GLP-1、肽类与万亿美元健康革命

1. The State of Modern Medicine

You and I have had these conversations for many years. We've been partners and friends for a long time, so it's hard to know where to begin the conversation because I suspect we'll go for hours talking about drugs, bio, healthcare, and a million things that affect us all.

You have this cockpit-like view into what's going on in the state of medicine today. How would you describe the state of the union—the daily cockpit view that you get of the whole industry? Give us a dispatch from that room. What do you see today?

Alex Cornell

When I look at this moment in terms of where we are in medicine, and look back over my 20 years of building and backing biotech companies, I would say that 2025 is probably the single most exciting year in my entire journey.

To unpack that, what we're seeing is that GLP-1 medicines are showing us what happens when we get to the root of disease. These medicines have the potential to do everything from protect us from being diabetic after being pre-diabetic, all the way through lowering our risk of having a heart attack or a stroke, protecting our kidneys, and soon, we're going to see the opportunity to protect us from developing addictions to alcohol and drugs. So, it's a profoundly important single medicine.

Because these medicines are incredibly powerful and can do wonders for people's long-term health, what we're seeing is that the adoption of these medicines has exceeded almost everyone's expectations, including my own, which were pretty darn high. I think it's easy now to conclude that this class of medicines will easily be in excess of 100 billion dollars a year in revenue.

What gets me fired up about that is not necessarily this once-in-a-decade, 100-billion-dollar revenue opportunity that exists within GLP-1s. What gets me fired up is that it's actually the first commercial proof that we are ready for what I think we're going to look back on in time as a once-in-a-lifetime, trillion-dollar revolution in all of public health. In order for that to be true, there are going to be layers of attack that are needed to help us live our longest and best lives.

I think one of the things a lot of people don't appreciate when I meet them and we start talking about where medicine is and what it can do is that incredible scientists have already cracked the code on most of the medicines we need to protect us from most of the diseases that will claim most of our lives.

Mm-hmm. That's a really important point, because what that means is that there are tons and tons of people who have traveled through all different mazes to arrive at the biological target and come up with a medicine against that target that can help us to live longer and better lives. When we think about the gap that exists in the world today, the reality is that when we look at any life expectancy charts, they haven't budged in decades.

In fact, the last major advancement where we had an inflection was decades ago, on the back of antibiotics, vaccines, and better hygiene. We've gotten nowhere since then. The gap is not necessarily needing more medicines; it's actually pointing those medicines at the impact that they can have.

Alex Cornell

And so, to me, what I'm excited about with the GLP-1 opportunity is that we're seeing the first commercial proof that we're ready to head in that direction. The reason those sales have exceeded our expectations is that people are taking their future into their own hands. People are basically voting with their feet, saying, "I'm done waiting to reactively go and treat myself for the diseases that I backward-lookingly manifest. I'm ready to go get after and help myself to the—"

2. Designing the Modern Health Stack

Longest and fullest. I wanted to zoom in on a concept that you and I have been riffing on a lot recently, which we're calling the health stack. Stack is a term in technology, like your tech stack is all the various components that you use to create your overall thing. We thought this idea could be applied to health.

We're all interested in our own health. It's a universal interest and concern. Maybe riff a little bit to begin on this notion of the modern, evolving, and emerging health stack.

Alex Cornell

A health stack has a couple of different elements to it. It has elements of offense and defense. On the offensive side of the equation are some of the basics that we all know about. It's everything from proper nutrition, strength training, proper monitoring and testing, and doing those activities in a systematic way, tracking that data, and building off of it over time. Later on, we could talk about how AI can play a big role in enabling that to reach its final chapter of what it takes for impact.

What I find most interesting about it is that if we think about 5 core dimensions, not only are they within our hands to be proactive about protecting ourselves, but we have the medicines to do that. To me, the 5 key layers are lipid optimization, cardio-metabolic health, neurocognitive health, inflammatory health, and our blood pressure.

When we think about lipid optimization, we have—and our bodies produce—cholesterol. There's a type of cholesterol called LDL cholesterol that's really dangerous, and it's dangerous because this cholesterol builds up in our bodies over time. It's slowly accumulating in our vasculature, and as it accumulates, it gets to a point where it causes a blockage. That's a heart attack and a stroke.

We have medicines today, whether they're statins or PCSK9 inhibitors, that can do wonders to reduce our level of cholesterol. Most middle-aged men and women walking around have somewhere between a 30% and a 50% probability of having a heart attack or a stroke sometime between the time that they turn 40 and the time that they turn 80. To me, that's tragic, because we have medicines that can help us dramatically lower that risk to sub-10%.

Looking at the next layer, cardio-metabolic health, what we're talking about is the glycemic environment in our bodies combined with visceral fat. These are 2 major drivers or impediments to our long-term health. To give you an intuition for these, the higher the level of glucose in our bodies, think about it as making our vasculature more brittle.

If you are both having lipids accumulate in your body and your vasculature is getting more brittle, you're only force-multiplying the risk that you ultimately have one of those horrific heart attacks or strokes. But we can do something about that. We've got amazing GLP-1 medicines. Clear data from Eli Lilly show a 94% reduction in your risk of moving from being pre-diabetic to diabetic.

We see amazing data in terms of what it does to both help us lose weight and have category shifts, going from obese to overweight and from overweight to normal weight. It's a game-changer in terms of our long-term health.

Moving down to neurocognitive health, the data is not out yet, but later on this year, we're going to see the next step for what are called anti-amyloid medicines—medicines that can go right at the heart of the accumulation of plaques, this time not in our vasculature but in our brains, that lead to all sorts of damage and cognitive decline.

We've got medicines today that can go right at those plaques and bust them. What Lilly's probably going to show later on this year—it's my guess, but I think the data really supports it, and we'll see—is that getting at those plaques earlier, before they accumulate as significantly, is going to show dramatic effects on protecting us from developing Alzheimer's.

Moving on to inflammatory health, one of the things I think people don't appreciate is that the food we eat is actually quite inflammatory. Over time, we've moved from being hunters and gatherers to being able to have as much access to Pop-Tarts as we want. I love them, too. You don't get 1; you get 2.

We overeat to a point where it drives an inflammatory response in our bodies. You can think about that whole equation: if we have both lipids accumulating and our body has a high-glycemic environment making our vasculature brittle, and the same food that we're eating is driving an inflammatory environment around it, oh my goodness, it's like a ticking time bomb for all of that to go off.

Not only is the inflammatory environment of our body implicated in driving an increase in cardiovascular events, strokes, and heart attacks, but it's also implicated in a whole set of inflammatory diseases that span everything from atopic dermatitis to ulcerative colitis and Crohn's disease.

And then, finally, blood pressure. Maybe this one is very intuitive to people, but you can imagine that if we're living high-stress lives, if we're not working out, if we're developing obesity, and we have this high-glycemic environment, our vasculature is brittle, our LDL is mounting, and on top of that, the pressure going through that system is getting higher and higher as we're aging and doing nothing about it.

Oh my God, that’s just another force multiplier. So all of these axes that I define as the 5 key layers of defense, the defensive side of a health stack, each of them has medicines available to help us control our fate. Each of them has medicines available that, if we could get on them early and be proactive about where we’re going with our health, will undoubtedly add an extra decade of life to our expected lifespan and have the potential to take curves that have been dead flat for decades and drive one of the first inflections ever.

I want to spend a little bit of time on each—maybe not all 5, but at least 4 of the 5 levers—to let you explain what you’re seeing and learning, especially from your perch as an investor. One of the things that makes you so unique is that ultimately you’re trying to make money on all this stuff, and you’re doing so with extreme care and precision, on a very sophisticated team, and with lots of data. There’s money on the line here, so this isn’t just you reading something and trying something. It comes out on a scoreboard.

I want to start with GLP-1s because it’s obviously the thing everyone understands the most. It’s visceral. Maybe to begin, it would be for you to tell us what specifically you’re seeing in 2025 and 2026 that is so exciting, because these things have been around for a little while and people are starting to get on them earlier than that. What is the inflection? And then I want to get into the actual mechanics of how it works.

The one that’s about to come out next year, which seems maybe even more revolutionary than semaglutide and tirzepatide—what happened recently that has you so extra excited about them?

Alex Cornell

Maybe one of the things most people don’t realize is that there are a couple of different injectable GLP-1s on the market today. We have some of the first oral versions coming to market now, and more that are coming. These medicines exist at lots of different doses.

I think one of the most interesting discoveries that I made over the past year, just looking at all of the data that we get to consume as investors, was that I wanted to know the answer to this: Wall Street is very focused on the next GLP-1 having more weight loss. I’m sitting back and thinking to myself, I don’t know if that’s the right focal point.

One of the most interesting findings from diving into the data is that people are not solving for this massive bazooka. People are solving for something that helps them lose some weight, stabilize, and be there. I think that’s really interesting because what that means to me is that what people really want is something that’s going to give them a health advantage but be incredibly tolerable.

What we find is that as you go higher and higher in doses, the unintended consequence is that, yes, you’re going to have more weight loss, but there’s going to be a whole host of other side effects that come with it. That is different from most medicines, where we’re trying to maximize the efficacy of the medicine—really where Wall Street minds typically tend to go. What people are maximizing for here is, how do I get on these things and then stay on them?

So that, to me, was one of the big unlocks for 2025: this idea that people want to protect themselves. If you marry that with the next big discovery from 2025, it’s that typically the way medicines are commercialized is that you have big pharmaceutical companies—Eli Lilly, Novo Nordisk—that have armies of sales reps out everywhere, calling on doctors, making sure they know about their medicines, pitching the attributes and why they’re the best in class, and why there’s no other option that their patient should be pursuing other than their medicine.

As you can imagine, that’s a very capital-intensive exercise. It’s a very human-talent-intensive exercise. What we saw, interestingly, was that Eli Lilly, pretty early on last year, pushed more aggressively into a nontraditional way to get these medicines into the hands of people. They added to their legions of salespeople a digital front end in LillyDirect that allowed people to get a prescription from their doctor and get the medicine directly from Eli Lilly.

It was one of the first big insights that consumers want to be able to get these medicines themselves and not have to go through traditional means to get them. As you fast-forward toward the end of 2025, what we started to see was that, oh my goodness, more than half of the new people joining were coming in directly.

Hold that with the third point that comes from 2025, which was all sorts of theater and dramatics around compounded GLP-1s. What we learned from the compounded GLP-1s was that not only do people want something that’s going to defend them and be tolerable, and not only do they want something that they can get through all the frictions of the system—just hit a button and have it come to their homes, a real consumer-like product—but price matters a ton.

Through most of 2025, the average monthly cost of a GLP-1 was north of $500. Thanks to our administration, those prices are coming down, and I think that’s really good. It’s particularly good because what we learned from the compounded versions of GLP-1s was that there is massive price elasticity in this market.

Compounded GLP-1s cost about half as much per month as the traditional, approved GLP-1s by Lilly and Novo. We were collecting data that was suggesting somewhere between 15% and 20% of the market that you couldn’t capture through scripts was actually flowing through groups like Hims & Hers and other sources, where people knew they wanted the benefits and wanted to be proactive about their health. They wanted to get these GLP-1s, but they couldn’t possibly afford $400 or $500 a month. They could afford $200 or $250 a month.

To me, that’s profound because you’ve got a compounded version that hasn’t gone through any clinical trials. You know nothing about the manufacturing, but you know that these medicines are so important to your health that you’re willing to take the risk—not only the safety risk of the medicine, but all these risks and unknowns of where it’s even coming from.

Mhm.

Alex Cornell

I left 2025 thinking to myself, oh my goodness, we’re finally starting to see people step up and vote with their feet. They said, “I want the benefits of these medicines.”

Now you get to 2026, and this is the absolute game changer. In 2026, we now have an oral version of Wegovy. This medicine has launched over the last couple of months. We are seeing every week that the oral version of Wegovy is setting record after record after record.

3. The Biological Mechanisms of GLP-1

You might think, yeah, of course—who wants to inject themselves once a week for the rest of their life? But I don’t really think that’s what’s driving an almost 4× relative launch cycle for oral Wegovy versus the most recent injectable launch, Zepbound. People want these medicines, and the lowest end of the curve doesn’t cost $500 a month or $250 a month; it costs $150 a month.

Now we’ve seen that, at the lower end of the curve, if we get to an $1,800-a-year cost, these medicines fly off the shelves. To put that in context, prior to the launch of oral Wegovy, just a few months ago, the GLP-1 market was moving at about 200,000 recorded new scripts per week. That meant 200,000 new people getting on these medicines per week.

The most recent data that I looked at this past Friday says that this has now moved from 200,000 a week to 300,000 a week in just a few months’ time.

Crazy.

We have to take these incredible learnings from the commercialization of GLP-1s, and the most logical conclusion is that, yes, people are ready and people do want to go and be proactive. Arming them with the stack that can help us all live an extra decade means really focusing hard on what it takes to close that gap between invention and impact.

When I say this trillion-dollar revolution, what that means, really, is this trillion-dollar reduction in our annual health care spend. I think that’s really possible now.

I want to spend some time explaining what’s actually going on with this class of drugs. Starting with semaglutide, the single-acting one, going to tirzepatide, the dual-acting one, and then going to the triple-acting one that’ll be coming out this year or next year, can you do your best to explain what this thing is and what it does?

I think people’s original conception was, “It’s a drug I take and I lose weight.” I think you have a really interesting way of explaining and understanding these things as maybe the most important modern drug. It seems worth spending some time just explaining literally what it is, what the science progression has been, and where you see it continuing to go. This isn’t static.

A lot of people don’t realize these medicines have actually been around for 20 years. Some of my first exposure to GLP-1 as a drug class happened in my early days entering the industry as a young biotech investor back in 2005, with Amylin Pharmaceuticals having what we thought at the time was the most miraculous breakthrough.

GLP-1 is a hormone that our bodies naturally produce. The problem with this naturally produced hormone is that once it’s produced by our bodies, it only lasts for about 2 minutes before it’s gone. If we just pause there, what does that mean practically? If you were to take human GLP-1 and we were injecting it, we’d have to inject ourselves 30 times an hour for the rest of our lives to get the benefit of what we can get today with either one pill a day or one injection a week.

The science behind moving from a protein that lasts for 2 minutes to a protein that can last over a week is a dramatic transformation. What’s good about that is it’s a hormone that’s already in our bodies, and it’s a medicine that we’ve got data on for over 20 years. We know a remarkable amount about it, not just because it’s been around for 20 years, but because it’s now been in millions and millions of people.

So, how does it actually work? When we eat food, at some point that food makes its way to our small intestine. When food gets to our small intestine, that’s what triggers the release of GLP-1 in our bodies naturally. That GLP-1 molecule travels all over our bodies and interacts with receptors in our stomachs that help to slow the digestion of food.

It also interacts with receptors in our brains that help us to feel fuller longer, to feel satiated. The combination of those 2 mechanisms of action is what allows us to turn off the food noise and seek out and consume far fewer calories than we’ve ever done before. In addition to that, it plays an important role in regulating the production of our insulin. It interacts with the receptors on our pancreas that trigger the release of insulin.

It plays a big role in not just having that sugar not affect our vasculature, but also making sure that sugar isn’t destroying our kidneys. The mechanism and the science behind it are actually pretty well elucidated. Biologically, we know how it’s produced, and we understand all the different places in the body that it interacts.

When you think about all the places in the body that it interacts, it then becomes no surprise that it’s had such an incredible range of effects: protecting us from becoming diabetic, reducing the risk of having heart attacks and strokes, and lowering our level of inflammation because we’re consuming less food and having less of an inflammatory response to that. It goes all the way through to helping us lose weight, which is a bit of a virtuous cycle in terms of lowering our blood pressure.

When you look across the 5 axes, the 5 layers of defense that are mission-critical for us maximizing the number of years that we can live and having the most life in those years, I fundamentally believe there’s no molecule that’s more important than GLP-1 across that entire axis.

When we think about the different forms that it’s available to us in, we could really crack the most important code, which is moving from something impractical—30 shots an hour—to the early days with Amylin Pharmaceuticals of a twice-a-day shot, to where we are today. Today, we have not just longer-acting, once-a-week versions, but far more potent versions, meaning we need far less of it, and it starts to get to levels that we can inject that have incredible pharmaceutical properties.

As we think about it, I think the next axis to think about is not just the form by which you get it, oral or injectable, and not just the duration of the dosing. Orals we take every day; today, we take injectables once a week. There are some amazing ones that Pfizer just acquired that look like they might be once a month. Amgen is also working on a once-a-month version that might be once a quarter.

The duration of time between those doses is really important because the easier it is to take a medicine, the more likely you will be to stay on these medicines and have the longest-term benefit from them. I think the next important axis to focus in on is how we think about dose and the tradeoffs between semaglutide and tirzepatide.

Semaglutide is Ozempic and Wegovy; tirzepatide is Zepbound and Mounjaro. Our team’s fundamental perspective is that they all achieve the same goals. They were just novel IP strategies to achieve those same goals, and I would say that they’re all pretty much interchangeable.

How do we think about them from an investment perspective and a human-impact perspective? Those 2 perspectives actually come together because when we think about investing in medicine, the key question that we’re focused on is, “Why does a medicine have a right to win?” For a medicine to have a right to win, what we’re essentially saying is that this medicine is going to have a differential impact for people such that people should choose it.

The right-to-win analysis also comes down to the different segments of the market that we’re thinking about. To put a framework around this, we always think about the obesity market as having 3 main segments: people that are overweight, which are basically BMIs between normal—roughly 25—and 30; obese, which is between 30 and 40; and morbidly obese, which is north of 40.

When we look at the aperture from a BMI of 25 up to a BMI of just under 40, that’s where most of the patients are today that require reactive treatment. I would argue that in the future, we could talk about why GLP-1s might be appropriate for just about everyone. That’s because the reality of it is, as you go from your adolescence to your 50s and 60s, on average people are going to pick up about 5 BMI points.

Being able to take a medicine, even at low doses, even though they haven’t been tested in those populations, I’m willing to bet would help protect people from that 5-point increase that puts them in harm’s way and puts that to bed. But when we look at the market today, pretty much from that BMI of 25 to 39, people are well served with any of the available options on the market.

Where we still need some help, and where I think there’s a right to win, is really in that BMI zone of 40 and above. Sadly, these people are at a level of body weight that requires incredibly long titration to get up to these high levels of the hormone. They need a much more dramatic reduction in their food noise to be able to bring their weights down from a zone that is incredibly dangerous, given the amounts of visceral fat that they’re carrying around, to levels that are going to give them much more sustainable life and a much longer life.

I have a very basic question. Would there be any difference in outcomes if we simply ate the same exact input that we eat on these medicines? If, instead of taking the medicine, I just ate exactly what I would eat on them, but figured out a psychological way to deal with the food noise and just didn’t eat when I was hungry, effectively, is there any difference in outcomes, do we think?

I’m especially thinking here about alcohol addiction. It seems to be one of the things that gets addressed by these drugs, and that seems unrelated to how much I eat. It seems like an independent thing that’s being positively affected by the drug beyond just which calories I’m putting into my body. Is there something else going on here beyond just literally what I’m eating as a result of taking these drugs?

Alex Cornell

Eating is definitely a part of it, and it’s a major part of it. If we could all be disciplined and get on a proper diet where we’re selecting the right foods, eating the right amounts of them, and staying disciplined to that, you wouldn’t really need these medicines for the purposes of managing our weight.

But I think that’s only going to cut at the weight part of it. Unfortunately, if your biology is wired such that you have a family history of diabetes and you’re prediabetic and on the precipice of turning diabetic, we’re starting to be in a place where we’re just not producing the insulin that’s required to be able to take up that glucose that’s coming from the food that we’re eating.

By consuming fewer calories and less food, we can hit part of that, but I think it’s unknown as to whether that’ll be enough to be able to undo your progression to diabetes. I might say you probably still need those medicines for that. On the other side of the equation, connected to that, has to do with addiction.

4. Overcoming Frictions in Healthcare

In some sense, you could say that food is a form of addiction. While consuming fewer calories will help protect us from the vicious cycle of overconsuming food, I would say that, in terms of the addiction data that will start coming out over the next year or so, you would lose that benefit. You would lose the free gift of protecting yourself from being addicted to drugs, alcohol, or gambling.

That comes from the signaling in the brain—the satiety axis in the brain—that cuts across both food and some of these other not-great behaviors. I think there's also an open question about what just consuming food would do for cardiovascular outcomes. We've got compelling data from Novo Nordisk over the last year that basically shows that, by taking GLP-1 medicines, there is a reduction north of 20% in our risk of having a heart attack or a stroke.

What I thought was pretty profound about the full data that they put out is that this was independent of weight loss. I think that speaks to me that there's just another axis and another biological driver that's driving this cardioprotective result. We might forfeit that, but without a doubt, if we could actually get access to great food, eat the right amount of it, and stay disciplined, that would take us a long way.

But it seems like, summarized, there is more going on than just that. The data seems to suggest that even if I could eat perfectly, I might still reap benefits in these other ways from these drugs.

I want to talk about the next layer—the first layer you listed—in cardiovascular and PCSK9 drugs, to really drive home the point of existing drugs before we get to all the exciting new stuff, which we'll talk about as well. There are existing drugs that could have a radical impact if everyone were on them.

Alex Cornell

There are basically 3 different dimensions that are preventing people from getting the maximal benefit of a breakthrough medicine that exists and is right here for all of us. In my mind, those break up into complexity, cost, and convenience.

I think all of us have had the experience of learning that we have some health problem and wanting to go do something about it. I've kept you up to date along the way, but it was amazing to me to actually realize—to practically have to deal with our health system—and all of the different branches that it took from recognizing that I had a cholesterol problem to, 2 years later, finally getting access to the medicine that could help protect me from that problem.

It's everything from wanting to go see a doctor because you get a blood test that says, “Hey, I have a problem,” to learning that the next appointment is only 6 weeks out. Then I go, and of course they want to redo the blood test. You can just see the friction in our system mounting and mounting and mounting. Eventually, I think a lot of people just give up. It is really hard to navigate that system.

Given what we're seeing with GLP-1 medicines, and the fact that the direct-to-consumer side of that is driving most of the adoption today, I think we have to start asking ourselves, “Why is it that I can go on my iPhone, go to Amazon, click a button, and the next day have toothpaste, but it takes me an incredible journey—hundreds of phone calls, multiple doctor visits, being pricked and prodded multiple times—just to protect myself from having a heart attack?” That doesn't make sense.

5. Cardiovascular Disease

I think we have to balance the opportunity for health impact of this amazing medicine that we have with the reality of how darn complicated it is to navigate through our system. Next is cost. Most medicines that we need to be on for the rest of our lives—those that are going to provide the chronic care and the different layers of that defensive health stack that will protect us from these diseases—are priced similarly to acute treatments today, yet they need to be taken over decades.

We have a timeline problem. We have a horizon problem. I think that there's a lot of innovation that can occur around pricing models if the world moves from where we are today—which is waiting until there's a problem, waiting until it's almost too late, and reactively treating it—to proactively getting out ahead of disease.

The final part of that is compliance. We all know that medicine only works if we take it. Because of the complexity of the system in getting it, because of how expensive these things are, and, at the end of the day, because we're all human, the more frequently we have to take a medicine, the harder it is to go get it. The more times we have to go to the pharmacy, the more times we have to make that decision over the course of the year, the higher the probability that we're just going to quit.

That's just human nature, myself included. Compliance is this invisible barrier to all of us realizing our best health outcome. On one hand, GLP-1 medicines are miraculous. We went from twice a day to once a week, and now we've got versions that are once a month, maybe once a quarter. That's a huge unlock, in my opinion.

Maybe now's the time to tell a second drug story, a far less well-known one than GLP-1, which is PCSK9. I find this story to be so interesting for so many different reasons, but maybe most of all because it seems closest to what I'll call a free-lunch drug that exists.

Because it helps deal with cardiovascular disease, which is something that everyone has probably dealt with in their family or personally at some point, it seems incredibly important—close to as important as the first one we talked about. Can you tell the story of this specific drug—what it does, how it works, and the impact it might have?

Alex Cornell

The headline here is that PCSK9 medicines are amazing because what they do is, today, they can lower our bad cholesterol—that LDL cholesterol—by 50%. We now have outcome studies in patients at different degrees of having high cholesterol showing significant protection from ever developing or having a heart attack or a stroke.

In patients who have previously had a heart attack or stroke, we can reduce that risk by over 20% in the future. For people who are at high risk of having a heart attack or a stroke, the medicines that are approved and on the market today can lower that risk by about 25%. These are incredible medicines, particularly because heart disease is still the number-one killer in the U.S. today.

The way these medicines were discovered is through human genetics. From a human-genetics perspective, we can go around the world, look at different populations of people, and study some of the attributes and advantages of those different populations. It turns out that there's a population of people in the world that has a genetic mutation conveying a massive advantage. They have a mutation in their PCSK9 gene, which means they don't produce the PCSK9 protein.

What we've learned from observing that village and understanding the cardioprotective nature of that genetic defect is that the production of this PCSK9 protein actually interferes with our body's own ability to clear LDL cholesterol. The more PCSK9 we're producing, the fewer particles of LDL we can clear. Our cholesterol grows higher over time, and more of those little particles invade our vasculature and start to mount up until we get to a point where there's a blockage.

Recognizing the importance of that PCSK9 protein—driven by the observation of human genetics and by data from longitudinal studies over 15 years showing that people in these populations were genetically deficient in producing the PCSK9 protein—led to the finding that they had an 88% reduction in the risk of ever developing cardiovascular disease. That was miraculous.

What the pharmaceutical industry sought to do was, “How can we replicate this?”

Exactly.

Alex Cornell

How do we get that advantage into the hands of people? They came up with injectable biologic medicines at first that you could inject and that would find their way through your body to that PCSK9 protein, bind to it, and prevent that protein from binding to your LDL receptor.

That was the beginning of those medicines. What innovators then sought to do next was, “How do we make it easier for people to take those medicines and get the benefit?” The next big innovation in that space was moving from injectable biologics, or monoclonal antibodies, to a new modality called RNA interference.

These are another form of subcutaneously injected medicine that makes its way down into your liver. They have the attribute of being very long-duration molecules, making it so that we don't have to inject ourselves 26 times a year, but maybe only twice.

It's incredible when you think about seeking out a population that has a natural advantage, figuring out what it is, and then conferring it to others through a drug like this. The dramatic reduction in cardiovascular incidence in people—the genetic group had an 88% reduction, but the people who take this drug also see a dramatic reduction—is so interesting.

I always wonder: The body is such a complex system. There seem to be very few things in biology that are just one use or have one explanation. There's all sorts of stuff going on.

What are the trade-offs? I’m interested in both PCSK9 and GLP-1 since we’ve talked about both. It just seems like there’s always a trade-off. There really aren’t usually free lunches in markets, in nature, and in biology.

So, what’s the skeptic’s point of view? If I could somehow fly in the smartest, data-driven scientific skeptic of the use of these drugs, what would that person say?

Alex Cornell

PCSK9s are much more of a free lunch than GLP-1s. GLP-1s are easy. GLP-1s have real toxicity associated with them. Without a doubt, we see in the clinical studies significant rates of nausea, vomiting, and diarrhea. Those are the first symptoms that emerge, and they cause a lot of people to quit these medicines early.

If you look past that and look at people who have been on these medicines for longer and longer periods of time, you look at the labels of these medicines and the clinical studies, and there’s a risk of developing gallstones and pancreatitis. Of course, these are issues that would emerge just from having weight loss in general, which adds muscle decline to that list as well. These are all consequences of losing weight and losing weight quickly over a period of time.

But when you look at the other side of the equation—the benefit that you get, the fact that these are so protective across so many different axes—the data is pretty clear. Not only will they protect us from developing diabetes, obesity, and cardiovascular disease, but when you look at the implication of those diseases on expected human lifespan, we’re talking about the aggregate of those diseases costing us 5 to 10 years.

It’s very much well worth it for people to take the risk of developing these other liabilities that you can do something about by just stopping the medicine, for the benefit. I think there is a real trade-off. Without a doubt, it is not a free lunch for GLP-1s. But for PCSK9, it is pretty much a free lunch.

There was a ton of concern in the early days: What happens if your LDL goes down to zero?

Doesn’t LDL do good things, like—

Exactly. It’s there for some reason. It turns out that LDL is produced in lots of different places in our bodies. It turns out that you can basically pin that PCSK9 bad protein down to zero.

The best we can do in terms of reduction of our LDL—not even in humans, but in animal models—is something in the 80% to 90% zone. Because we have people walking around with mutations where they don’t produce any PCSK9, and they live incredibly long, healthy lives and don’t have the vicious fate of having a heart attack or stroke, I think we’ve got a combination of animal model evidence that suggests we really can’t get LDL to zero, combined with the fact that we’ve got genetically advantaged people walking around who aren’t even producing the protein to the same degree as others. This one is very much a free lunch in that—

Do you think everyone in the world will be on this particular drug at some point?

Alex Cornell

I would. That would be a dream for me. A big dream for me is that everybody, anywhere, who wants to have the maximum level of cardio protection could get access to this medicine and could stay on it.

I would argue that because it is more asymmetric, more in the degree of that free lunch, if you just project down the road longer term, this medicine should be far bigger in terms of the number of people that are on it and the revenues that are associated with it than GLP-1s.

6. Addressing Alzheimer's

That’s not what’s playing out right now. It’s not playing out right now really for 2 reasons. One, GLP-1s have this amazing attribute to them: You take them, and very quickly you start to have some side effects, so you know you’re on them, and you start to see the benefits.

When you compare the 2, it’s easier for medicines where there’s an acute, clear, easily measurable benefit for people to stay on them. Unfortunately, in the setting of cardiovascular disease, and particularly thinking about bad cholesterol, this is to me the most dangerous setup because you don’t feel anything if you have a high level of cholesterol.

You could think of it as a silent killer that’s just working in the background, slowly accumulating in our bodies. You can be doing everything right and be at your peak physical shape, and then all of a sudden, out of nowhere, you can have a heart attack or a stroke. If we don’t pay attention to the levels of this bad cholesterol in our body, they can sneak up on us and claim our lives.

To me, because the reward is so asymmetrically favorable versus the risk, because the earlier we can intervene with the accumulation of cholesterol in our body and keep that at bay, the greater the likelihood is that we’re going to get through the rest of our lives. Even if other things manifest, like diabetes or high inflammation, or our blood pressure goes up, we’re going to be right at the core of the problem and keep that as low as possible, meaning that we’ve got the lowest level of accumulation across our vasculature.

I think the number 3 and 4 killers, after we talked about metabolic disorders and cardiovascular disease, are neurodegenerative diseases and cancers. I’d love to spend a couple of minutes on each of those.

Neurodegenerative disease in particular—Alzheimer’s drugs seem to have been this wasteland. We really don’t understand what’s going on, and as a result, we haven’t made a lot of progress at either protecting against or treating something like dementia or Alzheimer’s.

What is going on in the world of science and in the business of pharmaceuticals to address this specific problem?

Alex Cornell

It’s been a wasteland for decades, and I think we finally cracked the beginning of the code, but not the full answer. What we’ve found today is that in patients who have confirmed levels of plaques that have developed over decades in their brains, we now have medicines that people can take that will start to break up those plaques and remove them.

Unfortunately—and this will be intuitive—if you get to the patient that late in the disease, a lot of damage to the brain has already happened. You can imagine that these plaques are building; they have to go somewhere, and they’re causing death and destruction of the tissue around them.

7. The Future of Cancer

Today, we’ve got some amazing medicines from both Biogen and Eli Lilly that, if you are late in the disease progression of Alzheimer’s, can start to slow the decline. We can slow that decline by about 30%. Intuitively, that gives us a lot more years at the baseline level of cognition that we have versus declining much more rapidly.

It turns out that if we can identify a patient who’s at risk for Alzheimer’s disease earlier and earlier and earlier—if we had a test available to do that—then it makes perfect sense that, if we can start giving people these medicines as early as possible, not only will we be there in the early stages before a lot of damage is done, but we can think about it as turning off the faucet.

As these new amyloid plaques are produced, you can be attacking them with a medicine that helps to accelerate their clearance. Oh my goodness, maybe that has a dramatic effect on long-term decline. Maybe it reduces those rates by 40%, 50%, or more over a longer period of time.

The earlier we can get them, the better those medicines are at interacting with those plaques, and the easier it is for people to stay on those medicines, the more we might be able to wake up in a world where we live without this disease.

We know that’s possible with GLP-1s for diabetes and obesity. If you take them early enough, you will not become diabetic; you will not become obese. We know that’s possible for cardiovascular disease. If you start taking a PCSK9 inhibitor earlier in your life—which, by the way, I think has a risk-reward profile that’s actually even more favorable than statins in terms of human health—we know that you won’t progress to cardiovascular disease. The same is true for Alzheimer’s.

So, up to this point, we can imagine a future world, as I know you do, where everyone can enjoy the benefits of protective, defensive measures in our health stack for these 3 specific killers. What about cancer? Cancer is the last one that, in some ways, feels the most visceral and the scariest.

Alex Cornell

If we are successful in mobilizing people around a health stack and can move from reactively treating a disease to helping people be as proactive about their health as possible, I think the unintended consequence of that is that, because people live longer, eventually something is going to get us. I think what we find is that the incidence of cancer—the disease that brings us down—could rise. So I think we would be remiss not to talk about where we are with cancer and what needs to be treated to really start beating it in a way that matters.

Cancer is hard both because we often identify it too late and because, when we do, cancer is like a sneaky devil. You might have an angle of attack to go and beat that cancer that presents itself early, and as soon as you’re making progress with a medicine against that angle of attack, all of a sudden the cancer has a survival instinct and redirects.

Now, the medicine that was working incredibly well, that had shrunk a tumor completely to zero, is having no effect because, while that medicine eliminated the cells that were most vulnerable to it, the cells that were left behind—even if it’s just a few—now have the advantage in growing rapidly, causing a new set of harm, and setting a patient on a horrific direction. So it’s hard because we tend to identify cancer too late, and then, when we do, it’s shifty.

I think there’s also the opportunity for optimism around it, and I think it gets to the topic you and I have spent some time talking about, which is testing. I would say the areas of testing today that I find most exciting are being proactive and identifying the risk early, and then, once a cancer emerges, what we do about it. So let’s talk about both of those modalities and then come back to the medicines that are associated with them.

In terms of identifying cancer early, there are companies like Exact Sciences and Guardant Health that have gone really hard at breakthrough innovations to help us screen for colorectal cancer. Of course, we have the gold standard that’s available, which is a colonoscopy, and I have to go get one next year. None of us are ever looking forward to that, and because it’s something people don’t look forward to, even though everybody should be getting them with regular periodicity, most people don’t. I think that’s really tragic because, by not getting your colonoscopy, you’re putting yourself at risk for colon cancer, which is an incredibly slow-growing cancer. If you just got the colonoscopy, I think we could very much live in a world today with a very low incidence of colorectal cancer.

Guardant Health and Exact Sciences went directly at this problem. Exact Sciences has a stool-based test with an incredible ability to predict people being at risk of cancer. The same thing is true for Guardant Health. Guardant Health took it to the next step, knowing that you can go after markers that would predict colorectal cancer but recognizing that the commercial model around getting people not just to receive the prescription for a stool-based test, but also to complete the test and get that sample back, was one that could never have the scale of a simple blood test.

Guardant learned from Exact Sciences’ advancement and then came up with a next-generation version that’s a simple blood test you can get done just about anywhere. It’s amazing to see that not only are both of those markets continuing to grow, but the blood test is inflecting. That, to me, is exciting because it means that people care, doctors care, and people are getting it done. That means we’re going to be safer and safer from these cancers.

I think it’s important for people to realize that not all tests are created equally. When I look at a new diagnostic in the space, I care deeply about 2 metrics. One is sensitivity, and the other is specificity.

One of them tells us, of all the people who could have cancer, what percentage of those samples actually come back with a direct and accurate diagnosis of cancer. If there are 100 cancers in a sample, what percentage of them actually get picked up as cancer? That’s the sensitivity. Specificity is, if there are 100 samples that don’t have cancer, what percentage of those give us a false positive, saying that you have cancer when you don’t? I think both of those are really important metrics.

At the same time, I think there’s a whole other industry around multi-cancer early detection that’s evolving right now and unfolding right before our eyes. These are companies moving from not just having single-cancer tests to having multi-cancer tests across large numbers of tumor types that can be really dangerous.

When you think about how I described the offensive and defensive sides of the health stack, the defensive medicines that we can take to keep us maximally protected don’t include anything to protect us directly from cancer. That’s because I tried to attack cancer from the screening perspective. I made that part of offense.

Over time, I think, at a minimum, people should be doing a colonoscopy. I think the next best-in-class version of that is a colonoscopy married with either a blood test or a stool-based test with some regular periodicity to it. Over the next 3 to 5 years, particularly with how AI and the evolution of these tests are really converging to help them move faster and faster and be better and better, I think we’re going to wake up within the next 5 years with really awesome multi-cancer early-detection tests.

When we have them, shame on us if we’re not getting them, and shame on us if we’re not acting on the learnings that come from them. This will be obvious, but the earlier we know that we have a cancer, the greater the range of options we have to do something about it. I think we’re finding that across lots of different cancers, there are opportunities to have amazing results.

Sadly, my brother-in-law’s father passed from multiple myeloma maybe almost a decade ago. If he had been diagnosed today with multiple myeloma, his outcome—his prognosis—would be dramatically different. Not only is our ability to test and identify that people are developing cancers getting better, and not only do we have other types of tests that can show us the mutational drivers of that cancer and help connect not just the cancer but the type of cancer to the best medicine we have today to treat it, but the medicines are getting better and better.

8. Drug Discovery

Cancer medicines began as many medicines do, with pills and injectable biologics. Today, we have an entirely new class of medicines: CAR T cells. These are either cells that we take out of a patient’s body and arm with the ability to attack the cancer directly, or, as Capstan just came up with in the next-generation version, cells that can be injected on an IV basis and attack the cancer cells directly without even having to take cells out of a patient’s body. That can happen within the patient’s own body.

What we’re seeing from these medicines is dramatic efficacy. We’re seeing that they have the potential to reduce tumors by 100%, do that in 70% plus of patients, and keep them at bay for really long periods of time. While we haven’t yet cured cancer, to me, the slope of the line is really exciting, both from the testing angle—the earlier we can identify these cancers—and from the increasing range of modalities and options we have to go after and destroy them.

What about imaging? There are interesting companies doing skin imaging, like Neko, and deep-body imaging, like Prenuvo. It’s quite expensive, but as I think about the health stack as something that we could do that’s preventative, how do you feel about those technologies, which are relatively new but do try to take a picture—if a picture is worth a thousand words—inside your body and identify a tumor earlier? Do you think that’s worth it?

Alex Cornell

To me, more data is worth it so long as you can put it in the right context. When we get the result of a colorectal cancer screening test, we know the context for that, and we actually know whether we have something that’s useful or not.

I think the pictures we can get from groups like Prenuvo and others are powerful because we can see progression over time and use that data. Particularly as AI is increasingly going to become our medical home, arming our AI system with that information will be super helpful.

The thing I worry about, though, is that as you measure more and more different dimensions, with each of them having a material false-positive rate, the odds that you come out of that experience with a false positive that can be disruptive in life becomes material. It’s not to discourage anybody from doing these; it’s just to make sure that any data we’re collecting is put into the right context so that we can have a framework for how we deal with whatever information comes from taking that test.

For me personally, I’m not yet pursuing those. I’m very much focused on areas where, if we’re going to do a test, it’s going to have a high probability of capturing what I’m testing for and a low probability of giving me a false reading.

And I think the more information that we can accumulate with really high fidelity, the better we'll be at being proactive about our health.

Everything we talked about today was discovered and developed by incredibly talented people—scientists, people in the medical field, and business builders who turn these things into great products and great companies. Maybe just describe, so as not to take it for granted, what that process is in the first place.

But biology is complicated. It is unfreaking believable that we can do the things you've been describing so far in this conversation, and that we're on a trajectory to do even more. The granularity with which we can make edits, for lack of a better term, into what's going on in biology is probably just going to continue to accelerate. So I want to understand that process itself, and then we can talk about how AI figures into that discovery process.

Alex Cornell

First of all, what are the 2 key ingredients for discovery to happen?

Yep.

Alex Cornell

You need scientific instinct married with tremendous amounts of capital. And I think you need both of those to converge in order for there to be a breakthrough that allows us to live healthier and longer lives.

So let's break those into their pieces, with the science of medicine and the business of medicine, because I think they're both independently interesting. Oftentimes, what ends up happening to discover a medicine is a scientist, for whatever reason in their journey, gets inspired to spend their lives trying to crack the code in a certain disease.

And what tends to happen is, as you've identified a problem that you want to solve, just like in any consumer tech product, what's the problem we're trying to solve? You then have to go through a tremendous amount of research to understand every single thing you can about that problem, and most importantly, what could be driving it.

And so what's developed over time is a method, probably one of the most important methods in the history of humanity, called the scientific method, which is the systematic way by which a scientist moves from focusing on a problem they want to solve to actually solving it. And there are a couple of discrete steps in that scientific method, and a tremendous amount of iteration, at least to cracking that code.

And so, once you've identified the problem that you want to solve, the first step to solving that is to come up with a hypothesis for what could be driving that disease. And the way scientists tend to do that is everything from the PCSK9 example, where scientists are observing nature: Where are there populations of people that have an advantage? Okay, let's go figure that out. That's cool. Let's go understand it.

All the way to combing through thousands and thousands of pages of the literature to understand what people have tried to crack—a code that still exists today that you want to go crack. And that's a deep literature review. Fortunately, there are tons of papers that exist on successes or tiny steps to successes that are available for anybody. I think the unfortunate part of the literature is that what's often missing is all the failures, which would be even more informative than successes.

Generally speaking, when a scientist wants to go solve that problem, they're either going to observe a population, they're going to start reading a ton of research, or they're going to put both of those insights together and use that foundation to form their first hypothesis for what could be the solution to the problem.

Okay, so from having a hypothesis, the amazing scientist can then go figure out: What experiments do I need to run to test that hypothesis? And even more, what's my prediction for what should happen in those experiments? Those are really important steps, because the design of the experiment and the quality of the data that comes out from that experiment will either confirm your hypothesis and you move forward, or it will reject your hypothesis and then you go back through and loop to your next hypothesis and your next set of experiments, and you continue to loop and loop and loop.

And so what the scientific method generally looks like is: hypothesis, experimental design, execution of that experimental design, review of the data that comes from that experiment, reading out and testing that data result versus your original hypothesis, either confirming the hypothesis or re-looping and re-looping and re-looping and re-looping.

And so there's this iterative process that tends to begin its journey from the literature, very quickly move into what we call in vitro experiments, or experiments that are done in petri dishes. And as we start to develop evidence in support of a hypothesis in cell-based experiments, it tends to move on to small animals and then larger animals.

And then it gets to the point where the totality of the data and the evidence that you've collected, from a hypothesis perspective to cell-based experiments to the animal-based experiments, you put that all together in a beautiful package that you present to regulators, and you say, “I think I've cracked the code. I think I can move us forward against disease A, B, or C. And here's the hypothesis that we had. Here's how we tested it. Here's all of the data we've generated that helps me, the scientific team, to believe that we might have cracked this code, and now we would like your approval to go start and agree on what studies should look like to test how toxic or how dangerous this breakthrough could be for somebody.

9. AI and Scientific Super Intelligence

“And if we can show that there's good margin between really high doses and where that toxicity starts to come in, and the doses that we've proven from our experiments are likely to help somebody live a longer, better, healthier life, we want your permission to then go and actually test that in a person for the first time.”

This is incredible. And in that process that I just described, you can imagine most of them fail. But for the ones that do succeed and get the chance to then go into toxicity studies and then ultimately into humans, those are the ones that get really exciting. They take years and years of iterating and looping to go from that beginning idea through the literature, ultimately to the animal study that makes you believe you've actually cracked that code.

And then, of course, from there, this is so much more of a marathon than a sprint, because you've spent years trying to crack the code, and now that you have, guess what? Now you've got another 5 to 7 years' worth of clinical studies you have to do to prove that, in people, the idea you had for a medicine actually has the effect that it's intended to, and that, per our discussion earlier, that benefit-to-risk equation is favorable to the point that the regulator should approve it and let it come to the market.

I have 2 questions here.

Yeah.

The process itself is beautiful and has driven so much discovery and progress, not just in medicine, but in scientific-method-driven progress everywhere. But I'm curious about 2 dimensions of shortening that feedback loop or increasing the velocity of new discoveries and progress.

One is AI, and the second is what I'll call citizen pharmacology, which is people—this is becoming really prevalent in what I'll call the peptide community. People love talking about peptides these days. Gelatin is a peptide. Collagen is a peptide. There are well-known things that are peptides, but there's this whole class of things that we can talk about.

But it seems like if you take to Reddit, for example, you will find groups of people organizing to test new things on themselves outside of the normal RCT, FDA-approved process. And if you shorten it, you probably increase the danger, but you decrease the time to learning or something. So you've got both of these things as interesting aspects to me of what will drive forward progress in drug discovery.

I want to riff on each, maybe starting with AI. What is real already? What do you think will become real by virtue of the increasing skill level or reasoning level of the models?

Alex Cornell

What you're basically describing on the AI side is our quest to try to get to a level of scientific superintelligence. You can imagine that, from an AI perspective, if scientists are armed with an agentic infrastructure that has a scientific intelligence that's at an Einstein level or a multiple of Einstein's level, oh my goodness, the force multiplication that can occur between a superstar scientist armed with that agentic resource means that they will do science faster and with higher probability, for lower cost, and have greater impact.

So I think that's an important conceptual framing. And you can imagine that any human scientist on their own, tinkering in the way that I just described—the scientific method and that wheel of science spinning and spinning and spinning—will always be constrained by what we can retain in our human minds and by our ability to use our human hands to go run those experiments.

And so there are super-talented, incredibly smart people that can retain volumes and volumes of scientific papers. They can't retain all of them. AI can. If humans are running experiments, not AI-driven robotics, there's just a certain throughput that is going to be limited by human hands that would be unlimited if you had an agentic, robotically driven system.

And so at the simplest level, I think AI coming into the discovery of medicines is one of the biggest unlocks that we will see in the history of medicine, because it means that we're no longer constrained by our minds, we're no longer constrained by our hands.

We can generate not just a few hypotheses for what the answer can be from the total sample set of knowledge that exists. We can identify all N number of hypotheses that could exist and should exist, and then figure out what is the greatest and best next experiment to run, and run those in real time, 24 hours a day, 7 days a week.

The sheer ability to be more comprehensive and complete in our hypothesis set, and then the sheer ability to run experimentation at a scale that's unprecedented, practically means we are going to be able to speed breakthroughs from timelines that would typically take 3 to 5 years to timelines that can take less than a couple of years. I think the other important element when we think about AI and its impact on drug development is not just the potential of what could be from that conceptual frame, but where are we today?

I think it's really exciting. Today, I would say we're in the early innings of being able to discover novel targets, and I would say that we have not yet, in a systematic way, been able to discover a target that didn't exist yet. But what we can do is, for targets that we know exist but that we have really struggled to develop medicines against, we're starting to see that code be broken by AI. AI is a big force multiplier in enabling that to happen.

What we have today are companies that can go from what would historically have been running these massive screens that are incredibly time-consuming to doing that screening work in silico, and can go from model to molecule in a month's time, when it would have taken a couple of years.

That's a lot. That's already true today.

Alex Cornell

Already true today. Yep. There are companies like Lila Sciences and Enabla. You can basically ask the agentic system to develop a molecule against a certain target, and it can crack that code and give us something that we can work with and start running in experiments in a month's time.

Is it your impression that this is just going to happen? Is there no major risk left that AI will not have a major impact on the entire target and therapeutic discovery process? Are we now on a curve that just feels inevitable to you?

Alex Cornell

To me, we're on that curve.

When did that flip?

Alex Cornell

Very recently. I think for most of my career, there's been some version of machine learning and the hopes of AI really driving drug discovery and the development of novel medicines against those discoveries. I always worried that, in order for that paradigm to be true, it required data that didn't actually exist in any easy place.

If all you do is train AI models based on the research that's available, you unfortunately have a paradigm of garbage in, garbage out. One of the things that people don't appreciate when I start talking to them about what data exists is that, unfortunately, a lot of the recorded literature is actually incorrect. There have been tons of studies that show if you go try to replicate the experiments that are in the literature, you don't even get the same results.

Definitionally, if that is true and these AI companies don't have a source of creating novel data, what are you going to do? How are you going to train? We've seen just how powerful LLMs have been and how impactful they are across so many different areas of life because they've been trained on trillions and trillions of novel tokens.

And so data ends up being a big part of what drives advanced levels of intelligence and drives an intelligence revolution. The same has to be true in science. The AI companies that I believe are going to be most set up for success are the companies that have incredible AI talent, have access to significant amounts of capital, and can combine both of them in a novel way by which they can generate science tokens that don't exist in the public domain.

10. Citizen Pharmacology and the Peptide Movement

In fact, the generation of those tokens becomes a big driver of their moat, and not only the driver of the moat but actually what enables them to get to an increasing level of scientific intelligence that starts to separate from what can be achieved with LLMs without the benefit of those tokens. We're starting to see that. We've got one company that we're really close to today that's actually starting to show the bending of that curve and helping us to see that the idea of getting to scientific superintelligence is likely to follow a pretty deterministic set of scaling laws.

I think it was OpenAI that came out with this announcement, maybe working with Ginkgo or somebody, where they've created a closed-loop, automated lab and discovery process, and not just models but physical-world testing as well. If you close your eyes and think 5, 7, 10 years from now, what do you think the discovery process will look like at that point? I know it's hard to predict the future, but what's your best guess, knowing what you know?

Alex Cornell

I expect it to be completely automated. I was up at Lila Sciences the other day, and you go into their labs and what you see is all of these robotic arms. You see Petri dishes moving around in an automated fashion, moving from one spot to the next spot.

To me, I think what that means is the scale of data that's going to be required to be able to train these models—the trillions of tokens that are required—has got to move beyond the constraints of human hands, because it would just cost so much money to do it in a human-capital-driven manner. It has to be done robotically, and for that to be done, it has to have an agentic engine behind it and needs to produce data at a scale that's kind of unprecedented.

What I think the future of discovery looks like is agentic systems that can drive robots to do most of the experimentation that we're doing today with human hands.

That's the top of the funnel, right?

Yeah, exactly. Superstar, brilliant, amazing scientists who go down their life journey to become scientists that want to fight against disease and want to do work that matters are no longer going to spend 2/3 of their careers at the side of a bench, pipetting all day long. They're going to have all that time back to point their energy, enthusiasm, and optimism toward trying to figure out, “How do I use the systems and machines that I have and point them in the right direction, at the codes that we should be cracking?”

That's really enabled when you have the combination of brilliant human scientists force-multiplied by the agentic power of these systems that are being built. The more those agentic systems can be fully automated, where all of that lab experimentation is happening in real time and without the need for human interaction, I think the quicker and quicker it can scale, and I think the quicker and quicker we can achieve that level of scientific superintelligence.

What do you make of this whole peptides-plus-citizen-pharmacology side of things? I think they just came out and said there's going to be 14 or something peptides that are allowed to be compounded, and it seems to be a kind of deregulation happening in this space. People say “peptides,” I think, not really knowing what that even means, so maybe define it. I'm just curious what you think of this.

It really plays to your earlier point about these younger generations especially seeming to have a new attitude toward all of this stuff, which is, “I want to own this.” Part of owning it is a willingness to take risks that are above and beyond what I'm allowed to take. I'm just curious for your take on this subculture. It's fascinating to me.

You read about BPC-157 or these different kinds of—I think that's the number—all these interesting, different things that are being tried. Do you have a take on the impact that this will have?

11. Background and Career Journey

Alex Cornell

I think it's hard to know. The reality of it is, whether you look to the commercial success of GLP-1s or the massive movement around peptides, it's honestly not even limited to just peptides. You can go on Reddit and see people experimenting across all sorts of different dimensions.

I think what's happened is we live in a world where people want to go and figure things out that help other people, and now we've got platforms that allow people to share that. So we see the creation of groups that can exist today that couldn't exist in the past, before we had the technology we have today, and the communities that can get formed.

Whether you're looking at it from the perspective of people coming together under shared missions, that's happened throughout the history of humanity. This is a shared mission where people are saying, “I want to take my future health into my own hands, and I'm not willing to wait for scientists to take on this problem independently and for it to go down the traditional pathways. I don't have the time. I need to know the answers now, because I think for myself this is going to really matter.”

People have a hypothesis and they want to test it, and so they're fighting really hard to get those hypotheses tested. At the same time that you see what I would call that grassroots peptide movement, you also have a recognition by the FDA that we've got to move a lot faster.

So long as we have all these frictions in the system of going from a hypothesis for a medicine to the testing of a medicine in people and then ultimately to an approval, disease is going to keep winning. I think we're seeing, under Marty Makary, real leadership in wanting to break down those barriers and frictions that make the drug discovery and drug development process incredibly time-consuming and complex.

Some of the manifestations of the real-world impact of that span everything from Marty bringing in an AI system to help them comb through the thousands of pages of filings that sponsors behind medicines have to submit in record time, versus the armies of people that would have to comb through that and the days and days of time that are wasted. That goes all the way through to challenging every aspect of the process: In what settings do we not need nearly as much evidence in animals and can rely on cell-based experiments? In what settings do we no longer need multiple redundant studies that show us the same thing? We can cut through it with 1 study. Anywhere you look, we are seeing a movement to be able to do things more efficiently and faster, and have a greater impact.

I've had this experience with you countless times where I'll introduce you to somebody, we'll have a conversation like this, and somewhere between 30 minutes in and 230 minutes in, the person has a thought, which they rarely say, which is, “Who the hell is this guy?” We've done the same thing yet again, which is gone hours into the conversation without laying any sort of groundwork for your background. Can you just tell us your

Sure.

personal story a little bit?

Alex Cornell

I've just been super lucky. It's funny, now that you ask the question. I think, reflecting back on my childhood, I guess my parents were training me to be a biotech builder and investor since the time I was 5, but I had the greatest childhood ever.

I grew up in a typical American home. My dad was this relentless entrepreneur. He was the type of person who worked harder than anybody I knew, and he was so all-in on any business endeavor he was pursuing. Our entire family was all-in on it. Mom was doing the billing. My brother and I were in the garage refinishing furniture. I kind of grew up around business by being around my dad, and he was such an inspirational force in my life.

Despite the fact that he was such a relentless businessman, he was never really successful at any of those businesses. I think if he were sitting here today—and sadly, he passed from Parkinson's over a decade ago—one of the things he told me in those last few days was that he felt like he never stuck with anything long enough to see it through the tougher moments, and we'd quickly move on to the next thing and the next thing. I learned that lesson from watching him in real life and being in business with him.

You pair my dad with my mom, who's been an absolute force in my life. My mom is this incredible optimist, and from my earliest memories of my mom, I can remember her drilling into my mind, “We always commit and we never quit.” She pretty much convinced me that I could do anything I wanted if I put my mind to it.

I feel like from my dad, I got to experience and see what it means to take risks, and that you can fail and life goes on. From my mom, I developed this sense of resilience, and I think both of those attributes are probably very much connected to why, when I found medicine, I fell in love with it, particularly the discovery and development of it.

From that early childhood, I was the first in my family who got a chance to go to college. I graduated from MIT and had an amazing experience there. For me, being at MIT, learning more and more about business, economics, and science, and connecting it back to my early days of working alongside my dad and getting a chance, at the time not realizing it, to put money into some of the deals that my dad was doing was really meaningful.

I could put $2 into a rocking chair that we bought, and if we sold it for $200, I thought that was amazing. If we didn't sell it, I was pissed. I didn't realize I was learning in those early days about risk and reward from my dad. Then, when you get to a place like MIT and start to see the black-and-white version of the equations associated with that, it was a major step forward for me.

That inspired me to want to go on to New York City and Wall Street. I thought to myself, “No better place to really learn about business and how capital connects to business and what it takes than to come to the epicenter of that here in New York City.” So I ended up at Merrill Lynch and had some amazing mentors who were really inspiring to me.

I had 2 major stops at Merrill, 1 on the capital-markets side, and then, after doing that for a while, I wanted to go see how these crazy derivative securities traded. I had a chance to move to the Merrill Lynch derivatives desk.

What was so fun for me about reflecting back on that time is that I actually never picked biotech. When I got moved over to the derivatives desk, I was just put into biotech. I was assigned to the biotech subgroup of the derivatives desk and knew nothing about it, but I fell in love with it so quickly because the risk-reward in that setting was about life and death.

When I was looking at what was going on and the companies that I needed to understand to be able to price risk, it was wild to me. I had no idea about this entire field of the development of medicine. I had no real appreciation for the sheer amount of capital that's required to move it forward.

Here I am, through total serendipity, finding myself at the epicenter of needing to understand these companies deeply enough to price risk and getting a chance to be in front of all of the buy-side investors who were building and backing these companies. I became inspired by the work that they were all doing.

I was so inspired by it that, in my seat, I got to be out with these people a lot because they were curious about what activity was going on on the trading desk and what it meant for them and their investments. I was always interested in learning more about how they built and backed these companies.

What I quickly realized, in talking to all these people from all these different investment firms, was that their strategies were actually very similar. I said, “Huh.” Knowing what I knew about derivative securities from my days at MIT and my time at Merrill Lynch, and recognizing that most people in the life-science investment world were just using equity securities, it struck me that there was a better way to either build these portfolios or select securities.

There might be ways in which we could either maintain the type of return that they needed for their investors but at lower risk, or maintain the risk and produce a higher rate of return. So I went off and spent my nights and weekends writing this beautiful deck that I thought had really cracked the code on what portfolios needed to look like in the life-sciences sector that would allow a scale of capital to get behind these amazing medicines that had never before been achieved.

When it was done, I could not wait to send it out. I remember telling my roommate, Tom, “Tom, I'm ready to send this out. I'm going to send it to everybody, and you just watch. My phone is going to be ringing off the hook. Everybody in the world is going to want to do this and put this strategy to work, and my days at Merrill Lynch are numbered. I'm going to be out of here soon enough.”

I sent it out. Crickets. I didn't get 1 single response, and I couldn't believe it. I was like, “How does nobody want to do this? How does nobody want to run a portfolio that can produce the same amount of reward with lower risk, or produce more reward for the same risk?” It didn't make any sense to me.

It turns out that months went by before my phone finally rang, but then 1 day it did. It was Jeff Kaplan, who is today a dear friend and mentor of mine. He was the head of trading at that time, in 2005, at a tiny little firm named Deerfield Management, in its early days, when Jim Flynn had just taken over as general partner.

Jim was a really unique leader of Deerfield, because one of the things that I learned from spending time with him was that he obsessed over every way in which our investment firm could have every type of advantage in producing our returns, so that we could attract more and more capital and have more and more impact on the future of human health. How do we create advantages that would allow Deerfield to become the epicenter of capital to move innovation?

I got lucky. I found the 1 person in the world who cared about the things that I had to say. After going and presenting my ideas to what was, at that point, a tiny team of about 12 people, I got hired to join Deerfield.

I spent the next 15 years of my career helping to build Deerfield into that dream state of being the go-to source of capital for the industry. I didn't realize it at the time, but I guess I was 24 when I joined, and I think the next-youngest person at the firm was probably 40.

These were all people who were super-seasoned and had incredible experience. I think I was a bit of a novelty in the room because I would ask almost 1,000 questions every single day, and these amazing people would spend the time to teach me. The apprenticeship that I was able to get from my time at Deerfield was like nothing I could have ever imagined.

And I was all in. I was fully in love with investing in, building, and backing anything—whether that was a medical device, a diagnostic, a medicine, anything that could move human health forward. That spanned everything from helping these companies figure out how to finance their innovation all the way through to spending time with our team on how to design and help a company design a clinical study in a way that would give them an advantage in showing something that’s really special. And that stayed true for about the first decade of my time at Deerfield.

Then something really tragic happened. At Deerfield, we were constantly building capabilities and constantly wanting new sources of data. One of the sources of data that we had acquired and built out was taking us deeper and deeper into understanding a patient’s journey, from the moment when they are prescribed the medicine to when they actually get the insurance approval to get that medicine, and then how long they stay on the medicine. What I was quickly learning about a decade into my obsession with all the amazing work that was going on around me is that, yes, medicine only works if people take it, but they weren’t.

That was a really dark period for me in my own journey, because as I was reflecting on all the time and effort and capital that I was a part of putting behind innovation, it became pretty quickly evident to me that you have to start asking the question: For what purpose? If people need to be on a medicine for the rest of their lives, and they’re taking it for a year on average and then quitting, are we just optimizing for maximum expected returns, but no impact on public health?

12. Braidwell's Investment Approach

I had been married at the time. I got married in 2012, so I’d been married for some number of years. I started thinking about what my life means, and how I am as a partner to my wife if I’m spending my time just focused on making money and not actually doing something that can move the world forward. We had had our first baby at that point, and I was reflecting on just how impactful my parents were in terms of teaching me and what they armed me with as I went forward. I thought, well, what lessons would I be teaching my daughters?

I got to the point where the combination of thinking across all of those dimensions made me question: Am I just doing the wrong thing? Do I need to go in a different direction? The answer was no. What I needed to do was take the innate entrepreneurial energy that comes from my upbringing and my childhood, along with the skill set that I was able to develop from this amazing apprenticeship that I had at Deerfield, and point those talents not just at the discovery side of invention, but at the impact that’s required to actually see these medicines have the impact that they’re intended to have.

A lot of that was my inspiration for leaving Deerfield and wanting to go build Bridgewell. I’m so fortunate because one of our dear friends, Brian Kreiter, who is an incredible person—an amazing husband and father, and an incredibly talented businessperson—was also just as inspired as I was about where we found ourselves in the world and the type of impact that could happen but wasn’t yet happening. He was the chief operating officer for Bridgewater. I was co-running Deerfield, and we decided to spend some really deep time trying to put our lessons learned and our insights together and try to design, from a first-principles perspective, what the operating system for human health would look like. And what could we do to be the driving force behind making that happen?

13. The Kindest Thing

How could we be the force that is not just okay with a once-in-a-decade, $100 billion GLP-1 revolution, but become the force behind making sure that this once-in-a-lifetime, trillion-dollar cost-savings revolution happens? We can be the force behind medicines having their moment, where they could prevent diseases that are already preventable today. That really inspired us, and after seeing it, we couldn’t unsee it. We spent many more months thinking about how we would do it and how we would build it, and that became Bridgewell, where I’m spending my time today. We’re having the most fun that we’ve ever had.

And if you could sum up the investment approach in its simplest form, how would you do it?

I think I’d just bring you into what we call our morning meeting. At Bridgewell, we get the team together every morning from 9:15 until we’re done. I want you to imagine that you’re in this room—you’ve seen it—so, in this room, it’s a big room, and we’ve got an amazingly talented team of scientists, biostatisticians, commercial experts, AI experts, investors, operating people, traders, and structured finance people. We have a pretty significant team, and everybody on the team has some special superpower that they contribute to helping us figure out what companies have amazing technologies that we should be getting behind, backing, and helping to go as fast as possible to have human impact.

That cuts at some of those big unlocks that would be the difference between having something and having it make an impact. As we look across the ecosystem of everything that is moving forward today, where do we also see the major gaps where medicines should exist but don’t yet? To me, being in that room is the most fun part of the day, and I think it very much epitomizes what our philosophy is: In order to be a great backer of innovation, we essentially need to be able to answer 3 questions.

Are the innovations we’re getting behind going to work or fail? Are they ultimately going to be relevant from a market-potential perspective or not? And is there a way by which we could back this company, invest in this company, and enable this company to move forward faster with capital that produces a return that’s attractive enough for the investors who are trusting us with their capital?

We want to bring together the most talented minds in each of those different areas of domain expertise to give us an advantage that we can deploy in a replicable manner, day after day after day, to both back the companies that should be moving forward faster and make the companies that don’t exist but should exist.

It’s an incredible room to be in. It makes me wonder: If everyone could design their own room to be in from 9:15 to whatever every day, it’d be a fun exercise. Unfortunately, we’re out of time. I could literally—I have pages of notes. You and I do this every time we talk. We set aside an hour; we should have set aside a day.

I’ll go to my traditional closing question for this session, and I’m sure we’ll do this many times together over the years to come. What is the kindest thing that anyone’s ever done for you?

That’s my wife. I’m pretty darn hard at it every day. Every minute of the day, I can be hard at it, and that drives me to different levels of stress. I can get so myopically deep into trying to figure something out that I lose track of everything else around me. My wife, Cass, has this amazing ability to just know when I’m at that point, just on the precipice of a breaking point, and she can find some way to distract me, make me laugh, and get me back to neutral.

I think that’s a big force and an advantage for me, because I don’t have to worry about going so hard when I’ve got a partner who’s right there by my side and can help make sure that I can not just be going after things I really care about doing, but can have some fun along the way.

Knowing Cass, I know that’s true. Alex, thanks so much for your time.

Thank you. I had a great time.