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Opening Keynote with Nobel Laureate Carolyn Bertozzi
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Opening Keynote with Nobel Laureate Carolyn Bertozzi
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Language: EN.
Segment:0 .
KEVIN DAVIES: Welcome to the opening session of the State of Biotech, 2023. I'm Kevin Davis. We are thrilled to welcome our very special guest, Carolyn Bertozzi. Since 2015, Carolyn has been at Stanford, helping launch the ChEM-H Institute, Chemistry, Engineering and Medicine for Human Health. Although I dare say, her spiritual home might still be UC Berkeley, where she spent the better part of two decades.
ALEX PHILIPPIDIS: I'm Alex Philippidis. In addition to being an HHMI investigator for the past 23 years, Carolyn is a co-founder and advisor to at least half a dozen biotech and pharma companies, something we'll talk about. And, of course, she is the winner of the 2022 Nobel Prize in chemistry. Congratulations on being the 2022 Nobel laureate. Has that sunk in?
CAROLYN BERTOZZI: By now, it has, since it's almost a year ago. So first of all, thank you Alex and also Kevin. You're very kind in your introductory remarks. And I'm very happy to be here.
KEVIN DAVIES: What was the phone call like, Carolyn?
CAROLYN BERTOZZI: Well, the Nobel committee, which is organized by the Royal Swedish Academy of Sciences, they make their big decision. And they make their announcement on a pre-scheduled date and time, every year. And so the whole world knows that people, who care, in the world know that on October 5, at what turns out to be about, 1: 43 AM, California time
1: is when the Nobel committee chair makes a phone call in the hopes of reaching the laureates and giving them the good news. And so my phone is my alarm clock. So it's always next to my bed. And it went off and I was confused, because it didn't seem like it was 6:00 AM. It was 1:43. And then I saw that-- you know how it is, I have an iPhone and it tells you where the call is coming from.
1: And it said, Stockholm.
KEVIN DAVIES: So at least you heard from them directly. Rather than, Jennifer Doudna, I understand, had to hear it from a nature reporter, because she slept through the original call.
CAROLYN BERTOZZI: Well, yeah. I mean, think if my phone hadn't been right there, I would have slept right through it. It was a bit confusing.
KEVIN DAVIES: Your name, of course, has been-- this wasn't an outside pick. Your name had been regularly floated as a potential winner-- seemed, to me more, a matter of when rather than if. So did you go to bed that night thinking, I'm curious. This could be the year.
CAROLYN BERTOZZI: No, I did not. And for the simple reason is-- you're right, there's buzz. There's the gossip channels in the little world of chemistry. People like to make predictions, and make bets, and play games, and tweet their speculations and stuff. But at the end of the day, all the people in the world can tweet and speculate and bet. But if nobody actually nominated you, for a Nobel Prize, you're not a contender. And so you don't even know if you've been nominated.
CAROLYN BERTOZZI: I mean, it's flattering that people would even have a hunch that maybe you're somewhere on the list. But just because it's on Twitter, it doesn't say anything about the real world.
KEVIN DAVIES: Yeah, but unlike the laureates of the, I guess, the previous two seasons, you were actually able to go-- I think with them, as well-- to Stockholm for the prize ceremony. What sticks in your mind about that?
CAROLYN BERTOZZI: That it was an unbelievable, magical event. And people I know who've been there and have experienced this told me that it would be. It was spectacular. And it was extra special to have the 2021 and 2020 laureates there as well, because I know many of them. And Jennifer Doudna was one of them. And She was there with her family. And so there's a lot of Berkeley people who were there celebrating with her and with other laureates.
CAROLYN BERTOZZI: So it just became even more of a party to have so many great people and friends there.
KEVIN DAVIES: Your prize or your share of the prize was for click chemistry. And for those watching who aren't card-carrying chemists, what could you briefly describe click chemistry? And what is the relationship, if any, to glycobiology, which is really the field that you've helped propel forward over the last couple of decades?
CAROLYN BERTOZZI: Yes, so my fraction of the Nobel Prize was actually in recognition of a type of chemistry that my lab invented back in the late 1990s. And we call it bioorthogonal chemistry. And then I shared the prize with Morten Meldal and Barry Sharpless. And their chemistry is I think more recognizable as click chemistry. And in fact, that's a term that has been attributed to Barry Sharpless.
CAROLYN BERTOZZI: But in Stockholm, last December, I learned that actually his wife coined the term. She's a writer and has a gift with language. And she came up with that beautiful soundtrack for the chemistry. And the bioorthogonal concept and the click concept have some overlap. But they also are distinct. And so for me, the term bioorthogonal was something we coined to describe chemical reactions that would take place amongst two different reactive groups that do not interact or interfere with anything in a biological system.
CAROLYN BERTOZZI: And by having that quality, you can actually take these two reagents and have them form a bond. And do a chemical reaction in a living system, like in cells, or in a laboratory animal, and now, today, inside a human patient. And the chemistries are so selective, and so clean, and harmless that you can literally do chemistry in a person the same way that 20 years ago chemistry would be done in a glass flask.
CAROLYN BERTOZZI: And we did that. We had a lot of applications in mind for that. Click chemistry, Barry coined that term. And he describes it as chemical reactions that are very robust, reliable, high yielding, don't produce like a lot of byproducts. And therefore, are very useful in chemical synthesis. And it turns out that some of those qualities of selectivity, reliability are also important in a bioorthogonal reaction.
CAROLYN BERTOZZI: But the click chemistries that Barry and Morton developed and were recognized for with the prize are chemistries that you wouldn't do. You wouldn't be able to do in a living system, because they require a toxic catalyst.
KEVIN DAVIES: OK, let's talk about glycobiology. How did you first get interested in this field? And what is the medical relevance of understanding and working on glycobiology?
CAROLYN BERTOZZI: I first learned about glycoscience more broadly as a grad student. And I had never-- I knew nothing before that period of my life. I hardly learned anything about sugars when I was an undergraduate. Generally, the mainstream biology student has very little exposure to this. I mean, the textbooks don't cover it very well, if at all. And the mainstream biologist doesn't know much about it.
CAROLYN BERTOZZI: And so I walked into graduate school with zero exposure to this. And then a new professor had just arrived at Berkeley named, Mark Bednarski. And he's the person who introduced me to the field. So it was in grad school that I started learning more about sugars, first, as targets for chemical synthesis. So I was focused on carbohydrate chemistry. But then I started reading more about the biology of sugars in human health and in human disease.
CAROLYN BERTOZZI: And, in particular, the sugars that are on the surfaces of cells. So our cells have a sugar coating. Every cell type has a different sugar coating. And the sugars are molecular information. And they interact with receptors on other cells. And they're involved in all facets of human biology just as much as proteins, or nucleic acids, or the other biopolymers.
CAROLYN BERTOZZI: But back when I started grad school, this was in the late 1980s, the field of biology and biochemistry, which decades earlier, represented carbohydrates as much as it represented nucleic acids and proteins. But the molecular-- excuse me. The molecular biology revolution had focused the attention of biologists so much on DNA and the central dogma-- DNA to RNA to proteins and genetic engineering.
CAROLYN BERTOZZI: That the carbohydrates fell out of fashion. And then a whole generation of scientists, like lost the expertise. So there I was in grad school doing chemistry on sugars and reading about their importance in biology. But hardly any labs were really studying them at that time. They had kind of drifted into a niche area. And it seemed to me that there would be a huge opportunity to improve human health by understanding the carbohydrates better.
CAROLYN BERTOZZI: And chemical tools turned out to be very empowering for this.
KEVIN DAVIES: And it's glycobiology is still the central thrust of your research laboratory?
CAROLYN BERTOZZI: Yes, it is. And it always was. So in chemistry circles, people might recognize me for bioorthogonal chemistry, which has lots of applications outside of glycoscience. It has applications in all walks of biology, and in medicine, and biotechnology. But originally, the motivation for developing these chemistries came from my lab's interest in imaging cell surface glycans.
CAROLYN BERTOZZI: And so that was our motivation. We invented the chemistries, because we knew we could apply them to molecular imaging of cell surface sugars. But it turns out you can apply them to all other kinds of stuff too. So now, those chemistries are just part of the fabric of chemical biology. People use them for all kinds of applications.
CAROLYN BERTOZZI: But we did use those chemistries to image cell surface glycans. We learned with those tools how glycans change in disease, especially cancer. And that led us to define a role for certain types of cancer-associated glycans in immune modulation, which has then led to new technologies for cancer immune therapies that are based in glycoscience. So glycoscience has always been the epicenter for me.
KEVIN DAVIES: Alex is going to talk to you, in just a minute, about some of your work in industry with numerous affiliations in the biotech sector and some big ones in big pharma as well. But tell us a little bit-- before we do that-- about ChEM-H, which was one of the major reasons, I'm sure, that you left Berkeley to cross over to Stanford. It's an important and, perhaps, groundbreaking interdisciplinary institute.
KEVIN DAVIES: I wonder if you could just help us understand what really sets it apart.
CAROLYN BERTOZZI: Sure, yes. And thank you for asking. My virtual background here is an atrium in the middle of the building, which houses the institute.
KEVIN DAVIES: That's very cool.
CAROLYN BERTOZZI: The institute is now called Sarafan ChEM-H. And for Lily Sarafan who gave a very generous gift to help us support the institute. And the ChEM-H part is an acronym. So that stands for Chemistry, Engineering, and Medicine. That's the ChEM, Chemistry, Engineering and Medicine for Human Health. And that's the H. So H is humans. And the institute is focused around translational molecular science.
CAROLYN BERTOZZI: And our philosophy is that, by bringing scientists from biology, chemistry, physics, data science, engineering, and also, clinician scientists into this one physical space, that we can solve big problems in human medicine, which includes defining the molecular mechanisms of disease, more clearly. And then developing new types of therapies and diagnostic tools to improve human health.
CAROLYN BERTOZZI: And so that's what we're doing. And you're right, the opportunity to move to Stanford to help launch this institute was very compelling, especially since my research interests at that time-- this is now eight years ago when I made the transition. My research interests were kind of shifting more and more translational at Berkeley. And Berkeley is a wonderful world-leading institution in basic science and engineering.
CAROLYN BERTOZZI: But it's not a place with a medical center and/or a hospital system. So there's only so far I felt that I could take my research, at least at that time, at Berkeley. Whereas, Stanford offered the opportunity to have a very tight connection with the clinical sciences.
KEVIN DAVIES: Yeah, well, that's a great segue. Alex, over to you.
ALEX PHILIPPIDIS: Thanks, Kevin. Carolyn, you've been an advisor to some big pharma companies and you are now on the board of directors at Eli Lilly, have those relationships led to greater recognition of glycobiology that's now reflected in some actual drug programs? And how so?
CAROLYN BERTOZZI: Oh, yeah. Well, let me just clarify my involvement with biopharma companies. I was on the board of Lilly from around like 2016 to 2021-ish. And then I had to resign from the board, because of a conflict of interest, actually. So Lilly did a deal with one of my startup companies that I had co-founded. And it was determined that there was a conflict for me to be on the board and also have the company involved with my company.
CAROLYN BERTOZZI: So I stepped off the board. So I'm not on the board of Lilly, right now. I am on the board of directors of Alnylam and also, Omniab. So I do have board seats but not with Lily. And then I have founded several companies. I think, right now I'm trying to finance company number 12-- I think it is. It's the headcount. And the companies I have co-founded are companies, for the most part, which are based on technologies that spun out of my academic lab.
ALEX PHILIPPIDIS: And one of those the company I think you're referring to is Elysia Therapeutics, which a couple of years back, launched an exciting collaboration with Lilly to develop and commercialize targeted therapeutics based on light tech with a potential-- as announced, back then-- for up to $1.6 billion in milestones. What progress have been made on that since then?
CAROLYN BERTOZZI: Oh, it's a wonderful partnership. Lisa and Lily are prosecuting several interesting pre-clinical candidates. So, yeah, I think that's going to be a very fruitful partnership.
ALEX PHILIPPIDIS: Great. And you've also co-founded-- among companies, in addition to Elysia-- Redwood and Enable, and Palleon, and InterVenn Bio, and OliLux. This might be a bit like naming your favorite child. But which of these companies stands out to you and why?
CAROLYN BERTOZZI: Oh, yeah, you can't ask that question. I love them all, equally and for different reasons. And they're all different. Every one of these companies is based on a different technology. OliLux, Enable, and InterVenn are diagnostics companies, clinical diagnostics. Whereas Redwood, which was acquired by Catalant-- so now, it's part of Catalant Biologics. And Palleon, and Elysia, and some other companies I've formed since then are therapeutics companies.
CAROLYN BERTOZZI: And they're all based on different technologies. So Palleon and Redwood are the two that I formed earlier. And they now have clinical candidates. So they have molecules in the clinic. Redwood is an antibody drug conjugate company, which was a very next generation, site-specific, controlled dar, focused technology. Palleon is a glycoscience, rooted company that's making cancer immune therapies that are targeted enzymes.
CAROLYN BERTOZZI: So it's a totally different modality from other cancer therapies. And they're also a clinical stage company. Whereas, Elysia is still preclinical. And the LYTAC technology as we call it, which stands for Lysosome Targeting Chimera. That platform, basically, executes a targeted protein degradation, where the targets of interest are extracellular proteins.
CAROLYN BERTOZZI: So the LYTAC technology of lycia, you can think of as kind of a cousin to the PROTAC technology of companies, like Seefor, Chimera, Arvinas, and so on.
ALEX PHILIPPIDIS: OK, and you've also worked with tech entrepreneur, Matt Wilsey, who co-founded the non-profit Gray Science Foundation. And then, he and you co-founded for profit Gray Science, focused on NGLY1 deficiency. Now, I Gray Science was developing a gene therapy for that disorder. And one time, as of last year, there was talk about starting clinical trials this year, has that been launched or otherwise how soon can we expect the first patient to be dosed?
CAROLYN BERTOZZI: Yes, so the trial has not initiated yet. Right now, Gray Science is in back and forth discussions with the FDA about what needs to be in their IND package. And they're still completing some of the experiments, animal, preclinical experiments that the FDA would like to see in that package. But if all goes according to plan, they should be able to initiate their trial-- let's see, we're still in the end of 2023. So sometime mid to late 2024.
CAROLYN BERTOZZI: And they're in the manufacturing stage right now. So they're generating the material. It's a gene therapy, adenoviral associated vector-based gene therapy. And it's being manufactured for that first clinical study. So we're getting there. The path is, I think, it's fairly clear at this point.
ALEX PHILIPPIDIS: Great. And speaking of whether small or especially a larger biopharmas, many have spoken out publicly against the Biden administration plan to negotiate with developers of 10 blockbuster drugs, including some familiar names like Jardiance, and Eliquis, and Xarelto. How much of a headwind will that be on drug development and commercialization? And will generic pressures, on those drugs, offset the impacts?
CAROLYN BERTOZZI: Well, it's early days. And we'll see. And so far, they've only named these 10. And the rules for drug pricing negotiations are for drugs that are covered by medicare. So these are drugs that target large populations of people that tend to be older people, which is a lot of medicines but not all of them. What I find most frustrating about that component of the Inflation Reduction Act is the fact that it targets small molecules in a different way than biologics.
CAROLYN BERTOZZI: And they're treated differently. And for small molecules, they've basically shortened the period of exclusivity during which a company can benefit from revenue, from their drug before the generic competition comes in. And it's so short now that, I think you're already seeing changes in behavior, in decision making, in the pharma industry, because the clock starts to tick on your very first approval for this new, shortened, exclusivity period.
CAROLYN BERTOZZI: And in the past, a pharmaceutical company could make decisions. They would develop a new drug, which had potential applications across a lot of different indications. But they'll start with a smaller indication just to get the clinical proof of concept in a setting where the clinical trial might be a little less expensive.
CAROLYN BERTOZZI: And so it's less risky, because you're not spending quite so much money on an untested drug yet. And then once they get approval, in one indication, they can then pursue new-- sort of, they call them-- nylex, which is new indication extensions. But the problem is now, as soon as they get that first approval, the clock is ticking. And they're going to run out of exclusivity.
CAROLYN BERTOZZI: And there's no time to explore all the other potential indications before generic competition comes in. So there's no incentive. And so that means either companies won't bother exploring extensions to other indications. Or at the very beginning of their clinical development program, they'll just forget about small indications that aren't going to be very lucrative and just go right into big lucrative indications, which means that a lot of medical need will go unmet.
CAROLYN BERTOZZI: And the drug won't get tested in smaller indications, which is a bummer for those patients. So these are the things that I am most concerned with, not so much the top 10 that they just named. Those were pretty predictable, I think. But more, the sort of the way that it changes the incentive structure so that pharma companies will have to make different kinds of decisions that I don't think are in the best interest of patients.
ALEX PHILIPPIDIS: Kevin, over to you.
KEVIN DAVIES: Thank you. Carolyn, just a few more questions before we let you get back to work. I want to go back to the Nobel, for a second. You are the latest in a, unfortunately, short line of very high profile female scientists who've won the prize, of course, in chemistry-- Doudna and Charpentier. You mentioned partying with Jennifer and her family in Stockholm last year-- Frances Arnold, of course.
KEVIN DAVIES: And a theme, over the last couple of years, has been trying to elevate or promote the cause of women in science. I wonder, what have you been able to use your new platform for over the last 11 months or so?
CAROLYN BERTOZZI: That's a great question. Enhancing the participation of and the due recognition of women in science is something that I've been devoting energy to throughout my entire career. So that's been going on for a long time. And so I've been in this business, let's call it, 30 years. And 11 months of that I'm a Nobel laureate. So I don't think I know yet whether having or not having a Nobel Prize makes a difference in terms of the messaging and the impact I could have, I don't know.
CAROLYN BERTOZZI: But I'll say that, I have noticed, after I was awarded the Nobel Prize, that I get invited to do a lot of things like this, where I get interviewed. And I make remarks. And it's on YouTube, or it's on Twitter, or something. And so definitely, I've been given a platform that has more visibility. But the messages don't change.
CAROLYN BERTOZZI: I mean, there's nothing different in my philosophies now than 11 months ago. And really, I think the question is, will people listen more? Will the words that have been coming out of my mouth, all along, fall with more gravity now? I don't know. But I would like to think that every time there's a little bit more representation of women at in the most visible spheres of science, that younger scientists who are making life changing career decisions-- they might be choosing a major in college, right now.
CAROLYN BERTOZZI: Or deciding whether to go to grad school, or med school, or law school, or something. Or just finish their PhD and trying to figure out what kind of career to pursue. And maybe, along the way, people who see me maybe that's a positive influence in their decision making. And so maybe that's-- and I'll never know. But I'm sure there's more I can do as a Nobel laureate. And I'll find out, right.
KEVIN DAVIES: Yeah, yeah, what's the strangest, or perhaps, funniest, or most peculiar thing, or request that's happened to you over the last year?
CAROLYN BERTOZZI: Oh, well, strange and peculiar would be things like, when I was in Stockholm with the other Nobel laureates in December last year, the hotel we were staying in, every time we came and left that hotel, there were lines of people wanting autographs. I've never been asked for an autograph before. That's like Kobe Bryant was the autograph guy. And now, Taylor Swift, but me? So that that's a little interesting. Strangers in airports have recognized me, which is a surprise, and asked me for autographs, or selfie, photos, and things like that.
CAROLYN BERTOZZI: So I think being a small time celebrity is a very new experience for most scientists, I think.
KEVIN DAVIES: Perhaps, they're recognizing one of your viral karaoke videos rather than the Nobel Prize.
CAROLYN BERTOZZI: Yeah, yeah, I don't think those are going to do much to help my reputation. But anyways, I'm grateful that somebody like cares about science, I think.
KEVIN DAVIES: Yeah, you briefly talked, just a minute ago, about younger scientists. We have probably a very large group of young scientists from around the world watching today. What is your advice to young scientists maybe wrapping up their PhD or perhaps, trying to decide whether to stay in academia or abandon it for industry? Do you have any words of wisdom for them?
CAROLYN BERTOZZI: Oh, I mean, I think there's so many great opportunities. That you can do great science in lots of different environments. And I think, old tropes about the difference between academia and industry-- I think, a lot of that stuff has largely gone irrelevant. To the point where nowadays, you can do just as, if not more exciting science in a biotech company, then you could do in an academic center. You often have access to more resources, and more technology, and more human capital than an academic does.
CAROLYN BERTOZZI: And so the science in industry is very cutting edge. And I'm envious, sometimes, of what I'm seeing in companies that they can do. And I'm like, gosh, I wish we could do that but we have the infrastructure. So that's number one. Number two, is I think what's also drifting away is this idea that it's either, or. So now, you can see plenty of examples of people who might have spent some time in industry and then transitioned to an academic position or vice versa.
CAROLYN BERTOZZI: Or kind of bouncing back and forth. Or maybe taking a turn into the world of venture capital and then coming back to academia. And one of the early hires in my institute was Peter Kim who after an illustrious academic career at MIT and the Whitehead Institute, was recruited to run Merck Research Labs. So he was the head of research at Merck for about 12 years. And then when he was ready for something new, we hired him at Stanford.
CAROLYN BERTOZZI: And I think you'll just see more and more of this kind of blending, because I think that the training and the experience you get in industry can be really transformative in an academic setting and vice versa. It's a very exciting time, because a new scientist has so many opportunities to choose from. And all of them are great.
KEVIN DAVIES: And finally, Carolyn, what are you most looking forward to as far as your own research program and your own scientific career as they blossom in this post Nobel era?
CAROLYN BERTOZZI: Well, on the one hand, when I woke up back in San Francisco after two magical weeks in Stockholm and around Europe, is business as usual. In many ways, I had to get my lectures together for the class that I was teaching in the winter quarter. I had NIH grant deadlines that I had to meet. I still have to keep my lab funded. So students need thesis projects. And students need qualifying exams and thesis defenses.
CAROLYN BERTOZZI: And so in a way, everything is the same as it was before. On the other hand, I mean, we'll see if opportunities arise, where I might be able to be a little bit more bold in the science that we do. Take some risks on things that have a longer horizon than typical projects that you feel are fundable and using normal mechanisms. I'll just say, I am open to opportunities to have more flexibility in the research that I do.
CAROLYN BERTOZZI: But at the same time, it really has been business as usual to be honest.
KEVIN DAVIES: Yeah, very good. Well, Carolyn, I think that's about all the time we have. We made it through without a single Tom Morello reference.
CAROLYN BERTOZZI: It's the first.
KEVIN DAVIES: You have to share that story very quickly for the people, thousands of people, watching who maybe aren't aware of who Tom Morello is--
CAROLYN BERTOZZI: Apparently, even more notable than getting a Nobel Prize, was the fact that when I was like 19 years old, I played in a band, a college band, with the musician who later became well known. And it was Tom Morello. Tom graduated from Harvard about two years ahead of me. And so while I was back at Harvard taking midterms in chemistry classes and stuff, he went to Los Angeles and made it in the music business.
CAROLYN BERTOZZI: He formed the band, Rage Against the Machine. And I think they were just inducted into the Rock and Roll Hall of Fame, actually. So yeah, great. And then he also formed another band called Audioslave. And he has a very distinctive style of musicianship. And he's also a composer. He is well known for writing songs that have political messages.
CAROLYN BERTOZZI: And he still performs, you know. And he tours. And he records. So anyways, he's very famous-- much more famous than I am on the global scale, certainly. And that was my big brush with fame.
KEVIN DAVIES: That's right. Well, you're both rock stars as far as we're concerned. So anyway, Alex, I let you close it out.
ALEX PHILIPPIDIS: Sure. Thanks, Kevin. And our thanks to Carolyn Bertozzi of Stanford University-- in the 2022, Nobel laureate-- for launching the State of Biotech, 2023. Our next session is about to get underway. Kevin will moderate the state of CRISPR and genome editing. A panel discussion featuring Rachel Horowitz, the CEO of Caribou Bioscience, and Rodolphe Barrangou from North Carolina State, NC State, and the editor and chief of the CRISPR Journal.
ALEX PHILIPPIDIS: You're watching the State of Biotech, 2023, sponsored by Cytiva and supported by the Rosalind Franklin Society. Enjoy the rest of the program.
Segment:0 .
KEVIN DAVIES: Welcome to the opening session of the State of Biotech, 2023. I'm Kevin Davis. We are thrilled to welcome our very special guest, Carolyn Bertozzi. Since 2015, Carolyn has been at Stanford, helping launch the ChEM-H Institute, Chemistry, Engineering and Medicine for Human Health. Although I dare say, her spiritual home might still be UC Berkeley, where she spent the better part of two decades.
ALEX PHILIPPIDIS: I'm Alex Philippidis. In addition to being an HHMI investigator for the past 23 years, Carolyn is a co-founder and advisor to at least half a dozen biotech and pharma companies, something we'll talk about. And, of course, she is the winner of the 2022 Nobel Prize in chemistry. Congratulations on being the 2022 Nobel laureate. Has that sunk in?
CAROLYN BERTOZZI: By now, it has, since it's almost a year ago. So first of all, thank you Alex and also Kevin. You're very kind in your introductory remarks. And I'm very happy to be here.
KEVIN DAVIES: What was the phone call like, Carolyn?
CAROLYN BERTOZZI: Well, the Nobel committee, which is organized by the Royal Swedish Academy of Sciences, they make their big decision. And they make their announcement on a pre-scheduled date and time, every year. And so the whole world knows that people, who care, in the world know that on October 5, at what turns out to be about, 1: 43 AM, California time
1: is when the Nobel committee chair makes a phone call in the hopes of reaching the laureates and giving them the good news. And so my phone is my alarm clock. So it's always next to my bed. And it went off and I was confused, because it didn't seem like it was 6:00 AM. It was 1:43. And then I saw that-- you know how it is, I have an iPhone and it tells you where the call is coming from.
1: And it said, Stockholm.
KEVIN DAVIES: So at least you heard from them directly. Rather than, Jennifer Doudna, I understand, had to hear it from a nature reporter, because she slept through the original call.
CAROLYN BERTOZZI: Well, yeah. I mean, think if my phone hadn't been right there, I would have slept right through it. It was a bit confusing.
KEVIN DAVIES: Your name, of course, has been-- this wasn't an outside pick. Your name had been regularly floated as a potential winner-- seemed, to me more, a matter of when rather than if. So did you go to bed that night thinking, I'm curious. This could be the year.
CAROLYN BERTOZZI: No, I did not. And for the simple reason is-- you're right, there's buzz. There's the gossip channels in the little world of chemistry. People like to make predictions, and make bets, and play games, and tweet their speculations and stuff. But at the end of the day, all the people in the world can tweet and speculate and bet. But if nobody actually nominated you, for a Nobel Prize, you're not a contender. And so you don't even know if you've been nominated.
CAROLYN BERTOZZI: I mean, it's flattering that people would even have a hunch that maybe you're somewhere on the list. But just because it's on Twitter, it doesn't say anything about the real world.
KEVIN DAVIES: Yeah, but unlike the laureates of the, I guess, the previous two seasons, you were actually able to go-- I think with them, as well-- to Stockholm for the prize ceremony. What sticks in your mind about that?
CAROLYN BERTOZZI: That it was an unbelievable, magical event. And people I know who've been there and have experienced this told me that it would be. It was spectacular. And it was extra special to have the 2021 and 2020 laureates there as well, because I know many of them. And Jennifer Doudna was one of them. And She was there with her family. And so there's a lot of Berkeley people who were there celebrating with her and with other laureates.
CAROLYN BERTOZZI: So it just became even more of a party to have so many great people and friends there.
KEVIN DAVIES: Your prize or your share of the prize was for click chemistry. And for those watching who aren't card-carrying chemists, what could you briefly describe click chemistry? And what is the relationship, if any, to glycobiology, which is really the field that you've helped propel forward over the last couple of decades?
CAROLYN BERTOZZI: Yes, so my fraction of the Nobel Prize was actually in recognition of a type of chemistry that my lab invented back in the late 1990s. And we call it bioorthogonal chemistry. And then I shared the prize with Morten Meldal and Barry Sharpless. And their chemistry is I think more recognizable as click chemistry. And in fact, that's a term that has been attributed to Barry Sharpless.
CAROLYN BERTOZZI: But in Stockholm, last December, I learned that actually his wife coined the term. She's a writer and has a gift with language. And she came up with that beautiful soundtrack for the chemistry. And the bioorthogonal concept and the click concept have some overlap. But they also are distinct. And so for me, the term bioorthogonal was something we coined to describe chemical reactions that would take place amongst two different reactive groups that do not interact or interfere with anything in a biological system.
CAROLYN BERTOZZI: And by having that quality, you can actually take these two reagents and have them form a bond. And do a chemical reaction in a living system, like in cells, or in a laboratory animal, and now, today, inside a human patient. And the chemistries are so selective, and so clean, and harmless that you can literally do chemistry in a person the same way that 20 years ago chemistry would be done in a glass flask.
CAROLYN BERTOZZI: And we did that. We had a lot of applications in mind for that. Click chemistry, Barry coined that term. And he describes it as chemical reactions that are very robust, reliable, high yielding, don't produce like a lot of byproducts. And therefore, are very useful in chemical synthesis. And it turns out that some of those qualities of selectivity, reliability are also important in a bioorthogonal reaction.
CAROLYN BERTOZZI: But the click chemistries that Barry and Morton developed and were recognized for with the prize are chemistries that you wouldn't do. You wouldn't be able to do in a living system, because they require a toxic catalyst.
KEVIN DAVIES: OK, let's talk about glycobiology. How did you first get interested in this field? And what is the medical relevance of understanding and working on glycobiology?
CAROLYN BERTOZZI: I first learned about glycoscience more broadly as a grad student. And I had never-- I knew nothing before that period of my life. I hardly learned anything about sugars when I was an undergraduate. Generally, the mainstream biology student has very little exposure to this. I mean, the textbooks don't cover it very well, if at all. And the mainstream biologist doesn't know much about it.
CAROLYN BERTOZZI: And so I walked into graduate school with zero exposure to this. And then a new professor had just arrived at Berkeley named, Mark Bednarski. And he's the person who introduced me to the field. So it was in grad school that I started learning more about sugars, first, as targets for chemical synthesis. So I was focused on carbohydrate chemistry. But then I started reading more about the biology of sugars in human health and in human disease.
CAROLYN BERTOZZI: And, in particular, the sugars that are on the surfaces of cells. So our cells have a sugar coating. Every cell type has a different sugar coating. And the sugars are molecular information. And they interact with receptors on other cells. And they're involved in all facets of human biology just as much as proteins, or nucleic acids, or the other biopolymers.
CAROLYN BERTOZZI: But back when I started grad school, this was in the late 1980s, the field of biology and biochemistry, which decades earlier, represented carbohydrates as much as it represented nucleic acids and proteins. But the molecular-- excuse me. The molecular biology revolution had focused the attention of biologists so much on DNA and the central dogma-- DNA to RNA to proteins and genetic engineering.
CAROLYN BERTOZZI: That the carbohydrates fell out of fashion. And then a whole generation of scientists, like lost the expertise. So there I was in grad school doing chemistry on sugars and reading about their importance in biology. But hardly any labs were really studying them at that time. They had kind of drifted into a niche area. And it seemed to me that there would be a huge opportunity to improve human health by understanding the carbohydrates better.
CAROLYN BERTOZZI: And chemical tools turned out to be very empowering for this.
KEVIN DAVIES: And it's glycobiology is still the central thrust of your research laboratory?
CAROLYN BERTOZZI: Yes, it is. And it always was. So in chemistry circles, people might recognize me for bioorthogonal chemistry, which has lots of applications outside of glycoscience. It has applications in all walks of biology, and in medicine, and biotechnology. But originally, the motivation for developing these chemistries came from my lab's interest in imaging cell surface glycans.
CAROLYN BERTOZZI: And so that was our motivation. We invented the chemistries, because we knew we could apply them to molecular imaging of cell surface sugars. But it turns out you can apply them to all other kinds of stuff too. So now, those chemistries are just part of the fabric of chemical biology. People use them for all kinds of applications.
CAROLYN BERTOZZI: But we did use those chemistries to image cell surface glycans. We learned with those tools how glycans change in disease, especially cancer. And that led us to define a role for certain types of cancer-associated glycans in immune modulation, which has then led to new technologies for cancer immune therapies that are based in glycoscience. So glycoscience has always been the epicenter for me.
KEVIN DAVIES: Alex is going to talk to you, in just a minute, about some of your work in industry with numerous affiliations in the biotech sector and some big ones in big pharma as well. But tell us a little bit-- before we do that-- about ChEM-H, which was one of the major reasons, I'm sure, that you left Berkeley to cross over to Stanford. It's an important and, perhaps, groundbreaking interdisciplinary institute.
KEVIN DAVIES: I wonder if you could just help us understand what really sets it apart.
CAROLYN BERTOZZI: Sure, yes. And thank you for asking. My virtual background here is an atrium in the middle of the building, which houses the institute.
KEVIN DAVIES: That's very cool.
CAROLYN BERTOZZI: The institute is now called Sarafan ChEM-H. And for Lily Sarafan who gave a very generous gift to help us support the institute. And the ChEM-H part is an acronym. So that stands for Chemistry, Engineering, and Medicine. That's the ChEM, Chemistry, Engineering and Medicine for Human Health. And that's the H. So H is humans. And the institute is focused around translational molecular science.
CAROLYN BERTOZZI: And our philosophy is that, by bringing scientists from biology, chemistry, physics, data science, engineering, and also, clinician scientists into this one physical space, that we can solve big problems in human medicine, which includes defining the molecular mechanisms of disease, more clearly. And then developing new types of therapies and diagnostic tools to improve human health.
CAROLYN BERTOZZI: And so that's what we're doing. And you're right, the opportunity to move to Stanford to help launch this institute was very compelling, especially since my research interests at that time-- this is now eight years ago when I made the transition. My research interests were kind of shifting more and more translational at Berkeley. And Berkeley is a wonderful world-leading institution in basic science and engineering.
CAROLYN BERTOZZI: But it's not a place with a medical center and/or a hospital system. So there's only so far I felt that I could take my research, at least at that time, at Berkeley. Whereas, Stanford offered the opportunity to have a very tight connection with the clinical sciences.
KEVIN DAVIES: Yeah, well, that's a great segue. Alex, over to you.
ALEX PHILIPPIDIS: Thanks, Kevin. Carolyn, you've been an advisor to some big pharma companies and you are now on the board of directors at Eli Lilly, have those relationships led to greater recognition of glycobiology that's now reflected in some actual drug programs? And how so?
CAROLYN BERTOZZI: Oh, yeah. Well, let me just clarify my involvement with biopharma companies. I was on the board of Lilly from around like 2016 to 2021-ish. And then I had to resign from the board, because of a conflict of interest, actually. So Lilly did a deal with one of my startup companies that I had co-founded. And it was determined that there was a conflict for me to be on the board and also have the company involved with my company.
CAROLYN BERTOZZI: So I stepped off the board. So I'm not on the board of Lilly, right now. I am on the board of directors of Alnylam and also, Omniab. So I do have board seats but not with Lily. And then I have founded several companies. I think, right now I'm trying to finance company number 12-- I think it is. It's the headcount. And the companies I have co-founded are companies, for the most part, which are based on technologies that spun out of my academic lab.
ALEX PHILIPPIDIS: And one of those the company I think you're referring to is Elysia Therapeutics, which a couple of years back, launched an exciting collaboration with Lilly to develop and commercialize targeted therapeutics based on light tech with a potential-- as announced, back then-- for up to $1.6 billion in milestones. What progress have been made on that since then?
CAROLYN BERTOZZI: Oh, it's a wonderful partnership. Lisa and Lily are prosecuting several interesting pre-clinical candidates. So, yeah, I think that's going to be a very fruitful partnership.
ALEX PHILIPPIDIS: Great. And you've also co-founded-- among companies, in addition to Elysia-- Redwood and Enable, and Palleon, and InterVenn Bio, and OliLux. This might be a bit like naming your favorite child. But which of these companies stands out to you and why?
CAROLYN BERTOZZI: Oh, yeah, you can't ask that question. I love them all, equally and for different reasons. And they're all different. Every one of these companies is based on a different technology. OliLux, Enable, and InterVenn are diagnostics companies, clinical diagnostics. Whereas Redwood, which was acquired by Catalant-- so now, it's part of Catalant Biologics. And Palleon, and Elysia, and some other companies I've formed since then are therapeutics companies.
CAROLYN BERTOZZI: And they're all based on different technologies. So Palleon and Redwood are the two that I formed earlier. And they now have clinical candidates. So they have molecules in the clinic. Redwood is an antibody drug conjugate company, which was a very next generation, site-specific, controlled dar, focused technology. Palleon is a glycoscience, rooted company that's making cancer immune therapies that are targeted enzymes.
CAROLYN BERTOZZI: So it's a totally different modality from other cancer therapies. And they're also a clinical stage company. Whereas, Elysia is still preclinical. And the LYTAC technology as we call it, which stands for Lysosome Targeting Chimera. That platform, basically, executes a targeted protein degradation, where the targets of interest are extracellular proteins.
CAROLYN BERTOZZI: So the LYTAC technology of lycia, you can think of as kind of a cousin to the PROTAC technology of companies, like Seefor, Chimera, Arvinas, and so on.
ALEX PHILIPPIDIS: OK, and you've also worked with tech entrepreneur, Matt Wilsey, who co-founded the non-profit Gray Science Foundation. And then, he and you co-founded for profit Gray Science, focused on NGLY1 deficiency. Now, I Gray Science was developing a gene therapy for that disorder. And one time, as of last year, there was talk about starting clinical trials this year, has that been launched or otherwise how soon can we expect the first patient to be dosed?
CAROLYN BERTOZZI: Yes, so the trial has not initiated yet. Right now, Gray Science is in back and forth discussions with the FDA about what needs to be in their IND package. And they're still completing some of the experiments, animal, preclinical experiments that the FDA would like to see in that package. But if all goes according to plan, they should be able to initiate their trial-- let's see, we're still in the end of 2023. So sometime mid to late 2024.
CAROLYN BERTOZZI: And they're in the manufacturing stage right now. So they're generating the material. It's a gene therapy, adenoviral associated vector-based gene therapy. And it's being manufactured for that first clinical study. So we're getting there. The path is, I think, it's fairly clear at this point.
ALEX PHILIPPIDIS: Great. And speaking of whether small or especially a larger biopharmas, many have spoken out publicly against the Biden administration plan to negotiate with developers of 10 blockbuster drugs, including some familiar names like Jardiance, and Eliquis, and Xarelto. How much of a headwind will that be on drug development and commercialization? And will generic pressures, on those drugs, offset the impacts?
CAROLYN BERTOZZI: Well, it's early days. And we'll see. And so far, they've only named these 10. And the rules for drug pricing negotiations are for drugs that are covered by medicare. So these are drugs that target large populations of people that tend to be older people, which is a lot of medicines but not all of them. What I find most frustrating about that component of the Inflation Reduction Act is the fact that it targets small molecules in a different way than biologics.
CAROLYN BERTOZZI: And they're treated differently. And for small molecules, they've basically shortened the period of exclusivity during which a company can benefit from revenue, from their drug before the generic competition comes in. And it's so short now that, I think you're already seeing changes in behavior, in decision making, in the pharma industry, because the clock starts to tick on your very first approval for this new, shortened, exclusivity period.
CAROLYN BERTOZZI: And in the past, a pharmaceutical company could make decisions. They would develop a new drug, which had potential applications across a lot of different indications. But they'll start with a smaller indication just to get the clinical proof of concept in a setting where the clinical trial might be a little less expensive.
CAROLYN BERTOZZI: And so it's less risky, because you're not spending quite so much money on an untested drug yet. And then once they get approval, in one indication, they can then pursue new-- sort of, they call them-- nylex, which is new indication extensions. But the problem is now, as soon as they get that first approval, the clock is ticking. And they're going to run out of exclusivity.
CAROLYN BERTOZZI: And there's no time to explore all the other potential indications before generic competition comes in. So there's no incentive. And so that means either companies won't bother exploring extensions to other indications. Or at the very beginning of their clinical development program, they'll just forget about small indications that aren't going to be very lucrative and just go right into big lucrative indications, which means that a lot of medical need will go unmet.
CAROLYN BERTOZZI: And the drug won't get tested in smaller indications, which is a bummer for those patients. So these are the things that I am most concerned with, not so much the top 10 that they just named. Those were pretty predictable, I think. But more, the sort of the way that it changes the incentive structure so that pharma companies will have to make different kinds of decisions that I don't think are in the best interest of patients.
ALEX PHILIPPIDIS: Kevin, over to you.
KEVIN DAVIES: Thank you. Carolyn, just a few more questions before we let you get back to work. I want to go back to the Nobel, for a second. You are the latest in a, unfortunately, short line of very high profile female scientists who've won the prize, of course, in chemistry-- Doudna and Charpentier. You mentioned partying with Jennifer and her family in Stockholm last year-- Frances Arnold, of course.
KEVIN DAVIES: And a theme, over the last couple of years, has been trying to elevate or promote the cause of women in science. I wonder, what have you been able to use your new platform for over the last 11 months or so?
CAROLYN BERTOZZI: That's a great question. Enhancing the participation of and the due recognition of women in science is something that I've been devoting energy to throughout my entire career. So that's been going on for a long time. And so I've been in this business, let's call it, 30 years. And 11 months of that I'm a Nobel laureate. So I don't think I know yet whether having or not having a Nobel Prize makes a difference in terms of the messaging and the impact I could have, I don't know.
CAROLYN BERTOZZI: But I'll say that, I have noticed, after I was awarded the Nobel Prize, that I get invited to do a lot of things like this, where I get interviewed. And I make remarks. And it's on YouTube, or it's on Twitter, or something. And so definitely, I've been given a platform that has more visibility. But the messages don't change.
CAROLYN BERTOZZI: I mean, there's nothing different in my philosophies now than 11 months ago. And really, I think the question is, will people listen more? Will the words that have been coming out of my mouth, all along, fall with more gravity now? I don't know. But I would like to think that every time there's a little bit more representation of women at in the most visible spheres of science, that younger scientists who are making life changing career decisions-- they might be choosing a major in college, right now.
CAROLYN BERTOZZI: Or deciding whether to go to grad school, or med school, or law school, or something. Or just finish their PhD and trying to figure out what kind of career to pursue. And maybe, along the way, people who see me maybe that's a positive influence in their decision making. And so maybe that's-- and I'll never know. But I'm sure there's more I can do as a Nobel laureate. And I'll find out, right.
KEVIN DAVIES: Yeah, yeah, what's the strangest, or perhaps, funniest, or most peculiar thing, or request that's happened to you over the last year?
CAROLYN BERTOZZI: Oh, well, strange and peculiar would be things like, when I was in Stockholm with the other Nobel laureates in December last year, the hotel we were staying in, every time we came and left that hotel, there were lines of people wanting autographs. I've never been asked for an autograph before. That's like Kobe Bryant was the autograph guy. And now, Taylor Swift, but me? So that that's a little interesting. Strangers in airports have recognized me, which is a surprise, and asked me for autographs, or selfie, photos, and things like that.
CAROLYN BERTOZZI: So I think being a small time celebrity is a very new experience for most scientists, I think.
KEVIN DAVIES: Perhaps, they're recognizing one of your viral karaoke videos rather than the Nobel Prize.
CAROLYN BERTOZZI: Yeah, yeah, I don't think those are going to do much to help my reputation. But anyways, I'm grateful that somebody like cares about science, I think.
KEVIN DAVIES: Yeah, you briefly talked, just a minute ago, about younger scientists. We have probably a very large group of young scientists from around the world watching today. What is your advice to young scientists maybe wrapping up their PhD or perhaps, trying to decide whether to stay in academia or abandon it for industry? Do you have any words of wisdom for them?
CAROLYN BERTOZZI: Oh, I mean, I think there's so many great opportunities. That you can do great science in lots of different environments. And I think, old tropes about the difference between academia and industry-- I think, a lot of that stuff has largely gone irrelevant. To the point where nowadays, you can do just as, if not more exciting science in a biotech company, then you could do in an academic center. You often have access to more resources, and more technology, and more human capital than an academic does.
CAROLYN BERTOZZI: And so the science in industry is very cutting edge. And I'm envious, sometimes, of what I'm seeing in companies that they can do. And I'm like, gosh, I wish we could do that but we have the infrastructure. So that's number one. Number two, is I think what's also drifting away is this idea that it's either, or. So now, you can see plenty of examples of people who might have spent some time in industry and then transitioned to an academic position or vice versa.
CAROLYN BERTOZZI: Or kind of bouncing back and forth. Or maybe taking a turn into the world of venture capital and then coming back to academia. And one of the early hires in my institute was Peter Kim who after an illustrious academic career at MIT and the Whitehead Institute, was recruited to run Merck Research Labs. So he was the head of research at Merck for about 12 years. And then when he was ready for something new, we hired him at Stanford.
CAROLYN BERTOZZI: And I think you'll just see more and more of this kind of blending, because I think that the training and the experience you get in industry can be really transformative in an academic setting and vice versa. It's a very exciting time, because a new scientist has so many opportunities to choose from. And all of them are great.
KEVIN DAVIES: And finally, Carolyn, what are you most looking forward to as far as your own research program and your own scientific career as they blossom in this post Nobel era?
CAROLYN BERTOZZI: Well, on the one hand, when I woke up back in San Francisco after two magical weeks in Stockholm and around Europe, is business as usual. In many ways, I had to get my lectures together for the class that I was teaching in the winter quarter. I had NIH grant deadlines that I had to meet. I still have to keep my lab funded. So students need thesis projects. And students need qualifying exams and thesis defenses.
CAROLYN BERTOZZI: And so in a way, everything is the same as it was before. On the other hand, I mean, we'll see if opportunities arise, where I might be able to be a little bit more bold in the science that we do. Take some risks on things that have a longer horizon than typical projects that you feel are fundable and using normal mechanisms. I'll just say, I am open to opportunities to have more flexibility in the research that I do.
CAROLYN BERTOZZI: But at the same time, it really has been business as usual to be honest.
KEVIN DAVIES: Yeah, very good. Well, Carolyn, I think that's about all the time we have. We made it through without a single Tom Morello reference.
CAROLYN BERTOZZI: It's the first.
KEVIN DAVIES: You have to share that story very quickly for the people, thousands of people, watching who maybe aren't aware of who Tom Morello is--
CAROLYN BERTOZZI: Apparently, even more notable than getting a Nobel Prize, was the fact that when I was like 19 years old, I played in a band, a college band, with the musician who later became well known. And it was Tom Morello. Tom graduated from Harvard about two years ahead of me. And so while I was back at Harvard taking midterms in chemistry classes and stuff, he went to Los Angeles and made it in the music business.
CAROLYN BERTOZZI: He formed the band, Rage Against the Machine. And I think they were just inducted into the Rock and Roll Hall of Fame, actually. So yeah, great. And then he also formed another band called Audioslave. And he has a very distinctive style of musicianship. And he's also a composer. He is well known for writing songs that have political messages.
CAROLYN BERTOZZI: And he still performs, you know. And he tours. And he records. So anyways, he's very famous-- much more famous than I am on the global scale, certainly. And that was my big brush with fame.
KEVIN DAVIES: That's right. Well, you're both rock stars as far as we're concerned. So anyway, Alex, I let you close it out.
ALEX PHILIPPIDIS: Sure. Thanks, Kevin. And our thanks to Carolyn Bertozzi of Stanford University-- in the 2022, Nobel laureate-- for launching the State of Biotech, 2023. Our next session is about to get underway. Kevin will moderate the state of CRISPR and genome editing. A panel discussion featuring Rachel Horowitz, the CEO of Caribou Bioscience, and Rodolphe Barrangou from North Carolina State, NC State, and the editor and chief of the CRISPR Journal.
ALEX PHILIPPIDIS: You're watching the State of Biotech, 2023, sponsored by Cytiva and supported by the Rosalind Franklin Society. Enjoy the rest of the program.
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