The Peter Attia Drive - #401 ‒ How curiosity transforms medicine: extraordinary discoveries that changed modern healthcare

Episode Date: July 27, 2026

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter's Weekly Newsletter In this episode of The Drive, Peter explores how seemingly obscure basic science discoveries have laid the foundation for some of the most important medical breakthroughs of the past half century. Rather than focusing on the clinical applications of modern therapies, he traces the fascinating stories behind the scientists, experiments, and unexpected discoveries that ultimately led to transformative drug classes, revealing how groundbreaking advances often emerge from research with no obvious clinical goal. Through these historical case studies, Peter provides a new perspective on the unpredictable path of medical innovation and makes the case for why investing in basic scientific research remains essential for driving the next generation of life-changing therapies. We discuss: The discovery of green fluorescent protein (GFP): how curiosity about glowing jellyfish transformed modern biology [2:30]; Why basic research and nature's biological innovations are the foundation of medical progress [10:45]; The discovery of statins: how fungi provided the blueprint for cholesterol-lowering drugs [15:15]; From snake venom to ACE inhibitors: the discovery of a cornerstone therapy for cardiovascular disease [21:00]; From Yellowstone hot springs to PCR: how Thermus aquaticus transformed modern biology and medicine [28:00]; The discovery of CRISPR: from salt flats to gene editing and genetic medicine [37:15]; The discovery of GLP-1 receptor agonists: from Gila monster venom to a new era in metabolic medicine [47:30]; Why curiosity-driven basic research is essential for the future of medical innovation [54:15]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure

members get back much more than the price of the subscription. If you want to learn more about the benefits of our premium membership, head over to peteratia-md.com forward slash subscribe. Welcome to a special episode of the Drive. Today we're going to take a look at some critical pieces of here. history in modern medical science. Now, we normally focus on this podcast on the findings and applications of medical research, but in this episode, we're going to instead look at that process with an emphasis on how apparently and at times seemingly irrelevant basic research can be

the stepping stone upon which medical revolutions are built. Now, we could have presented this as a series of findings, but I think the argument works best if you actually actually actually see it play out, to see who these scientists were, what they were genuinely trying to do, and what it looked like in the moment before anyone understood what they stumbled into. So rather than argue the thesis, I want to show it to you, story by story. By the time we're done, you should hopefully understand where several of the most consequential drug classes of the last 50 years actually came from. And hopefully more than that, you'll have a different friend.

for thinking about where medical progress actually comes from and how that informs how we as a society should value the basic science research that fuels medical innovation. So without further delay, I hope you enjoy this special episode of The Drive. In the summer of 1961, a young Japanese biochemist named Osamu Shihamu, Shimamuro and his wife, Akemi, and his mentor, Frank Johnson, loaded into a station wagon in Princeton, New Jersey, and drove 3,000 miles to the northwest corner of Washington State. Their destination was a place called Friday Harbor on San Juan Island. They went there for jellyfish, specifically Acoria, Victoria, a small, mostly transparent jellyfish that drifts in the cold waters of the Pacific Northwest.

Its umbrella is rimmed with tiny organs that emit a faint green light. Shimamura was building a career studying the chemistry of bioluminescence. They scooped them up one at a time with shallow dip nets, brought them ashore, and cut the luminous rings off the umbrellas with scissors, by hand, one jellyfish at a time. The goal, that first summer, was 50,000. They came back the next summer. And the next, for 19 consecutive years, Shimamura and his family, and a rotating cast of students, returned to Friday Harbor.

By the time they finally stopped in 1988, they had cut the bells off approximately 850,000 jellyfish, drawn from a population of about one million pulled from the bay. 19 summers, a million jellyfish. If you had walked up to Shamimora on a dock in 1965 and asked him what he was doing, he would have told you, honestly, that he was trying to understand how a jellyfish produces light. That was the whole project. He wasn't trying to cure a disease. He wasn't designing a drug. And he wasn't setting out to revolutionize the very process of scientific discovery.

He was a man with scissors cutting rings off jellyfish because he wanted to know how the animal glowed. Here's what he found. When he ground up the jellyfish rings and purified the proteins, the first thing he isolated was a protein that emitted blue light, not green, and only emitted that light in the presence of calcium ions. He called it Aquarin. That by itself was a beautiful piece of biochemistry. Nobody had ever seen a calcium-triggered light-producing protein before. But while he was purifying aquarin, he kept noticing in the background a trace contaminant, a second protein that didn't glow on its own. But when you shone the right wavelength of blue light on it, it fluoresced bright green. He purified it, and he named it plainly green fluorescent protein, or GFP. The jellyfish,

it turned out, was running a two-protein optical system. Aquarin generated blue light from a calcium signal. That blue light then excited GFP sitting right next to it, which absorbed the blue light and re-emitted the energy as green. And that's the glow you see in the water, an elegant piece of jellyfish biology. Shimamura published it, and he and his family went back, to catching more jellyfish, mostly to study aquarin. GFP, the green protein, sat there in the literature, basically ignored for almost 30 years. And here's where the story becomes extraordinary. Because GFP, it eventually turned out, has three properties that nobody had any reason to expect from a random jellyfish protein. First, it folds itself.

You don't need any helper machinery to make it work. Second, it builds its own fluorescent core all by itself from three of its own amino acids and using nothing but oxygen. And third, and this is the part that changes biology, GFP works in almost any cell, in almost any organism on Earth. Because it's a protein, that means we can put the gene into an organism. and the organism will make GFP. Because GFP folds itself and creates its own fluorescent core,

doesn't rely on any jellyfish specific signal. So we can put the gene for GFP into a bacterium and it glows. Put it in a worm, the worm glows. Put it into a mouse, into a plant, into a human cell in a dish. They all glow under the presence of blue light. Think about what that means. we can make specific parts of biology glow. And if you can attach the gene for GFP to any other gene you care about,

the protein made from that gene will carry a little green flashlight with it, everywhere it goes, inside a living cell. For the first time in history, you could watch biology happen in real time in living tissue. You could watch a single protein move from one part of a cell to another. You could watch a cancer cell crawl through tissue and metastasize in a living mouse under a microscope. You could watch an embryo develop, cell by cell, in a transparent zebrafish. You could mark a stem cell and follow every one of its descendants for the lifetime of an organism. None of this was possible before GFP.

None of it. Now it's so routine you develop GFP transgenic bacteria in the world. a freshman lab class. Once biologists figure out what they had in the 1990s, the biology research exploded. A researcher at Columbia named Martin Shelfi expressed GFP in bacteria and worms. They glowed. A chemist at UCSD named Roger Chen spent the next decade engineering variants, cyan, yellow, orange, eventually red. Another team developed G-camp using GFP to a calcium binding protein, so G-Camp would only grow green light in the presence of calcium signals. We could now watch neurons fire and watch sperm fertilize an egg. We have an

entire palette of fluorescent reporters used in modern biology. All of them are descendants in one way or another from the protein Shimamura pulled out of the jellyfish on a dock in Washington State. I cannot overstate how much much of modern biology runs on this. If you walk into essentially any major biology or biomedical research lab in the world today, GFP, or one of its descendants, is in use somewhere on the bench. Drug development pipelines depend on it. Cancer research depends on it. Neuroscience depends on it. Molecular cellular systems biology. GFP is in virtually every lab. There is essentially no significant an area of modern biology that isn't touched somewhere in its toolkit by a protein that came out

of a jellyfish. Because Shimamura had a seemingly medically irrelevant, simple, basic curiosity, he wanted to know what makes jellyfish glow. In 2008, the Nobel Prize in Chemistry was awarded to Oshamo, Shimamura, Martin, Chalfi, and Roger Chen for the discovery and development of green fluorescent protein. And every single one of those advances, the gene therapies, the cancer screens, the neuroscience, all of it exists because a man and his family spent 19 summers in a small bay in Washington state cutting the bells off a million jellyfish, figuring out how jellyfish glow. I want to start there because I think the jellyfish story makes a point about a persistently underappreciated truth in modern medicine.

A staggering fraction of what we now consider modern medicine, the drugs in your medicine cabinet, the diagnostic tests, you had run on your blood, the gene therapies that are now starting to cure diseases we used to consider death sentences, or even the foundational tools used every day by the laboratories that fuel these discoveries, so much of it traces back to research that at the moment it began looked like it had nothing to do with treating human disease. somebody was studying a jellyfish, studying this snake or that lizard's venom, studying fungus growing on rice, a microbe in a hot spring, a repeating pattern in some single-celled organisms DNA, and later, sometimes decades later, that research turned out to be the foundation of work that has improved or even saved millions of lives.

I think this is worth pausing on. The reflexive way we typically talk about medical progress is in terms of intent, in terms of medical goals. We say things like, we're working on a cure for Alzheimer's, or they're developing a drug for obesity. And of course, there is enormous, important, intentional problem-solving science. In fact, some of the most important advances in modern medicine have come from highly directed efforts. RT therapy, checkpoint inhibitors, monoclonal antibodies, kinase, andes.

inhibitors, antiviral therapies, MRNA vaccines, these required extraordinary intentional engineering optimization, clinical development, and persistence. The point isn't that directed science doesn't work. It obviously does. The point is that many of those successes ultimately rest on a foundation of biological discoveries that came first. But what I want us to think about today is that an enormous amount of the most consequential medical progress does not come from people sitting in a room asking how to cure a disease. It comes

from people sitting in a room or going out in the field and asking, how does this thing in nature actually work? The reason this can be so productive is something I find to be genuinely humbling. Nature hasn't solved the problems we care about in medicine. Evolution is not optimizing for longevity, and it certainly isn't optimizing for preventing Alzheimer's disease, atherosclerosis, osteoporosis, or any of the chronic diseases that emerge long after reproduction. But evolution has generated something else. An almost unimaginably vast toolkit of molecules, signaling pathways, defense systems, metabolic adaptations, and biological strategies.

Nature has been running experiments across millions of species for roughly 4 billion years. And while it hasn't solved our problems for us, it has often already created some of the components of the solutions we're looking for. The challenge is recognizing them when we see them. While modern medicine is perhaps a few hundred years old, nature has been running experiments across millions of species in parallel for billions of years. We often find that the mechanisms we need already exist. The molecule we need may already exist. Sometimes we don't even know what the problem is, and nature already has a trick up at sleep. We just have to be paying attention long enough and close enough to notice it. And once you internalize that, a lot of medical

history starts to look different. The methods look different. The methods should look different, because if nature has already touched so many of these problems, then sometimes the most productive thing a scientist can do is not invent something new, it's to find the organism that already invented it. That principle is where we're going to spend our time today. The natural world has solved a lot of problems. Once we find those solutions and really recognize them for what they are, we can build on them and translate them into research and clinical tools. And I think the next story is perhaps one of the cleanest illustrations of that idea, finding a lot of the a tool developed by nature and directly putting it into medical practice.

In the late 1960s, a Japanese biochemist named Akiro Endo was working at the Sanquio Drug Company in Tokyo, and he was thinking about cholesterol. By that point, the basic biochemistry of cholesterol synthesis was understood. Conrad Block and Fyodor Linen had won the Nobel Prize for working it out in 1964. Every biochemist in the field knew that the rate-limiting step in cholesterol synthesis was a single enzyme called HMG-CoA reductase. And everyone understood, in principle, that if you could just inhibit that enzyme, you should be able to lower the body's cholesterol levels. The problem was nobody had any idea how to find such an inhibitor.

The medicinal chemistry of the era was not capable of designing one from scratch. So Endo asked a different question. He didn't ask how do I design a molecule that inhibits HMG coa reductase. He asked who in nature is already working on one. His reasoning went something like this. Fungi and molds spend their entire existence at war with bacteria. They live in the same wet, decaying, nutrient-rich environments, and they're in constant chemical competition for resources.

For hundreds of millions of years of that competition, fungi have evolved an enormous arsenal of weapons. Small molecules designed to poison, disable, or starve their bacterial competitors. We already had one famous example. Penicillin, discovered by Alexander Fleming, is exactly that kind of weapon, a chemical that a fungus uses to kill bacteria. Endo's insight was this. bacteria in order to grow need sterols, or sterile-like molecules to build their cell membranes.

And if you were a fungus trying to starve out your bacterial neighbors, one extremely effective weapon would be a molecule that blocks bacterial sterile synthesis, which means somewhere out there in the near endless catalog of compounds that fungi have spent hundreds of millions of years inventing, there ought to be a molecule that inhibits the cholesterol synthesis pathway. Specifically, there ought to be a molecule that inhibits HMG-CoA reductase. Some fungus, somewhere, had already designed the drug to solve this problem. Endo sought out to find it. So he and his colleague, Massiao Corota, started screening.

Over the next two years, they tested more than 6,000 microbial strains. most of them, fungal, for the ability to inhibit HMG-CoA reductase. For two years, nothing. Finally, in March of 1972, they got a hit. A strain of penicillium citronum, growing on a rice sample from a grain shop in Kyoto, produced an extract with potent inhibitory activity against the enzyme. Endo shared his results with the pharmaceutical company Merck, who went searching for fungi on their own for a related compound they could in turn bring to the clinic.

Shortly thereafter, they isolated a closely related compound from Aspergillus Terius, a different fungus, called it lovastatin and got it approved in the United States in 1987. From lovastatin, you eventually get simvastatin, pravastatin, atorvastatin, resuvastatin, the entire class of drugs that by any reasonable estimate has prevented millions of cardiovascular events and millions of premature deaths. I want you to notice the structure of what just happened, because it's the cleanest possible version of the argument I made a few moments ago. Akiro Endo did not invent the starting point for statins. Penicillium citronum invented it. Aspergillus Terius invented it. What endo and the generations of medical chemists who followed did was transform

that starting point into a safe, scalable, clinically useful class of medications. These fungi needed a way to inhibit sterile synthesis in order to survive for a different reason than ASCVD prevention to be sure, but a need to inhibit sterile synthesis all the same. So Endo asked the right question of nature, who has already solved this problem? And nature, sitting in a grain shop in Kyoto, handed him the answer. A mold growing on a piece of rice that had been working on the cholesterol problem for a few hundred million years before Icaro Endo started looking for the answer. He just had to be the one who thought to ask. Now, I say this as the cleanest case, because Endo went looking on purpose. He had a hypothesis about where nature might have already solved the problem, and he turned out

to be right. But most of the stories I want to tell you next are not like that. And most of them, people who found a paradigm-shifting answer were not even looking for it at all. They were looking at something else entirely. A snake, a hot spring, a salt pond, a desert lizard, and what they found there turned out in retrospect to change everything. Which takes us to South America. In Brazil, in the first half of the 20th century, Bothrop's Gerarica, the Brazilian lancehead pit viper, was a serious public health problem. It still is. The Gerarica Lancehead is a beautiful, irritable, zigzag patterned pit viper, about three to five feet long, and its venom causes a sudden catastrophic drop in blood pressure.

In 1901, the Butonton Institute in Brazil was founded, in no small part to understand venomous snake bites. They began collecting, studying, and stockpiling pit viper venom. Eventually, venom began to be leveraged as a research material, liophilized, abundant, locally available, and it stopped being just an object of study itself. Pharmacologists could use it as a reagent to probe mammalian physiology. In the late 1940s, the Brazilian pharmacologist Mauricio Rocha and Silva was working on circulatory shock. At the time, circulatory shock was thought to be mediated by histamine. He wanted to know whether proteolytic enzymes, common ones like Tripsin or proteases in gerarica venom, released histamine from plasma. So he exposed blood to

gerarica venom. The venom did not release histamine from blood samples. It released something else. This was the discovery of a new peptide, a potent vasodilator, which also produced a slow contraction in the small intestines of guinea pigs. He named this peptide Brady Kinen from the Greek for slow movement. This was a massive discovery. In the decades since, Brady Kinen has turned out to be a fundamental player in mammalian cardiovascular biology, an endogenous regulator of blood pressure, vascular permeability, and inflammation. But our story doesn't stop here. A decade and a half later, Rocha and Silva had a graduate student named Sergio Ferreira, and he handed Ferreira a puzzle. Brady-Kinen generated in plasma by venom was more

active than a synthetic Brady-Kiden produced in a test tube. Why? Ferreira's answer, published in 1965 was that the venom also contained a separate family of peptines that potentiated Brady Kiden's effects, Bradykinen potentiating factor, or BPF, by blocking the breakdown of Brady Kinen. The venom proteases caused Bradykinen to be released in the plasma, and BPFs in the venom protected that Brady Kinen from degeneration. The BPF work landed. Ferreira, a postdoctoral position in London, in the vein lab at the Royal College of Surgeons. In the lab, another postdoc named Kevin Inc. was studying angiotensinsinsinsins in pulmonary circulation, having found that angiotensin 1 is converted to angiotensin to a vasoconstrictor

in the lungs. Ferrarra brought powdered BPF with him to London from Brazil, and his work with Kevin converged on an unexpected finding. By adding BPF to Kevin's preparations, it turned out that the same enzyme that was degrading Bradykinen was also converting angiotensin 1 to angiotensin 2. Both jobs were inhibited by BPFs. This enzyme apparently had two synergistic jobs. Destroy the vasodilator, Gradykinen, and produce the vasodilator. of constricting angiotensin 2. They found that this enzyme was angiotensin converting enzyme, or ACE. Now, Ace had previously been discovered, but the identification of a potent ACE inhibitor caught the attention of chemists at Squibb. The venom peptides themselves were not viable

drugs. They're not orally active, and they have a short half-life. Squibb's chemists took the smallest, active BPF peptide from the Gerarica Venom and used it as their structural lead and designed a small orally active molecule that inhibited ACE in the same way that Venom peptide did. This is conventionally remembered as one of the earliest examples of rational mechanism-based drug design. They called the molecule Captapril, and it was approved by the FDA in 1981 as the first oral ACE inhibitor in clinical use. And captapril, begat, analapril, lysinapril, ramapril, and the rest of the ACE inhibitor class. And conceptually began the angiotensin

receptor blockers, Losartan, Valsartan, and so on. The renin angiotensin aldosterone system is now one of the most heavily drugged pathways in all of medicine. These drugs are foundational in the treatment of hypertension, heart failure, chronic kidney disease, post-MI remodeling, and diabetic nephropathy. They are plausibly among the most consequential drug classes ever developed. So let's sit with the causal chain for a moment. Millions of lives saved or extended because the Butantan Institute was stockpiling local snake venom. A clinical question, how does this venom kill people produced a research reagent. The reagent used to probe a wrong hypothesis about shock produced the accidental discovery of bradychinine, a fundamental signaling molecule in cardiovascular

and inflammation biology. A discrepancy in a bradyquinine bioassay produced BPFs. BPS, carried to a London lab, studying lung vascular, produced the recognition that one enzyme sat at a enzyme, sat at a the center of two opposing blood pressure systems, and that recognition handed to two medicinal chemists produced a world-changing drug class. For the first 70 years of the 20th century, nobody was trying to develop a hypertension drug. The molecule fell out of 70 years of fieldwork and basic biology, each step asking a question the previous step hadn't anticipated.

The question of how a Brazilian pit viper venom kills its prey could have saved thousands of lives in Brazil. Instead, through the curiosity of basic medicinal scientists, tens of millions of lives around the world have been saved or extended. For a more technical audience, you already know the importance of the next story, and it's therefore somewhat impossible to overstate. Anyone who has spent any time in a biology lab, including simply taking a freshman year biology lab class at university, knows that how fundamentally this work has changed biology and medicine forever. It is the technique that opened the door to the last few decades, the golden age of biology

research, and it begins at a hot spring. In the mid-1960s, a microbiologist at Indiana University named Thomas Brock started taking summer trips to Yellowstone National Park. He wasn't a typical hiker. He was a microbial ecologist who became interested in extremified. fossils, organisms that live in extreme environments. Yellowstone, with its hundreds of geothermal features, has a higher concentration of accessible high-temperature aquatic habitats than just about anywhere else on Earth. At the time, the prevailing belief in microbiology was that bacteria could grow in conditions up to about 55 degrees Celsius, after which they might survive, but the heat prevented their

molecular machinery from successful reproduction. As temperatures keep rising, the belief was that proteins may be denaturing, membranes dissolving, and the whole thing a mess of chaos and thermodynamics. Nothing could survive. Hot springs near boiling temperatures were therefore assumed to be necessarily sterile. Brock didn't believe it. He started looking through Yellowstone's hot springs, and he was right. At a place called Octopus Spring, he observed pink, filamentous bacteria growing in water at 88 degrees Celsius, well above the supposed ceiling for life. Over the next several years, he and an undergraduate student named Hudson Freeze 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 thermos 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. Now we jump forward 15 years. In 1983, a biochemist named Carrie 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. You 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 manually at every cycle. It 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 thermos Aquaticus. Polymerase is fundamentally necessary for life to continue.

Every organism necessarily requires a means of copying their own DNA in order to pass that DNA onto new cells or new generations. Thermos Aquaticus could apparently do this at temperatures of at least 88 degrees Celsius. In the mid-1970s, the thermos 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 CETIS team built on this, purified TACPolymerase in their lab, and plugged it into their PCR protocols. With this, the entire technique and all of biological sciences transformed. Now 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 Freeze 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. And 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. All 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 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 this 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 are caya that have adapted to thrive at salinity levels that would kill virtually anything else. A young Spanish microbiologist named Francesco Mojica was doing his PhD on one of these archaes. Hello, Phorex Mediterranean 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 saline.

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 spacer 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 red left to right and right to left is the same. So the word race car is a palindrome 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 Ishino had noted similar repeating patterns in E. coli in 1987, left as effectively a footnote in the discussion section of their paper. Mojika 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. Mojika 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. 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. That was the Mojika realized that the repeats weren't random junk. They were a record. Each 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 phages genomes and using that information to recognize and destroy them on future encounters. This was a stunning insight. It implied that bacteria and Archaia, the simplest organisms in biology, had a sophisticated adaptive immune system with memory

We now call that system CRISPR, clustered, regularly, interspaced, short palindromic repeats, and the nearby proteins were deemed CAS, short for CRISPR Associated. Mohika 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. 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 Archaia. He was a Spanish microbiologist with a small lab and his finding sounded like esoteric microbial biology.

It took a lesser journal to publish what is in retrospect an absolute landmark paper. From there, the timeline is short. Labs around the world began to catch on or discover other features on their own. Denisco, 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. Denisco's 2007 paper in the journal Science validated Mohica's hypothesis

and identified Cas 9 as the protein that recognizes CRISPR encoded sequences to cut and destroy bacteriophage DNA. In 2012, Jennifer Dowdna and Immanuel Shepo, Sharpoonier, and around the same time, a group at the Broad Institute and MIT, led by Feng Jung, 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. In bacteria, the goal of the cut was to destroy the phage's ability to reproduce. Daoudna and Sharputier 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 variance efficacy could be limited by the competition with the host's own pathological gene. 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 vasoeclusive crisis that define their lives essentially stop. From a strange DNA pattern in a Spanish salt pond Archaia to a therapy that durably treats sickle cell disease. And even recently, a phase 1B trial posted incredibly promising results for a CRISPR-derived treatment of familial hyper-cholestrolemia. 30 years since the salt ponds, CRISPR is curing diseases. And again, look at the structure of what happened. Francisco Mohica did not set out to cure sickle cell disease. he set out to understand why the genome of an obscure salt-loving arcane 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. Mohika 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. 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 Yellow, the Nobel Prize winning physicist and biochemist who decades earlier had invented the radioimmune assay 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. 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?

Heng 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. Whatever the lizard's pancreas was doing, it was doing it differently from hours. So Eng ordered some dried Gila monster venom and started running it through the assays he's inherited from Yalo's lab. Working with his colleague Jean-Pierre Rothman, who would shuttle

samples back and forth from Brooklyn to the Bronx in his Toyota Camry, Eng 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 Exenden 4. When he sequenced Exenden 4, the result was remarkable. The peptide showed about 53% amino acid sequence similarity to a human hormone called GLP1, glucagon-like peptide 1, a gut hormone produced in the intestine that stimulates insulin secretion in response to a meal. 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 GLP1 receptors like a hammer. Excendant 4 had a key property that GLP1 does not. Native GLP1 has a half-life in the bloodstream of about two minutes. An enzyme, called DPP4 choose 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. Excendant 4, by contrast, is resistant to DPP4. Its half-life is on the order of hours, not minutes. It acts on the GLP 1 receptor with a durability that GLP1 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 Amalin. In 2005, the FDA approved synthetic extenin, 4 under the trade name, Bayetta, generic name Exenotide, for the treatment of type 2 diabetes.

It was the first GLP1 receptor agonist ever brought to market. And then the floodgates opened. Excendant 4 was a foreign heila 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. Novanoridis, Lily, and others realized that this was an enormous biological lever,

not just a way to improve glycemic control and diabetes, but as it turned out, an extraordinary tool for weight loss. As we've talked about at length, GLP1 signaling also suppresses appetite, slows gastric emptying, and changes how the brain weighs reward signals around. food. Subsequent drugs were not direct extend in four analogs, but modifications of the native

human GLP1 sequence engineered to reduce immunogenicity, increase half-life, and in some cases, add alternative targets in addition to GLP1. We now have Lyraglutide and semi-glutide, along with tersepotide, which adds GIP agonism in addition to GLP1. 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. 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 lizards bite cause pancreatic inflammation. 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. CRISPR, the foundation of modern gene editing, came from the genome of a salt pond organism, and the GLP1 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. Mojika 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. 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. 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. I think we are systematically bad

at predicting which curiosity-driven work 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.

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. It seems obvious once you take a step back. Nature has been doing experiments for longer than we have. Four billion years, give or take. Every problem we're trying to solve in medicine, cholesterol regulation, blood pressure regulation, glucose metabolism. 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 venom, 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. The history of medicine is 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 of the work that turns out of 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. Curiosity may drive an initial discovery, but intentional translation is obviously a pivotal part of the process too. An immune system in salt pond archa 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 intentional, humans-made car T-cells, and checkpoint inhibitors for cancer therapy, monoclonal antibodies, kinase inhibitors, MRI, and RNA vaccines. What can be more difficult to see is that these products of human ingenuity would be impossible without scientists dissecting the natural world first. P-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. 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 someone's 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. 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 peter atiyahmd.com forward slash show notes if you want to dig deeper into this episode.

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