10. DNA Synthesis with a Twist w/ Emily Leproust

In this episode, we interview Dr. Emily Leproust, CEO and co-founder of Twist Bioscience, a leading and rapidly growing synthetic biology and genomics company that is well-known for its disruptive DNA synthesis platform. We talk to Dr. Leproust about the future of DNA synthesis, making cloning obsolete, and eating challenges for breakfast.

This episode was recorded in September 2021. During the interview, Emily mentions the publication of an article "last week" that happened in September of 2021. You can find this article here.

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Episode transcripts are the unedited output from Whisper and likely contain errors.

Transcript

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Hello and welcome back to EBRC and Translation. We're a group of graduate students and postdocs working to bring you conversations with members of the engineering biology community. I'm Fatima Inam, a postdoc in the Sonnenberg lab at Stanford University. And I'm Katherine Brink, a postdoc in Megan Palmer's group at Stanford University. This episode, our guest is Dr. Emilie Lepruist, CEO and co-founder of Twist Bioscience. Twist is a leading and rapidly growing synthetic biology and genomics company that is well known for its disruptive DNA synthesis platform. Emilie, it is so great to have you on our show and thank you so much for joining us. Thank you for having me. It's a great pleasure. So we like to start off our interview by asking our guests to introduce themselves. So could you tell us a little bit about your background and a little more specifically about how you got interested in DNA synthesis? Sure. So I was born in France. I came to the US to do my PhD at the University of Houston. And I learned English in Texas, but I didn't pick up the accent, but I knew that you all is one person and all yours is two or more. So I did learn that. So I got interested in DNA synthesis was a little bit by accident. I joined the group of Dr. Charlene Gao, and she was doing DNA synthesis at U of H. And so you make those massive fundamental decisions in your life when you're 21, 22 years old and you don't even realize how incredibly important those decisions are. But that's how I got introduced to DNA synthesis. Actually, when I came to the US, I'm not sure I knew how to spell DNA. Were there any particular projects that you worked on in your graduate career that specifically got you interested in commercializing DNA synthesis or kind of the more industry aspects? Yeah. So the first project that I worked on was to add deuterium to some positions on the four bases of DNA. And the idea was to silence some hydrogens to facilitate NMR studies and being able to study longer pieces of DNA. And if you add deuterium, it just cleans up quite a bit the NMR spectra if you do it carefully. But that was really my first DNA synthesis project ever. I thought that was super cool. And then at the time when I was doing my PhD, it was the beginning of microarray synthesis. The idea was a high throughput multiplex DNA synthesis, so making multiple oligos at the same time instead of making one. Asymmetrics were just started. There was a number of companies that were going into the field. And so what we used in my PhD group was a digital macro marrow. So kind of the projector can hook up onto a computer to project a presentation. And we use the micro marrows to turn on or off a chemical reaction on a laser glass or silicon. And I think in my PhD, I would have to go back, but I think I was able to make a thousand oligos in parallel. Like the big thing, a thousand oligos. And now at least every day we make a silicon chip with a million oligos. And in our data storage unit, we are working on a technology that makes a trillion oligos at the same time. So quite a bit of growth in the last few years, but basically I spent most of my time in my PhD trying to think about ideas to make as many oligos at the same time as possible. So high throughput multiplex synthesis of DNA, which this is still what I do today. So could you tell us more about your trajectory to founding TWIST? You talked about the research that you did in the lab, but did you always know that you wanted to be an entrepreneur and how did you decide to go about starting a company? So my parents were entrepreneurs, so I always had the idea that it would be cool to be an entrepreneur. I was always to be daunted because I thought that in biology, you needed to raise a lot of money to get things going. It's not like a software idea where in your bedroom, we can build a software company with just a computer. So I was able to be daunted by the amount of capital needed. And one of my friends in college in France, 10 years after we last met, and he had started two companies and sold them. And when I told him, wow, you know, it's too bad in biotech, it takes a lot of capital. He said, well, why don't you just raise it? And that kind of opened my eyes like, yeah, why don't you just raise it? But I didn't really have a great idea. And I was super lucky that my co-founders Bill Banyan and Bill Peck had an idea, and which is the idea of Twist. And they needed a CEO to run the company, do the fundraising, and so on. And so they came to me and I am the victim in some ways. So they recruited me to be the CEO. And the rest is kind of history. We had a good idea. We raised money, hired great people, built a great culture of innovation and commercial violence, which is very important as well. And we've been able to go after very aggressive milestones and for the most part, meet them. And so now we have very happy customers and growing revenues. And it's just the end of the beginning. There is many more that we can do. You have to definitely be innovative, especially in such a competitive space. What do you think really makes Twist technology different from others that are in this DNA synthesis space? Yeah. So I think there's the idea of, look, the chemistry of attaching ACGT together is just fine. It works really well. Published in 1984, optimized for thousands by thousands of grad student years. I put my four years and a half in there. And the chemistry is just really amazing when you think about it. 99.9% efficiency at each step. The chemistry works. And actually, the insight of the two builds was that when you order a PCR primer, customers never run out of the PCR primer. It's a lifetime supply. And that is because you get just so much DNA that you never run out. And the reason why you get so much DNA is because it's done in 96 web blades and you put a lot of beads and you get a lot of DNA. And their insight was to say, well, what if we shrank everything and just made the amount of DNA we needed? And because our engineers, they knew everything about silicon, about doing chemical reaction in 10 picoliters in the lab. You're struggling with one microliter piping. And so now it's like 10 picoliters. And when you shrink everything down to 10 picoliters reaction, yeah, you make just enough DNA. And so now a couple of things happen. One, it's a lot cheaper to make because there's a lot less regions. And then two, 10 picoliters is super tiny. And in the footprint of a 96 web blade, you can put a million droplets together. So then your throughput, it's just much increased. So that's the good news. It's kind of simple conceptually. You just shrink everything. And in life, there are two kinds of news. That is the good news. And then there's the news. And so the good news is that it's super simple, but the news is that it's really hard to make it happen. And many times that twist people came to me saying, I mean, this is impossible. How are we going to do that? And I said, I don't know. But that's why I have you. And they found a way to make it work. And now when people come back for the next project and they say, well, you know, this is impossible. I say, well, that's what you said last time. And you made it work. Go find out the way. And they're like, oh, no, no, no, it's really, really, impossible. And you know what? You know, when you set impossible goals, people find a way to rise up. And that's the amazing thing about science and about the Silicon Valley philosophy of choosing very hard problems. And then you just go at it and you make it work. And if it was easy, every other idiot would be doing it. And so picking hard projects is important. Now that you mentioned that something that comes up quite a bit when discussing not just DNA synthesis, but sequencing as well, is that some of these technologies have been improving at a rate that is much faster than Moore's law. And this exponential improvement in the ability to program this DNA is really driving this revolution. You expect this trend to continue? Well, yes. I mean, there's always more demand from scientists to do new things. And that's why we try to do a twist is to enable our customers who actually we see as the heroes, where our customers are the Batmans and we're Robins to help them achieve that. And we're always constantly trying to push the boundaries. And there's different directions for that. One, of course, is price. I strongly believe that our customers have more ideas than they have a budget. And so if we were the price, it's a win-win. It's going to be a win-win because the scientists will be able to try more pieces of DNA. And so there'd be more shots on goals. It would be a win for twist because they're going to spend all their budgets with us and that's good. And then it's going to be a win for science because if you have more shots on goal, you're just going to advance more with what you're going to find. So that's kind of our philosophy on price. Always try to get as low price as possible. But at the same time, it has to be very high quality. So of course, when you sell a clonal gene, it has to be perfect. It's clonal perfect. So you can't do better than perfect. But when we sell fragments, for instance, we have some of the highest quality fragments out there. You pick two clones. You have one that is perfect. And then the way that we make those amazing high quality fragments is to start from amazingly high quality oligos. And our oligos actually have such high quality that we've been pushing the field in terms of how long can you make an oligo. So it used to be when I was a grad student, there was a paper published that said that you could never make an oligo that's more than a hundred base pair. Like it's the law of science of reaction called depurination that you could never make an oligos more than a hundred base pair. And so of course, it was true that there was depurination and we found ways to overcome depurination. And so at first we started to sell oligos at 150 base pair, which is nice because it's a guide RNA. So if you want to do a genome wide experiment and silence million pieces of the genome in parallel to find a relation between phenotype and genotype, you can do it. And then we pushed the size of oligos to 200 base pair. And then when enzymatic synthesis said that DNA chemistry was really bad and you had to do enzymes just to mess with them. We did some already and we now sell oligos that are 200, sorry, 300 bases. So now we sell oligos that are 300 bases. And what's great when you have 300 bases is that suddenly you can put two guides RNA together. And instead of silencing one piece of the genome, you can silence two pieces of the genome at the same time. And so now you can look at interactions between two different regions. So quality is the second axis. And then the third axis is the speed in our view. Right now, at least we are not faster than the market. Right now we are average, same speed as everybody else. It takes about 11 to 15 days to make an Oclonal gene, which is good, especially when it's added to the massive capacity that we have in terms of making gene. We can make one gene in 11 to 15 days, but we can make 10,000 genes in 11 to 15 days. So you can back up the truck. You can't break us making DNA, but 11 to 15 days is still too long. And we think that a lot of our potential customers, for instance, grad students, postdocs and so on, frankly, they'd rather go in the lab, spend the weekend and clone to get their gene faster. And so we are actually investing $90 million in our factor of the future, which will enable to make clonal genes from scratch faster than if you're going to do it yourself in the lab. So our motto, a twist is that friends don't let friends clone. And we're definitely pushing on price, pushing on quality, pushing on speed to make sure that silence just goes faster. That's really exciting. I ordered jeans and primers from Twist in graduate school. And that's kind of the main way that I was aware of the work that you guys are doing. But I know that Twist has also been involved in other types of biotechnology applications. So things like digital data storage and biologics drug discovery. Could you talk a little bit more about some of these other areas that you are working in? Yeah. So we have a great platform. Our silicon chip, we talked about it. We miniaturize the chemistry. It's a great platform. And we make DNA. And you know that sometimes when you have a hammer, everything looks like a nail. And so that's a little bit what happened. We started Twist to be in synthetic biology. So we can make oligo pools and jeans and fragments and laboratories and so on. So that's great. But then we realized that there was another market that needed millions of super high quality oligos and that's in genomics for targeted sequencing. Instead of sequencing the entire genome, if you want to do, for instance, liquid biopsy, you're only interested or you can only afford to sequence 200, 500 genes because you have to sequence down to 50,000 X coverage. So if you sequence that entire genome, it would be unaffordable. And so we entered that market as well. Again, with high disruption. And I think we were one of the leaders in that field as well. So those are the two initial markets at Twist, synthetic biology and genomics. And then in my travel, I would meet all those pharma companies and say, oh, twist oligos and jeans. Amazing. We changed the way we were developing drugs. And yeah, it's great. Super happy to do that. And then we realized that when our customers discover a drug, when you look at the number of bases in that antibody, the value can be $15 million per base for that drug. And we got $0.09 per base. So we were being a little bit greedy and we said, well, maybe we can as well at Twist offer a service where we will discover the drug for the customer. So you come to us, you can buy the jeans, no problem. But if you want to just give us a target and we'll use our own DNA, we have an unlimited DNA buffet, and we'll find drug, find antibodies. And hopefully get a little bit more than $0.09. So it's a bit more expensive. We want milestones and royalties, but that has been working really well. That's one of the fastest growing segments at Twist. And then last, there's a data storage business. Actually, before starting Twist, I had a paper. My last year before Twist, I was working, I had a CNS paper in cell nature and science. So probably last time in my life, I think it was in 2013. And one of those papers in nature was around using oligos for DNA data storage. And when we pitched Twist, the investors were saying, you know, our funds are a 10-year fund. This is a 10-year project. Forget about data storage. And they were right. And so we didn't speak about data storage, but at Twist, we always invested maybe a few hundred thousand dollars a year in data storage and were able to move the technology forward. And then a few years ago, it became real. And so now we have a division of Twist working on data storage. And back in 2013, those investors were right. It was a 10-year project, but I'm glad that we started in 2013 because now we're just a few years away from this being a product. So from the platform, we have built four different businesses and they are both super innovative in their own way. And we're saying at Twist that we're building a large company. And when we go into a market, we're building a conglomerate. And when we go into a market, we want to be number one in a world where there's no number two. So not only we have deep technology innovation, but as I mentioned earlier, we try to bring in commercial violence, being very aggressive in how we sell, which is very helpful and very complementary to the technology. That is super cool. I just had a question about, you mentioned that it has to be super accurate, especially when you're building these oligos for screens, for example. When you're looking at this DNA data storage, does it still have to be that accurate? That's a very great question. And actually, as we are working in the field of data storage, I've learned that magnetization, which is used on hard drive and tape, is actually incredibly inaccurate. And I think on your hard drive, one in eight bytes is wrong. But there is massive error correction software. And so it's fine. Even though you have one in eight that is wrong, there is so much redundancy that everything is fine. You will never even know it. So that's one of the advantages that we have in DNA data storage is in order for it to be viable commercially, the price has to be much lower. We need to be able to store a terabyte of data for a hundred dollars. So we're far away from it for now, although we're getting close very quickly. But the lever that you have is quality. You actually can let the quality drop if it saves you costs because of those error correction. And so actually, we pride ourselves of making oligos that are one error in 2000 base pairs. And that is all included. So it's error of insertions, errors of deletion, and errors of substitution. Most companies, they only look at deletions, but we look at all in together. If we just look at deletions, probably one error in 15,000 bases. So it's amazing quality. But for data storage, one error in 10 bases will be fine. So that's definitely a lever that we use to kind of, in a sense, let the quality drop and be able to decrease the cost. However, I will say that I think we have a bias, a twist that we want everything to be high quality. So even though it could be as low as one error in 10 bases, I think we'd be much better than that. But the same is true in sequencing. I think all the sequencing companies rightly have been focused on quality because it's for human health in many cases. But when you're going to reread DNA to get your data back, again, because of redundancy and the error correction software, you could be successful with much lower quality of sequencing. And I think that's key commercially is to understand what is the problem you're trying to solve and focus on that because it's not because it's cool that you should do it. We always say a twist that we rather be wealthy than be smart. And so it's important to have the right products for the right customer. And yes, in data storage, quality does not matter as much. And that's fine. We're using that to our advantage. So speaking of these different areas that Twist is involved in, I was wondering if you might be able to comment on what you see as some opportunities for the DNA synthesis industry going forward and what might be some potential challenges for the industry over the next, say, 10 years or so? Yeah, that's a great question. And we love thinking about challenges because to us, challenges are opportunities. And so we love to eat challenges for breakfast. That's a really good thing. And I think when we look and listen to the user, I think there is a trend for always getting longer and longer DNA. What if you could make a 500 base pair primate? What if you could make a full chromosome? So there's definitely a challenge there, but slow opportunities in making longer DNA. I mentioned earlier, there is a huge challenge in being faster at making DNA. Again, there's a lot of people that are making DNA that are cloning all day long. And to me, cloning is the 21st century of coal mining, right? You're moving clear liquid from one tube to another. And you're just doing that to get the clone that then you can do the fun, you can do the science, you can do your experiments. So if we could be faster, we can eliminate, make cloning obsolete. And then the other challenge and opportunities is that there are 100,000 scientists that clone. And so as a company, how do you reach 100,000 people? We can't have a salesperson walking the whole ways of universities. And so even though we're into science, we're into technology, into engineering and chemistry and biology, you have to learn digital marketing. How can you stalk people on the internet and remarket them until the biogen from you? So those are some of the challenges that also can kind of exciting. So thanks for talking about some of those challenges. I know Twist has also been heavily involved with issues around the pandemic. So can you tell us a little bit about how the pandemic really changed some of the development areas that Twist is exploring? Yeah, so the pandemic has been just terrible for society and the human suffering and the devastation of the economy. But in some ways, we had built Twist for an event like that. And we've been able to deploy a lot of our tools, probably all of our tools, except the test storage against the pandemic. So early on when the pandemic happened, there was a big push for vaccine and antibodies. And so to develop those products, you need DNA. And definitely we were a source of DNA to vaccine makers and to antibody drug discoverer in the field of diagnostics. A lot of the tests at the beginning were PCR. Yes or no, do I have COVID? But over time, it became clear that the variants and the identification of variants was important. And so very early, I think in March last year, we launched an NGS kit that would sequence the entire COVID virus. So not only you get the yes, no, do I have COVID, but you also know the variants that the patient had. And at the beginning of the pandemic, we identified a new product that was missing on the market, and that is a synthetic control. A manufacturer of diagnostic tests needed COVID in a tube to test whether their assays were working. And hospitals, labs, needed also COVID in a tube to make sure once a day or once every 100 patients or 96 patients to make sure that the diagnostic test was still working. And so very quickly, we launched COVID in a tube. So it's the full 29,000 base pairs of COVID in RNA form. And it's safe. It's cut into five locations. So you can brush your teeth with it. Don't do it. But you could. And since then, we've launched, I think, 17 different variants. We've launched all the respiratory diseases, again, as positive control. And actually, that has been a very appreciated new product in the market, which even ourselves, we didn't thought we would need. And so that's a kind of innovation we'll do. And then last but not least, we used our own drug discovery engine, and we discovered antibodies against COVID very quickly. And now they've been tested in many different studies. And actually, there was a report in Science last week where we did really well. And antibodies are neutralized against a number of variants. And so not only we have antibodies against the initial strain of COVID, but they have some universal aspect of it in how they can stimulate the virus that have evolved. So again, we are there in service of our customers, service of science, but we're super glad that we were able to participate in the fight against COVID and make the world a better place. Another area that I think Twist has been a leader in has been this area of biosecurity. In particular, I really enjoyed a paper that you co-authored back in 2019 related to issues around safety and security for DNA synthesis. It's especially been an important issue lately with the recent bill in California, AB70, that would mandate sequence screening for gene synthesis providers. And so I was wondering if you could tell us a little bit more about the work that Twist is doing in this space. Yeah, thank you. I'm glad you enjoyed the paper. Biosecurity is very, very near to our art. And you're right that it's long been a very important part of Twist and a priority for Twist. And really, the idea is to make sure that our products are used responsibly. We've been following the California state law proposal very closely. And for the first time, there's a state that could require that the funding that it provides for research is only spent with vendors that take biosecurity seriously. And I'm glad that California is doing it. And actually, we are advocating a similar effort federally at the U.S. level. And the idea for us is not to limit researchers, but there is a good number of companies that do screening and that do DNA synthesis responsibly. You can find them on the IGSC website. And I think it's important to reward those companies that are doing the hard work. And that work is hard because the incentives are actually against biosecurity. Because what happens is there is a drive to lower the cost of DNA synthesis. We talked about that. That makes sense. But at the same time, screening becomes harder and harder. The more sequences there are, the more screening is hard. And so there's this weird incentive that the work of doing biosecurity is getting more expensive. And at the same time, you're making less money. And that's why the IGSC is great. And what we do at IGSC is we want to help new companies that are going to DNA synthesis do the screening the right way. And those laws will encourage that. At the same time, I think we also have to be aware of the true biosecurity risk. And I'm on record for saying that the biggest bioterrorist is nature. And everybody thinks, oh, mother nature. We actually know nature is trying to kill you every day in the way it can. And so we have to do biosecurity, but we also have to do surveillance of nature to make sure that we catch evolving diseases. So both have to be made, and at which we like to bring the entire industry forward. So whatever innovation we do in biosecurity, we want to share it so that everybody can use it. And right now, there's a huge loophole in biosecurity practice, and that's around oligo synthesis. Oligos are not screened. And frankly, we think they should be screened, because there could be someone that orders smallpox in small pieces. It never gets screened, and then it could be reassembled. And so we are developing technology to also screen oligos, which is a lot harder, frankly, because there's many more false positives. So there's a lot more computation to be done. But again, that's available. We want everybody to have access to it. It's really amazing to see, not just doing amazing science, but also focusing on being socially responsible. I also wanted to ask you about Petri. I know you're a co-founder of this accelerator for startups, and would love to hear some of the advice that you have for young entrepreneurs that are thinking of starting companies, especially in the biotech field. Yeah, I'm happy to do that. First of all, you're going to have to learn to love fundraising. Capital is available, but you do have to do the work to get it. And there's a great book. It's called Venture Deals from Bradfels. Definitely splurge and invest the $40. It's my Bible. I used to say that I read it 10 times. I think now I read 20 times. So it's everything I've learned from fundraising. I've learned from that book. And then you need to have a great vision. But the next step is to bring people on board. You can have a great vision. You can have a lot of money, but if you're alone, you can't do anything. So I will very much focus on the human aspect of it. And it's kind of counter-intuitive in some ways, because what makes you great as a graduate student is that you can do everything yourself. You have to have that paper with your first author. So you have to be the one man, one woman show. And it's the opposite. Once you're in a company, you need to work as a team. And really, it's the team that guides you forward. And my view is that if I want a boat, I don't go to my people and say, this is the boat I want. Make me that boat. Instead, what I try to do is I give them the longing for the high seas. And then they're going to make their own boat. And every time their boat is better than my boat. And so empowering, inspiring people to do great things, in my view, is a lot more productive than macro managing. And so as a leader, as an entrepreneur, make sure that you not only have a great idea, I have money in the bank, but you empower your leaders to do great work. And then maybe the last one I'll mention is try to find mentors. I'm in Petri, for instance. I spend 30 minutes on a phone call with an entrepreneur, and I sent them two months of work. And so reach out to people. I have mentors. I call them. They don't even know they're my mentors. You don't have to be. I just call them five minutes here and there. They don't know that they're helping, but I ask a question. And every entrepreneur, they're amazingly generous with their time. I've never had someone help me know I don't have time for you. And yeah, so reach out to people. And you don't always have to do what they say. Ultimately, you're responsible. The buck stops with you. But it's super useful to hear different perspectives. It's amazing that you brought up mentorship, sponsorship. You being a female chief executive, which is really, really rare in the biotech industry. I would love to hear your experience, how it's been as a female executive. And do you think this is getting better as we move forward? Yeah. I mean, actually, last time I checked my business card, it didn't say CEO. It didn't say female CEO. It said CEO. In some ways, you have to abstract it. It's definitely much harder because investors do a lot through pattern recognition. And that's one of the secretes that they have. They've seen that problem before, and they've seen things that work, things that don't work, and that's their strengths. And if you ask often an investor, draw me a CEO, they're going to draw a male. And it's hard. And when we were starting with me and my two co-founders, actually one investor told us, oh, yes, we'll give you the money, but we need a male CEO. And I went back to the bills and I'm like, well, maybe we should hire a male CEO and I'll do a different job in the company. I was ready to give away the title. And to their credit, or to his credit, Bill Baney was like, F that guy. We don't want his money. And so we were either going to be a diverse company from the beginning, or we were not going to be. And so it's helpful to have co-founders that believe in that. And it is harder, but in some ways, because it's harder, you end up working harder. And because you work harder, you are more prepared and you get there. And actually, the research shows that diverse teams are, yes, less happy because there's more conflict, but diverse teams are more productive and more successful. And so diversity is good for business. So if you're a female entrepreneur and you're wondering, you know, just go for it. Don't self-censure yourself. Just take the risk and go for it. Maybe one last question before we let you go about your busy day. This is a fun question. If you weren't CEO of Twist, what would you be doing instead? What other types of career paths might you have considered? Yeah, so maybe two. One is serious. Actually, when I was a kid growing up, I wanted to be a doctor or medical doctor. And there's a weird thing in France that the state of France needs engineers. And so they take the top two in each class in high school and they put them into engineering school. And so even though I wanted to be a doctor, I was not allowed to go to medical school because my grades were too good. I was not CEO of Twist. That's what I would have loved to do. And the less serious one is if I was not CEO of Twist, I would be a ski bum. I just love skiing. And so I get to do it every weekend. So I'm very, very fortunate that way. But that would be my fallback if this does not work out. Well, we're really glad you did not go with the medical side and you're leading this amazing company. It's just great being an inspiration, especially for women entrepreneurs and others who are thinking of going that route. So thank you for that. And thank you for this great conversation. We'd love to see how you take Twist forward. Thank you so much. Thanks for the invitation. And thanks for the kind words about Twist. Frankly, if it's good, it's the team. If it's bad, it's me. So I'm only in front of that stuff at Twist, where the team does the rest. So all the credit goes to them. Thank you so much. This has been another episode of EBRC in Translation, a production of the Engineering Biology Research Consortium's Student and Postdoc Association. For more information about EBRC, visit our website at ebrc.org. If you are interested in becoming a member of the EBRC Student and Postdoc Association, you can find our membership application on our website. A big thank you to the entire EBRC SPA podcast team, Katherine Brink, Fatima Inam, Andrew Hunt, Adam Silverman, Kevin Reed, Ross Jones, David Mai, and Koxie Lee. Thanks also to EBRC for their support and to you, our listeners, for tuning in. We look forward to sharing our next episode with you soon.