Three Nobel laureates on finding answers in unexpected places

How can scientists compose DNA to convert carbon dioxide and sunlight into things we need in our daily lives? Nobel laureates Frances Arnold, Carolyn Bertozzi, and Steven Chu took up that question and more in a wide-ranging conversation about biology, chemistry, and developing sustainability solutions. 

“Science is more exciting than it ever has been,” said Arnold, a Caltech professor of chemical engineering, bioengineering, and biochemistry. “It offers the opportunity to invent, to discover, to do.” 

Bertozzi, a professor of chemistry at Stanford, called for basic science and interdisciplinary collaborations. She imagined throwing a dart at the periodic table to identify the still largely unstudied elements that could hold the key to global sustainability. 

“The more exposure I get to the interesting problems of sustainability, the more I realize that when you get down to the molecular scale, the processes and the problems are actually all quite similar,” she said. “Much of what we’ve learned in biomedicine about the biology of the human body has parallels in the environment in ways that affect planetary health.”

The three scientists spoke on April 30 at the Stanford Sustainability Forum, hosted by the Stanford Doerr School of Sustainability.

Bertozzi is the Baker Family Director of Sarafan ChEM-H, and the Anne T. and Robert M. Bass Professor in the School of Humanities and Sciences. Chu is the William R. Kenan, Jr. Professor of Physics in the School of Humanities and Sciences, Professor of Molecular and Cellular Physiology in the School of Medicine, and of Energy Science & Engineering in the Stanford Doerr School of Sustainability.

Transcript:

[00:17] Steve Chu: So it’s my real pleasure to be able to moderate the conversation of two extremely distinguished scientists, Carolyn Bertozzi, who is the inventor of bioorthogonal chemistry and some of you can ask her, maybe she can tell you what that’s about, and Frances Arnold, who invented and applied directed evolution. So both of these scientists have used biology and organisms to make stuff – make chemicals, drugs, therapeutics, inorganic materials – that could be useful to society. 

[00:17] Steve Chu: They’ve also founded multiple companies, many, many companies. So in addition to being a pure academic, they have been also movers in trying to get their discoveries and their work and the work of their colleagues out into the marketplace. So let me begin with Frances because I get to quote or paraphrase Carl Sagan, who used to say “billions and billions” all the time. And Frances developed directed evolution where on the upper level you actually have billions of organisms in separate experiments trying to be directed to make some chemical compound and remarkably with only a few generations – four or five generations – you can arrive there because you’re doing these billions of experiments all at once.

[01:51] Steve Chu: So beginning with you, Frances, how do you see what you’ve done and your expertise in actually addressing these incredibly important questions – climate sustainability, health, agriculture, you name it?

[02:03] Frances Arnold: Thanks, Steve. First of all, I just want to say this is such an exciting venue, collection of people, ideas. We’re dealing with some of the biggest problems that humanity has faced and we need great ideas. We need great science. Science will play a big role in solving that. And I’m thrilled to be here with one of the best chemists on the planet to do that because physicists – they’re okay – but chemistry is all about ... chemistry is about making things and we do need to move into the physical world, the hard technology of making things. I got interested in this way back in the ’70s, in making things. I was one of the first employees at the Solar Energy Research Institute when Carter was president. We had a national goal of 20% renewable energy by the year 2000. Can you imagine if we had stuck with that?

[03:13] Frances Arnold: Well, anyway, I decided to stay in the science of sustainability and I moved into biotech after solar at the beginning of the DNA revolution. And I’m just going to say, I’ll say more about the technology if the audience really wants it, but I just want to say the future has never been more exciting. The unanswered scientific question is how does DNA encode making trees, making people, [...] making sustainable aviation fuel. Biology can make just about anything and we can expand the scope of biology if we learn the rules of writing DNA. So to me, that unanswered scientific question is how do you compose – not edit, not write, not read – but actually compose DNA to convert CO2 and sunlight into what we need in our daily lives. That’s going to happen maybe not in my scientific lifetime because I’m old, but it will happen, let’s say in the next 10 years or so.

[04:20] Frances Arnold: And I think that’s super, super exciting. I also will point out, Carolyn, you’re a great chemist, but biology is an even greater chemist and I’m an engineer – more about that later. Biology is by far the best engineer and her process is evolution.

[04:45] Steve Chu: Carolyn, how you’re going to come back from that?

[04:49] Carolyn Bertozzi: Well, I’m humbled to be on stage with Steve and with Frances because you are two of my role models from whom I’ve learned a lot. Steve, I think I first got to know you when you were the director of the Lawrence Berkeley National Lab. At the time that I was appointed by you to direct the Molecular Foundry, which was a nanoscience institute there. And this was, I guess it would have been 20 years ago now, something like that. And at the time I saw how you brought together, up at LBNL, a diversity of scientists and engineers and put us all together in the same physical space and resourced us to solve some of the big problems. And for me, that was around nanoscience. And then Frances, when I was in graduate school, you were a young professor at Caltech and you came and gave a lecture at Berkeley when I was just a student.

[05:46] Carolyn Bertozzi: And what you taught us was the magic that happens when you take a scientist – and historically a scientist is somebody who wants to discover things – with an engineer. Historically, an engineer [was] somebody who wanted to make things and solve problems. But of course the lines between science and engineering are completely blurred and what we should have been. And I’ve also learned that interdisciplinary teams of people that include the brilliant biologists, the chemists, a little more humble and lowly, even the physicists if space permits, with the computational scientists and the engineers, and the people who understand public policy, and the economists. And when you bring them all together, you can solve big problems, not as well as biology can because she’s had hundreds of millions of years’ headstart on us. But ever since that time, it’s been my focus to try to enable interdisciplinary science and bring together teams of people so that we can learn each other’s languages and help work together to solve these big problems. So thank you for being so inspiring to me.

[06:51] Frances Arnold: Well, you have such an advantage of being here at Stanford. I’m at Caltech. To us, diversity is mix a little chemistry in with physics, but here you’ve got everything and doesn’t it get overwhelming sometimes?

[07:08] Carolyn Bertozzi: Yes. I mean, it’s very humbling to be in a place where you have so many brilliant scholars across all the different walks of the sciences, engineering, humanities, medicine, law, business, and so on. So a person could spend every day for the rest of her life here and still be in the early part of the learning curve and that’s what I find so exciting about this environment.

[07:28] Steve Chu: So I’ve got to break in, otherwise they don’t need me as a moderator.

[07:33] Frances Arnold: The chemist will take over.

[07:35] Steve Chu: So to say even physicists, in my defense, the last 10 people who left my group got faculty positions in chemistry departments, not physics. And then maybe a dozen years ago, I knew very little chemistry. I went to the Khan Academy and had to take Khan Academy chem courses – what’s oxidation, what’s reduction? [...] Now I have three or four courses in Khan Academy chemistry and so I’m hoping that someday they would allow me to peek under their tent. But anyway, going back to the theme at hand, I’ve always been a big believer that science – the goal of science is: number one, understand how nature works; but number two, with this understanding, how do you actually change the world and change the world for the better? And this challenge that we face, the long-term challenge of climate change, mitigating, adapting, sustainability in general, I think is an incredible challenge.

[08:55] Steve Chu: And when they say necessity is the mother of invention, well, this is the biggest mother of all necessities is that we need these solutions. And so I want you both to comment on how you see in the larger view both from your own personal vantage point, but how do you think science will actually change this? And I’m going to start with things like agriculture, which was talked about a lot yesterday, food supplies, the sensitivity, the changing rainfall patterns could collapse local agriculture, but there’s other problems. For example, when you put in fertilizer in the ground and it’s not absorbed by the plants, microbes in the soil turn this into N2O, nitrous oxide. It’s 300 times worse a greenhouse gas than carbon dioxide and is stable for a hundred years. And if you look at what the developing world, especially sub-Saharan Africans do – much more fertilizer – South Asia, much more fertilizer. I see this becoming [a] double-digit addition to greenhouse gases in the near-term future. So can you guys comment on this challenge in particular

[10:04] Frances Arnold: On fertilizers?

[10:06] Steve Chu: Fertilizer and agriculture, food in general.

[10:08] Steve Chu: I thought yesterday’s session was really eye-opening with José Andrés and I love the idea of a national food security advisor, because food is really important and we’re very privileged in this country to have more than enough, but that’s not easily accessible to the rest of the world. The kinds of disruptions that they talked about are very likely to happen. I think there’s so many opportunities for improving food distribution, food waste – lessening that. One of the examples that I use, I started a company that makes, this will make you laugh, authentic insect pheromones. Why would you want to make insect pheromones? These are the sex pheromones that they use to attract their mates. Well, what happens is that if you spray a little bit of a moth Chanel No. 5 into the field, suddenly she’s everywhere and the males get very confused. They don’t mate and they don’t make the caterpillars that eat the corn.

[11:19] Frances Arnold: This is a chemistry problem because if you look at the structure of insect pheromones, they’re pretty complicated. So synthesizing, actually producing these things at scale has always been too expensive, but biology knows how to make that. So we started making these things biologically and now hundreds of thousands of acres of corn and cotton in Brazil are now being protected, not with pesticides, but with insect pheromones. And these are really simple solutions that we’ve known about, but then bringing the cost down is so important. And fertilizers, I mean, I’ll go back to you. What are the opportunities for improving fertilizers?

[12:07] Steve Chu: Well, I would say there’s been an inspiration in the last couple of decades based on soy plants and other legumes that enter into symbiotic relationships with the plants and these little microbes feed the plant. And so they’re right at the boundary of the roots and the soil. There was a company called Pivot Bio used – another company, Zymergen – to do synthetic biology that could actually induce microbes to enter into the symbiotic relationship with corn. It was a partial success. Half the fertilizer corn was eliminated, but it took eight years. And because of that, the synthetic biology company went bankrupt. And you want not half the fertilizer, you want all the fertilizer.

[13:00] Steve Chu: You want it for all the major grains. And so I saw as a bottleneck, can you introduce a dozen genes at a time? I’m not at the scale of billions of little experiments, but hundreds of thousands of experiments, but you can type out the DNA. And if you can start to do that, then you can accelerate the combinatorial discovery process. And so my own group is trying to figure out how to do this. Unfortunately, we found that electroporation is much more complicated than we saw it, and it’s not even clear how big DNA gets into cells, but that’s a side story. It’s one of the wonderful things about science. You go and do something useful, then you discover there are more scientific problems.

[13:42] Frances Arnold: Are these scientific problems or are they engineering problems?

[13:46] Steve Chu: I’m not going to draw a distinction between science and engineering. I think it’s seamless. Unlike and chemists learn physics, but physicists can’t learn chemistry except if they go to Khan Academy, but nevermind that.

[14:01] Frances Arnold: I’m not a chemist. I won the Nobel Prize in chemistry. I’m an engineer. I get accused of being a chemist, but I’m not a chemist. It just shows the blur of the fields.

[14:12] Steve Chu: That you see. But Carolyn’s a hardcore chemist. 

[14:16] Carolyn Bertozzi: And proud of it.

[14:19] Steve Chu: Don’t you love this? And you started your life being both in nanotechnology, but also being an expert on things that weren’t getting a lot of attention way back when, like carbohydrates, really boring stuff, things that coat cells. But tell us from your point of view, can your knowledge and what you’ve done be applied to [these] sustainability questions?

[14:48] Carolyn Bertozzi: Well, historically, my research has been focused more in the biomedical science space, trying to understand what are the molecular problems that underlie human diseases and can we invent new ways of intervening in those diseases with molecules we invent in the laboratory. So drug development is a big part of what we do, but the more exposure I get to the interesting problems of sustainability, the more I realize that when you get down to the molecular scale, the processes and the problems are actually all quite similar. And this really struck me when we were at our evening dinner the night before last over there in the Stanford Shopping Center and I spoke to one of the students who was giving a little talk on the work he’s doing in studying colonization of coral by microbes. So coral is alive and it’s alive because there are organisms that live symbiotically with the coral and with each other and create an environment, and we all know how important coral is as kind of an early stage in the food chain.

[15:54] Carolyn Bertozzi: And it turns out that coral can become bleached. In other words, it gets baked and the organisms die and it’s dead and this harms the entire ecosystem. So to bring it back to life, the student is interested in colonizing coral with microbes and understanding how to rejuvenate coral. And I couldn’t help but think about the parallels between that problem and the problem of trying to recolonize the human microbiome in the gut, which is a very active area of research in my institute here. And one of our scientists is actually starting a clinical trial to take people who have had a gut microbiome problem and repopulate their gut with, like, a healthy microbiome. And I was thinking that these problems are very different on their surface, but when you boil down to the kind of molecular details, they’re very similar. And so I realized that much of what we’ve learned in biomedicine about the biology of the human body has parallels in the environment in ways that affect planetary health.

[16:54] Carolyn Bertozzi: And that’s a really interesting intersection that we want to explore in my institute over the next decade. 

[17:00] Steve Chu: Speaking of these gut microbiomes, when I was director of LBNL, I got really interested in this because I found that in the soil, there are soil microbiomes, thousands of different microbes. And so I said, okay, and we had this joint genome institute that LBNL and Livermore were running. And I said, “We need, really, a practical application.” So I said, “What’s the most important, most expensive thing you can think of in raising? It’s like really good wine. And could you go back and figure out what was magic in the soils of France and Napa Valley and various places?” Because it turns out a lot of it is in the soil, but from that and the fact that you can now think of microbiomes and do experiments, before we couldn’t even do experiments, we couldn’t even isolate, we couldn’t even grow them in the lab. And so reflect on what has happened since those early days on microbiomes and what we think we can do with them.

[17:59] Carolyn Bertozzi: Well, the genomic revolution changed everything because when we had the ability to sequence genomes quickly and cheaply and ultra-high-throughput massively parallel ways, suddenly we could get a read literally on the composition of microbes in its soil or in the microbiome or in the coral. So that has really transformed and accelerated the way we do science. And I know that combining genomics and our ability to acquire big data sets quickly and cheaply with AI and machine learning is something that I think Frances is really leading the charge in pioneering that for bioengineering. Maybe you can talk about that.

[18:39] Frances Arnold: I love how this conversation on unanswered scientific questions is now centered on synthetic biology. But honestly, it doesn’t surprise me because the most complex engineered systems on the planet is life, and life even at the level of a single enzyme is more complex than we can comprehend, much less a whole microbiome, much less the microbiome in a human being. So the unanswered scientific questions is a whole universe of things to explore. The billions and billions are out there. So AI, where’s that going to play in? Oh, I’ve had a lot of fun with that over the last actually 13 years applying machine learning because we do billions and billions of experiments, although we take data on maybe a few thousand using machine learning to analyze those data and now using generative AI based on all the data that are out there in these sequences to generate new forms of life.

[19:43] Frances Arnold: I mean, that’s really a frontier of the science and we never could use physics-based models well enough to get useful outputs, but the AI revolution has empowered our understanding, understanding, ability to manipulate, I would say, so that we can make useful new DNA and I find that very exciting and so do the students for sure. Carolyn?

[20:12] Carolyn Bertozzi: Well, I’m struck listening to you talk about this, how so many of these transformative revolutions in biology and sustainability have their origins in fields that were kind of outside at the outset like our ability to sequence DNA, right, high-throughput, massively parallel ways. The technology for that came from the semiconductor industry originally, how to miniaturize things onto chips, how to design robots with precision that could manipulate things quickly. And now a lot of biology and drug development is being disrupted by AI, machine learning from the world of applied math and statistics and algorithms. And I think a lot of the problems of the day, you look at them on their face and you don’t realize that the answer might come from a completely unexpected place.

[21:01] Frances Arnold: All right. But now we talk a lot about cross-disciplinary science. What is the role of, say, deep chemistry and what kind of portfolio and you asked this, I’m sure, what kind of portfolio of the deep disciplinary science should be mixed in with the interdisciplinary science?

[21:22] Carolyn Bertozzi: I think we’re all channeling the kinds of discussions we have in our faculty meetings when we’re talking about curriculum development and how important is it to teach what we would call the core disciplines of our field. 

[21:34] Frances Arnold: It’s not just teach, it’s actually do the research.

[21:37] Frances Arnold: There must be many unanswered questions in chemistry that are just deep chemistry questions.

[21:45] Carolyn Bertozzi: You guys know the periodic table of the elements, right? If you took a dart and threw it, chances are it would have hit an element that nobody understands the chemistry of, to be fair, right? We’re really good at the chemistry of a couple of rows, carbon. Yeah, carbon, oxygen, nitrogen, right? Sort of the elements of life, I guess you could say. But most of the periodic table does not fall into that category. Most of those elements, if you saw the initials, you wouldn’t even really know what the element was. 

[22:16] Frances Arnold: But someday it could be important for sustainability.

[22:19] Carolyn Bertozzi: Could be the answer to lots of problems we don’t know. So I think there is a rationale to invest in very basic science of the unknown and one would have to motivate people with the resources like our federal agencies to share that priority.

[22:35] Steve Chu: So when Carolyn was mentioning, “Do you guys know about the periodic table?” I think she was asking physicists, and to be frank, many of my colleagues are dimly aware of it, but in the closing few minutes, I mean these are great questions. It’s centered on biology because, as pointed out by both of you, it’s an incredible technology that’s had billions of years of practice, but then you can accelerate the timeline millions of fold, maybe much faster, and so very, very exciting stuff. So any closing thoughts for you in the one minute you have apiece?

[23:19] Frances Arnold: I just want to say science is more exciting than it ever has been, that it offers the opportunity to invent, to discover, to do, to train people for great careers, and I find it distressing that our current administration does not support basic science or even applied science in such important areas. They support certain specific applications, but without the basic science that has enabled these applications, 20 years from now we’ll be behind and will be missing so much that could have solved these problems. So I hope that we get some rationality soon in the support for science.

[24:12] Steve Chu: Carolyn, you have the last word. 

[24:14] Carolyn Bertozzi: What she said. Ditto. Yeah. I mean, I echo that.

[24:19] Frances Arnold: I mean, I should say I spent four years in the Biden White House as the co-chair of the President’s Council of Advisors on Science and Technology. That’s the job that David Sacks has now. I had it as a deep scientist. I had 30 scientists from all disciplines who volunteered their time on the council and it was an extremely rewarding experience, but it taught me one thing and I’ll end with that. It taught me that science is easy compared to people. People are hard.

[25:00] Steve Chu: That is definitely true, but without people, we need the people. And as pointed out by a number of people, I’ll end in the last four seconds that I think – let’s just close with, in the end the world revolves around trust, and I think the scientists have to rebuild some trust and we have to reach across in many, many areas, but that’s true in general. So I hope we can enter into this thing where you’re not labeling people as good, bad, evil, Democrat, Republican, any of this. We have common goals and we need to build trust. Thank you very much.

[25:43] Carolyn Bertozzi: Thank you.