Ground Truths Eric Topol

If there’s one person you’d want to talk to about immunology, the immune system and Covid, holes in our knowledge base about the complex immune system, and where the field is headed, it would be Professor Iwasaki. And add to that the topic of Women in Science. Here’s our wide-ranging conversation.

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Transcript with many external link and links to the audio, recorded 30 April 2024
Eric Topol (00:06):
Hello, it's Eric Topol and I'm really thrilled to have my friend Akiko Iwasaki from Yale, and before I start talking with Akiko, I just want to mention there aren't too many silver linings of the pandemic, but one for me was getting to know Professor Iwasaki. She is my go-to immunologist. I've learned so much from her over the last four years and she's amazing. She just, as you may know, she was just recently named one of the most influential people in the world by TIME100. [and also recognized this week in TIME 100 Health]. And besides that, she's been elected to the National Academy of Medicine, National Academy of Sciences. She's the president of the American Association of Immunologists and she's a Howard Hughes principal investigator. So Akiko, it's wonderful to have you to join into an extended discussion of things that we have of mutual interest.
Akiko Iwasaki (01:04):
Thank you so much, Eric, for having me. I equally appreciate all of what you do, and I follow your blog and tweets and everything. So thank you Eric.
Eric Topol (01:14):
Well, you are a phenom. I mean just, that's all I can say because I think it was so appropriate that TIME recognize your contributions, not just over the pandemic, but of course throughout your career, a brilliant career in immunology. I thought we'd start out with our topic of great interest on Long Covid. You've done seminal work here and this is an evolving topic obviously. I wonder what your latest thoughts are on the pathogenesis and where things are headed.
Long Covid
Akiko Iwasaki (01:55):
Yeah, so as I have been saying throughout the pandemic, I think that Long Covid is not one disease. It's a collection of multiple diseases and that are sort of ending up in similar sets of symptoms. Obviously, there are over 200 symptoms and not everyone has the same set of symptoms, but what we are going for is trying to understand the disease drivers, so persistent viral infection is one of them. There are overwhelming evidence for that theory now, all the way from autopsy and biopsy studies to looking at peripheral blood RNA signatures as well as circulating spike protein and nucleocapsid proteins that are detected in people with Long Covid. Now whether that persistent virus or remnants of virus is driving the disease itself is unclear still. And that's why trials like the one that we are engaging with Harlan Krumholz on Paxlovid should tell us what percentage of the people are suffering from that type of driver and whether antivirals like Paxlovid might be able to mitigate those. If I may, I'd like to talk about three other hypotheses.
Eric Topol (03:15):
Yeah, I'd love for you to do that.
Akiko Iwasaki (03:18):
Okay, great. So the second hypothesis that we've been working on is autoimmune disease. And so, this is clearly happening in a subset of people, again, it's a heterogeneous disease, but we can actually not only look at reactogenicity of antibodies from people with Long Covid where we can transfer IgG from patients with Long Covid into an animal, a healthy animal, and really measure outcomes of a pathogenesis. So that's a functional evidence that antibodies in some people with Long Covid is really actually causing some of the damages that are occurring in vivo. And the third hypothesis is the reactivation of herpes viruses. So many of us adults have

“Where do I think the next amazing revolution is going to come? … There’s no question that digital biology is going to be it. For the very first time in our history, in human history, biology has the opportunity to be engineering, not science.” —Jensen Huang, NVIDIA CEO

Aviv Regev is one of the leading life scientists of our time. In this conversation, we cover the ongoing revolution in digital biology that has been enabled by new deep knowledge on cells, proteins and genes, and the use of generative A.I .
Transcript with audio and external links
Eric Topol (00:05):
Hello, it's Eric Topol with Ground Truths and with me today I've really got the pleasure of welcoming Aviv Regev, who is the Executive Vice President of Research and Early Development at Genentech, having been 14 years a leader at the Broad Institute and who I view as one of the leading life scientists in the world. So Aviv, thanks so much for joining.
Aviv Regev (00:33):
Thank you for having me and for the very kind introduction.
The Human Cell Atlas
Eric Topol (00:36):
Well, it is no question in my view that is the truth and I wanted to have a chance to visit a few of the principal areas that you have been nurturing over many years. First of all, the Human Cell Atlas (HCA), the 37 trillion cells in our body approximately a little affected by size and gender and whatnot, but you founded the human cell atlas and maybe you can give us a little background on what you were thinking forward thinking of course when you and your colleagues initiated that big, big project.
Aviv Regev (01:18):
Thanks. Co-founded together with my very good friend and colleague, Sarah Teichmann, who was at the Sanger and just moved to Cambridge. I think our community at the time, which was still small at the time, really had the vision that has been playing out in the last several years, which is a huge gratification that if we had a systematic map of the cells of the body, we would be able both to understand biology better as well as to provide insight that would be meaningful in trying to diagnose and to treat disease. The basic idea behind that was that cells are the basic unit of life. They're often the first level at which you understand disease as well as in which you understand health and that in the human body, given the very large number of individual cells, 37.2 trillion give or take, and there are many different characteristics.
(02:16):
Even though biologists have been spending decades and centuries trying to characterize cells, they still had a haphazard view of them and that the advancing technology at the time – it was mostly single cell genomics, it was the beginnings also of spatial genomics – suggested that now there would be a systematic way, like a shared way of doing it across all cells in the human body rather than in ways that were niche and bespoke and as a result didn't unify together. I will also say, and if you go back to our old white paper, you will see some of it that we had this feeling because many of us were computational scientists by training, including both myself and Sarah Teichmann, that having a map like this, an atlas as we call it, a data set of this magnitude and scale, would really allow us to build a model to understand cells. Today, we call them foundational models or foundation models. We knew that machine learning is hungry for these kinds of data and that once you give it to machine learning, you get amazing things in return. We didn't know exactly what those things would be, and that has been playing out in front of our eyes as well in the last couple of years.
Spatial Omics
Eric Topol (03:30):
Well, that gets us to the topic you touched on the second area I wanted to get into, which is extraordinary, which is the spatial omics, which is related to the ability to the single cell sequencing of cells and nuclei and not just RNA and DNA and methylation and chromatin. I mean, this is incredible that you can track the evolution

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