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- [00:07]
Elise Hu
You're listening to TED Talks Daily, where we bring you new ideas to spark your curiosity every day. I'm your host, Elise Hu. Could the scientific study of proteins and protein design save the world? For computational biologist David Baker, the answer is yes. His belief in this led to his popular 2019 TED Talk, receiving funding from TED's Audacious Project and a Nobel Prize. He sat down with TED curator Whitney Pennington Rogers for a recent TED membership event to dig into how much the science of protein design has progressed in the last six years, the surprising problems his team is able to solve for, and why he continues to believe wholeheartedly that designing new proteins can save the world. This episode is sponsored by Dell introducing the new Dell AI PC powered by the Intel Core Ultra processor. It's not just an AI computer, a computer built for AI. That means it's built to help do your busy work for you so you can fast forward through editing images, designing presentations, generating code, debugging code, running lots of apps without lag, creating live translations and captions, summarizing meeting notes, extending battery life, enhancing security, finding that file you are looking for, managing your schedule, meeting your deadlines, responding to Jim's long emails, leaving all the time in the world for more you time and for the things you actually want to do. No offense, Jim. Get a new Dell AI PC starting at $699.99 at Dell.com AI PC how those ahead? Stay ahead. This episode is sponsored by McDonald's. Okay, confession time. I love a good comeback story, especially when it's delicious and totally unexpected. Back in 2006, McDonald's released the snack Wrap and it quickly became the go to Bite, which portable, crunchy, juicy perfection. Then it vanished. Gone. Poof. But the fans like me, oh, they never gave up. I'm talking nine years of petitions, Facebook groups, memes, international snack wrap scouting missions. People built entire identities around this thing. It was intense in the best way. And now it's back. Yes, really. Thanks to relentless sauce loving dedication, McDonald's brought back the snack wrap. The think crispy, juicy white meat, shredded lettuce, melty cheese, all hugged in a soft tortilla and drizzled with ranch or your pick of sauces. It was never supposed to return, but the fans made it happen. Because sometimes passion wins. And sometimes it tastes like a snack wrap. Try the snack wrap that broke the Internet at a McDonald's near you. This episode is brought to you by Nordstrom. Okay, if you're like me, you wait all year for the Nordstrom Anniversary sale because it's not about clearing out old stuff stuff. It's about scoring new arrivals on sale. Think of it as a rare moment when time bends in our favor. Fresh styles, beauty exclusives, even home goods up to 33% off. It's the perfect time to stock up on those pieces you'll wear or use on repeat. And yes, there are great finds for under $100 from brands like Madewell, Free People, and Charlotte Tilbury. The sale is on now, but not forever. Prices go up August 1st forth. And Nordstrom makes it easy, which honestly, we all need. There's online order pickup, free shipping, free returns, and even free style help. If you're stuck in decision fatigue, check out all the fun anniversary events happening at Nordstrom near you, like in store promotions and daily beauty events. Shop now. Your future self will thank you.
- [03:52]
Whitney Pennington Rogers
Hi David, Great to be here. Thank you for being with us. First, congratulations on the Nobel Prize. I know that all of us at TED were really elated to see your work celebrated and recognized in that major way.
- [04:11]
David Baker
Yeah. And in fact, much of the work that I talked about in my Nobel Prize address was supported by the TED Audacious Project. So I'm grateful, very grateful to TED as well, and excited to be back here.
- [04:24]
Whitney Pennington Rogers
It's definitely meaningful that TED could be part of your journey in that really important way and part of this important work. And we definitely get into all of that. But before we talk about the Nobel Prize and sort of where things have gone since 2019 when you joined us as a speaker and as an Audacious grantee, I think it would be helpful to sort of set the stage with some background on your work, sort of detailing the science that was recognized here connected to proteins. So you've referred to proteins as the workhorses of all living things. You said in your talk, in fact, that almost everything that happens in the biology happens because of proteins. They do everything from transporting nutrients to repairing damaged tissue to supporting our immune system. And your work, of course, has been focused around creating new proteins. Why has this been such a challenging thing for humanity to accomplish?
- [05:23]
David Baker
Well, for many, many years, scientists studied the proteins that exist in nature, and they, I think they seemed almost like these sort of magical elfin runes passed down from, you know, billions of years of evolution. They're really special. They're very different from anything that occurs in the outside of biology because they have these very precise properties. They have these exquisite functions. And so the notion that you could design new ones that would do new things was really quite foreign. And when people tried to do was very, it was very difficult. So it was both that they seemed almost unattainable and that the attempts that were made were not successful, and that even thinking about the methods for even how you would go about designing a protein with the new function didn't really exist. So I think there were a number of reasons why it didn't happen a much longer time ago.
- [06:30]
Whitney Pennington Rogers
And of course, the groundbreaking thing that you've done, the Nobel Prize winning thing that you've done is, is using a computer program to design proteins from scratch. Can you talk about how exactly you did this?
- [06:43]
David Baker
Yes. And in fact, there's been a very big transition between 2019, when I gave the TED talk and today. So we began quite a few years ago to try to understand how the amino acid sequences of proteins determine their three dimensional structures. And just as a little bit of background, so everyone's on the same page, the genes in our genomes each encode a protein. That's what they do. And the way they encode that protein is by specifying the sequence of amino acids in the protein. And once that sequence is known, then that specifies what the three dimensional structure is. And so when I first began at the University of Washington, we studied how proteins actually fold up from their amino acid sequences to their three dimensional structures. We studied that experimentally. As we began to learn more and more, we developed computer programs to mimic that process and to try to be able to go from, take a sequence and predict the structure. Then after we had been doing that for some time, we realized that we could go backwards, not go from like in biology, from the sequence to the structure and the function of the protein, but instead start with a new structure and a new function that don't exist and work backwards towards an amino acid sequence that would encode that new protein. The difference is that in the biology case, the proteins are encoded in the genes in our genomes and the genes of all living things. In the design case, it's a completely new protein, so it doesn't exist. There's no gene that exists. So we have to make a synthetic gene, a synthetic piece of DNA that encodes this new protein. Once we have that synthetic piece of DNA, we can put it into a bacterium and it will produce the protein and we can see whether it actually does what we designed it to do. The first class of models we developed were traditional physical models where we tried to describe all the interactions between all the atoms in the protein and how those interactions guide the protein to fold up. We made quite a Bit of progress which I described, some of which I briefly described in my 2019 talk. Now, since then, we've completely switched over to developing AI based methods for protein design. And in these methods we take the many, many examples of protein structures, proteins whose structures have been determined by scientists really over the last 50 years. And there are about 250,000 of these structures now. And so we can learn by training AI models on these structures. We can develop methods that actually will generate new proteins with new structures. And we can condition this process on a specification of the function we want to create. For example, and our methods are very similar to image generation methods. So whereas you might say to Dolly or an image, image generation program, generate an image of a giraffe walking on a horse or something absurd like that, and you would get an image something like that that represents that. In the same way we can specify to rfdiffusion the design protein program we have created. We can say, design a protein which binds to this virus and blocks it, or binds to this cancer cell and stops it from dividing, and the program will generate a new protein and then we make it in the lab and see whether it actually does what we designed it to do.
- [10:32]
Whitney Pennington Rogers
It's incredible. And it seems like there are seemingly endless applications for this. And in 2019 you shared a few of them. And I'd love to talk about those that you shared in that talk. But also I'm really curious to know what excites you today when you think about applications for this.
- [10:51]
David Baker
Yes, so many of the grand challenges that I described in my 2019 talk, we've really made huge progress on and now gone beyond. But I'll highlight one example. I spoke about vaccines and during the pandemic, my colleague Neal King here at the Institute for Protein Design, actually developed a vaccine for Covid which is approved for use in humans. It's the first de novo design medicine. And he's well on his way to making advanced vaccines for many different viruses, including influenza. Since 2019, we've gotten into. As the methods we've developed have become more powerful, we've expanded the range of applications quite a bit more broadly. For example, sustainability is a new emphasis. So we're working on new proteins to break down plastic and other other pollutants and polymers. We're working on new ways to fix carbon and remove methane from the atmosphere. And we're working on green chemistry approaches to enable the synthesis creation of molecules without using toxic solvents and in much lower energy ways. So the grand challenges seem very ambitious at the time. But as the methods have progressed and with all the brilliant people who have come here to work on solving them, we've actually been able to go well beyond now and tackle new problems as well.
- [12:22]
Whitney Pennington Rogers
It's incredible, and it seems exciting to think about all the ways that this could improve life for really all of us in different ways. And you mentioned the sustainability work, which was something that you touched on very slightly in your 2019 talk. And it sounds like that's really ramped up since then. How did you begin to think about sustainability work as a potential use case for this?
- [12:47]
David Baker
One of the advances that we've made since 2019 is in developing methods for designing proteins which can make or break chemical bonds. This is something that happens in nature. There are many proteins which do this, which catalyze chemical reactions. And now that we've mastered that, we can design proteins that will break bonds. Problems like plastic degradation or breaking down other toxic compounds in the environment become really. They start to become things that can be approached. And it's particularly interesting with compounds that weren't present during evolution, like forever chemicals, PFAS compounds, there was never any evolutionary pressure for nature to develop, to evolve proteins to break down such compounds. And so there's a lot. So there are many problems we face today. And this is sort of a general theme. In places where nature was already trying to optimize heavily to solve a certain problem, there's not really a need for us to design new proteins, but in areas where either because we live longer, so things like neurodegeneration are more of a problem, or because we're putting new things in the environment, like plastic or PFAS compounds, those are the places where there's a huge opportunity for protein design. Because we always already know from nature that proteins can solve a really can solve almost any problem. And so for protein design, it's the problems that nature didn't have to deal with because, you know, humans didn't, you know, people didn't live as long, or because they hadn't polluted or heated up the planet, for example.
- [14:32]
Whitney Pennington Rogers
Well, it seems like that work is obviously very necessary. And I'm interested to also hear what other sorts of uses have revealed themselves in the years since you joined us. It seems like sustainability, of course, health medicine. What other areas have been sort of surprising places that you've been able to find protein design can be helpful?
- [14:54]
David Baker
Yeah, well, one area that's related to sustainability is that that's also become more pressing since 2019 is trying to design to make crop plants more thermo tolerant because, you know, temperatures are rising and it's very important that major crops like rice be able to grow and thrive at, at higher temperatures. And so one of the things that we've become very good at with protein design is to make proteins more stable. So we're excited now about applying those methods to problems like making plants thrive at higher temperatures. In other areas in technology, we're very excited about sensing and sort of intrigued by the ability of a human or a dog to smell and distinguish between many, many different compounds. So that the way that a dog does that is with proteins receptors in its nose that can respond differentially to different compounds that are in the environment. And we're now designing synthetic proteins that can respond to many, many different molecules. And so we're very excited about building things like an artificial nose towards that end. And for more general technology applications, we're learning how to interface proteins with electronics because then you can have a more direct coupling of a readout from a design protein to something that we can quickly read out on a cell phone, for example. And one example of that is we're designing proteins to sense compounds in the environment that are embedded, would be embedded directly in silicon nitride chips. And that's again a problem that nature never had to deal with because proteins in nature were never interfacing with, you know, with electronic devices. And we've made quite a bit of progress there.
- [16:59]
Whitney Pennington Rogers
How do we ensure and what role do you see yourself playing in ensuring that what you're creating is accessible and available to a wide range of people?
- [17:10]
David Baker
Yes, I think we start off on with the methods we develop. We make those widely available. And so that's start. We're particularly interested in enabling protein design in countries where there isn't as much advanced infrastructure for large scale drug screening, for example, because with protein design really cuts down the cost in making proteins that to deal with with, with a challenge. For example, if you are a farmer in, in Africa, for example, and you're dealing with a new type of, of pests, say a fungus or an insect, we want to empower scientists and researchers in the country that has the problem to actually use our methods to develop their, their own solutions to those problems which may be pretty local as things, as things come out of here. The we well we work. One of the things that we do is we, when we license things that we have created to other entities, we always require that there be a carve out for, for global health applications. And that's something that the Gates foundation has really pioneered. And so we try in every way we can to make sure that things we develop will be as broadly applicable as possible. I think it's a challenge currently that goes well beyond protein design to motivate the world to put the resources into ways of combating things like, you know, global warming and, you know, the accumulating plastic. There's been a lot of talk, but it's going to take a lot of resources too, and we can't really control that. I'll give you an example of something that I am disappointed in. During the pandemic there was a lot of talk about how we needed better methods for rapidly creating ways to deal with pandemic viruses. And immediately after the pandemic or during the end of the pandemic, there even some initiatives started to work on sort of faster approaches to develop ways to protect against new pathogens if they emerged. But within six months of the pandemic ending, the world kind of forgot about it. So the, so there are some issues with the sort of the way that the pull from the outside world in different areas is different depending on how much profit can be made, which is a little bit too bad.
- [20:00]
Whitney Pennington Rogers
Sort of keeping people's attention focused on this is, seems like the challenge of your work. Well, I think this is also a really nice segue to talking about the Nobel Prize, which is a great way to sort of put focus on this incredible work you're doing. So late last year, of course you get word that you've been awarded the Nobel Prize in Chemistry. Can you tell us about how you received this news and what that experience was like?
- [20:26]
David Baker
Yeah, it was very exciting and got the phone call and then I think what I remember the most that day was when I came into the lab and we had this huge party here and that was really, really special. And then in Stockholm that I think we, I really felt that the work, that the prize was a celebration of the work of, you know, the many people, the many brilliant students and postdocs and others I've had over the years who contributed to all the things that, you know, end up going into the Nobel Prize winning work and that I actually talked about in my talk. And so I want to. We asked people, former colleagues to come and then I think we actually set a record. There were one hundred and eighty five people who came, you know, who, former colleagues, former graduate students and postdocs, mostly former, almost all actually former trainees at one level or another at different times. And that was really special. I think we set a record and this really hit home to me when I gave my talk, my Nobel speech. And then, you know, when you're up there on stage, you can't really see who's on the audience. And then when the late lights came on, I saw that there was a quarter of the room, the whole, there was this whole big section which were all former graduates and postdocs from many years back up till the current. And that was really, really special. And I think it made it clear to me, I guess I had always known it, but I was really impressed upon the fact that, you know, for me, really, you know, the scientific advances are one thing, but really training and mentoring all these amazing people are going on to do all these really amazing things is really, I think that's, that's the most important thing I do. And, and so anyway, that, and then in Stockholm we had a number of really fantastic parties with all these 185 people, including, you know, family and extended family. And it was, it was really wonderful.
- [22:26]
Whitney Pennington Rogers
That's great. Well, David, I don't think you'll be surprised to know that we're getting tons of questions from the member community. And so I want to start to bring some of those to you to integrate into the conversation. We have one from Les B. Who asks, how do you see technologies like CRISPR and gene editing intersecting with your AI driven protein design? Could combining these tools accelerate the development of targeted therapies or sustainable biological solutions?
- [22:53]
David Baker
Yeah, it was a wonderful, it's a great question. Yesterday I had a very long conversation with the world's experts at CRISPR in Jennifer Doudna's institute at Berkeley. And we're going to join forces, just as suggested by that question, for the problem of sustainable agriculture. We can design new proteins, but then they have to get into the plants and so we can improve, say, plant thermotolerance. We can design proteins that in principle could implant, improve plant thermal tolerance or protect against funguses like wheat blight. But we need to get the proteins in and CRISPR and the IGI are really experts at that. So I think this is a perfect time to partner in many areas.
- [23:42]
Whitney Pennington Rogers
Lachlan F. Is curious about the pros and cons of your scientific work being either a completely open source like open fold, or proprietary like AlphaFold. And can both of these options accelerate progress and, and possibly maybe limit public benefits as well?
- [24:03]
David Baker
Yeah, I'm a big believer in making everything open. And I think you, you know, we find that people build on what we create and also it's, you know, as scientists really that one of the goals is to really have broad impact. And the more you share, the more impact there is. And I think that's also held for the people leaving my group who are starting their own group. We stayed there now over 100 former graduate students and postdocs who left my group to start their own labs in the US and around the world. And I've encouraged them to keep working in this area. And so now we have this amazing community. We have yearly meetings where everyone's working together and everyone, everyone meets and, and shares what they've done. And things just have moved really, really quickly. So I think in general have. Having everything open is, is, is, is really a big advantage now if you're at a company, there's, that has to be moderated by the fact the company needs ultimately to make money. And so there are different constraints. But at a public institution like the University of Washington, or really in any university, I think making everything open is the right way to go. And we've just, we've seen that really from the beginning, we made, well, even for our earlier generation, non AI software called Rosetta. We made it widely available. And that just created this whole community around it, which has really been wonderful.
- [25:33]
Whitney Pennington Rogers
I mean, and that's, and that speaks to something that we're seeing a lot from the community which are just questions around how to ensure that the proteins you're designing and just as we think about just AI and technological acceleration in general, that it remains in the best interest interests of humanity, global peace, kindness, how do we safeguard against misuse in a world where some people are, you know, there are some bad actors and looking to use things for.
- [26:00]
David Baker
Yeah, that's a, that's a very good question. And we are. Let me first give you an overall framing for it and then I'll tell you about specific actions we're taking. The things that are really dangerous. The types of pathogens are like viruses like the 1918 Spanish flu or Ebola, which obviously can cause death and destruction on a huge, huge scale. Those are extremely complex things. And because they have to do many, many, many different things. And even, even with the advances in protein design, it's still very challenging to, to make a protein that, that has one function, whereas a virus has to do many, many things. And so if you want to cause death and destruction on a large scale, you don't really, the design methods don't help you. You just go to nature and you can, you can remake the 1918 Spanish flu. And so what the protein design methods are really good at today is blocking, for example, viruses, either pandemic viruses or new viruses. The idea of making a synthetic virus is still. Well, first of all, there's not really any reason to do it because virus. I said at the beginning that design is very powerful where there hasn't already been extensive evolutionary optimization. So viruses. There's been extensive optimization for really rapid spreading and infection. So the first point is that if you want for bad actors, there already are many, many bad things all the way around, ranging from, you know, things like botulinum toxin to major viruses. And I really think the primary role of protein design will be to protect against these threats and new threats. But of course it is possible that a bad actor really has their mindset to try and create something new and dangerous. So we had a workshop at the University of Washington a year and a half ago. That was that we convened together with the National Security Council in the White House and we convened a panel of experts to really think about this problem. And our conclusion was, first of all that the current generation of design methods did not pose a threat compared to the huge threats that already are present in nature. But second, that the way to control things is. And to make sure and is, was to. Was through the synthetic gene manufacturing step, where you go from the computer to the real world. And as I said earlier, that's a key step in this process and that's the one where having like gating and control, or at least logging, we concluded would be really, really important. And so we are urging DNA synthesis companies to keep track of everything that's that they're making so that in the event that there is a suspicious outbreak somewhere in the world, you can quickly track where the DNA came from if it was synthetic rather than being of natural origin.
- [29:22]
Whitney Pennington Rogers
Excuse me. That's great. It seems like there is some thought to how to create this responsibly as we're. It feels like a really a brave new world and that there. You believe that there are more benefits to pursuing this than the risks that are presented.
- [29:39]
David Baker
Right. And that's very clear so far. I mean the. I mean there's huge numbers of beneficial things have been done. I mean, even in the area of pathogenic disease, you know, I described the vaccines, the antivirals, and so the. Yeah, I think the upsides far outweigh the downside. The other thing we're doing is we are setting up sort of a committee that's, that's reviewing new software as it's created to make sure that. To vet the release, to make sure that there aren't unforeseen consequences. I would say overall, the risks, if you think about AI and biology compared to AI generally, I think the immediate risk from AI more generally in the form of, of computer viruses, you know, things that you don't have to instantiate in the real world, but that work in software. We're already seeing problems there. And then of course, we're seeing more broader problems with employment and AI replacing people. I think those are probably the places where AI is going to be really a problem, a negative, rather than AI in the biological realm.
- [30:47]
Whitney Pennington Rogers
When you think about the future and sort of where this is headed, we have a question from Nicholas D. If you see a future where computational design of proteins could potentially displace approaches like evolution, or will it never reach those heights?
- [31:04]
David Baker
No, I think that already with problems like antibody design, antibody generation, antibodies are really kind of the pharmaceutical industry. Antibodies have been a mainstay. And generally the way that antibodies are developed now, it's either from sort of pulling antibodies out of an individual or immunizing an animal, or screening through very, very large collection of very large random libraries for an antibody that has the right property. I think those will be displaced by design because you can be much more intentional and design an antibody that not only binds to the right place on your target to have the effect you want, but also has all the properties needed to really be developed as a drug. So I think more and more we're going to see random selection, random sort of library screening methods which are kind of emulating evolution, where, you know, evolution is also all random mutation generation and selection. We're going to see that replaced by, by intentional protein design. And that harks back to what I said in my TED talk, where I sort of made the point that human technology outside of biology, you start from first principles. If you want to build a bridge across a river or a flying machine, you don't go looking for a log that has the right shape, but you actually construct it from first principles. And so I think now that's becoming more and more a reality throughout sort of bio biotechnology.
- [32:40]
Whitney Pennington Rogers
And when you, you think about your, your work in protein development, you know, so we work so much of what this conversation has been focused on the things you said in 2019 and when you gave your talk, what do you, what do you foresee, you know, in six years from now, when we speak again, where do you think things will be? What do you, will you be focused on?
- [32:59]
David Baker
I think predicting the future of science is far harder than predicting the structure of a protein. Or predicting the weather tomorrow. So I think predicting how fast science will progress is a famously impossible challenge. But I can say, broadly speaking, six years from now, I expect to see medicines, many more medicines approved for use in humans. I expect to see, you know, solutions to major problems and really across the areas that, that I've described. And then I also anticipate that we'll be working in the field, we'll be working on problems that I haven't even mentioned, I haven't mentioned today because I haven't thought of them. So things are changing so fast that what I really hope most is we're solving problems I can't even conceive of now.
- [33:46]
Whitney Pennington Rogers
That's wonderful. Well, David, I feel like this has been a wonderful conversation and just really grateful to you for joining us. We have had so many member questions, so thank you to the members as well. Thank you so much, David, for sharing all of this.
- [34:04]
David Baker
Thanks to everyone who's listening and contributing questions. It's been great. Thanks to TED for organizing this. I just want to thank again all the amazing students and postdocs and others I'm working with now and in the past who really made all this work possible and who've actually done all the work, really.
- [34:23]
Elise Hu
That was David Baker in conversation with Whitney Pennington Rogers at a TED membership event. This conversation took place on June 11, 2025, and to watch David's 2019 TED Talk, just visit ted.com if you're curious about Ted's curation, find out more@ted.com curationguidelines and that's it for today's show. TED Talks Daily is part of the TED Audio Collective. This episode was produced and edited by our team, Martha Estefanos, Oliver Friedman, Brian Greene, Lucy Little, Alejandra Salazar and Tonsika Sal Song Marnivon. It was mixed by Christopher Faizy Bogan. Additional support from Emma Tobner and Daniela Ballarezzo. I'm Elise Hu. I'll be back tomorrow with a fresh idea for your feed. Thanks for listening. This message is brought to you by Apple Card. Each Apple product, like the iPhone 16, is thoughtfully designed by skilled designers. The Titanium Apple Card is no different. It's laser Etch has no numbers and it earns you daily cash on everything you buy, including 3% back on everything at Apple. Apply for Apple Card on your iPhone in minutes, subject to credit approval. Apple Card is issued by Goldman Sachs Bank USA Salt Lake City Branch terms and more@applecard.com.
- [35:47]
D
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- [36:38]
Elise Hu
The Snack Wrap is Back. This episode of Giggly Squad is brought to you by McDonald's, and I'm so excited to tell you that the snack wrap featuring juicy white meat, chicken, shredded lettuce, melty cheese, creamy ranch. Sorry, I'm drooling on the microphone right now. All wrapped in a soft tortilla. Back on the menu, they have it in ranch or spicy a spicy pepper sauce. If you're feeling frisky, try the snack wrap that broke the Internet at a McDonald's near you.