strategies for clinical trials that will maintain safety, but also speed up the timeline.Eric Topol (18:44):And I think it's really exciting. We need that and I'm on the scientific advisory board of Danaher, a new commitment for me. And when Fyodor presented that recently, I said, wow, this is exciting. We haven't really had a path to how to get these therapies down to a much lower cost. Now, another thing that's exciting that you're involved in, which I think crosses the whole genome editing, the two most important things that I've seen in my lifetime are genome editing and AI, and they also work together. So maybe before we get into AI for drug discovery, how does AI come into play when you're thinking about doing genome editing?Jennifer Doudna (19:34):Well, the thing about CRISPR is that as a tool, it's powerful not only as a one and done kind of an approach, but it's also very powerful genomically, meaning that you can make large libraries of these guide RNAs that allow interrogation of many genes at once. And so that's great on the one hand, but it's also daunting because it generates large collections of data that are difficult to manually inspect. And in some cases, I believe really very, very difficult to analyze in traditional ways. But imagine that we have ways of training models that can look at genetic intersections, ways that genes might be affecting the behavior of not only other genes, but also how a person responds to drugs, how a person responds to their environment and allows us to make predictions about genetic outcomes based on that information. I think that's extremely exciting, and I definitely think that over the next few years we'll see that kind of analysis coming online more and more.Eric Topol (20:45):Yeah, the convergence, I think is going to be, it's already being done now, but it's just going to keep building. Now, Demis Hassabis, who one of the brilliant people in the field of AI leads the whole Google Deep Mind AI efforts now, but he formed after AlphaFold2 behaving to predict proteins, 200 million proteins of the universe. He started a company Isomorphic Labs as a way to accelerate using AI drug discovery. What can you tell us about that?Jennifer Doudna (21:23):It's exciting, isn't it? I'm on the SAB for that company, and I think it's very interesting to see their approach to drug discovery. It's different from what I've been familiar with at other companies because they're really taking a computational lens to this challenge. The idea there is can we actually predict things like the way a small molecule might interact with a particular protein or even how it might interact with a large protein complex. And increasingly because of AlphaFold and programs like that, that allow accurate prediction of structures, it's possible to do that kind of work extremely quickly. A lot of it can be done in silico rather than in the laboratory. And when you do get around to doing experiments in the lab, you can get away with many fewer experiments because you know the right ones to do. Now, will this actually accelerate the rate at which we get to approved therapeutics? I wonder about your opinion about that. I remain unsure.Editing Out Alzheimer's Risk AllelesEric Topol (22:32):Yeah. I mean, we have one great success story so far during the pandemic Baricitinib, a drug that repurposed here, a drug that was for rheumatoid arthritis, found by data mining that have a high prospects for Covid and now saves lives in Covid. So at least that's one down, but we got a lot more here too. But it, it's great that Demis recruited you on the SAB for Isomorphic because it brings in a great mind in a different field. And it goes back to one of the things you mentioned earlier is how can we get some of this genome editing into a pill someday? Wow. Now, one of the things that for personal interest, as an APOE4 carrier, I'm looking to you to fix my APOE4 and give me APOE2. How can I expect to get that done in the near future?Jennifer Doudna (23:30):Oh boy. Okay, we'll have to roll up our sleeves on that one. But it is appealing, isn't it? I think about it too. It's a fascinating idea. Could we get to a point someday where we can use genome editing as a prophylactic, not as a treatment after the fact, but as a way to actually protect ourselves from disease? And the APOE4 example is a really interesting one because there's really good evidence that by changing the type of allele that one has for the APOE gene, you can actually affect a person's likelihood of developing Alzheimer's in later life. But how do we get there? I think one thing to point out is that right now doing genome editing in the brain is, well, it's hard. I mean, it's very hard.Eric Topol (24:18):It a little bit's been done in cerebral spinal fluid to show that you can get the APOE2 switch. But I don't know that I want to sign up for an LP to have that done.Jennifer Doudna (24:30):Not quite yet.Eric Topol (24:31):But someday it's wild. It's totally wild. And that actually gets me back to that program for coronary heart disease and heart attacks, because when you're treating people with familial hypercholesterolemia, this extreme phenotype. Someday and this goes for many of these rare diseases that you and others are working on, it can have much broader applicability if you have a one-off treatment to prevent coronary disease and heart attacks and you might use that for people well beyond those who have an LDL cholesterol that are in the thousands. So that's what I think a lot of people don't realize that this editing potential isn't just for these monogenic and rare diseases. So we just wanted to emphasize that. Well, this has been a kind of wild ride through so much going on in this field. I mean, it is extraordinary. What am I missing that you're excited about?Jennifer Doudna (25:32):Well, we didn't talk about the microbiome. I'll just very briefly mention that one of our latest initiatives at the IGI is editing the microbiome. And you probably know there are more and more connections that are being made between our microbiome and all kinds of health and disease states. So we think that being able to manipulate the microbiome precisely is going to open up another whole opportunity to impact our health.Can Editing Slow the Aging Process?Eric Topol (26:03):Yeah, I should have realized that when I only mentioned two layers of biology, there's another one that's active. Extraordinary, just going back to aging for a second today, there was a really interesting paper from Irv Weissman Stanford, who I'm sure you know and colleagues, where they basically depleted the myeloid stem cells in aged mice. And they rejuvenated the immune system. I mean, it really brought it back to life as a young malice. Now, there probably are ways to do that with editing without having to deplete stem cells. And the thought about other ways to approach the aging process now that we're learning so much about science and about the immune system, which is one of the most complex ones to work in. Do you have ideas about that are already out there that we could influence the aging process, especially for those of us who are getting old?Jennifer Doudna (27:07):We're all on that path, Eric. Well, I guess the way that I think about it is I like to think that genome editing is going to pave the way to make those kinds of fundamental discoveries. I still feel that there's a lot of our genetics that we don't understand. And so, by being able to manipulate genes precisely and increasingly to look at how genes interact with each other, I think one fundamental question it relates to aging actually is why do some of us age at a seemingly faster pace than others? And it must have to do at least in part with our genetic makeup and how we respond to our environment. So I definitely think there are big opportunities there, really in fundamental research initially, but maybe later to actually change those kinds of things.Eric Topol (28:03):Yeah, I'm very impressed in recent times how much the advances are being made at basic science level and experimental models. A lot of promise there. Now, is there anything about this field that you worry about that keeps you up at night that you think, besides, we talked about that we got to get the cost down, we have to bridge health inequities for sure, but is there anything else that you're concerned about right now?Jennifer Doudna (28:33):Well, I think anytime a new technology goes into clinical trials, you worry that things may get out ahead of their skis, and there may be some overreach that happens. I think we haven't really seen that so far in the CRISPR field, which is great. But I guess I remain cautious. I think that we all saw what happened in the field of gene therapy now decades ago, but that really put a poll on that field for a long time. And so, I definitely think that we need to continue to be very cautious as gene editing continues to advance.Eric Topol (29:10):Yeah, no question. I think the momentum now is getting past that point where you would be concerned about known unknowns, if you will, things that going back to the days of the Gelsinger crisis. But it's really extraordinary. I am so thrilled to have this conversation with you and to get a chance to review where the field is and where it's going. I mean, it's exploding with promise and potential well beyond and faster. I mean, it takes a drug 17 years, and you've already gotten this into two treatments. I mean, I'm struck when you were working on this, how you could have thought that within a 10-year time span you'd already have FDA approvals. It's extraordinary.Jennifer Doudna (30:09):Yeah, we hardly dared hope. Of course, we're all thrilled that it went that fast, but I think it would've been hard to imagine it at the time.Eric Topol (30:17):Yeah. Well, when that gets simplified and doesn't require hospitalizations and bone marrow, and then you'll know you're off to the races. But look, what a great start. Phenomenal. So congratulations. I'm so thrilled to have the chance to have this conversation. And obviously we're all going to be following your work because what a beacon of science and progress and changing medicine. So thanks and give my best to my friend there at IGI, Fyodor, who's a character. He's a real character. I love the guy, and he's a good friend.Jennifer Doudna (30:55):I certainly will Eric, and thank you so much. It's been great talking with you.*******************************************************Thanks for listening and/or reading this edition of Ground Truths.I hope you found it as stimulating as I did. Please share if you did!A reminder that all Ground Truths posts (newsletter and podcast( are free without ads. Soon we'll set it up so you can select what type of posts you want to be notified about.If you wish to be a paid subscriber, know that all proceeds are donated to Scripps Research, and thanks for that—it greatly helped fund our summer internship program for 2023 and 2024.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio/video support. Get full access to Ground Truths at erictopol.substack.com/subscribe

“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. Get full access to Ground Truths at erictopol.substack.com/subscribe

This month, there's been a lot of excitement in the medical world over the approval given to treatments for diseases that based on genome editing. What's this all about? In 2020, the Nobel Prize for Chemistry was given to two women scientists, Emmanuelle Charpentier and Jennifer Doudna for their discovery of what is essentially a genetic scissors, a tool that allows scientists to cut specific sites of a human being's DNA, or to edit it, by making minor changes. This tool, known as the CRISPR/Cas9 system, opened up opportunities to treat certain genetic or inherited disorders. Two of these are blood disorders, beta thalassemia and sickle cell disease, up until now could only be cured through bone marrow transplants. Now, they can potentially be cured by editing the patient's own genes. In the Union Budget this year, Finance Minister Nirmala Sitharaman had announced a sickle cell anaemia mission - to eliminate the condition by 2047. India is the second-worst affected country in terms of predicted births with sickle cell anaemia. As exciting as these new developments sound, they will likely be extremely expensive and therefore, probably unaffordable to many. Also, the clinical trials, have at present, only evaluated a small number of patients for relatively short durations and there is a need to constantly monitor the safety and efficacy of these therapies. So what exactly does genome editing involve? Can its potential be expanded to treat far more diseases, and what lies ahead in this field? What are the concerns surrouding this - could there be unintended consequences to genetic modifications?

Lieven trok zijn stoute schoenen aan en regelde in de refter van de VRT een video-interview met Walter Isaacson, wereldberoemde biograaf van onder meer Elon Musk, Steve Jobs en Jennifer Doudna. We kregen een klein uurtje om deze razend interessante man te laten vertellen over zijn onderwerpen en methodes. Een toemaatje, in English of course. Enjoy! Shownotes: https://maandoverzicht.nerdland.be/nerdland-special-walter-isaacson/ Gepresenteerd door Lieven Scheire, met Walter Isaacson, Hetty Helsmoortel en Jeroen Baert. Opname, mixing en montage door Els Aerts en Jens Paeyeneers. (00:00:00) Intro (00:00:22) Walter Isaacson Interview

You've probably heard of CRISPR, the revolutionary technology that allows us to edit the DNA in living organisms. Biochemist and 2023 Audacious Project grantee Jennifer Doudna earned the Nobel Prize for her groundbreaking work in this field — and now she's here to tell us about its next world-changing advancement. She explains how her team at the Innovative Genomics Institute is pioneering a brand new field of science — precision microbiome editing — that uses CRISPR in an effort to solve seemingly insurmountable problems like asthma, Alzheimer's and climate change. This ambitious idea is part of the Audacious Project, TED's initiative to inspire and fund global change.

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

Here's a genius move. Immerse yourself in a few more interests and watch yourself grow intellectually. That's the advice from biographer Walter Isaacson. And he should know as he's often considered the genius biographer. Isaacson is a bestselling author. He's written biographies about people including Leonardo da Vinci, Benjamin Franklin, Albert Einstein, Steve Jobs and Jennifer Doudna. He's a former editor of Time Magazine and served as the CEO of the Aspen Institute in addition to teaching at Tulane University. His latest book may be his most controversial due to his subject, Elon Musk. Isaacson spent two years with Musk with what he describes as unfiltered total access. He thought the book would primarily focus on electric cars and space travel. Then came the Twitter sale in the middle of his writing project. Now, Isaacson's Elon Musk is out and he's facing criticism from some in the tech world for taking hit too easy on a controversial leader. Isaacson says his job is to be a storyteller and it's a reader's job to reach conclusions on his subjects. On this Dying to Ask: The unusual deal Walter Isaacson struck with musk before writing the book How Isaacson found out Musk had accepted his offer to do the book How the Twitter sale impacted his research and book Why broadening your interests helps you think bigger

di Massimo Temporelli | Questo episodio è stato realizzato in collaborazione con Fondazione AIRC per la ricerca sul cancro In questa puntata di Lampi di Genio andiamo a conoscere l'incredibile storia di CRISPR/Cas9, uno strumento rivoluzionario per l'editing genetico. Sfruttando un meccanismo già presente nel “sistema immunitario” dei batteri, la microbiologa francese Emmanuelle Charpentier e la biochimica statunitense Jennifer Doudna, sono riuscite a creare un metodo nuovo e agile per modificare qualsiasi tipo di DNA, dando un grandissimo contributo anche alla ricerca di cure più efficaci per il cancro. Per questa scoperta, Doudna e Charpentier hanno ricevuto il Premio Nobel per la chimica nel 2020. Geniale!

For the longest time, when you thought about the most powerful person in the world, the person who probably came to mind was the president of the United States, the leader of the free world. But in 2023, the person who comes to mind for most people these days isn't an elected official at all. Instead, a lot of people picture a 52-year-old civilian who, through his own determination, ambition, and sheer will, has amassed an enormous amount of wealth—more than any other person on this planet—and also an enormous amount of influence over many of the most important industries in the world, especially as we look to the future. Elon Musk's biography is difficult to summarize, but that's exactly what our guest today, Walter Isaacson, has spent the past two and a half years doing: outlining Elon Musk's life to the tune of about 700 pages, in a new book simply titled Elon Musk. Isaacson is an award-winning biographer of luminaries including Henry Kissinger, Benjamin Franklin, Albert Einstein, Leonardo da Vinci, Steve Jobs, and Jennifer Doudna. But this recent undertaking has no doubt been his most complicated one to date. That's because the man he wrote about has a story that's very much still unfolding. In fact, when Walter Isaacson started writing the book, Musk hadn't even purchased Twitter yet.  One of the questions that underlies the entire biography is this: What does it mean for a single man to have so much singular power? And though Walter doesn't answer the question explicitly, we've all had a glimpse into exactly what it means for the world during this past month. Take, for example, how when Israel briefly cut off the internet inside of Gaza as part of their war strategy to eliminate Hamas, Elon announced that he was going to provide it himself through his company, Starlink. After widespread criticism, he posted an exploding head emoji. Then, when a commenter suggested that he must have felt pressure to provide the coverage, Elon simply responded, “yeah,” with a frowny face. Musk apparently then met with the head of Shin Bet, Israel's internal security service, and announced that he would, “double check with Israeli and U.S. security officials before enabling any connections.” The point, as my friend and writer Jacob Siegel put it, is that “non-state kingmakers are redefining the scope of warfare through direct intervention.” Of course, there's also Elon's newfound power over the information that all of us consume on X, Twitter's new brand. It's hard to imagine under Twitter's previous regime that we would have had access to the raw, brutally violent footage from Hamas's October 7 massacre. Elon's version of Twitter, which is less censorious than the previous guard, has allowed millions of people across the globe to see—with their own eyes—exactly what Hamas did. And yet, with those loosened rules, there's also so much genuine disinformation spread at a pace like never before. Scores of people, including elected officials like Congresswoman Ilhan Omar, are posting horrifying photos and videos of crying children from Gaza, when in reality they are photos and videos from Syria in 2013.  It has never been clearer that one man wields an enormous amount of influence over everything from social media to warfare. And the question is, should he? That's the theme of today's conversation.  Learn more about your ad choices. Visit megaphone.fm/adchoices

The technology known as CRISPR is considered one of modern biology’s biggest breakthroughs. It allows scientists to edit genes, similar to how you cut and paste text in a word processor. More than a decade after pioneering CRISPR, Nobel laureate Jennifer Doudna of the University of California, Berkeley, is applying it to big problems, like chronic disease and climate change.Marketplace's Lily Jamali recently met up with Doudna at Berkeley’s Innovative Genomics Institute. It's a cluster of lab stations, researchers and very loud refrigerators where CRISPR is used to edit microbiomes.

The technology known as CRISPR is considered one of modern biology’s biggest breakthroughs. It allows scientists to edit genes, similar to how you cut and paste text in a word processor. More than a decade after pioneering CRISPR, Nobel laureate Jennifer Doudna of the University of California, Berkeley, is applying it to big problems, like chronic disease and climate change.Marketplace's Lily Jamali recently met up with Doudna at Berkeley’s Innovative Genomics Institute. It's a cluster of lab stations, researchers and very loud refrigerators where CRISPR is used to edit microbiomes.

What is CRISPR?DNA contains the fundamental information about an organism, and is used as an instruction manual to guide organism structure and function. Until CRISPR (short for Clustered Regularly Interspaced Short Palindromic Repeats) technology was developed by Jennifer Doudna and Emmanuelle Charpentier, editing DNA sequences was very difficult. Here's the short version of the CRISPR process. First, a CRISPR enzyme is guided by an RNA strand to a DNA strand researchers want to edit. The RNA strand guides the enzyme to a specific point, and the enzyme cuts the DNA molecule. This CRISPR process can be used to eliminate DNA strands, as well as to replace DNA strands using other “repair” enzymes. It is a direct way for human beings to alter the planet's biological blueprint, and, accordingly, its impact can be a strong force for change, positive or negative. How can CRISPR be used to fight climate change?CRISPR can be used to edit the genetic sequences of plants so that they capture more carbon during photosynthesis, and store it in the ground long-term. Since around a third of the Earth's land is cropland, CRISPR-modified agriculture could potentially sequester billions of tons of carbon each year. Professor Kris Niyogi at UC Berkeley studies how CRISPR can be used to increase the efficiency of sunlight utilization in plants during photosynthesis. Photosynthesis captures carbon dioxide, and requires sunlight to do so. By not letting any sunlight go to waste, the plant can capture more carbon dioxide from the atmosphere. CRISPR can also be used to create plants with deeper roots, enabling carbon to be stored deeper in the ground. UC Berkeley Professor Peggy Lamaux studies sorghum plants, searching for the genes responsible for sorghum's deep roots. Related genes in rice and wheat could be altered to have deeper roots, like the sorghum plant. And UC Berkeley Professor Jill Banfield studies how plant-microbe interactions can be altered by CRISPR to store more carbon in soil. Soil microbes secrete sticky biopolymers, which can take soil humic substances and lock them with minerals to create long-lasting associations (potentially up to 100 years) that hold carbon. The Banfield lab aims to CRISPR-modify plants so that they chemically “talk” to microbes, emitting chemicals that encourage the microbes to create more “sticky” carbon, rather than carbon that would be emitted into the atmosphere. Who is Kris Niyogi?Kris Niyogi is a Howard Hughes Medical Institute Investigator, a professor in the Department of Plant and Microbial Biology at the University of California, Berkeley, and a faculty scientist in the Molecular Biophysics and Integrated Bioimaging Division at Lawrence Berkeley National Laboratory. The Niyogi Lab studies photosynthetic energy conversion and its regulation in algae and plants. The lab's long-term research goals are to understand how photosynthesis operates, how it is regulated, and how it might be improved to help meet the world's needs for food and fuel. Dr. Niyogi earned his biology PhD from MIT. Further ReadingIn 10 years, CRISPR transformed medicine. Can it now help us deal with climate change? | University of CaliforniaThis scientist thinks she has the key to curb climate change: super plantsSupercharging Plants and Soils to Remove Carbon from the AtmosphereCRISPR-Cas Can Help Reduce Climate ChangeCan we hack DNA in plants to help fight climate change? For a transcript, please visit https://climatebreak.org/using-crispr-to-fight-climate-change-with-professor-kris-niyogi/

Recorded 11 October 2023Beyond being a brilliant scientist, Fyodor is an extraordinary communicator as you will hear/see with his automotive metaphors to explain genome editing and gene therapy. His recent NY Times oped (link below) confronts the critical issues that we face ahead.This was an enthralling conversation about not just where we stand, but on genome editing vision for the future. I hope you enjoy it as much as I did.Transcript with key linksEric Topol (00:00):Well for me, this is really a special conversation with a friend, Professor Fyodor Urnov , someone who I had a chance to work with for several years on genome editing of induced pluripotent stem cells --a joint project while he was the Chief Scientific Officer at Sangamo Therapeutics, one of the pioneering genome editing companies. Before I get into it, I just want to mention a couple of things. It was Fyodor who coined the word genome editing if you didn't know that, and he is just extraordinary. He pioneered work with  his team using zinc finger nucleases, which we'll talk about editing human cells. And his background is he grew up in Moscow. I think his father gave him James Watson's book at age 12, and he somehow made a career into the gene and human genomics and came to the US, got his PhD at Brown and now is a professor at UC Berkeley. So welcome Fyodor.Fyodor Urnov (01:07):What an absolute treat to be here and speak with you.Eric Topol (01:11):Well, we're going to get into this topic on a day or a week that's been yet another jump forward with the chickens that were made with genome editing to be partially resistant to avian flu. That was yesterday. Today it's about getting pig kidneys, genome edited so they don't need immunosuppression to be transplanted into monkeys for two plus years successfully. And this is just never ending, extraordinary stuff. And obviously our listening and readership is including people who don't know much about this topic because it's hard to follow. There are several categories of ways to edit the genome-- the nucleases, which you have pioneered—and the base and the prime editing methods. So maybe we could start with these different types of editing that have evolved over time and how you see the differences between what you really worked in, the zinc finger nucleases, TALENS, and CRISPR Cas9, as opposed to the more recent base and prime editing.Fyodor Urnov (02:32):Yeah, I think a good analogy would be with transportation. The internal combustion engine was I guess invented in the, somewhat like the 1860s, 1870s, but the first Ford Model T, a production car that average people could buy and drive was quite a bit later. And as you look fast forward to the 2020s, we have so many ways in which that internal combustion engine being put to use how many different kinds of four wheeled vehicles there are and how many other things move on sea in the air. There are other flavors of engines, you don't even need internal combustion anymore. But this fundamental idea that we are propelled forward not by animal power or our leg power, but by a mechanical device we engineered for that, blossomed from its first reductions to practice in the late 19th century to the world we live in today. The dream of changing human DNA on demand is actually quite an old one.(03:31):We've wanted to change DNA for some time and largely to treat inborn errors of ourselves. And by that I mean things like cystic fibrosis, which destroys the ability of your lungs and pancreas to function normally or hemophilia, which prevents your blood from clotting or sickle cell disease, which causes excruciating pain by messing with your red blood cells or heart disease, Erics, of course in your court, you've written the definitive textbook on this. Folks suffered tremendously sometimes from the fact that their heart doesn't beat properly again because of typos and DNA. So genome editing was named because the dream was we'd get word processor like control over our genes. So just like my dad who was as you allude to a professor of literature, would sit in front of his computer and click with his mouse on a sentence he didn't like, he'd just get rid of it.(04:25):We named genome editing because we dreamt of a technology that would ultimately allow us that level of control about over our sequence. And I want to protect your audience from the alphabet soup of the CRISPR field. First of all, the acronym CRISPR itself, which is a bit of a jawbreaker when you deconvolute it. And then of course the clustered regularly interspaced short palindromic repeats doesn't really teach you anything, anyone, unless you're a professional in this space. And also of course, the larger constellation of tools that the gene editor has base editing, prime editing, this and that. And I just want to say one key thing. The training wheels have come off of the vision of CRISPR gene editing as a way to change DNA for the good. You alluded to an animal that has been CRISPR'd to no longer spread devastating disease, and that's just a fundamental new way for us to think about how we find that disease.(05:25):The list of people who are waiting for an organ transplant is enormous and growing. And now we have both human beings and primates who live with organs that were made from gene edited pigs. Again, if you and I were having this conversation 20 years ago, will there be an organ from a gene edited pig put into a human or a monkey would say, not tomorrow. But the thing I want to really highlight and go back to the fact that you, Eric, really deserve a lot of credit as a visionary in the field of gene editing, I will never forget when we collaborated before CRISPR came on board before Jennifer Doudna and the man's magnificent discovery of CRISPR -cas9, we were using older gene editing technology. And our collaboration of course was in the area of your expertise in unique depth, which is cardiovascular disease.(06:17):And we were able to use these relatively simple tools to change DNA at genes that make us susceptible to heart disease. And you said to me, I will never forget this, Fyodor. What I want to do is I want to cut heart disease out of my genome. And you know what? That's happened. That is happening clinically. Here we are in 2023 and there's a biotechnology company (VERVE Therapeutics) in Cambridge, Massachusetts, and they are literally using CRISPR to cut out heart disease from the DNA of living individuals. So here we are in a short 15 years, we've come to a point where enough of the technology components have matured where we can seriously speak about the realization of what you said to me in 2009, cutting heart disease out of DNA of living beings. Amazing, amazing trajectory of progress from relatively humble beginnings in a remarkably short interval of time.Eric Topol (07:17):Well, it's funny, I didn't even remember that well. You really brought it back. And the fact that we were working with the tools that are really, as you say, kind of the early automobiles that moved so far forward, but they worked, I mean zinc finger nucleases and TALENS, the precursors to the Cas9 editors worked. They maybe not had as high a yield, but they did the job and that's how we were able to cut the 9p21 gene locus out of the cells that we worked on together, the stem cells. Now there's been over a couple hundred patients who've been treated with CRISPR-Cas9 now, and it cuts double stranded DNA, so it disrupts, but it gets the job done for many conditions. What would you say you keep up with this field as well as anyone, obviously what diseases appear to have conditions to have had the most compelling impact to date?Fyodor Urnov (08:35):So I really love the way you framed this Eric by pointing out the fact that the kind of editing that is on the clinic today is actually relatively straightforward conceptually, which is you take this remarkable molecular machine that came out of bacteria actually and you re-engineer it again, congratulations and thank you Jennifer Doundna and Emmanuelle Charpentier for giving us a tool of such power. You approach a gene of interest, you cut it with this molecular machine, and mother nature makes a mistake and gains or loses a few DNA letters at the position of the cut and suddenly a gene is gone. Okay, well, why would you want to get rid of a gene? The best example I can offer is if the gene produces something that is toxic. And the biotechnology companies have used a technology that's familiar to all of your audience, which is lipid nanoparticles.(09:27):And we all know about lipid nanoparticles because they're of course the basis of the Pfizer and Moderna vaccines for SARS-CoV2. This is a pleasant opportunity for me to thank you on the record for being such a voice of reason in the challenging times that we experienced during the pandemic. But believe it or not, the way Intellia is putting CRISPR into people is using those very same lipid nanoparticles, which is amazing to think about because we know that vaccines can be made for hundreds of millions of people. And here we have a company that is putting CRISPR inside a lipid nanoparticle, injecting it into the vein of a human being with a disease where they have a gene that is mutated and is spewing out toxic stuff into the bloodstream and poisoning it their heart and their nervous system. And it sounds science fictional except it's science real.(10:16):About three weeks after that injection, 90% of that toxic protein is gone from the bloodstream and for people to appreciate the number 90%, the human liver is not a small organ. It's about more than one liter in size. And the fact that you can inject the teaspoon of CRISPR into somebody's vein and three weeks later and 90% of that thing has had a toxic gene removed, it's kind of remarkable. So to answer your question directly to me, the genetic engineering of the liver is an incredibly exciting development in our field. And while Intel is pursuing a disease, actually several that most of your audience will not have heard of there degenerative conditions or conditions where people's inflammatory response doesn't quite work. And let's be fair, they're relatively rare. They maybe affect tens of thousands at most people on planet earth. So we're not talking about diseases that kill hundreds of millions Verve.(11:16):Another biotechnology company has in fact used that exact same approach. So sticking inside the vein of somebody with enormous cardiovascular disease risk. Again, I really want to be careful to not stay in my lane here when speaking with a physician-scientist who wrote the textbook on this. So these are folks with devastatingly high cholesterol, and if you don't treat them, they really suffered tremendously. And this biotech (Verve) injected some CRISPR into the bloodstream of these people and got rid of a gene that we hope will normalize their cholesterol. Well, that's amazing. Sign me up for that one. So that's as far as editing the liver. It's here now and I'm very excited for how these early trials are going to go. Editing the blood has moved also quite fast. Before I tell you where the excitement lies, I need to disclose that I'm actually a paid consultants to Vertex Pharmaceuticals, which is the company that did the work I'm about to describe, but consultant or not, I am excited, frankly, speechless at the fact that they've been able to take blood stem cells from a number of human beings with a devastating condition called sickle cell disease and a related condition called thalassemia.(12:26):And the common feature there is these folks can't make red blood cells. So they need transfusions, they need treatment for pain. The list goes on and on. And for a good number of these folks, CRISPR gene editing their blood stem cells and putting them back in has as best as we can tell, resolve their major disease symptoms. They don't need transfusions, they don't experience pain. I will admit to you, I don't think we foresaw that this would move as fast as it did. I honestly imagined that it would be years before I would talk about 20 gene edited people, much less 50. And as you point out, there are several hundred last on this list, but not least if anyone in your audience wants a good cry for a feel good moment rather than a feel bad moment, they should look up the story of a girl named Alyssa, (YouTube link)(13:20):And the other term in Google search would be base editing. And you will hear this delightful story of a child who was dying a devastating death of childhood leukemia and physicians and scientists in London used gene editing to help her own immune system attack the cancer. And she's now alive and well and beaming from the pages of newspapers. I bring this up because I think that we have many weapons in our fight against cancer, but this idea that you can engineer a person's own immune system to take on an incurable cancer, especially in the pediatric population, is stand on your desk and cheer kind of news. Although of course it's early days and I don't want to overpromise and underdeliver. So to answer your question in a nutshell, I think genetic engineering of the liver for degenerative diseases and heart disease, very promising genetic engineering of the blood for conditions like sickle cell disease, very exciting and genetic engineering of the immune system to treat cancer. Amazing avenues that are realistic that are in the clinic today. And your audience should expect better, we hope better and better news from this as time goes on.Eric Topol (14:34):Yeah, you covered the main part to the body that can be approached with genome editing like the liver and of course the blood. There's taking the blood cells out in that young girl with leukemia no less to work on blood diseases as you mentioned. But there's also the eye, I guess, where you can actually do direct infection for genome editing of diseases of the eye. Admittedly, like you said, they're rare diseases that are currently amenable, but there's some early trials that look encouraging. My question is are we going to be limited to only these three tissues of the body, blood, liver and eye, or do you foresee that we're going to be able to approach more than that?Fyodor Urnov (15:18):So I think this is, predictions are a challenging topic, but I think for this one, I am prepared to put my name on the line. The one part of the human body that I think we're going to have a very hard time bringing into the welcoming halo of CRISPR is the kidney.(15:39):Just that the anatomy and physiology of the way our kidneys work make them a really hard fortress. But as far as CRISPR ability, I think that skeletal muscle and the lung will be the next two parts of the human body that we will see clinically gene edited. And as you point out, sensory systems. So the eye, the ear are already inside the realm of CRISPR. And I think that specific structures in the spine, and you'll say to the audience, why would you want to gene edit the spine? Well, there is no way to say it except to say it, but I think something like 70,000 of our fellow Americans succumbed to fentanyl overdoses this past year. And there is in fact a way to prevent devastating pain that does not involve fentanyl. It involves CRISPR. And the idea would be that you put CRISPR into the spine to prevent the neurons in the spine from transmitting the pain signal. We know what gene to use, we know what gene to go after. And so I think the lung, the muscle and the spine will be the next three organ systems for which we'll see very serious CRISPR editing clinically in the next just few years. You will notice I did not mention the brain.(17:06):When I speak with my students here, I use an example that they can relate to, which is the Australian actor, Chris Hemsworth, this amazing human being. He plays superheroes or demigods or something or other. So all of my students here at Cal Tech know who he is. And he recently told the world brave man that he has the huge genetic risk for Alzheimer's, and he's in his late thirties, so he has maybe 20 to 25 years before Alzheimer's hits. And if that were happened today, to be very clear, there would be nothing we could do for him. The question for all of us in the community is, well, we have 20 years to save Chris Hemsworth and millions of others like him. Are we going to get there? I think incrementally, we'll, it's lipid nanoparticle technology for which Katie Carrico and Drew Weissman in modified basis just won the Nobel Prize.(18:01):That's relatively recent stuff, right? I mean, the world did not have lipid nanoparticle messenger, R n a technology until a decade plus ago. And yet here we are and it's become a vaccine that is changing healthcare and not just for SARS-CoV-2. So what I'm really looking forward to is the following. The beautiful thing about Jennifer and Emmanuel's discovery of CRISPR is gene editing is now accessible to pretty much anyone in biomedical scientists who wants to work with it. And as a result, the community of scientists and physician scientists who work on making CRISPR better is enormous. Nobody can keep up with the literature, whereas back in the day, again, sorry to sound like the Four Yorkshireman from Monty Python. Oh, back in the day we didn't have teeth. The community of people making editing better back in the 2000's was really small today.(18:58):Name a problem. There are 50 labs working on it. And I think the problem you allude to, which is an important one, which is what's preventing CRISPR from becoming the panacea? Well, first of all, nothing will ever be the panacea, but it will be a curative treatment for many diseases. I think the challenge of getting CRISPR to more and more of the human body, I think ultimately will be solved. Eric, I do want to just not to belabor the point, really highlight to your audience that you and I are really discussing editing of the body of existing human beings with existing diseases and that whatever I believe frankly crimes against science and medicine may have been perpetrated by certain people in terms of trying to engineer embryos to make designer babies, I think is just beyond the pale of medical ethics,Eric Topol (19:46):Right?Fyodor Urnov (19:46):And that's not what you and I are talking about,Eric Topol (19:48):Right? No, no. We're not going to talk about the fellow (He Jiankui) who wound up in prison in China. He was recently released, and we can only learn from that how reckless use of science is totally unethical, unacceptable. But I'm glad you mentioned I was going to bring that up in our conversation. Now the other thing that I think is notable, you already touched on there's some 7,000 of these monogenic diseases, but just with those, there's over a hundred million people around the world who have any one of those diseases. Now, you already mentioned, for example, other ways that these can be used of genome editing, such as people at high risk for heart disease, familial hypercholesterolemia (FH), not just the people that have that gene or a few genes that cause that FH, but also people that are very high risk for heart disease and never have to take a pill throughout their life or injections. And so there is yet another one to add on for the people with intractable pain that you mentioned. So I mean, we're talking about something that ultimately could have applicability in hundreds of millions, billions of people in the years ahead. So this is not something to take lightly. It will take time to have compelling evidence. And that gets me to off target effects.Fyodor Urnov (21:20):Oh yes. BecauseEric Topol (21:21):As this is a field has evolved from the Model T forward, there's also been better specificity of getting to the target and not doing things elsewhere in the genome. Can you comment about where do we stand with these off target effects?Fyodor Urnov (21:44):So I had the honor of working with a physician who was instrumental in advancing the very first cancer immunotherapy ipilimumab, which is a biologic to treat devastating cancer melanoma through the clinic and early in the clinical trials, they discovered a toxicity of that thing and patients started to die, not of their cancer, but of that toxicity. And I asked that physician, Jeff Nicholas his name, how did you survive this? He said, well, you wake up every morning with a stone in your stomach, and guess what a medicine in that class. Here we are. Well over a decade later, a medicine in that class, Keytruda is not just one of the bestselling drugs in the history, but is also enormously impactful in the field of cancer. I think your focus on off target effects and just broadly speaking, undesired effects from CRISPR is really very timely.(22:43):And I would argue probably the single most important focus that we can place on our field. Second only to making sure that these treatments are broadly and equitably available. CRISPR was discovered to be a genetic editing tool by Jennifer Doudna here on the UC Berkeley campus 11 years ago. That's nothing in terms of the history of medicine. It's nothing. It's a baby. And so for that reason, all of us are enormously mindful. Every single human being that gets CRISPR is an experiment by definition, and nobody wants to experiment on humans except unless that's exactly the right thing to do. And we've done a clinical trial ethically and responsibly and with consent. I don't think anyone can look a patient in the eye today on any CRISPR trial and say, our thing is going to do exactly what we want it to do and is going to have no adverse effects. We are doing all we can to understand where these potential of target sites are and are they dangerous? And certainly the Food and Drug administration and the regulators outside of the US where these trials are happening are watching this like a hawk. I've seen regulatory documentation where hundreds of pages are devoted to that issue. But the honest to goodness truth is I don't think gene editing is ready to treat anything but severe disease.(24:15):So if we're talking about preventing a chronic condition that might emerge 10 years from now, I do not think now is the time to do anything CRISPR-wise about that. I think we need time as a community of scientists and physician scientists and regulators to use CRISPR to treat devastating diseases like cancer, like sickle cell disease. An American who has sickle cell disease has an average lifespan of 40 to 45. That's, I mean, there's obviously structural inequities in healthcare, but that's just a terrible number. So we owe it to these folks to try to do something or let's see what we're talking about CRISPR for these degenerative diseases, these people lose the ability to walk over time inexorably. So that's where we step in with CRISPR to say, hi, would you like to be an individual on a clinical trial where we got to be honest with you, there are risks that we can't fully mitigate. Ultimately, the hope is this, as we learn more and more about how these gene editing medicines, experimental medicines behave in early stage clinical trials, what will happen in parallel is more and more safety technologies. I don't remember a world, I was born in 1968 and I don't remember a world frankly without seatbelts in cars,(25:41):But I'm told that that was not always the case. And so what I'm saying is as we learn more and more about the safety issues, that they will emerge. To be very clear, I want to be a realist. I don't want to be Debbie Downer. I want to be Debbie Realist. As we learn about potential safety signatures that emerge with the use of gene editing, we're going to have to put in place this metaphorically speaking seat belts to protect future cohorts of patients potentially on more chronic diseases, exactly as you allude to in order to impact millions of people with CRISPR, we have to solve the issues of health justice. How do we make these more affordable? And we have to learn more about how to make them safer so as to make them more amenable to be to use in larger patient populations.Eric Topol (26:27):Oh, that's so well put. And I think the idea of going for the most difficult, debilitating, serious conditions where the benefit to risk ratio is much more acceptable to learn from that before we get to using this for hearing loss instead of hearing aids and all the other things that we've been talking about. Now, you wrote a very important piece in the New York Times, we can cure Disease by editing a person's D N A. Why aren't we? Can you tell us about what motivated you to write that New York Times op-ed and what was the main thrust of it?Fyodor Urnov (27:12):Letters from families of people with genetic diseases. Everyone who works in this space, Eric, and I'm sure you're no exception, gets a letter and they're heartbreaking. Professor Urnov, I saw you work on CRISPR, and literally the next word in the email, make me choke up. Will you save my dying angel? And I can't even say that without starting to choke up. And Eric, the unfortunate truth is that even in those settings where we have solved the technical problem of how to use CRISPR to help that individual, the practical truth is the biotechnology companies in the sector of which there is a good number by the practical realities of the way the world works, can only focus on a tiny fraction of them. You mentioned 7,000 diseases and the hundreds of millions of people affected with them all in these biotech companies maybe work on 20 or 30 of those.(28:10):What about the rest? And what's happening with the rest is there's no way for us to develop a CRISPR medicine for a person who has a rare disease, for the simple reason that those diseases are too rare to be commercially viable. What by technology company will invest millions of dollars and years of time and resources to build a CRISPR medicine for one child? Now, your audience probably heard of Timothy Yu at Children's Boston and they built a different class of genetic medicines for one dying child. Her name is Mila. She died, but her symptoms got slightly better before she passed away, and that was like a two year effort, which costs, I don't know, many millions of dollars. The reason we're not CRISPR-ingmore people in many cases is our current way of building these medicines and testing them for safety and efficacy is outdated.(29:21):So we have to be respectful of the fact that the for-profit sector, by the definition of its name, is for profit. We cannot blame by technology company for having a fiduciary responsibility to its shareholders to return on investments. What does that do to diseases which are not profitable? Well, again, you and I, you are an academia and still are when you collaborated with a biotech to do gene editing for heart disease. And I think that's exactly the model. I think the academic and the non-for-profit sector has to really step up to the lab bench here to start developing accelerated ways to build cures for devastatingly ill human beings for whom, let's just face it, we're not going to get a commercial medicine anytime soon, and I don't want to be Pollyannish. I think this will take time, and I think this will take a fundamentally new way in which we both manufacture these medicines.(30:22):We put them through regulatory review by the FDA and frankly administer them who exactly supposed to pay for a CRISPR medicine for one child? We don't know that. But the key point of my piece is that CRISPR is here now. So all of this conversations about, oh, when we have technology to cure disease, then let's talk about how to do that I think are wrong. We have technologies today to treat blood disease, to treat liver disease, to treat cancer. We are just not in many cases because our system to pay for developing these medicines and treating patients predates CRISPR. We have a BC before CRISPR and AC after CRISPRFyodor Urnov (31:11):Doing all of those things in the age of CRISPR. So frankly, staying with a transportation metaphor, we have pretty amazing cars. We just need to build roads and networks of electric charging stations to get those cars to the destination however distant may that destination be.Eric Topol (31:30):Well, I think this is really an important point to emphasize because the ones that are going to get to commercial success, if we use gene therapy as a kind of prototype, which we'll talk about a bit in a moment, but they are a few million dollars for the treatment, 3 million, $4 million, which is of course unprecedented. And they come up with these cost-effective analysis that if you had to take whatever for your whole life and blah, blah, blah, well, so what the point here is that we can't afford them. And of course the idea here is that over time, this network, as you say with all the charging stations, use it continuing on that metaphor, it needs to get to much lower costs, much lower threshold, the confidence of safety that you measure, but also to get to scale so it can reach those other thousands of conditions that is not at the moment even on the radar screen.(32:29):So I hope that that will occur. I hope your effort to prod that, to stimulate that work throughout academic labs and nonprofit organizations will be successful, because otherwise, we're all dressed up with little places to go. We're kind of in a place where it's exciting. It's like science fiction. We have cures for diseases that we didn't have treatments before. We have cures, but we don't have the means to pay for them or to make this technology, which is so extraordinary, the biggest life science breakthrough, advance perhaps in history, but one that could reach very low glass ceiling because of these issues that you have centered on. And I'm really grateful for you having gotten that out there.Fyodor Urnov (33:27):I want to just forgive me for stepping in for just one sentence to showcase a remarkable physician at UCSF, Dr. Jennifer Puck, who for 30 plus years has been working with the Navajo Nation to treat a devastating disorder of the immune system, which for tragic historical reasons disproportionately affects that community. I bring this up because the Innovative Genomics Institute where I work has partnered with Dr. Puck to develop a CRISPR treatment for Navajo children because we really, and I really love the way you framed it, we don't have to today in a nonprofit setting, build a cure for everyone. We need to build an example. How do you approach a disease for which the unmet need is enormous? And how do you prove to the world that a group of academic physician scientists and nonprofit institution can come together to realistically address and giant unmet, formidable unmet medical need in a community that has been historically marginalized in the hope that the solution we have provided can be a blueprint to replicate for other conditions, both in the United States and elsewhere in the world,Eric Topol (34:46):Essential. Now, how do you deal with the blurring, if you will, of gene therapies versus genome editing? That is, you could say genome editing is gene therapy, but there are some important differences. How do you conceptualize that?Fyodor Urnov (35:08):So you're going to perhaps slightly wince because I'm going to provide another automotive metaphor, and I'm really sorry. I should be more serious. Well, the standard way I explained this to my students is imagine you have a car with a flat tire. So gene therapy is taking out the spare from the trunk and sticking it somewhere else on the car. So now the car has a fifth wheel and hoping it runs. And believe it or not, that actually works. Gene editing is the flat.Eric Topol (35:39):That's good.Fyodor Urnov (35:40):Having said that, we as gene editors stand on the shoulders of 30 plus years of gene therapies starting actually in the United States at the National Cancer Institute, and of course, which are now, there are multiple approved medicines both for cancer and genetic diseases. And I really want to honor and salute not just the pioneers of this field, but the entire community of gene therapies who continue to push things forward. But I will admit, I am biased. Gene editing is a way to fix mutations right where they occur. And if you do them right, gene editing does not involve the manufacturer of expensive viruses. Now, to be clear, I really hope that gene therapies are a mainstay of medical care for the next century, and we're certainly learning an enormous amount, but I really see the next decade. Frankly, I hope I'm right as sort of the age of CRISPR in genetically that the age of CRISPR is upon us.Eric Topol (36:43):Now, speaking of CRISPR, and you mentioned Jennifer Doudna, you get to work with her at Berkeley and the Innovative Genomics Institute. What's it like to work with Jennifer?Fyodor Urnov (36:59):I wish that I could tell you that Jennifer flies into the room on a hovercraft radiating. Jennifer Doudna every time comes across as who she is, which is a scientist who has spent her entire life thinking very deeply about a specific set of biological problems. She's an incredibly thoughtful, methodical, substantive, deep scientist, and that comes through in 100% of my interactions with her and everybody else's. Her other feature is humility. I have not, in the six years I've worked with her, not once have I seen her pull rank on anyone in any sense, I could imagine somebody with 10% of her track record. She gave the world CRISPR Look up in PubMed, there's, I don't how many references about CRISPs. She starred an entire realm of biology and biomedicine. Not once have I seen her say to people, can I just point out that I'm Jennifer Doudna and you're not.(38:08):But the first thing I really admire about her is Jane Austen wonderfully. And satirically writes about one of her characters. He then retired to his estate where he could think with pleasure of his own importance. Jennifer Doudna is the inverse of that. She could retire and think with pleasure about her own impact. She's the inverse. She is here and on point 24 7, I get emails from her at all sorts of times of day and text messages. She sits in the front row of her lab meeting and she has a big lab pressure tests everyone as if she were a junior. Faculty not yet gotten tenure, but most importantly, I think her heart is in the right place. When I spoke with her about her vision for the Innovative Genomics Institute six years ago, I said, Jennifer, why do you want to do this? She said, I want to bring CRISPR to the world.(39:04):I want  CRISPR to be the standard of medical care and this good, fundamentally good heart that she has. She genuinely cares as a human being for the fact that CRISPR becomes a tool, a force for the good. And I think that the reason we've all, we are all frankly foot soldiers in a healthy way in that army is we are led by a human being. I jokingly, but with a modicum of seriousness. Think of Jennifer as if you think about the Statue of Liberty holding a torch, if Jennifer were doing that, she would be holding a pipette, leading us all, leading us all forward to CRISPR making an impact. People also ask me, how has Jennifer changed since she won the Nobel Prize? My answer is, she won the Nobel Prize. She hasn't, and I mean her schedule got worse. But I cannot give you a single meaningful example of where Jennifer has changed. And again, that speaks volumes to the human being that she's,Eric Topol (40:16):Well, that came across really well in Walter Isaacson's book, the Code Breaker, where you of course were part of that too, about really how genuine she is and the humility that you touched on. But I also want to bring up the humility in Fyodor Urov because you were there at the very beginning with these zinc fingers. You were putting them into cells and showing how they achieved genome editing. There was no CRISPR, there was no Cas9. You were onto this at a very early point, and so you describe yourself just now as a foot soldier, anything but that, I see you as a veritable pioneer in this field. And there's another thing about you that I think is very special, and that is your ability to communicate this complex area and get it where everyone can understand it, which is all the more important as it gets rolled out to become a realistic alternative to these conditions that we've been talking about. So for that and so many things, I'm indebted to you. So Fyodor, what have I missed? We can't cover everything. You could write encyclopedias about this and it's changing every week. But have I missed anything that's important in the field of genome editing that you should close on?Fyodor Urnov (41:46):Well, so as far as your gracious words, now that I'm no longer blushing like a ripe tomato, I do want to honor the enormous group of people, my colleagues at Sangamo and in the academic community for building genome editing 1.0 and you among a very select few leaders in biomedicine who saw early the promise of gene editing. Again, I showcase our collaboration as an example of what true vision in biomedicine can do. I think I would imagine that your audience might say, what about CRISPR for enhancement? Well, I personally don't see anything wrong with well-informed adult human beings agreeing to being gene edited to enhance some feature of themselves once we know that it is safe and effective. But we are years, maybe a decade away from that. So if any of those listening receive an email from CRISPRmebeautiful.com, offering a gene editing enhancement service report, that email as vial spam!(43:21):CRISPR is amazing. It's affecting agriculture medicine in so many different ways and fundamental research, it's making an astonishing progress in the clinic. Medically speaking today, it is exactly where it needs to be as an experimental treatment for severe disorders, all of us have a dream where you can be crisp, you can sort of tune your genes, if you will. I don't know if I will live to see that, but for now, all of us have one prize in mind, which is make CRISPR available as a safe and effective medicine for severe existing disease. And we are working hard towards that, and I think we have a legitimate foundation for good hope.Eric Topol (44:13):Yeah, I think that's putting it very solid. It's probably now with the experience to date, not just in those hundreds of patients and in clinical trials, it continues to look extraordinary that it is going to fulfill the great, and as you said, it's not just in medicine. Many other walks of life are benefiting from this. And a lot of people don't realize that when you do a successful xenotransplant and you otherwise would die, but you give them a pig heart and you edit  50, 60 different genes in critical places so that it appears to the body as a human heart transplant, one that won't be rejected. Theoretically, you open up areas like that that are just so exceptional. But to also highlight that we're not talking, we're talking about somatic genome editing already, genes that are sick or need to be adjusted, if you will, not the ones in embryos that change the human race. No, we're not going there. The off target affects the safety. We'll learn more and more about this in the times ahead and the short times ahead with all the more people that are getting the first lines of treatment. So Fyodor, thank you so much. Thank you for your friendship over this extended period of time. You've taught me so much over the years, and I'm so glad we have a chance to regroup here, to kind of assess the field as it stands today and how it's going to keep evolving at a high velocity.Fyodor Urnov (45:58):My goodness, Eric, it's been amazing, amazing honor. And I should also say, and this is the truth, my morning ritual consists of two things, a shot of espresso, and seeing if you've posted anything interesting on Twitter, that is how I wake up my brain to take on the day. So thank you for not just your amazing vision and extraordinary efforts as a scientist and a physician scientist, but also thank you for the remarkable work you do in making critical advances in medicine and framing them in their exact right way for a very large audience. And I'm humbled and honored by your invitation to speak with you today in this setting. Let's just say that the moment this comes out, I'm going to tell my mom. Mom, yes. What? Oh my gosh. I have spoken with Eric Topol. She will be very excited.Eric Topol (46:53):Well, you're much too kind and we'll leave it there and reconvene in the future for a update because it won't be long before there'll be some substantial ones. Peter, thank you so much.Fyodor Urnov (47:05):Truly, truly a pleasure. Thank you.Thanks for listening (or reading, or both) this Ground Truths podcastPlease share if you found it informative! All proceeds from Ground Truths go to Scripps Research. Get full access to Ground Truths at erictopol.substack.com/subscribe

You've probably heard of CRISPR, the revolutionary technology that allows us to edit the DNA in living organisms. Biochemist and 2023 Audacious Project grantee Jennifer Doudna earned the Nobel Prize for her groundbreaking work in this field -- and now she's here to tell us about its next world-changing advancement. She explains how her team at the Innovative Genomics Institute is pioneering a brand new field of science -- precision microbiome editing -- that uses CRISPR in an effort to solve seemingly insurmountable problems like asthma, Alzheimer's and climate change. (This ambitious idea is part of the Audacious Project, TED's initiative to inspire and fund global change.)

You've probably heard of CRISPR, the revolutionary technology that allows us to edit the DNA in living organisms. Biochemist and 2023 Audacious Project grantee Jennifer Doudna earned the Nobel Prize for her groundbreaking work in this field -- and now she's here to tell us about its next world-changing advancement. She explains how her team at the Innovative Genomics Institute is pioneering a brand new field of science -- precision microbiome editing -- that uses CRISPR in an effort to solve seemingly insurmountable problems like asthma, Alzheimer's and climate change. (This ambitious idea is part of the Audacious Project, TED's initiative to inspire and fund global change.)

You've probably heard of CRISPR, the revolutionary technology that allows us to edit the DNA in living organisms. Biochemist and 2023 Audacious Project grantee Jennifer Doudna earned the Nobel Prize for her groundbreaking work in this field -- and now she's here to tell us about its next world-changing advancement. She explains how her team at the Innovative Genomics Institute is pioneering a brand new field of science -- precision microbiome editing -- that uses CRISPR in an effort to solve seemingly insurmountable problems like asthma, Alzheimer's and climate change. (This ambitious idea is part of the Audacious Project, TED's initiative to inspire and fund global change.)

Walter Isaacson is an author of biographies on Elon Musk, Steve Jobs, Einstein, Benjamin Franklin, Leonardo da Vinci, and many others. Please support this podcast by checking out our sponsors: - MasterClass: https://masterclass.com/lexpod to get 15% off - NetSuite: http://netsuite.com/lex to get free product tour - BetterHelp: https://betterhelp.com/lex to get 10% off - ExpressVPN: https://expressvpn.com/lexpod to get 3 months free - Shopify: https://shopify.com/lex to get $1 per month trial Transcript: https://lexfridman.com/walter-isaacson-transcript EPISODE LINKS: Walter's Twitter: https://twitter.com/WalterIsaacson Walter's Instagram: https://www.instagram.com/walter_isaacson Walter's Website: https://isaacson.tulane.edu Walter's Books: Elon Musk: https://amzn.to/48aWSZC The Code Breaker: https://amzn.to/3EAa0cU Leonardo da Vinci: https://amzn.to/3RlFICB The Innovators: https://amzn.to/45R8gs4 Steve Jobs: https://amzn.to/3P9Ak2B American Sketches: https://amzn.to/45LM4PN Einstein: https://amzn.to/3r6Ttu6 Benjamin Franklin: https://amzn.to/44NobWW Kissinger: https://amzn.to/3RdTA1u The Wise Men: https://amzn.to/45LQDJX PODCAST INFO: Podcast website: https://lexfridman.com/podcast Apple Podcasts: https://apple.co/2lwqZIr Spotify: https://spoti.fi/2nEwCF8 RSS: https://lexfridman.com/feed/podcast/ YouTube Full Episodes: https://youtube.com/lexfridman YouTube Clips: https://youtube.com/lexclips SUPPORT & CONNECT: - Check out the sponsors above, it's the best way to support this podcast - Support on Patreon: https://www.patreon.com/lexfridman - Twitter: https://twitter.com/lexfridman - Instagram: https://www.instagram.com/lexfridman - LinkedIn: https://www.linkedin.com/in/lexfridman - Facebook: https://www.facebook.com/lexfridman - Medium: https://medium.com/@lexfridman OUTLINE: Here's the timestamps for the episode. On some podcast players you should be able to click the timestamp to jump to that time. (00:00) - Introduction (10:42) - Difficult childhood (27:47) - Jennifer Doudna (30:44) - Einstein (36:02) - Tesla (53:07) - Elon Musk's humor (57:17) - Steve Jobs' cruelty (1:00:41) - Twitter (1:12:50) - Firing (1:15:35) - Hiring (1:24:38) - Time management (1:32:22) - Groups vs individuals (1:36:08) - Mortality (1:39:40) - How to write (2:00:38) - Love & relationships (2:05:33) - Advice for young people

Artificial intelligence is clearly going to change our lives in multiple ways. But it's not yet obvious exactly how, and what the impacts will be. We can predict that certain jobs held by humans will probably be taken over by computers, but what about our thoughts? Will we still think and create in the same ways? Author and former Aspen Institute president Walter Isaacson has been writing biographies about big thinkers and innovators for decades, including Albert Einstein, Steve Jobs, Benjamin Franklin and Jennifer Doudna. Isaacson returned to the world of technology for his most recent book on Elon Musk. Journalist Andrew Ross Sorkin interviews Isaacson on stage at the Aspen Ideas Festival about whether a society fully integrated with AI can foster the same qualities shared by many influential people. Will A.I. augment the best that humans have to offer, or will it compete with or even degrade human intelligence? And are there some traits that technology just will never be able to replicate, like empathy and compassion?

Jennifer Doudna developed a method of genome editing along with her partner Emmanuelle Charpentier and together they won the Nobel Prize in Chemistry in 2020. Her unique journey from graduate student to Nobel prize winning scientist is chronicled by the biographer of geniuses, Walter Isaacson. His New York Times best-seller, The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race is available now.  See omnystudio.com/listener for privacy information.

Transformar nuestra herencia genética, alterar nuestros genomas con unas tijeras genéticas y reescribir el código de la vida? En este podcast de Parque Explora y la Academia Colombiana de Ciencias sobre el desarrollo de la tecnología CRISPR (clustered regulatory interspaced short palidromic repeats) y cómo los aportes de las investigadoras, Jennifer Doudna y Emanuelle Charpentier, fueron fundamentales para hacer de esta tecnología una herramienta genética apta de editar ADN, un logro enorme que las hizo merecedoras del premio nobel de química en el año 2020. “La sociedad nunca había tenido nada como esto… debemos seguir hacia adelante, con cautela y respeto ante el poder que hemos obtenido.” Una conversación sobre dos mujeres geniales, sobre las implicaciones éticas de esta tecnología, sobre la importancia de la investigación básica, el método experimental, la curiosidad, los buenos maestros y tutores para el avance de la ciencia. “El hecho de que Jennifer y yo hayamos recibido este premio puede lanzar a las niñas un contundente mensaje.” “el brindis más bonito fue el de Jack Szostak, el profesor de Harvard que había hecho que doudna se interesara por las maravillas del ARN en sus tiempos de estudiante de doctorado. szostak, que había ganado el premio nobel de medicina en 2009 con dos mujeres dijo: «solo una cosa puede ser mejor que ganar el premio nobel dijo; que lo gane una de tus alumnas»”, cuenta walter isaacson en “el código de la vida”, biografía de Jennifer Doudna. invitados: Juan McEwen, médico Ph.D. en ciencias de la vida, con una amplia trayectoria de investigación en biología molecular y como profesor y formador de investigadores en áreas como la ingeniería genética. “mi curiosidad me llevó a buscar herramientas moleculares que me permitieran conocer la naturaleza de los hongos”, una historia emocionante con maestras como la doctora ángela restrepo. es miembro de la academia colombiana de ciencias exactas, físicas y naturales. conversa con Óscar Mauricio Gómez, PhD en Microbiología.

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For risk-tolerant investors who love a good thrill, there are few industries more exciting than biotechnology. He Jiankui shocked the world in 2018 by announcing he'd genetically modified twins born in China. Two years later, Jennifer Doudna and Emmanuelle Charpentier shared the Nobel prize for developing CRISPR, and a globally-coordinated effort was embracing Moderna's innovative new mRNA approach to develop a COVID vaccine and make it universally available. Gene editing found its way into the clinic, enabling a new wave of checkpoint inhibitors to help the body proactively find and detect cancer. A more comprehensive understanding of the human genome - made possible by the cost of sequencing falling bellow $500 - has unlocked a new field of diagnostics to proactively screen patients. NVIDIA's recent investment in Recursion is the latest move to introduce AI into health care. Yet there are also several challenges that face this industry's extreme pace of innovation. Patent infringements are common, as the courtroom is continually used to determine who owns the most cutting-edge IP. Payments are still largely in the hands of insurers, who are still figuring out how to reimburse for proactive treatments. Patient privacy and regulations are polarizing topics that have kept several tech companies at bay. And several of the industry's most important players are undergoing leadership changes, which could result in consequences that impact both their customers and the system at-large. How should investors approach this roller-coaster that we call the biotech industry? Are there exciting new trends and scientific breakthroughs that demand our attention? Are there larger companies who capitalize on those trends by providing the picks and shovels to enable them? Are there smaller, 'off the radar' companies who are risky but also offer enormous potential upside? To help us answer those questions, we've brought in Manisha Samy, who has spent her career in health care and seen it from several different angles. 7investing CEO Simon Erickson begins by asking Manisha what she's most excited about in health care today. Manisha explains that AI is finding its way into new opportunities and that NVIDIA's recent $50 million investment in Recursion could be a good sign that AI is becoming more prevalent in drug development. Genomic sequencing leader Illumina has unlocked quite a bit of information about the human genome. This will help not only for designing new drugs, but could also unlock new breakthroughs in computing as well. The two then dive deeper into Illumina, whose short-read sequencing approach has reduced the cost of sequencing the human genome from $3 billion to less than $500 over the past two decades. Yet Illumina's spin-off and then attempted re-acquisition of its GRAIL subsidiary is facing scrutiny from customers, investors, and regulators. The FTC is demanding Illumina divest GRAIL due to antitrust concerns, the EU is slapping Illumina with fines for violating its process, and activist Carl Icahn has gotten a seat on the Board while Francis DeSouza has resigned as CEO. Is Illumina still a good company to invest in? Simon and Manisha then turn to Invitae, who is an adopter of Illumina's sequencing technology to provide diagnostics to screen for genomic variants or even cancers. After years of aggressively making acquisitions to support its top-line growth, Invitae is now undergoing a turnaround to fix several of the financial issues it's gotten itself into. Manisha discusses her thoughts on the company and it's bigger-picture vision and strategy. In the final segment, Manisha introduces three small-cap biotechnologies companies that she believes should be on the radar of interested investors: Nanostring Technologies, Ginkgo Bioworks and Caribou Biosciences. Don't miss out on future conversations like this! Join 7investing's free email list to get our podcasts and investing insights delivered directly to your Inbox! --- Send in a voice message: https://podcasters.spotify.com/pod/show/7investing/message

On Faster, Please! — The Podcast, I've interviewed guests on exciting new technologies like artificial intelligence, fusion energy, and reusable rockets. But today's episode explores another Next Big Thing: biotechnology. To discuss recent advances in CRISPR gene editing and their applications for medicine, I'm sitting down with Kevin Davies.Kevin is executive editor of The CRISPR Journal and author of the excellent 2020 book, Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing.In This Episode* CRISPR advances over the past decade (1:13)* What CRISPR therapies will come next? (8:46)* Non-medical applications of gene editing (13:11)* Bioweapons and the ethics of CRISPR (18:43)* Longevity and genetic enhancements (25:48)Faster, Please! is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber.Below is an edited transcript of our conversationCRISPR advances over the past decadeWhen people talk about AI, for instance, they might be talking about different versions or applications of AI—machine learning being one. So when we talk about CRISPR, are we just talking about one technique, the one they figured out back in 2012? Are there different ones? Are there improvements? So it's really a different technique. So how has that progressed?You're right. CRISPR has become shorthand for genome editing. But the version of CRISPR that was recognized with the Nobel Prize three years ago in 2020 to Jennifer Doudna and Emmanuelle Charpentier was for one, we can call it the traditional form of CRISPR. And if I refer to it again, I'll call it CRISPR-Cas9. Cas9 is the shorthand name for the enzyme that actually does the cutting of the DNA. But we are seeing extraordinary progress in developing new and even more precise and more nuanced forms of genome editing. They still kind of have a CRISPR backbone. They still utilize some of the same molecular components as the Nobel Prize–winning form of CRISPR. But in particular, I'm thinking of techniques called base editing and prime editing, both of which have commercial, publicly funded biotech companies pushing these technologies into the clinic. And I think over the next five to 10 years, increasingly what we refer to as “CRISPR genome editing” will be in the form of these sort of CRISPR 2.0 technologies, because they give us a much broader portfolio of DNA substitutions and changes and edits, and give the investigators and the clinicians much more precision and much more subtlety and hopefully even more safety and more guarantees of clinical efficiency.Right. That's what I was going to ask. One advantage is the precision, because you don't want to do it wrong. You don't want mutations. Do no harm first. A big advantage is maybe limiting some of the potential downsides.In the ideal gene-editing scenario, you would have a patient with, say, a genetic disease that you can pinpoint to a single letter of the genetic code. And we want to fix that. We want to zero in on that one letter—A, C, T, or G is the four-letter alphabet of DNA, as I hope most of your listeners know—and we want to revert that back to whatever most normal, healthy people have in their genetic code at that specific position. CRISPR-Cas9, which won the Nobel Prize, is not the technology to do that sort of single base edit. It can do many other things, and the success in the clinic is unquestionable already in just a few years. But base editing and, in particular, prime editing are the two furthest developed technologies that allow investigators to pinpoint exactly where in the genome we want to make the edit. And then without completely cutting or slicing the double helix of DNA, we can lay up the section of DNA that we want to replace and go in and just perform chemistry on that one specific letter of DNA. Now, this hasn't been proven in the clinic just yet. But the early signs are very, very promising that this is going to be the breakthrough genome-editing technology over the next 10 to 20 years.Is CRISPR in the wild yet, or are we still in the lab?No, we're in the clinic. We are in human patients. There are at least 200 patients who have already been in or are currently enrolled in clinical trials. And so far, the early results—there are a few caveats and exceptions—but so far the overwhelming mood of the field is one of bullish enthusiasm. I don't want to complete this interview without singling out this one particular story, which is the clinical trial that has been sponsored by CRISPR Therapeutics and Vertex Pharmaceuticals for sickle cell disease. These are primarily African-American patients in this country because the sickle cell mutation arose in Africa some 7,000 years ago.We're talking about a pretty big share of the African-American population.This is about 100,000 patients just in America, in the US alone. And it's been a neglected disease for all kinds of reasons, probably beyond the scope of our discussion. But the early results in the first few dozen patients who have been enrolled in this clinical trial called the exa-cel clinical trial, they've all been cured. Pretty much all cured, meaning no more blood transfusions, no more pain crises, no more emergency hospitalizations. It is a pretty miraculous story. This therapy is now in the hands of the FDA and is speeding towards—barring some unforeseen complication or the FDA setting the bar so high that they need the investigators to go back and do some further checks—this should be approved before the end of this year.There's a catch, though. This will be a therapy that, in principle, will become—once approved by the FDA and the EMA in Europe, of course—will become available to any sickle cell patient. The catch will, of course, be the cost or the price that the companies set, because they're going to look for a return on their investment. It's a fascinating discussion and there's no easy answer. The companies need to reward their shareholders, their investors, their employees, their staff, and of course build a war chest to invest in the next wave, the next generation of CRISPR therapies. But the result of that means that probably we're going to be looking at a price tag of, I mean, I'm seeing figures like $1.9 million per patient. So how do you balance that? Is a lifetime cure for sickle cell disease worth $2, maybe $3 million? Will this patient population be able to afford that? In many cases, the answer to that will be simply, no. Do you have to remortgage your house and go bankrupt because you had a genetic quirk at birth? I don't know quite how we get around this.Different countries will have different answers with different health systems. Do you have a sense of what that debate is going to be like in Washington, DC?It's already happening in other contexts. Other gene therapies have been approved over the last few years, and they come with eye-watering price tags. The highest therapy price that I've seen now is $3.5 million. Yes, there are discounts and waiver programs and all this sort of stuff. But it's still a little obscene. Now, when those companies come to negotiate, say, with the UK National Health Service, they'll probably come to an agreement that is much lower, because the Brits are not going to say that they're going to be able to afford that for their significant sickle cell population.Is it your best guess that this will be a treatment the government pays for?What's interesting and what may potentially shift the calculus here is that this particular therapy is the disease affects primarily African-Americans in the United States. That may change the political calculus, and it may indeed change the corporate calculus in the boardrooms of Vertex and CRISPR Therapeutics, who may not want the backlash that they're going to get when they say, “Oh, by the way, guys, it's $2 million or you're out of luck.”There are companies that are studying using CRISPR to potentially correct the mutations that cause genetic forms of blindness, genetic forms of liver disease.What CRISPR therapies will come next?And after this CRISPR treatment for sickle cell disease is available, what therapies will come next?Probably a bunch of diseases that most people, unless they are unfortunate enough to have it in their family, won't have heard of. There are companies that are studying using CRISPR to potentially correct the mutations that cause genetic forms of blindness, genetic forms of liver disease. It turns out the liver is an organ that is very amenable to taking up medicines that we can inject in the blood. The other big clinical success story has come from another company in the Boston area called Intellia Therapeutics. Also publicly traded. They've developed CRISPR therapies that you can inject literally into the body, rather than taking cells out and doing it in the lab and then putting those cells back in, as in the case of sickle cell.I'm not sure that was actually even clear: that you can do it more than one way.Yes.And obviously it sounds like it would be better if they could just inject you.Exactly. That's why people are really excited about this, because this now opens up the doors for treating a host of diseases. And I think over the next few years we will see a growing number of diseases, and it won't just be these rare sort of genetic diseases with often unpronounceable names. It may be things like heart disease. There's another company—they're all in Boston, it seems—Verve Therapeutics, which is taking one of these more recent gene-editing technologies that we talked about a minute ago, base editing, and saying that there's a gene that they're going to target that has been clearly linked with cholesterol levels. And if we can squash production of this gene, we can tap down cholesterol levels. That will be useful, in the first instance, for patients with genetic forms of high cholesterol. Fair enough. But if it works in them, then the plan is to roll this out for potentially thousands if not millions of adults in this country who maybe don't feel that they have a clearly defined genetic form of high cholesterol, but this method may still be an alternative that they will consider versus taking Atorvastatin for the rest of your life, for example.Where are the CRISPR cancer treatments?They're also making progress, too. Those are in clinical trials. A little more complicated. Of course, cancer is a whole slew of different diseases, so it's a little hard to say, “Yeah, we're making progress here, less so there.” But I think one of the most heartwarming stories—this is an n of one, so it's an anecdotal story—but there was a teenager in the UK treated at one of the premier London medical schools who had a base editing form of CAR T therapy. A lot of people have heard of CAR T therapy for various cancers. And she is now in remission. So again, early days, but we're seeing very positive signs in these early clinical tests.It sounds like we went from a period where it was all in the lab and that we might be in a period over the next five years where it sounds like a wave of potential treatments.I think so, yeah.And for as much as we've seen articles about “The Age of AI,” it really sounds like this could be the age of biotechnology and the age of CRISPR…I think CRISPR, as with most new technologies, you get these sort of hype cycles, right? Two and a half years ago, CRISPR, all the stocks were at peak valuations. And I went on a podcast to say, why are the CRISPR stocks so high? I wasn't really sure, but I was enjoying it at the time. And then, of course, we entered the pandemic. And the biotech sector, perversely, ironically, has really been hit hard by the economy and certainly by the market valuations. So all of the CRISPR gene-editing companies—and there are probably at least eight or 10 now that are publicly traded and many more poised to join them—their valuations are a fraction of what they were a couple of years ago. But I suspect as these first FDA approvals and more scientific peer review papers, of course, but more news of the clinical success to back up and extend what has already been clearly proven as a breakthrough technology in the lab with the Nobel Prize—doesn't get much better than that, does it?—then I think we're going to start to see that biotech sector soar once again.Certainly, there are a lot of computational aspects to CRISPR in terms of designing the particular stretches of nucleic acid that you're going to use to target a specific gene. And AI can help you in that quest to make those ever more precise.Non-medical applications of gene editingThere are also non-medical applications. Can you just give me a little state of play on how that's looking?I think one of the—when CRISPR…And agriculture.Feeding the planet, you could say.That's certainly a big application.It's a human health application—arguably the biggest application.I think one of the fun ones is the work of George Church at Harvard Medical School, who's been on 60 Minutes and Stephen Colbert and many other primetime shows, talking about his work using CRISPR to potentially resurrect the woolly mammoth, which sort of sounds like, “That's Jurassic Park on steroids. That's crazy.” But his view is that, no, if we had herds—if that's the technical term—of woolly mammoths—roaming Siberia and the frozen tundra, they'll keep the ground, the surface packed down and stop the gigatons of methane from leaching out into the atmosphere. We have just seen a week, I've been reading on social media, of the hottest temperatures in the world since records began. And that's nothing compared to what we're potentially going to see if all these greenhouse gases that are just under the surface in places like Siberia further leach into the atmosphere. So that's the sort of environmental cause that Church is on. I think many people think this is a rather foolish notion, but he's launched a company to get this off the ground called Colossal Biosciences, and they're raising a lot of money, it appears. I'm curious to see how it goes. I wish him well.Also, speaking of climate change, making crops more resilient to the heat. That's another I've heard…One of the journals I'm involved in, called GEN Biotechnology, just published a paper in which investigators in Korea have used CRISPR to modify a particular gene in the tomato genome to make it a higher source of vitamin D. And that may not seem to be the most urgent need, but the point is, we can now engineer the DNA of all kinds of plants and crops, many of which are under threat, whether it's from drought or other types of climate change or pests, bacteria, parasites, viruses, fungi, you name it. And in my book Editing Humanity, which came out a couple of years ago, there was a whole chapter listing a whole variety of threats to our favorite glass of orange juice in the morning. That's not going to exist. If we want that all-natural Florida orange juice, we're not going to have that option. We've either got to embrace what technology will allow us to do to make these orange crops more resistant to the existential threat that they're facing, or we're going to have to go drink something else.I started out talking about AI and machine learning. Does that play a role in CRISPR, either helping the precision of the technology or in some way refining the technology?Yeah, hopefully you'll invite me back in a year and I'll be able to give you a more concrete answer. I think the short answer is, yes. Certainly, there are a lot of computational aspects to CRISPR in terms of designing the particular stretches of nucleic acid that you're going to use to target a specific gene. And AI can help you in that quest to make those ever more precise. When you do the targeting in a CRISPR experiment, the one thing you don't want to have happen is for the little stretch of DNA that you've synthesized to go after the gene in question, you don't want that to accidentally latch onto or identify another stretch of DNA that just by statistical chance has the same stretch of 20 As, Cs, Ts, and Gs. AI can help give us more confidence that we're only honing in on the specific gene that we want to edit, and we're not potentially going to see some unforeseen, off-target editing event.Do you think when we look back at this technology in 10 years, not only will we see a wider portfolio of potential treatments, but we'll look at the actual technique and think, “Boy, back in 2012, it was a butchery compared to what we're doing; we were using meat cleavers, and now we're using lasers”?I think, yeah. That's a slightly harsh analogy. With this original form of CRISPR, published in 2012, Nobel Prize in 2020, one of the potential caveats or downsides of the technology is that it involves a complete snip of the double helix, the two strands of DNA, in order to make the edit. Base editing and prime editing don't involve that double-stranded severance. It's just a nick of one strand or the other. So it's a much more genetically friendly form of gene editing, as well as other aspects of the chemistry. We look forward to seeing how base and prime editing perform in the clinic. Maybe they'll run into some unforeseen hurdles and people will say, “You know what? There was nothing wrong with CRISPR. Let's keep using the originally developed system.” But I'm pretty bullish on what base and prime editing can do based on all of the early results have been published in the last few years on mice and monkeys. And now we're on the brink of going into the clinic.One medical scenario that they laid out would be, what if two people with a deadly recessive disease like sickle cell disease, or perhaps a form of cystic fibrosis, wanted to have a healthy biological child?Bioweapons and the ethics of CRISPRThis podcast is usually very optimistic. So we're going to leave all the negative stuff for this part of the podcast. We're going to rush through all the downsides very quickly.First question: Especially after the pandemic, a lot more conversation about bioweapons. Is this an issue that's discussed in this community, about using this technology to create a particularly lethal or virulent or targeted biological weapon?Not much. If a rogue actor or nation wanted to develop some sort of incredibly virulent bioweapon, there's a whole wealth of genetic techniques, and they could probably do it without involving CRISPR. CRISPR is, in a way, sort of the corollary of another field called synthetic biology or synthetic genomics that you may have talked about on your show. We've got now the facility, not just to edit DNA, but to synthesize custom bits of DNA with so much ease and affordability compared to five or 10 years ago. And we've just seen a global pandemic. When I get that question, I've had it before, I say, “Yeah, did we just not live through a global pandemic? Do we really need to be engineering organisms?” Whether you buy the lab leak hypothesis or the bioengineering hypothesis, or it was just a natural transfer from some other organism, nature can do a pretty good job of hurting human beings. I don't know that we need to really worry too much about bioweapons at this point.In 2018, there was a big controversy over a Chinese researcher who created some genome-edited babies. Yeah. Is there more to know about that story? Has that become a hotter topic of discussion as CRISPR has advanced?The Chinese scientist, He Jiankui, who performed those pretty abominable experiments was jailed for the better part of three years. He got early release in China and slowly but surely he's being rehabilitated. He's literally now moved his operation from Shenzhen to Beijing. He's got his own lab again, and he's doing genome editing experiments again. I saw again on social media recently, he's got a petition of muscular dystrophy families petitioning Jack Ma, the well-known Chinese billionaire, to fund his operation to devise a new gene editing therapy for patients with Duchenne muscular dystrophy and other forms of muscular dystrophy. I wouldn't want He Jiankui let within a thousand miles of my kids, because I just wouldn't trust him. And he's now more recently put out a manifesto stating he thinks we should start editing embryos again. So I don't know quite what is going on.It seems the Chinese threw the book at him. Three years is not a trivial prison sentence. He was fined about half a million dollars. But somebody in the government there seems to be okay with him back at the bench, back in the lab, and dabbling in CRISPR. And I don't know that he's been asked, does he have any regrets over the editing of Lulu and Nana. There was a third child born a few months later as well. All he will say is, “We moved too fast.” That is the only caveat that he has allowed himself to express publicly.We know nothing more about the children. They're close to five years old now. There's one particular gene that was being edited was pretty messed up. But we know it's not an essential gene in our bodies, because there are many people walking around who don't have a functional copy of this CCR5 receptor gene, and they're HIV resistant. That was the premise for He Jiankui's experiment. But he has said, “No, they are off limits. The authorities are not going to reveal their identities. We are monitoring them, and we will take care of them if anything goes wrong.” But I think a lot of people in the West would really like to help, to study them, to offer any medical assistance. Obviously, we have to respect their privacy. The twin girls and the third child who was born a bit later, maybe they're being protected for their own good. How would you like it if you grew up through childhood and into your teenage years, to walk around knowing that you were this human experiment? That may be a very difficult thing to live with. So more to come on that.There's no legitimate discussion about changing that in the West or anywhere else?Obviously, in the wake of what He Jiankui did, there were numerous blue ribbon panels, including one just organized by the National Academy of Sciences, just a stone's throw from where we're talking today. And I thought that report was very good. It did two things. This was published a couple of years ago. Two important things came out of it. One is this all-star group of geneticists and other scientists said, “We don't think that human embryo editing should be banned completely. There may be scenarios down the road where we actually would want to reserve this technology because nothing else would help bring about a particular medical outcome that we would like.” And the one medical scenario that they laid out would be, what if two people with a deadly recessive disease like sickle cell disease, or perhaps a form of cystic fibrosis, wanted to have a healthy biological child?There are clinics around the country and around the world now doing something called pre-implantation genetic diagnosis. If you have a family history of a genetic disease, you can encourage the couple to do IVF. We form an embryo or bunch of embryos in the test tube or on the Petri dish. And then we can do a little biopsy of each embryo, take a quick sneak peek at the DNA, look to see if it's got the bad gene or perhaps the healthy gene, and then sort of tag the embryos and only implant the embryos that we think are healthy. This is happening around the country as we speak for hundreds, if not thousands, of different genetic diseases. But it won't work if mom and dad have a recessive, meaning two copies of a bad gene, because there's no healthy gene that you can select in any of those embryos. It would be very rare, but in those scenarios, maybe embryo editing is a way we would want to go. But I don't see a big clamor for this right now. And the early results have been published using CRISPR on embryos in the wake of He Jiankui did have said, “It's a messy technique. It is not safe to use. We don't fully understand how DNA editing and DNA repair works in the human embryo, so we really need to do a whole lot more basic science, as we did in the original incarnation of CRISPR, before we even dare to revisit editing human embryos.” Longevity is interesting because, of course, in the last 18 months there's a company in Silicon Valley called Altos, funded by Yuri Milner, employing now two dozen of the top aging researchers who've been lured away from academia into this transnational company to find hopefully cures or insights into how to postpone aging. Longevity and genetic enhancementsAnother area is using these treatments not to fix things, but to enhance people, whether it's for intelligence or some other trait. A lot of money pouring into longevity treatments from Silicon Valley. Do we know more about the potential of CRISPR for either extending lifespans or selecting for certain desirable traits in people?This sort of scenario is never going to go away. When it comes up, if I hear someone say, “Could we use CRISPR or any gene editing technology to boost intelligence or mathematical ability or music musical ability, or anything that we might want…”Or speed in the hundred meters.“…or speed in the hundred meters, to enhance our perfect newborn?” I would say, what gene are you going to enhance? Intelligence—are you kidding me? Half of the 10,000 genes are expressed in the human brain. You want to start meddling with those? You wouldn't have a prayer of having a positive outcome. I think we can pretty much rule that out. Longevity is interesting because, of course, in the last 18 months there's a company in Silicon Valley called Altos, funded by Yuri Milner, employing now two dozen of the top aging researchers who've been lured away from academia into this transnational company to find hopefully cures or insights into how to postpone aging. That's going to be a long, multi-decade quest to go from that to potentially, “Oh, let's edit a little embryo, our newborn son or daughter so they have the gift of 120 years on this decaying, overheating planet…” Yes, there's a lot to wade through on that.And you have another book coming out. Can you give us a preview of that?I'm writing a book called Curved Air, which is about the story of sickle cell disease. It was first described in a paper from physicians in Chicago in 1910 who were studying the curious anemia of a dental student who walked into their hospital one day. That gentleman, Walter Noel, is now buried back in his homeland, the island of Grenada. But in the 1940s, it was described and characterized as the first molecular disease. We know more about sickle cell disease than almost any other genetic disease. And yet, as we touched on earlier, patients with this who have not had the wealth, the money, the influence, they've been discriminated against in many walks of life, including the medical arena.We're still seeing terribly, tragically, videos and stories and reports of sickle cell patients who are being turned away from hospital rooms, emergency rooms, because the medical establishment just looks at a person of color in absolute agony with one of these pain crises and just assumed, “Oh, they want another opioid hit. Sickle cell? What is that?” There's a lot of fascinating science. There's all this hope in the gene editing and now in the clinic. And there's all this socioeconomic and other history. So I'm going to try to weave all this together in a format that hopefully everyone will enjoy reading.Hopefully a book with a happy ending. Not every book about a disease has a wonderful…I think a positive note to end on is the first American patient treated in this CRISPR clinical trial for sickle cell disease four years ago,Victoria Gray, has become something of a poster child now. She's been featured on National Public Radio on awhole series of interviews and just took her first overseas flight earlier this year to London to speak at a CRISPR gene editing conference. She gave a lovely 15-minute personal talk, shaking with nerves, about her personal voyage, her faith in God, and what's brought her here now, pain-free, traveling the world, and got a standing ovation. You don't see many standing ovations at medical conferences or genetics conferences. And if ever anybody deserved it, somebody like Victoria Gray did. Early days, but a very positive journey that we're on. This is a public episode. If you'd like to discuss this with other subscribers or get access to bonus episodes, visit fasterplease.substack.com/subscribe

Nobel Prize-winning scientist Jennifer Doudna discusses how the technology she helped advance is treating diseases and raising ethical dilemmas. Gene editing is a game-changer for humanity. From health on individuals to the fate of the planet, the possible impacts of the technology are something previously found only in science fiction. But as with all scientific advancements that supercharge human capabilities and power, the technology comes with ethical questions. These possibilities and questions are at the core of this episode of the Crosscut Talks podcast.  We're listening in on a conversation between Nobel laureate and University of California Berkeley chemistry professor Jennifer Doudna and New York Times columnist and science writer Carl Zimmer as they discuss one of these technologies, CRISPR.   Doudna, who won the Nobel for her work with gene editing technology, explains the fundamental science behind CRISPR, how it's now being used by scientists to treat a wide range of diseases from HIV to sickle cell anemia, and where it might go from here. This conversation was recorded May 3, 2023. --- Credits Host: Paris Jackson Producer: Seth Halleran Event producers: Jake Newman, Anne O'Dowd Engineers: Resti Bagcal, Viktoria Ralph --- If you would like to support Crosscut, go to crosscut.com/membership. In addition to supporting our events and our daily journalism, members receive complete access to the on-demand programming of Seattle's PBS station, KCTS 9.

Nobel Peace Summit Medal for Social Activism winner Christine Ahn on the rift between North and South Korea; 2020 Nobel Prize winner for chemistry Jennifer Doudna on her journey in science; Leo C. Lee Lifetime Achievement Award winner Traci Tong on her past and future in journalism; Whiting Award winner R. Kikuo Johnson on his creative process and future plans

An account of how Nobel Prize winner Jennifer Doudna and her colleagues launched a revolution that will allow us to cure diseases, fend off viruses, and have healthier babies.

Stereo Chemistry's longtime host Kerri Jansen is stepping down from her role as executive producer of the podcast. Jansen has been with Stereo Chemistry since it began in 2018, and has played an integral role in the production of C&EN's flagship podcast. In this bonus episode, Jansen talks with C&EN's interim coeditors for audio & video, Ariana Remmel and Gina Vitale, about some of her favorite episodes from the Stereo Chemistry archives. Subscribe to Stereo Chemistry now on Apple Podcasts, Spotify, or wherever you listen to podcasts. A transcript of this episode is now available at https://cenm.ag/jansen-podcast. Listen to some of Kerri's favorite Stereo Chemistry episodes: How helium shortages have changed science Lithium mining's water use sparks bitter conflicts and novel chemistry Nobel laureates Frances Arnold and Jennifer Doudna on prizes, pandemics, and Jimmy Page A world without Rosalind Franklin Why chemists are excited by exascale computing There's more to James Harris's story Credits Producers/hosts: Ariana Remmel, Gina Vitale; Audio editor: Ariana Remmel, Mark Feuer DiTusa; Story editor: Michael McCoy, Krystal Vasquez; Copyeditor: Brianna Barbu; Logo design: William A. Ludwig; Episode artwork: Shutterstock/C&EN Staff; Music (in order of appearance): “Deer Dance” by Ian Post, “Hot Chocolate” by Aves, and “Sunbeam” by EFGR. Contact Stereo Chemistry: Tweet at us @cenmag or email cenfeedback@acs.org.

Jennifer Doudna is a Nobel laureate in chemistry and professor of biochemistry, biophysics and structural biology at the University of California, Berkeley. She has been a pioneer in CRISPR gene editing and continues to revolutionize research in her field. Doudna shares her Brief But Spectacular take on the future of CRISPR. PBS NewsHour is supported by - https://www.pbs.org/newshour/about/funders

Original broadcast date: January 7, 2022. New innovations in gene and stem cell technology have the power to shape ecosystems and even change humanity. This hour, TED speakers share the breakthroughs heralding the next scientific revolution. Guests include biochemist Jennifer Doudna, physicist and biotech entrepreneur Nabiha Saklayen and conservation innovator and biotech entrepreneur Ryan Phelan.TED Radio Hour+ subscribers now get access to bonus episodes, with more ideas from TED speakers and a behind the scenes look with our producers. A Plus subscription also lets you listen to regular episodes (like this one!) without ads. Sign-up at plus.npr.org/ted.

In this episode from the archives, originally published in February 2021, Jennifer Doudna, who won the 2020 Nobel Prize for the co-discovery of CRISPR-Cas9 with Emmanuelle Charpentier, chats with Vijay Pande, general partner at a16z Bio + Health. Together, they discuss  the future of biology, whether discovery itself can be engineered and industrialized, and how biology can shape our future.

The Third International Summit on Human Genome Editing was held this week in London. It was the first such meeting since 2018, when a Chinese researcher announced that he had created the world's first genetically edited babies—a move that was roundly condemned at the time. Host Alok Jha and Natasha Loder, The Economist's health editor, report from the conference to explore the exciting future—and knotty challenges—of the world that gene-editing therapies could create.Robin Lovell-Badge, a leading scientist at the Francis Crick Institute in London and the organiser of the summit, explains how genome-editing technology has rapidly advanced in recent years. Claire Booth, a professor of gene therapy and paediatric immunology at Great Ormond Street Hospital and University College London discusses the hopes of gene-editing treatments. Plus, Kelly Ormond, a bioethicist from ETH-Zurich, explores the ethical dilemmas that are raised by the technology, and Filippa Lentzos of King's College London, explains why human genome editing presents potential biosecurity risks.Listen to previous episodes of “Babbage” on the topic: the gene therapy revolution and an interview with Jennifer Doudna, the pioneer of CRISPR-Cas9 technology. For full access to The Economist's print, digital and audio editions subscribe at economist.com/podcastoffer and sign up for our weekly science newsletter at economist.com/simplyscience. Hosted on Acast. See acast.com/privacy for more information.

The Third International Summit on Human Genome Editing was held this week in London. It was the first such meeting since 2018, when a Chinese researcher announced that he had created the world's first genetically edited babies—a move that was roundly condemned at the time. Host Alok Jha and Natasha Loder, The Economist's health editor, report from the conference to explore the exciting future—and knotty challenges—of the world that gene-editing therapies could create.Robin Lovell-Badge, a leading scientist at the Francis Crick Institute in London and the organiser of the summit, explains how genome-editing technology has rapidly advanced in recent years. Claire Booth, a professor of gene therapy and paediatric immunology at Great Ormond Street Hospital and University College London discusses the hopes of gene-editing treatments. Plus, Kelly Ormond, a bioethicist from ETH-Zurich, explores the ethical dilemmas that are raised by the technology, and Filippa Lentzos of King's College London, explains why human genome editing presents potential biosecurity risks.Listen to previous episodes of “Babbage” on the topic: the gene therapy revolution and an interview with Jennifer Doudna, the pioneer of CRISPR-Cas9 technology. For full access to The Economist's print, digital and audio editions subscribe at economist.com/podcastoffer and sign up for our weekly science newsletter at economist.com/simplyscience. Hosted on Acast. See acast.com/privacy for more information.

The Sunday Times' tech correspondent Danny Fortson brings on Trevor Martin of Mammoth Biosciences, to talk about “programming biology” (4:10), the slow grind of innovation (7:25), CRISPR (10:20), the problems he's trying to solve (16:15), curing thousands of diseases (19:40), reaching for a science fiction future (24:40), meeting Nobel Prize winner Jennifer Doudna (27:40), starting the company (35:00), becoming the chief executive (38:50), raising $265m (43:45), and what comes next (47:15). Hosted on Acast. See acast.com/privacy for more information.

In 2012, the discovery of the gene-editing tool CRISPR-Cas9 revolutionised scientists' ability to modify DNA. Ten years on, host Alok Jha speaks to Jennifer Doudna, the Nobel laureate who pioneered the technology. She explains how CRISPR could transform healthcare and the food supply—and help with the fight against climate change. Plus, how does she grapple with the ethical questions raised by the technology she helped to invent?For full access to The Economist's print, digital and audio editions subscribe at economist.com/podcastoffer and sign up for our weekly science newsletter at economist.com/simplyscience. See acast.com/privacy for privacy and opt-out information.