Interview transcript

William Knowles, Ryoji Noyori and Barry Sharpless, my congratulations for this year’s Nobel Prize in Chemistry. And also welcome to this Nobel interview. All three of you are organic chemists and this means that you are looking into the chemistry of life. How would you describe the work of an organic chemist? Is the work that you are doing in your laboratories trying to imitate what nature does in the real world? Is this the right description?

Ryoji Noyori: Not really so.

William S. Knowles: We make big molecules, that’s what nature does and we try to copy nature. And I think big complicated molecules.

And you can find them in nature?

William S. Knowles: Nature is full of them. We’re all great big molecules.

K. Barry Sharpless: I feel like we copy nature because we are nature. There’s a reverence for life’s chemistry that came from the origin of our field. In the beginning, Berzelius, here in Sweden, he didn’t really believe this. Stories about him were marvellous because he discovered selenium, which my first love is a research element. But I think he died believing in the vital force.

But his student, Wöhler, was the first person who made an organic compound. It was thought that you had to have an animal to make organic compounds. It was called vitalism or vis vitalis. So that monopoly was broken by Wöhler and he said I have to tell you Professor Berzelius that I found I can make urea without the help of a kidney or the dog or its kidney, or whatever. And that was the beginning of organic chemistry. We suddenly found we could actually make them.

Ryoji Noyori: And there are many important and useful compounds in nature. But that’s not enough. We need many other, more important artificial compounds, which can be synthesised by chemists.

We need artificial compounds for what?

Ryoji Noyori: For pharmaceutical drugs, in many cases artificial. So we have to synthesise using our chemical knowledge. That is our aim.

K. Barry Sharpless: Most of the drugs on the market today are no longer natural compounds, the only one I can think of is morphine.

William S. Knowles: Aspirin. There isn’t enough aspirin available to provide the demand, we have to make aspirin. And that was a tough synthesis in its day.

But organic chemistry is much more than making drugs, isn’t it?

William S. Knowles: Much more.

As for example?

Ryoji Noyori: So we are treating molecules and any molecules, by definition, can be designed and can be synthesised at will. That is synthesis.

If I come back to the vital force, do you think that you ever can make something that’s alive in the laboratory?

K. Barry Sharpless: In principle, I don’t see why not. But in practice, there’s a lot of hubris involved in even imagining you could. But I don’t see why not in principle. In fact I could even imagine somehow on this planet, if the evolution of life continues long enough, that DNA could be replaced as the replicator. There’s many things that you could imagine that life would move on and discover a better replicator, or a different one. It’s almost impossible right now to conceive, but we’re involved in evolution now right?

… you could almost say the blind watch-maker is using us to see if we can do some good for life …

We do chemistry, Ryoji, Bill and I, but we’re humans and so we’re natural. And so what we’re doing is not man-made in my opinion, it’s kind of on the side and you could almost say the blind watch-maker is using us to see if we can do some good for life, right? Because if we do succeed, we may end up using chemistry that we can do better than nature and just enhancing her functions because that enhances our functions. It’s a kind of a circular thing.

Ryoji Noyori: So, nature is using the enzymes, that is a bio-catalyst. However, the utility is limited by the lock and the key specificity. The chemistry is more general. We can synthesise a variety of artificial compounds, either natural or unnatural.

You use the words ‘blind watch-maker’, Barry, can you just talk about that?

K. Barry Sharpless: It’s a book by Richard Dawkins and I particularly enjoy reading his works. He wrote The Selfish Gene and The Blind Watch-Maker. The Selfish Gene really hits you in the face because it says that everything, the grass, the flowers, the poinsettia’s behind you are us, the weed in the field. A lot of us have the gene. Some of the proteins and the genetic compounds are in insects and us. There’s so much that’s there just as a piece of boiler plate material that’s been there for billions of years. We are survival machines for genetic material, if you look at it coldly. And the genetic material picks combinations of genes, travelling companions that have survival value. In a sense, the cold-blooded way of viewing this is our organism part, our system that’s closed and functioning, is just a way to push genetic material into the future.

And then coming along behind that, Dawkins wrote The Blind Watch-Maker, which is if you look at life it seems impossible to imagine it wasn’t somehow created from above because it’s too invested in so many complexities. How could you get there if you weren’t there? There’s a chicken and egg problem that’s massive. And the idea of The Blind Watch-Maker, Dawkins says well how else could you get there? We had four billion years and a planet for this system to evolve and if you just cobble together things, and when life discovers a new way, it never throws out totally the old stuff. You know, it’s not the nature of the way that organisms can function. They learn something, it’s not quite perfect, they learn something else. This whole thing is so then complicated that we don’t know how it really works and we can’t imagine, so that’s why it’s The Blind Watch-Maker. In a sense, the only way it could have gotten there is by the way it got there.

William S. Knowles: But it’s interesting, we are capable of making all the parts, we don’t know how to put them together for the living cell. We can’t think of any of the parts of the living cell that we can’t make. But we have no idea how to put them together to get something that works like that. No idea.

Do you think that this is a problem of science, that it’s so reductionistic, that you see only the small details, the atoms and molecules, or as you say even big molecules, but these are very, very tiny parts of the whole? How can you get this whole picture then?

Ryoji Noyori: It’s difficult at this moment.

William S. Knowles: It’s beyond us at this moment. It may not be by the next 100th anniversary though. When one looks ahead it’s very dangerous to say that it’s not impossible.

K. Barry Sharpless: But you hit the nail in that reductionist is the problem humans have and we get attracted to things we can understand and we go in deep on solving puzzles, but we don’t notice, and we like to see things sitting still. If something is moving it’s blurry usually and that’s what our area is, the three of us, we work on catalysts. Everything that’s moving, by definition, and if you see it sitting still, you can’t gather the essential facts about it. So that’s kind of a nice metaphor for complexity. Catalysts in life are always moving. Life itself is not what we see here in front of you. If the energy is not pouring through the system, the message that’s being read out is there are selective catalysts in our bodies, they’re burning energy. If you froze me and sent me to the other side of the universe and I was just the corpse then, there is no easy way to tell what the function of this machine was.

Ryoji Noyori: Understanding is rather easy, however more important is the creation of new functions. That’s very difficult.

As for example, what do you mean?

Ryoji Noyori: I mean understanding of the nature is of course difficult, but much easier than the creation of a new function. You don’t understand?

Yes, I understand but I still wonder if we can come …

Ryoji Noyori: So if you consider I understand it, that’s it.

What does it mean, understand? Can we tell what is life?

Ryoji Noyori: No, I mean if you go to school and you have a class and the teacher will tell something, and you understand it. And that’s easy. But is that really full understanding?

William S. Knowles: But your question can we understand and define what life is? And this would take a lecture. You can’t just sit down and define life, can you? I don’t think we can. We can define the characteristics of life and it’s about five or six characteristics that all life seems to have, but we have a hard time saying this is not life and this is life. But we seem to know this, don’t we? That’s funny.

K. Barry Sharpless: But I think that distinction is going to be more and more blurred. There’s this new school of thought, the born and the made are going to move together in the next thousand years. And I definitely think it’s got to happen. These people that have always this cell phone here, I mean why not have it somehow built in? Some people don’t function without one. So there’s going to be a way to integrate the born and the made a little bit.

I think the amazing thing is that we think we understand as much as we do …

It’s a little strange idea but no, this is the way the world seems to be heading. It’s almost like science fiction but its not because if you think about it, well one thing I read, if you get to another planet, you know how they test to see if there’s any amino acids or life there, if you saw a little box with four wheels on it, you wouldn’t have to search any further, you’d know there had been life on that planet. I mean there are certain complexities that only can exist through living things. I think the amazing thing is that we think we understand as much as we do.

Take one little cell, as far as I’m concerned, the medium is the message there. And people thing the genome is going to solve things, I think they’re absolutely crazy. And because this is a linear message and it’s all entangled in itself and you can probably get different functions out of that box that’s called a cell, thousands of different ways, you could tweak it in a thousand ways and every one of them would end up in the same function. That would be a drug function. So you think you had this target, but if you did three other things you would have the same result, you know? It’s just a matter of we don’t go at it that way, we go right there and we think we know that target is there, and we’re going to hit it. And then it doesn’t work when they do it and six things that were compensated and the thing doesn’t have a prayer from the beginning, but they assume it did.

Ryoji Noyori: The function or life itself is an integrative issue. And a global issue. And it’s very hard to make it, on the other hand you can understand in detail just by analysis.

K. Barry Sharpless: You can understand within our sciences about what we know and how we know it. But it’s not about any absolute knowledge, we just have ways of knowing things that enable us to carry forward with so called advances. But I do think that the life issue, the complexity, is a fascinating area. My favourite book these days is Out of Control by Kevin Kelly and that’s a book that really describes some things that all of us can learn from.

Have you read this book?

William S. Knowles: I have not read it.

What is so fascinating with this one?

K. Barry Sharpless: It’s a book about emerging behaviour and about some of the wonderful things in it, they’ve been able to take a little glass ball and put three or four brine shrimp in and some algae, and they have some minerals and they seal it. And they put it on the windowsill in your room. And often, if they get it right, apparently 20 years later there’s still a few brine shrimp in there in the algae. That’s a sealed system. That’s about as close to being an earth model, of us floating in space, as you could get.

William S. Knowles: And they run it for that long, 20 years?

K. Barry Sharpless: Yes. That’s my understanding from this book. But as a boy he raised bees. So the hive mentality, the hive mind. The bees don’t know what they’re doing but as a group they’re very amazing and when the hive gets to a certain temperature, certain behaviour begins to emerge and they start making other queens and then they leave and go hang on a telephone pole somewhere and people scout for a new nest and all that stuff is embedded in them, they’re almost like they’re different types of like our liver, I mean, there’s the drones, but all that that information comes out when it’s needed.

But this means, if we come back to science, that the way of doing science, starting from tiny parts and coming up to the next level and the next level and so on, it is quite impossible to get it together. And neither can you deduce when you see the whole how these small parts do work. To find a bee from a bee swarm.

William S. Knowles: Actually the cells of our body are each individually a living system, if you want to look at it that way. And they don’t know what they’re doing, I don’t think. They don’t know what they’re doing but they’d better do it well or we don’t survive. And it’s almost like the bees on a smaller scale. Doing something, dying, somebody else replaces him, they go on. Knowing when they’re supposed to stop doing is just as important as when they start. And this is beyond our comprehension how this all works really.

If we go back to the start of the research that gave you the Nobel Prize, William Knowles, when you started the research at Monsanto, you were not aiming at L-Dopa, but now so many people …

William S. Knowles: No, we didn’t even know L-Dopa was a need to aim at.

So what was the idea?

William S. Knowles: I think that every organic chemist has felt frustrated about having to resolve racemic mixtures. And this has limited what organic chemists have done. They say, oh god, I’ve got to resolve that, I don’t want to do that if I don’t really have to. And it’s a chore. And so I think they’ve all felt there should be a nicer way to get around this, but you have to wait until some good idea comes along. You see what others have done and they’re not really getting very far on the thing, there was a big Japanese programme with Akaburi on this rule, all aware of this I’m sure, but it didn’t look as if I could add anything to what they had done.

It didn’t look a thing, then suddenly something comes along and they say, well Jesus, this is a great new approach to this. Be worth trying. And that’s exactly what it was. But I wasn’t really thinking of any particularly molecule, I’d have settled for any molecule that I do around this, it wouldn’t make any difference. Any sort of what we call a pro-chiral molecule, pro-chiral molecule is your hydrogenates, you get a new asymmetric centre, racemic form. And so I would’ve settled for any one. Actually I chose one that never did work with us very well.

Ryoji Noyori: 150 years ago, Pasteur mentioned the dissymmetry is only in the strict boundary between the biological system and chemical or physical system. And he mentioned that it’s impossible to generate that dissymmetry by using a chemical or physical force.

You mean it’s impossible to imitate the one hand of nature by chemistry?

Ryoji Noyori: So the distinction between the right and the left, because the right and the left has the same physical energy or same free energy.

William S. Knowles: And it’s still that way.

But do you recognise this way of making discoveries, that you have a problem and you are somehow waiting how to solve it? The solution comes just by random. Is this called serendipity?

I don’t like the word serendipity. I prefer luck …

William S. Knowles: I don’t like the word serendipity. I prefer luck. Because I think serendipity, in my mind, doesn’t seem to imply much intelligence. It seems there were these guys wandering around and lucky things happened to them. To me it doesn’t, I like to think I had luck, but I like there was a little intelligence behind this.

K. Barry Sharpless: I think you’re right, the serendipity one is a bit too much like really luck. Sometimes people are calling intuitive as well, which is related to this idea of they’re going to be able to take advantage of serendipity more because they’re actually open to it. And I think intuitive is a way that people who aren’t creative will describe creative people because they don’t see the method by which the information leads these people to the answer they get. I mean people that are intuitive often take in as much, if not more information, facts and feelings and connections than the people who are linear. So I think intuitive people actually are just using their information in a different way.

William S. Knowles: It’s also that, at least certainly the breakthroughs in science, you almost have to be active and your lucky break comes along. Never where or when you expect it, and the ones that succeed take advantage of that lucky break. And most people don’t bother to take advantage.

Ryoji Noyori: So we should be lucky. But I think discoveries are made accidentally, but that’s not real accident.

You had to be prepared for the accident.

Ryoji Noyori: Yes.  And Barry, he got many good lucks. Why so?

But what does intuition mean in that, that you look at the right things?

K. Barry Sharpless: You worked it, you kind of get attracted to the areas where you have a better chance. In this book, Kevin Kelly’s book, it’s kind of interesting, life itself is attracted to instabilities though. I mean it’s obviously connected, in my belief, all these things connect back to facts in the end. That the DNA does contain the information that leads these systems to where they go, but it almost seems like life systems want to be near the edge of chaos because his image is riding a wave, you know, surfer riding a wave.

If you’re up high on the wave and the wave goes forever and you can stay in the zone and you have movement, you have power, potential energy. If you get over the top of the wave, you could die. But if you’re down back on the wave in a trough, you can’t move. And move means evolve. You have to be having movement and life is attracted to instability and creative discoveries come from points of instability in chaos. You have chaos in catalysis. And catalysis is life really. You need to be near this slippery area, partly because you need speed. Speed is really crucial.

Ryoji Noyori: So the discovery is a matter about kinetics rather than thermal dynamics. We need some thermal dynamics and then we need some basic knowledge. But that’s not enough.

Barry, you were talking about understanding of molecules better than people.

K. Barry Sharpless: I feel like molecules are pretty easy for me to understand compared to people. I put myself in molecule shoes probably better than I do in people shoes.

William S. Knowles: I think that would go for all of us. I’m more comfortable with molecules and manipulating them than people. People are really difficult.

K. Barry Sharpless: Complex.

Molecules are not so easy.

William S. Knowles: Well they’re not so easy, but I’d feel more comfortable manipulating them.

People are not so easy to manipulate.

K. Barry Sharpless: But one of the things you might be interested in, in this book by Kevin Kelly, a cell has 30,000 things maybe or more, but suppose it only has 100 things inside of a closed system, and this is working by consensus. It’s a closed system, it just needs energy and food. And how many of those little units should talk to each other directly? In other words, if there was 100, it turns two or three directly feed back, they talk directly to each other. That’s good but more than three and you get a gridlock.

But of course they’re all connected really because they’re living under the same roof by consensus doing a job that they couldn’t do without all the others there. But the minimal connection, I think that’s where you see that we don’t understand because how those things got together is what makes life so hard to understand. Because it’s all sort of veiled in a mesh that plays out only through the motion of this system in the life that it supports. So you can’t really quickly de-convolute it in any way.

William S. Knowles: We understand the parts but we don’t know how they fit.

But it’s not only that you understand the parts, but you are also fascinated by this world. So I have a final question, you live with the molecules or the chemistry, you see the beauty and fascination of this world, but there is still all those people out there that cannot understand what you see is the most beautiful thing in the world. How do you manage to bridge over this gap? Do you see it as a problem?

William S. Knowles: Not very well. This is a big frustration, bridging over the gap. We’ve talked a lot about that this week but we really haven’t come up with terribly good ideas for doing it, I don’t think. But it is desirable to bridge it.

K. Barry Sharpless: I do it as best I can through the sensual approach, that is chemistry organic is right in there for you because they almost all have a taste and a smell. And the big ones don’t smell but the little guys smell. So we notice flowers, fragrances, body odours, oils on your skin, all those things are easy for people to get interested in. But as far as life goes, I’ve found myself being attracted back, having the adventure we’ve had, finding we can be promiscuous and not be very selective but still get right and left. I find to get at the complexity of life maybe I need to use her proteins and things as reaction vessels themselves.

So I have an idea where I’m going to try and go back to mother. Mother inspired us, she’s the enzyme to do the right and left. It turns out that’s easier than many parts of making complex structures. So my thought is to go back and now use the real power of nature. Put the real message in completely. The actual encoding of all those touches, the molecules are touched, everyone’s touching each other. When we do it we use our hands. Our hands are very big and we’re actually pretending to run reactions at the molecular level by using our hands. That’s what it comes down to.

… now we can fully understand the structure, but that’s not enough …

Ryoji Noyori: So the chemists are being interested in the structure of molecules. And now we can fully understand the structure, but that’s not enough. So important is the creation of functions from organic molecules, that’s integrated matter and very difficult to understand. I think that we should know more about biology and also physics. That’s really an integrated pro-gender issue.

K. Barry Sharpless: The function is really what we need to deliver faster, especially at affordable price, medicine and materials that people can build with. And we just don’t have much experience with speeding up. This speed is a thousand times less than it should be if we’re going to try to provide for the rest of the world at a decent level, like we have here in Sweden and Japan and the United States.

Ryoji Noyori: And I think the scientific research has been analytical. However that should be more scientific. So the integration of many simple elements generating anew our functions.

William S. Knowles: We can go on this discussion forever really. It’s absolutely fascinating.

Yes of course, I would like to have more time.

K. Barry Sharpless: Where it’s going is the fun part because that’s the part that we didn’t talk about but it came up this week quite a bit, that doubt is really a wonderful friend to life. The comfort with doubt is what enables one to be more curious than others. You can’t be really a curious person unless you’re comfortable with doubt. And you like to imagine that whole could this really happen? Sometimes you look for the unimaginable, you’re open even to find the unimaginable like cold fusion for example.

Ryoji Noyori: How do you think of the relation between education and creativity? I think we may teach too much to our young people.

K. Barry Sharpless: They’re worried about getting A’s on everything and getting the facts. And that’s why the problem’s in graduate school. I find that by the time you get to graduate school, there are still courses and I didn’t like it, I wanted to go to the lab. And so I didn’t do very well in graduate courses. I’d been a real nerd up till then, getting A’s in everything and the highest grades, when I got to graduate school I said, to hell with it, I’m just going to do research. So I hardly went to the courses. And that means that I just had to do stuff for myself finally. And that’s where I think you can’t, and I was lucky but my professor was not a hands-on guy, he just left me alone to do my thing.

William S. Knowles: I think you are I were very well prepared before we went to graduate school, we didn’t really need the courses there.

K. Barry Sharpless: That’s true.

William S. Knowles: And an awful lot of my associates in graduate school had not been very thoroughly prepared. They hadn’t had more than two chemistry courses or something like that.

K. Barry Sharpless: That’s the problem.

William S. Knowles: There wasn’t much of a science background or anything.

Ryoji Noyori: So research should be driven by curiosity. So I wonder whether the young people are curious enough or not.

K. Barry Sharpless: Which is understandable. The chemist has a set of intuitions that enables him to control reaction and understand reactivity. The biologist has the same kind of creativity, it’s a different set of blocks and principles. And we shouldn’t be doing both jobs because the human mind is really needed to encompass those areas, they can overlap a little, but we need to collaborate. I don’t like this idea that we have to know, we’re not going to be able to know molecular biology, cell physiology, chemistry, physics, no, it’s not going to be possible. I don’t even think Goethe or Leonardo da Vinci could do it. So I think you need to have collaboration. More communication between the biology people and work with them hand in hand. But you do what you do best and they do what they do.

Thank you very much for taking your time.

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