#401 ‒ How curiosity transforms medicine: extraordinary discoveries that changed modern healthcare

30:05Peter Attia:Over the next several years, he and an undergraduate student named Hudson Fries worked out the technique to isolate and culture these organisms. No small task given their preferred resting temperature. And in 1969, they published a paper successfully characterizing a species of thermophilic bacteria they'd isolated from mushroom spring in Yellowstone's lower geyser basin. They fittingly named it Thermus aquaticus, Latin for hot and of the water. And that was their project. Two scientists asking whether anything was alive in nearly boiling water. The answer was yes. They published the paper. They moved on.

30:51Now we jump forward 15 years. In 1983, a biochemist named Kerry Mullis was working at a biotech company in California called Cetus. and he was thinking about how to copy DNA in a test tube. The conceptual idea which he famously had on a drive up to Mendocito was beautiful. You separate the two strands of DNA double helix by heating it near boiling, effectively melting the hydrogen bonds that keep the sister strands together. You then cool the solution which allows short specific DNA sequences called primers to bind to the regions you want to copy as the temperature returns to normal. Then you have a polymerase enzyme extend the DNA, which will start at those primers bound to their target sequence, thus creating copies of the parent strand in your region of interest.

31:50You now have two copies of double-stranded DNA sequence of your choosing, having started with a single double-stranded parent, and then you repeat the process. Each cycle doubles your DNA. After 30 cycles, you have turned one molecule into a billion copies. This technique is known as polymerase chain reaction, or PCR. But there was just one problem. The DNA polymerases people used at the time were derived from E. coli, and they fell apart when you heated them. So when every cycle of PCR required denaturing the DNA at near boiling temperatures, the polymerases could not survive the process, which meant you had to add fresh enzyme manually at every cycle.

32:44It worked, but it was tedious, expensive, error prone, and basically not practical at any meaningful scale. The scientists at CETUS famously developed a robot to add fresh polymerase after each round of PCR in its thermocycler, dubbed Mr. Cycle. But this was still nowhere near a high-throughput, high-fidelity, cost-effective means for amplifying DNA. The team at Cetus needed a polymerase that could survive being heated to 95 degrees Celsius over and over without falling apart. They needed an enzyme that could survive in near boiling water. They turned to Thermus aquaticus. Polymerase is fundamentally necessary for life to continue.

33:35Every organism necessarily requires a means of copying their own DNA in order to pass that DNA onto new cells or new generations. Thermus aquaticus could apparently do this at temperatures of at least 88 degrees Celsius. In the mid-1970s, the thermus aquaticus polymerase, commonly referred to as TAQ, or TAC polymerase, had been isolated and partially characterized, in part because the species had been deposited in public culture collections after Brock's work. The CETUS team built on this, purified TAC polymerase in their lab, and plugged it into their PCR protocols. With this, the entire technique and all of biological sciences transformed.

34:24Now you could load the reaction, set the thermocycler, walk away, and come back to a billion copies of your sequence. We had a near endless supply of any DNA sequence we desired from any species we desired ready to go after a few hours of incubation on a cycling heating block. Mullis won the Nobel Prize in chemistry and 1993 for inventing PCR, and deservedly so. But it was only possible because Brock and Freese had asked, decades earlier, whether anything lived in extreme temperatures. They found life in an 88 degree Celsius hot spring. They found a way to collect and culture those species, and they shared that species with scientists everywhere to see, study, and utilize on their own.

35:19And I want us to think about what that unleashed. PCR is not a drug. PCR is something more fundamental than a drug. PCR is the enabling technology for essentially all of modern molecular biology. I'm sorry, this list is long. It's long enough to make the point, but it's not long enough to be nearly exhaustive. DNA is the code upon which all of life is programmed, and PCR is the tool we use to interact with that code. PCR is everywhere. It's the basis of genetic testing, forensic DNA analysis, cancer mutation panels, prenatal screening, vaccine development, ancestry testing, transgenic lab animals, fluorescent reporters like GFP, the cloning of any recombinant therapeutic protein, the entire field of genomics, the development of every gene therapy, and viral infection testing.

36:19All of it depends on PCR. So all of it depends on TAC polymerase. And all of it traces back to a microbiologist wondering whether anything could live in hot water. Without that 1969 paper, modern biology, as it exists today, simply could not exist. There's no plausible alternative history in which we get to where we are without somebody somewhere going to look in the boiling water for life. We just got lucky that that somebody was Tom Brock, and perhaps we got especially lucky that he got to do it in advance without anybody asking what disease he was trying to cure. And yet the discovery is so fundamental, so irrevocably intertwined with modern biology and medicine, that it's hard to imagine how any disease at all could have been cured in the last

37:11Peter Attia:30 years without his work, his curiosity leading him to search for signs of microbial life inside of Yellowstone hot springs. This next story is, to me, a particularly exciting illustration of the principle because its ramifications were understood so recently that we are really in the midst of watching the timeline play out. The story begins in the late 1980s in the small Spanish coastal town of Santa Pola near Alicante on the Mediterranean. Santa Pola is famous for its salt flats, vast shallow evaporative ponds where seawater concentrates, creating dramatically saline pools of water. These salt ponds support a strange community of organisms, salt-tolerant or even salt-requiring microbes called halophiles, many of them archaea, that have adapted to thrive at salinity levels that would kill virtually anything else.

38:11A young Spanish microbiologist named Francesco Mojica was doing his PhD on one of these archaeas,

38:20Peter Attia:Halophorex mediterinae, at the University of Alicante. His original project, in fact, was almost a different project entirely. He was studying how this organism responds to changes in salinity, but someone beat him to the punch and published it first. So along the way, he kept stumbling over a weird feature of its genome. There were these clusters of short, regularly spaced palindromic repeats, sequences of about 30 base pairs that repeated over and over, separated by unique non-repeating space or sequences of regular length. Now, just parenthetically, for those of you who might not be familiar with a palindrome, a palindrome is something that when read left to right and right to left is the same.

39:06So the word race car is a palindrome

39:09Peter Attia:because regardless of which way you read it, it's the same way. And of course, my favorite palindrome, which I just learned of recently from one of our research analysts, is the phrase, go hang a salami, I'm a lasagna hog. I encourage you to prove to yourself that that is indeed a palindrome. Anyway, these were everywhere in the genome, but he didn't know what they were. In fact, nobody knew what they were. He wasn't the first to see them, exactly. A Japanese group led by Yoshizumi Isshino had noted similar repeating patterns in E. coli in 1987, left as effectively a footnote in the discussion section of their paper.

39:48Mojica was the first to identify them explicitly as a feature to investigate. The function was a complete mystery, and most molecular biologists who came across these sequences shrugged and moved on. Mojica didn't move on. He spent the better part of a decade, the entire 1990s and into the early 2000s, trying to figure out what these repeats were doing. The breakthrough came in 2003.

40:17Peter Attia:By that point, the genomics revolution was in full swing, and there were enough sequenced genomes in the public databases that Mojica could do something he couldn't do before. He could take the unique spacer sequences, the bits between the repeats, and ask the sequencing database, have you seen this sequence before? He sent it through the NIH database known as BLAST, and the answer came back, yes. Some of those spacer sequences exactly matched DNA from bacteriophages, viruses that infect bacteria and archaea. That was the key. Mojica realized that the repeats weren't random junk. They were a record.

41:03Each spacer was a snippet of DNA that the organism had captured from a past bacteriophage infection. The clusters of repeats were the index. Between the repeats were the codes for memories of past infections. This looked like an immune system, specifically an adaptive immune system. The bacterium, or archaean, was in effect vaccinating itself against viruses by holding onto fragments of the phage's genomes and using that information to recognize and destroy them on future encounters. This was a stunning insight. It implied that bacteria and archaea, the simplest organisms in biology, had a sophisticated adoptive immune system with memory.

41:57We now call that system CRISPR, clustered regularly interspaced short palindromic repeats, and the nearby proteins were deemed CAS, short for CRISPR-associated.

42:13Peter Attia:Mojica wrote up the paper. He submitted it to Nature in 2003. It was rejected without external review. He sent that to the Proceedings of the National Academy of Science. Rejected. Lacking, quote, novelty and importance. He sent it to Molecular Microbiology. Rejected. Nucleic Acids Research. Rejected. Increasingly desperate and now afraid he was going to be scooped, he eventually submitted it to a smaller journal called the Journal of Molecular Evolution, which, after 12 months of review and revision, finally published it in February 2005. This is another place where we see that revolutionary science isn't simply underfunded.

42:59Peter Attia:Once the revolutionary insight is seen and documented, even then, the field can still miss what it's looking at. The discovery that bacteria have an adaptive immune system, arguably one of the most important findings in molecular biology over the past 50 years, was rejected by four of the top journals in the field. The reviewers and editors did not see the significance of what they were looking at. Mojica was studying salt pond archaea. He was a Spanish microbiologist with a small lab, and his findings sounded like esoteric microbial biology. It took a lesser journal to publish what is, in retrospect, an absolute landmark paper.

43:39From there, the timeline is short. Labs around the world began to catch on

43:44Peter Attia:or discover other features on their own. Danisco, yeah, the yogurt company, provided direct experimental evidence that CRISPR really does work as an adaptive immune system in bacteria. Bacteria are necessary for dairy fermentation. Bacteria are susceptible to outbreaks of phage infections. This is an enormous practical problem for industrial dairy. Danisco's 2007 paper in the journal Science validated Mohica's hypothesis and identified Cas9 as the protein that recognizes CRISPR-encoded sequences to cut and destroy bacteriophage DNA. In 2012, Jennifer Doudna and Emmanuel Charpentier, and around the same time, a group at the Broad Institute and MIT led by Feng Zhang, who we've previously had on the podcast, showed that you could take this bacterial immune system, program it with a custom guide RNA, and use it to cut DNA at any specific location in any genome you wanted.

44:48In bacteria, the goal of the cut was to destroy the phage's ability to reproduce.

44:54Peter Attia:Doudna and Charpentier showed that you could instead provide a new template of DNA alongside the CRISPR system, and instead of destroying the genome, you could incorporate new DNA into the cut site. You could modify genes within the genome of a living organism. Doudna and Charpentier won the 2020 Nobel Prize in Chemistry for this. The implications here are enormous. Most gene therapy trials had been discontinued. Their typical goal was to add a new gene to people with genetic disorders. These extra genes don't always stick around for long, so durability could be a concern. And if the gene itself was toxic, not just losing function like in Huntington's disease, the normal variant's efficacy could be limited by the competition with the host's own pathological gene.

45:45Peter Attia:We had no way to actually modify the gene variant that led to a disease, but now we do. And in December of 2023, the FDA approved Cascovy, the first CRISPR-based therapy ever brought to clinic. It's the treatment for sickle cell disease. Sickle cell disease until very recently was a disease with limited options and shortened lifespans. CRISPR therapy isn't a cure in the simple sense. It's complex, expensive, and requires bone marrow conditioning. But for the patients who can access it, the results are extraordinary. The vaso-occlusive crisis that defined their lives essentially stopped. From a strange DNA pattern in a Spanish salt pond archaea to a therapy that durably treats sickle cell disease.

46:30Peter Attia:And even recently, a phase 1b trial posted incredibly promising results for a CRISPR-derived treatment of familial hypercholesterolemia. 30 years since the salt ponds, CRISPR is curing diseases. And again, look at the structure of what happened. Francisco Mojica did not set out to cure sickle cell disease. He set out to understand why the genome of an obscure, salt-loving Archeon had repeated sequences in it. The system he uncovered turned out to be a programmable molecular tool of staggering power. We, humans, the species that builds the technologies, didn't invent CRISPR. Bacteria invented CRISPR somewhere around 3 billion years ago as a defense against viruses that have been trying to exploit them since shortly after life began.

47:21Peter Attia:Mohica just noticed it. We didn't go looking for a tool to edit the genome. We found it when wandering through salt flats. The last story I want to tell is perhaps the most relevant story in terms of disease burden. It's a little less basic exploration than some of our previous examples, but it's also the most tangibly relevant. Every listener to this podcast, hell, probably every person in the English-speaking world at this point knows these drugs, but very few may know where they came from. In the late 1980s, a clinical endocrinologist named John Eng was working at the Bronx VA Medical Center in New York.

48:02Peter Attia:He was a hands-on primary care endocrinologist who spent most of his time taking care of veterans with diabetes. But he had a side project. He worked on the bench in the laboratory of Roslyn Yalo, the Nobel Prize winning physicist and biochemist who, decades earlier, had invented the radioimmunoassay technique. Yalo's lab had developed unusually sensitive methods for detecting and characterizing peptide hormones. And as an endocrinologist working with diabetic patients, Ang wanted to use the tools to hunt for novel peptides that affected the pancreas. He'd read something interesting in the literature.

48:40Peter Attia:Researchers at NIH had reported that the bite of certain venomous reptiles, including notably the Gila monster, a stocky, slow-moving, beaded-skinned lizard native to the deserts of the American Southwest, caused dramatic inflammation and enlargement of the pancreas in bitten animals. Something in the venom was hitting the pancreas hard. Why would a desert lizard have a venom that targets the pancreas? Eng didn't know, but he thought it was worth investigating. The Gila monster also had another biologically interesting property. It eats very rarely, sometimes only three or four meals a year. And yet between meals, it appears to maintain remarkably stable blood glucose levels through long stretches of fasting.

49:35Whatever the lizard's pancreas was doing, it was doing it differently from ours. So Aang ordered some dried Gila monster venom and started running it through the assays

49:46Peter Attia:he's inherited from Yalo's lab. Working with his colleague Jean-Pierre Roffman, who would shuttle samples back and forth from Brooklyn to the Bronx in his Toyota Camry, Aang systematically separated the peptide components of the venom. He found two peptides. One had been described before. The second was new. Published in 1993, he named it XenDIN-4. When he sequenced XenDIN-4, the result was remarkable. The peptide showed about 53 % amino acid sequence similarity to a human hormone called GLP-1, glucagon-like peptide 1, a gut hormone produced in the intestine that stimulates insulin secretion in response to a meal.

50:38Oddly, the lizard had a venom peptide that activated, in a mammal that it had bitten, the same receptor as our own meal-induced insulin stimulating hormone. That explained the pancreatic inflammation. The bite was hitting GLP-1 receptors like a hammer. Xsendin-4 had a key property that GLP-1 does not. Native GLP-1 has a half-life in the bloodstream of about two minutes. An enzyme called DPP-4 chews it up almost as fast as the gut makes it. That's actually fine for what GLP-1 normally does, but it makes the native hormone useless as a drug. You'd have to be infusing it in constantly. Xsendin-4, by contrast, is resistant to DPP-4.

51:27Its half-life is on the order of hours, not minutes. It acts on the GLP-1 receptor with a durability that GLP-1 itself lacks. Eng had found a long-acting GLP-1 receptor agonist sitting in the saliva of a desert lizard, ready to use. Eng tried to get the VA to patent the discovery. The VA declined. Eng eventually patented it himself, licensed it to a small biotech, and the rights eventually made their way to Eli Lilly and Amelin. In 2005, the FDA approved synthetic Exendin-4 under the trade name Bieta, generic name Exenatide, for the treatment of type 2 diabetes. It was the first GLP-1 receptor agonist ever brought to market.

52:17And then the

52:18Peter Attia:floodgates opened. Exendin-4 was a foreign Gila monster peptide, so many patients developed immune responses to the therapy. The therapy required twice daily injections, provided carefully around meal windows and included side effects like kidney strain and nausea. That said, in patients who tolerated it, it worked. Novo Nordisk, Lilly, and others realized that this was an enormous biological lever, not just a way to improve glycemic control in diabetes, but as it turned out, an extraordinary tool for weight loss. As we've talked about at length, GLP-1 signaling also suppresses appetite, slows gastric emptying, and changes how the brain weighs reward signals around food.

53:03Peter Attia:Subsequent drugs were not direct XenDen-4 analogs, but modifications of the native human GLP-1 sequence engineered to reduce immunogenicity, increase half-life, and in some cases add alternative targets in addition to GLP-1. We now have liraglutide and semaglutide, along with terzepatide, which adds GIP agonism in addition to GLP-1. We've talked about these drugs at length, and we'll continue to talk about them as the science develops. Suffice it to say, these drugs are reshaping medicine in real time. They're reshaping the treatment of type 2 diabetes, and they're reshaping the treatment of obesity.

53:43Peter Attia:The cardiovascular outcome data is changing how we think about metabolic disease as a driver of atherosclerotic risk, and there are ongoing trials in heart failure, kidney disease, sleep apnea, alcohol use disorder, addiction more broadly, and possibly Alzheimer's disease. We don't yet know how broad the indication space will turn out to be. We do know that this is one of the most consequential drug classes of the last 50 years. And the proximate origin was a clinician at a Bronx VA hospital wondering what he might learn about endocrinology by studying how a desert lizard's bite caused pancreatic inflammation.

54:22Peter Attia:Now, these stories are, I think, incredibly interesting in their own right, and maybe I'm just a sucker for research. They are each, in my opinion, fascinating illustrations of the scientific process. But I also want to bring this back to the larger argument because I think that point matters. Let's look at what we just walked through. Modern cell biology runs on a protein from a jellyfish. Statins come from a fungus growing on rice. The ACE inhibitor class came from a snake whose venom kills by dropping blood pressure. PCR, and by extension, essentially all modern molecular biology, came from a microbe in a Yellowstone hot spring.

55:00Peter Attia:CRISPR, the foundation of modern gene editing, came from the genome of a salt pond organism. And the GLP-1 class of drugs came from a desert lizard that's hardly known outside of trivia. With the exception of statins, the original scientist was not trying to cure a disease. Shimamura wasn't trying to revolutionize cell biology. Ferreira was studying proteins in snake venom. Brock was studying life in hot springs. Mojica was studying salt ponds. Eng was curious about pancreatic function. If you had taken any one of these projects in the year it started and put it in front of a Translational Impact Review Panel, a panel that asks what disease will this cure and on what timeline, many of them would have struggled to get funded.

55:48Peter Attia:Some almost certainly would have failed outright. I want to study how a jellyfish glows is not a fundable proposal in that framework. In fact, Douglas Prasher, who cloned the GFP gene, could not get NIH to fund him to continue. The system failed in exactly the way I'm describing. And yet, collectively, this body of work, this catalog of seemingly irrelevant, curiosity-driven, what-is-going-on-in-nature type of science produces foundational tools and therapies that are now improving or saving the lives of conservatively hundreds of millions of people. There's almost nothing you can do in modern medicine that doesn't, at some step in its supply chain, depend on at least one of the discoveries I just described.

56:36I think we are systematically bad at predicting which curiosity-driven work

56:41Peter Attia:is going to matter, but I'm not convinced there is actually a way to become systematically good at it. I think this is just one of the most important and most underappreciated facts about how scientific progress actually happens. And I think it has real consequences for how we should think about science funding, science policy, and the cultural framing of research as something that needs to justify itself by proximity to a cure. Now, I want to be careful here. I am not arguing that all basic science is good or that we should fund every grant proposal that comes through the door regardless of merit.

57:17Peter Attia:There is an obvious element of survivorship bias here. The basic science that we are talking about today is the basic science that is worth talking about today. Almost none of today's curiosity-driven projects will become GFP or CRISPR. But that's actually the point. The lesson is not that every exploratory project will become transformative. The lesson is that we are extraordinarily bad at predicting ahead of time which ones will. There is bad basic science, there is uninteresting basic science, and there is rigorous, accountable peer review that we should absolutely preserve. What I'm arguing is something more specific, that the criterion of near-term translational obvious impact, the criterion that asks of every project what disease will this cure, is not always the right filter to apply.

58:10It seems obvious once you take a step back. Nature has been doing experiments for longer than we have,

58:17Peter Attia:four billion years, give or take. Every problem we're trying to solve in medicine, cholesterol regulation, blood pressure regulation, glucose metabolism, immune memory, repairing damaged DNA, surviving extreme stress. Every single one of these problems has been encountered in some form by some organism at some point in evolutionary history, either to exploit these pathways, in the case of things like snake venoms, or to survive them in the case of extreme environments. And in many cases, through millions or billions of years, evolution has shaped a reasonable solution. Nature has, at a minimum, developed a remarkable toolkit.

58:57The history of medicine is

58:58Peter Attia:full of examples where we didn't invent the underlying mechanism. We discovered it, understood it, and then engineered it into something useful. Many of the molecules are just sitting out there, the mechanisms already laid out. We just have to be willing to go look, including, and perhaps especially, in places that don't at first look medically relevant. In retrospect, the work that turns out to matter almost always begins as a question that is not yet obvious about a disease. It begins with somebody who wants to understand how some piece of nature actually works. It's driven by curiosity. And I want to make sure this is not interpreted as discounting the enormous amount of work that follows.

59:45Peter Attia:Curiosity may drive an initial discovery, but intentional translation is obviously a pivotal part of the process too. An immune system in salt pond archaea cannot cure sickle cell disease. We need scientists directly characterizing the human disease, manipulating the CRISPR system, and going through years of dedicated, focused experimentation before the basic discovery becomes a human therapeutic. So I do think it's worth seeing biomedical science as existing on a continuum, with necessary time, attention, and resources devoted to each step in the chain. It is easy to look at recent medical advances and see something human-driven, human-designed, and unintentional, humans-made CAR T-cells, and checkpoint inhibitors for cancer therapy, monoclonal antibodies, kinase inhibitors, mRNA vaccines.

1:00:39Peter Attia:What can be more difficult to see is that these products of human ingenuity would be impossible without scientists dissecting the natural world first. Chimeric T-cells cannot exist without understanding fundamental T-cell biology first. Checkpoint and kinase inhibitors can't be developed if we don't know the checkpoints and kinases worth inhibiting. Monoclonal antibodies make no sense without first understanding natural polyclonal antibody expression. And you get the point. While it's true that many of these basic questions begin in obviously disease-relevant systems, it still is in service of this thesis.

1:01:20Peter Attia:The basic science, the foundational base of knowledge, is an irrevocably necessary part of the process of curing human disease. Someone, hundreds of thousands of someones really, had to be curious about how the natural world worked at its fundamental level. Only then, with the knowledge they gained, can we effectively supplement our labs and our bodies with designer molecules of our own creation. What I hope you'll leave with today is an appreciation for this idea. The drugs in your medicine cabinet did not just come from a clean idea in a lab. They started with a million small acts of curiosity about how the world works.

1:02:04Peter Attia:And the lesson in humility here, for me, the thing I genuinely take from all of this, is that we should be much more generous as a culture and as a funding apparatus with the people who are out there asking those small, strange, sometimes apparently irrelevant questions, because we are demonstrably terrible at predicting which one of them is going to change everything. We need people who translate curiosity into human outcomes, but I can't help but be struck by the fact that the apparently impractical question is sometimes the one that matters most. Thank you for listening to this week's episode of The Drive, head over to peteratiamd.com forward slash show notes.

1:02:51Peter Attia:If you want to dig deeper into this episode, you can also find me on YouTube, Instagram, and Twitter, all with the handle peteratiamd. You can also leave us review on Apple podcasts or whatever podcast player you use. This podcast is for general informational purposes only, and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment.

1:03:30Peter Attia:Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peteratiamd.com forward slash about where I keep an up-to-date and active list of all disclosures.