Nobel Prize Conversations

“If you’re interested in something, you’d be amazed what interest can do”

Meet the only living individual that has been awarded two Nobel Prizes in an intimate conversation. In October 2022 Barry Sharpless made history when he was awarded his second Nobel Prize in Chemistry. In this podcast episode we speak to Sharpless about curiosity, creativity and how he comes up with new ideas.

The host of this podcast is nobelprize.org’s Adam Smith, joined by Clare Brilliant. This podcast was released on 22 June, 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. 

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Barry Sharpless: “I can’t resist taking a chance on something, in nature anyway, that looks like a place I haven’t been. I wonder what it’s like there.”

Adam Smith: I think everybody who talks to Barry Sharpless wants really to know the same thing, which is how can you be the sort of person who is so creative and brings so many new ideas into the world that you’re awarded not just one but two Nobel Prizes. If you could get the secret and bottle it, maybe even sell it, you’d be very happy. It’s a hugely pleasurable trip to talk to Barry. He himself would be the first to say that his conversation veers quite wildly around as new topics occur to him and that’s an absolute joy and quite a challenge to the listener to follow along with and concentrate hard to see where you’re going to go next. Do join me for this conversation with Barry Sharpless which I think does give at least me a greater insight into how he comes up with ideas and what an idea actually means to him and in particular how dangerous ideas can be.

Clare Brilliant: This is Nobel Prize Conversations. Our guest is two-time chemistry laureate Barry Sharpless. He shared the 2022 Nobel Prize in chemistry with Carolyn Bertozzi and Morten Meldal, for the discovery of click chemistry. Twenty-one years earlier, he was awarded for his work on chirally catalysed oxidation reactions.

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

Barry Sharpless is the W M Keck Professor of Chemistry at the department of Chemistry of Scripps Research in La Jolla, California.In this conversation he takes Adam on a journey into his fascinating mind. He explains how impatience has shaped his career, why he abhors writing research proposals and why he loves being terrified on a regular basis. But we start, with a frequently asked question.

Smith: I suppose what everybody wants to know from you is how it’s possible to generate so many good ideas. Let me start by just saying, have you got an answer to that question?

Sharpless: That’s probably the question that I’ve been asked to think about ever since it started happening. It’s a really good question. In fact, the most important question, if I could answer it, for advice for humanity and humans who want to have possibly more ideas that are really worthwhile. I guess I realised that it was happening to me – I was in Japan with a lot of experts on asymmetric synthesis, and Kagan and Noyori and Eric Jacobson and others at a meeting years ago. It was before the first Nobel Prize, I think, in asymmetric synthesis. Since I had done a number of different things that were asymmetric and also had other types of reactivity I’d found, I mean, Noyori’s a strong personality, but he’s very thoughtful because he said, well, Barry, we’ve all been talking, but one question I really think we need to ask you is how did you have so many ideas? That was a sort of kick-off for the thing when I realised Ryoji had this question. I didn’t have an answer at that time, and I just sort of shook my head. But the more I did think about it, Jan helped me with it, my wife. Basically it comes down to things like if you can’t plan ahead, you’re in a different boat than the rest of the team because you don’t know how you’re going to get through the day or what’s going to happen to you. You’ll tend to notice things in a different way, I think, in the events of the day, in the events of the chemistry you’re trying to do in front of you.

Smith: Let’s focus on that one first, because that in itself is an extraordinary statement that you can’t plan at all, that you’re living almost by the sort of seat of your pants. It’s not how most of us live. Is that really what it feels like, that you can’t plan ahead, that you’re just kind of living in the moment?

Sharpless: Jan knows the frustrations of it more than anything. She finally realised that that’s why I’m so difficult sometimes. I don’t know why I can’t do it. It’s like an aphasia in the mind. That’s why research proposals were painful as hell. I always just wanted to go down to the lab and try it, instead of more BS on the paper saying why it might work, why it might not work. I said, well, I’ll just try it. I took a week in the lab instead of writing. By the time it came time to get the thing across the transom to the government for the proposal, I was just desperate. I sent things and I started to have things to publish to talk about before I didn’t have support for them, but I’d done them. Then I could talk about the things that already work and just keep going. That seemed to patch along pretty well, at least with the study section I had in the National Science Foundation. Then came the asymmetric epoxidation. That got me in with the National Institutes of Health more firmly. They kept supporting asymmetric chemistry for me. Those are the only two grants I ever had continuity on. It wasn’t enough money to run my group on. I ended up going from dowry to dowry by having the success and moving and getting a dowry and then going through it. Finally, I ended up at Scripps with Richard Lerner, who’s really a visionary. He just said, Barry, I like what you’re doing. I’m going to support it and we’ll support it with the Skaggs Foundation and with the Annenberg Foundation. We’ve got money. We can support research, direct research here at Scripps. That’s what happened. I was able to keep this click chemistry going.

Brilliant: Let’s talk a little bit about the many discoveries of Barry Sharpless. What was he first awarded a prize for in 2001?

Smith: He was given that prize for a very brilliant piece of organic synthesis. At the time, many people said it was the most exciting development in organic synthesis for decades. It was a way of doing what chemists call asymmetric synthesis. In order to understand that, one has to understand the word asymmetric. Many molecules have the property of handedness, which chemists refer to as chirality. But if you look at your two hands, you’ll see that they’re mirror images of each other.

Brilliant: I’ve got them in front of me now.

Smith: Good. Now try superimposing them.

Brilliant: Okay.

Smith: You’ll see that somehow you can’t superimpose them despite the fact that they have the same things attached to them. Your fingers and thumb. They’re arranged in a different way in space, and you cannot superimpose one over the other.

Brilliant: I see that I can clap them together, but if I try and put them one on top of the other, they don’t overlap.

Smith: Exactly. Now, if your hands were organic molecules with this property of handedness, you’d find the same thing. Carbon atoms always have four bonds attached to them. If those four bonds lead to four different groups, so in other words that carbon atom has four different things arranged around it, then it will have this property of handedness or chirality. In that there are two ways of arranging those things that are non-superimposable, if you like, a left-handed form and a right-handed form. Those two molecules, despite behaving in the same way with respect to their physical properties, their boiling point or their melting point, have different chemical properties. That’s incredibly important because the different-handed forms of those molecules behave differently. When chemists are trying to make a molecule with a chiral carbon, they really probably want to make one form or the other, the left-handed form or the right-handed form. But most chemical reactions don’t give you one form or the other. They give you equal amounts of both forms. What you want to be able to do is to synthesise those things asymmetrically. In other words, make one form and not the other.

Brilliant: Oh, I see.

Smith: Barry Sharpless’ innovation for which he was awarded the 2001 Nobel Prize was a reaction called the Sharpless Epoxidation, which allows you to do that in a very selective way and produce just the form you want and then introduce all sorts of different functionality.

Brilliant: It’s pretty unusual to be awarded one Nobel Prize, let alone two. What was Barry’s second Nobel Prize awarded for?

Smith: Yes, it’s an incredibly rare thing. Interestingly, he was awarded the prize for click chemistry, and I remember when I spoke to him in 2001, 21 years before that prize, he wasn’t so interested in talking about what he was being awarded the prize for then, that epoxidation. He wanted to talk about what he was doing now, which was click chemistry. He was already very much focused on that when the first Nobel Prize came. Click chemistry describes a very small group of reactions, which are almost perfect. In most organic chemistry, the reactions that chemists use are far from perfect. They’re very difficult to make happen. You have to heat the system or put lots of energy into it to make molecules stick together. When they do, they don’t do so in very high yield. They also tend to produce lots of byproducts. They’re not the greatest thing for making exactly what you want. In click chemistry, you have reactions which happen under mild conditions with almost total efficiency, a hundred percent yield, and they produce no byproducts. They’re, if you like, the Holy Grail of chemical reactions. There aren’t very many of them, as I say, but those that there are incredibly valuable. It was for the development of those, and I suppose partly for dreaming of the possibility of making such reactions that Barry Sharpless was awarded his second Nobel Prize.

Brilliant: You mentioned when you spoke to Barry back in 2001, Adam, that he was already thinking ahead. What must it be like to always be sort of one step ahead of where everyone else is at.

Smith: I suppose broadly all scientists are trying to think of what’s to come. It’s just a bit extreme in Barry’s case that he’s just constantly focused on a new problem. I suppose sometimes that can be a bit of a disadvantage. In fact, it’s interesting to hear him speak about that.

Sharpless: Frankly, it wasn’t easy because the Germans who had come to me who were really marvelous chemists, they still are. They always will be. But they came and they want to do asymmetric things. I kept, oh, no, I can we try this new click chemistry thing? Basically it shut down the conduit that was bringing the Germans to La Hoya. They loved it here, of course, because all northern Western Europeans, especially those up north and probably in England and Scandinavia and Germany, they love Southern California for its contrast with their home. They wanted to come. I must say, I felt bad because I would just neglect them if they didn’t want to work on click chemistry.

Smith: I’m getting the view of you as an impatient person. 

Sharpless: Yeah, you’re right. 

Smith: It’s nice that that chimes with your own view of yourself. You just want to get things done.

Sharpless: The bad thing is that in everyday life, impatient leads usually to impulsive. The impulsive things really are – I don’t know. I did have an eye blown out when I was a young professor. Probably if I was less impulsive, that wouldn’t have happened. But basically, the impulsive part is what makes me want to get the reaction going in some way that we can get within a day’s work or overnight. At least we can get some answers about some crucial things that are hinging on this experiment. Yes or no things as far as being a go ahead for something more interesting than the average.

Smith: We’ll stick with impatience, but I just can’t let the comment about the eye go without just exploring that a bit more. That was an NMR tube exploding, wasn’t it? 

Sharpless: Yes.

Smith: That’s a pretty enormous thing to happen to you to have an eye blown out. Or rather, you were blinded in one eye by the by the –

Smith: Yes, and that was for a while. But then I got an operation here in California years later that helped me get vision back in. You would have thought that having just one eye would have been really a huge disadvantage. But I couldn’t ride motorcycles anymore. Stuff like that. For a while, I had to learn to take the information in. Maybe there is something to the left/right brain, but it seemed to work fine.

Smith: OK, you mentioned motorcycles. Riding fast motorcycles, I suppose, goes along with an impetuous, impatient person.

Sharpless: I’m not too coordinated. That’s a problem. Skiing was a nightmare for me because I didn’t have that coordination. I wanted to go fast, but always got banged up because I couldn’t. On a motorcycle, a dirt bike especially, in the woods, in the logging trails of California, around San Francisco, you feel like you’re a wailing skier. Just amazing amount of things can be done, sliding and slipping. It was just so good. It was better than going out and drinking with the boys. It was so relaxing for me to get a little frightened. This has always been true for me. Getting frightened is really erasing somehow the nervous system, which is making me worry and stuff. It just sort of releases the tension. It’s addicting to get a little scared if you can. That’s sort of, I think, well-known human self-medication method.

Smith: I suppose so. But a lot of people try and get themselves out of situations of being scared. When did it start for you? What’s your earliest memory of wanting to be frightened?

Sharpless: It was out on the river, in the Manusquin River, which was really quiet in those days. It was almost like a private estuary of freshwater, saltwater and all these creatures. I could putter around. But I was told by my parents, I think I was nine or eight, and I was told not to go out in the ocean because the ocean was about two and a half miles away downriver. I ended up not being able to resist going out in the ocean because the fish were more reliable there. I felt that was something I was doing that was not allowed. I felt pretty excited and worried that I would get caught or something would go wrong. That’s sort of an example of it. I can’t resist taking a chance on something in nature anyway that looks like a place I haven’t been. I wonder what it’s like there.

Smith: Which I think also sums up your attitude to ideas. That’s the remarkable thing, because when you talk about having ideas in science, in chemistry, I get the impression that the excitement of it, the danger of those ideas, is one of the things that you find so appealing. That’s different from a lot of us. Most of us don’t have ideas that are that dangerous, but you do. Ideas for you are on the edge and thrilling. Is that right?

Sharpless: I think so. The ones that I’ve been able to stoke myself up to having since I was successful in my first go at research at MIT, I keep asking myself, well, what does this mean? The general phenomenon of seeing something about reactivity and realising why wasn’t it found before? What does it imply about what might be out there that hasn’t been seen? That’s the part that I do naturally now. People focus on things that are interesting in chemistry, and a lot of people are really good at that. But to focus on them from the standpoint of what they imply about things that haven’t been tried or haven’t been seen yet, I do it every time I hear something interesting, or at least a couple of days later, I sit down. I’m like, what does that mean, really? Then I try to say, well, maybe it means this. This means a set of conditions that might, if it worked, jump you a little, another little jump over a stream or a brook that might have held most people back. You just try it and it didn’t work and you come right back. Somebody tells you, oh, I’ve got this great new thing and it’s going to do this and that and the other thing. If you know a lot about your science and how you can do things in your field, then their idea is something you’re automatically going to analyse, because that’s what you’re about when you’re doing the chemistry the way I’m doing. You’re trying to find something that’s more useful in the long run. It’s not somebody’s idea of what they were told when they started writing their grant. This is important. People have these objectives for science. The country has needs for energy things and whatever. If people tell you that they’re doing something important in that regard, namely they’re aiming to solve the problem that has no linear solution – it’s a big problem – they’re not anchored to the foundation of what makes things possible on the larger scale where everything’s integrated. Even though I’m not a logical person when I’m speaking, I just go over and over like repetitively in my mind. I keep asking myself, wait a minute, why am I doing this? If something works really beyond your wildest imagination, then sometimes that thing that you’re seeking or hoping for may not amount to much from a certain point of view. It’s kind of bad to fool yourself when it comes to things like that, if you can avoid it. I’m afraid of being embarrassed by doing something not exciting.

Smith: Yes. Your threshold is very high indeed. I’ve heard you. I’ve heard you quote this beautiful thing from Einstein that if at first the idea doesn’t seem absurd, it’s not worth doing it.

Sharpless: He seemed like such a nice avuncular man. I guess he was a pretty difficult guy, too.  Somebody told a story about him. It sounds like talking to me. Once I get started, you can’t stop me. This person had talked to Einstein. He was, ”well, he can talk your head off”. I had never thought about that from Einstein. He seemed like a gentle old man when we knew him from the news anyway.

Smith: It’s a different view. It’s a nice view. How do your colleagues in chemistry take your approach? Because it must in a way be a bit challenging for them. They present you with their latest and greatest idea and you immediately take it apart and see what you can do with it and whether you can extend it or knock it down.

Sharpless: That’s true. I grew up in a continuum of rapid change, but it really was more or less trying to enrich the world that people believed in, making very complicated molecules and having more reactions almost endlessly because they might be useful, just somewhere. It kind of grew away from that naturally because I realised that man is really paying for its research. Most countries pay dearly and they have other things where people are suffering and they need money, but they give it to groups and scientific establishments for education and they don’t have the luxury of that money not being useful. Yet if you do useful research, academics scream about it. We want, what’s it called, curiosity driven research and not sort of, well, we’re supposed to make this compound or we’re supposed to solve that pollution problem. I guess really at the end of the day, the chemistry, if it can evolve, keep up with mankind’s ever-increasing needs. We really do need to keep up with the inventions that enable man to do what he continues to want to do. That’s something that people don’t want to hear. To me, practical is even part of the recipe. That’s part of the answer, that it’s practical, it’s conceivable at the beginning, not having to be reduced to practice at the end after you’ve got a very complicated scenario to solve a problem and you can’t afford it. I guess that’s where I get hard on myself. I’m trying to realise that you can’t do certain things. In this world, too much energy… like if I was to use osmium for a lot of reactions, it’s a wonderful metal and catalyst, but there’s just not enough osmium on the earth to deal with that many reactions.

Smith: The urgency comes both from your own impatience and also the urgency of doing something ”useful” for the planet.

Sharpless: That’s for sure. The urgency to do something important is just because it’s been done and it continues to be done by people. There’s no reason why you can’t think you’re going to do it.

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Sharpless: What gets me is that in the history of human progress, literature and science and finding out a way to look at something for the first time, people ask you how the breakthrough occurred or how you were able to do something that looked hard. What happens is really weird. I can find over and over again examples where the person who made the discovery, who knows bloody well that it was a surprise the moment it happened, but they come up with ways to make it not a surprise. They start telling a story that slips into a just so-story. That is really something, our tribe can’t take this accidental thing. It wants to have the connection. I’m not a politician or anybody intelligent in that area, but I got to wonder here, the stories that people told around the campfires 200,000 years ago when man was struggling to really literally survive from animals attacking and getting food. The person that told the story that lets you lie down and sleep at night and somehow it didn’t have any more logical next day prediction than anybody could. Something terrible might happen. But no, the person who can make you feel like it’s OK to go to sleep and wake up again, that’s the leader. We see that in governments where they scare us a lot and they say they are the only ones who can keep us alive in a way. That gives them real power. I’m not saying it’s bad. Man really needs to be comforted. But they’re like our psychiatrists at large or something. I don’t know.

Smith: Such an interesting point that we do the same thing in science and that we make scientific stories more comforting by giving the rationale or inventing the rationale.

Sharpless: Yes, that’s right.

Smith: Again, it all fits in with your own uncomfortable view of chemistry. It shouldn’t be comfortable. If it’s comfortable, it’s wrong. Obviously, you also want to know a great deal. I was very struck by when you came to that water meeting we ran. You’re asking the simple question, why is water blue? Why does it look blue? It’s such a good question, which is the sort of question that most people never ask, even though they spend their life observing blue water and admiring it. There are so many questions. Life like that, which either don’t occur to us or if they do occur to us, we put them aside and don’t bother to think about it more.

Sharpless: Yes. Water is really the be all and end all of life. 

Smith: It’s the fact that you ask the question. Is it just an insatiable appetite for knowing? Does everything make you question?

BS: No, I think it’s that I drove people crazy when I was younger asking questions. Why this? Why that? My wife points out that I sort of grew up specialising in throwing out answers right away when she asked questions and she before she knew I was not a genius that way. She was just taking it. But I can’t answer questions directly. I don’t usually do that. I just sort of get off into a zone of that question and start talking and then always thinking what really makes this work, in life systems everything is connected at some level. It’s so surprising how things are connected. We just won’t believe it if we last another 100 000 years and we have we keep some sort of system together where we have a history and we record what we’ve learned. It’s going to be amazing. Some of the things that we don’t even know are life and death right now that have to do with the way that our bodies work will no doubt surprise everybody, but they’ll be accepted and life will go on.

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Sharpless: I never knew I had an idea that was worth much in anything until a college my senior year, I think I took a course in oceanography, which was, of course, a man in science and biology offered. It was fantastic. We got to do the fruit fly experiment, the cross of hybrids. I had the idea about how the eel, the American and European eel get back to the Sargasso Sea and how the come up every year and float in the North Atlantic Drift, one for one year and one for two years. I had this idea and I wrote this paper and I couldn’t find it since then. But I knew that was a new idea. That was the thing that started me thinking, well, gee, it’s really great fun having ideas. But I didn’t have an idea that I felt that way about until I was a senior in college. That’s probably good for people to know because if you’re interested in something, you’d be amazed what interest can do.

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Smith: I better finish with a comparison to the only other person to have been awarded two chemistry prizes, Fred Sanger. Now, Fred Sanger famously retired at the end of his research career. Two Nobel Prizes was enough, and he went off and spent his time gardening. 

Sharpless: Good for him.

Smith: There doesn’t seem any danger of you doing that ever.

Sharpless: I get to the point where I feel pretty old and tired and dull. Then I think, God, I can’t do this. Because if you really know what it was like to have excitement and want to keep that up. But you’re right. I have friends like me. I just can’t imagine them retiring. But Sanger, I think, had a life. During his time as a scientist, he got the really great ways of analysing things for what? Both of them for genetic purposes, I think. That was so timely. My way of looking at it is that physics is the really underlying thing. Chemistry emerges from it. Then we got to do something to make that connection real more than we are. We have all this discipline. We’re doing amazing things. Science is dead, some people say, well, that’s the dumbest thing I ever heard, because we got a bunch of theories. It’s not about the theories. It’s about what happens because of the theories, right? What kind of things evolve and what you can make. I really feel that this idea that science can stop because we got the book written. I just don’t get it. I mean, it’s not possible. It’s too rich.

Smith: Barry, it’s really lovely speaking to you.

Sharpless: Really, you actually help support conversation between me and the world better than anybody. I’m glad to talk to you whenever I can.

Smith: Let’s continue another time. But for now, this has been just gorgeous. Thank you.

Sharpless: OK, thanks, Adam.

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Brilliant: You just heard Nobel Prize Conversations. If you’d like to learn more about Barry Sharpless, you can go to nobelprize.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.

If you’d like to explore the mind of another brilliant thinker with irons in many fires, listen to our earlier episode with the 2020 physics laureate, Roger Penrose.

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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