My guest today, Carolyn Bertozzi, is an absolute superstar chemist. She created a new field of chemistry called bio-orthogonal chemistry, and she’s also had a transformational impact in the area of glyco-biology. She’s been elected to the National Academy of Sciences and won all sorts of awards, including a MacArthur Genius grant. And her ideas have been the basis for launching almost a dozen startups.
BERTOZZI: Part of it is just the challenge — can we actually make a medicine that is like a lawn mower? Can we actually make a tuberculosis diagnostic test from these fluorescent sugars?
Welcome to People I (Mostly) Admire, with Steve Levitt.
Of all the guests I’ve had on this show, I would say Carolyn is the one whose work I understand the least going into the conversation. I tried reading a few of her academic papers, but I couldn’t make any sense of them. I’m really looking forward to the challenge of trying to keep up with her and learn something new. And if that fails, well, I guess we’ll be reduced to talking about our favorite metal bands because believe it or not, in addition to her academic exploits, in college, Caroline played in a band with legendary Rage Against the Machine guitarist Tom Morello.
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LEVITT: Carolyn, so let me be totally straight with you. I know virtually nothing about chemistry and what tiny bits I’m familiar with would be examples of chemistry from the 1800s. Sir Humphry Davy using electrodes to identify new elements and Mendeley and the periodic table; discovery of DNA and the double helix, via of the work of Rosalind Franklin and Watson and Crick, but I honestly have no idea what a 21st century chemist does.
BERTOZZI: First of all, what you just said about your knowledge of chemistry is actually quite far ahead of most nonchemists.
LEVITT: Well, I do study trivia. So I know trivial things about chemistry. I just don’t know real things about chemistry.
BERTOZZI: When you learn chemistry in high school, you learn exactly what you just said, which is classic stuff from the 1800s. And to be honest, I hated chemistry in high school because it didn’t really present itself as relevant to my life. But modern chemists are doing everything that matters, from making sure the water is clean and the air is clean, to making the medicines that save lives. Chemistry is everywhere. And that’s why chemistry is often referred to as the central science.
LEVITT: In economics we have a taxonomy. There’s micro economics and there’s macro economics. And those are two broad classifications. Do similar classifications exist in chemistry?
BERTOZZI: There are many sub-disciplines of chemistry. Organic chemistry: So that’s what I study. That’s the chemistry of the molecules of life. There’s inorganic chemistry and that’s the chemistry of metals and other elements. There’s physical chemistry, and those people are skirting on the edge of physics. There’s materials chemistry, there’s agricultural or food chemistry, atmospheric chemistry. If you put me in the room with any type of chemist, outside of my own limited area of organic chemistry, it would be really hard for me to follow a description of their work. That’s how different it is. But you could put me in a room with any biologist and I probably understand what they’re doing, at least at a superficial level.
LEVITT: Yeah, I was really surprised as I began to read about your work, how blurry the line is between biology and chemistry. Many of the things I would have thought were biology are being done by chemists.
BERTOZZI: Yes, and it’s getting more and more blurry as time goes on. Fifty years ago, when people studied biology, they really couldn’t understand it below the level of the cell because they just didn’t have the tools. But as time went on, biologists became ever more able to get right down to the structures of the molecules that are in that cell, like the structure of D.N.A. And the more that you dig into a smaller scale, the more it goes into the realm of chemistry, because now you’re talking about molecules and how the molecules work together.
LEVITT: I have to say reading about your research, I was shocked at how little we knew. Until reading your work, I never had any idea that part of the cell was made up of a bunch of sugars that are dangling off the outside of it. You call them glycans, and it seems like our understanding of their existence and their purpose is really new. And in large part, thanks to your research. Is that right?
BERTOZZI: I became cognizant of that field — we call it glycobiology — when I was a grad student and already there had been some very important discoveries about this coding of complex sugars all over the surface of a cell. But there was a whole lot that we didn’t know and still don’t know. When I first learned that our cells have basically a sugar coating, the analogy that was put forth was that of like a peanut M & M. And a cell is often described with that level of simplicity. There’s a sugar coating, then there’s some fats and lipids, that’s the chocolate part. And then there’s all the proteins and stuff and that’s the nut. That sugar coating analogy reflected what a lot of people thought in biology, at least in the middle part of the previous century, which is that the sugar coating was a protective shell, which paints a picture of it not being very interesting.
LEVITT: So what made you think of all the universal possibilities within or outside of chemistry that the sugar is on the outside of a cell would be the answer to anything? I mean, people just didn’t think they were important.
BERTOZZI: So by the time the 1980s came along and when I started my Ph.D. research, the chemistry techniques had advanced to the point where people could actually figure out that different types of cells have different types of sugar structures. And also it was known that when cells go bad, when you get a cancer in your body, there’s dramatic changes in the sugars on those cancer cells compared to the healthy cells around them. So that had been described, but nobody really understood why that happens.
LEVITT: You don’t know whether it’s causal, whether the cancerous nature of the cell is causing the sugar, or the sugar is causing the cancerous nature of the cell, which if it were, then suddenly the sugar becomes really important.
BERTOZZI: That’s right. And I was fascinated by that in graduate school I started looking at the structures of these molecules. They’re beautiful and complicated and spectacular. They’re just gorgeous. And I had a mental picture in my head of the surface of your cell being coated with a kelp forest. These complex chains of sugars, swaying back and forth on the surface of a cell. But I like now to think of it as a two-dimensional barcode — every cell now is coded on its surface with a QR code. There’s information in that QR code. And it’s the pattern of the sugars. And other cells of your body have the reader to scan the code, to understand what’s going on with the cell.
LEVITT: That’s super powerful. I went to Google and I typed in “structure human cell” and a bunch of diagrams, visualizations of human cells with mitochondria and vacuoles come up — not a single one of the first 20 included glycans. Isn’t that interesting? ‘Cause you have faith that these pictures of cells are representing what’s going on. And yet what are those pictures doing if they’re not actually even telling you what’s in the cell, which I always assumed that they were.
BERTOZZI: Those pictures haven’t changed in the textbooks since I was in college. It’s the same picture. So all the advances in glyco science, very few of them have actually made their way into the common curriculum for a student or the textbook. It’s frustrating. I could really use the help of someone who’s a really good graphic artist who does computer graphics and make me some really nice slides with metaphors that today’s 20-something-year-old would understand.
LEVITT: It sounds like glycobiology needs public relations to advance its position. ‘Cause I expect if I asked you, you would tell me that the glycans may just be central to addressing some of the most important issues in human health, and yet nobody’s even heard of them.
BERTOZZI: If only a famous economist would put a glyco-scientist on a podcast that could help a lot.
LEVITT: Now we just got to find a famous economist who could get you on their podcast and then we’ll be all set.
LEVITT: So let’s get into some of the applications of your research and the obvious place to start is with cancer. You want to tell us about what you’ve been doing on cancer?
BERTOZZI: It’s been known, in the field of cancer biology, that those sugar structures change when a cell becomes part of a tumor. The one that is really striking because it’s so common among cancers from totally different tissue types. So breast cancers, colon cancers, skin cancers, leukemias, all of these cancer types have been characterized as having a sudden explosion and high population density of a particular type of sugar. And the technical word for that sugar is sialic acid. One shouldn’t confuse it with like other acids. The acid term has a broader meaning than what the average lay person might think. But sialic acid is just a building block. It’s one of the simple sugars that get linked together into chains to make these complex glycans. And so your normal, healthy cells have what I like to think of as a well-manicured garden of those sialic acids. But then these cancers, there’s a sudden explosion of sialic acids and there’s way more than the healthy cells. And it’s almost like dandelions are suddenly growing in your backyard, they’re all over the place. And people have reported this observation over and over, but no one really had a good explanation as to why that happens. We’ve been thinking about this in my lab for more than a decade now and other groups have as well. And there was a convergence of thought around maybe 2010, because there was a big advance in the field of cancer immunology that led to the development of some new cancer drugs that are called immune therapies.
LEVITT: So how do those immune therapies work?
BERTOZZI: So the white blood cells are your immune cells and there’s different types of immune cells. One type is called the T-cell. And T-cells, one of their jobs is to identify cells that have become cancerous and kill them. And so most of the time, this works out quite nicely for us because our immune system is killing off cancer cells before we actually get a disease. But once in a while, a cancer cell figures out how to trick the T-cell and put it to sleep. And if a cancer figures that out, your immune system becomes helpless, and the cancer grows and grows and spreads and you have a disease. And so what these immune therapies do is they basically interfere with the mechanism that the cancer cell is using to put the T-cell to sleep. And that allows the T-cell to wake up and do its job. But it turns out that these immune therapies, when they work, it’s amazing. They cure people, but they only work for a minority of patients.
LEVITT: And do we understand why it works for one person and not the others?
BERTOZZI: So that is one of the biggest questions in the field: Why doesn’t everybody respond to these drugs? And for the people who don’t respond to the drugs, is there some other pathway that’s important for this, what we call immunosuppression, that we could use to wake up the immune system. So it turns out those sialic acids are a different mechanism that puts the immune cells to sleep.
LEVITT: That’s not what the immune therapies are doing now. They’re not overcoming the sialic acid. They’re doing some other pathway.
BERTOZZI: That’s right. They hit a totally different pathway. And if you want the technical words, there’s a protein on the T-cell called PD-1 that’s a big player here. And it’s a protein and most people in the world of drug discovery focus on proteins as the targets for their drugs. And it turns out if they had been thinking more about the glycans, they might’ve recognized that the glycans are probably even better targets for immune therapies. But since nobody knows much about glycobiology, no one had made that leap. So there’s a handful of us that work on this. And we had made this discovery back in 2010, 11, 12. And again, it was by watching what was happening with those other immune therapies and drawing the analogy to what we knew about the sialic acids. So now fast forward to the year 2022, there are several biopharma companies that are making a next generation of immune therapy targeting the sialic acids and some receptors that they engage on the immune cells.
LEVITT: I’ve heard you use this analogy about mowing the grass. Could you just tell me about that?
BERTOZZI: So you can see that I tend to use sort of vegetation metaphors. I like to refer to the sialic acids as grass. They’re grass that’s coating the surface of the cell, just like the planet earth is coded in vegetation. What we have done in my lab at Stanford and also I have a company that I formed, that’s making human medicines this way, is we developed medicines that basically park on the cell and then act like a lawnmower and just drive around on the surface of the cell and cut the grass, which means they literally chop the sialic acids off. The sugars are just getting mowed, right off.
LEVITT: So these are like enzymes or something?
BERTOZZI: Steven, that’s exactly what they are. They’re enzymes. In fact, there’s an enzyme called sialidase and sialidase basically cuts sialic acids off of the cell and they just float away. And once the cell has been mowed, and it’s lost the sialic acids, it becomes helpless. It can’t put the immune system to sleep anymore. And now the immune cells are going to see it for what it is and kill it.
LEVITT: It seems if you can identify the cancer cells well enough to mow their grass, is there a reason you can’t do more harm to them? Keeping the analogy alive, could you not inject a little weed killer at the same time that you’re cutting the grass?
BERTOZZI: You absolutely can. And in fact, there are other types of cancer medicines that are weed killers. We call them antibody drug conjugates. And those kinds of medicines, they have one part that targets the cancer cell, that’s the antibody part, and connected to that antibody is a toxin, that’s the weed killer. And the antibody basically allows the toxin to get into the cell and kill it. And that is another way to treat cancer. But one drug often doesn’t do the trick because cancers evolve and they become resistant. So as well as those antibody drug conjugates might work initially, eventually patient’s cancers figure out a way to spit the drug out or deactivate the drug and they just become resistant. So you need more than one strategy. And the nice thing about the immune therapies is that you’re basically harnessing the power of your own immune system to do the killing. You just need to make the cancer cell susceptible. So having the lawnmower, it’s a different approach and it would be a great approach for a cancer that has become resistant to the weed killer.
LEVITT: I love this analogy to mowing the grass. I know though that this must be unbelievably hard because of the nanoscale at which you’re operating and the complexity. Could you give the version that actually expresses the complexity around it?
BERTOZZI: Yeah, so the next level of description, would be to describe what form the lawnmower takes as a molecule.
LEVITT: Yeah. Uh-huh.
BERTOZZI: And you already guessed that an enzyme is an important part of it. So that’s the sialidate. It’s a protein. And we have to get that protein parked on the cancer cell so it can mow that lawn and not accidentally cut the grass from the healthy cells that might be around it. We have to chemically fuse the enzyme to some other molecule that will attach itself to the cancer cell. And for that, we actually use antibodies. Antibodies are wonderful proteins that we know how to engineer them. We know how to produce them. There’s lots of human medicines that are antibodies. So we had to figure out how to physically connect the antibody and the enzyme. And that turns out to be the hard part. For example, our first generation of antibody enzyme conjugates was one in which we actually did some chemistry to form bonds between the protein and the enzyme. So we mixed them together and actually did a chemical reaction to connect them. But that’s pretty challenging since the antibody and the enzyme are both large, highly functionalized proteins. So figuring out how to make a bond between them, where you’re controlling the chemistry and you know exactly what the structure will be after the chemistry happens, that was pretty tough.
LEVITT: How many years of work go into trying to solve a problem like that?
BERTOZZI: We use two different chemical reactions to connect the enzyme and the antibody together. And those were chemical reactions that were invented in my lab, like 15 years earlier for other purposes. And so if you count all of that, I would say that these antibody enzyme conjugates are the product of my academic career. So as long as my career is, we’ve been working on something that went into that problem, ultimately. But then we started a company, Palleon Pharmaceuticals, to basically make a drug candidate that was an antibody enzyme conjugate. And at Palleon what the scientists there realized was that it would be hard to develop a manufacturing process to do the coupling of the two proteins chemically. When you make a drug, there’s a lot more to it than just the structure of the molecule. You have to figure out how to manufacture it on a scale that’s adequate for selling this as a medicine. So they basically re-engineered the antibody enzyme conjugate so that it could be made entirely by a cell. So they have engineered cells that pump out a molecule that’s a hybrid of the antibody and the enzyme with no chemistry necessary.
LEVITT: So it’s interesting that you do this amazing basic research trying to figure out these problems and in this, and in other settings, you also work actively to commercialize these insights. So what’s the timeline for bringing something to market? What does it look like in this cancer domain?
BERTOZZI: Drug discovery is unpredictable. When everything goes well, from concept to medicine, I would say it would be amazing to pull that off in a five-year timeframe, which is why everyone is so mesmerized by what’s happened with the Covid vaccines, because they broke the sound barrier, which five years would have been incredible. And we did it in two. But at the same time, the average might be more like 10 or 12 years, and then there’s times when you have a great idea and it just doesn’t work in human patients the way you had hoped. Palleon just had what’s called an investigational new drug application approved at the F.D.A. What that means is they’ve been given a green light to start testing their first immune-therapy candidate in human cancer patients. And that’s going to start this quarter, first part of 2022.
LEVITT: Fantastic. And what kind of cancer are you targeting with that?
BERTOZZI: They are going to recruit patients with multiple different cancer types, actually. It’s a phase one study. So they’ll enroll patients with melanoma, with lung cancer. I think they’ve got colon cancer on their list and one or two others as well.
LEVITT: Because all of this we’ve talked about is… theoretical is probably the wrong word, but you’ve never actually tried this in a person is what you’re saying. Have you tried it in animals?
BERTOZZI: Yes. So mice can have their cancers cured. Mice have been having their cancers cured for decades now. And that doesn’t necessarily mean your medicine will cure human patients, of course. And there’s only one way to find out which is to do the human clinical trials.
LEVITT: So I know you’ve been doing work on tuberculosis as well. Could you tell us what the idea is there?
BERTOZZI: So my lab studies mycobacterium tuberculosis. And as you might guess, that is the bacterium that causes TB, or tuberculosis, which is a lung infection. And we started working on this around the year 2000. The complete genome sequence for that bacterium was reported around 1999. And it was a really big deal at the time because it was the first really serious global human pathogen to have a complete genome sequence. When there’s a big breakthrough like that, people get really excited because they feel like, gosh, if you know the whole genome sequence you can figure out drugs to cure the disease. That’s the promise of genomics is that it’ll accelerate the pace of curing diseases. So I had a graduate student in my lab, Joseph Mucho. And Joseph was just mesmerized by this genome sequence breakthrough. And he said, “Gosh, I really want to work on TB. And I knew nothing about tuberculosis but Joseph was so passionate about this and I was a rather young assistant professor at the time who naively thought we could work on anything we want, you know? And so I gave him the green light. And from scratch, we just booted up an interesting project studying the genetics of the biosynthesis of glycolipids on the surface of the TB cell. So there was a connection to glycoscience. And then I started learning more and more about the problem of TB. TB still kills more people every year than any other infectious disease, virus or bacterium.
BERTOZZI: It’s a nightmare.
LEVITT: I wouldn’t have guessed that.
BERTOZZI: You wouldn’t guess it because you live here in the United States as do I, and we don’t have a burden of TB. It’s considered a disease of more impoverished environments and developing nations. It is treatable, but it takes six months to a year of a cocktail of pills that are vicious and then there are strains of TB that are totally drug resistant. There’s not much a person can do to help those patients. It’s hard to diagnose even. So there’s just so many problems that make it a public health crisis as much as a scientific problem. Then I really started to understand the burden of this disease when I had a graduate student in my lab many years later who actually was from Africa as she grew up in Burundi. And she explained to me how the disease is really stigmatized there. Many people with TB also have H.I.V. So there’s the double stigma, you know, of having these two diseases. And this makes it really hard for people to even want to seek a diagnosis. For many years we did some basic science around TB and these glycolipids, but eventually I started to feel like it would be great if we could use the knowledge from the basic science to actually do something practical that might contribute to the public-health problem. And we decided to develop a new type of diagnostic test. So a person could get a TB diagnosis in an environment that has very low technical capability. And we formed a company around that. And my former student is the C.E.O. of the company. And we made a chemical, we made a reagent that you can basically mix together with somebody’s sputum sample. We have patients cough up some sputum and we mix it with this chemical. This chemical that we use it’s a sugar. It’s a sugar onto which we have attached a fluorescent-dye molecule. If there’s TB, the bacterium are that sputum, they’ll light up and turn colors and you can see them in a microscope.
LEVITT: Is it quick?
LEVITT: Minutes. So I had the ethnobotanist Cassandra Quave on this podcast a while back and she’s working on developing new antibiotics, from plants. And one of the interesting points she raised is that right now, when a patient comes to a doctor and is sick, it takes a day or two or more to determine whether the cause is bacterial and then what bacterium is underlying it. But in the meantime, it’s too late. So what do doctors do? They over-treat with antibiotics and they want to use very broad-spectrum antibiotics rather than the right antibiotics because they don’t know what the right one is to use right away. One could imagine there would be huge value if a patient could come in and within seconds know exactly what bacteria is affecting them. Is that conceivable given the kind of tools you’re doing?
BERTOZZI: So Steven, this point you’re making, from your previous podcast guest, is so on point. And it is even more amplified with TB because tuberculosis cells, they grow really slowly. Right now, using the old-school type of test, it might take you days to determine that a person has TB. But then if you want to figure out what drugs are the right drugs, the drug-sensitivity profile as it’s called, that can take six weeks. And so for six weeks, that patient is either untreated or potentially treated with the wrong drugs and it’s a nightmare. And the reason it takes so long is because you have to grow the bacteria in cultures. So this test that we developed, in principle, should be able to read out the drug-sensitivity profile in less than a day. And the reason is we don’t require the cells to grow in order to determine their drug sensitivity. We’ve actually rigged up the chemical that we use to light them up so that the chemical itself reports on the drug sensitivity. And that is one of the most exciting aspects of this test, even more so than being able to tell you, yes, there’s TB cells in your sputum, would be to tell you that, and these TB cells could be killed with this drug. So let’s get you on that drug right now. This is so important in very low-resource settings, because if I showed you what a TB clinic looks like in certain rural areas in Sub-Saharan Africa, it’s basically an aluminum-siding shed with no electricity, no plumbing, and a person might have traveled hours or days to get there. They need to know then and there, if they have TB and ideally you give them their drug right then and there, because once they leave, you might not be able to find them again.
LEVITT: Yeah. Especially if you give them the wrong drug the first time, right? Who’s going to come back and get the next dose of punishment in the form of toxic drug that doesn’t make me feel any better? And there’s even further implications of that, which are that the economics of the development of antibiotics, seems really broken to me, in the sense that why would anyone ever invest the hundreds of millions of dollars it takes to develop a new antibiotic, which is very specific when it will not be used in practice, if we don’t have these diagnostics there. And so it seems by you making these quick diagnostics reality, it actually can transform the entire chain of how we think about finding disease.
BERTOZZI: And also, leaving the problem of antibiotic drug development in the hands of the traditional pharmaceutical company is a losing proposition. That’s an effort that needs to be financed in some alternative way by governments or non-profit organizations or consortia or something. Jeff Bezos — I don’t know.
You’re listening to People I (Mostly) Admire with Steve Levitt and his conversation with Carolyn Bertozzi. After this short break, they’ll return to talk about Carolyn’s rockstar days.
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LEVEY: Hey, Levitt. So today’s question comes from our listener, Nate. He studied economics and now works as a data scientist and he says he often looks at averages when communicating with coworkers. He says averages are accessible and used ubiquitously. But he wonders how useful an average actually is. I mean, how many people are actually the average of something?
LEVITT: So Nate raises a great point, which is that averages are easy to get. They’re just in the data. But let me just remind you, the entire profession of economics is built on the notion that what you should care about is marginal rather than average. Every optimization problem involves setting marginal costs equal to marginal benefit, not average cost equal to average benefit. And indeed, one of the key ways in which non-economists make terrible mistakes in decision-making is by thinking about average costs and benefits rather than marginal costs and benefits. That comes up in what we call sunk costs all the time. Let me give you an example: On average, there are a few things that I love more than playing golf, but after I’ve played 36 holes in one day, that 37th hole is like torture, right? So the marginal benefit of golf for me, goes down very dramatically as I do it. And so any kind of calculation that’s based on average instead of marginal would be a mistake.
LEVEY: So your golf story’s cute, but do you have a better example of when averages actually are misleading?
LEVITT: I do have a favorite example that I teach in my course, the Economics of Crime. And it comes out of a paper written by two academics, John Dilulio and Anne Piehl. And they surveyed prisoners in Wisconsin and they asked each prisoner in a typical year when you’re not in prison. How many non-drug crimes do you do? So here I want to distinguish between medians and averages. The average is if you take all the crimes done across all of the prisoners and you divide it by the number of prisoners, that would be the average number of crimes. Okay. The median is if you lined up the prisoners from the least crimes to the most, and you took the one in the middle. So let me ask you, Morgan. If you take the median prisoner in Wisconsin, how many crimes did they say they do in a typical year when they’re free — non-drug crimes?
LEVITT: Okay, so it turns out the answer’s 12. So you overestimated how bad these criminals said they would be. How about the average? What do you think the average was?
LEVITT: It turns out the median was 12, but the average was 141. There’s this really long right tail of a few inmates who do an enormous number of crimes. So why does this matter? If I’m a parole officer and I’m trying to decide whether to let a prisoner out, if I have in mind the average, I’m never going to let anybody out because the average prisoner doing 141 crimes, I want to keep that person locked up. But in practice, your job is to figure out well, who’s a prisoner who’s maybe from the 25th percentile or the median, or the 75th percentile, and to make those distinctions. I just found those numbers really telling because if you were talking about a median prisoner, you’d have completely different policy implications than if you’re talking about the average prisoner. And in the classroom, it turns out to be a great launchpad for trying to figure out well, okay, so I’m on the parole board. should I be thinking of an average prisoner or a medium prisoner or maybe some completely different kind of prisoner?
LEVEY: What if you added drug-related crimes into the equation?
LEVITT: Then it gets even crazier because the median number of crimes reported is 26. But the average jumps to 1,834.
LEVEY: That’s so fascinating. Wild. Great question, Nate. Thanks so much for writing. If you have a question for us, you can reach us at firstname.lastname@example.org. That’s P-I-M-A@freakonomics.com. It is an acronym for our show. We read every email that’s sent and we look forward to reading yours.
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Wow, I haven’t run across many people who can explain complex ideas as simply and intuitively as Carolyn does. Within academics, that skill really isn’t rewarded very much, but it’s so valuable. Science has gotten so complex and specialized. Like I said at the top of the episode, I can’t even begin to read academic chemistry papers. But if society is going to make smart policy choices around science, we need people like Carolyn who can communicate to a broad audience. In the rest of our conversation. I’m hoping to talk about how she turns her academic ideas into real world solutions — that’s something I’ve struggled with. And of course, I can’t let her go without hearing about her rockstar days.
LEVITT: We’re jumping back and forth between basic research and commercialization. I’m curious how much of your choice about how you spend your time is driven by economic factors. So obviously, when you start a company, and you’ve done that a bunch of times, it’s because you hope there’ll be a financial return. But do the financial incentives actually feed back into your basic research? Do the kinds of questions you ask — obviously, it’s influenced by what you think it’s important or not, but is it also influenced by whether you think somebody will pay for it at some point down the road?
BERTOZZI: It’s interesting the way that you think about it as an economist. So no, if an academic starts a company, ‘cause they think they’re going to make a lot of money — 99 out of a hundred times, they’re going to be disappointed. Because even if the technology succeeds and a product is made and it’s sold and it’s commercial success, there’s so much dilution that occurs through the course of the company growth that the academic founder’s not going to have a big windfall, probably. Biotech where you’re making therapeutics — the failure rate is so high. It takes so much money over so many years, even decades to have a product, and you need so much money from investors that at the end of the day, you almost disappear.
LEVITT: So how many companies have you started, roughly?
BERTOZZI: I think I’m now just crossing the T’s and dotting the I’s on my 10th company.
LEVITT: And you’re not doing it to make money, it sounds like. You’re doing it for some other reason.
BERTOZZI: Well, a person can hope, of course, but no, that’s not the primary motivation. The primary motivation is to try to have a broader impact with the discoveries that come from the basic science. Earlier in my career, this was less important to me. We did science ‘cause it was cool and we were curious and we thought we could invent some things that people might find useful. But as the years went on, I more and more started feeling like there could be more benefit from our discoveries than is happening without my influence. And maybe I can influence the translation of some of these findings for the benefit of human patients, if I start companies and get more involved in things like that. Also, I was hired as a consultant for several biopharma companies early in my career. And so I got an inside view of the drug-discovery process and how it works. It was so interesting and fascinating and difficult that part of it is just the challenge — can we actually make a medicine that is like a lawn mower? Can we actually make a tuberculosis diagnostic test from these fluorescent sugars? And honestly, I wouldn’t just do it in a vacuum, but I often have graduate students and postdoctoral fellows — this was their work with their hands at the research bench. I’m in my office from a distance, just enjoying data and providing some advice like an armchair quarterback. But they’re really in the trenches making the discoveries and it’s hard work. And the students want their findings to end up in the hands of users, of patients, and doctors. So that’s a real motivation to start a company.
LEVITT: One thing I’ve observed is that there’s this gulf, this wasteland, between what academics do and what policymakers and corporations do. And academics have incentives to come up with ideas and prove they work, but just well enough to get published. And then firms and policy makers, they’re good at commercializing proven concepts, getting a new drug compound through the F.D.A. and figuring out how to mass produce it. But I get the sense in economics, and I assume in chemistry as well, that there are many potentially valuable academic insights just wither and die on the vine because they aren’t pushed far enough to entice corporations or policymakers to adopt them because this intermediary step, it’s time consuming. It’s tedious. It’s maybe expensive and it’s really not rewarded at all in academics. Sounds like you’re taking that step under your wing and said, “I’m willing to do that step. I need to form a company to do it, but I’m willing to do that because I believe in it.” It feels to me like what we call a market failure, that there should be room for an N.G.O., for a nonprofit to come in and to intelligently take the massive insights that are coming out of academics and nudge them along just far enough that they’re ready for commercialization. Does that resonate with you at all?
BERTOZZI: Steven, you are absolutely singing to me. Yes, you have identified a gaping hole in the translational science process. There are so many really promising gems of science, where the academic reaches the end of the line. They can’t afford to do the translational process. It’s so expensive. And the work doesn’t lend itself to a Ph.D. graduate student thesis. It’s the work of industrialization, it’s the work of scale-up. It requires a professional staff, but universities are not set up for professional staff. We can’t afford the salaries with our federal grant monies. And we don’t have the infrastructure, it’s like you throw a hail Mary and nobody catches it — there’s nobody there in the end zone to catch it. And you’re right, pharmaceutical companies have, for the most part, been averse to risk. They don’t like to work on things that are so early stage. And they’re lacking in innovation and they know it, but innovation leads to failure most of the time and that’s not how they want to spend their money and their shareholders wouldn’t like that. So what do we do about it? There’s some interesting things under foot. There’s entities that are trying to close the gap there. So for example, I’ll just call out my own institute at Stanford. The reason I moved my lab to Stanford back in 2015 was because Stanford had made a commitment towards building a new kind of institute, which we call CHEM.H. It stands for Chemistry, Engineering, and Medicine for Human Health. And our goal at CHEM.H. is to provide the infrastructure so the academic scientist can get a little bit further along in that translational process of trying to make a new medicine or a new device. At the same time, there are investment firms that have noticed this gap and are trying to take advantage of it. And one of them is Deerfield. So Deerfield now has arrangements with more than 30 universities and Stanford is now one of them. But basically, Deerfield is providing financial support for projects that are right there waiting for the hail Mary. And if it looks like a good pass, they’re going to stand in the end zone and catch it. And then they’re going to progress it to the point where it’s been de-risked and therefore more attractive as a licensing opportunity for a big company, or maybe as the fodder for a new start-up company that they then could invest in.
LEVITT: Yeah, that’s awesome. Usually if an idea is good, someone’s beating you to it. So it sounds like Deerfield’s beat me to it by a number of years, so good for them.
BERTOZZI: Maybe Deerfield is the first and others will follow.
LEVITT: You and I are about the same age and I’ve got to believe female chemistry Ph.D. students were pretty rare when you were getting started, right?
BERTOZZI: Yes, we were. I would say the numbers back then for a Ph.D. program, put us around 10 percent.
LEVITT: So that would be even lower than economics in almost any point in time. And I’ve often heard it said that in fields where men have dominated historically, that women are told, or maybe they just figure it out, that the path to success is to act like a man. But when people describe your research lab and your interactions with both colleagues and subordinates, they always highlight how kind, and thoughtful, and accessible, and generous you are. Now, maybe at the risk of gender stereotyping, it seems like you’ve managed to bring an incredibly powerful, inspiring female approach to running a team. Has that been a conscious thing? Or how would you describe that?
BERTOZZI: Chemistry as a discipline, at least my sub-field, which was organic chemistry, definitely had a culture of kind of macho, tough guy. I guess a stereotypically male, but toxic masculinity. It was not a very welcoming field overall for women. What women did to survive is they would find a lab where the culture wasn’t so bad and avoid other labs where it was horrible. So you could insulate yourself a little bit, if you could find a lab that was more tolerant of the non-toxic masculinity phenotype, and that’s what I did. But it limits your options. You’re also right on point that when I started my own lab, the messaging that I got from my senior colleagues who were purportedly my mentors, and they were all male, of course, was the kind of advice that might’ve worked for a toxic male, but it didn’t work for me. It took a couple of years for me to figure out how I was going to run my lab. And it was going to have to be different because I was different. And I had to come to terms with the fact that might mean I might fail. But if that transpired then so be it. It turns out that you can be a very successful scientist without having a lab that has festering toxic masculinity, Right? Imagine that. And many young researchers really appreciate having a lab where you don’t have to act like that, men and women both.
LEVITT: We were both undergraduates at Harvard at the same time, and you came out during college as a gay woman and you were very involved in social activism through a group called Act Up, which I remember very well was an incredibly powerful gay rights organization. And I’m curious, was it a conscious choice on your part to move from social activism to science as a way to address the world’s problems? Did you consider social activism as a career path?
BERTOZZI: Oh, that’s such a great question. Like many scientists, my social activism was just an integral part of my life as a scientist and many of us do both. I think it’s great when scientists also engage in social activism. Many friends and colleagues, especially at Berkeley, as you might imagine, continue to be very involved in social activism, but it just takes different forms now than it did when I was 22. In college, you and I remember the AIDS crisis.
LEVITT: Oh, yeah.
BERTOZZI: So you graduated in ’89 and I was in ’88. So this was several years into basically the mass death of gay men in New York and in San Francisco. And then transmitting out into the heterosexual populations and ultimately in Africa and other nations it was a death sentence. And I lost many a friend to H.I.V./AIDs during those years. And it got even worse when I went to graduate school. So I went to Berkeley to do my Ph.D. in 1988. And, by the early ‘90s, the death toll was horrific. So Act Up was a grassroots kind of in your face activist organization where we did protests. We marched on Washington and we marched in San Francisco and we would stage what used to be called die-ins, where you would lie on the street and block traffic on Market Street in downtown San Francisco and outline yourselves with chalk like a dead body. And of course, history will look back on all of that as an example where activism actually moved the needle in terms of how drugs are approved by the F.D.A. And in terms of how money is allocated even among stigmatized populations. ‘Cause gay men were very stigmatized back then, more than they are now. And so to have a disease that was a gay disease was horrible in so many ways. And then of course in the mid-‘90s, when the H.I.V. drugs hit the market, all of a sudden people stopped dying. And they lived and lived. And now, they could live almost a normal lifespan, which I think has caused H.I.V./AIDS to fall off the radar screen for younger people because it’s not in their face the way it was for you and I. That experience as a young person in that period of time, definitely informed how I think about the pharmaceutical industry and the government and their role and their partnership in taking on public-health crises and I think it’s fair to say if the transformations that the AIDS activists promoted hadn’t occurred, we would not have had such a rapid response to Covid because a lot of those mechanisms went into place with H.I.V./AIDS, fast tracking and stuff like that.
LEVITT: As I look back over our adult lives, there’ve been many social movements, many demands for societal change, but I think the L.G.B.T.Q. movement has been the most successful and transformative. Is that your perspective as well?
BERTOZZI: I agree. The whole conversation is so different now than it was when I was a teenager coming out at the age of 18. And just to put it in perspective, 1986 was the year of the Supreme Court decision called Bowers v. Hardwick, and that was a Supreme Court decision that basically codified the idea that a gay person was inherently a criminal. And it wasn’t until Lawrence v. Texas, another famous Supreme Court decision with a very different court, that had a different political leaning, struck down the last of the state sodomy laws and decriminalized homosexuality. So that only happened in 2003. And in 2003, I was a tenured professor at Berkeley decorated with a bunch of awards, and therefore a young, celebrated scientist by day and barely a criminal by night. It was a strange way to live.
LEVITT: There’s a large group of people, who would think the chemistry stuff you do is nice, but that your real claim to fame, is that you were once in a band with the legendary Tom Morello, the guitarist with Rage Against the Machine and Audioslave. Are there days when you say to yourself, “Damn, I wish I were a rockstar instead of a chemist.”
BERTOZZI: You better believe it. Like every time I hear Tom’s latest recording released, and hear him perform with The E. Street Band? Sure. First of all, Tom was a brilliant guitar player as long as I knew him, way back in the 1980s when he was just a teenager. And when he graduated from Harvard with the intention of becoming a professional musician, you knew he would succeed. Most of us, there’s no chance, but, he was a few years older than I was. So he graduated and I was still in the middle of college and I wouldn’t have quit my Harvard degree to follow him to Los Angeles. But, a few years later when he put out his first album with Rage and I was at Berkeley in graduate school, I was thinking, “Oh man, did I miss an opportunity here?”
LEVITT: Do you think you would’ve enjoyed life as a rockstar?
BERTOZZI: I don’t know that I would have made it very far. I didn’t have the talent that he had.
LEVITT: It sounds like you secretly would rather be a rock star than a rockstar chemist.
BERTOZZI: Oh yeah.
LEVITT: Is that really true?
BERTOZZI: I love music. I love performing. Yeah, I think, maybe?
LEVITT: Wow. That’s amazing.
BERTOZZI: If someone wants to give me my big break, I could give it a go and see.
What does it tell you about human nature that one of the world’s leading chemists, frequently mentioned as likely to win the Nobel Prize, would give it all up to be a rock star? Well, I suppose it’s not too different than my own fantasy of being a professional golfer. Thanks for listening, and we’ll see you next week.
People I (Mostly) Admire is part of the Freakonomics Radio Network, which also includes Freakonomics Radio, No Stupid Questions, and Freakonomics M.D. All our shows are produced by Stitcher and Renbud Radio. Morgan Levey is our producer and Jasmin Klinger is our engineer. We had help on this episode from Alina Kulman. Our staff also includes Alison Craiglow, Greg Rippin, Gabriel Roth, Rebecca Lee Douglas, Zack Lapinski, Julie Kanfer, Eleanor Osborne, Mary Diduch, Ryan Kelley, Emma Tyrrell, Lyric Bowditch, Jacob Clemente, and Stephen Dubner. Our theme music was composed by Luis Guerra. To listen ad-free, subscribe to Stitcher Premium. We can be reached at email@example.com, that’s P-I-M-A@freakonomics.com. Thanks for listening.
BERTOZZI: I have a piano. Strictly for relaxation and sanity. But get me at a party with a couple of cocktails and I’ll bang tunes.
LEVITT: What’s your go-to song?
BERTOZZI: Anything from Def Leppard to Christmas carols and everything in between.
- Carolyn Bertozzi, professor of chemistry at Stanford University.
- “The Fight Against AIDS Has Shaped How Potential Covid-19 Drugs Will Reach Patients,” by Marie-Amélie George (The Washington Post, 2020).
- “Rapid Detection of Mycobacterium Tuberculosis in Sputum With a Solvatochromic Trehalose Probe,” by Mireille Kamariza, Peyton Shieh, Christopher S. Ealand, Julian S. Peters, Brian Chu, Frances P. Rodriguez-Rivera, Mohammed R. Babu Sait, William V. Treuren, Neil Martinson, Rainer Kalscheuer, Bavesh D. Kana, and Carolyn R. Bertozzi (Science Translational Medicine, 2018).
- “What the Sugar Coating on Your Cells is Trying to Tell You,” by Carolyn Bertozzi (TEDx Stanford, 2016).
- “Precision Glycocalyx Editing as a Strategy for Cancer Immunotherapy,” by Han Xiao, Elliot C. Woods, Petar Vukojicic, and Carolyn R. Bertozzi (PNAS, 2016).
- Lawrence v. Texas, U.S. Supreme Court (2003).
- “Does Prison Pay? The Stormy National Debate over the Cost-Effectiveness of Imprisonment,” by John J. DiIulio Jr. and Anne Morrison Piehl (The Brookings Review, 1991).
- Bowers v. Hardwick, U.S. Supreme Court (1986).
- “Cassandra Quave Thinks the Way Antibiotics Are Developed Might Kill Us,” by People I (Mostly) Admire (2022).
- Palleon Pharmaceuticals.
- Stanford ChEM-H.