Ground Truths

Below is a brief video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The current one is here. If you like the YouTube format, please subscribe! This one has embedded one of my favorite TikTok’s from Will. There are several links to others in the transcript. The audios are also available on Apple and Spotify.

Transcript with links to both audio and videos, commencement addresses, NEJM article coverage

Eric Topol (00:06):

Hi, it's Eric Topol from Ground Truths, and I've got an amazing couple with me today. It's Will Flanary and Kristin Flanary, the Glaucomfleckens. I've had the chance to get to know them a bit through Knock Knock, Hi! which is their podcast. And of course, everyone knows Dr. Glaucomflecken from his TikTok world and his other about 4 million followers on Instagram and Twitter and all these other social media, and YouTube. So welcome.

Will Flanary (00:43):

Thanks for having us.

Kristin Flanary (00:44):

Thank you. Happy to be here.

By Way of Background

Eric Topol (00:45):

Yeah. Well, this is going to be fun because I'm going to go a quick background so we can go fast forward because we did an interview back in early 2022.

Kristin Flanary (00:56):

Yes.

Eric Topol (00:57):

And what you've been doing since then is rocking it. You're like a meteoric, right. And it was predictable, like rarefied talent and who couldn't love humor, medical humor, but by way of background, just for those who are not up to speed. I guess you got your start, Will, as a class clown when your mother was a teacher in the sixth grade.

Will Flanary (01:22):

Yep, yep. I misbehaved a little bit. It helped that I still made good grades, but I cut up a bit in class.

Eric Topol (01:32):

And then you were already in the comedy club circuits doing standup in Houston as an 18-year-old.

Will Flanary (01:40):

It was all amateur stuff, nothing, just dabble in it and trying to get better. I was always kind of naturally funny just with my friend group and everything. I loved making people laugh, but doing standups is a whole different ball game. And so, I started doing that around Houston as a high school senior and kept that going through college and a little bit into med school.

Kristin Flanary (02:02):

Houston was a good training ground, right? That where Harris Wittels was also coming up.

Will Flanary (02:07):

Yeah. A lot of famous comedians have come through Houston. Even going back to Bill Hicks back in the, was that the 80s, I think? Or 90s?

Eric Topol (02:17):

Well, and then of course, it was I think in 2020 when you launched Dr. Glaucomflecken, I think. Is that right?

Will Flanary (02:28):

That's when it really started to take off. I was on Twitter telling jokes back in 2016.

Kristin Flanary (02:39):

GomerBlog before that, that's actually where it was born.

Will Flanary (02:41):

I was doing satire writing. I basically do what I'm doing now, but in article form, trying to be The Onion of medicine. And then the pandemic hit, started doing video content and that's really with lockdown. That's when, because everybody was on social media, nobody had anything else to do. So it was right place, right time for me and branching out into video content.

On to Medical School Commencement Addresses

Eric Topol (03:11):

Alright, so that's the background of some incredible foundation for humor. But since we last got together, I'll link the Medicine and the Machine interview we did back then. What has been happening with you two is nothing short of incredible. I saw your graduation speeches, Will. Yale in 2022, I watched the UCSF in 2023 and then the University of Michigan in 2024. Maybe there's other ones I don't even know.

Kristin Flanary (03:45):

There’s a few others.

Will Flanary (03:45):

There's a few. But I feel like you've done, I'm sure your fair share of commencement addresses as well. It's kind of hard to come up with different ways to be inspirational to the next generation. So fortunately, we have together, we have some life experiences and learned a thing or two by doing all of this social media stuff and just the things we've been through that I guess I have enough things to say to entertain an interest.

Eric Topol (04:18):

Well, you're being humble as usual, but having watched those commencement addresses, they were the best medical commencement addresses I've ever seen. And even though you might have told us some of the same jokes, they were so great that it was all right. Yeah, and you know what is great about it is you've got these, not the students, they all love you of course, because they're probably addicted to when's your next video going to get posted.

(04:44):

But even the old professors, all the family members, it's great. But one of the things I wanted to get at. Well, I'll start with the graduation speeches, because you were such an inspiration, not just with humor, but your message. And this gets back to you as a couple and the tragedies you've been through. So you really, I think, got into this co-survivor story and maybe Kristin, since you are the co-survivor of two bouts of Will’s testicular cancer, and then the sudden cardiac death. I mean, people don't talk about this much, so maybe you could help enlighten us.

Tragedies and Being a Co-Survivor

Kristin Flanary (05:26):

Yeah, it’s funny because the experience of being a co-survivor is nothing new. It’s as long as we've had human beings, we've had co-survivors. But the concept around it and giving it a name and a label, a framework to be able to think about it, that is what I think is new and what people haven't talked about before. So co-survivor is just this idea that when a medical trauma happens to a patient, the patient has their experience and if they survive it, they are a survivor and they have a survivor experience. And also, most people are closely attached to at least one other person, if not many. And those people are co-surviving the medical event along with the survivor. That event is happening in their lives as was happening to them too. If someone comes in with a patient to the hospital, that person, you can just assume by default that their lives are pretty intimately or profoundly intertwined or else why would that person be there? And so, thinking of it as there's the patient and then there's also a co-patient, that family members in the past have only been thought of as caregivers if they've been thought of at all. And that is certainly one aspect of the role, but it's important to remember that whatever it is that's happening to the patient is also affecting the family members' lives in a really deep and profound way.

Eric Topol (07:04):

That's really helpful. Now, the fact that you recognize that in your graduation speech, Will, I think is somewhat unique. And of course, some of the other things that you touched on like playing to your creativity and the human factors, I mean, these are so important messages.

Will Flanary (07:23):

Well, in the discussion about co-survivorship and because I talk about that whenever I do my keynotes and when I do the commencement addresses, but all credit goes to Kristin for really being the driving force of this idea for me and for many others because as a physician, we take care of patients. Our focus is always on the patient. And it really wasn't until this happened to me and my family and Kristin in particular that I started to understand exactly what she's talking about and this idea. And so, Kristin gets a lot of credit for just really bringing that term and that idea to the forefront.

Eric Topol (08:09):

Yeah, well, you saved his life. It's just not many have that bond. And then the other thing I just want to mention now, you've been recognized by the American Heart Association and a whole bunch of other organizations awarded because of your advocacy for CPR. And you even mentioned that I think in one of your commencement addresses.

Will Flanary (08:31):

Yeah, I tried to get the crowd to do CPR. Like team up, partner up, and it kind of fell fl…

Above is a brief video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.

Transcript with links to audio and external citations

Eric Topol (00:06):

Well, hello it's Eric Topol with Ground Truths, and I'm really delighted to welcome Dr. Rachael Bedard, who is a physician geriatrician in New York City, and is actually much more multidimensional, if you will. She's a writer. We're going to go over some of her recent writings. She's actually quite prolific. She writes in the New Yorker, New York Magazine, New York Times, New York Review of Books. If it has New York in front of it, she's probably writing there. She's a teacher. She works on human rights, civil rights, criminal justice in the prison system. She's just done so much that makes her truly unique. That's why I really wanted a chance to meet her and talk with her today. So welcome, Rachael.

Rachael Bedard (00:52):

Thank you, Dr. Topol. It's an honor to be here.

Eric Topol (00:55):

Well, please call me Eric and it's such a joy to have a chance to get acquainted with you as a person who is into so many different things and doing all of them so well. So maybe we'd start off with, because you're the first geriatrician we've had on this podcast.

Practicing Geriatrics and Internal Medicine

Eric Topol (01:16):

And it’s especially apropos now. I wanted maybe to talk about your practice, how you got into geriatrics, and then we'll talk about the piece you had earlier this summer on aging.

Rachael Bedard (01:32):

Sure. I went into medicine to do social justice work and I was always on a funny interdisciplinary track. I got into the Mount Sinai School of Medicine through what was then called the Humanities and Medicine program, which was an early acceptance program for people who were humanities focused undergrads, but wanted to go into medicine. So I always was doing a mix of politics and activist focused work, humanities and writing, that was always interested in being a doctor. And then I did my residency at the Cambridge Health Alliance, which is a social medicine program in Cambridge, Massachusetts, and my chief residency there.

(02:23):

I loved being an internist, but I especially loved taking care of complex illness and I especially loved taking care of complex illness in situations where the decision making, there was no sort of algorithmic decision-making, where you were doing incredibly sort of complex patient-centered shared decision making around how to come up with treatment plans, what the goals of care were. I liked taking care of patients where the whole family system was sort of part of the care team and part of the patient constellation. I loved running family meetings. I was incredibly lucky when I was senior resident and chief resident. I was very close with Andy Billings, who was one of the founders of palliative care and in the field, but also very much started a program at MGH and he had come to work at Cambridge Hospital in his sort of semi-retirement and we got close and he was a very influential figure for me. So all of those things conspired to make me want to go back to New York to go to the Sinai has an integrated geriatrics and palliative care fellowship where you do both fellowships simultaneously. So I came to do that and just really loved that work and loved that medicine so much. There was a second part to your question.

Eric Topol (03:52):

Is that where you practice geriatrics now?

Rachael Bedard (03:55):

No, now I have ever since finishing fellowship had very unusual practice settings for a geriatrician. So right out of fellowship, I went to work on Rikers Island and then New York City jail system, and I was the first jail based geriatrician in the country, which is a sort of uncomfortable distinction because people don't really like to think about there being a substantial geriatric population in jails. But there is, and I was incredibly lucky when I was finishing fellowship, there was a lot of energy around jail healthcare in New York City and I wrote the guy who was then the CMO and said, do you think you have an aging problem? And he said, I'm not sure, but if you want to come find out, we'll make you a job to come find out. And so, that was an incredible opportunity for someone right out of fellowship.

(04:55):

It meant stepping off the sort of academic track. But I went and worked in jail for six years and took care of older folks and people with serious illness in jail and then left Rikers in 2022. And now I work in a safety net clinic in Brooklyn that takes care of homeless people or people who have serious sort of housing instability. And that is attached to Woodhull Hospital, which is one of the public hospitals in New York City. And there I do a mix of regular internal medicine primary care, but I preferentially see the older folks who come through, which is a really interesting, painful, complicated patient population because I see a fair amount of cognitive impairment in folks who are living in the shelter system. And that's a really hard problem to address.

Frailty, The Aged, and Longevity

Eric Topol (05:54):

Well, there's a theme across your medical efforts. It seems to me that you look after the neglected folks, the prisoners, the old folks, the homeless people. I mean that's kind of you. It's pretty impressive. And there's not enough of people like you in the medical field. Now, no less do you do that, but of course you are a very impressive author, writer, and of many topics I want to get into with you, these are some recent essays you've written. The one that piqued my interest to start to understand who you were and kind of discover this body of work was the one that you wrote related to aging and President Biden. And that was in New York Times. And I do want to put in a quote because as you know very well, there's so much interest in longevity now.

Eric Topol (06:51):

Interrupting the aging process, and this one really stuck with me from that op-ed, “Time marches forward, bodies decline, and the growing expectation that we might all live in perfect health until our 100th birthdays reflects a culture that overprizes longevity to the point of delusion.” So maybe if you could tell us, that was a rich piece, you got into frailty, you related it to the issues that were surrounding President Biden who at that time had not withdrawn from the race. But what were you thinking and what are your thoughts about the ability to change the aging process?

Rachael Bedard (07:36):

I am very interested in, I mean, I'm incredibly interested in the science of it. And so, I guess I think that there are a few things.

(07:49):

One thing is that the framework that, the part that gives me pause the most is this framework that anything less than perfect health is not a life worth living. So if you're going to have a long life, life should not just be long and sort of healthy in relative terms to your age cohort, but healthy that when you're 80 you should feel like you have the health of a 45-year-old is my understanding of the culture of longevity science. And while I understand why that's aspirational and everybody worry about my body's decline, I think it's a really problematic thing to say that sick bodies are bodies that have disability or people who have cognitive difference are somehow leading lesser lives or lives that are not meaningful or not worth living. I think it's a very, very slippery slope. It puts you in a place where it sort of comes up against another trend or another emerging cultural trend, which is really thinking a lot about physician-assisted suicide and end of life choices.

(09:04):

And that in some ways that conversation can also be very focused on this idea that there's just no way that it's worth living if you're sick. And that's just not true, I think, and that's not been true for many, many, many of my patients, some of whom have lived with enormous disability and incredibl…

Superimposed on an impressive body of work on the blood-brain-barrier and immune system, Prof Akassoglou and her collaborators just published an elegant study in Nature that centered on the direct binding os the SARS-CoV-2 spike protein to fibrin with marked downstream pro-inflammatory effects. The findings and potential treatments have implications beyond Covid, Long Covid to other neurologic diseases.

Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.

Transcript with links to audio and to relevant papers, graphics

Eric Topol (00:07):

Well, hello this is Eric Topol with Ground Truths, and with me today is Katerina Akassoglou. She is at the Gladstone Institute and she is a remarkable neuroimmunologist who has been doing extraordinary work for three decades to unravel the interactions between the brain, blood vessels and the role of inflammation. So Katerina, there's a lot to discuss, so welcome.

Katerina Akassoglou (00:40):

Thank you. Thank you so much. It's a great pleasure to join.

By Way of Background

Eric Topol (00:43):

It's really interesting going back in your career. First of all, we're thankful that you immigrated here from Greece, and you have become one of the leading scientists in this discipline of important discipline of neuroimmunology, which is not just about Covid that we're going to talk about, but Alzheimer's and neurodegenerative diseases. This is a really big hot area and you're definitely one of the leaders. And what I was impressed is that all these years that you've been working on the integrity of the blood-brain barrier, the importance of fibrinogen and fibrin, and then comes along the Covid story. So maybe what we can do is start with that, which is you've made your mark in understanding this whole interaction between what can get into the brain, through the blood-brain barrier and incite inflammation. So this has been something that you've really taken to the extreme knowledge base. So maybe we can start with your work there before we get into the important seminal Nature paper that you recently published.

Katerina Akassoglou (01:57):

Yes, of course. So since very early on, I was still a graduate student when we made the first discovery and at the time was like mid-90s, so it was really ahead of its time. That dysregulation of cytokine expression in the brain of mice was sufficient to induce the whole cascade of events, triggering neurodegeneration, demyelination in pathological alterations, very reminiscent of multiple sclerosis pathology. And it was really hard to publish that study at the time because it was not yet accepted that this regulation of the immune system modeling the brain can be linked to neurodegeneration. So that was 1995 when we made that discovery, and I became really interested, what are the pathogenic triggers that actually polarized the immune cells in the brain? So with this, of course, this transgenic animal was expressing TNF, it was an artificially made animal that we made, but naturally what were the triggers that would polarize the innate immune cells? So I looked really early on in this mice and what I found was that the very first event was leaks of blood-brain barrier. It was opening of the blood-brain barrier in this mouse before inflammation, before demyelination, before neuronal loss. And this is really what shaped the question that, is it possible that these blood leaks that happened very early in the pathology, could this be the instigators of pathogenic inflammation in the brain?

Eric Topol (03:34):

Yeah. So in a way, you got at this question because of the chicken-and-egg and what happens first, and you got to the temporal saying, which happened first as you said, the leak before you could see evidence of inflammation and being able to study this of course in the experimental model, which you couldn't really do in people. And what I love about the description of your career, which has been quite extraordinary contributions is connecting the dots between the blood, the inflammatory response and the brain. Perhaps no one has done that like you have. And before we get into the recent paper, a lot of people are not aware that a year ago, a group in the UK known as PHOSP-COVID, they published a really important paper in Nature Medicine of over 1,800 people who were hospitalized with Covid and they found that fibrinogen was the best marker for cognitive deficits at 6 and 12 months (Figure below)

(04:40):

So that's just one of many papers, but it's a particularly well done study that already before you got into this work that recently published had emphasized fibrinogen. And by the way, again, having spent a lot of years in clots in the arteries, for me, we have to just get it down to fibrinogen plus thrombin gets you to fibrin. Okay, so fibrin is a major player here when fibrinogen is cleaved. So here we have the basis that you established, which is the fibrinogen leakage into the brain, activating inflammation, activating microglia, which like the macrophages of the brain and inciting the whole process. And before we close, I want to not just talk about Covid, but Alzheimer's too. But now let's get into the study that you did, [Fibrin drives thromboinflammation and neuropathology in COVID-19] which is striking, I mean really striking. And can you kind of take us through, because you not only demonstrated the importance of fibrin in inciting neuroinflammation in this model, but also how you could reverse it or prevent it. So this, and you looked at it in many different ways, this was a systematic approach. Maybe you can take us through how you were able to make such compelling evidence.

The Multimodal Evidence

Katerina Akassoglou (06:09):

Yes, thank you. First of all, thank you for bringing up the human relevance because this was also our inspiration for the work that we did in the Covid study. So as you mentioned in Covid patients, fibrinogen unbiased mass spec analysis was identified as the predictive biomarker for cognitive impairment in Long Covid patients. And this was in addition to also neuropathology data about the abundance of fibrin deposition in the brain. And these were studies that were done by NIH that have found deposition of fibrin in the brain and the reports for the abnormal and puzzling coagulation in Covid that is not setting other infections and also in many cases not always relating with the severity of symptoms. So even mild cases of Covid also had increased coagulation. I was really intrigued by this human, all this evidence in human data, and I thought that maybe the way that we're thinking about this, that it's systemic inflammation that drives the clotting.

(07:24):

Maybe there's another aspect to this. Maybe there is a direct effect of the virus with the coagulation cascade, and in this way maybe this can be an instigator of inflammation. So this was the original idea to be able to reconcile this data from the clinic about why do we have this prevalence of coagulopathy in Covid. And of course, the second question is, could this also be a driver of the disease? And of course, we're in a unique position because we have been studying this pathway now for over 20 years to have all the toolbox, the genetic toolbox, the pharmacologic toolbox to be able to actually really address these questions with genetic loss of function studies, with a blood innate immunity multiomics pipeline that we have set up in the lab. And of course, with preclinical pharmacology in our ABSL3 facility. So we had the infrastructure in place and the source in place to actually really dissect this question with both genetic tools as well as also technology platforms.

Eric Topol (08:29):

And you had in vivo imaging, you're the director of in vivo imaging for Gladstone and UCSF. So you do have the tools to do this.

Katerina Akassoglou (08:38):

Yes. The imaging that you mentioned is really important because this is, we employed that very early in ou…

When I think of digital biology, I think of Patrick Hsu—he’s the prototype, a rarified talent in both life and computer science, who recently led the team that discovered bridge RNAs, what may be considered CRISPR 3.0 for genome editing, and is building new generative A.I. models for life science. You might call them LLLMs-large language of life models. He is Co-Founder and a Core Investigator of the Arc Institute and Assistant Professor of Bioengineering and Deb Faculty Fellow at the University of California, Berkeley.

Above is a brief snippet of our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.

Here’s the transcript with links to the audio and external links to relevant papers and things we discussed.

Eric Topol (00:06):

Well hello, it's Eric Topol with Ground Truths and I'm really delighted to have with me today Patrick Hsu. Patrick is a co-founder and core investigator at the Arc Institute and he is also on the faculty at the University of California Berkeley. And he has been lighting things up in the world of genome editing and AI and we have a lot to talk about. So welcome, Patrick.

Patrick Hsu (00:29):

Thanks so much. I'm looking forward to it. Appreciate you having me on, Eric.

The Arc Institute

Eric Topol (00:33):

Well, the first thing I'd like to get into, because you're into so many important things, but one that stands out of course is this Arc Institute with Patrick Collison who I guess if you can tell us a bit about how you two young guys got to meet and developed something that's really quite unique that I think brings together investigators at Stanford, UCSF, and Berkeley. Is that right? So maybe you can give us the skinny about you and Patrick and how all this got going.

Patrick Hsu (01:05):

Yeah, sure. That sounds great. So we started Arc with Patrick C and with Silvana Konermann, a longtime colleague and chemistry faculty at Stanford about three years ago now, though we've been physically operational just over two years and we're an independent research institute working at the interface of biomedical science and machine learning. And we have a few different aspects of our model, but our overall mission is to understand and treat complex human diseases. And we have three pillars to our model. We have this PI driven side of the house where we centrally fund our investigators so that they don't have to write grants and work on their very best ideas. We have a technical staff side of the house more like you'd see in a frontier AI lab or in biotech industry where we have professional teams of R&D scientists working cross-functionally on higher level organizational wide goals that we call our institute initiatives.

(02:05):

One focused on Alzheimer's disease experimentally and one that we call a virtual cell initiative to simulate human biology with AI foundation models. And our third pillar over time is to have things not just end up as academic papers, but really get things out into the real world as products or as medicines that can actually help patients on the translational side. And so, we thought that some really important scientific programs could be unlocked by enabling new organizational models and we are experimenting at the institutional scale with how we can better organize and incentivize and support scientists to reach these long-term capability breakthroughs.

Patrick, Patrick and Silvana

Eric Topol (02:52):

So the two Patrick’s. How did you, one Patrick I guess is a multi-billionaire from Stripe and then there's you who I suspect maybe not quite as wealthy as the other Patrick, how did you guys come together to do this extraordinary thing?

Patrick Hsu (03:08):

Yeah, no, science is certainly expensive. I met Patrick originally through Silvana actually. They actually met, so funny trivia, all three Arc founders did high school science together. Patrick and Silvana originally met in the European version of the European Young Scientist competition in high school. And Silvana and I met during our PhDs in her case at MIT and I was at Harvard, but we met at the Broad Institute sort of also a collaborative Harvard, MIT and Harvard hospitals Institute based in Kendall Square. And so, we sort of in various pairwise combinations known each other for decades and worked together for decades and have all collectively been really excited about science and technology and its potential to accelerate societal progress. Yet we also felt in our own ways that despite a lot of the tremendous progress, the structures in which we do this work, fund it, incentivize it and roll it out into the real world, seems like it's really possible that we'll undershoot that potential. And if you take 15 years ago, we didn't have the modern transformer that launched the current AI revolution, CRISPR technology, single-cell, mRNA technology or broadly addressable LNPs. That’s a tremendous amount of technologies have developed in the next 15 years. We think there's a real unique opportunity for new institutes in the 2020s to take advantage of all of these breakthroughs and the new ones that are coming to continue to accelerate biological progress but do so in a way that's fast and flexible and really focused.

Eric Topol (04:58):

Yeah, I did want to talk with you a bit. First of all before I get to the next related topic, I get a kick out of you saying you've worked or known each other for decades because I think you're only in your early thirties. Is that right?

Patrick Hsu (05:14):

I was lucky to get an early start. I first started doing research at the local university when I was 14 actually, and I was homeschooled actually until college. And so, one of the funny things that you got to do when you're homeschooled is well, you could do whatever you want. And in my case that was work in the lab. And so, I actually worked basically full time as an intern volunteer, cut my teeth in single cell patch clamp, molecular biology, protein biochemistry, two photon and focal imaging and kind of spiraled from there. I loved the lab, I loved doing bench work. It was much more exciting to me than programming computers, which was what I was doing at the time. And I think these sort of two loves have kind of brought me and us to where we are today.

Eric Topol (06:07):

Before you got to Berkeley and Arc, I know you were at Broad Institute, but did you also pick up formal training in computer science and AI or is that something that was just part of the flow?

Patrick Hsu (06:24):

So I grew up coding. I used to work through problems sets before dinner growing up. And so, it's just something that you kind of learn natively just like learning French or Mandarin.

New Models of Funding Life Science

Eric Topol (06:42):

That's what I figured. Okay. Now this model of Arc Institute came along in a kind of similar timeframe as the Arena BioWorks in Boston, where some of the faculty left to go to Arena like my friend Stuart Schreiber and many others. And then of course Priscilla and Mark formed the Chan Zuckerberg Institute and its biohub and its support. So can you contrast for one, these three different models because they’re both very different than of course the traditional NIH pathway, how Arc is similar or different to the others, and obviously the goal here is accelerating things that are going to really make a difference.

Patrick Hsu (07:26):

Yeah, the first thing I would say is zooming out. There have been lots of efforts to experiment with how we do science, the practice of science itself. And in fact, I've recently been reading this book, the Demon Under the Microscope about the history of infectious disease, and it talks about how in the 1910s through the 1930s, these German industrial dye manufacturing companies like Bayer and BASF actually launched what became essentially an early model for industrial scale science, where they were trying to develop Prontosil, Salvarsan and some of these early anti-infectives…

Arvind Narayanan and Sayash Kapoor are well regarded computer scientists at Princeton University and have just published a book with a provocative title, AI Snake Oil. Here I’ve interviewed Sayash and challenged him on this dismal title, for which he provides solid examples of predictive AI’s failures. Then we get into the promise of generative AI.

Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.

Transcript with links to audio and external links to key publications

Eric Topol (00:06):

Hello, it's Eric Topol with Ground Truths, and I'm delighted to welcome the co-author of a new book AI SNAKE OIL and it's Sayash Kapoor who has written this book with Arvind Narayanan of Princeton. And so welcome, Sayash. It's wonderful to have you on Ground Truths.

Sayash Kapoor (00:28):

Thank you so much. It's a pleasure to be here.

Eric Topol (00:31):

Well, congratulations on this book. What's interesting is how much you've achieved at such a young age. Here you are named in TIME100 AI’s inaugural edition as one of those eminent contributors to the field. And you're currently a PhD candidate at Princeton, is that right?

Sayash Kapoor (00:54):

That's correct, yes. I work at the Center for Information Technology Policy, which is a joint program between the computer science department and the school of public and international affairs.

Eric Topol (01:05):

So before you started working on your PhD in computer science, you already were doing this stuff, I guess, right?

Sayash Kapoor (01:14):

That's right. So before I started my PhD, I used to work at Facebook as a machine learning engineer.

Eric Topol (01:20):

Yeah, well you're taking it to a more formal level here. Before I get into the book itself, what was the background? I mean you did describe it in the book why you decided to write a book, especially one that was entitled AI Snake Oil: What Artificial Intelligence Can Do, What It Can't, and How to Tell the Difference.

Background to Writing the Book

Sayash Kapoor (01:44):

Yeah, absolutely. So I think for the longest time both Arvind and I had been sort of looking at how AI works and how it doesn't work, what are cases where people are somewhat fooled by the potential for this technology and fail to apply it in meaningful ways in their life. As an engineer at Facebook, I had seen how easy it is to slip up or make mistakes when deploying machine learning and AI tools in the real world. And had also seen that, especially when it comes to research, it's really easy to make mistakes even unknowingly that inflate the accuracy of a machine learning model. So as an example, one of the first research projects I did when I started my PhD was to look at the field of political science in the subfield of civil war prediction. This is a field which tries to predict where the next civil war will happen and in order to better be prepared for civil conflict.

(02:39):

And what we found was that there were a number of papers that claimed almost perfect accuracy at predicting when a civil war will take place. At first this seemed sort of astounding. If AI can really help us predict when a civil war will start like years in advance sometimes, it could be game changing, but when we dug in, it turned out that every single one of these claims where people claim that AI was better than two decades old logistic regression models, every single one of these claims was not reproducible. And so, that sort of set the alarm bells ringing for the both of us and we sort of dug in a little bit deeper and we found that this is pervasive. So this was a pervasive issue across fields that were quickly adopting AI and machine learning. We found, I think over 300 papers and the last time I compiled this list, I think it was over 600 papers that suffer from data leakage. That is when you can sort of train on the sets that you're evaluating your models on. It's sort of like teaching to the test. And so, machine learning model seems like it does much better when you evaluate it on your data compared to how it would really work out in the real world.

Eric Topol (03:48):

Right. You say in the book, “the goal of this book is to identify AI snake oil - and to distinguish it from AI that can work well if used in the right ways.” Now I have to tell you, it's kind of a downer book if you're an AI enthusiast because there's not a whole lot of positive here. We'll get to that in a minute. But you break down the types of AI, which I'm going to challenge a bit into three discrete areas, the predictive AI, which you take a really harsh stance on, say it will never work. Then there's generative AI, obviously the large language models that took the world by storm, although they were incubating for several years when ChatGPT came along and then content moderation AI. So maybe you could tell us about your breakdown to these three different domains of AI.

Three Types of AI: Predictive, Generative, Content Moderation

Sayash Kapoor (04:49):

Absolutely. I think one of our main messages across the book is that when we are talking about AI, often what we are really interested in are deeper questions about society. And so, our breakdown of predictive, generative, and content moderation AI sort of reflects how these tools are being used in the real world today. So for predictive AI, one of the motivations for including this in the book as a separate category was that we found that it often has nothing to do with modern machine learning methods. In some cases it can be as simple as decades old linear regression tools or logistic regression tools. And yet these tools are sold under the package of AI. Advances that are being made in generative AI are sold as if they apply to predictive AI as well. Perhaps as a result, what we are seeing is across dozens of different domains, including insurance, healthcare, education, criminal justice, you name it, companies have been selling predictive AI with the promise that we can use it to replace human decision making.

(05:51):

And I think that last part is where a lot of our issues really come down to because these tools are being sold as far more than they're actually capable of. These tools are being sold as if they can enable better decision making for criminal justice. And at the same time, when people have tried to interrogate these tools, what we found is these tools essentially often work no better than random, especially when it comes to some consequential decisions such as job automation. So basically deciding who gets to be called on the next level of like a job interview or who is rejected, right as soon as they submit the CV. And so, these are very, very consequential decisions and we felt like there is a lot of snake oil in part because people don't distinguish between applications that have worked really well or where we have seen tremendous advances such as generative AI and applications where essentially we've stalled for a number of decades and these tools don't really work as claimed by the developers.

Eric Topol (06:55):

I mean the way you partition that, the snake oil, which is a tough metaphor, and you even show the ad from 1905 of snake oil in the book. You're really getting at predictive AI and how it is using old tools and selling itself as some kind of breakthrough. Before I challenge that, are we going to be able to predict things? By the way, using generative AI, not as you described, but I would like to go through a few examples of how bad this has been and since a lot of our listeners and readers are in the medical world or biomedical world, I'll try to get to those. So one of the first ones you mentioned, which I completely agree, is how prediction of Covid from the chest x-ray and there were thousands of these studies that came throughout the pandemic. Maybe you could comment about that one.

Some Flagrant Examples

Sayash Kapoor (08:04):

Absolutely. Yeah, so this is one of my favorite examples as well. So essentially Micha…

Francis Collins is a veritable national treasure. He directed the National Institutes of Health from 2009 to 2021. Prior to that he led the National Human Genetics Research Institute (NHGRI) from 1997-2009, during which the human genome was first sequenced. As a physician-scientist, he has made multiple seminal discoveries on the genetic underpinnings of cystic fibrosis, Huntington’s disease, neurofibromatosis, progeria, and others. This brief summary is barely scratching the surface oh his vast contributions to life science and medicine.

A video clip from our conversation on hepatitis C. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.

Transcript with external inks and links to audio

Eric Topol (00:06):

Well, I am really delighted to be able to have our conversation with Francis Collins. This is Eric Topol with Ground Truths and I had the chance to first meet Francis when he was on the faculty at the University of Michigan when I was a junior faculty. And he gave, still today, years later, we're talking about 40 years later, the most dazzling Grand Rounds during his discovery of cystic fibrosis. And Francis, welcome, you inspired me and so many others throughout your career.

Francis Collins (00:40):

Well, Eric, thank you and you've inspired me and a lot of other people as well, so it's nice to have this conversation with you in the Ground Truths format.

Eric Topol (00:49):

Well, thank you. We're at the occasion of an extraordinary book you put together. It's the fifth book, but it stands out quite different from the prior books as far as I can tell. It's called The Road to Wisdom: On Truth, Science, Faith and Trust, these four essential goods that build upon each other. And it's quite a book, Francis, I have to say, because you have these deep insights about these four critical domains and so we'll get into them. But I guess the first thing I thought I'd do is just say, how at some point along the way you said, “the goal of this book is to turn the focus away from hyperpartisan politics and bring it back to the most important sources of wisdom: truth, science, faith and trust, resting upon a foundation of humility, knowledge, morality, and good judgment.” So there's a lot there. Maybe you want to start off with what was in the background when you were putting this together? What were you really aiming at getting across?

Reflections on Covid

Francis Collins (02:06):

I'm glad to, and it's really a pleasure to have a chance to chat with you about this. I guess before Covid came along, I was probably a bit of a naive person when it came to how we make decisions. Yeah, I knew there were kind of wacky things that had gone out there from time to time, but I had a sort of Cartesian attitude that we were mostly rational actors and when presented with evidence that's been well defended and validated that most people will say, okay, I know what to do. Things really ran off the rails in the course of Covid. It was this remarkable paradox where, I don't know what you would say, but I would say the development of the vaccines that were safe and highly effective in 11 months using the mRNA platform was one of the most stunning achievements of science in all of history up until now.

Francis Collins (03:02):

And yet 50 million Americans decided they didn't want any part of it because of information that came to them that suggested this was not safe or there was conspiracies behind it, or maybe the syringes had chips that Bill Gates had put in there or all manner of other things that were being claimed. And good honorable people were distracted by that, lost their trust in other institutions like the CDC, maybe like the government in general like me, because I was out there a lot trying to explain what we knew and what we didn't know about Covid. And as a consequence of that, according to Kaiser Family Foundation, more than 230,000 people died between June of 2021 and April of 2022 because of a decision to reject the opportunity for vaccines that were at that time free and widely available. That is just an incredibly terribly tragic thing to say.

Francis Collins (04:03):

More than four times the number of people who died, Americans who died in the Vietnam War are in graveyards unnecessarily because we lost our anchor to truth, or at least the ability to discern it or we couldn't figure out who to trust while we decided science was maybe not that reliable. And people of faith for reasons that are equally tragic were among those most vulnerable to the misinformation and the least likely therefore, to take advantage of some of these lifesaving opportunities. It just completely stunned me, Eric, that this kind of thing could happen and that what should have been a shared sense of working against the real enemy, which was the SARS-CoV-2 virus became instead a polarized, divisive, vitriolic separation of people into separate camps that were many times driven more by politics than by any other real evidence. It made me begin to despair for where we're headed as a country if we can't figure out how to turn this around.

Francis Collins (05:11):

And I hadn't really considered it until Covid how serious this was and then I couldn't look away. And so, I felt if I have a little bit of credibility after having stepped down after 12 years as the NIH Director and maybe a chance to influence a few people. I just have to try to do something to point out the dangers here and then to offer some suggestions about what individuals can do to try to get us back on track. And that's what this book is all about. And yeah, it's called The Road to Wisdom because that's really how I want to think of all this in terms of truth and science and faith and trust. They all kind of give you the opportunities to acquire wisdom. Wisdom is of course knowledge, but it's not just knowledge, it's also understanding it has a moral character to it. It involves sophisticated judgment about difficult situations where there isn't an obvious answer. We need a lot more of that, it seems we’re at short supply.

Deconvoluting Truth

Eric Topol (06:13):

Well, what I really loved about the book among many things was how you broke things down in just a remarkably thoughtful way. So truth, you have this great diagram like a target with the four different components.

in the middle, necessary truth. And then as you go further out, firmly established facts, then uncertainty and then opinion, and truth is not a dichotomous by any means. And you really got that down and you explained each of these different facets of truth with great examples. And so, this among many other things that you broke down, it wasn't just something that you read somewhere, you really had to think this through and perhaps this experience that we all went through, but especially you. But because you bring so much of the book back to the pandemic at times with each of the four domains, so that and the spider web. The spider web of where your core beliefs

are and then the ones further out on the web and you might be able to work on somebody out further periphery, but it's pretty hard if you're going to get to them in the middle where their main thing is science is untrustworthy or something like that.

Eric Topol (07:36):

So how did you synthesize these because the graphics are quite extraordinary?

Francis Collins (07:44):

Well, I will say the artist for the graphics is a remarkable graphic design student at the University of Michigan who happens to be my granddaughter. So it was nice having that ability to have my scratches turned into something actually looks like artwork. The concepts I got to say, Eric, I was feeling pretty unsure of myself. I never took a course in philosophy. I know there are people who've spent their entire careers going all the way back to Socrates and on up until now about what does truth mean and here's this scientist guy who's trying to say, well, let me tell you what I think ab…

Professor Joseph Allen directs the Healthy Buildings Program at Harvard Chan School of Public Health. His expertise extends far beyond what makes buildings healthy. He has been a leading voice and advocate during the Covid pandemic for air quality and ventilation. He coined the term “Forever Chemicals” and has written extensively on this vital topic, no less other important exposures, which we covered In our wide-ranging conversation. You will see how remarkably articulate and passionate Prof Allen is about these issues, along with his optimism for solutions.

A video snippet of our conversation: buildings as the 1st line of defense vs respiratory pathogens. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.

Transcript with External Links and Links to Audio

Eric Topol (00:00:06):

Well, hello. It's Eric Topol from Ground Truths and I am just delighted to have with me, Joseph Allen from the Harvard School of Public Health, where he directs the Healthy Buildings Program that he founded and does a whole lot more that we're going to get into. So welcome, Joe.

Joseph Allen (00:00:24):

Thanks. It's great to be here. I appreciate the invitation.

Joe Allen’s Background As A Detective

Eric Topol (00:00:28):

Well, you have been, as I've learned, rocking it for many years long before the pandemic. There's quite a background about you having been a son of a homicide detective, private eye agency, and then you were going to become an FBI agent. And the quote from that in the article that's the Air Investigator is truly a classic. Yeah, you have in there, “I guarantee I'm the only public health student ever to fail an FBI lie detector polygraph in the morning and start graduate school a few hours later.” That's amazing. That's amazing.

Joseph Allen (00:01:29):

All right. Well, you've done your deep research apparently. That's good. Yeah, my dad was a homicide detective and I was a private investigator. That's no longer my secret. It's out in the world. And I switched careers and it happened to be the day I took the polygraph at the FBI headquarters in Boston, was the same day I started graduate studies in public health.

Sick vs Healthy Buildings (Pre-Covid)

Eric Topol (00:01:53):

Well, you're still a detective and now you're a detective of everything that can hurt us or help us environmentally and my goodness, how grateful we are that you change your career path. I don't know anyone who's had more impact on buildings, on air, and we're going to get into chemicals as well. So if we go back a bit here, you wrote a book before the pandemic, talk about being prescient. It’s called Healthy Buildings: How Indoor Spaces Can Make You Sick - or Keep You Well with John Macomber, your co-author. What was it that gave you the insight to write a book before there was this thing called Covid?

Joseph Allen (00:02:41):

Yeah, well, thanks for making the connection too, my past career to current career. For many years, I thought there wasn't a connection, but I agree. There's actually a lot of similarities and I also am really appreciative. I am lucky I found the field of Public Health, it's clearly where I belong. I feel like I belong here. It's a place to make an impact that I want to make in my career. So yeah, the Healthy Buildings book, we started writing years before the pandemic and was largely motivated by, I think what you and others and other people in my field have known, is that buildings have an outsized impact on our health. Yet it's not something that comes to the forefront when you ask people about what matters for their health. Right, I often start presentations by asking people that, what constitutes healthy living? They'll say, I can't smoke, I have to eat well.

(00:03:30):

I have to exercise. Maybe they'll say, outdoor pollution’s bad for you. Very few people, if any, will say, well, the air I breathe inside my building matters a lot. And over the years I had started my public health career doing forensic investigations of sick buildings. People really can get sick in buildings. It can be anything from headaches and not being able to concentrate all the way to cancer clusters and people dying because of the building. And I've seen this in my career, and it was quite frustrating because I knew, we all knew how to design and operate buildings in a way that can actually keep people healthy. But I was frustrated like many in my field that it wasn't advancing. In other words, the science was there, but the practice wasn't changing. We were still doing things the wrong way around ventilation, materials we put in our building, and I would lecture over and over and give presentations and I decided I want to try something new.

(00:04:22):

I do peer-reviewed science. That's great. I write pieces like you for the public, and I thought we'd try a longer form piece in a book, and it's published by Harvard Press. John Macomber for those who know is a professor at Harvard Business School who's an expert in real estate finance. So he'd been talking about the economic benefits of healthier buildings and some hand waving as he describes around public health. I've been talking about the public health benefits and trying to wave an economic argument. We teamed up to kind of use both of our strengths to, I hope make a compelling case that buildings are good for health and they're also just good business. In other words, try to break down as many barriers as we can to adoption. And then the book was published right as Covid hit.

Indoor Air Quality and Cognition

Eric Topol (00:05:05):

Yeah. I mean, it's amazing. I know that typically you have to have a book almost a year ahead to have it in print. So you were way, way ahead of this virus. Now, I'm going to come back to it later, but there were two things beyond the book that are pretty striking about your work. One is that you did all these studies to show with people wearing sensors to show that when the levels of CO2 were high by sensors that their cognition indoors was suffering. Maybe you could just tell us a little bit about these sensors and why aren't we all wearing sensors so that we don't lose whatever cognitive power that we have?

Joseph Allen (00:05:56):

Well, yeah. First I think we will start having these air quality sensors. As you know, they're starting to become a lot more popular. But yeah, when I first joined the faculty full-time at Harvard, one of the first studies I conducted with my team was to look at how indoor air quality influences cognitive function. And we performed a double-blind study where we took people, office workers and put them in a typical office setting. And unbeknownst to them, we started changing the air they were breathing in really subtle ways during the day, so they didn't know what we were doing. At the end of the day, we administered an hour and a half long cognitive function battery, and like all studies, we control for things like caffeine intake, baseline cognitive performance, all the other factors we want to account for. And after controlling for those factors in a double-blind study, we see that indoor air quality, minor improvements to indoor air quality led to dramatic increases in cognitive function test scores across domains that people recognize as important for everyday life.

(00:06:59):

How do you seek out and utilize information? How do you make strategic decisions? How do you handle yourself during a crisis and importantly recover after that crisis? I don't mean the world's ending crisis. I mean something happens at work that's stressful. How do you handle that and how do you respond? Well, it turns out that amongst all the factors that influence how we respond there, indoor air quality matters a lot. We call that study the COGfx Study for cognitive function. We replicated it across the US, we replicated it across the world with office workers around the world, and again, always showing these links, the subtle impact of indoor air …

Steve Horvath made the seminal discovery of the—Horvath Clock— an epigenetic clock based on DNA methylation, which is now being used extensively in medical research and offered commercially for individuals (←we talk about that!). He was on the faculty at UCLA from 2000-2022 as a Professor of Human Genetics and Biostatistics, and now works on anti-aging research at Altos Labs.

A perspective on the importance of epigenetic clocks this week’s Nature”This insight is crucial for deriving reliable biological markers of ageing in tissues or blood. Such a feat has been accomplished through the ingenious identification of epigenetic clocks in our genome. But these insights are even more important for revealing targets that enable intervention in the ageing process.”

A video snippet on vegetable intake and epigenetic clocks. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.

Transcript with links to Audio and External Links

Eric Topol (00:06):

Hello, it's Eric Topol with Ground Truths, and I've got a terrific guest with me today, Steve Horvath. He's a geneticist, a statistician, a mathematician. He's got a lot of background that has led to what is a landmark finding in biomedicine, the Horvath clock. So Steve, welcome.

Steve Horvath (00:30):

Thank you for having me.

Eric Topol (00:33):

Well, it's really fascinating. I followed your work for well over a decade since you introduced the pan-tissue clock in 2013, and it's fascinating to go back a bit on that finding, which initially, I guess was in saliva a couple of years prior, and then you found it everywhere you looked, wherever cells had a nucleus and tissues. And what gave you the sense that these markers of methylation on the DNA would give us some clues about the aging process? How did you even come about to make this discovery?

Serendipity

Steve Horvath (01:17):

It was an accidental discovery because before the methylation clock, I had worked very hard on a gene expression clock, a transcriptomic biomarker. I mean, I was at the height of my energy levels. I worked really on weekends, really eight hour days during the week. But all the weekends I had collected a large set of gene expression data and I dredged the data. And for two years and I couldn't get anywhere, there was nothing I could do. But nowadays, of course, you see various publications where people built transcriptomic clocks. But back in the day when we had these arrays, I just couldn't see a signal. And then at some point I got roped into a study of homosexuality where my collaborator at UCLA wanted to see whether there's an epigenetic correlate of sexual orientation in saliva. And so yeah, being a biostatistician, I said, sure, I analyzed the data and I couldn't find any signal for homosexuality.

(02:48):

But then I just looked for an aging signal in the same, and really within an hour of analyzing the data, I knew that I have to completely drop gene expression. I need to go after methylation. And the signal is so profound, and as you said initially we looked at saliva samples and we thought, isn't it curious? You spit in a cup and you can measure someone's age. And we were of course, hoping that this could become a valuable readout of biologic age, but it took, of course, many years to realize that potential. Nowadays, there's several companies that offer a saliva based methylation clock test. But yeah, many years passed, and it was important to fill in the details and to build the case that methylation clocks are predictive of things we care about time to death or time to various forms of morbidity. So it took many, many years to analyze large cohort studies and to accumulate the evidence that it actually works.

Eric Topol (04:16):

Yeah, I mean, it was pretty amazing back almost a decade ago when I would see, we would take tissue or blood sample and look at your clock and it would say, age of the person is 75 years. And then we look at the actual age of the person who is 75 years to say, wait a minute, how can this be? So I mean, the plausibility of this discovery, if you look back, I mean you say, well, this is just kind of the rust of the pipes, or how do you process that the methylation is such a marker potentially of a person's biologic age? Of course, we're going to get into how it could be a way to intervene to change the aging process. But would it be fair to say that its epigenetic clocks are not the same as biologic aging or how do you put all that together?

Epigenetic Age vs Biologic Age

Steve Horvath (05:21):

Yes, for sure. An epigenetic age estimate is certainly not the same as a biologic age estimate. And the reason why I say it is because biologic age is really determined by so many things and by so many organs. And as I mentioned initially, we had a clock for saliva later for blood and so on. And so, if you only have an epigenetic readout of a certain cell type, it's really too limited to assess the whole organismal state. And arguably you would want to measure also proteomics, readouts and many other data modalities. So I typically avoid the terminology biologic age, because to begin with, we don't have a definition of it. Decades of discussions, nobody really has a precise definition of it.

Second Generation Epigenetic Clocks

Eric Topol (06:35):

Well, from the first generation Horvath clock then became this newer second generation, GrimAge, PhenoAge, the DunedinPACE of aging. How has that helped to advance the field? Because as you touched on, they're measuring different things and what is it meant by kind of a second generation clock?

Steve Horvath (07:03):

Yeah, so a second generation clock truly aims to predict mortality or morbidity risk. As opposed to simply chronologic age or what is known as calendar age. And fortunately, there's no doubt that the second generation clocks can do that. I often finish a talk on GrimAge by telling the audience that I give them a money back guarantee, that it will be predictive of mortality in their cohort study. I'm 100% certain that it works if you analyze a hundred people or so. The question is more whether an individual could benefit from such a test. And there are now many providers of various epigenetic clock tests. These biomarkers have different names, but they're quite pricey. A couple of hundred dollars are needed to get such a measurement. And the question is, is it helpful for the individual should you get such a test? And I would say we are not quite there yet for a variety of reasons. The main reason being we don't have good interventions against accelerated epigenetic age. So because when you think about it, why does a doctor order a test for you? For example, cholesterol levels. Well, because they have a drug against elevated cholesterol levels, the statin. And at the moment, we don't have validated interventions against accelerated epigenetic age. So that's kind of missing.

Eric Topol (09:13):

Yeah, we're going to get to that because obviously a lot of things are in the pipeline there, but are you saying then that these people that are getting these consumer tests, that they're getting a test that really wasn't validated at an individual level, so it predicts their mortality that it may be good at a cohort or population level, but maybe it's not so helpful, accurate, or would you say it is accurate? I mean, GrimAge is a good name because since it says when you're going to die. How do you make the differentiation between the individual level or beyond?

Steve Horvath (09:59):

Yeah, I think it's good to compare to other biomarkers. So take glucose levels, hemoglobin A1C, nobody doubts that these levels predict mortality risk when you study couples a hundred people. But how accurate is such a test for an individual? Clearly there is substantial noise associated with a prediction. Two people could have exactly the same hemoglobin A1C levels, but live very different lifespans. And the same holds for epigenetic clocks. They do pre…

Pradeep is a brilliant geneticist and Director of Preventive Cardiology, holds the Paul & Phyllis Fireman Endowed Chair in Vascular Medicine at Mass General Hospital and on faculty at Harvard Medical School and the Broad Institute. His prolific research has been illuminating for the field of improving our approach to reduce the risk of heart disease. That’s especially important because heart disease is the global (and US) #1 killer and is on the increase. We didn’t get into lifestyle factors here since there was so much ground to cover on new tests. drugs, and strategies.

A video snippet of our conversation on ApoB. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.

Transcript with links to key publications and audio

Eric Topol (00:06):

Well, welcome to Ground Truths. I'm Eric Topol and with me is Pradeep Natarajan from Harvard. He's Director of Preventative Cardiology at the Mass General Brigham Health System and he has been lighting it up on the field of cardiovascular. We're going to get to lots of different parts of that story and so, Pradeep welcome.

Pradeep Natarajan (00:31):

Thanks Eric, really delighted and honored to be with you and have this discussion.

Eric Topol (00:36):

Well, for years I've been admiring your work and it's just accelerating and so there's so many things to get to. I thought maybe what we'd start off with is you recently wrote a New England Journal piece about two trials, two different drugs that could change the landscape of cardiovascular prevention in the future. I mean, that's one of the themes we're going to get to today is all these different markers and drugs that will change cardiology as we know it now. So maybe you could just give us a skinny on that New England Journal piece.

Two New Lipid Targets With RNA Drugs

Pradeep Natarajan (01:16):

Yeah, yeah, so these two agents, the trials were published at the same time. These phase two clinical trials for plozasiran, which is an siRNA against APOC3 and zodasiran, which is an siRNA against ANGPTL3. The reason why we have medicines against those targets are based on human genetics observations, that individuals with loss of function mutations and either of those genes have reduced lipids. For APOC3, it's reduced triglycerides for ANGPTL3 reduced LDL cholesterol and reduced triglycerides and also individuals that have those loss of function mutations also have lower risk for coronary artery disease. Now that's a very similar parallel to PCSK9. We have successful medicines that treat that target because people have found that carriers of loss of function mutations in PCSK9 lead to lower LDL cholesterol and lower coronary artery disease.

(02:11):

Now that suggests that therapeutic manipulation without significant side effects from the agents themselves for APOC3 and ANGPTL3 would be anticipated to also lower coronary artery disease risk potentially in complementary pathways to PCSK9. The interesting thing with those observations is that they all came from rare loss of function mutations that are enriched in populations of individuals. However, at least for PCSK9, has been demonstrated to have efficacy in large groups of individuals across different communities. So the theme of that piece was really just the need to study diverse populations because those insights are not always predictable about which communities are going to have those loss of function mutations and when you find them, they often have profound insights across much larger groups of individuals.

Eric Topol (03:02):

Well, there's a lot there that we can unpack a bit of it. One of them is the use of small interfering RNAs (siRNA) as drugs. We saw in the field of PCSK9, as you mentioned. First there were monoclonal antibodies directed against this target and then more recently, there’s inclisiran which isn't an RNA play if you will, where you only have to take it twice a year and supposedly it's less expensive and I’m still having trouble in my practice getting patients covered on their insurance even though it's cheaper and much more convenient. But nonetheless, now we're seeing these RNA drugs and maybe you could comment about that part and then also the surprise that perhaps is unexplained is the glucose elevation.

Pradeep Natarajan (03:53):

Yeah, so for medicines and targets that have been discovered through human genetics, those I think are attractive for genetic-based therapies and longer interval dosing for the therapies, which is what siRNAs allow you to do because the individuals that have these perturbations, basically the naturally occurring loss of function mutations, they have these lifelong, so basically have had a one-time therapy and have lived, and so far, at least for these targets, have not had untoward side effects or untoward phenotypic consequences and only reduce lipids and reduce coronary artery disease. And so, instead of taking a pill daily, if we have conviction that that long amount of suppression may be beneficial, then longer interval dosing and not worrying about the pill burden is very attractive specifically for those specific therapeutics. And as you know, people continue to innovate on further prolonging as it relates to PCSK9.

(04:57):

Separately, some folks are also developing pills because many people do feel that there's still a market and comfort for daily pills. Now interestingly for the siRNA for zodasiran at the highest dose, actually for both of them at the highest doses, but particularly for zodasiran, there was an increase in insulin resistance parameters actually as it relates to hyperglycemia and less so as it relates to insulin resistance, that is not predicted based on the human genetics. Individuals with loss of function mutations do not have increased risks in hyperglycemia or type 2 diabetes, so that isolates it related to that specific platform or that specific technology. Now inclisiran, as you'd mentioned, Eric is out there. That's an siRNA against PCSK9 that's made by a different manufacturer. So far, the clinical trials have not shown hyperglycemia or type 2 diabetes as it relates inclisiran, so it may be related to the specific siRNAs that are used for those targets. That does merit further consideration. Now, the doses that the manufacturers do plan to use in the phase three clinical trials are at lower doses where there was not an increase in hyperglycemia, but that does merit further investigation to really understand why that's the case. Is that an expected generalized effect for siRNAs? Is it related to siRNAs for this specific target or is it just related to the platform used for these two agents which are made by the same manufacturer?

Eric Topol (06:27):

Right, and I think the fact that it's a mystery is intriguing at the least, and it may not come up at the doses that are used in the trials, but the fact that it did crop up at high doses is unexpected. Now that is part of a much bigger story is that up until now our armamentarium has been statins and ezetimibe to treat lipids, but it's rapidly expanding Lp(a), which for decades as a cardiologist we had nothing to offer. There may even be drugs to be able to lower people who are at high risk with high Lp(a). Maybe you could discuss that.

What About Lp(a)?

Pradeep Natarajan (07:13):

Yeah, I mean, Eric, as you know, Lp(a) has been described as a cardiovascular disease risk factors for quite so many years and there are assays to detect lipoprotein(a) elevation and have been in widespread clinical practice increasing widespread clinical practice, but we don't yet have approved therapies. However, there is an abundance of literature preclinical data that suggests that it likely is a causal factor, meaning that if you lower lipoprotein(a) when elevated, you would reduce the risk related to lipoprotein(a). And a lot of this comes from similar human genetic studies. The major challenge of just relating a biomarker to an outcome is there are many diffe…

A video snippet of our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.

Shane Crotty: A Landmark Study on Upper Airway Mucosal Immunity

Transcript

This is the first time a Ground Truths podcast is being posted simultaneous with a new publication, this one in Nature, by Professor Shane Crotty and his colleagues at La Jolla Institute for Immunology. Shane is one of the leading immunologists and virologists in the country; he and his group published in 2020 the first detailed analysis for how our immune system responds to SARS-CoV-2. Shane also, among many other notable contributions during COVID, illuminated the role of hybrid immunity vs COVID, the differences between and additivity of vaccination and infection.

Today’s paper in Nature is indeed a landmark contribution doing something that hasn’t been done before—to understand the underpinnings of mucosal immunity of the upper airway. 100 participants had monthly nasal and nasopharyngeal swabs throughout the pandemic. With a median of >100,000 cells per swab recovered, they undertook single-cell sequencing and full characterization of the cells (tissue-resident memory B cells, CD4+ and CD8+ T cells, germinal center follicular helper T cells and B cells, etc.) to determine optimal immune protection of the upper airway, the effect of infections by different variants, breakthrough infections, vaccination, and age.

Here is the transcript of our conversation about the new report with links to the audio:

Eric Topol (00:06):

Hello, it's Eric Topol with Ground Truths, and with me today is Professor Shane Crotty from the La Jolla Institute of Immunology (LJI), not too far away from where I work at Scripps. And Shane has been a go-to immunologist colleague here in the Mesa, and he and his colleagues were the ones that really first published the response to SARS-CoV-2 as far as the immunologic response. And today we're doing something very unique. We're going to go over for the first time in the two year plus history of Ground Truths, going to have a publication with at least simultaneous or near simultaneous podcast. Shane, welcome and congratulations on this really important paper in Nature.

Shane Crotty (00:57):

Thanks, Eric. Thanks for having me. Yeah, somebody asked if I was going to go over to Scripps for the podcast and I was like, yeah, we could.

Eric Topol (01:06):

You could. You could. But no, it's good. And it's nice having the logo of this great institute you work at right in the right corner. And you've done so many contributions with your colleagues at La Jolla Institute. It's really a privilege to have a chance to learn from you and particularly about what we're going to talk about today, which is mucosal immunity to upper airway infections, which is especially germane to COVID. And we're actually in the middle of a significant wave of COVID right now. And I guess it would maybe be fair to say, Shane, that we've never truly understood the underpinnings, the real details of upper airway mucosal immunity. Is that a fair statement?

Shane Crotty (01:53):

Yeah, it is a fair statement.

Eric Topol (01:56):

Okay. So today we're going to crack the case. This paper from you and your colleagues, of course, you're the senior author and first author, Sydney Ramirez did a remarkable study. I mean, just extraordinary. This is why we're doing a special podcast about it. Maybe you could just kind of give us the overview of the design because you were doing things that haven't been done before.

Shane Crotty (02:24):

Sure. And, I would say the genesis even of it goes back to what you were introducing. I mean, during the pandemic, we like a lot of scientists spent a lot of time and energy trying to help understanding immune responses to this virus, and immune memory to this virus, and what was involved in protective immunity. And we're certainly proud of the work that we did. And it was hard work. And after a while we were exhausted and we stopped.

Shane Crotty (02:59):

And then we came back to it after a while and said, well, the virus is still here. And so many people have contributed so much to better understanding the virus and creating vaccines. But there are clearly still things we don't understand. What are those biggest knowledge gaps and where might we be able to contribute? And really to me the biggest one was location, location, location. This is a virus that infects your nose, infects your upper airway—your nose, and throat, and oral cavity. And then obviously if you get severe disease, the severe disease and death are from the lungs. And it's just been a big knowledge gap in terms of understanding what actually occurs in those tissues immunologically and what is associated with protective immunity or what could be associated with protective immunity. And sort of looking forward what might be helpful for mucosal vaccine development from things that we could learn.

Shane Crotty (04:12):

So we started from what we would call the basics, and what does immune memory look like in the upper airways in normal people? And that hasn't been available really even in, and we started this two years ago, even in the biggest atlases published of the human body. There was no upper airway tissue representation at all. And that's because technically it's just tough to access and difficult to reproducibly get at. And so, we recruited people to a group of 20 to 30 people to come to LJI once a month, and just started testing out, published and unpublished sampling techniques to see were there ways where we could reproducibly sample immune cells in the upper airways from people. And once we got things, so the keys for us were you got to have enough cells that you can collect to learn something from. And luckily with modern techniques of flow cytometry and single cell sequencing, you don't need that many cells. And so, we could get a hundred thousand cells on a swab and that's enough to do a lot with. And second, how reproducible was it? So we showed, we had people come in every month for a year and we could reproducibly find the same things in their swab; same cell types in their swabs. And the third thing was that people would come back.

Shane Crotty (06:05):

We found that if you have good nurses doing the techniques, we could find ways that this would be a sampling approach that was tolerable and people would come back for repeat measures, which is really valuable to see what's happening in people over time. So that was what we started from in the study and built from.

Eric Topol (06:27):

And if I am correct, you sampled two places with the swabs, one in the nose and one of the throat. Or, I think one which you have in the paper as the MT for something about the median nasal turbinate and the other adenoid in the back of the throat. Is that right?

Shane Crotty (06:50):

So all the sampling is a swab into your nose. And when we were doing that, we were really excited to see the diversity of immune cells, particularly T cells and B cells, memory T cells and B cells that we isolated. They're like, wow, there's actually a lot of interesting immune memory up in there. And the lab said, oh, by the way, we're seeing T follicular helper cells (TFH). Now that happens to be my favorite cell type.

Eric Topol (07:22):

Why is that, Shane? Of all the cells, why do you say that's your favorite? I know you publish a lot on it.

Shane Crotty (07:31):

Because those are the T cells that are required for basically all neutralizing antibody responses. All high-quality antibody responses depend on—almost all high-quality antibody responses depend on—T cell help. That T cell help comes from T follicular helper cells. Antibody evolution is certainly one of the coolest processes of the immune system. And all of that depends on T follicular helper cells. So the fact that for example, you could get Omicron neutralizing antibodies even after only being vaccinated with ancestral vaccine, that's t…