Nobel Prize Conversations

“The main goal is to make discoveries and gift them to humanity”

“Your purpose as a scientist is not to achieve fame or money, that is not your purpose, those might be side effects and good for you, that could be wonderful for you but it is a side effect, it is not the main goal. The main goal is to make discoveries and gift them to humanity. And those discoveries and that knowledge stays with humanity long after you are gone.”

Meet chemist Carolyn Bertozzi in this new podcast episode, conducted in March 2023, where she speaks about her two life-long loves: organic chemistry and music. Her love of music lead to her playing in a college rock band with Tom Morello whilst her love of organic chemistry earned her a Nobel Prize in Chemistry. Bertozzi also speaks about her desire to create a diverse and open lab environment and how important that is for research. A true advocate of diversity, she sees clearly the advantages derived from diverse ideas and perspectives. The host of this podcast is nobelprize.org’s Adam Smith, joined by Clare Brilliant. This podcast was released on 11 May, 2023.

Below you find a transcript of the podcast interview. The transcript was created using speech recognition software. While it has been reviewed by human transcribers, it may contain errors. 

Transcript

Carolyn Bertozzi: I tell my students that the best armament that you can have as a scientist to navigate these realities is really great innovative ideas that put you, at least for a time being, in a kind of place of your own, so that you have your turf on the playing field, and it came from you, and it’s unique to you, and it’s personal to you.

Adam Smith: I wish I had been supervised by Carolyn Bertozzi. She says with such clarity the things that are so important. Don’t worry about all the extraneous stuff, but just focus on what you yourself can bring in terms of ideas. If you have good ideas, they will serve you well and protect you from the inevitable difficult things that you have to deal with as a scientist. She made it sound quite uncomplicated. I like that. I like the idea that this is open to everybody. She made that clear. There are lots of people with good ideas out there, good brains, and I suppose if you listen carefully and follow her advice, you can do this too. Let’s listen to my conversation with Carolyn Bertozzi.

MUSIC

Clare Brilliant: This is Nobel Prize Conversations. Our guest is Carolyn Bertozzi, the 2022 chemistry laureate. She was awarded the prize for extraordinary achievements in bio-orthogonal chemistry – a field she herself named – creating safe chemical reactions within living organisms.  She shared the prize with Barry Sharpless and Morten Meldal.

Your host is Adam Smith, Chief Scientific Officer at Nobel Prize Outreach. This podcast was produced in cooperation with Fundación Ramón Areces.

Carolyn Bertozzi is the Anne T and Robert M Bass professor in the School of Humanities and Sciences at Stanford University in Palo Alto, California. She is also an Investigator at the Howard Hughes Medical Institute.

She speaks to Adam about how different molecules have different personalities, why she became her own PhD supervisor, and her musical claim to fame: playing in a college band with a future superstar.

But we begin – with romance.

Smith: I wanted to start with a love affair, a love affair between you and organic chemistry. Tell me about your first encounter with serious organic chemistry.

Bertozzi: For me, it began with the class that I took as a sophomore in college, which at the outset I was looking forward to as my last ever chemistry class. I took that class because it was required as a pre-med student, not because I had any inclination that I would enjoy it. Again, I thought it would be the last chemistry class I would ever have to take and that would be a good thing. Then much to my surprise, a week or two into the class, I found myself really engaged with the subject and I felt like it had this beauty and elegance and it just made perfect sense to me and I just couldn’t get enough of it. It turned out to be far from the last chemistry class I would ever take.

Smith: For those not familiar with organic chemistry, it’s the combining together of carbon-based molecules in all sorts of wonderful ways. But for many people, it’s extremely daunting. You’ve got lots of structures that are kind of hard to decipher if you don’t know what you’re doing and so many different ways of joining them together and that’s terribly confusing until you really get into it. A lot of people find it quite off-putting and just bewildering. Why didn’t you?

Bertozzi: I’m aware of that reputation because I had heard that before I took the class. I found it to be very different from that description. I did not find it overwhelming and bewildering. I found it to be like logic, especially since you can break the molecules down into their individual components that have recognisable reactivities. We call them functional groups. Smaller collections of atoms can behave in predictable ways regardless of their surrounding. If you understand really just a handful of core principles, then you can predict how two molecules will engage with one another. Then you can also start to apply that logic to creating roadmaps to build larger, more complex molecules from simple building blocks. I guess my brain just is built in the right way to understand the deconstructions and to do the pattern recognition. It’s also about looking at a molecule and having intuition about its behaviors and being able to predict the personalities of molecules so that you can predict the outcomes of chemical reactions. It’s very visual and I’m a visually minded person. It’s all about seeing these molecules in three dimensions and imagining in your mind’s eye what happens when two molecules encounter each other and then understanding some core principles of chemical reactivity. People told me in advance, oh, you’re going to hate that class. You have to memorise so much stuff. I didn’t think you had to memorise much at all. It was just understanding some core principles.

Smith: It’s extraordinary. You make it seem so vivid. And the idea of personalities of molecules is absolutely beautiful. I’ve never heard that before. I love it.

Bertozzi: Oh, really? People who are practitioners of organic chemistry think this way. Every molecule has its own personality, right? Some are really chill, and others are aggressive and unpredictable and sort of particular and delicate. For every personality on earth, you can find a molecule that kind of matches up with that personality.

Smith: Then the vision of all these molecules dancing around, making connections, as you say, it must take a particular sort of visual way of looking at the world. I don’t know what it is, a visual imagination to put it together.

Bertozzi: Yes, it is very visual and very imaginative. I found it was unlike any other science or math class that I had ever taken. Whereas general chemistry as it’s taught, at least as it was taught when I was a freshman, was really centered around physical chemistry, which is more quantitative and for me a little bit more abstract. I had difficulty with that subject. I had difficulty with physics, especially as physics became more and more into complex mathematics. I hung in there through linear algebra, but I started to lose it in quantum mechanics and differential equations. It was just too abstract for my brain. I struggled through those kinds of classes. But when it came to organic chemistry, it was a totally different part of the brain that was engaged. For me, it was a stronger part.

Smith: The other thing about organic chemistry is that synthetic organic chemistry did have, I don’t know if it still does have a sort of slightly macho reputation, because when you get in the lab and you build these molecules and you do 35 step synthesis, it’s kind of yeah, it’s a slog. Do you recognise that picture of it?

Bertozzi: Yes, you’re right that the field of organic chemistry through, I’m sure there’s some idiosyncratic origin story to how this culture evolved, but it did have a macho culture, certainly in the 1980s when I discovered the subject and it probably still does now in certain areas. I don’t know that that has to do with anything inherent to the subject. I actually don’t think there’s anything about organic chemistry, which requires a macho culture in order to execute or to succeed. There’s really no connection between the intrinsic properties of the science and that culture. I think instead, you know, like most cultural, historical, evolutions, there were probably a handful of practitioners in the very early days of the field, and their particular personalities have an outsized influence on how the field unfolds. That’s true in academia in general, right? Because we know that in academia, one professor can influence hundreds of, or thousands even, of students. So if a handful of people have a certain personality type, and they happen to be the leaders of a field when the field is young, they will have an outsized influence on the culture for generations and generations, because their trainees inherit some of their philosophies. A culture evolves from that. I think it’s interesting, you can look through other branches of chemistry, other subdisciplines, and you’ll find different cultures within each subdiscipline, having nothing to do with any inherent difference in those subdisciplines. I think it really is something you trace back to individuals. Science is practiced by people, people have their personalities and their idiosyncrasies and their prejudices and all of their failings as human beings. Those are manifest in the way that we practice the science.

Smith: What a fantastic opportunity then, if you are a practitioner of science, and you have the potential to influence generations of people coming after you to set things on a good path, to start a more palatable way of viewing a particular field, if you like. Let me play you a clip of you speaking at the Nobel banquet in December.

Bertozzi: Okay.

CLIP with Bertozzi speaking: We are indebted to our students, students, postdoctoral fellows, and staff for their contributions that are embodied in this prize.

Smith: That was a beautiful moment. It’s not so usual for people to mention their students and lab in the banquet speech. Obviously, the lab is incredibly important to you and the culture of the lab, as we’ve just been discussing. How do you create that sort of desirable culture in a lab?

Bertozzi: I can only speak for my own lab, I guess. For me, it’s important that my lab is a place where people can do the best science most effectively. Then the next question is, what’s the culture that promotes the best science? What I mean by that is the most creative science, the most innovative science, productivity in science, integrity, quality. In my experience, those attributes come from a lab in which people feel like they belong there. They feel supported. They can make friends and collaborators within the lab and feel comfortable being transparent about their science and generous with their time. That’s the culture I try to create. It has to start with me demonstrating those values in the way that I treat my coworkers and in the way that I expect them to treat each other. I lay this out pretty clearly in presentations to my lab that I give every year so that new people who have just arrived can understand what I value and how I expect people to behave in my lab. I think mutual respect and giving people the freedom to exercise their own creativity and to make their own choices and bringing in diversity so that people can come in with different ideas and feel free to share those ideas and with different mindsets. You never know where the next big insight will come from. It usually comes from an unexpected place. So I try to create a diverse environment where the unexpected ideas can come up and thrive.

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Smith: As we go around the world talking to students, their concerns are always rather similar wherever they are. How do I make my mark? How do I negotiate the terrible publishing environment? How do I pick the right place to be? All of that is about me getting on. It’s about I’ve got to kind of drive through my own career. How do those things come together in your lab?

Bertozzi: You’re right. All of those pressures exist. As a group, the best I can do is acknowledge the reality of the ecosystem that we live in. We’re not cut off from the rest of science and society. We have to navigate those tensions, sometimes indirectly. My students worry about the world and all of these pressures and so on, and sometimes directly. Sometimes we find ourselves in competitive situations with other labs, or sometimes we might have a collaborator with whom we have a different philosophy or a different set of values, and we have to kind of negotiate around that. This is reality. The best I can do is try to create an environment where we can talk about it honestly and acknowledge the things we don’t like and can’t change, and the things that we don’t like and can change. I tell my students that the best armament that you can have as a scientist to navigate these realities is really great innovative ideas that put you, at least for a time being, in a kind of place of your own, so that you have your turf on the playing field, and it came from you, and it’s unique to you, and it’s personal to you. To the extent that you can have really innovative, cutting-edge ideas, there’ll be less competition to worry about. When the competition starts to pile up, that’s great. That means you’ve had an impact, and it’s time to think about the next big new innovative idea and keep moving forward. There’s that philosophy. Then the other philosophy is that you can’t control how other people behave. You can only control how you behave. At the end of the day, you have to look in the mirror and look at yourself and feel good about your behaviour and feel good about your contributions. Your purpose as a scientist is not to achieve fame or money. That’s not your purpose. Those might be side effects, and good for you. That could be wonderful for you, but it’s a side effect. It’s not the main goal. The main goal is to make discoveries and gift them to humanity. Those discoveries and that knowledge stays with humanity long after you are gone. You’re gone before you know it in this world, in the scheme of life on Earth. Your discoveries will have a much longer-lasting impact than you and your physical being. Keep that in mind, that regardless of your frustrations, because as a human being, you’re subject to feelings of anxiety, jealousy. There’s negative experiences all human beings have to deal with. But at the end of the day, it’s the discoveries you make and the contribution to humanity that long outlasts any of that.

Smith: I can just imagine a whole bunch of students leaving the room after you’ve just said that to them, feeling really buoyed up and fantastic.

Bertozzi: I hope.

Smith: At least it should last for a while before the next disaster hits. But yes, I love the thought that, yes, the best defense is having ideas. Those ideas will give you confidence to negotiate everything else.

Bertozzi: Try not to pile on to what everyone else is doing. Look for those areas where it’s just a wilderness with missing knowledge that needs to be filled in. For us, we work in biomedicine. We’re interested in discoveries that benefit human health. There’s so much we don’t understand about human biology. We’ve just scratched the surface as a field. After hundreds of years of knowledge, there’s so much we still don’t know, because there’s just so much there. If it takes hundreds of millions of years to evolve this being, one should expect it’s going to take a while to understand it all. There’s no reason to go out there and work on things that other people are already working on when there’s so much to do that no one is doing. That’s the mentality. Then again, at the end of the day, you just have to sort of take the high road, do the right thing, and focus on the science and not on the peripherals. I think that’s a mechanism that helps people to be happy and to minimize the stress about all those other things you mentioned. But having said that, you mentioned the publishing system, the pressures and the dysfunction of scientific publishing. That’s something that I would challenge my trainees to try to do something about. That is a changeable system. It was invented by humans. It can be changed by humans. To the extent that some of my trainees might end up working in the publishing industry or being in a position to affect change in publishing, maybe through policy, for example, I would encourage them to do that, to exercise that power.

Smith: Yes. It’s going to take a generational shift.

Bertozzi: Or more.

Smith: It’s such a massive problem. Of course, people try at the edges to change things, but somehow it’s got to come from within, as you say.

Bertozzi: That’s true. But again, I’ve lived long enough now to see what I thought were just immutable institutions actually change. I think things can change and online publishing was a huge disruption. You saw a big change in the publishing industry in the late 1990s, 2000s around that. I think we can change things and we should change them to the extent that they actually undermine scientific progress. That’s the ultimate litmus test. If some institution is actually impeding the progress of science and depriving humanity from discoveries that might otherwise have been made, that’s how you know it’s time to disrupt it.

Smith: Keeps coming back to the central message. It’s all about the discovery. That’s what matters.

Bertozzi: Right. Yes.

Smith: Yes. You mentioned your upbringing, a very scientific upbringing, surrounded by science. Was there ever any question in your mind that you would be a scientist?

Bertozzi: Oh, I mostly thought I wouldn’t be a scientist. Honestly, the closest I came before I discovered organic chemistry was declaring myself a pre-med. That’s somebody who wants to be a doctor, right? That’s the closest I really came to thinking of myself as a scientist before the age of 19, let’s say. And you’re right, I did grow up with a father who’s a physicist, and an older sister who was a mathematician and was kind of a declared mathematician starting around age six.

Smith: Right.

Bertozzi: She her whole life knew what her passion was and what she would be doing, but I did not. It was a surprise to me when I discovered my passion for organic chemistry. At that time, I really committed myself to the field. I knew that this was what I loved and what I wanted to do. Before that, no, I didn’t think of myself that way at all.

Smith: It’s hard enough figuring out maths as a kid. It must be even harder if your older sister is a maths genius.

Bertozzi: Yes, she was a super genius. She was the kid who outpaced all of her teachers in elementary school and middle school and had special math classes created just for her with older kids and stuff. When she was in college, she would help my father debug his quantum mechanics midterms for his students. That’s who she was. I tried keeping up with her when I was younger. She was just one year older than me. What that means is that every teacher who had her in school would have me a year later and they’d have these expectations that were I couldn’t meet. I think maybe that might have driven me to focus on other things besides science and math, because there was no hope of competing with her. I was more into sports and music and just not really academics so much.

Smith: I’d like to speak about both sports and music. Sports first. You’re pretty good at sports, I gather.

Bertozzi: I was when I was younger and that was a long time ago.

Smith: What was it that you liked about it?

Bertozzi: Anything with a ball is fun for me. I was decent. I don’t think I was anything close to being like a world class athlete or anything like that. But I was pretty good soccer player and I actually was recruited to Harvard to play on their team. That probably helped me get admitted to Harvard. Then what happened was when you play soccer at the college level, at least back then, this was in the mid 1980s. It was really hard back then. It probably still is difficult, but it was really hard to be on a team like that and also be a science major because the science classes like chemistry and biology and physics, they have labs in the afternoons. There’s also a lot of problem sets you have to work on every day and lab reports and midterms. There’s just a lot of work. You’re busy in the afternoons and evenings. It’s really hard to play on a team that practices in the afternoons. You can’t do it. Then also the teams travel for games that are away games. So you end up missing a lot of class. If you’re a science major, you’re missing labs. Those two things were totally incompatible. I quickly figured out that I probably couldn’t be on the pre-med track and also play on the soccer team. Freshman year, first semester, I gave it up and I ended up going out for the crew team instead because they would practice on the water in the morning, very early morning.

Smith: That’s the rowing thing, isn’t it?

Bertozzi: That’s the rowing thing. You get on the water at 5am in the dark and the cold in Massachusetts. Then by 7.30, you were done and you could go to your eight o’clock class, right? Your afternoons were free. I tried that. But I was so tired. The schedule was grueling. I really wasn’t very good at it. That doesn’t help. That lasted a few months. That was the end of my little college sporting career.

Smith: I think a few months of early mornings on the Charles, especially in winter, is surely enough for anybody.

Bertozzi: Yes.

Smith: OK, the other passion from childhood then you mentioned did take over at Harvard, music. You were in a band. You were a pretty successful band as far as it went.

Bertozzi: By college standards, yes, we were a successful band. So that’s true. I played the piano and the keyboards. When I was younger, I played a lot of music in school, like school performing arts groups, the choirs and the jazz singing groups. I played in a jazz combo. I spent a lot of time on the piano in middle school and high school. When I went to college, I was trying to figure out how to keep that up. I found some guys who were forming a band and needed a keyboard player. I played with them for a while. That was the band led by now famous Tom Morello, which is my claim to fame from college. He was our lead guitar player. He formed the band. He also composed music that we played. Then we also played cover music from the 80s at college parties. That was kind of our gigging music. That was really a lot of fun. He was such a phenomenal musician. He was the best musician I’ve ever played with. It was such a privilege to just see how he played and how he created music and how and his leadership of the band and so on. I really learned a lot from working with him. Then he graduated and went off to be a musician. The rest of us kind of drifted into the background and ended up going our own separate ways after college.

Smith: He went on to form successful bands such as Rage Against The Machine and Audioslave.

Bertozzi: He really had a unique style even then. That just carried right into Rage. He is also a very politically minded artist. Even the music he wrote for us in college when he was maybe 20 years old or something, was very politically minded. That still is one of his kind of signatures on a song. Most of his music is purposeful and thoughtful and deals with sort of difficult issues of the moment.

Smith: Is there something that carries over into the way you practice science from the way you practiced music together?

Bertozzi: Probably. It’s probably unconscious types of things. But I definitely took a liking of all the different forms of music that I was exposed to as a kid. Jazz and funk were the two that I really resonated with the most, no pun intended. What I like about them, those forms of music is the free form, the fact that there is a structure in the background, but then you have all of this latitude around that to express yourself. Sports are like that too, right? It takes a lot of rigorous and rote practice in order to develop the muscle memory so that you can be creative and in the moment do things that are almost subconscious. I would like to think that there’s some of that that goes into the scientific creativity, right? You have a structure of knowledge and you have to have command over that knowledge. You have to understand the literature deeply and you have to be rigorous and understanding experimental strengths and weaknesses and so on. But then within that structure, you can exercise a lot of creativity and push the boundaries. I also really like technology development. I like invention, especially if the invention flies in the face of dogma. I really like that. There’s something really appealing about that. Then at the end of the day, my favourite types of research projects are the type where maybe you invent something and it solves a problem or allows the creation of a new kind of medicine. Then when people see that, they say, oh, how come nobody thought of that? It seems so obvious, right? Those are my favourite types of things, things that in retrospect seem so obvious and so simple and so straightforward. But in the moment, they’re actually quite disruptive.

Smith: I suppose it’s one place it’s easy to be disruptive is at the interface between things, whether it’s in music or in science. In your case, you built up a solid grounding in biology and chemistry, and then were able to work at the interface between the two. I guess that served you very well indeed.

Bertozzi: It did. Actually, I think you’re right. It’s very insightful, that comment you just made about how disruption occurs at interfaces. It’s true in music. Bring a new instrument into an old genre, and that’s a disruption. In science, it’s the same way. For me, it was quite natural for me to develop knowledge both in chemistry and biology because I took an interest in the field of glycoscience. I learned about that field in my PhD through the window of chemistry. Then I did a postdoctoral fellowship where I studied glycobiology that was related to the immune system. So that was my biology training. Both my PhD and my postdoc shared the common thread of complex carbohydrates and glycobiology. That’s a field that I think quite naturally requires the convergence of chemical approaches and biological approaches. Glycoscience really brought all of those things together for me.

Smith: We’ll talk about glycoscience in a second because it is something that most people don’t think about. As you put it, it’s the sugar coating on our cells. Such a beautiful phrase of yours. But your move into that field also was accompanied by a physical move from the east coast of America to the west coast of America. You’ve done your undergraduate at Harvard, a male-dominated chemistry department, as you’ve spoken about before. You then found yourself in California at Berkeley. Was that an important transition apart from just being in a different place? Was there some kind of change in the air as you went from east to west?

Bertozzi: There was. I had really never been anywhere. I didn’t travel much as a kid. We were on a pretty modest budget as a family, so we didn’t take extravagant trips. When I went to visit graduate schools in 1988, when I was figuring out where to do my PhD, it was my second plane ride ever, and it was my first plane ride out of the east coast and to California. When I landed in California, and I’m 21 years old at this point, I’d never seen anything like it. It was just eye candy. I remember coming out in February to visit some PhD programs, and there was no snow, and with this nice temperate weather and people walking around with T-shirts. Even though in my head, intellectually, I knew that there were places on earth that weren’t buried in snow in February, I had actually never seen one. California was like a different planet for me. It was like I had just stepped off the plane and landed on Venus or something. It took me a little while to get used to it, because everything was really different to me. But it turned out to be a really good fit for me in my personality and the way I like to do science really works well on the west coast, maybe better than the east coast. I think, yes, I think I found it liberating and stimulating. Then really what happened was I was recruited to join the lab of a brand new assistant professor named Mark Bednarski. I was one of like three students that joined his lab in that very first class of students. He was brand new and enthusiastic with lots of energy. He just gave me the pitch on how sugars were so interesting and important and difficult to synthesize chemically and difficult to study biologically. I just was so intrigued by that. I really have to credit Mark with introducing me to the field and recruiting me to his lab. I’ve kind of stuck with it ever since then.

Smith: Your experience with Mark not only exposed you to the field, but it also exposed you to yourself, if you like, because he got ill and then had to step away from the lab. You found yourself having to really supervise yourself, which is a very unusual position to be in. You grew into it easily.

Bertozzi: Yes, you’re right. The story of Mark Bednarski was he started his lab with full throttle and recruited a bunch of students. We were off and running. Three years into it, he was diagnosed with colon cancer. He must have been 33 or 34 years old at the time. That’s a very unexpected diagnosis for a person that age. This changed his life. He took a leave of absence while he was having treatment. He had surgery and chemotherapy and so on. During that time, he had an epiphany about his own career. He made the decision that he wanted to be a doctor and he wanted to work with cancer patients. He quit his job at Berkeley and went to medical school at Stanford, of all places. There we were, a handful of students who were the senior students in the lab. We were just beginning our fourth year of graduate school or so. We found ourselves without a boss. There were a few students younger than myself who had to basically switch labs and start all over again. I was just far enough along that I could convince the department chair that I could just ride out the next two years knowing exactly what I needed to do and just doing it. It’s amazing.

Smith: He or she must have been so relieved to hear that. Good, I don’t have to worry about Carolyn. She can just take care of herself.

Bertozzi: In retrospect, you’re probably right that it was a problem that didn’t need to be solved as long as I acted confident in my ability to supervise myself and two other students with me. I think today in the year 2023, this probably wouldn’t go down the same way. I think there’s much more attention to, first of all, safety, right? You can’t have students working in labs with no safety oversight. There’s liability issues that we didn’t care so much about back in the late 1980s and early 90s. But now that wouldn’t fly and also just mentorship. Now I think there’s a lot more attention paid to the infrastructure for student mentorship and for student experiences, where when I was a student, once you joined a lab, nobody cared about you anymore except for your advisor. If your advisor stopped caring about you, you’re kind of on your own, right? For good and bad right? The good news for me is that I was able to continue working on my research and I didn’t have to start all over again in a different lab, which meant that I got to stay in the field of carbohydrate chemistry and glycobiology, which I otherwise would have been pulled out of that field, right? That was the good thing. It was difficult and frustrating because there are things that are hard to do without a graduate advisor, right? So getting papers published was a bit of a struggle, but we managed but it was probably harder than it would have been otherwise. But in retrospect, even though at the time I complained a lot about the situation, I’m sure now in hindsight, I do see how valuable that was as a training experience for me to take ownership of my research, my publications, my future, my postdoc applications at the end of the day, if I had to do it and if I didn’t do it, it wouldn’t happen.

Smith: I guess again, it’s that confidence. It’s developing so much self-confidence early on stands you in very good stead for all the rough and tumble to come.

Bertozzi: That’s right. And it also, honestly, liberated me from having to follow in a channel in my career. I think if I had been in a large lab with a professor who was there every day and with a kind of an infrastructure in which everyone was sort of standing in line and following the same path, then I probably would have done something different. Because I was on my own, left to my own devices, it gave me the latitude to figure out what do I really want to do next in the absence of having too many people whispering in my ear, right? That’s when I decided to leave chemistry and do this postdoctoral fellowship in an immunology lab. Some other senior professors who were my kind of backup advisors at the time, they counseled me against this. They told me it was not a good idea. It was too far astray from the path that was familiar to them. Again, if I had been in one of their labs as their student, I would have taken this advice to heart and probably chosen a more conservative path. Because I really didn’t have someone steering me, this kind of negative advice was in the distant. It was once removed. I didn’t really take it to heart. I just decided I should do what I want to do.

Smith: You’ll have legions of graduate students listening to this and thinking, oh, right, the thing to do is to dump my supervisor, go off and be so…

Bertozzi: They’ve become very good at ignoring my advice. I think that’s some metric of success, I think.

Smith: Yes, the sidestep into immunology and then staying with glycobiology all proved very successful. Can you tell me what is it that is so exciting about, to reuse your lovely phrase, the sugars that coat our cells?

Bertozzi: To start with, I get really excited about the field. That excitement has not waned in 30 years now because there’s so much we don’t know. Those sugars are on every cell in every living organism on Earth. Different organisms have different structures of their sugars, but even within our own bodies, different cell types have different patterns of sugars. There’s many diseases that have been described where there are changes in the sugars that are central to the disease, but we don’t really understand at the molecular level, like how the sugars contribute to both healthy biology and disease biology for the most part. In my career, there have been a couple of big breakthroughs where some clarity has been achieved. Every time there is a breakthrough in understanding, it has a huge impact. People make new medicines, come up with new diagnostic strategies, and there’s so much you can do with the knowledge. Yet there’s so much still to be learned that I feel like it’s just a great place to work because again, every discovery you make has a big impact because there’s just so much we don’t know. I love glycoscience. It’s a wonderful field.

Brilliant: Carolyn Bertozzi was awarded the Nobel Prize for developing bio-orthogonal chemistry.  What is bio-orthogonal chemistry, Adam?

Smith: Bio-orthogonal chemistry is any chemical reaction that can go on in the body without interfering in the biochemistry that’s already happening in the body, and in turn also not being interfered with by that biochemistry. It’s happening completely independently to everything else that’s going on.

Brilliant: Where does the name bio-orthogonal come from?

Smith: The ‘bio’ piece is from the fact that it’s happening in a biological system, and the word orthogonal means something that is at 90 degrees to something else, and so this is describing chemistry that’s happening in, if you like, a different dimension to the dimension of normal body biochemistry.

Brilliant: This sounds quite tricky. How has Carolyn Bertozzi enabled this to happen inside a living organism?

Smith: Utilising these amazing click chemistry reactions, which are rather rare reactions where two functional groups just want to get together. They just click together without interfering with anything else going on around them, and without being interfered with. Because you’ve got these new reactions, they’ve only been around for about 20 years, you can make use of them and make click chemistry happen inside the body.

Brilliant: This is probably a silly question, but how do you get these functional groups into the living organism?

Smith: It’s not a silly question at all. That is absolutely the challenge, that for any click chemistry to happen, you need two functional groups because you need two things to snap together. You’re using this chemistry to do things like label protein molecules inside the body. One of those groups has to be stuck onto the protein you want to label, and the other of the groups has to be on the label that you want to stick onto the protein. The first thing to do is you need to get the functional group, that little chemical entity onto your protein. That’s part one. Part two is you need to introduce your label with the other chemical entity into the body so that they meet and snap together. That requires some sophisticated chemistry and biology to make happen. Carolyn Bertozzi and others have been able to develop this amazing technology.

Brilliant: It’s interesting because it sounds both sophisticated and simple at the same time, the fact that you can snap these molecules together.

Smith: I think that’s a lovely observation. The name click chemistry does imply that it’s all lovely and simple. If you look at the chemical functionalities that are involved, they look rather scary sometimes like an azide group, two nitrogens joined by three bonds. Not the sort of thing that you possibly encountered if you did a little bit of chemistry at school. There’s some sophisticated chemistry going on, acting in what in the end turns out to be a rather beautifully simple way.

Brilliant: How is this science beneficial to humankind?

Smith: Basically, it allows us to understand more of what’s happening in living systems. Because of this bio-orthogonal chemistry, you can label things in ways that you never could before, track their progress, see what’s going on. You can also change the function of molecules in the body. If you put the right sorts of labelled attachment onto these molecules in the body, you can turn them into, for instance killer molecules that will go around and potentially target a cancer cell and get rid of it. There are enormous numbers of potential benefits, and many of them are being actively developed now. It’s interesting to reflect on the fact that, of course, there’s a huge literature and history of the development of synthetic organic chemistry. Almost all of that happens on the lab bench. This is very rare in that it happens in living systems. It fits into this history of the development of synthetic organic chemistry, and it’s quite interesting to listen to her reflect on how she sees her own place in that history.

Smith: We began by talking about the importance of organic chemistry to you and you gave your chemistry textbook to the Nobel Prize Museum. That organic chemistry textbook is full of named reactions after famous chemists of the past. Kleisen condensation, Diels-Alder. Indeed one of your fellow laureates, the Sharpless epoxidation, all these reactions named after people. Your bio-orthogonal chemistry isn’t named the Bertozzi reaction, but it could be. How does it feel to be part of that kind of pantheon of chemists?

Bertozzi: It’s funny that you mentioned that because the very first bio-orthogonal reaction that we invented, we called it the Staudinger ligation. We named it because it was an adaptation of one of those old reactions from the textbook called the Staudinger reaction from the, like 1920, it was a hundred-year-old chemistry. Then the community at large, not myself, but other people started to rename it the Staudinger-Bertozzi ligation. Now I think I technically have a named reaction. That does put me in a kind of a pantheon, I guess. The naming of reactions after people who first invented them was quite fashionable in the previous century. Nowadays there’s less of that, I think people are a little bit more shy maybe about the grandiose, statement of naming chemistry after yourself. It doesn’t happen as much. I guess I should be fortunate that somebody out there decided to tack my name onto my own reaction.

Smith: I guess also, since you could only have one named reaction after you, it kind of discourages further discovery, which is exactly the opposite of what one wants to achieve.

Bertozzi: Maybe the hyphenated Staudinger-Bertozzi ligation is a solution to that problem, right?

Smith: Yes, exactly. That is a way to go. It’s been an enormous pleasure speaking to you. Thank you very much indeed for giving us your time.

Bertozzi: Thank you for everything. I appreciate it.

MUSIC

Brilliant: You just heard Nobel Prize Conversations. If you’d like to learn more about Carolyn Bertozzi, you can go to nobel prize.org, where you’ll find a wealth of information about the prizes and the people behind the discoveries. 

Nobel Prize Conversations is a podcast series with Adam Smith, a co-production of Filt and Nobel Prize Outreach. The producer for this episode was Karin Svensson. The editorial team also includes Andrew Hart, Olivia Lundqvist, and me, Clare Brilliant. Music by Epidemic Sound 

For another listen from the crossroads of medicine and chemistry, listen to our episode with Emmanuelle Charpentier. 

You can find previous seasons and conversations on Acast, or wherever you listen to podcasts.  

Thanks for listening. 

Nobel Prize Conversations is produced in cooperation with Fundación Ramón Areces.

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