Podcasts about lasker award

Virology vanguard Dr. Bob Gallo is far from ready to slow down. Now in his seventh decade as one of America's top scientists, he could easily sit back and enjoy the fruits of his numerous and pioneering achievements. His groundbreaking work began in the 1970s with research into human retroviruses, including the discovery of the T-cell growth factor (IL-2) and the identification of the Human T-Cell Lymphotropic Virus (HTLV-1) in 1980, earning him his first Lasker Award, often referred to as “America's Nobel Prize.” His subsequent research led to the identification of HIV-1 as the cause of AIDS, securing him a second Lasker Award. In the 1980s, he was the world's most cited scientist. Along with his team, he developed the first HIV blood test, crucial for understanding the spread of AIDS and managing HIV patients. In the mid 1990's Gallo and his collaborators discovered chemokines, naturally occurring compounds that were essential for understanding how HIV infects cells. Dr. Gallo later founded the Institute of Human Virology at the University of Maryland School of Medicine in 1996 and co-founded the Global Virus Network (GVN) in 2011 to enhance global virus detection and management. Recently, Dr. Gallo and his team moved to Tampa, the new global headquarters for GVN, where he now serves as director of the University of South Florida (USF) Virology Institute and Head of the Microbial Oncogenesis Program at the Cancer Institute at Tampa General Hospital (TGH).   In the first part of this wide-ranging interview, Dr. Gallo shares insights into his entry into virology and his initial research into the etiology of certain cancers. This work included crucial discoveries around T cell growth factors, paving the way for identifying HTLV-1. He discusses his collaboration with CDC epidemiologists, which led to recognizing AIDS as being caused by a retrovirus. Once the HIV virus was identified as the cause, creating the first blood test for HIV had profound impacts on the epidemic and patient care.   In the second segment, Dr. Gallo discusses the origins of the HIV virus and its early global spread. He also reflects on the COVID-19 pandemic, why the focus on its origins is irrelevant and reflects on how to rebuild public trust in science and medicine, which may have been damaged during the pandemic.   In the concluding segment, Dr. Gallo talks about his reasons for joining USF Health and TGH and the research areas he finds most promising going forward. He speculates on the prospects for an HIV vaccine, the impact of artificial intelligence on virology, and why he doesn't necessarily worry about the threat of the next global pandemic. Finally, Dr. Gallo opens up about how the early loss of his young sister deeply affected his life and his desired legacy. Dr Vega would like to thank her friend Job Meiller, her YES Man, for the wonderful musical contributions and coming through on every idea she has. This time he contributes his renditions of Bruce Springsteen's "Streets of Philadelphia" and "Your Song," by Elton John. Thank you Job! Thanks also to Dr. Ana Velez, our artistic contributor, for her painting, "HIV," used in our episode thumbnail.

The Chief Scientific Advisor at Novo Nordisk, Lotte Bjerre Knudsen, was the key force who pushed hard to develop GLP-1 drugs for treating obesity and subsequently for Alzheimer's. She was recently recognized by the 2024 Lasker Medical Research Award, and the 2024 AAAS Bhaumik Breakthrough of the Year Award. That recognition is richly deserved, since it is unclear if the GLP-1 drug path to obesity treatment, and all of the associated benefits, would have been seen at this time without her influence. That's especially true given the mystery for why people with Type 2 diabetes (for which these drugs were used for many years) did not exhibit much in the way of weight loss. We discussed that and the future of these drugs, including their potential to prevent neurodegenerative diseases. And about dressing up in pink!The Ground Truths podcasts are also available on Apple and Spotify.Our entire conversation can also be seen by video at YouTube along with all of the Ground Truths podcasts. If you like the video format, please subscribe to this channel. Even if you prefer video, please take a look at the transcript with graphics and useful links to citations.A Video Clip below on the barriers of a woman scientist to push Novo Nordisk to develop GLP-1 for obesity. “I was always just been a nerdy little scientist who kind of found home here in this company for 35 years.”—Lotte Bjerre Knudsen, 60 MinutesTranscript with Links to audio and external referencesEric Topol (00:06):Well, hello, it's Eric Topol with Ground Truths, and I have with me a special guest. She's the Chief Science Officer of Novo Nordisk and it's Lotte Bjerre Knudsen, and we're delighted to have her. She's a recent recipient of the Lasker Award, which I think is considered like the pre-Nobel Award here in the United States. And I was involved with her in terms of researching who was the principal person who brought the GLP-1 drugs to the forefront for obesity, and it turned out to be Lotte. So welcome, Lotte.Lotte Bjerre Knudsen (00:48):Thank you very much. And also very, very happy to be here. I'm not the Chief Science Officer for Novo Nordisk, I'm the Chief Scientific Advisor of working for the Chief Science Officer of Novo Nordisk, but maybe too many people, not so different, right?From Laundry Detergents to GLP-1 DrugsEric Topol (01:06):Yes. Thank you, I actually meant to say advisor, but yes, I'm glad you cleared that up. I know from speaking to some of your colleagues, I actually spoke to Robin yesterday that you are looked to very highly, the most highly regarded person in science there, so not surprisingly. What I want to do is first talk about the glucagon-like peptide-1 (GLP-1) that got its legs back in, I guess 1984. So we're going way back. And what's also interesting is that you go way back at Novo Nordisk to 35 years in 1989. And so, there had been this work with this extraordinary hormone and neurotransmitter with a very short half-life that you knew about. But when you first started in Novo Nordisk, you weren't working on this. As I understand it, you're working on laundry detergent enzymes. How did you make this pivot from the laundry enzymes to getting into the GLP-1 world?Lotte Bjerre Knudsen (02:16):Yeah, thank you for that question. I'm from the technical University of Denmark, so I'm trained in biotechnology, and we're a small country, so not that many companies to work for. And I always had my mind set on, I wanted to work for Novo as it was called back then, and it just happened to be in the industrial enzyme part that I got my foot in first. And then I had a very interesting boss at the time. Unfortunately, he's not alive anymore, but he was both a medical doctor as well as a chemist. So he was actually put in charge of actually, let's see if we can do something new in diabetes. And then since he hired me and I had not been there that long, I simply tagged along as the youngest scientist on the team, and then suddenly I became a diabetes researcher. Around the same time, I think you remember that all of pharma was interested in obesity in the early 90s, everyone wanted to do diabetes as well as obesity, but they were separate teams and they all wanted to do small molecules, but it just happens to be so that the best idea we could find at that time was actually GLP-1, because we actually had clinical data relatively early that GLP-1 was a really good candidate as a treatment for diabetes because of the glucose sensitivity of the actions.(03:43):So you'd have efficient lowering of glucose through a dual mechanism with increasing insulin, lowering glucagon, and then it was safe because there wasn't this hypoglycemia you get from insulin. But then I had other colleagues who were working on obesity, and I was just kind of listening, right, what's going on there? And then also a colleague that I had, we had, I don't know if you remember the old Hagedorn Research Institute, but Novo actually had kind of like an academic research institute that was affiliated with us. And there was this group that were working on this glucagon tumor model that produced high levels of glucagon, GLP-1 and PYY. And these rats, they starved themselves to death. And I knew about that from 1994. So that actually inspired my thinking. So when Stephen Bloom's paper came out in January of 1996, and he was the first one to call GLP-1 a neurotransmitter, I think, but I was already way into actually screening these kind of molecules that later then became liraglutide.No One Else Thought About This [Obesity](04:54):And then I thought, why on earth should we not actually do both things at the same time? If we have an idea that can both work in diabetes in a much safer way than in insulin, and then also at the same time work in obesity. But the reality is that no one else thought about this, or if they thought about it, they didn't really think that it would a good idea. But I think I had the luxury of being in a biotech company, so everyone was working with peptides and proteins. So I don't think I got the same challenge that the other people in the other pharma's got when they all wanted small molecules.Eric Topol (05:36):Well, also just to set the foundation here, which you alluded to, there had been so many attempts to come up with a drug that would work, not just of course in diabetes where there are many classes of drugs, but moreover, to treat the condition of obesity. Actually, I was involved with one of them, Rimonabant and did the large trial, which as you know, led to having to stop the drug, discontinue it because it was associated with suicidal ideation and actual some suicide. So there had been such a long history of checkered inability to come up with a drug. But what was striking is the challenge, and this is one of the first important questions about, when you had the extended half-life of the first GLP-1 drug, that instead of having to take multiple times a day, you could actually, with liraglutide get to a point where you were starting to get to an extended half-life. This is now going back to 1997 with approval in 2010, still 14 years ago. But when you came up with this drug, because this was certainly one of your great contributions, this drug was just a step along the way in this kind of iterative process, wouldn't you say? It wasn't the long half-life and the potency that eventually got us to where we are today. Is that true?Lotte Bjerre Knudsen (07:15):Yeah, it was a stepwise process. And what's super interesting about this class of medicines is that they're actually so different. If you talk about a class of medicine where small molecules, they can be different, but they're usually more alike than they're different. And when it comes to this class with these medium-sized peptides, people tried a whole bunch of different things. So they're actually really, really different. Some are simple peptides. So the idea that I came up with was to use this fatty acid isolation principle, and that's then a subclass in the class. And then the first, once weekly, for example, was an antibody-based molecule liraglutide. So they're much, much, much larger molecule compared to the small peptides. So they're very different. And neither the simple peptides nor the really big antibody derived molecules, they don't give a lot of weight loss. So we actually get more weight loss with these kinds of molecules, which is also why you can now see that it has actually kind of inspired a whole industry to kind of try and go and make similar kinds of molecules.Eric Topol (08:27):Well, inspired a whole industry is an understatement. It's become the most extraordinary class of drugs, I think in medical history, having been a student of various, I mean obviously statins have been a major contribution, but this seems to have transcended that already. We're going to talk about more about where things are headed, but this fatty acid acetylation was a major step forward in extending the half-life of the drug, whereby today you can give semaglutide once a week. And this, I think, of course, there are many ways that you might've been able to extend the half-life, but you were starting with a hormone, a natural hormone neurotransmitter that had such an exquisitely short half-life of basically second or minutes rather than that you could give for a week. So I know there were many different ways you could have protected or extended the half-life one way or another, but this seemed to be a breakthrough of many along the chain of breakthroughs. But the question I have is when you were giving this to the diabetics, which was the precedent, that was really what these drugs were first intended, they didn't lose that much weight, and they never, still today when it's looked at for obese non-diabetics versus diabetics, there's a gap in weight loss. Why is that at the exact same dose, with the exact same peptide that the weight loss differs for people with type 2 diabetes as compared to those who have pure obesity?The Mystery of Why People With Type 2 Diabetes Don't Lose Weight Like Those With Obesity Lotte Bjerre Knudsen (10:09):Yeah, I can't give you a molecular answer to that, right. But I think the notion, I think it's the same for example with metformin, even though it gives less weight loss because that has also been tried in both people with diabetes and people without diabetes. So I think it's just for somehow people with diabetes are more resistant to weight loss. I think it's a really good question that I'm hoping maybe we could get through, for example, with proteomics and actually comparing people with diabetes and people without diabetes and looking at people who have the similar kind of weight loss. That could be really interesting. But I really don't have a good molecular answer for you, but it's just a really, really strong fact. But it also leads me to wanting to say it's interesting, because if that had been our motivation to actually say, oh, there's weight loss in diabetes, let's pursue it in people with obesity, I don't think we would've done that because the weight loss in people with diabetes wasn't that impressive. So it was very important for our chain of thought and decision early on that we actually knew that GLP-1 had these separate effects and that they could work in the brain and have a separate effect on well-known pathways in the brain. And that was more our motivation to actually continue to invest in obesity.Eric Topol (11:42):Yeah, no, I think this is when we did the research on the committee for the American Association for Advancement of Science (AAAS) award, the Mani L. Bhaumik Award, that you were recognized for the breakthrough of the year, this year. We tried to scour all the work and we actually had to hit Danish translations and all sorts of other papers they reviewed. And we learned through that process working on this committee that you were the one to be the champion of pushing this towards obesity, and it would've easily been missed because as we've been discussing, the weight loss in people with diabetes was small, but you push for it. And this was an extraordinarily important push because what it has resulted in, of course, has been spectacular. And obviously as we're going to get into much more than just obesity and obesity related conditions. But before we get to those other conditions, and as you've been known in the medical community as “the mother of GLP-1”, you were dubbed that term. The GLP-1 receptor is expressed in many parts of the body. Maybe you could just tell us about the distribution because this, I think is tied into these central nervous system effects that are not just related to the gut hormone type of axis.GLP-1 Receptors and the BrainLotte Bjerre Knudsen (13:17):So I spent a lot of time on that together with my amazing colleague, Charles Pyke, who's an histology expert because it turned out to be so very important. In general, when you're trying to make new medicines, understanding the mechanism, sometimes people say, yeah, who cares? But actually, it should matter, I think because where it becomes really important can be an understanding what they do not do. We've had to do a lot of proving the negatives for GLP-1. We went through these issues with thyroid cancer, pancreatitis, pancreas cancer. In all of that work, it was actually really important that we could show where the GLP-1 receptor was not expressed. So in the pancreas, we know that it's primarily on the insulin producing cells, and then we also have them in the intestine where they're probably involved in regulating inflammation and really creating a much healthier gut.(14:15):And then we have a lot of receptors in the brain. They're typically expressed on neurons, but they're also on astrocytes, they're also on smooth muscle cells. We have them on the heart and the sinus node. That's why there's a small increase in heart rate. We have them in the kidney, on again some smooth muscle cells that are renin positive. So there we can start thinking blood pressure and other things. So it turns out that you can go around the body and there are all of these specific GLP-1 receptor population, that you can see how they tie into the pharmacology. But obviously in physiology, they're not as important as they have turned out to be in pharmacology when we suddenly come with 24 hours a day exposure for a day or a week or for as long as the administration interval is. So, but specifically for obesity, I think it's in the vein, it's hard to, you should always be careful.(15:18):That's something I've learned to never say never. Of course, there could be a contribution from the peripheral nervous system as well to the effects in obesity. But I do think there are so many important and well described neuronal populations that have the GLP-1 receptor and which are accessible from the periphery. So just to mention, maybe one of the most, well-known is a POMC/CART neuron in the hypothalamus. They have the GLP-1 receptor, they're activated, but there also is an inhibitory tone on the AgRP and NPY neurons, and it fits very well with that. We know that people report that they feel more sated, they feel less hungry. But then there are also effects in the hindbrain and in some of the reward centers also have GLP-1 receptors. And we know that also now, we have really good actually clinical studies that show that there is a change in food choice and people can control their food intake better. So I think that fits very well with effects on the reward system. So it's a whole myriad, or maybe you could say that GLP-1 orchestrates a number of different neuronal populations to have these overall effects that reduce energy intake.Eric Topol (16:42):Yeah, it's pretty striking. It's almost like we're all walking around with GLP-1 deficiency, that if we had this present at higher levels around the clock, and of course eventually we'll see things that are well beyond obesity, how well this has an impact. Now, there was an extraordinary review in Cell Metabolism on the brain and GLP-1, and not just the brain, but the essential nervous system, the neurovascular, it's called the “GLP-1 programs and neurovascular landscape.”(17:20):And in this review, it got into the brain effects that were well beyond, I think what are generally appreciated. Not only the protection of the integrity of the blood-brain barrier, this whole neuroglial vascular unit, the myelin sheath protection, reducing inflammation within the brain, improving the glymphatic flow, which is of course critical for clearing waste and promoting cerebral vascular remodeling and more, so the brain effects here is what it seems to be. You mentioned the reward circuit, of course, but the brain effects here seem to be diverse, quite a bit of breath and extraordinary. And as we've seen in the clinic now with the work that's been done, we're seeing things about addiction, even gambling, alcohol, drugs, I mean neuropsychiatric impact, it's pretty profound. Maybe you could comment about that.On to Alzheimer's and Parkinson's DiseasesLotte Bjerre Knudsen (18:23):Yeah. I haven't read that paper yet, but I just saw it earlier. And I have been following this for about actually more than 10 years because when I was kind of over the big work of actually getting the approval for diabetes and obesity. I thought I had a little bit of capacity to actually look at Alzheimer's and Parkinson's disease because I just thought there's such an insane unmet need and what if GLP-1 could actually make a difference? And the first big paper that talked about this was actually in Nature Medicine in 2003, and it was originally, I think I should credit Nigel Greig. Greig, he's from NIH or from NIA, I can't remember, right. But he was actually the first one, I think to say if GLP-1 has all of these important effects in the pancreas and to protect cells, and there are all these GLP-1 receptors in the brain, maybe it also protects neurons.(19:25):So that was the first hypothesis. And the paper on Nature Medicine in 2003 describes how the GLP-1 receptor in the hippocampus is involved in cognition. And then we did a couple of studies in different animal models, and I was, to be honest, really confused. But then there was a new paper in Nature Medicine in 2018 that started to focus in on neuroinflammation. And by that time, I knew much more about inflammation and knew GLP-1 actually lower CRP by about 50% in the different trials. So I was really tuned into the potential importance of that in cardiovascular and kidney disease. But I was like, oh, what if that's also something that is important in the brain? Then it made more sense to me to try and build some evidence for that. So that was how we actually started looking at a hypothesis for Alzheimer's and Parkinson's.(20:21):And we now have a really large phase three study ongoing, but of course, it's a hypothesis, right? And no one has yet, I think, proven that GLP-1 has really important effects on these indications, but we are testing it in 4,000 people with Alzheimer's disease. So our hypothesis is around neuroinflammation, but defined in a way where you could say it's both peripheral inflammation and the effect it has on the vasculature, it's the effect on the blood-brain barrier. It's the astrocytes and the microglia, and there are probably also some T cells that have the GLP-1 receptor that could be important. And then couple that up also with some of the new information from neurons, because there are two papers to think in the last year that has highlighted neurons either in the hindbrain or a little bit further on. Both of them are probably hindbrain populations that actually seem to be really important in regulating both peripheral as well as central information.(21:27):So what if neurons are actually also an overlooked mechanism here, and both of these neuronal populations have the GLP-1 receptor and are accessible from the periphery, even though the child super paper in Nature doesn't mention that, but they do have the GLP-1 receptor. So there are all these different mechanisms that GLP-1 can have an impact on the broad definition maybe of neuroinflammation. And maybe the way one should start thinking about it is to say it's not an anti-inflammatory agent, but maybe it induces homeostasis in these systems. I think that could maybe be a good way to think about it, because I think saying that GLP-1 is anti-inflammatory, I think that that's wrong because that's more for agents that have a really strong effect on one particular inflammatory pathway.Eric Topol (22:22):That's a very important point you're making because I think we conceive of these drugs as anti-inflammatory agents from these more diverse actions that we've just been reviewing. But I like this restoring homeostasis. It's an interesting way to put it. This brings us, you mentioned about the Parkinson's, and when I reviewed the three randomized Parkinson's trials, they're all small, but it appears to be the first disease modifying drug ever in Parkinson's. Of course, these were done with different drugs that were older drugs. We haven't seen the ones that yet to be with semaglutide or other agents. And I wondered if you pushed, just like you did for obesity within Novo Nordisk, you pushed to go into obesity. Did you also force to push for Alzheimer's?Lotte Bjerre Knudsen (23:19):Yes. So that is also me who had to argue for that. I'm happy to do these things. I was born brave. I am happy to do these things.Eric Topol (23:31):That's wonderful. Without you, we would be way behind, and it took decades to get to this point. But look where we are now, especially with all the rigorous trials, the large clinical trials. You're into one right now of some 20,000 participants to see whether not just people with prior heart disease, but people without known heart disease to see whether or not this will have an effect. And there's so much data now, of course, already a completed trial with reduction of heart attacks and strokes. But now to extend this to people who are not such high risk, but these large trials, we keep learning more. Like for example, the reduction of inflammatory markers is occurring even before the weight loss that starts to manifest. So we learned a lot from the trials that are just even beyond some of the major primary outcomes. Would you agree about that?Lotte Bjerre Knudsen (24:34):So I'm not sure we can say that it comes before the weight loss because the energy intake reduction happens instantly. The glycemic response happens instantly. And all of these improvements will of course also have an effect to dampen inflammation. We do not have data that supports that it comes before because we haven't sampled that much in the beginning.Eric Topol (25:04):Okay.Lotte Bjerre Knudsen (25:05):I wouldn't be able to say that, and I don't think there are any, well, it's hard to keep up that the entire literature on GLP-1 these days, but I don't think anyone has actually shown that there is a separation because it's super hard to separate when things are occurring at the same time.Eric Topol (25:24):Yeah, I'm just citing the heart disease trial where in the New England Journal that point was made. But I think your point also that there was already a change in energy intake immediately is apropos for sure. Now, when we get into this new paper of yours, the proteomics, can you tell us about that because that's really exciting. We're in a high throughput proteomics era right now that we can analyze thousands of plasma proteins in any given individual. What are you learning about proteomics with the GLP-1 drug?The GLP-1 Drug Impact on ProteomicsLotte Bjerre Knudsen (26:07):Yeah, yeah. So I'm also the super excited about omics, right? Because I have worked in a wonderful organization of people who can do these large scale clinical trials, and we used to not collect a lot of samples for future use, but we've done that for some years now. So now we have this amazing collection of samples we can learn from and actually both inform the patients and the physicians, but also inform future research. So we have been doing that in our semaglutide trials, and we've just published the proteomics data from the step one and step two trials. So the phase 3a trials that supported the approval of semaglutide for the treatment of obesity. So one of them in people with obesity and one in people with obesity and diabetes, and those data are now published in Nature Medicine. [3 January 2025]. And we were learning a lot of things because you can compare the proteome effects to what has been done in the decode cohort.(27:11):So they have all these disease signature. So that's one thing that you can for sure see, and you can see a lot of things there with hints towards addiction. And then also you can take more predefined signatures also to look into what actually might be driving the cardiovascular risk. So I think there are so many things that you can learn from this, and of course it can also inform when you look at what's actually mediating the effect and probably something around inflammation is important. We have already also shown a more standard mediation analysis that shows that actually the most explainable factor for the effect on MACE [major adverse cardiovascular events] in the select trial is inflammation. It doesn't explain everything, but it actually looks like it's more important than BMI and weight loss. So that's really interesting how much we can learn from there. We're making the data are available at the summary statistic level so people can go and play with them ourselves.(28:23):And I think as we have more different kinds of medicines available in obesity, it's also a way to kind of compare how these different medicines work. And as we get more and more better at maybe also characterizing people with obesity, because I think that's a great thing that's going to happen now is there's going to be more funding for obesity research. Because I think that's what the attention that we are seeing right now is also giving. Then we can better start to understand. We always, we've been saying that people probably have different kinds of obesity, but we don't really know. So now we can actually start to understand that much better and maybe also understand how these different classes of medicines will work if we have the proteome data from different trials.Eric Topol (29:10):No, I'm absolutely fascinated about the proteomics. I call it a quiet revolution because many people don't know about it. [My recent post on this topic here.](29:18):The ability to assess thousands of proteins in each individual, and it's giving us new insights about cause and effect as you alluded to, the relationship with as you said, MACE (major adverse cardiovascular events) and the actions of this drug class. I mean, there's just so much we can learn here from the proteomics. Another thing that's fascinating about the GLP-1 is its effect on epigenetic clocks. And recently at one of the meetings it was presented, this is Steven Horvath that we had on Ground Truths not long ago. He talked about at this talk that for the first time to see that you could basically slow the epigenetic clock with a GLP-1. Is there any further information about that?Lotte Bjerre Knudsen (30:16):Yeah, no. We've never had enough of a sample size to actually be able to look at it, so unfortunately, no. But there is something else, right, because there is this group at the Stanford, Tony Wyss-Coray or something.Eric Topol (30:33):Yes, Tony Wyss-Coray.Lotte Bjerre Knudsen (30:35):Now he published a paper, is it two years ago? Where he did it using proteomics. He defined an anti-aging signature for various different organs.Lotte Bjerre Knudsen (30:46):We are in the process of trying to see if we could take those signatures and apply them on to our data.Eric Topol (30:55):Well, what's interesting is we're pretty close friends, and he, not only that paper you mentioned on organ clocks, which is a phenomenal contribution, but he has a paper coming out soon in Nature Medicine, the preprint is up, and what he showed was that the brain and the immune system was the main organ clocks that were associated with longevity. And so, it takes another step further and it's looking at 11,000 plasma proteins. So it's really interesting how this field is evolving because the omics, as you put it, whether it's proteomics, and now we're learning also about the epigenome and what brings us to the potential that this class of drugs would have an impact on health span in all people, not just those who are obese. Would you project that's going to be possible in the years ahead?Lotte Bjerre Knudsen (32:02):I don't know about health span, but because certainly there's been so many studies with metformin and there's been a lot of wonderful data showing an effect on the epigenetic clocks, but not really an effect on lifespan because that metformin is so widely used. If that was the case, it would be easy to dig those data out of different registries. But certainly a healthier aging is the most obvious one because when you have one class of medicine that actually has so many different effects. Right now we are looking at them at a one by one case, but we really should be looking at them so you are getting the benefits on the heart and the vasculature on the brain and the kidneys and the diabetes and the knees. You're getting all of that at the same time, and that certainly should lead to much, much healthier lives. And then of course, we just need to get people to eat healthier. Also, maybe we should talk a little bit about the food industry. I heard you did that in some of your podcast, right?Eric Topol (33:17):Yes. That is the big food, if you will. It's a big problem, a very big problem, and the ultra-processed foods. And so, lifestyle is not good and trying to compensate for that with a drug intervention strategy is like chasing your tail. So you're absolutely right about that. I mean, I guess what I'm getting into here is that whereas today we keep seeing the effects, whether it's the liver, the kidney, the heart, obesity, and people with diabetes. But for example, in the Alzheimer's trial, do you have to be obese to be enrolled in the Alzheimer's trial, or is it just people who are at risk for developingAlzheimer's?Lotte Bjerre Knudsen (34:01):Yeah, no, you do not have to be obese. It's a standard Alzheimer's trial.GLP-1 PillsEric Topol (34:07):So this will be one of the really important trials to get a readout in people who are not having an obesity background. Now, the future, of course, gets us to oral GLP-1 drugs, which obviously you have there at Novo Nordisk. And it seems to me once that happens, if it can simulate the effects we see with the injectables, that would be another big step forward. What do you think about that?Lotte Bjerre Knudsen (34:39):Yeah. Isn't it interesting, what we've learned is that people actually don't mind the injections, right? Also, because I think it's simple, once a week injection and the needles are so small, obviously there are people who really have needle phobia, but take those aside, it's relatively few. I would argue if you close your eyes and somebody else used this needle on you, you would not be able to feel where it was inserted, right? They're so small. So it becomes maybe a personal preference. Would you like to have once a day or maybe twice a day tablets, or are you fine with once a week injection? And I think there probably will be quite a few once they've tried it. And now so many have tried it and they actually, maybe it gives us a simple lifestyle. You don't have to do it every day, right? You can just have a weekly reminder.Eric Topol (35:46):Yeah, no, I think that's really interesting what you're bringing up. I never thought we would evolve to a point where injectables were becoming some common, and I even have some physician colleagues that are taking three different injectable drugs.Lotte Bjerre Knudsen (36:00):That's also just mentioned Richard DiMarchi, who I shared the Breakthrough Prize with, and also Svetlana Mojsov, who I was one of the other two recipients for the Lasker prize because they both been at Rockefeller, and they both have worked a lot with peptides, and they both say the same thing. They were told so many times, this is not medicines, these kinds of molecules just they're not medicines. Forget about it. It turns out people were wrong. And peptides can be medicines, and they can even be produced also in a sustainable manner with fermentation, which is not a bad way of producing medicines. And people actually don't mind. Maybe some people actually even like it because it's once a week and then it's done.Confronting BarriersEric Topol (36:58):Yeah, no, that's a very important point. And the quest for the oral, which have more issues with bioavailability versus the peptides that are having such pronounced impact is really interesting to ponder. Well, before we wrap up, it's very clear the impact you've had has been profound, not just obviously at Novo Nordisk, but for the world of advancing health and medicine. And you've mentioned some of the key other people who have made seminal contributions, but I think you stand out because when we went deep into who took this field forward into obesity and who might also wind up being credited for Alzheimer's, it was you. And as a woman in science, especially in an era that you've been at Novo now for three and a half decades, there weren't many women in science leaders. And for one to be, as you said, you're brave for the good old boys to listen to the woman in science. Tell us about that challenge. Was this ever an issue in your career? Because obviously we want to have this whole landscape change. It is in the midst of change, but it's certainly still a ways to go. So maybe you can give us insight about that.Lotte Bjerre Knudsen (38:27):Yeah. Well, it for sure was a thing. It was a very male dominated world, and in a way, it might have prevented other people from doing it. But then, as I said, I was born brave for some reason. I'm not really sure why. It actually motivated me to kind of like, yeah, I'm going to show them. I'm going to show them. So it never really got to me that people, not everyone was nice to say. There was the first 10 years of my career, I think they were quite lonely, but then I was really inspired. I was so happy to be allowed to work on this. I thought it was super fun. And I did find people who wanted to play with me. And I also have to say that the CSO back then, Mads Krogsgaard Thomsen, he always supported me. So maybe I didn't get everything I wanted, but I always got what I needed in order to progress.(39:29):So on the women's side, and I think that yes, and there's still a change to be made, and I'm actually a little bit on behalf of my generation, maybe not too proud of the change we made because we didn't do a lot of change. It was all the women coming from the arts and the culture. They were the ones who actually make the big change here like 5 or 10 years ago. So I've also started to be more open about sharing my journey and advocating for women in science. So that's why I show up in pink to some of these award sessions just to be a little bit different and to maybe also just show that you don't have to be a certain type in order to fit into a certain job. But there is still a change to be made where people should be better at listening to what a person say and what ideas they say.(40:28):And they should be mindful about not always labeling women as passionate. When people call me passionate, I say like, no, thank you. I'm actually not too happy about the mother of either, because men always are being told. They're being told that they're brave and ambitious and courageous and strategic, whereas we we're, oh, you're so passionate. No, thank you. I'm also brave and strategic and ambitious and all of that. So we simply put different vocabulary on. I don't think people don't do it on purpose. I think we need to be better at actually giving people at work the same kind of vocabulary for their contributions. And I think that would mean that we get listened to in the same way. And that would be important. And then I also have to say that science, whether it comes from men or women, doesn't really matter.(41:32):Successful science is always the work of many. And I hope that some of you will actually listen to my last speech because that's what I speak about, how it's always the work of the many. And also, how if you want to do something novel, then you actually have to do it at a time when no one else is doing it, and you should believe in your ideas. So believe in it, listen to the critique, but believe in it, and then come back with new arguments or give up if you can't come up with any new arguments, right?Eric Topol (42:05):Well, we'll definitely put a link to the Lasker Awards speech that you gave. And I just want to say that the parallels here, for example, with Kati Karikó , my friend who had the Nobel Award for mRNA, she spent three decades trying to get people to listen to her and never got a grant from the NIH or other places [our conversation here]. And it was a really tough battle. And as you already touched on Svetlana Mojsov, who did some of the seminal work at Rockefeller to isolate the portion of GLP-1, that really was the key part peptide, and it was overlooked for years. And so, it's a tough fight, but you're paving the way here. And I think the contributions you've made are just so extraordinary. And I hope that over the years we will continue to see this momentum because people like what you've done, deserve this extraordinary recognition. I'm glad to see. And the Lasker Award is really capping off some of that great recognition that is so well deserved. We've covered a lot of ground today, and I want to make sure if I missed anything that you wanted to get into before we wrap up.Lotte Bjerre Knudsen (43:30):I think we've been around all the exciting biology of GLP-1, both in diabetes, obesity, cardiovascular, kidney, potential in Alzheimer's and addiction. We'll see, we need the clinical data and we've put out a message to inspire people to do new science. There's still a lot of unmet need out there. There's a lot of diseases that don't have good treatments. Even in the diseases we've talked about there's a lot of money for diabetes. There are no disease modifying therapies for diabetes. It's not really changing the course of the disease. So there's a lot of things that needs great scientists.Eric Topol (44:17):And I guess just in finishing the discovery of this class of drugs and what it's led to, tells us something about that, there's so much more to learn that is, this has taken on perhaps the greatest obstacle in medicine, which was could you safely treat obesity and have a marked effect. Which decades, many decades were devoted to that and gotten nowhere. It's like a breakthrough in another way is that here you have an ability to triumph over such a frustrating target, just like we've seen with Alzheimer's, of course, which may actually intersect with Alzheimer's, with a graveyard of failed drugs. And the ones that it were approved so far in certain countries, like the US are so questionable as to the safety and efficacy. But it gives us an inspiration about what is natural that can be built on the basic science that can lead to with people like you who push within the right direction, give the right nudges and get the support you need, who knows what else is out there that we're going to be discovering in the years ahead. It's a broad type of lesson for us.Lotte Bjerre Knudsen (45:38):Yeah, there is another hormone that's also in phase three clinical development, right? The amylin hormone. We've had pramlintide on the market for years, but we have this long-acting version that is in phase three clinical development. That could be the same kind of story because there's also additional biology on that one.Eric Topol (45:58):Yeah, this is what grabs me Lotte, because these gut hormone, we've known about them, and there's several more out there, of course. And look what they're having. They're not just gut hormones, like you said, they're neurotransmitters and they're body-wide receptors waiting to be activated, so it's wild. It's just wild. And I'm so glad to have had this conversation with you. Now, congratulations on all that you've done, and I know the Nature Medicine paper that just came out is going to be just one of many more to come in your career. So what a joy to have the chance to visit with you, and we'll be following the work that you and your colleagues are doing with great interest.Lotte Bjerre Knudsen (46:45):And thank you very much, and thank you for your wonderful podcast. They're really great to listen to on the go. Very easy listening.*****************************************Please complete the quick poll question above.Thank you for reading, listening and subscribing to Ground Truths.If you found this podcast informative please share it!All content on Ground Truths—its newsletters, analyses, and podcasts, are free, open-access.Paid subscriptions are voluntary and of course appreciated. All proceeds from them go to support Scripps Research. Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. I welcome all comments from paid subscribers and will do my best to respond to each of them and any questions.Thanks to my producer Jessica Nguyen and to Sinjun Balabanoff for audio and video support at Scripps Research.Ground Truths now has subscribers in 203 countries! Get full access to Ground Truths at erictopol.substack.com/subscribe

“The natural history of heart valve disease had not changed in hundreds of years—until Dr. Starr stepped in.”   In September 1960, Albert Starr performed the first successful valve-replacement surgery on a human patient. He placed a mechanical valve in the patient's heart that he and his collaborator, Lowell Edwards, developed. The patient survived for 10 years. Building on Starr's success, Alain Carpentier developed a method to use heart valves from pigs. Patients with mechanical valves need to take anticoagulants (blood thinners) for the rest of their lives. Carpentier's use of natural valves eliminated that need. Starr and Carpentier became good friends and colleagues. They shared the 2007 Lasker Award for the development of prosthetic heart valves; Edwards passed away before the Award was given.

“By the time we finished walking across this great lawn, we had decided on this exciting experiment.” —Elizabeth Blackburn on meeting her collaborator, Jack Szostak at a research conference. Elizabeth Blackburn, Carol Greider, and Jack Szostak won the 2006 Lasker Award for the prediction and discovery of telomerase, the enzyme that maintains the ends of chromosomes (telomeres). Blackburn and Szostak predicted the existence of such an enzyme, based on experiments they did in yeast and tetrahymena. Blackburn and Greider showed that this enzyme, telomerase, really does exist. The research of these three scientists broke open a new field and forever changed science and medicine.  

Lester Kiewit speaks to Professor Salim Abdool Karim who, along with his wife Professor Quarraisha Abdool Karim, were recently announced as winners of the prestigious Lasker Award for public service, a top recognition for medical research described as the “US equivalent of a Nobel prize” for science.See omnystudio.com/listener for privacy information.

Roderick MacKinnon won the 1999 Lasker Award for elucidating the structure of potassium channels. His work provided the first molecular description of an ion selective channel and helped knock down what he called “psychological barriers” in the field. After MacKinnon, the structure of transmembrane ion channels went from being seen as unsolvable to solvable. In this 1999 interview with Chris Miller, Professor of Biochemistry at Brandeis University, MacKinnon shares anecdotes from his early career, discusses how the field reacted to his groundbreaking work, and talks about what motivates him scientifically. This interview has been edited for clarity and brevity. Find the full 55-minute interview here: https://laskerfoundation.org/winners/function-and-structure-of-ion-channels/  

Dr. David Huang joins the show to share his story of developing optical coherence tomography (OCT), for which he, Dr. James Fujimoto, and Eric Swanson won the National Medal of Technology, the highest award for innovators in the United States, as well as the 2023 Lasker–DeBakey Clinical Medical Research Award, often called "America's Nobel Prize." For all episodes or to claim CME credit for selected episodes, visit www.aao.org/podcasts.

This is one of the most enthralling and fun interviews I've ever done (in 2 decades of doing them) and I hope that you'll find it stimulating and provocative. If you did, please share with your network.And thanks for listening, reading, and subscribing to Ground Truths.Recorded 4 December 2023Transcript below with external links to relevant material along with links to the audioERIC TOPOL (00:00):This is for me a real delight to have the chance to have a conversation with Geoffrey Hinton. I followed his work for years, but this is the first time we've actually had a chance to meet. And so this is for me, one of the real highlights of our Ground Truths podcast. So welcome Geoff.GEOFFREY HINTON (00:21):Thank you very much. It's a real opportunity for me too. You're an expert in one area. I'm an expert in another and it's great to meet up.ERIC TOPOL (00:29):Well, this is a real point of conversion if there ever was one. And I guess maybe I'd start off with, you've been in the news a lot lately, of course, but what piqued my interest to connect with you was your interview on 60 Minutes with Scott Pelley. You said: “An obvious area where there's huge benefits is healthcare. AI is already comparable with radiologists understanding what's going on in medical images. It's going to be very good at designing drugs. It already is designing drugs. So that's an area where it's almost entirely going to do good. I like that area.”I love that quote Geoff, and I thought maybe we could start with that.GEOFFREY HINTON (01:14):Yeah. Back in 2012, one of my graduate students called George Dahl who did speech recognition in 2009, made a big difference there. Entered a competition by Merck Frost to predict how well particular chemicals would bind to something. He knew nothing about the science of it. All he had was a few thousand descriptors of each of these chemicals and 15 targets that things might bind to. And he used the same network as we used for speech recognition. So he treated the 2000 descriptors of chemicals as if they were things in a spectrogram for speech. And he won the competition. And after he'd won the competition, he wasn't allowed to collect the $20,000 prize until he told Merck how he did it. And one of their questions was, what qsar did you use? So, he said, what's qsar? Now qsar is a field, it has a journal, it's had a conference, it's been going for many years, and it's the field of quantitative structural activity relationships. And that's the field that tries to predict whether some chemical is going to bind to something. And basically he'd wiped out that field without knowing its name.ERIC TOPOL (02:46):Well, it's striking how healthcare, medicine, life science has had somewhat of a separate path in recent AI with transformer models and also going back of course to the phenomenal work you did with the era of bringing in deep learning and deep neural networks. But I guess what I thought I'd start with here with that healthcare may have a special edge versus its use in other areas because, of course, there's concerns which you and others have raised regarding safety, the potential, not just hallucinations and confabulation of course a better term or the negative consequences of where AI is headed. But would you say that the medical life science AlphaFold2 is another example of from your colleagues Demis Hassabis and others at Google DeepMind where this is something that has a much more optimistic look?GEOFFREY HINTON (04:00):Absolutely. I mean, I always pivot to medicine as an example of all the good it can do because almost everything it's going to do there is going to be good. There are some bad uses like trying to figure out who to not insure, but they're relatively limited almost certainly it's going to be extremely helpful. We're going to have a family doctor who's seen a hundred million patients and they're going to be a much better family doctor.ERIC TOPOL (04:27):Well, that's really an important note. And that gets us to a paper preprint that was just published yesterday, on arXiv, which interestingly isn't usually the one that publishes a lot of medical preprints, but it was done by folks at Google who later informed me was a model large language model that hadn't yet been publicized. They wouldn't disclose the name and it wasn't MedPaLM2. But nonetheless, it was a very unique study because it randomized their LLM in 20 internists with about nine years of experience in medical practice for answering over 300 clinical pathologic conferences of the New England Journal. These are the case reports where the master clinician is brought in to try to come up with a differential diagnosis. And the striking thing on that report, which is perhaps the best yet about medical diagnoses, and it gets back Geoff to your hundred million visits, is that the LLM exceeded the clinicians in this randomized study for coming up with a differential diagnosis. I wonder what your thoughts are on this.GEOFFREY HINTON (05:59):So in 2016, I made a daring and incorrect prediction was that within five years, the neural nets were going to be better than radiologists that interpreting medical scans, it was sometimes taken out of context. I meant it for interpreting medical scans, not for doing everything a radiologist does, and I was wrong about that. But at the present time, they're comparable. This is like seven years later. They're comparable with radiologists for many different kinds of medical scans. And I believe that in 10 years they'll be routinely used to give a second opinion and maybe in 15 years they'll be so good at giving second opinions that the doctor's opinion will be the second one. And so I think I was off by about a factor of three, but I'm still convinced I was completely right in the long term.(06:55):So this paper that you're referring to, there are actually two people from the Toronto Google Lab as authors of that paper. And like you say, it was based on the large language PaLM2 model that was then fine-tuned. It was fine-tuned slightly differently from MedPaLM2  I believe, but the LLM [large language model] by themselves seemed to be better than the internists. But what was more interesting was the LLMs when used by the internists made the internists much better. If I remember right, they were like 15% better when they used the LLMs and only 8% better when they used Google search and the medical literature. So certainly the case that as a second opinion, they're really already extremely useful.ERIC TOPOL (07:48):It gets again, to your point about that corpus of knowledge that is incorporated in the LLM is providing a differential diagnosis that might not come to the mind of the physician. And this is of course the edge of having ingested so much and being able to play back those possibilities and the differential diagnosis. If it isn't in your list, it's certainly not going to be your final diagnosis. I do want to get back to the radiologist because we're talking just after the annual massive Chicago Radiologic Society of North America RSNA meeting. And at those meetings, I wasn't there, but talking to my radiology colleagues, they say that your projection is already happening. Now that is the ability to not just read, make the report. I mean the whole works. So it may not have been five years when you said that, which is one of the most frequent quotes in all of AI and medicine of course, as you probably know, but it's approximating your prognosis. Even nowGEOFFREY HINTON (09:02):I've learned one thing about medicine, which is just like other academics, doctors have egos and saying this stuff is going to replace them is not the right move. The right move is to say it's going to be very good at giving second opinions, but the doctor's still going to be in charge. And that's clearly the way to sell things. And that's fine, just I actually believe that after a while of that, you'll be listening to the AI system, not the doctors. And of course there's dangers in that. So we've seen the dangers in face recognition where if you train on a database that contains very few black people, you'll get something that's very good at recognizing faces. And the people who use it, the police will think this is good at recognizing faces. And when it gives you the wrong identity for a person of color, then the policemen are going to believe it. And that's a disaster. And we might get the same with medicine. If there's some small minority group that has some distinctly different probabilities of different diseases, it's quite dangerous for doctors to get to trust these things if they haven't been very carefully controlled for the training data.ERIC TOPOL (10:17):Right. And actually I did want to get back to you. Is it possible for the reason why in this new report that the LLMs did so well is that some of these case studies from New England Journal were part of the pre-training?GEOFFREY HINTON (10:32):That is always a big worry. It's worried me a lot and it's worried other people a lot because these things have pulled in so much data. There is now a way round that at least for showing that the LLMs are genuinely creative. So he's a very good computer science theorist at Princeton called Sanjeev Arora, and I'm going to attribute all this to him, but of course, all the work was done by his students and postdocs and collaborators. And the idea is you can get these language models to generate stuff, but you can then put constraints on what they generate by saying, so I tried an example recently, I took two Toronto newspapers and said, compare these two newspapers using three or four sentences, and in your answer demonstrate sarcasm, a red herring empathy, and there's something else. But I forget what metaphor. Metaphor.ERIC TOPOL (11:29):Oh yeah.GEOFFREY HINTON (11:29):And it gave a brilliant comparison of the two newspapers exhibiting all those things. And the point of Sanjeev Arora's work is that if you have a large number of topics and a large number of different things you might demonstrate in the text, then if I give an topic and I say, demonstrate these five things, it's very, anything in the training data will be on that topic demonstrating those five skills. And so when it does it, you can be pretty confident that it's original. It's not something it saw in the training data. That seems to me a much more rigorous test of whether it generates new stuff. And what's interesting is some of the LLMs, the weaker ones don't really pass the test, but things like GPT-4 that passes the test with flying colors, that definitely generates original stuff that almost certainly was not in the training data.ERIC TOPOL (12:25):Yeah. Well, that's such an important tool to ferret out the influence of pre-training. I'm glad you reviewed that. Now, the other question that most people argue about, particularly in the medical sphere, is does the large language model really understand? What are your thoughts about that? We're talking about what's been framed as the stochastic parrot versus a level of understanding or enhanced intelligence, whatever you want to call it. And this debate goes on, where do you fall on that?GEOFFREY HINTON (13:07):I fall on the sensible side. They really do understand. And if you give them quizzes, which involve a little bit of reasoning, it's much harder to do now because of course now GPT-4 can look at what's on the web. So you are worried if I mention a quiz now, someone else may have given it to GPT-4, but a few months ago when you did this before, you could see the web, you could give it quizzes for things that it had never seen before and it can do reasoning. So let me give you my favorite example, which was given to me by someone who believed in symbolic reasoning, but a very honest guy who believed in symbolic reasoning and was very puzzled about whether GT four could do symbolic reasoning. And so he gave me a problem and I made it a bit more complicated.(14:00):And the problem is this, the rooms in my house are painted white or yellow or blue, yellow paint fade to white within a year. In two years' time, I would like all the rooms to be white. What should I do and why? And it says, you don't need to paint the white rooms. You don't need to paint the yellow rooms because they'll fade to white anyway. You need to paint the blue rooms white. Now, I'm pretty convinced that when I first gave it that problem, it had never seen that problem before. And that problem involves a certain amount of just basic common sense reasoning. Like you have to understand that if it faded to yellow in a year and you're interested in the stage in two years' time, two years is more than one year and so on. When I first gave it the problem and didn't ask you to explain why it actually came up with a solution that involved painting the blue rooms yellow, that's more of a mathematician solution because it reduces it to a solved problem. But that'll work too. So I'm convinced it can do reasoning. There are people, friends of mine like Jan Leike, who is convinced it can't do reasoning. I'm just waiting for him to come to his sense.ERIC TOPOL (15:18):Well, I've noticed the back and forth with you and Yann (LeCun) [see above on X]. I know it's a friendly banter, and you, of course, had a big influence in his career as so many others that are now in the front leadership lines of AI, whether it's Ilya Sutskever at OpenAI, who's certainly been in the news lately with the turmoil there. And I mean actually it seems like all the people that did some training with you are really in the leadership positions at various AI companies and academic groups around the world. And so it says a lot about your influence that's not just as far as deep neural networks. And I guess I wanted to ask you, because you're frequently regarded to as the godfather of AI, and what do you think of that getting called that?GEOFFREY HINTON (16:10):I think originally it wasn't meant entirely beneficially. I remember Andrew Ng actually made up that phrase at a small workshop in the town of Windsor in Britain, and it was after a session where I'd been interrupting everybody. I was the kind of leader of the organization that ran the workshop, and I think it was meant as kind of I would interrupt everybody, and it wasn't meant entirely nicely, I think, but I'm happy with it.ERIC TOPOL (16:45):That's great.GEOFFREY HINTON (16:47):Now that I'm retired and I'm spending some of my time on charity work, I refer to myself as the fairy godfather.ERIC TOPOL (16:57):That's great. Well, I really enjoyed the New Yorker profile by Josh Rothman, who I've worked with in the past where he actually spent time with you up in your place up in Canada. And I mean it got into all sorts of depth about your life that I wasn't aware of, and I had no idea about the suffering that you've had with the cancer of your wives and all sorts of things that were just extraordinary. And I wonder, as you see the path of medicine and AI's influence and you look back about your own medical experiences in your family, do you see where we're just out of time alignment where things could have been different?GEOFFREY HINTON (17:47):Yeah, I see lots of things. So first, Joshua is a very good writer and it was nice of him to do that.(17:59):So one thing that occurs to me is actually going to be a good use of LLMs, maybe fine tune somewhat differently to produce a different kind of language is for helping the relatives of people with cancer. Cancer goes on a long time, unlike, I mean, it's one of the things that goes on for longest and it's complicated and most people can't really get to understand what the true options are and what's going to happen and what their loved one's actually going to die of and stuff like that. I've been extremely fortunate because in that respect, I had a wife who died of ovarian cancer and I had a former graduate student who had been a radiologist and gave me advice on what was happening. And more recently when my wife, a different wife died of pancreatic cancer, David Naylor, who you knowERIC TOPOL (18:54):Oh yes.GEOFFREY HINTON (18:55):Was extremely kind. He gave me lots and lots of time to explain to me what was happening and what the options were and whether some apparently rather flaky kind of treatment was worth doing. What was interesting was he concluded there's not much evidence in favor of it, but if it was him, he'd do it. So we did it. That's where you electrocute the tumor, being careful not to stop the heart. If you electrocute the tumor with two electrodes and it's a compact tumor, all the energy is going into the tumor rather than most of the energy going into the rest of your tissue and then it breaks up the membranes and then the cells die. We don't know whether that helped, but it's extremely useful to have someone very knowledgeable to give advice to the relatives. That's just so helpful. And that's an application in which it's not kind of life or death in the sense that if you happen to explain it to me a bit wrong, it's not determining the treatment, it's not going to kill the patient.(19:57):So you can actually tolerate it, a little bit of error there. And I think relatives would be much better off if they could talk to an LLM and consult with an LLM about what the hell's going on because the doctors never have time to explain it properly. In rare cases where you happen to know a very good doctor like I do, you get it explained properly, but for most people it won't be explained properly and it won't be explained in the right language. But you can imagine an LLM just for helping the relatives, that would be extremely useful. It'd be a fringe use, but I think it'd be a very helpful use.ERIC TOPOL (20:29):No, I think you're bringing up an important point, and I'm glad you mentioned my friend David Naylor, who's such an outstanding physician, and that brings us to that idea of the sense of intuition, human intuition, versus what an LLM can do. Don't you think those would be complimentary features?GEOFFREY HINTON (20:53):Yes and no. That is, I think these chatbots, they have intuition that is what they're doing is they're taking strings of symbols and they're converting each symbol into a big bunch of features that they invent, and then they're learning interactions between the features of different symbols so that they can predict the features of the next symbol. And I think that's what people do too. So I think actually they're working pretty much the same way as us. There's lots of people who say, they're not like us at all. They don't understand, but there's actually not many people who have theories of how the brain works and also theories of how they understand how these things work. Mostly the people who say they don't work like us, don't actually have any model of how we work. And it might interest them to know that these language models were actually introduced as a theory of how our brain works.(21:44):So there was something called what I now call a little language model, which was tiny. I introduced in 1985, and it was what actually got nature to accept our paper on back propagation. And what it was doing was predicting the next word in a three word string, but the whole mechanism of it was broadly the same as these models. Now, the models are more complicated, they use attention, but it was basically you get it to invent features for words and interactions between features so that it can predict the features of the next word. And it was introduced as a way of trying to understand what the brain was doing. And at the point at which it was introduced, the symbolic AI peoples didn't say, oh, this doesn't understand. They were perfectly happy to admit that this did learn the structure in the tiny domain, the tiny toy domain it was working on. They just argued that it would be better to learn that structure by searching through the space of symbolic rules rather than through the space of neural network weights. But they didn't say this is an understanding. It was only when it really worked that people had to say, well, it doesn't count.ERIC TOPOL (22:53):Well, that also something that I was surprised about. I'm interested in your thoughts. I had anticipated that in Deep Medicine book that the gift of time, all these things that we've been talking about, like the front door that could be used by the model coming up with the diagnoses, even the ambient conversations made into synthetic notes. The thing I didn't think was that machines could promote empathy. And what I have been seeing now, not just from the notes that are now digitized, these synthetic notes from the conversation of a clinic visit, but the coaching that's occurring by the LLM to say, well, Dr. Jones, you interrupted the patient so quickly, you didn't listen to their concerns. You didn't show sensitivity or compassion or empathy. That is, it's remarkable. Obviously the machine doesn't necessarily feel or know what empathy is, but it can promote it. What are your thoughts about that?GEOFFREY HINTON (24:05):Okay, my thoughts about that are a bit complicated, that obviously if you train it on text that exhibits empathy, it will produce text that exhibits empathy. But the question is does it really have empathy? And I think that's an open issue. I am inclined to say it does.ERIC TOPOL (24:26):Wow, wow.GEOFFREY HINTON (24:27):So I'm actually inclined to say these big chatbots, particularly the multimodal ones, have subjective experience. And that's something that most people think is entirely crazy. But I'm quite happy being in a position where most people think I'm entirely crazy. So let me give you a reason for thinking they have subjective experience. Suppose I take a chatbot that has a camera and an arm and it's being trained already, and I put an object in front of it and say, point at the object. So it points at the object, and then I put a prism in front of its camera that bends the light race, but it doesn't know that. Now I put an object in front of it, say, point at the object, and it points straight ahead, sorry, it points off to one side, even though the object's straight ahead and I say, no, the object isn't actually there, the object straight ahead. I put a prism in front of your camera and imagine if the chatbot says, oh, I see the object's actually straight ahead, but I had the subjective experience that it was off to one side. Now, if the chatbot said that, I think it would be using the phrase subjective experience in exactly the same way as people do,(25:38):Its perceptual system told it, it was off to one side. So what its perceptual system was telling, it would've been correct if the object had been off to one side. And that's what we mean by subjective experience. When I say I've got the subjective experience of little pink elephants floating in front of me, I don't mean that there's some inner theater with little pink elephants in it. What I really mean is if in the real world there were little pink elephants floating in front of me, then my perceptual system would be telling me the truth. So I think what's funny about subjective experiences, not that it's some weird stuff made of spooky qualia in an inner theater, I think subjective experiences, a hypothetical statement about a possible world. And if the world were like that, then your perceptual system will be working properly. That's how we use subjective experience. And I think chatbots can use it like that too. So I think there's a lot of philosophy that needs to be done here and got straight, and I didn't think we can lead it to the philosophers. It's too urgent now.ERIC TOPOL (26:44):Well, that's actually a fascinating response and added to what your perception of understanding it gets us to perhaps where you were when you left Google in May this year where you had, you saw that this was a new level of whatever you want to call it, not AGI [artificial general intelligence], but something that was enhanced from prior AI. And you basically, in some respects, I wouldn't say sounded any alarms, but you were, you've expressed concern consistently since then that we're kind of in a new phase. We're heading in a new direction with AI. Could you elaborate a bit more about where you were and where your mind was in May and where you think things are headed now?GEOFFREY HINTON (27:36):Okay, let's get the story straight. It's a great story. The news media puts out there, but actually I left Google because I was 75 and I couldn't program any longer because I kept forgetting what the variables stood for. I took the opportunity also, I wanted to watch a lot of Netflix. I took the opportunity that I was leaving Google anyway to start making public statements about AI safety. And I got very concerned about AI safety a couple of months before. What happened was I was working on trying to figure out analog ways to do the computation so you could do these larger language models for much less energy. And I suddenly realized that actually the digital way of doing the computation is probably hugely better. And it's hugely better because you can have thousands of different copies of exactly the same digital model running on different hardware, and each copy can look at a different bit of the internet and learn from it.(28:38):And they can all combine what they learned instantly by sharing weights or by sharing weight gradients. And so you can get 10,000 things to share their experience really efficiently. And you can't do that with people. If 10,000 people go off and learn 10,000 different skills, you can't say, okay, let's all average our weight. So now all of us know all of those skills. It doesn't work like that. You have to go to university and try and understand what on earth the other person's talking about. It's a very slow process where you have to get sentences from the other person and say, how do I change my brain? So I might've produced that sentence, and it's very inefficient compared with what these digital models can do by just sharing weights. So I had this kind of epiphany. The digital models are probably much better. Also, they can use the back propagation algorithm quite easily, and it's very hard to see how the brain can do it efficiently. And nobody's managed to come up with anything that'll work in real neural nets as comparable to back propagation at scale. So I had this sort of epiphany, which made me give up on the analog research that digital computers are actually just better. And since I was retiring anyway, I took the opportunity to say, Hey, they're just better. And so we'd better watch out.ERIC TOPOL (29:56):Well, I mean, I think your call on that and how you back it up is really, of course had a big impact. And of course it's still an ongoing and intense debate, and in some ways it really was about what was the turmoil at OpenAI was rooted with this controversy about where things are, where they're headed. I want to just close up with the point you made about the radiologists, and not to insult them by saying they'll be replaced gets us to where we are, the tension of today, which is our humans as the pinnacle of intelligence going to be not replaced, but superseded by the likes of AI's future, which of course our species can't handle that a machine, it's like the radiologist, our species can't handle that. There could be this machine that could be with far less connections, could do things outperform us, or of course, as we've, I think emphasized in our conversation in concert with humans to even take it to yet another level. But is that tension about that there's this potential for machines outdoing people part of the problem that it's hard for people to accept this notion?GEOFFREY HINTON (31:33):Yes, I think so. So particularly philosophers, they want to say there's something very special about people. That's to do with consciousness and subjective experience and sentience and qualia, and these machines are just machines. Well, if you're a sort of scientific materialist, most of us are brain's just a machine. It's wrong to say it's just a machine because a wonderfully complex machine that does incredible things that are very important to people, but it is a machine and there's no reason in principle why there shouldn't be better machines than better ways of doing computation, as I now believe there are. So I think people have a very long history of thinking. They're special.(32:19):They think God made them in his image and he put them at the center of the universe. And a lot of people have got over that and a lot of people haven't. But for the people who've got over that, I don't think there's any reason in principle to think that we are the pinnacle of intelligence. And I think it may be quite soon these machines are smarter than us. I still hope that we can reach a agreement with the machines where they act like benevolent parents. So they're looking out for us. They have, we've managed to motivate them, so the most important thing for them is our success, like it is with a mother and child, not so much for men. And I would really like that solution. I'm just fearful we won't get it.ERIC TOPOL (33:15):Well, that would be a good way for us to go forward. Of course, the doomsayers and the people that are much worse at their level of alarm tend to think that that's not possible. But we'll see obviously over time. Now, one thing I just wanted to get a quick read from you before we close is as recently, Demis Hassabis and John Jumper got the Lasker Award, like a pre Nobel Award for AlphaFold2. But this transformer model, which of course has helped to understand the structure 3D of 200 million proteins, they don't understand how it works. Like most models, unlike the understanding we were talking about earlier on the LLM side. I wrote that I think that with this award, an asterisk should have been given to the AI model. What are your thoughts about that idea?GEOFFREY HINTON (34:28):It's like this, I want people to take what I say seriously, and there's a whole direction you could go in that I think Larry Page, one of the founders of Google has gone in this direction, which is to say there's these super intelligences and why shouldn't they have rights? If you start going in that direction, you are going to lose people. People are not going to accept that these things should have political rights, for example. And being a co-author is the beginning of political rights. So I avoid talking about that, but I'm sort of quite ambivalent and agnostic about whether they should. But I think it's best to stay clear of that issue just because the great majority of people will stop listening to you if you say machines should have rights.ERIC TOPOL (35:28):Yeah. Well, that gets us course of what we just talked about and how it's hard the struggle between humans and machines rather than the thought of humans plus machines and symbiosis that can be achieved. But Geoff, this has been a great, we've packed a lot in. Of course, we could go on for hours, but I thoroughly enjoyed hearing your perspective firsthand and your wisdom, and just to reinforce the point about how many of the people that are leading the field now derive a lot of their roots from your teaching and prodding and challenging and all that. We're indebted to you. And so thanks so much for all you've done and we'll continue to do to help us, guide us through the very rapid dynamic phase as AI moves ahead.GEOFFREY HINTON (36:19):Thanks, and good luck with getting AI to really make a big difference in medicine.ERIC TOPOL (36:25):Hopefully we will, and I'll be consulting with you from time to time to get some of that wisdom to help usGEOFFREY HINTON (36:32):Anytime. Get full access to Ground Truths at erictopol.substack.com/subscribe

Fresh from his exciting win of the Lasker Award - often dubbed the American Nobel Prize - Professor David Huang (USA) - the inventor of optical coherence tomography (OCT) - joins Prof Pearse Keane (UK) and Tunde Peto (Hungary/UK) to talk about how he and colleagues developed the technology and about the impact it has had on retinal medicine

Optical coherence tomography (OCT) is a powerful imaging tool used across multiple clinical disciplines. JAMA Executive Editor Gregory Curfman, MD, speaks with 2023 Lasker Award recipient James G. Fujimoto, PhD, professor of electrical engineering at MIT, about his role in developing OCT and OCT's advancements in clinical practice. Related Content: Optical Coherence Tomography—History, Evolution, and Future Prospects

Featuring articles on dexamethasone for TB meningitis in HIV-positive adults, the timing of complete revascularization after myocardial infarction, catheter ablation for advanced heart failure and AFib, ceftobiprole for Staph. aureus bacteremia, and on AlphaFold being recognized through a Lasker Award; a review article on Shiga toxin–producing E. coli and the hemolytic–uremic syndrome; a case report of a man with involuntary movements and unresponsiveness; and Perspective articles on whether pandemics ever end, on the new over-the-counter oral contraceptive pill, and on a reason to retire.

“The idea of spending your time digging into mysteries…I thought that would be a wonderful way to spend your life.” Evelyn Witkin did spend her life digging into mysteries, and she was recognized with the 2015 Lasker Award for her work that solved one—how some bacteria survived 100x the radiation that killed other cells. Witkin discovered the DNA-damage response, a genetically regulated emergency system that protects the genomes of all living organisms. In an interview with Emmy-nominated writer/director/podcaster Flora Lichtman, Witkin talks about what it was like to be at Cold Spring Harbor in the 1950s, when many major discoveries in molecular biology were made, and tells us a little bit about her hobby in retirement: Victorian poetry.

Howie and Harlan are joined by Mallika Mendu to discuss how innovations in operations can lead to improved inpatient care and her work as both a practicing nephrologist and associate chief medical officer at Brigham and Women's Hospital. Harlan highlights the Lasker Award in medicine; Howie reports on a promising $650 million pilot in North Carolina to comprehensively address the social determinants of health. Links: US Bureau of Labor Statistics | Skilled Nursing Facilities Employment “What Went Right? A Mixed-Methods Study of Positive Feedback Data in a Hospital-Wide Mortality Review Survey” “The Advancing American Kidney Health Initiative: The Challenge of Overcoming the Status Quo” Haven Free Clinic | Home Page “A Holy Grail — The Prediction of Protein Structure” Wikipedia on AlphaFold “Lasker Award for Revolutionizing Protein Structure Predictions” “A.I. Predicts the Shape of Nearly Every Protein Known to Science” NC Medicaid Managed Care Healthy Opportunities Pilot Fee Schedule and Service Definitions Meanings and Misunderstandings: A Social Determinants of Health Lexicon for Health Care Systems NCDHHS | Healthy Opportunities Pilots “In North Carolina, a radical experiment targets social determinants of health with fresh produce and safe housing” Learn more about the MBA for Executives program at Yale SOM. Email Howie and Harlan comments or questions.

Howie and Harlan are joined by Mallika Mendu to discuss how innovations in operations can lead to improved inpatient care and her work as both a practicing nephrologist and associate chief medical officer at Brigham and Women's Hospital. Harlan highlights the Lasker Award in medicine; Howie reports on a promising $650 million pilot in North Carolina to comprehensively address the social determinants of health. Links: US Bureau of Labor Statistics | Skilled Nursing Facilities Employment “What Went Right? A Mixed-Methods Study of Positive Feedback Data in a Hospital-Wide Mortality Review Survey” “The Advancing American Kidney Health Initiative: The Challenge of Overcoming the Status Quo” Haven Free Clinic | Home Page “A Holy Grail — The Prediction of Protein Structure” Wikipedia on AlphaFold “Lasker Award for Revolutionizing Protein Structure Predictions” “A.I. Predicts the Shape of Nearly Every Protein Known to Science” NC Medicaid Managed Care Healthy Opportunities Pilot Fee Schedule and Service Definitions Meanings and Misunderstandings: A Social Determinants of Health Lexicon for Health Care Systems NCDHHS | Healthy Opportunities Pilots “In North Carolina, a radical experiment targets social determinants of health with fresh produce and safe housing” Learn more about the MBA for Executives program at Yale SOM. Email Howie and Harlan comments or questions.

Leroy Hood, MD, developed the DNA sequencing technology that made possible the Human Genome Project and is cofounder of the Institute for Systems Biology. A pioneer in the fields of systems biology, proteomics, and P4 medicine, he has won the Kyoto Prize, the Lasker Award, the Heinz Award, and the National Medal of Science. He is in all three national academies of science: medicine, engineering and science and falls among 20 who share this honor out of more that 6000 members of these academies. Nathan Price is Chief Science Officer of Thorne HealthTech, helping to architect a scientific wellness company serving millions of people. A longtime professor at the Institute for Systems Biology, he was selected as an Emerging Leader in Health and Medicine by the National Academy of Medicine, receiving the Grace A. Goldsmith Award for his work on scientific wellness and has co-authored over 200 peer-reviewed scientific publications.Topics covered in this episode:Disease PreventionDisease TreatmentAI in HealthcareEthical AIMedical ErrorsP Four MedicineParticipatory In Your HealthcareEducational EffortsDigital TwinDiabetesHealth SpansEconomy of HealthcareBlood AnalysisImmediate ActionsExerciseMicrobiomeReferenced in the episode:The Lindsey Elmore Show Ep 137 | Understanding cognitive decline | Dr. Rana MafeeTo learn more about Leroy Hood and Nathan Price and their work, head over to https://isbscience.org/bio/nathan-price/__________________________________________________________If you haven't been feeling like your best self, maybe you've been struggling with your metabolism and weight loss, or are just not in a good mood and are stressed out all the time, maybe your sex life isn't what it once was. Enter the Amare Happy Hormones Pack.If you wanna get going and try the Happy Hormones pack head to  http://www.learnamare.com/hormones between now and the end of July, when you shop the Happy Hormones Pack, you will also receive a free bottle of Omegas. Don't worry. If you're listening to this after the end of July, just go to http://www.lindseyelmore.com/amare to save $10 at any point.__________________________________________________________Wellness Made Simple is my functional medicine education website where you can learn the practical skills that you need to build a healthy lifestyle. If you want to live healthy, but you're over temporary diets and exercises, you don't know where to find reliable health information, you don't know what wellness options are even out there, and you definitely don't have enough time to cook or go to the gym every single day, Wellness Made Simple is for you.  When you go to http://www.wellnessmadesimple.us and shop the code "Pod", you can save 20% off a monthly subscription or $100 off an annual subscription to Get access to the site, watch the courses, and feel better as you implement simple daily changes that can positively transform your health!____________________________________________________________________________________________________________________We hope you enjoyed this episode. Come check us out at www.lindseyelmore.com/podcast.

The venom of the Brazilian pit viper Bothrops jararaca causes a sudden and catastrophic drop in blood pressure. Armed with this knowledge, David Cushman and Miguel Ondetti set out to isolate the active component. In this 1999 interview with Princeton University professor Leon Rosenberg, Cushman tells the story of their Lasker Award-winning work that resulted in ACE inhibitors for the treatment of hypertension. Cushman and Ondetti were recognized not only for their development of a life-saving medication, but also for their innovative approach to drug design. Listen to the incredible story of captopril, one of the first drugs developed through rational design. This interview has been edited for brevity and clarity. The transcript of the entire 43-minute interview, along with the transcript for a 54-minute interview with Ondetti, can be found here: http://ow.ly/wGL750Oo4uQ

Taking us to the cutting edge of the new frontier of medicine, a visionary biotechnologist and a pathbreaking researcher show how we can optimize our health in ways that were previously unimaginable. They say we are on the cusp of a major transformation in health care—yet few people know it. At top hospitals and a few innovative health-tech startups, scientists are working closely with patients to dramatically extend their "healthspan"—the number of healthy years before disease sets in.  Using information gleaned from our blood and genes and tapping into the data revolution made possible by AI, doctors can catch the onset of disease years before symptoms arise, revolutionizing prevention. Current applications have shown startling results: diabetes reversed, cancers eliminated, Alzheimer's avoided, autoimmune conditions kept at bay. This is not a future fantasy: it is already happening, but only for a few patients and at high cost. Proponents say it is time to make this gold standard of care more widely available.  MLF ORGANIZER Robert Lee Kilpatrick SPEAKERS Leroy Hood M.D., Ph.D., Founder and CEO, Phenome Health; Co-founder, The Institute for Systems Biology; Recipient, the Kyoto Prize, the Lasker Award, the Heinz Award, and the National Medal of Science Nathan Price Ph.D., Chief Science Officer, Thorne HealthTech; Professor, The Institute for Systems Biology; Recipient, Grace A. Goldsmith Award  Robert Lee Kilpatrick Ph.D., Chief Strategic Development Officer, Phenome Health; Visiting Academic, Oxford Martin School Research Institute, University of Oxford; Chair, Health & Medicine Member-led Forum, The Commonwealth Club of California—Moderator In response to the COVID-19 pandemic, we are currently hosting all of our live programming via YouTube live stream. This program was recorded via video conference on April 5th, 2023 by the Commonwealth Club of California. Learn more about your ad choices. Visit megaphone.fm/adchoices

JCO PO authors Dr. Edward Esplin and Professor Heather Hampel share insights into their JCO PO commentary, “Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer” and discuss practical implications of testing for patients, geneticists, and clinicians. Host Dr. Rafeh Naqash, Dr. Esplin, and Professor Hampel discuss standard of care guidelines, insurance coverage, and benefits of testing. Click here to read the article! TRANSCRIPT Dr. Abdul Rafeh Naqash: Welcome to ASCO's JCO Precision Oncology Conversations, where we bring you the highlights and overview of Precision Oncology. Episodes will feature engaging conversations with authors of clinically relevant and highly significant JCO PO articles. These articles can be accessed at ascopubs.org/journal/po. Hello and welcome. My name is Dr. Abdul Rafeh Naqash. I'm a medical oncologist and assistant professor at the OU Health Stephenson Cancer Center. I'm also the social media editor for JCO Precision Oncology, and you're listening to JCO Precision Oncology Conversations podcast.  Today I am thrilled to be talking with Dr. Edward Esplin and Professor Heather Hampel about their recent paper, ‘Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients with Solid Tumor Cancers'. Heather Hampel is the associate director in the Division of Clinical Cancer Genomics and is a professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center. Dr. Edward Esplin is a clinical geneticist and also the Head of Clinical Trials at Invitae in San Francisco, California.  For the purpose of this podcast, we'll be referring to each other using our first names. So welcome both Heather and Ed. Thank you for joining us today.  Dr. Edward Esplin: Thank you, Rafeh.  Professor Heather Hampel: Thanks for having us.  Dr. Abdul Rafeh Naqash: Well, first of all, I'd like to start by discussing some of the context behind this very interesting commentary. For the sake of our listeners, this is one of our first commentaries that we're doing a podcast on because this is very clinically relevant, especially for patients with cancer and without cancer, as I was reading through this commentary. So could you tell us, Ed, what prompted you to start this commentary, and what was the context of and the importance behind why something like this would make a difference in the clinical care of patients with cancer?  Dr. Edward Esplin: Yes, I'd be glad to. I think that we have seen over the past couple of years an ever-growing application and opportunity for application of precision therapies in patients with cancer of various kinds. And there has been with that a growing amount of evidence connecting germline genetic variants of a pathogenic nature with various types of cancer, breast cancer being one of the ones that is the most prominent. And as we've seen this evidence accrue in cancer types such as breast, which has probably got the longest history of a connection to germline genetics, but also accruing in other cancer types such as pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, it became clearer and clearer that there is evidence to support a broader application of germline genetic testing than is currently the standard of practice. In part driven by the desire for access to these precision therapies that are driven in part by patients' germline genetic makeup and for the opportunity that germline genetic testing results have for affording patients potential access to clinical treatment trials - so the cutting edge of what is driving some of these treatment opportunities - and reviewing the amazing amount of work that has been done by a number of people across the country and across the world to support these opportunities and support this becoming more and more the standard of care really motivated us to do this project together, and we've been fortunate to have been involved in a number of the studies that we review in this commentary.  Dr. Abdul Rafeh Naqash: Thank you so much for that explanation, Ed. So, Heather, you, and both Ed, have obviously led and been part of a lot of work in this space and have developed guidelines in this space. For the sake of our listeners, whether they are clinicians or patient advocates, what are the current guidelines behind germline testing for patients with cancer and patients without cancer?  Professor Heather Hampel: That's a really good question, and that's a lot of what's driving it for me, just from a clinical perspective.  So currently, we mainly use the NCCN guidelines in the US for deciding when a patient is appropriate for germline genetic testing. And they only recommend or suggest considering germline genetic testing for all cases of three particular cancers: all cases of ovarian, pancreatic, and, most recently, this summer, all cases of colorectal cancer, they've said you could consider offering germline testing to. The other one that has a recommendation is prostate cancer, but that's restricted to patients with metastatic or advanced prostate cancer, so it's not all prostate cancers. When you look at the guidelines, you ask yourself, how did they decide that? Was it based on the prevalence of finding a germline mutation? Because if it was, there are several other cancers where germline mutations are just as prevalent, but that recommendation has not been made.  And what is happening really on the front lines is that some patients are not having access to genetic testing because we have very complex criteria requiring ages of diagnosis, certain tumor markers, particular family history constellations that make the criteria difficult to use for frontline primary care physicians and patients deciding who needs referred, and do I need to see cancer genetics? And how much more straightforward would it be if we just said everybody with cancer needs gene testing? At this point, we pulled the data together for this commentary. We feel like the odds of testing positive are high enough in every single solid tumor to support a change in the recommendations like that.  Dr. Abdul Rafeh Naqash: Thank you. And from the data that you highlight in this commentary, apart from the tumors that you mentioned, Heather, that have recommendations for germline testing, what other tumors would you try to incorporate this in subsequently as a first, second, third approach, maybe if you can't get to all tumors at the same time?  Dr. Edward Esplin: I would say that one of the ones that we would highlight, I think, also, is breast cancer, right? That's one that there's a clear link. And as Heather appropriately noted, while a universal guideline per se has not been established by the NCCN for breast cancer, about three years ago now, based on a publication in Journal of Clinical Oncology, there was the observation that the guidelines that existed at that time did not find a significantly increased number of pathogenic germline findings in patients who met the criteria as they existed at that time compared to those patients who did not meet the criteria. And based in part upon that data, the American Society of Breast Surgeons came out with guidelines that recommended, indeed, the time is now for universal germline genetic testing for all patients who have been diagnosed with breast cancer. So I think that one's another one that there's a great deal of opportunity for that to be implemented, consistent with what Heather has already noted.  And I think there is also data that's been presented at ASCO here very recently, suggesting that similar evidence supports testing not just for metastatic prostate cancer but possibly for a broader collection of prostate cancer patients as well, perhaps all of them with a similar finding where in a prospective observational cohort of unselected patients with prostate cancer. Again, when you applied the current guidelines for testing, there was no statistically significant difference in the number of actionable pathogenic germline findings in patients who met the current criteria compared to those who do not. Which unfortunately suggests that all those patients who are being excluded when we adhere to these guidelines are not able to access the genetic information that could be crucial to their treatment. And it's just because they're not being considered, even though there is a significant fraction of those individuals who do have germline genetic information that could impact their care and possibly the preventive care of their at-risk family members as well.  Professor Heather Hampel: And, Ed, let me add a study I did with you and your team on endometrial cancer. So the truth is, Rafeh, we don't want to pick. We want all solid tumor patients to get germline genetic testing through a multigene panel. But I think if we did have to pick, I would also add endometrial. We did a study of nearly 1000 unselected endometrial cancer patients in the state of Ohio and found just over 10% had a pathogenic variant in a cancer susceptibility gene. And you really could not predict, based on personal or family history factors, who was going to test positive.  Dr. Abdul Rafeh Naqash: And that was definitely something interesting that I caught in this commentary as I was going through it. One of the sentences that was definitely interesting for me was where you mentioned that these guidelines should include risk factors beyond family history and just testing for genes beyond BRCA1 and BRCA2, which are commonly identified entities associated with germline testing, that prompt germline testing.  But one of the other things is the financial aspect of it, which you have highlighted in your commentary. So, I wanted to briefly touch on that and understand what are the policies. It seems like different coverage policies cover different aspects of germline testing, so that's number one. Could you comment on that? And number two, a few years back, there has been an effort you might have heard of related to TMB or Tumor Mutational Burden Harmonization. Could there be some sort of harmonization to identify what are the most important testing genes that are or should be covered by some of these insurance policies? And could you highlight some of the aspects around that?  Dr. Edward Esplin: That's an excellent point. And what we have found has been the course this usually proceeds through is when the guidelines have established what the criteria should be for testing, then, over a certain period of time, naturally, the various insurance payers will then incorporate this into their medical policies. And, for better or for worse, this takes time. I think, in the opinion of most, the time that it takes is unfortunately prolonged for reasons that I don't personally understand.  But noting a bright spot, I'll highlight that UnitedHealthcare has actually taken the step of instituting a very patient-first medical policy. They did this back in 2020, where they recommend and consider medically necessary standard of care germline genetic testing for any patient who has a diagnosis of any cancer that is associated with Lynch syndrome. So meaning that any patient covered by their policy who has a personal diagnosis of colon cancer, endometrial  cancer, the long list of cancers associated with Lynch syndrome, qualifies for germline genetic testing. And that's covered as part of the standard of care, which is a great move in the right direction for this, the largest private commercial insurance provider in the United States.  Now, do we need to see more of that? We absolutely do, because, as Heather's already noted, there is an access issue, and there is a disparity issue for those individuals that don't meet the criteria of their own insurance policies, medical policy, they don't have access. And that requires them, if they choose, to get germline genetic testing, to pay an out-of-pocket cost of $250 or more, depending. And that may be something that is simply not accessible to individuals. And so there's a tremendous amount of effort that needs to be done to incorporate the guidelines as they currently exist into medical policy.  And I think, to your point as well, the discrepancies between various medical policies is certainly a challenge, and I don't have a good answer for how to address that. But it is frustrating, to say the least, that any clinician has to guess what their own particular patient that's sitting in front of them right now has in terms of medical policy coverage for germline genetic testing. And then that should in any way cause them to have to second guess ‘How am I going to get the standard of care to this patient?' One of the other challenges that that potentially raises is, as we noted in our commentary as well, unfortunately, even for those cancer types where there is an established recommendation for universal germline testing, there is nowhere near the implementation of that that there ought to be.  For ovarian cancer, I think it's in the neighborhood of 30% of patients with ovarian cancer are getting this testing. For breast cancer, I think it's 25%. I can't remember if this was cited in this paper or not, but in a recent publication that we did with collaborators from Optum Health, we found that 5% or less of colorectal cancer patients who fell under this very progressive UnitedHealthcare policy were getting testing where everyone qualified for it under the medical policy. And so it really raises concerns about these missed opportunities in the setting of not effectively implementing germline genetic testing even when it is already recommended as the standard of care for the guidelines as they currently exist and not to be available to many more patients with various cancer types, as we've already noted.  Dr. Abdul Rafeh Naqash: Thanks for highlighting some of those very extremely important points. And, to your point, it's not implemented as much as it should.  Heather, have you, or others in this field, tried to understand what are those exact barriers that maybe me, as a clinician who sees at least patients with cancer, should know, or any other community-based oncology practice physician, should know that these are patients where testing is important and will have clinical implications. But what would be the barriers that potentially do not result in as much of a higher implementation of this testing than one would expect?  Professor Heather Hampel: Well, you may be surprised to hear this coming from a genetic counselor, but I've become convinced over the years that requiring pretest genetic counseling is one of the biggest barriers that actually keeps patients from getting genetic testing when it's appropriate. And not that we're trying to be, but just that we have long wait times. Patients may have a lot of appointments because of a new cancer diagnosis, and they're overwhelmed. It just adds one more thing that's a little difficult.  And so, I really am interested in flipping the paradigm, and this is what we're doing at City of Hope now, currently, which is offering a precision medicine or a mainstreaming approach, where every single patient at the institution is offered germline genetic testing regardless of age, regardless of family history, regardless of tumor type. And then, believe it or not, this actually supports hiring more genetic counselors because you're dealing then with thousands of results that need to be hand-reviewed, and all positives, of course, get invited in for full post-test genetic counseling. And that saves that resource, that scarce resource of genetic counseling for the people who need it the most, the people who tested positive, whose family members need testing, who need to implement all the management that comes with testing positive.  I find those sessions much more rewarding because I can be much more helpful for the patient and the family, and our negative patients, or patients with variants of uncertain significance, get templated letters. We've got a team of genetic counseling assistants that are helping get those out because, of course, that's the majority of patients. But if they have questions or concerns or a strong family history, they can, of course, come in for post-test genetic counseling, too. But I think we're on the cusp of switching the paradigm of how cancer genetics is delivered, and that's really the only way to get it at scale to the large number of patients who actually need it.  Dr. Abdul Rafeh Naqash: Thank you. And, to that point, I wanted to say that, as cancer care becomes more and more multidisciplinary, it's right there in front of us that, I think, genetic counselors or clinical geneticists need to be part of these multidisciplinary teams, whether it's through molecular tumor boards or outside of molecular tumor boards. But I think that's where the gap is, at least from what I see on my end. And that's where communication gaps create issues. I recently had at least two patients in their 30s and 40s, one with a PALB2 and another with the CHEK2 alteration and initially identified on liquid biopsy, actually, and that prompted me to check for germline testing. And lo and behold, both were positive. And that resulted, as Ed, you mentioned, cascade testing and eligibility for trials, both ended up on different DNA damage-based trials. So, definitely a lot of clinical implications.  In your practice, when you were on the academic side, Ed, did you have instances where you definitely could see a lot of difference with respect to clinical management of a patient when such an event was identified when a pathogenic germline alteration was identified? And could you give us a few examples so that listeners maybe could try to understand better how some of these things can have significant clinical implications?  Dr. Edward Esplin: Well, I practiced when I was at Stanford in perhaps a little bit of a skewed environment, skewed to the better, where much of my interaction with patients with cancer and with molecular tumor board as well was in the setting of the Stanford Cancer Genetics Clinic. And so that's certainly highly enriched for well-informed individuals, very genetic-savvy medical oncologists. Obviously, the genetic counselors were the foundation there, and me, as a clinical geneticist, was actively involved in such a way that, yes, I think it made a lot of difference from the standpoint of patients with cancer, knowing what all of their options were. And in a number of cases also, the first thing, I think that at least from my standpoint, thinking about genetics a lot that many patients want to know is: why do I have this cancer? Did I do something to cause this? What's the underlying reason for this? And being able to either provide them reassurance that this was not something that was genetic, that this was not something that anyone in their family needed to be particularly concerned about, or that there was anything further that needed to be done about that. Versus the alternative, each of those answers was incredibly valuable to the patient and the patient's family for the reasons I think that you already alluded to.  If there is a genetic cause, then there are known actions that can be taken, whether it's an approved precision therapy or a clinical treatment trial. But then I think equally important, especially in those families where there was a known history of various cancers, and this is the first person who had any genetics done, then being able to share with that patient and with the patient's family that they're going through an excruciating disease course, but there is an opportunity for some of that to be mitigated, some of that risk to be mitigated in their family members; I think brought a certain amount of, I don't know if reassurance is the right word, but it was valuable and was greatly appreciated by those individuals.  One situation that I recall actually was a patient that– I can't remember what her age was, she was probably in her 40s or 50s, but she had developed a colorectal cancer. She had had appropriate germline genetic testing performed and had had a variant identified; I believe it was one of the Lynch syndrome genes, I'm not recalling exactly right now. But while she was undergoing her treatment, I mean, to her credit, she went right away to her family in particular, to, it happened to be her son who was one that got tested, and he was, I think, late teens, maybe early 20s, he had tested positive for the same thing. She made sure that he went in, he got his colonoscopy right away, and lo and behold, right, they find an advanced polyp in this 20-year-old kid that, had that not been done, that would have been identified in just a very tragic way. And yet, as a result of her taking charge and having the information that she needed to take charge for herself and for her family members, a cancer was literally prevented. And that individual's life was prolonged, if not saved, because of that action being taken on behalf of that individual who had the information they needed to do that.  Professor Heather Hampel: Yeah, I would just add I was talking to some of the docs at one of our network sites recently and talking about all of these benefits, which are 100% clear and really also hitting on the targeted therapy benefit quite a bit. And they reminded me of another benefit which we all often forget, and that is even surgical decision-making. So if we got this done early enough, there are certainly patients who have BRCA mutations who might elect to have bilateral mastectomies instead of a unilateral mastectomy or a lumpectomy and patients with Lynch syndrome who might elect to have a subtotal colectomy instead of a segmental resection. And again, this is where not only do we need to be offering this to everybody, but we need to be offering it early at the time of biopsy-proven cancer in some cases, where it could actually affect even their surgery.  Dr. Abdul Rafeh Naqash: Absolutely. And thanks, Ed, for highlighting some of those interesting and important examples.  Now, Heather, when we talk about 80%-85% of the places in the country, at least in the US, they may or may not likely have access to experts like yourself or elaborate, broad, experienced teams that you guys have been part of. So on the oncology side, in a clinic, we get a patient who gets next-generation sequencing done, a 500-600 gene panel where we may or may not have a geneticist, or the wait times are longer. What is your suggestion for individuals, both clinicians and for patients, in that setup? What are the things that one should think of to mitigate some of those delays in that setup where you may not get a geneticist to see that patient or a counselor to see that patient immediately? Looking at that sequencing panel, what couple of things would you think of should prompt a physician to refer a patient to a genetic counselor if it's on a need basis and not available for everybody?  Professor Heather Hampel: And you're talking about a tumor panel that's coming back.  Dr. Abdul Rafeh Naqash: Correct. I'm talking about NGS 600 gene panel because that's what gets done clinically every day, all day, when you're talking about patients with cancer. What are the few things that one should look out for?  Professor Heather Hampel: So there's some nice ESMO guidelines around this, and that's what we were using. Where I used to work, I would actually hand-review the tumor test that came in and kind of send an email to the docs when I said, "Hey, this may be germline. I think this patient needs a referral." Some of the labs are now calling those out themselves, which is nice. So if they're calling it out themselves, definitely pay attention to those boxes that say "Potential germline finding," and make sure you refer any patients with anything there. If you're using a lab that's not calling it out, certainly some of the rules—there's already guidelines - anyone with a BRCA1 or BRCA2 mutation found in their tumor should be referred, regardless of what kind of tumor they have. So that one's easy.  Some of the things I like to look at is what was the variant allele fraction. If it's around 50% or anything over 35%, you start thinking maybe that's germline, that's a nice red flag. Cautionary tales - every colon tumor has an APC mutation in it, so we don't want those referred to genetics. Most of them don't have familial adenomatous polyposis. So only send a patient with an APC mutation in their colon tumor if they– in the setting of polyposis. Same goes for TP53. You're going to find that in almost every tumor, and very few of them are going to have Li-Fraumeni Syndrome.  So in the ESMO guidelines, I believe in addition to having a TP53 and an APC around a VAF of over 35%, they want to see it in a young age tumor so that you have an indication that you might be dealing actually with Li-Fraumeni syndrome. The Lynch syndrome genes, I think the common genes, if you see a mutation in them, go ahead and refer. Consider the variant allele fraction and then beware of genes that are commonly mutated in all cancers because most of those won't be hereditary, and genetics can't handle seeing every single patient who has a TP53 mutation in their tumor. So we need to see an early age or some strong family history in those cases.  The other thing just to point out, because there are long waits and not everybody has a genetic counselor or geneticist on staff is COVID turned out to have a little silver lining for the genetics community, and that is cancer genetics transition very well to televideo medicine. And there are now multiple companies providing televideo medicine. And you can usually get your patient in within a day or two for a televideo genetic counseling appointment. And so, just be aware if you can't get them to an in-person clinic in a timely manner, there are many, many televideo companies now providing genetic counseling services remotely from the comfort of their own home within two days' notice, evening appointments, weekend appointments to make it convenient for the patient. I don't work for any of those companies, but I would say just that people should be aware that those options exist so that their patients don't have to have a long wait time. Dr. Edward Esplin: Just one quick thought along those lines. And in the context of the commentary that we talked about, I think there is a good rationale that if the patient that we're talking about with respect to receiving the tumor profiling NGS they're having any of those solid tumor types that we're discussing, it does make a lot of sense now to order that Germline genetic test at the same time that they're getting that tumor test. And doing that via what I've heard described in the literature is a mainstream approach where the clinical oncologist can be the person who is initiating both the tumor test and that germline genetic test. Get both those things cooking at the same time, such that when you're getting those results back, and in many cases, you'll probably get the germline results back sooner, then you don't have to ask those questions. And the referral to genetics can take place at the same time as well, potentially, where those results can then be discussed in detail. And I say that in part because testing all these patients with these tumor types that we've described and taking a more universal approach can make a lot of difference, for example, in patients having the information they need to actually prevent or mitigate the risk for a second primary cancer.  We did a retrospective here a little while ago where we looked at patients who had received germline testing as a reflex to the tumor testing they'd received already. And appropriately so, I think, these savvy clinicians doing exactly what Heather described and referring them for germline testing. The unfortunate thing we found is in about 10% of the individuals that had a positive finding in their germline genetic test that was done as a downstream effect from their tumor profiling test, they had had this done on the second cancer that they had developed. And the genetic result that they received in their germline test was consistent with their first cancer that they had developed. In fact, if they had the germline testing done with the first cancer that they had developed, they would have the opportunity to have had that second cancer either downstaged by screening or completely avoided in its entirety with that information being at hand. And of course, it's practically unconscionable that a patient who has successfully defeated cancer, beat it back into remission, would need to be at unknown increased risk of a second primary tumor simply for lack of getting germline genetic testing at the time when they were first diagnosed with cancer.  Professor Heather Hampel: And not to pile on, but I'm a big fan of paired tumor and germline testing as well. And I'll just mention a Memorial Sloan Kettering paper which showed that about 10% of the mutations found on germline testing had been missed on the tumor testing because they were large rearrangements or some other type of mutation that tumor testing is really not designed to detect. So you also can't feel reassured by a normal tumor test that there isn't a germline mutation because that's not the purpose of the test, and it doesn't find every type of mutation. And so I am also a big fan of paired testing when you can get it. I also think it gives you some potential for sorting out variants of uncertain significance because you can look for second hits, et cetera. So again, I think that's the future of cancer genetics. Dr. Abdul Rafeh Naqash: Absolutely. And I learned a lot from all the stuff that you guys mentioned. And one of the things that you just mentioned that was on my mind was VUSs or Variants of Undetermined Significance. And briefly, I wanted to touch on VUSs. If I have a BRCA1, BRCA2 VUS, what should I do?  Dr. Edward Esplin: Nothing. Absolutely nothing.  Dr. Abdul Rafeh Naqash: Should I refer to genetics or just wait and watch? Dr. Edward Esplin: Well, I'll speak with my Invitae hat on. The waiting and watching, like you describe, I think, is very relevant because Invitae and other labs are actively involved in interrogating these VUSs on a routine basis. We see thousands of patients every day, and we see these VUSs popping up, and we're combing the literature on an ongoing basis. We're depositing new variants into ClinVar all the time, and that is part of what we consider to be our responsibility to continuously review the evidence underlying these VUSs.  And in fact, in a paper published, I think it was in JCO Global Oncology here pretty recently, we noted that over the course of about, I think it was a five-year retrospective of patients who had undergone breast cancer testing, that we looked at how many of those individuals had a variant of uncertain significance, for example, in BRCA 1 and BRCA 2, and over that period of time how many of them got reclassified, and if so, what was the reclassification. There was some small fraction that over that time period got reclassified. I think I'm going to say it's in the order of like 10% or 20% and I'm saying that wrong. But more importantly, of all of the ones that got reclassified over that five-year period of time, 10% or less ended up being pathogenic or likely pathogenic. The vast majority of them ended up being benign or likely benign, which just underscores there's nothing that needs to be done for VUS when the evidence might ever accrue that would help to reclassify that. The vast majority of the time, it's going to end up downgrading it. That's not even the right term to use for a VUS. It's going to reclassify it as a benign or likely benign variant. And if it is something that should be actionable at some point in time, all of the reputable labs out there will notify clinicians of that change in status, and that is the time when action ought to be taken. Professor Heather Hampel: Yeah, I think that's one of the biggest cons people will have against offering germline testing to every patient is the high variant of uncertain significance rate and a fear that those patients will be mismanaged as positives, particularly in settings where there aren't genetics professionals on staff. And so I think that's a really important point. I remember when Mary-Claire King was with her Lasker Award recommending germline genetic testing for all breast cancer, all women actually, unaffected, to try and prevent breast cancer. She had suggested that in that setting, they maybe should not report variants out at all because of the risk of them being mismanaged, and I think it's an interesting idea. Most of the academic centers like to have them; sometimes, they like to work on getting some of them reclassified. But I think it's something we need to consider if we start doing testing at this large of a scale or just being sure that everybody knows that a variant of uncertain significance should be treated like a negative until proven otherwise. Dr. Edward Esplin: I'll pile on that just briefly to note that at ASHG American Society of Human Genetics just last year there was an entire session devoted to exactly that kind of topic, and it was broadly discussed, the potential opportunity to, for example, within a cancer gene multigene panel is that a panel where returning VUS is just not a useful thing to do, restricted to pathogenic, likely pathogenic. We do that on other panels already. We do that on panels for ostensibly healthy folks and other situations. So I think that is a very worthwhile approach to consider.  And at the same time, we've also seen in the literature, Heather brings up a concern that is broadly raised and repeatedly raised, we've seen evidence that clinicians are not acting inappropriately as much as they had done, perhaps in the past, that we're getting our house in order. Breast surgeons and other physicians are treating these things like the negative results that they, in reality, are, and so that in my opinion, the potential for increased VUS identification should not be an obstacle to folks getting clinically indicated testing because that's what's needed for them to have appropriate treatment and appropriate prevention. Dr. Abdul Rafeh Naqash: Absolutely. Well, this has been very engaging and very interesting, and hopefully, our listeners will feel the same. Thank you, both Heather and Ed, for joining us today and especially choosing JCO PO as one of the destinations for your very interesting commentary.  Thank you for listening to JCO Precision Oncology Conversations. If you like today's episode, please leave a rating and review. You can find all our shows, including this one, at asco.org/podcasts and continue to stay updated by following JCO PO on Twitter with the handle @jcopo_asco. All JCO PO articles and series can be found at ascopubs.org/journal/po. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Guest bios Prof. Heather Hampel, MS, is an Associate Editor of JCO Precision Oncology. She is the associate director in the Division of Clinical Cancer Genomics and is a professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center. Dr. Edward D. Esplin, MD, PhD, FACMG, CGAF, FACP is board-certified in clinical genetics and internal medicine and completed his clinical fellowship training in medical genetics at Stanford University. He now works at Invitae. Guest disclosures (See also: Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients with Solid Tumor Cancers) Heather Hampel Stock and Other Ownership Interests: Genome Medical, GI OnDemand Consulting or Advisory Role: InVitae, Genome Medical, Pomega, 23andMe, GI OnDemand, Natera   Edward D. Esplin Employment: Invitae Stock and Other Ownership Interests: Invitae Consulting or Advisory Role: Taproot Health Inc  

In this 2002 interview, Lasker Award and Nobel Prize winner Eric Kandel speaks with the then-newly minted Lasker Laureate James Darnell Jr. Darnell won the 2002 Albert Lasker Special Achievement Award in Medical Science for an exceptional career that opened two fields in biology—RNA processing and cytokine signaling—and for his dedication to the development of many creative scientists. Darnell shares his journey from his childhood home in rural Mississippi to training alongside preeminent scientists at the NIH, details how he made his discoveries, and talks about important findings made by other groups. This interview has been edited for brevity and clarity. Find the entire 42-minute interview here: http://ow.ly/36MY50Kgi2e

Featuring articles on cerebral embolic protection during TAVR, intravenous immune globulin in dermatomyositis, omicron-containing mRNA vaccine booster immunogenicity, an extravascular implantable cardioverter–defibrillator, the Lasker Award for discovery of circulating cell-free DNA, and on going from the eyeball test to the algorithm; a review article on drowning prevention and initial treatment; a Clinical Problem-Solving on thinking outside the heart; and Perspective articles on public carry versus public health, on intimate-partner violence after Dobbs and Bruen, and on the macro-harm of micro-geography.

“If we're smart enough to figure out the cause of something, we can intervene to change the effects.” William Foege won the 2001 Lasker Award for Public Service for his courageous leadership in improving worldwide public health. Here, Foege is interviewed by Allan Rosenfield of Columbia University. Foege talks about working to eradicate smallpox in a country torn by civil war, reveals his moment of greatest pride as the director of the CDC, and shares a story about introducing a new strain of corn in Africa. Read about the 2001 Mary Woodard Lasker Public Service Award: http://ow.ly/9vIQ50JhLMg

We've been hearing a lot about immunology the past two years since the outbreak of the Covid-19 pandemic. But can you explain how our immune system works? 2007 Lasker Laureate Ralph Steinman discovered dendritic cells, the preeminent component of the immune system that initiates and regulates the body's response to foreign antigens. He discusses how he got interested in science, what it felt like to receive a Lasker Award, and eloquently explains how dendritic cells protect us from pathogens.   Read more about Steinman's Award-winning work: http://ow.ly/UH7R50J0C5R

“I was forty-seven years old before I did anything that people would really look at twice.” Janet Rowley's discovery of chromosomal translocations made it possible to diagnose cancer at the molecular level, and her work earned her a Lasker Award. But getting there wasn't easy. In this interview, given before the 1998 Awards, Rowley talks to former NIH Director Francis Collins and shares stories of her life before she made her groundbreaking discoveries. She had to wait nine months to start medical school because the quota for women (3 out of a class of 65) had been filled, she worked part time for twenty years while she raised her four sons, and it took almost ten years before anything noteworthy came out of her research. Through it all, she chose to enjoy what she had instead of getting discouraged. This conversation has been edited for brevity and clarity. Find the entire 40-minute interview here: http://ow.ly/ZJrB50Iumei

In this 1996 interview between Lasker Award winner Paul Zamecnik and three-time Emmy Award-winning journalist Richard Cohen, Zamecnik tells us about how he got into basic research as WWII was imminent, about not winning the Nobel prize, and his chance encounters that led him to ask the question: “How do you make a protein, anyway?”. Zamecnik was recognized for six decades of brilliant and original science, including the development of antisense DNA, a technology that enables selective inhibition of gene expression and revolutionized biochemistry.   Learn more about Zamecnik's Award-winning work: http://ow.ly/2j0N50IcYNM 

With the invention of new ways to explore the brain, Karl Deisseroth has revolutionized neuroscience – work that has just now been recognized with the highest honor in medical research, the Lasker Award. Support the show: https://www.patreon.com/clearandvivid See omnystudio.com/listener for privacy information.

Featuring articles on a randomized trial of a pan-PPAR agonist in NASH, outcomes in nonalcoholic fatty liver disease, the AQP1 promoter variant and peritoneal dialysis, obesity in childhood and GNAS mutations, and optogenetics recognized through the Lasker Award; a review article on point-of-care ultrasonography; a case report of a girl with swelling of the jaw and hypercalcemia; and Perspective articles on blood donation by gay and bisexual men, on the case for wage equity for essential health care workers, and on peak moments.

Corona-Booster-Impfung - Wer braucht die dritte Dosis? / Gewächshaus 2.0 - Neue Wege in der Lebensmittelproduktion / Albert-Lasker Award - Ausgezeichnete medizinische Grundlagenforschung / Der Supersonic Aviators Club in Uganda - Wie Mädchen Programmieren lernen.

Two Top Virologists' Frightening Warnings About COVID Injections: Ignored by Government and Big Media By Joel S. Hirschhorn NOQ Report, August 21 2021     When two great minds come to similar conclusions about the current global push to vaccinate everyone with the COVID experimental vaccines, we should pay close attention.  Both highly experienced scientists have a totally negative view of the vaccination effort.  Worse than being ineffective, they point to negative health outcomes for the global population.  These two truth-telling acclaimed medical researchers make Fauci look as inept, deceitful and dangerous as he is. The point made in this article is not only has Fauci pushed the wrong potentially disastrous pandemic solution, he has blocked the right one. Much of what the two virologists say is very technical in nature.  This article simplifies their controversial messages without losing their essential meanings.  The public needs to understand their warnings that refute all the propaganda pushing vaccines from government and public health agencies as well as big media. Warning: Keep reading and you may become depressed. * Dr. Luc Montagnier First considered is the thinking of Dr. Luc Montagnier, a French virologist and recipient of the 2008 Nobel Prize in Medicine for his discovery of the human immunodeficiency virus (HIV).  He has a doctorate in medicine.  But there is a lot more to conclude he is a great expert: He has received more than 20 major awards, including the French National Order of Merit and the Légion d'honneur.  He is a recipient of the Lasker Award, the Scheele Award, the Louis-Jeantet Prize for medicine , the Gairdner Award  the Golden Plate Award of the American Academy of Achievement, King Faisal International Prize (known as the Arab Nobel Prize), and the Prince of Asturias Award. He has worked hard to expose the dangers of the COVID-19 vaccines, still experimental but sadly may soon be fully approved.  The vaccines don't stop the virus, argues the prominent virologist, they do the opposite — they “feed the virus,” and facilitate its development into stronger and more transmittable variants.  These new virus variants will be more resistant to vaccination and may cause more health implications than their “original” versions. Montagnier refers to the mass vaccine program as an “unacceptable mistake” and are a “scientific error as well as a medical error.”  His assertion is that “The history books will show that…it is the vaccination that is creating the variants.”  In other words: “There are antibodies, created by the vaccine,” forcing the virus to “find another solution” or die.  “This is where the variants are created.  It is the variants that “are a production and result from the vaccination.”  Stop and think about these thoughts.  Have you heard a better explanation of variant creation?  I doubt it. He is talking about the mutation and strengthening of the virus from a phenomenon known as Antibody Dependent Enhancement (ADE).  ADE is a mechanism that increases the ability of a virus to enter cells and cause a worsening of the disease. Data from around the world confirms ADE occurs in SARS-CoV-2, which causes COVID-19, says Montagnier. “You see it in each country, it's the same: the curve of vaccination is followed by the curve of deaths.”  Sounds like what we are now hearing more about, namely escalating breakthrough infections that kill some people.  And this spiral into disaster may have no end. In a November 2020 documentary he emphasized harmful and irrational mask mandates as well as lockdowns, quarantines, abuses of government overreach, and supported use of effective COVID treatments such as hydroxychloroquine.  The film was banned by YouTube and most other mainstream outlets.  At that time Fauci had succeeded in blocking wide use of the cheap generic based treatments for COVID and pursued the wait for the vaccine strategy. Montagnier has been a vocal critic of the mass vaccination campaign.  In a letter to the President and Judges of the Supreme Court of the State of Israel, which unrolled the world's speediest and the most massive vaccination campaign, Montagnier argued for its suspension.  He said: “I would like to summarize the potential dangers of these vaccines in a mass vaccination policy.”  Here they are: 1. Short-term side effects: these are not the normal local reactions found for any vaccination, but serious reactions involve the life of the recipient such as anaphylactic shock linked to a component of the vaccine mixture, or severe allergies or an autoimmune reaction up to cell aplasia.  In this group we should include a number of lethal blood problems involving clots and loss of platelets that cause strokes, brain bleeds and other impacts. Lack of vaccine protection: 2.1 In induced antibodies do not neutralize a viral infection, but on the contrary facilitate it depending on the recipient.  The latter may have already been exposed to the virus asymptomatically.  Naturally induced antibodies may compete with the antibodies induced by the vaccine. 2.2 The production of antibodies induced by vaccination in a population highly exposed to the virus will lead to the selection of variants resistant to these antibodies.  These variants can be more virulent or more transmissible.  This is what we are seeing now.  An endless virus-vaccine race that will always turn to the advantage for the virus. Long-term effects: Contrary to the claims of the manufacturers of messenger RNA vaccines, there is a risk of integration of viral RNA into the human genome. Our cells have the ability to reverse transcriptase from RNA into DNA. Although this is a rare event, its passage through the DNA of germ cells and its transmission to future generations cannot be excluded. His bottom line: “Faced with an unpredictable future, it is better to abstain.”  But most people will find it extremely difficult to resist all the coercion and vaccine mandates. Back in April 2020, before all the talk of variants and before the rollout of the experimental vaccines, Montagnier urged people to refuse vaccines against COVID-19 when they become available.  His main point should always be remembered: “instead of preventing the infection, they [would] accelerate infection.”  Today, the newly occurring variants of SARS-CoV-2 that affect vaccinated people prove his thesis.  With his scientific thinking, mass vaccination may cause a new, more deadly wave of pandemic infection. As to the much talked about and hope for herd immunity, he has said: “the vaccines Pfizer, Moderna, Astra Zeneca do not prevent the transmission of the virus person-to-person and the vaccinated are just as transmissive as the unvaccinated.  Therefore the hope of a ‘collective immunity' by an increase in the number of vaccinated is totally futile.” On the positive side, he advocated this: “The early treatment of infection with ivermectin and bacterial antibiotic because there is a bacterial cofactor that amplifies the effects of the virus. “ Dr. Vanden Bossche The stark views of Montagnier have been shared by the esteemed Belgium virologist Dr. Vanden Bossche.  He too has considerable credentials that make his views worth consideration.  He has PhD degree in Virology from the University of Hohenheim, Germany.  He held faculty appointments at universities in Belgium and Germany.  He was at the German Center for Infection Research in Cologne as Head of the Vaccine Development Office.  He has been in the private sector at several vaccine companies (GSK Biologicals, Novartis Vaccines, Solvay Biologicals) where he worked on vaccine R&D as well as vaccine development.  He also worked with the Global Alliance for Vaccines and Immunization (GAVI) in Geneva as Senior Ebola Program Manager. His views have been analyzed in a recent article.  He too has loudly called for a halt to mass-vaccination programs.  He believes that if the jabs are not halted, they could lead to the evolution of stronger and stronger variants of the virus until a “supervirus” takes hold and wipes out huge numbers of people. This is his bold view: “Given the huge amount of immune escape that will be provoked by mass vaccination campaigns and flanking containment measures, it is difficult to imagine how human interventions would not cause the COVID-19 pandemic to turn into an incredible disaster for global and individual health.” Here is an essential element of his thinking.  Pretty much everything being done in the pandemic doesn't guarantee elimination of the virus.  What is happening is selective viral ‘immune escape' where viruses continue to be shed from those who are infected [both vaccinated and nonvaccinated] because neutralizing antibodies fail to prevent replication and elimination of the virus. The evolutionary selection pressure on the virus through ‘immune escape,' creates ever more virulent strains of the virus that have a competitive advantage over other variants and will increasingly have the potential to break through the antibody defenses.  Defenses provided by the vaccine induced immune system.  This is ‘vaccine resistance.'  What happens is that vaccine makers keep trying to outsmart variants, but fail.  So, they keep pushing boosters and yearly vaccine shots.  This is the more is better approach.  This is aided by suppression of many negative facts about the vaccines by big media. A frightening forecast by Bossche is that the worst of the pandemic is still to come.  Hard to believe considering all the bad news propaganda about cases, hospitalizations and deaths.  But he thinks we are now experiencing the calm before the ultimate storm.  Imagine a new wave of infection far worse than anything we've seen so far is how Bossche thinks. How does this happen?  There will be more mutants or variants to which the adaptive immune system from vaccine shots provides little resistance.  At the same time there will be decreased innate or natural immune effectiveness.  Unless people take a number of steps to boost their natural immunity. Bossche consistently points to a lack of evidence that the existing global, mass vaccination program that has been mounted while there is still significant infection around, is unprecedented and there is no scientific evidence that this will work.  This is why he is largely ignored. He stresses that historic vaccination programs have always emphasized the importance of vaccinating populations prophylactically in the absence of infection pressure. He also argues that if different types of vaccine were used that provided sterilizing immunity i.e., that prevented immune escape and killed all viruses in those vaccinated, the situation would be entirely different.  Most people do not understand that the current experimental vaccines do not actually kill the virus; and that both the vaccinated and nonvaccinated shed the virus.  These vaccines do not stop viral transmission.  And all the contagion control measures simply to not work effectively enough to stop wide spread of the virus in its various forms. Here is his big picture view: “There is only one single thing at stake right now and that is the survival of our human race, frankly speaking.” But there are more strong words recently said by Bossche to pay attention to: “every person out there who is ‘partially' or ‘fully' vaccinated is a walking disease incubation system that puts everyone else at risk of contracting a deadly, vaccine-caused ‘variant' that could kill them.  The ‘vaccinated' are walking murderers spreading disease to others.  Getting injected for the Fauci Flu is not only foolish; it is also a form of murder in that unvaccinated people are now at risk of contracting the deadly diseases being manufactured inside the bodies of the vaccinated.  If Trump had never introduced the vaccine in the first place, the pandemic would have long ago fizzled out.  Since his vaccines continue to be pushed … however, the ‘Delta' variant is spreading like wildfire, soon to be followed by other ‘variants' as we enter the fall season.” This too is a very strong view.  The “mass vaccination program is…unable to generate herd immunity.”  If true, there is little hope of seeing the COVID pandemic ending. What is the solution?  Bossche has identified the needed alternative to the current massive vaccine effort.  It is this; “This first critical step can only be achieved by calling an immediate halt to the mass vaccination program and replacing it by widespread use of antiviral chemoprophylactics while dedicating massive public health resources to scaling early multidrug treatments of Covid-19 disease.”  This is referring to the early home/outpatient treatment protocols based on cheap, safe and fully approved generics like ivermectin and hydroxychloroquine; these also work as preventatives.  Pandemic Blunder provides much data and advice on using this treatment approach.  So, both virologists support use of what Fauci has blocked. These action recommendations were also made by Bossche “Provide – at no cost – early multidrug treatment to all patients in need.  Roll out campaigns to promote healthy diets and lifestyle.”  In other words, people need to take actions to boost their natural immunity, this should include vitamins and supplements, including this cocktail: vitamin C, vitamin D, zine and quercetin. Conclusions Take a moment to consider that Patrick Wood on the Bannon show on August 21 concluded that all the available data from the US and Europe shows some 100,000 people have died from the COVID experimental vaccines.  I agree with that assessment.  And by the time you read this FDA may have given full approval to the Pfizer vaccine. After considering what these two experts have said it is appropriate to criticize what current government officials say, namely blame the unvaccinated for the surges in COVID cases, hospitalizations and deaths.  The major alternative to this thinking is that it is the vaccinated people who are creating pandemic problems, including the variants.  The strong conclusion is that the current vaccines are ineffective, nonprotective and dangerous. What is needed is an entirely new approach to COVID vaccines. Perhaps there are companies working on this.  This would threaten the trillion-dollar business of the current vaccine makers. If the people, agencies and institutions with all the power listening to these two very smart people they would devote all their energies to using alternatives to the current vaccines.  We have them.  Notably, the treatment protocols that so many great doctors have created and used to help their patients. Many other physicians and medical researchers have called for a halt to the current vaccine bonanza for big drug companies.  In the meantime, on a daily basis for all those willing to look at the facts, it is clearer and clearer that the experimental vaccines are not effective.  It is insanity to keep doing or expanding what is not working.  That is the insane world we are now experiencing even as more and people die from breakthrough infections, blood problems and other bad vaccine health impacts. Perhaps the ugly truth about the vaccines will be widely revealed only when there are massive, widespread deaths despite all the shots and jabs.  That will be too late to change pandemic management from money-driven stupidity to life-saving, medically moral actions. * Dr. Joel S. Hirschhorn, author of Pandemic Blunder and many articles on the pandemic, worked on health issues for decades.  As a full professor at the University of Wisconsin, Madison, he directed a medical research program between the colleges of engineering and medicine.  As a senior official at the Congressional Office of Technology Assessment and the National Governors Association, he directed major studies on health-related subjects; he testified at over 50 U.S. Senate and House hearings and authored hundreds of articles and op-ed articles in major newspapers.  He has served as an executive volunteer at a major hospital for more than 10 years.  He is a member of the Association of American Physicians and Surgeons and America's Frontline Doctors and has been a long-time contributor to the sites of Kettle Moraine.

The fight for a cure to Parkinson’s Disease has been a decades-long battle, with several treatments evolving alongside the evolution of medicine as a practice. In this episode, host Richard Miles sits down with Dr. Michael Okun, the Chair of Neurology, and Professor and Executive Director of the Norman Fixel Institute for Neurological Diseases at the University of Florida College of Medicine. He is an expert on deep brain stimulation, and author of over 400 peer reviewed articles as well as the book Parkinson’s Treatment: 10 Secrets to a Happier Life. Here, Dr. Okun dispels myths surrounding Parkinson’s, talks about his research and clinical work, and discusses his involvement with several non-profits raising awareness on other conditions and diseases. “Every day that I practice medicine, I know less,” says Dr. Okun. “It’s a profession where you have to have a lot of humility. You have to have an open mind and things change over time.” TRANSCRIPT: Intro (00:01): Inventors and their inventions. Welcome to Radio Cade, a podcast from the Cade Museum for Creativity and Invention in Gainesville, Florida. The museum is named after James Robert Cade, who invented Gatorade in 1965. My name is Richard Miles. We’ll introduce you to inventors and the things that motivate them, we’ll learn about their personal stories, how their inventions work and how their ideas get from the laboratory to the marketplace. Parkinson’s Disease. What do we know about it? Why does it seem to be more common and how do we treat it? Welcome to Radio Cade. I’m your host Richard Miles today. I’m pleased to welcome Dr. Michael Okun the Chair of Neurology and Professor and Executive Director of the Norman Fixel Institute for Neurological Diseases at the University of Florida College of Medicine. Dr. Okun’s also an expert on deep brain stimulation and author of over 400 peer-reviewed articles, as well as the book “Parkinson’s Treatment: 10 Secrets to a Happier Life.” Welcome to Radio Cade, Dr. Okun. Dr. Michael Okun (01:11): My pleasure to be here, Richard. Richard Miles (01:12): So before we start, I have to mention you’re also a poet and that caught my eye mostly because I find myself in middle age becoming very interested in poetry, but only as a reader, not an actual poet. So I have to start, is this something you’ve always done or is it because being a brain doctor wasn’t challenging enough for you? What got you into poetry? Dr. Michael Okun (01:28): My original bent was in humanities, and I have a degree in history. And so, I love to write, and I love to try to express myself in different ways. I love poetry, because there’s a new precision towards, and I think that through poetry, you can express concepts using emotions and other modalities to reach your readers. And so, over the years I’ve done a number of poems, and I have an old book called “Lessons From the Bedside” and have done some writings in said time as well. Richard Miles (02:01): I love that analogy too, to the work that you do. Cause one of the things I have noticed in my very limited foray into studying poetry is precisely what you said, that the precision of the use of certain words versus not other words. And that reveals a lot of the thinking and so on. And I imagine studying medicine, there is some similarities there. Dr. Michael Okun (02:18): That’s right, and really keeping an open mind. And I am also a neurologist by training. And so I practice medicine and I say often that every day that I practice medicine, I know less. It’s a profession where you have to have a lot of humility. You have to have an open mind and things change over time. And we’re really like cabinet advisors to people. We’re here to help with the best information that we can, but we really shouldn’t be so prescriptive, and so sure of ourselves. And I think anybody, whether you’re an inventor, you’re a scientist, you’re a clinician or all of the above, will look back and say what I did five years ago, versus what I’m doing now, is different. And it might seem subtle because you lived it, but if you think in those terms, that’s, I think what I would term as wisdom and you realize that practice of medicine and the understanding of diseases evolves and that there’s not one solution for everyone. Richard Miles (03:15): That’s a great way of looking at it. And that really helps, I think, for what we’re about to talk about now, and that is you have developed, or you’re known as really one of the world’s experts on a technique to treat Parkinson’s. But before we get into the details of what that is and how it works, I’d like to talk more broadly about Parkinson’s itself, which is a disease that most people probably have heard of or know somebody with Parkinson’s, but they may not know exactly how it works and what are some of the underlying causes. And I noticed that a few years ago, you wrote a paper called “The Emerging Evidence of the Parkinson Pandemic,” which caught my eye, obviously because we’re in the midst of another pandemic. And so pandemics in general, I think are of higher interest to everyone. But in that paper, you said that neurological disorders are now the leading source of disability globally, and the fastest growing neurological disorder in the world is Parkinson’s disease. And you said that from 1990 to 2015, so about a quarter century time period, the number of people with Parkinson’s disease doubled to over 6 million. And finally your quote, “for most of human history, Parkinson has been a rare disorder, but various factors have now created” what you call Parkinson’s pandemic. There’s a lot there, but why don’t we start by briefly describing for listeners who are maybe not exactly sure how Parkinson’s differs from other types of neurological diseases. Define it for us. And then why don’t we spend some time talking about those various factors that have caused it apparently to go from a rare condition to pandemic-level proportions. Dr. Michael Okun (04:40): So first Parkinson’s Disease, it’s a neurological syndrome, and it comes with symptoms that people can readily detect. Oftentimes when you’re in a crowd, you see somebody might be shaking, they might be shuffling their feet, their handwriting might be small when they’re at the bank, and they may be struggling with some of these, what we call motor features and also what we call non-motor features. So it’s a brain disease that affect depression, anxiety, and quality of life. And it turns out that Parkinson’s Disease is not just a disease of dopamine. And so a lot of people believe that you lose dopamine in the brain and you get Parkinson’s, it’s actually degeneration of multiple circuits. I’ve spent my career studying the circuits and Parkinson and in other diseases. And when we think of Parkinson, I remember when I was at the White House in 2015, I was quoted as saying, “Parkinson is,” and I’m not the first person that said this and won’t be the last, “the most complex medical disorder period,” because there’s over 20 motor features and non-motor features. So tremor, stiffness, slowness, (and not everybody gets tremors and not everybody gets stiff necessarily, it could be different varieties) in depression, anxiety, sexual dysfunction, other issues too. And then you throw in dopamine replacement therapies, you throw in deep brain stimulation ,what you mentioned, and it’s something that we’ve been researching now for a few decades here at University of Florida with one of my partners, Kelly Foote, and Mendez and many other people in the laboratory. And so Parkinson’s Disease is a neurological disorder. It is rapidly expanding. And about eight years ago in the book, 10 Secrets to a Happier Life, in the prologue, I said: “Parkinson has all the same characteristics of a pandemic.” And that was very controversial at the time. That’s eight years ago. And our most recent book that just came out from Hatchette publishing, “Ending Parkinson’s Disease,” it was originally titled the Parkinson’s pandemic. The publisher changed the title, and they wished they could have that back because it came out in March, 2020. So, “pan” means “all” in Greek, “demos” means “people.” And when you apply the concepts of a pandemic, they can apply to other diseases. Although, I was just on a call with the World Health Organization last week, and I think it’s fair to keep the term pandemic reserved for infectious diseases. Although people should know that the rapid expansion, the geography, the people not being immune to it, it all applies to other diseases like Parkinson’s. Richard Miles (07:06): So tell us, what are some of the factors that researchers have uncovered, or maybe that you hypothesized are at work here that are causing it to grow, I’m guessing, dramatically on a per capita basis? Are there geographic differences, for instance, in range between different countries or different demographic groups? What is going on here, and what do you think is behind it? Dr. Michael Okun (07:25): So we just had a conference with our colleagues in Geneva, Switzerland at the World Health Organization that have taken this on. And there’s a working group of us from all different countries, from rich countries, from poor countries, from countries somewhere in the middle…Parkinson occurs in all of the above. Now, one of the myths of Parkinson is that it’s all due to aging. And so as you get older, you get a higher prevalence of Parkinson and that’s true. Now, many people might be surprised when I tell you in our waiting room, I see people in their teens, and twenties and thirties with Parkinson’s, and it becomes more of a common as you get older, but it doesn’t mean it can’t occur in young people, as well as people–I don’t say old people–I say more seasoned people. And it turns out that age, it’s a myth. Age is not the only thing that’s driving this increase. There is going to be a doubling of Parkinson between 1990 and 2015. That’s already happened. It’s going to double again from 2015 to 2040 and could collapse healthcare systems, cause lots of suffering if we don’t get out in front of it. And so there are other factors that are driving this. And one of the ones that we talked about in the latest book is about pesticides and chemicals and environmental factors, and how those factors and the industrialization of society and how that’s changed the game. Richard Miles (08:47): That’s fascinating. So let’s move on to, what are some of the treatments that are available? You mentioned deep brain stimulation that you and Dr. Foote and others have been working on for a couple of decades. What led you to that I guess, and tell us how it works and what sort of improvements that you see? Dr. Michael Okun (09:02): Back in the 1930s and 40s, there weren’t treatments for Parkinson’s and for other diseases of movement. Some of the early attempts were actually making holes in people’s minds and disrupting these abnormal conversations. So if we think of the brain as a group of islands and the islands are all talking to each other, if you disrupt the conversation, people discovered that this is a potential way to treat specific symptoms, depending on which circuit you disrupt that conversation. And as time evolved, we were able to modulate conversations by using medicines. And the first major medicine was introduced by George Cotzias in the 1960s, and that was dopamine replacement therapy. And that actually modulates, it changes the way the brain’s oscillations are moving, and everybody, whether you’re awake or you’re asleep, your brain is always oscillating. And when you have a disease, particularly in neurological disease, that oscillates in different ways. So surgeries came back; when we have better technology to get to very specific sub millimeter zones of the brain, we started burning out pieces of the brain and that’s what I did during my training. And then as we moved along, we began to understand how the different areas were talking to each other, and we develop what’s called neuromodulation, so sticking straws in, introducing electricity into those circuits, I’m trying to change the way that they would talk to each other. And so my mentor and one of Kelly Foote’s mentors who I work with is a man named Mahlon DeLong at Emory University. He’s retired now, but a tremendous human being, and he was the one that really spent years and years at the National Institute of Health, and then at Hopkins, and at Emory decoding what the circuits are. And in 2015, he received the Lasker Award, which is one of the highest awards in medicine, just under the Nobel, for this work. Richard Miles (10:50): Doctor, now that this is becoming more common and will become more common, walk us through what happens when, let’s say someone’s parent they’re 60, 65, 70 years old, they’re brought in to a doctor like you or a clinic somewhere, and they’re diagnosed with Parkinson’s. What are some of the first steps of treatment? And coming back to deep brain stimulation, is this a one and done type of treatment, or is this a continuous regimen of treatments over time? And then what does the outcome look like for, say, someone in their mid-fifties or early sixties? Dr. Michael Okun (11:20): So when we think about Parkinson’s Disease, the first thing we think about is when somebody comes in, we need to understand when you say those words, “you have Parkinson’s Disease,” it’s not the end of the world. Okay? There are a lot of different forms of Parkinson’s Disease. And I have folks in my practice I’ve taken care of for 20, 30, 40 years. Okay? So it’s important for us to dispel that myth. And as we dispel the myth and begin to deliver treatment, we recently wrote in the Lancer last week, a seminar on Parkinson’s Disease, 20 page-seminars, get your coffee if you want to read it. But we talk about, in that seminar, there’s a picture of when we started here at University of Florida, we had this concept of model for caring for the Parkinson person. And we said, the person’s the sun, and we should all orbit around the person and the family, because this is such a complex condition. And there are so many, you know, specialists; you need an archeologist, a neurosurgeon, neuropsychologist, PT, OT, and speech, or maybe you need a nutritionist, access to clinical trials… We have over a hundred clinical trials, it becomes confusing. And so, we need to integrate the care, and if we integrate the care into what we call a multidisciplinary team, we’ve learned that it isn’t just–I call myself the drug dealer as a neurologist. It isn’t just the drug dealer or the device dealer, where we take people to the operating room and put a device in that provides the best possible care. It’s this model of interdisciplinary care, and it continuously changes over time, and you have to actually listen to the people, so it’s a different specialty, and to actually listen to the clues that they give you on how they’re living in order to change timing and change doses. There’s over a dozen different medications, there’s all sorts of infusions, there’s deep brain stimulation. And I like to teach, and we have fellows here who, after they’re done with their neurology residency, spend two years with us to train in this, and we’ve trained about 70 of these were all over the world. And what I like to tell people is Parkinson is like a lifetime disease. Think of all these different therapies, and you need to understand how the disease evolves and when is the right window to apply each one. So deep brain stimulation isn’t for everyone at all times, but there are points in the treatment where it can provide extremely beneficial effects on things like just suppressing tremor or movements we call dyskinesia. And so knowing the disease and knowing the person, and then creating the right multidisciplinary plan is important. And the last point is, we wrote something for the Journal of the American Medical Association last year with Melissa Armstrong here at UF. And we, as experts said, a first-line therapy now is exercise. We now recognize that exercise is so beneficial for this disease, that it’s now considered a first-line therapy, right along with the medications. And so that should tell you something about the humility of treating this disease for so many years and us understanding what’s good for folks and what’s not. Richard Miles (14:18): If we compare this to a disease like cancer, is Parkinson’s something that could actually be put into remission, or is this a steadily degenerative disease? All the treatments are just slowing down or resting that trajectory, but essentially it’s going down, or can you stabilize somebody for a decade, for instance, with no decline? How does that compare to something like cancer? Dr. Michael Okun (14:37): Parkinson’s is a progressive neurodegenerative disorder. Now there are multiple what we call phenotypes. So we have what some people call benign Parkinson, because it progresses so slowly. And then there are other forms that progress faster. We’re just beginning–it’s like Genesis of the Bible–we’re just the in first couple of days in understanding actually the differences between some of these entities, but it is progressive. Now people might say, well, tell me, how did Pope John Paul get anointed as a Saint, right? Didn’t he cure a nun of Parkinson disease, and that’s how he achieved sainthood. Well, we’d like to leave that story alone because it turns out that many people who are presumed to have Parkinson’s disease do not. And so if you get better then you may not have Parkinson’s, and then there’s a group of people who have tremors and other symptoms that look like Parkinson’s. About 10%, about one in 10, very early on, when you first see them, then never progress. And a lot of times people don’t go back and realize, wait, this person’s not progressing at all — hey actually don’t have Parkinson, they have something else that’s more benign. And we realized that, and we gave this crazy name to that called scans without evidence of dopaminergic denervation. I would never call a person a sweat, that’s what it stands for. But, if you’re not progressing, you may not have Parkinson’s. And sometimes early on the diagnosis can be made in the wrong direction as well. And so it’s very important, but when you do have Parkinson right now, it’s progressive. Now we are searching for things that will slow the disease down and, or provide precision medicine or other treatments for it, but we haven’t gotten there yet. Richard Miles (16:15): So let me come back to something you just said about perhaps a faulty diagnosis. It sounds like the ideal treatment or regimen of treatment is this interdisciplinary approach, which you’ve got multiple people looking at it and working on it from different angles for a patient, but I’m guessing that that level of complexity of care is not available to everyone. Do you have to be next to, say a major research hospital, like University of Florida, or some major metropolitan area to get that kind of care? And if you’re not, and you’re in a rural area or in a very poor country, for instance, what is the outlook for somebody in their mid-sixties? Dr. Michael Okun (16:44): So in general, if you can get access to one of these multidisciplinary teams, it’s better. We know from Medicare data done by Allison Willis, who is at the University of Pennsylvania, that if you have access to even a neurologist, and most people don’t actually see a neurologist, if you have access to a neurologist, your morbidity and mortality, your nursing home placement, all of those things that are super important, those numbers get better. Just having access. If you have access to multidisciplinary care, the data is beginning to point that this is also better. There are centers of excellence that have been set up through foundations, ike I work as a medical advisor and former medical director for the Parkinson Foundation. We have 47 centers all over the globe, but these aren’t widely available to people. What we do at the University of Florida is we see people from all over the world, we always have, and we try to construct plans for them, so these plans can be carried out by people within local zip codes, whether your local zip code is in Australia or Asia, or you have flown in to be seen, you know, from there where we set the plans, and then we ask the therapists to follow them out. Beause a lot of therapists and other members of a multidisciplinary team, they may be giving you the wrong therapy. And sometimes the wrong therapy, Richard, is worse than no therapy in a disease like this. And so setting the right plans, communicating and creating public health value is important. And one of the three things, we just had a campaign it’s still ongoing called the Give a Dime for Parkinson’s Disease campaign, and our first goal was to get to 10,000 red cards to the White House. We’ve now reached 25,000. One of the three points, while we asked for three things– because if you ask for too many people get distracted–we’re asking the White House and congressional members to consider as one of the three things is to maintain telehealth access for people in the United States. That didn’t happen before COVID-19, and many people don’t realize that that’s not permanent. That has to be made permanent, and then we have to develop these types of interdisciplinary models, so that people who don’t have access or don’t live right next door can still get access and the right advice, and then put the right team together, so they can have the best outcomes. The best outcomes mean less falls, less fractures, billions of dollars in healthcare savings, happier people. And so I think it’s in everybody’s best interest, particularly as the disease has exploded. Richard Miles (19:06): And Dr. Okun, In addition to your research and your clinical work, I know you are involved in at least several nonprofits that I know of, probably more. Tell us a little bit about what you’re doing in those areas, like Tyler’s Hope and so on, and what has been the response as you’re trying to raise awareness on some of these conditions or diseases that are not as well known. Dr. Michael Okun (19:23): Yeah. So I think when you look at other diseases and what they’ve done to change the trajectory, the story of polio, the story of HIV, and in HIV, it took what we call four pillars to do that. So you have to develop a system with any of these nonprofits for any of these really important diseases that are going to affect society. P is for prevent, A is for advocate, C is for care, and T is for developing new treatments through research. We call it the PACT. So when we went and we researched, we said, what do you need to do? So we need to get all of our non-for-profits together and we need to organize and sum our voices, and reach that inflection point where we can become loud enough. We can advocate with enough force to actually push change. And that’s what happened in HIV. For example, they went from a few hundred million in funding to 3 billion, a year in funding. And now HIV, when I was an intern, my first year out of medical school, 25 years ago, this was a bad word to be on. If you have HIV, it was kind of the death word, and it was really not great. And now, it’s a chronic livable condition, the trajectory has changed for literally tens of thousands, if not more people, worldwide. And there’s a reason why that happened: prevent, advocate, care, and treat them. And advocacy was huge. And so I’m a big believer in non-for-profits and even more than opening the checkbook and writing the check, getting involved. And I’m a believer that when you sum voices together, if you can get to a certain level–and nobody knows exactly what that is, maybe we can ask them out loud while our tipping point lives through these things. But there is a moment where things tip. And so one of the things in Perkinson, for example, we’re trying to tip, one of the three things we’re asking for us increase the funding from 200 million to 2 billion a year, by 10 times, because we know that if you increase it by two times, you’re going to get twice as much research, twice as many young researchers. And so this is going to have a multiplicative effect. When it comes for Tyler’s Hope for just only a cure, here, this is a disease where we know the deletion. We know where it lives. We know quite a bit about it. We have a lot of technology, we just need to, sum our voices, push more money into this, and that’s what Tyler’s Hope is doing, push the advocacy, and we can create a precision medicine treatment. And I think we’re on our way and that disease as well, there’s still a way to go, but the same for Tourette. So I’ve been in the tourette world with a non-for-profit called the Tourette Association of America. So I think the story is the same, but I think part of the formula to reach impact is you have to bring together globally voices. And when we were speaking with World Health Organization, there were representatives from all countries talking about Parkinson and creating that grassroots movement. And we have a grassroots movement called the PD Avengers on Twitter. Now there’s 3000, like really loud, obnoxious people on one of them that are really making a lot of noise. And that’s what we need. We don’t need to be polite anymore. We need to be aggressive and charismatic and a bit obnoxious for these diseases. Richard Miles (22:26): I like how you put that and, as a comment, as an aside, I spent a good portion of my career overseas. And one thing that non-Americans are amazed by is the level for nonprofit activity that we have in the United States, directed towards all sorts of things, but in particular medicine or health, and the vibrancy of that sector really is something almost distinctly American. They obviously exist in other countries, but not nearly at the level and scope of what you see all over the place in small towns, big towns, and so on. Dr. Michael Okun (22:53): It’s a very special thing. And you’re absolutely right. I’ve done outreach to other countries. And I, I won’t say which country I was in, we actually brought some devices in and probably could have been arrested for doing that. And we were helping the doctors with some devices and some implants. And we were out seeing people all over, who just needed help. And it struck me in that experience, and I’ve seen it in other countries as well, that we helped a woman, and then they invited us to dinner, and we realized that, Oh my God, this woman that we helped is the mother of somebody huge in the country that has these huge business interests all over the country. And we said, why don’t you give a whole bunch of money to Parkinson’s disease? And they said, “give money to Parkinson disease? We don’t give money. This is an American thing.” You know, too, we’re having this discussion. “You all give away your money. We don’t do that. We don’t do charity.” And I thought, wow, it is really something special. And, and then I think they felt a little bit embarrassed. And then they said, well, we do give charity. But the charity we give is we support our sports teams. And so we explained to them, well, that’s not exactly charity. And so I do think that it is a uniquely American thing. It’s one of the things that differentiates us, makes us stronger and gives us the potential to mobilize and galvanize against diseases and other issues that face society. Richard Miles (24:12): And it’s also a perfect way to mediate between the individual who alone can’t do much, and the government, which often has a lot of resources, but is not terribly efficient in how it distributes them, so it creates this whole layer between small groups and very large governments. Dr. Okun, one final question or a couple of questions actually. At the Cade Museum, we like to not just tell a story of inventions, but the inventors, and not just the story of technology, but the researchers behind the technology. So tell us a little bit about pre-professional Michael Okun: what were you like as a kid? Did you know, early on you wanted to be a doctor or a researcher? What were some of your early influences? Dr. Michael Okun (24:48): Yeah, so I had it pretty good as a kid. I grew up with a good house. I had two parents. My father was a dentist, my mother was teacher. And so I kind of got left brain, right brain. They had very different ways of looking at the world. I was always memorizing things like the backs of baseball cards, statistics, things like that. And my life I’ve always had a joy. I’ve always been a person that’s had pure joy to be part of things. And so for me, a lot of my joy was in reading history and humanities and things like that. And so I saw myself more as a teacher and a teacher of history and even going into medicine for me, I saw myself as a black bag family practice doc. But what happened to me was life as a journey. And it’s like a lot of Chinese philosophers say, Lu Zhen is a famous Chinese philosopher who talks about roads, and there are no roads, and when there are no roads, a road is formed because people walk on that road. And so you walk your journey and you take your opportunities. And sometimes you don’t know exactly what you’re interested in or not interested in. And so even when I ended up saying, I want to go to medical school now and try to help people in underserved communities, I couldn’t tell you the difference between a neurologist and neurosurgeon you know, at that point in my life, and you just keep walking the road, and it turns out I’ve always been fascinated by people with tremors and movements and saying why. And I said, I would never do research. I’m a teacher. I would never do research. And then I realized that the government will give you a whole bunch of money to study things that you’re super passionate about that can help people. And so I was super passionate about figuring out where in the brain ticks came from. And so I’ve spent 20 years working on that problem, and we’ve developed devices, systems and things to try to address that problem, same with Parkinson and tremors and certain movements and funny walks. And so I’ve always been fascinated by that. I think the secret is, you find your passion, you spend as many minutes as you can doing your passion. And if you can get somebody to actually pay you to do it, then that’s the bonus, but the bonus doesn’t always happen. And I think in my life, all of those things have aligned and I have great joy every day that I come to work ,every day that we go to the operating room, Kelly and I, I have great joy. We’re always thinking, we’re always innovating. And we consider our labs a continuous beta test. We’re always writing papers. We’re always thinking about stuff. Now, one thing we’re not for people that are listening to this podcast, we’re not like business entrepreneurs. So we patented a whole bunch of different things: how you do a cap on this, how you do reporting on that, how a device would do this, how one side might turn this side on. And, we get involved with all of these things–vaccines–but our job is we just keep innovating, and then we hand that over to someone else and innovations square and let other people run with it, because our passion and our impact is trying to help as many people as we can. And so there are various different aspects to the creativity process, to the invention and the innovation process. And we have kind of a human laboratory, you know, in the operating room and in the clinics and in seeing people and they tell us what the problems are and we try to innovate for them. And the next steps happen as we try to create that, we try to write it down. Remember I like to write poetry and other things. We try to write it down and tell people what we did, and then the next steps will happen. So there is this beautiful process of innovation that happens, and there are a lot of people that quietly do that in the background like Kelly Foote and groups here that are just quietly doing their jobs, writing down what they’re doing, and then letting other people take it to the next level and commercialize these things and make sure that they get out there to help people. And there’s a great quote, I think it was Jonas Salk who they said, are you going to patent polio vaccine? And he said, well, that would be like patenting the sun. And so we’re all into patents and innovations and everything. But at the end of the day, we have a certain amount of minutes on the planet, and if we can come up with innovations that are going to help and impact people’s lives, I think that’s what most of the people, at least on the medical disease side of innovation, are interested in. And so you asked me what my message would be for kids or young people would just be follow your road, spend as many minutes doing the passion that you can, impact as many lives as you can. Don’t worry about the money. Don’t worry about that. Just worry about how much joy you have in your heart. That’s all you need to do. Richard Miles (29:14): That’s a great answer. And whether intentionally or not, you summarized also a good chunk of the origin story of the Cade Museum and Dr. Robert Cade, who invented as you know, Gatorade, because he didn’t have any idea how to take that product to market. He liked to write poetry. He had just a real joy in life for helping others and to his final day, he and his co-inventors, the number one thing they were proudest about, about Gatorade, was the fact that it became the cheapest and most widely available treatment for infant diarrhea in the third world. Wasn’t intended to do that, but that’s what they are really the proudest to have, not that it became a culture or a sports icon. And so it’s nice to hear you say that, but just in different words. Dr. Michael Okun (29:50): I think it’s a great story, and one I hope kids are listening to, but so many people will give you advice about your career and everything, and I think they make it more complicated than it needs to be. Richard Miles (30:01): You precluded my last question, was what would your career advice be? And you just gave it to me anyway, but it’s great advice and really appreciate having you on the show. You’re doing tremendous work, keep doing it. It’s inspiration on all sorts of different levels and wish you the best of luck. Dr. Michael Okun (30:13): It’s my pleasure, and we love the Cade Museum. We talked about being involved in non-for-profits, my wife and I are involved in, and we think it’s just a great thing for not only this community, but for the world. So thanks for all you do. Outro (30:25): Thank you. Radio Cade is produced by the Cade museum for creativity and invention located in Gainesville, Florida. Richard Miles is the podcast host and Ellie, Tom coordinates, inventor interviews, podcasts are recorded at Heartwood, soundstage and edited and mixed by Bob McPeak. The radio Cade theme song was produced and performed by Tracy Collins and features violinist Jacob Lawson.

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