Ground Truths Eric Topol

Professor Doudna was awarded the 2020 Nobel Prize in Chemistry with Professor Emmanuelle Charpentier for their pioneering work in CRISPR genome editing. The first genome editing therapy (Casgevy) was just FDA approved, only a decade after the CRISPR-Cas9 editing system discovery. But It’s just the beginning of a much bigger impact story for medicine and life science.
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Transcript with links to audio and relevant external links
Eric Topol (00:06):
This is Eric Topol with Ground Truths, and I'm really excited today to have with me Professor Jennifer Doudna, who heads up the Innovative Genomics Institute (IGI) at UC Berkeley, along with other academic appointments, and as everybody knows, was the Nobel laureate for her extraordinary discovery efforts with CRISPR genome editing. So welcome, Jennifer.
Jennifer Doudna (00:31):
Hello, Eric. Great to be here.
Eric Topol (00:34):
Well, you know we hadn't met before, but I felt like I know you so well because this is one of my favorite books, The Code Breaker. And Walter Isaacson did such a wonderful job to tell your story. What did you think of the book?
My interview with Walter Isaacson on The Code Breaker, a book I highly recommend
Jennifer Doudna (00:48):
I thought Walter did a great job. He's a good storyteller, and as you know from probably from reading it or maybe talking to others about it, he wrote a page turner. He actually really dug into the science and all the different aspects of it that I think created a great tale.
Eric Topol (01:07):
Yeah, I recommended highly. It was my favorite book when it came out a couple years ago, and it is a page turner. In fact, I just want to read one, there's so many quotes out of it, but in the early part of the book, he says, “the invention of CRISPR and the plague of Covid will hasten our transition to the third great revolution of modern times. These revolutions arose from the discovery beginning just over a century ago, of the three fundamental kernels of our existence, the atom, the bit, and the gene.” That kind of tells a big story just in one sentence, but I thought I’d start with the IGI, the institute that you have set up at Berkeley and what its overall goals are.
Jennifer Doudna (01:58):
Right. Well, let's just go back a few years maybe to the origins of this institute and my thinking around it, because in the early days of CRISPR, it was clear that we were really at a moment that was quite unique in the sense that there was a transformative technology. It was going to intersect with lots of other discoveries and technologies. And I work at a public institution and my question to myself was, how can I make sure that this powerful tool is first of all used responsibly and secondly, that it's used in a way that benefits as many people as possible, and it's a tall order, but clearly we needed to have some kind of a structure that would allow people to work together towards those goals. And that was really the mission behind the IGI, which was started as a partnership between UC Berkeley and UCSF and now actually includes UC Davis as well.
The First FDA Approved Genome Editing
Eric Topol (02:57):
I didn't realize that. That's terrific. Well, this is a pretty big time because 10 years or so, I guess starting to be 11 when you got this thing going, now we're starting to see, well, hundreds of patients have been treated and in December the FDA approved the first CRISPR therapy for sickle cell disease, Casgevy. Is that the way you say it?
Jennifer Doudna (03:23):
Casgevy, yeah.
Eric Topol (03:24):
That must have felt pretty good to see if you go from the molecules to the bench all the way now to actually treating diseases and getting approval, which is no easy task.
Jennifer Doudna (03:39):
Well, Eric, for me, I'm a biochemist and somebody who has always worked on the fundamentals of biology, and so it's really been extraor

Note: This podcast is a companion to the Ground Truths newsletter “A Big Week for GLP-1 Drugs”
Eric Topol (00:06):
It is Eric Topol with Ground Truths, and with me today is Dr. Daniel Drucker from the University of Toronto, who is one of the leading endocrinologists in the world, and he along with Joel Habener and Jens Juul Holst from the University of Copenhagen and Denmark, have been credited with numerous prizes of their discovery work of glucagon-like peptide-1 (GLP-1) as we get to know these family of drugs and he's a true pioneer. He's been working on this for decades. So welcome, Daniel.
Daniel Drucker (00:43):
Thank you.
Eric Topol (00:45):
Yeah, it's great to have you and to get the perspective, one of the true pioneers in this field, because to say it's blossom would be an understatement, don't you think?
Daniel Drucker (00:57):
Yeah, it's been a bit of a hectic three years. We had a good quiet 30 plus years of solid science and then it's just exploded over the last few years.
Eric Topol (01:06):
Yeah, back in 30 years ago, did you have any sense that this was coming?
Daniel Drucker (01:14):
Not what we're experiencing today, I think there was a vision for the diabetes story. The first experiments were demonstrating insulin secretion and patents were followed around the use for the treatment of GLP-1 for diabetes. The food intake story was much more gradual and the weight loss story was quite slow. And in fact, as you know, we've had a GLP-1 drug approved for people with obesity since 2014, so it's 10 years since liraglutide was approved, but it didn't really catch the public's attention. The weight loss was good, but it wasn't as spectacular as what we're seeing today. So this really has taken off just over the last three, four years.
Eric Topol (01:58):
Yeah, no, it's actually, I've never seen a drug class like this in my life, Daniel. I mean, I've obviously witnessed the statins, but this one in terms of pleiotropy of having diverse effects, and I want to get to the brain here in just a minute because that seems to be quite a big factor. But one thing just before we get too deep into this, I think you have been great to recognize one of your colleagues who you work with at Harvard, Svetlana Mojsov. And the question I guess is over the years, as you said, there was a real kind of incremental path and I guess was in 1996 when you said, well, this drug likely will inhibit food intake, but then there were gaps of many years since then, as you mentioned about getting into the obesity side. Was that because there wasn't much weight loss in the people with diabetes or was it related to the dose of the drugs that were being tested?
Why Did It Take So Long to Get to Obesity?
Daniel Drucker (03:11):
Well, really both. So the initial doses we tested for type 2 diabetes did not produce a lot of weight loss, maybe 2-3%. And then when we got semaglutide for type 2 diabetes, maybe we were getting 4-5% mean weight loss. And so that was really good and that was much better than we achieved before with any glucose lowering drug. But a lot of credit goes to Novo Nordisk because they looked at the dose for liraglutide and diabetes, which was 1.8 milligrams once daily for people with type 2 diabetes. And they asked a simple question, what if we increase the dose for weight loss? And the answer was, we get better weight loss with 3 milligrams once a day. So they learn that. And when they introduced semaglutide for type 2 diabetes, the doses were 0.5 and 1 milligrams. But in the back of their minds was the same question, what if we increased the dose and they landed on 2.4 milligrams once a week. And that's when we really started to see that the unexpected spectacular weight loss that we're now quite familiar with.
Eric Topol (04:16):
Was there also something too that diabetics don't lose as much weight if you were to have match dose?
Daniel Drucker (04:22):
Yeah, that's a general phenomenon. If one goes from either diet to baria

Siddhartha Mukherjee is a Professor at Columbia University, oncologist, and extraordinary author of Emperor of All Maladies (which was awarded a Pulitzer Prize), The Gene, and The Song of the Cell, along with outstanding pieces in the New Yorker. He is one of the top thought leaders in medicine of our era.

“I have begun to imagine, think about what it would be to be a digital human..”—Sid Mukherjee

Eric Topol (00:06):
Well, hello, this is Eric Topol with Ground Truths, and I am delighted to have my friend Sid Mukherjee, to have a conversation about all sorts of interesting things. Sid, his most recent book, SONG OF THE CELL is extraordinary. And I understand, Sid, you're working on another book that may be cell related. Is that right?
Sid Mukherjee  (00:30):
Eric, it's not cell related, I would say, but it's AI and death related, and it covers, broadly speaking, it covers AI, longevity and death and memory —topics that I think are universal, but also particularly medicine.
Eric Topol (00:57):
Well, good, and we'll get into that. I had somehow someone steered me that your next book was going to be something building on the last one, but that sounds even more interesting. You're going in another direction. You've covered cancer gene cells, so I think covering this new topic is of particularly interest. So let's get into the AI story and maybe we'll start off with your views on the healthcare side. Where do you think this is headed now?
A.I. and Drug Discovery
Sid Mukherjee  (01:29):
So I think Eric, there are two very broad ways of dividing where AI can enter healthcare, and there may be more, I'm just going to give you two, but there may be more. One is on what I would call the deep science aspect of it, and by that I mean AI-based drug discovery, AI-based antibody discovery, AI-based modeling. All of which use AI tools but are using tools that have to do with machine learning, but may have to do less directly with the kind of large language models. These tools have been in development for a long time. You and I are familiar with them. They are tools. Very simply put, you can imagine that the docking of a drug to a protein, so imagine every drug, every medicine as a small spaceship that docks onto a large spaceship, the large spaceship being the target.
(02:57):
So if you think of it that way, there are fundamental rules. If anyone's watched Star Wars or any of these sci-fi films, there are fundamental rules by which that govern the way that the small spaceship in this case, a molecule like aspirin fits into a pocket of its target, and those are principles that are determined entirely by chemistry and physics, but they can be taught, you can learn what kind of spaceship or molecule is likely to fit into what kind of pocket of the mothership, in this case, the target. And if they can be learned, they're amenable to AI-based discovery.
Eric Topol (03:57):
Right. Well, that's, isn't that what you'd call the fancy term structure-based discovery, where you're using such tools like what AlphaFold2 for proteins and then eventually for antibodies, small molecules, et cetera, that you can really rev up the whole discovery of new molecules, right?
Sid Mukherjee  (04:21):
That's correct, and that's one of the efforts that I'm very heavily involved in. We have created proprietary algorithms that allow us to enable this. Ultimately, of course, there has to be a method by which you start from these AI based methods, then move to physical real chemistry, then move to real biology, then move to obviously human biology and ultimately to human studies. It's a long process, but it's an incredibly fruitful process.
Eric Topol (04:57):
Well, yeah, as an example that recently we had Jim Collins on the podcast and he talked about the first new drug class of antibiotics in two decades that bind to staph aureus methicillin resistant, and now in clinical trials. So it’s happening. There’s 20 AI drugs in clinical trials out there.
Si

There was so much to talk about—this is the longest Ground Truths podcast yet. Hope you’ll find it as thought-provoking as I did!
Transcript, with audio and external links, edited by Jessica Nguyen, Producer for Ground Truths
Video and audio tech support by Sinjun Balabanoff, Scripps Research

Eric Topol (00:00:05):
This is Eric Topol from Ground Truths, and I am delighted to have with me Holden Thorp, who is the Editor-in-Chief of the Science journals. We're going to talk about Science, not just the magazine journal, but also science in general. This is especially appropriate today because Holden was just recognized by STAT as one of the leaders for 2024 because of his extraordinary efforts to promote science integrity, so welcome Holden.
Holden Thorp (00:00:36):
Thanks Eric, and if I remember correctly, you were recognized by STAT in 2022, so it's an honor to join a group that you're in anytime, that's for sure, and great to be on here with you.
Eric Topol (00:00:47):
Well, that's really kind to you. Let's start off, I think with the journal, because I know that consumes a lot of your efforts and you have five journals within science.
Holden Thorp (00:01:02):
Oh, we have six.
Eric Topol (00:01:03):
Oh six, I'm sorry, six. There's Science, the original, and then five others. Can you tell us what it's like to oversee all these journals?
Overseeing the Science Journals
Holden Thorp (00:01:16):
Yeah, we're a relatively small family compared to our commercial competitors. I know you had Magdalena [Skipper]on and Nature has I think almost ninety journals, so six is pretty small. In addition to Science, which most people are familiar with, we have Science Advances, which also covers all areas of science and is larger and is a gold open access journal and also is overseen by academic editors, not professional editors. All of our other journals are overseen by professional editors. And then the other four are relatively small and specialized areas, and probably people who listen to you and follow you would know about Science Translational Medicine, Science Immunology, Science Signaling and then we also have a journal, Science Robotics which is something I knew nothing about and I learned a lot. I've learned a lot about robotics and the culture of people who work there interacting with them.
Holden Thorp (00:02:22):
So we have a relatively small family. There's only 160 people who work for me, which is manageable. I mean that sounds like a lot, but in my previous jobs I was a provost and a chancellor, and I had tens of thousands of people, so it's really fun for me to have a group where I at least have met everybody who works for me. We're an outstanding set of journals, so we attract an outstanding group of professionals who do all the things that are involved in all this, and it's really, really fun to work with them. At Science, we don't just do research papers, although that's a big, and probably for your listeners the biggest part of what we do. But we also have a news and commentary section and the news section is 30 full-time and many freelancers around the world really running the biggest general news operation for science that there is. And then in the commentary section, which you're a regular contributor for us in expert voices, we attempt to be the best place in the world for scientists to talk to each other. All three of those missions are just really, really fun for me. It's the best job I've ever had, and it's one I hope to do for many years into the future.
Eric Topol (00:03:55):
Well, it's extraordinary because in the four and a half years I think it's been since you took the helm, you've changed the face of Science in many ways. Of course, I think the other distinction from the Nature Journals is that it's a nonprofit entity, which shows it isn't like you're trying to proliferate to all sorts of added journals, but in addition, what you've done, at least the science advisor and the science news and all these t

Transcript
Eric Topol (00:06):
Well, hello, this is Eric Topol with Ground Truths and I am absolutely thrilled to welcome Daphne Koller, the founder and CEO of insitro, and a person who I've been wanting to meet for some time. Finally, we converged so welcome, Daphne.
Daphne Koller (00:21):
Thank you Eric. And it's a pleasure to finally meet you as well.
Eric Topol (00:24):
Yeah, I mean you have been rocking everybody over the years with elected to the National Academy of Engineering and Science and right at the interface of life science and computer science and in my view, there's hardly anyone I can imagine who's doing so much at that interface. I wanted to first start with your meeting in Davos last month because I kind of figured we start broad AI rather than starting to get into what you're doing these days. And you had a really interesting panel [←transcript] with Yann LeCun, Andrew Ng and Kai-Fu Lee and others, and I wanted to get your impression about that and also kind of the general sense. I mean AI is just moving it at speed, that is just crazy stuff. What were your thoughts about that panel just last month, where are we?
Video link for the WEF Panel
Daphne Koller (01:25):
I think we've been living on an exponential curve for multiple decades and the thing about exponential curves is they are very misleading things. In the early stages people basically take the line between whatever we were last year, and this year and they interpolate linearly, and they say, God, things are moving so slowly. Then as the exponential curve starts to pick up, it becomes more and more evident that things are moving faster, but it’s still people interpolate linearly and it's only when things really hit that inflection point that people realize that even with the linear interpolation where we'll be next year is just mind blowing. And if you realize that you're on that exponential curve where we will be next year is just totally unanticipatable. I think what we started to discuss in that panel was, are we in fact on an exponential curve? What are the rate limiting factors that may or may not enable that curve to continue specifically availability of data and what it would take to make that curve available in areas outside of the speech, whatever natural language, large language models that exist today and go far beyond that, which is what you would need to have these be applicable to areas such as biology and medicine.
Daphne Koller (02:47):
And so that was kind of the message to my mind from the panel.
Eric Topol (02:53):
And there was some differences in opinion, of course Yann can be a little strong and I think it was good to see that you're challenging on some things and how there is this “world view” of AI and how, I guess where we go from here. As you mentioned in the area of life science, there already had been before large language models hit stride, so much progress particularly in imaging cells, subcellular, I mean rare cells, I mean just stuff that was just without any labeling, without fluorescein, just amazing stuff. And then now it's gone into another level. So as we get into that, just before I do that, I want to ask you about this convergence story. Jensen Huang, I'm sure you heard his quote about biology as the opportunity to be engineering, not science. I'm sure if I understand, not science, but what about this convergence? Because it is quite extraordinary to see two fields coming together moving at such high velocity.
"Biology has the opportunity to be engineering not science. When something becomes engineering not science it becomes...exponentially improving, it can compound on the benefits of previous years." -Jensen Huang, NVIDIA.
Daphne Koller (04:08):
So, a quote that I will replace Jensen's or will propose a replacement for Jensen's quote, which is one that many people have articulated, is that math is to physics as machine learning is to biology. It is a mathematical foundation that allows you to tak

“A few years ago, I might have chuckled at the naiveté of this question, but now it's not so crazy to think that we will be able to take some sort of medicine to extend our healthy lifespans in the foreseeable future.”—Coleen Murphy



Transcript with external links
Eric Topol (00:06):
Hello, this is Eric Topol from Ground Truths, and I'm just so delighted to have with me Professor Coleen Murphy, who has written this exceptional book, How We Age: The Science of Longevity. It is a phenomenal book and I'm very eager to discuss it with you, Coleen.
Coleen Murphy (00:25):
Thanks for having me on.
Eric Topol (00:27):
Oh yeah. Well, just so everyone who doesn't know Professor Murphy, she's at Princeton. She's the Richard Fisher Preceptor in Integrative Genomics, the Lewis-Sigler Institute for Integrative Genomics at Princeton, and director of the Paul Glenn Laboratories for Aging Research. Well, obviously you've been in this field for decades now, even though you're still very young. The classic paper that I can go back to would be in Nature 2003 with the DAF-16 and doubling the lifespan of C. elegans or better known as a roundworm. Would that be the first major entry you had?
Coleen Murphy (01:17):
Yeah, that was my postdoctoral work with Cynthia Kenyon.
Eric Topol (01:20):
Right, and you haven't stopped since you've been on a tear and you’ve put together a book which has a hundred pages of references in a small font. I don't know what the total number is, but it must be a thousand or something.
Coleen Murphy (01:35):
Actually, it's just under a thousand. That's right.
Eric Topol (01:37):
That's a good guess.
Coleen Murphy (01:38):
Good guess. Yeah.
Eric Topol (01:39):
So, because I too have a great interest in this area, I found just the resource that you've put together as extraordinary in terms of the science and all the work you've put together. What I was hoping to do today is to kind of take us through some of the real exciting pathways because there's a sentence in your book, which I thought was really kind of nailed it, and it actually is aligned with my sense. Obviously don't have the expertise by any means that you do here but it says, “A few years ago, I might have chuckled at the naivety of this question, but now it's not so crazy to think that we will be able to take some sort of medicine to extend our healthy lifespans in the foreseeable future.” That's a pretty strong statement for a person who's deep into the science. First I thought we'd explore healthy aging health span versus lifespan. Can you differentiate that as to your expectations?
Coleen Murphy (02:54):
So, I think most people would agree that they don't want to live necessary super long. What they really want to do is live a healthy life as long as they can. I think that a lot of people also have this fear that when we talk about extending lifespan, that we're ignoring that part. And I do want to assure everyone that the people in the researchers in the aging field are very much aware of this issue and have, especially in the past decade, I think put a real emphasis on this idea of quality of life and health span. What's reassuring is actually that many of the mechanisms that extend lifespan in all these model organisms also extend health span as well and so I don't think we're going to, they're not diametrically opposed, like we'll get to a healthier quality of life, I think in these efforts to extend lifespan as well.
Eric Topol (03:50):
Yeah, I think that's important that you're bringing that up, which is there's this overlap, like a Venn diagram where things that do help with longevity should help with health span, and we don't necessarily have to follow as you call them the immoralists, as far as living to 190 or whatever year. Now, one of the pathways that's been of course a big one for years and studied in multiple species has been caloric restriction. I wonder if you could talk to that and obviously there's now mimetics that could s