S3 | E6 Anton Jackson Smith (Founder of b.next) on building synthetic cells, programmable biology, and the future of biotech

0:00 David Booth: You're listening to a Day One.fm show. Maybe the synthetic cell now can fight cancer directly. It detects it and fights back. And the reason a synthetic cell is more powerful for that, we have this amazing technology right now called CAR-T, where we program some of your own cells to fight cancer in your body.

0:21 Anton Jackson Smith: You've developed the processes, all of the DNA, the cell membrane, You've got the synthetic cell. What do we do with it?

0:28 David Booth: To make biology engineerable. You know, imagine if you built a car and every time you took it out of the garage, something had changed just overnight, right? That, that's sort of biology right now. So you can design it to not mutate. You can design it to not be able to share its DNA with other cells. And particularly the way synthetic cells are right now, which is a huge intrinsic safety feature, is they can't replicate themselves.

0:47 Speaker C: Welcome back to Diaspora.nz, where we're on a mission to seek out and profile the hidden gems the best founders, operators, researchers, and emerging leaders of the great Kiwi expat community. Today's guest is Anton Jackson-Smith, a synthetic biologist, Stanford PhD, and the founder of bNextBio, a company that's building synthetic cells from scratch to make biology truly programmable.

1:11 Anton Jackson Smith: Now, if you want to know what that means, like I did, listen on.

1:15 Speaker C: We start with some of the easiest stuff, define the terms and the territory, then go in the deep end, building cells from the ground up. Using DNA synthesis, custom proteins, and lipid membranes. We dive into Nucleus, his open-source toolkit inspired by the open-source software movement, and why it was the right approach to advancing his tech as rapidly as possible. And then we talk about how and why doing so could unlock the next generation of cancer therapies, diagnostics, even things like lab-grown foods, smart crops that self-monitor for disease, and more. Anton's journey started back in Queenstown. He was writing code and engineering networks as a teenager, but a chance encounter with an article about programming E. coli flipped a switch, and he realized that biology could be engineered like software and could be the next big industry. We also talk about some of his Kiwi roots and how they've impacted him over his life, the future of biotech back in NZ, and what it means to return brainpower, even if folks like him plan on staying where he is in San Francisco for now.

2:14 Anton Jackson Smith: Yeah.

2:14 Speaker C: This is the Diaspora.nz podcast, and here is my conversation with Anton Jackson-Smith.

2:23 Anton Jackson Smith: Anton Jackson-Smith, it is an absolute pleasure to be sitting with you here in San Francisco, live out of San Jose, out of the Fort Mason Blitzy offices that we've been loaned for the purpose of having this jam. Um, but you've been living here for 10 years now.

2:37 David Booth: Yeah, 8 or 9 years.

2:38 Anton Jackson Smith: Yeah. Um, but thank you for coming on the Diaspora.nz pod.

2:41 David Booth: It's Matt. Thanks for having me.

2:42 Anton Jackson Smith: This is going to be fun. I, I'm going to have to ask lots of dumb questions as we go. You are building synthetic cells to make biology engineerable. And that means you can do lots of things with biology with those, you know, all sorts of use cases from medicines to agriculture to everything else. A lot of potential, a lot of excitement. But tell me about the, what is a moment that you decided to work on this? So what is the moment that you realized this might be possible?

3:09 David Booth: Yeah, it's actually not quite working on synthetic cells, but I know it's the moment I felt that we could make biology work this way. And, um, so when I was growing up, I was hugely into computers, like taught myself to program, taught myself Linux, um, got myself a job at a small company in Queenstown writing code and doing network engineering. And that turned into the job I worked all through high school. Um, and when I finished high school, I didn't want to go straight to university. So I went traveling. I ended up living in Vietnam for a year. Um, and I remember I was sitting there doing some work and I read an article about something called iGen, the International Genetically Engineered Machines competition. It's actually happening right now in Paris. They have an annual competition. It's like on the order of 4,000, 5,000 undergraduates who form teams to solve problems with biology. And there was a team that was programming E. coli, and the goal was to make E. coli detect when it— you could take a pill of it, it would detect when it had moved into your intestine. It would start a little timer, it would become sticky, it would stick to the side of your intestine, and it would produce transporters that pull toxins across the intestinal wall the other way than it usually works to like pull stuff out of your blood into the E. coli. Timer goes off, E. coli flushes out of your system. And their goal was to perform dialysis, but in a pill. And I read that, and as someone who'd been doing all this work in computers, I was like, you can program cell?

4:30 Anton Jackson Smith: Yeah, that was going to be my next question. Like, in that case, what does it mean to program a cell?

4:36 David Booth: Yeah, well, the next part of that story, I guess, is, you know, so I was enamored with this idea. I got to Stanford, um, to do my PhD because I, I really wanted to do research in what's called synthetic biology, which is this task of how do we make biology engineerable? And like, I'm here to program the cells. And their answer is kind of like, well, you still can't really. And in that case, it was using pieces of DNA and things called promoters that turn genes on and off. The genes that make it sticky or produce the transporter to pull stuff out of your blood and joining them together like you would like write lines of code, um, to do the task. But the problem is it turns out that's incredibly difficult. You know, the undergraduate project was probably better as an idea than, you know, they didn't make that thing fully work, um, as part of the competition. And so. It's really, really difficult. It's not at all like downloading a library off the internet and setting up a web server and making an app in a weekend. And I wanted it to be that way. And so early in my PhD, I was talking to people at Stanford, talking to people in my lab, and we were like, well, could we, instead of trying to, you know, change a cell that already exists, like what would we have to program so that everything in the cell was programmed by us? Because if everything in the cell was programmed by us, we'd understand what all the pieces were. We could predict what they would do. There wouldn't be, you know, random other effects that we weren't expecting.

6:01 Anton Jackson Smith: In which case, in the E. coli, the problem being is it's a biological cell to start with, or a, a unit to start with, and it's got all sorts of genes that do all sorts of things. And if you're only pre-programming one of those pieces, then you can't control the rest.

6:14 David Booth: So that's it. Yeah, so exactly. And you know, so E. coli has on the order of 3,500 genes. It's probably one of the, if not the best studied living small organism we have.

6:24 Anton Jackson Smith: They started like, I, I'm gonna try to just stop here and just try to grab concepts like E. coli. People probably know as a, disease. It's something that caused all sorts of problems right throughout history. Um, why are we even talking about E. coli?

6:35 David Booth: It's a good point. I mean, E. coli is kind of the, the go-to bioengineering cell or species. Um, and there's some E. coli that are pathogenic that make you sick, but there's others that are totally fine. There's E. coli in your stomach right now. It's doing a good job as part of your microbiome. It turns out that back in the day, I'm actually at the Palo Alto Hospital. They took a sample of E. coli from someone's stomach, and that happens to be useful, and that happens to be one of the major cell lines that everyone in biology uses today for doing everything from amplifying DNA to this kind of synthetic biology work.

7:09 Anton Jackson Smith: So your, your vision, this is sort of, we're going to have to jump around here, but coming into the PhD was that if you could, instead of just using E. coli, you could construct the cell and you could write all of the code. Tell us what that means.

7:22 David Booth: Yeah. So that actually wasn't the first idea was just, could I program all the DNA, make DNA and then make that work maybe in a cell that already exists. As we started to do that, we realized even that was hard because we didn't know what all the proteins were and it was, you know, you run into challenges with the tools. And so that then became what we do now, which is what we'd call bottom-up synthetic cells. So that's a synthetic cell where we make the DNA and put it inside. We mix together the exact proteins we want, the small molecules, things like energy molecules, um, things like salts. And then we make what's called a cytosol. That's what's inside of a cell. And then we wrap that whole thing in a lipid bilayer. So that's the simplest kind of cell wall, cell membrane that you can imagine.

8:03 Anton Jackson Smith: Each of those things needs another question. You make the DNA. How do you make the DNA? What is DNA?

8:11 David Booth: So yeah, DNA is kind of the, I guess let's call it the, the information.

8:16 Anton Jackson Smith: I'm going to do the 101 version of everything you say.

8:19 David Booth: Information's the trait of life. It's the DNA is the, you know, a double-stranded molecule that holds all the information that tells the cell what to do.

8:30 Anton Jackson Smith: And you say one of the major advancements in the medical history in the journey was, was understanding how to decode the DNA, which would then understood how to, how and where to edit, like CRISPR editing is editing certain sort of components of that, but you're talking about actually writing the DNA from—

8:46 David Booth: Exactly. So one of the things that's been really well developed, and you're right, there is sort of, there's this heroic effort in the late '90s to sequence the whole human genome. So first we learned how to read DNA, that's called DNA sequencing. But what followed kind of alongside and has become huge over the last 20 years is DNA synthesis. And that's instead of just editing DNA that already exists. You pretty much write down a DNA sequence on a computer and there's companies out there, uh, like Twist, like Ansa, who will print that DNA out for you. So you order it, they ship it to you, and it's the DNA molecule you wanted. Um, so—

9:21 Anton Jackson Smith: This is where you start getting the programmable biology piece. You've tackled— you've, you know, whatever process come to understand exactly what DNA you need, send it to them, comes back in some form. What does come back to you?

9:31 Speaker C: What—

9:32 Anton Jackson Smith: this is— we're talking about microscopic or smaller particles, pieces, molecules. What is this, uh, sort of process in the middle? The next step was to, to get to the, to the synthetic cell. And is this the work that you're doing in your lab, or is there different pieces of the ecosystem that come together?

9:47 David Booth: Yeah, a bit of, a bit of both, I'd say. So, so there's, when we started this, I would say synthetic cells, particularly in the United States, you know, very small field. It was just like a nascent idea. Since then, the community's grown a lot. Um, we were part of the sort of founding set of labs of something called Build-A-Cell, which is the US kind of coordination network, um, research collaboration for, for synthetic cell work. So there's people in a lot of academic labs working on this. There's a huge contingent in Europe. Um, there's some amazing people in Japan. There's like other growing synthetic cell work happening across Asia. Relative to all of biology and biology research is still pretty small. And then what we're doing in our company is, you know, we're trying to make products with synthetic cells, but We're also building an open source toolkit called Nucleus to, as part of a sort of open core model to enable all those researchers. And some of the work on Nucleus is actually some of that more baseline, how to make synthetic cell research, because it's still a pretty hard task and we want to make it easier for those researchers to do their job.

10:49 Anton Jackson Smith: So Nucleus is your open source toolkit developed by your startup, bNext. And what is it exactly? It's a software and also set of protocols and playbooks that they can use in order to develop the same cells and to run their own experimentation. And then part of being under the sort of the open source philosophy means that if they take your code, your playbooks, your protocols, use them, run experiments, they have to sort of share it back into the community. Is that a reasonable summary?

11:17 David Booth: Um, reasonable. It's, it's not quite right. So I'll still fit. I'll, yeah, I'll do the thing. So Nucleus is a set of different things. It's like you said, protocols to how to make things. Um, it's technical tools, like digital tools. So software that helps you work with synthetic cells and the kind of data you produce. Critically, it's also open source materials, which is different from in computers, right? Um, it's actually open source DNA because it turns out most DNA that you get from somewhere, you're not necessarily allowed to share and you're not necessarily allowed to share things. You know, if you, I give you DNA, you modify it, you're not necessarily allowed to share that modified version. So the open source DNA is hugely enabling.

11:55 Anton Jackson Smith: And there are, I mean, there are libraries of DNA available through sort of the Human Genome Project or through, through variety, but is it the editing and the sharing onwards? And what is the, What is the limitation that's been placed and why is that limitation?

12:06 David Booth: Yeah, this gets kind of technical. Um, but the biggest thing, yeah, exactly. Not so much, not so much the, um, Human Genome Project, but so the go-to place for, for getting DNA for research is a place called Addgene. It's a nonprofit. They basically bank useful DNA. So you make something useful in your lab, you send it to them. Any other lab can order it from Addgene. Now the challenge is that comes under usually, almost certainly, something called the UBMTA, the Universal Biological Material Transfer Agreement. Yeah. Um, and that's a contract that you have to sign to get the material. And yeah, it says that you can have it in your lab, but you can't pass it on to the next person, even if it's someone on the other side of your university who also needs it. Um, and it also says if you modify that thing, under certain circumstances you can share the modifications. Um, but under others you can't. You might need the permission of the original maker of the DNA. And beyond that, it's only available for academic research use. So if you wanted to start a startup, now you have to start from scratch.

13:05 Anton Jackson Smith: Right. What is the motivator for that? Is it like a prevention of the malicious use of DNA, or is it genetic engineering, you know, but the, the going wrong version? It feels like this is a limitation on progress in a way.

13:16 David Booth: It's definitely a limitation on progress. I think particularly for that interface between the academy and industry. Um, and I'd, and I'd like to think it's, it's driven by, yeah, a higher sort of moral purpose, like safety. But it, it's mainly about business. It's that, you know, the companies who produce DNA and people who produce it want to retain control over their things. Unlike something like copyright, which eventually expires, or a patent, which expires in 20 years, because the MTA is a contract, it works in perpetuity. So there's companies making money selling DNA under MTAs that have been doing so with the same DNA for 60, 70 years because it never expires.

13:55 Anton Jackson Smith: Hell of a business to be in if you can, if you can get it. But yeah, exactly. Let's sort of circle back in on the, on the core of the technology and then I want to, I want to cast it in the future and perhaps we can learn more about it by applying it. So you've developed the processes, all of the DNA, the cell, the membrane, you've got the synthetic cell. What do we do with it? What, why, what comes next?

14:17 David Booth: Why build a synthetic cell? Yeah, exactly. Um, so there's different reasons people, um, particularly in research work on synthetic cells. Some people want to investigate the origins of life. They think by building doing very simple cells, we might learn something about how, you know, life on Earth came to be in the first place. There are people who want to do it to just understand biology better. Like, uh, the physicist Richard Feynman has this quote, um, what I cannot create, I do not understand. It's like, if you think you know all the pieces that a cell needs to work and you go to build the cell and it doesn't work, well, you just learned that you don't know everything. And maybe you now have some new pointers to what you need. The reason we truly want to do it is, as you said, to make biology engineerable. If you think about writing code for a computer building a microprocessor or building even a car, right? We know what all the pieces are and we have the plans and therefore we can put it together and we can also modify it much more easily.

15:07 Anton Jackson Smith: So an engineerable cell allows somebody with an idea to do X. What is X?

15:12 David Booth: What is X? So in, there's, it's sort of depending on different timescales, uh, you can do different things. So in the near term with a synthetic cell, um, what we're seeing it as being really useful for is a few things. One is what we call like the platform for discovery. Like let's imagine you want to make an antibody as a therapeutic, being able to test that in an environment, the synthetic cell, where you totally know the components gives you new options for both, you know, what's the environment you're testing it in, because you can change things. You can make it more viscous, more jelly-like, or you could make it more fluid, or you could, uh, add an extra component that you know is relevant.

15:47 Anton Jackson Smith: To translate this into more, like, so relatable term to somebody is a, is a cancer treatment. And, uh, you have a therapeutic, which would be delivered a chemical therapy or whatever it might be, and the body will often react to that. So the antibody is the reaction to the chemo that the cancer patient might have to go through. And you can say, well, we can design a cell which might have less of an antibody reaction, thus the treatment is more effective and more delivered more clearly. And then clearly that becomes a business on the other side of it. Is that— or run me through another example.

16:19 David Booth: Yeah, actually what I was thinking of grabbing is the other way around, but let me just run you through it. Let me run you through another example. For this sort of early platform for discovery idea. So there's a lot of people deploying like artificial intelligence right now to do really cool things in biology, particularly designing proteins. So making better proteins for various things, whether that's an enzyme that goes into laundry detergent or something that produces like a flavor that goes into food, as well as therapeutic drugs. And so what you want to do when you're just making, designing that protein, your, your system spits out potential upgrades for the protein. protein and you need to test those upgrades. The synthetic cell and this kind of composed cytosol where you understand all the pieces might allow you to test those AI-designed proteins, both like more cheaply, more effectively, because you can, you can again change the environment and you can also get more information out of the system about how your protein's performing more easily. So all of those things make it cheaper and faster to go through that initial R&D process. And that's that's a pretty near-term, like almost right now application of the synthetic cells.

17:29 Anton Jackson Smith: So who are the people who are going through that process? If you're the technology platform that enables them to do it faster.

17:34 David Booth: Yeah.

17:35 Anton Jackson Smith: For a therapeutic, it's going to be a big pharmaceutical company. Who else have you seen sort of the early adopters that you've been engaging with? Don't name them, or even just sort of describe like what are the most obvious early use cases?

17:46 David Booth: Yeah, early use cases. So, so on the AI side, there's a lot of companies now playing in this space, but One of the bigger and more advanced ones is, um, Arzeda. Uh, they came out of the Baker Lab, who have a long history in this kind of protein design. And so, yeah, basically using artificial intelligence to design proteins. Um, there's another near-term application that we're really excited about, um, which is using synthetic cells kind of like debugger or a sensor for other biological systems. And so Biology has this like really exquisite ability to measure itself, right? Because obviously your cells have to know what they're doing in order to pick how to do the next thing. What if we could use those pieces to measure biology that we care about? Um, and so one application of that is in what's called precision fermentation, and that gets used in the field of molecular agriculture, like the people who are making, for instance, uh, lab-grown meats or lab-grown milk or lab-grown, uh, whatever food products, but without farms. It also is really important when you're, say, let's imagine I have a Petri dish full of human cells and I'm trying to develop again a new medicine. I want to understand what those cells are doing. So what if we could use the biology to measure itself by programming a synthetic cell to measure the things we care about and spit out the signals?

19:06 Anton Jackson Smith: So in, in those examples, in the lab-grown mice or in the human Petri dish, human cell Petri dish, which is used for sort of therapeutic development, usually the human cells are inside a human body. Usually the animal cells are inside the animal body. The animal body is biology, as you say, biology is uniquely good at measuring itself.

19:23 David Booth: Right.

19:24 Anton Jackson Smith: But if you're trying to grow meat in a lab, you don't have that measurement layer. So you're saying you can reproduce the measurement, the measurement layer through this insert.

19:31 David Booth: Exactly. And you have some measurements, they're just not very good and you can only measure certain things.

19:35 Anton Jackson Smith: So then to extrapolate that forward a bit, well then you can talk about the impact of, um, you know, if we can truly scalably efficiently figure out how to grow meat in lab, then it means we can reduce the impact of farming globally, or we can, you know, we can produce protein for the world's population. Do you think about the impact, uh, on that sort of a next order scale, or like, if this is true, then that, but this is really why it matters?

19:59 David Booth: Yeah, exactly. And so what I described to you is sort of what I think of the near-term applications was the Dick Cells that we could do, you know, approximately right now. But what, what really motivates me and my co-founders to do this is, is the long-term view, which is, biology is so powerful for solving all kinds of problems across, you know, obviously human health is, is the one people tend to focus on, but things like climate, agriculture, just from, I mean, from the scientific angle, there's also just like, as the more deeply we understand biology, the better we can work with it rather than against it. Um, so there's this promise out there of, you know, a world where we use far less or no oil to make all the products we need and where we can make food and medicine much more effectively available. And that's enabled, you know, partly by just the synthetic cells, maybe the work we specifically are doing, but the reason we're building synthetic cells is it provides this platform in the long term for other people, for people like though that team that made the dialysis. To much more effectively actually solve whatever problem they're confronting with biology. And so what I'm most excited about there is across all the things that biology touches, which is basically everything, the thousand ideas I can't think of that we can enable other, enable other people to work on by making biology more effectively engineered.

21:19 Anton Jackson Smith: So to draw a cruise metaphor, uh, you'd be like the, the AWS of software and that everybody else can come and they can build Uber and they can build Airbnb and it sits on top of the scaffolding that you've created. That's it. It's the technology platform. I'm curious that, um, it maybe it's, maybe it's too early to say, maybe the the nature of this is that the use cases, the applications aren't knowable yet, but what is the, is there like, is there an application that you say, this is the thing that was, you know, the big hairy goal, the thing that most motivates me, or the biggest sort of, from an impact lens, out, your use case that's built on top of this technology platform?

21:56 David Booth: Yeah, there's sort of 2 or 3 immediate ones I can give you. And so the, something I would really like to build, like imagine the synthetic cell that right now I just described, it can detect something in the research setting, because that's really useful to us for developing things. That proves you can detect things. The next step is, well, what if we could take that same synthetic cell and actually use it as a medical diagnostic? Maybe it could float around in your bloodstream and detect if you were, what you're, what's wrong with you.

22:26 Anton Jackson Smith: Um, so you're looking for, uh, like a very early, uh, diagnosis of a cancer or, or a, you know, genetic disease and notifications through some kind of biomarker.

22:36 David Booth: Exactly. And again, and for things we can't detect right now. If you can detect it, the thing about a synthetic cell is it can do the things a cell can do, so it can also respond. So the next step is that is the actual therapeutic, and that gets us to the, you know, nanotechnology therapeutic. Maybe the synthetic cell now can fight cancer directly. It detects it and fights back. And the reason a synthetic cell is more powerful for that, we, we have these amazing, this amazing technology right now called CAR-T, where we program some of your own cells to fight cancer in your body. Challenge with that is the same challenge I described. It's very expensive to make, a lot because you have to modify someone's cells, and there might be what's called an off-target effect. You do something you didn't expect, um, or it doesn't respond in the right way. The beauty of a synthetic cell is it's an engineering system. So you control all the pieces, you can make sure that doesn't mutate, that it does exactly what you expect it to do. Mm-hmm. Um, and again, if you can develop that faster, you can respond to new diseases or new cancers more quickly and more safely.

23:39 Anton Jackson Smith: And as you say, if, if you are engineering a cell, not only is it more expensive and complicated, but it's less consistent or unknowable. You don't know what the rest of the genes in that cell you're modifying might be doing.

23:50 David Booth: One way we describe this is, you know, right now every kind of bioengineering task is still research. Like you make a new thing, it's like a 5-year research program. I make a new thing, it's a 5-year research program. If I want to put those two things together the way I would put two libraries together in Python, it's a 5-year research project. And what we want is not research, but engineering.

24:10 Anton Jackson Smith: Yep. So one thing I'm very interested in, funnily enough, is like this, this is the output of a long research career at Stanford. This is now a company that is at the cutting edge of research and, um, sort of the frontier of synthetic biology. How does that translate into a business model? And in particular, in the sort of the short-term, midterm, long-term, how do you build this as a business as opposed to as a sort of a research institution.

24:37 David Booth: Yeah, absolutely. We've, um, and it's interesting when we're starting the company, we sort of were looking at different ways of bringing synthetic cell technology to the next level. The question was, well, would this be more appropriate as a research institution, for instance? And we decided it wasn't because there's applications, um, right now that one can use to make money with and that could support, you know, the development of the technology. Because like we just talked about, the real win is in the mid to long term where there's just so much potential for, for really high value products as well as like really awesome positive outcomes for, for, you know, biology and humans in the world. And so the business model has kind of 3 stages, should we say. In the very near term, uh, it turns out these researchers who are, who are working with synthetic cells, they need certain things. And part of that is what we're trying to solve with Nucleus, the information you need to be effective.

25:27 Anton Jackson Smith: Mm-hmm.

25:27 David Booth: Because right now, if someone starts a new PhD, they want to work with synthetic cells and they have this really cool problem, like maybe we're using a synthetic cell to to help mitigate heart disease. Someone's done some of that work and it looks awesome, but they have to spend the first year of that PhD. And if you're in, you know, New Zealand or the UK, it's a 3-year PhD. Spend the first year just figuring out how to make the synthetic cell. How, what if we could bring that down to 2 weeks?

25:50 Anton Jackson Smith: So now they take your open source materials, they basically have the whole body of research to start with. Right.

25:55 David Booth: Which, but that's not the product.

25:57 Anton Jackson Smith: So we have a— But that's different. Just to quickly call out when, I mean, research is generally published. I mean, you do a PhD, you often publish it. All of that is available in this big corpus of it. What's different about having open source research and product and different to what's generally put out there into the public eye through the scientific publication?

26:17 David Booth: What's different is, and again, this kind of comes, I think, from, for me, from the, this engineering mindset that I got through computers, right? Like when I was a kid, I could teach myself how to program because there was awesome documentation on the internet and I could download the stuff I needed. The process right now from just the scientific literature is you want to make a synthetic cell, go read two dozen papers, try and, you know, they have the method section, but it's pretty terse. It assumes a lot of understanding and knowledge. Um, and sometimes details are left out. It's not like the Getting Started Guide and it's not the print it out and just follow the instructions recipe. It's, it's something kind of higher level. So what we're trying to do is bridge that gap like an engineer would and produce the you know, the read the docs of making synthetic cells. So it's, you can effectively learn what you need, get the context that isn't written in the paper, but you get by talking to the person who did it.

27:06 Anton Jackson Smith: Yeah.

27:07 David Booth: And provide you the open source materials you need. But there's another layer on top of that, which is even if I can give you the DNA to make the proteins that you put into your synthetic cell, making those proteins is a hard job, right? And making, you know, some of the other reagents you need, like there's something called tRNA, which is used by the cell as part of the process to make, make new proteins. There was like a supplier everyone used for tRNA. That supplier just stopped selling it. And there's one other one. They're often out of stock and the tRNA doesn't work as well. Uh, so the most near-term business is this enabling layer of the pieces you need by selling those actual reagents.

27:44 Anton Jackson Smith: So you said 3 phases to the business model. Phase 1 is everybody needs the same core building blocks to do a variety of things. You have a methodology, uh, you're not actually producing those core building blocks, or you could be in some cases, but it's actually the open source sort of methodology that they can take your research, take your protocols, they can do that themselves. And when they do, and when they, under the open source license, I assume if they sort of develop it or make new discoveries, then they're, they're compelled to share it again, or, or is that really more part of the culture?

28:14 David Booth: Yeah, they're actually, actually not. We've, we're, you know, this is a little bit of an experiment. I think we're, maybe not the first, but the first I know about company to have this kind of open core business model in the same way that tech companies here do.

28:27 Anton Jackson Smith: Yes. The parallel I'm trying to draw is one of an open source software company where the whole code base is forkable and perhaps there's a one or two little elements that aren't. Yeah, exactly. And this is, as you say, one of the first times this has been attempted in, in the biotech wear space.

28:40 David Booth: And so the one thing is, so, so our open source license right now is more, um, think BSD license rather than GPL. So you're not actually compelled to— For us, the BSD what they mean. It's like a lot. Everything you said was right. But, um, our open source license allows you to use, you know, the pieces commercially. Um, but it also allows, you're not compelled to share your changes back. Although our experience of this ecosystem is that particularly obviously on the academic side that people do, and we would hope they would, but for now we went with the lightest weight way of getting things out there.

29:16 Anton Jackson Smith: You're maximizing the number of people who want to work with it and you're creating a culture that that, you know, if not requires, then hopefully encourages them to share their research back. That makes sense.

29:27 David Booth: Absolutely. Um, but to, to come back to the product. So that first layer that builds on top of the open, open source side is using those open source pieces. We, we are actually manufacturing those building blocks too. So you can download the instructions and you can make it yourself.

29:38 Anton Jackson Smith: Okay.

29:38 David Booth: Or you can buy it from us.

29:39 Anton Jackson Smith: Which is again, a little bit of an open source software parallel. You can fork the code and do it yourself, or you can pay for our hosted instance and, you know, build a great business. So that makes a lot of sense.

29:50 David Booth: Yeah, absolutely. Um, and we, what we hope to do with that is enable all these amazing people who are, who are doing research in the space to just work much more effectively. And, and you put your finger on it, like also be more building on a shared platform, right? The closer the pieces I use are to the pieces you use as your underlying system, the more likely our two things will work together so we can make something even cooler.

30:11 Anton Jackson Smith: Right. So let's keep on track.

30:14 David Booth: First phase, phase 2, what happens once you've Phase 2 is, uh, what I gave you the examples of, um, which is actually deploy synthetic cells for the, like, near-term applications, detecting things in bioreactors, detecting things out in the field. So maybe like a synthetic cell that detects a crop disease that you want to respond to and gives you information on that.

30:37 Anton Jackson Smith: Find, uh, willing customers for that within kiwifruit or, uh, stone fruit industries where a single disease can wipe out a crop. And if you had an early notice on that, then It'd be a very valuable, you know, opportunity for sure.

30:51 David Booth: Yeah, exactly. Um, and then as—

30:54 Anton Jackson Smith: Would you actually, again, sorry to keep cutting in, but would you actually be developing that early biomarker for the kiwifruit industry, or would you be— you're building the tooling and the platform that somebody else, say Zespri, you know, comes through and they develop their own?

31:07 David Booth: Right. I would say that latter example is the, like, long-term view. For, for, for the, this whole middle stage of the company, what we expect to do is work really closely with, yeah, a vertical, but someone who has a problem that needs solving, that's enabled by our technology. We bring the synthetic cells and all the knowledge to do that. They bring the problem and we work together to make this specific solution for them. And what that gives us is a few different things. I mean, A, we develop this new product with an expert, but B, as we're doing that, we're building out our technology to work for that really concretely against this useful problem, as well as for other problems that are like that one.

31:45 Anton Jackson Smith: And you do that and then stage 3, big hairy audacious future.

31:49 David Booth: Yeah, big hairy audacious future. I guess, yeah, it's, it's the two things. That's where we go from. I mean, even that, oh, let's detect the crop disease on the kiwi fruit. What if we can just respond to it right there, produce the antimicrobial, and then that goes to, okay, now human therapeutics, bigger, more complicated cells. As the underlying cell technology evolves, the cells are able to do more and more things. They maybe have more energy. They're able to respond to more inputs. They can last for even longer in the environment. So we start using those to go after more complicated problems to get to the, you know, human diagnostic or, you know, actual cancer treatment or other therapeutic that you could implement with synthetic cells. And then the final stage is that sharing that ability with others. So now Zespri can hire some bioengineers, and instead of a 5-year research program, in a few months or a year, they can program up the exact sensor that they need to detect their problem without us being involved.

32:48 Anton Jackson Smith: Yep. Phase 1, building blocks and testing the open source business model, interlocking pieces, working with partners, building relationships with other labs. Phase 2, validating that you could use some of those building blocks to yourself develop sensors for perhaps more obvious use cases or, you know, ability to detect, um, or observe cells in action. Phase 3 is actually act upon those sensors in order to have a molecule or cell that can not only detect the presence of something that you wanted to detect, but also take some kind of action to treat or to deliver a therapeutic. Score me out of 100.

33:25 David Booth: Yeah, that's a solid 85, I think. Right. I would say that, yeah, it's a philosophy. Building, building blocks, synthetic cells to solve specific problems and discover, um, and then allow people to build with synthetic cells. Um, the way we've been describing this to people is as boot, boost, bizarre. Right. Where, you know, boot is the building blocks, boost, solve problems, accelerate ecosystem. And then bizarre is like, you know, the marketplace.

33:50 Anton Jackson Smith: Yeah. What could go wrong? Uh, there's a lot of excitement and potential about AI to draw another software parallel. There's a lot of things that are going to be phenomenally better in unknowable ways. There's also a lot of fear that comes from the unknowables of AGI, or, you know, what if the models fall into the wrong hands and teach someone how to make a bioweapon?

34:10 David Booth: Happen.

34:11 Anton Jackson Smith: There's been doom and gloom around genetic engineering. It's kind of a dirty term in some circles. And a lot of those circles probably don't realize the benefits that humanity has had from genetic engineering, or it's like perhaps it's, you know, designing a crop that can grow in harsher conditions or less water or more disease resistant. So there's, there's two sides to this coin. Um, if everything you say is true, can it be abused? as well by malicious actors. How do you help to sort of educate the public as to like the risks as well as the rewards of doing what you're doing?

34:46 David Booth: Yeah, that's a really good question. Um, and it's, it's worth pretty serious thought. Um, we've been very involved and, and still are in the kind of, you know, safety and bioethics around synthetic biology in general, um, as well as synthetic cells, because that's a newer field. You know, there's obviously risks with, with anything you could do. Um, you know, when you're, when you're testing anything new, One of the things that I think is really powerful about synthetic cells is relative to some other biotechnologies, there's a very strong argument that they're actually safer, right? Because if it's, it's the exact problem I described, if I'm genetically engineering a cell that already exists, I don't necessarily know exactly how it's going to behave. So you've got to do all this testing out in the environment, whereas if I have a cell where I I both put it together and can predict what it's going to do, I can design something that's only going to do what I want. You can also, because we have this compositional way of choosing what's in the cell, you can actually design the cells to be intrinsically safer. So you can make—

35:49 Anton Jackson Smith: They can't pollinate with the other or—

35:52 David Booth: Yeah, no, that was the right— yeah, you just design a cell that doesn't mutate. You know, imagine if you built a car and every time you took it out of the garage, something had changed just overnight. Right? That, that's sort of biology right now. So you can design it to not mutate. You can design it to not be able to share its DNA with other cells. And particularly the way synthetic cells are right now, which is a huge intrinsic safety feature, is they can't replicate themselves. So it's not going to make more of itself out on your field.

36:16 Anton Jackson Smith: If I, if I recall, or could try to sort of distill the, the fear about genetic engineering, it's not so much even the cell that you've engineered. It's the fact that that cell might afterwards crop, like it's a, it's a unique strand of corn and sure, that's going to be fine. But what happens if that unique strand of corn cross-pollinates with another one, another one, and it's the mutations that you don't understand of 3 or 4, you know, orders.

36:39 David Booth: Yeah, exactly.

36:40 Anton Jackson Smith: Away. Um, so what you're saying is by having a purely or 100% synthetic cell as opposed to an edited organic cell, you can design it to not be able to mutate or evolve beyond that point.

36:54 David Booth: Exactly.

36:55 Anton Jackson Smith: A really interesting counter.

36:56 David Booth: Yeah. And again, if you can predict more effectively what it's going to do, maybe you can, maybe you can learn, oh wait, this isn't the right design, but in a computer rather than when you actually test it. I mean, there's different reasons people get worried about these things, you know? Yeah. I think the genetic engineering, there's sort of an ick factor to it too, right? Like we're modifying something nature produced, which—

37:14 Anton Jackson Smith: Needs a rebrand. It's like nuclear energy needs a rebrand. Somebody put this out there. It's actually, it's elemental energy.

37:22 Speaker C: Yeah.

37:22 Anton Jackson Smith: Genetic engineering needs to rebrand. I don't know if you've got the catchy phrase for it, but yeah. Another thread to type, something you mentioned earlier of possibilities. You know, there's a synthetic cell that could be sort of circulating in your body and it detects a disease and it can quickly and easily and non-intrusively alert a biomarker that can, you know, summon the doctor or, you know, cause you to seek treatment or could even treat it itself. Is a terrifying side of that other coin as it's sort of circulating and then it can actually, upon some trigger, it could introduce a disease or it could sort of cause harm is like, again, thinking about the, how do we build this design, this technology in a way that is understood and de-risked?

38:06 David Booth: Yeah, absolutely. Yeah. And there's, you know, these problems come up with lots of different kinds of technology and it's, there are definitely efforts to say, well, you know, how do we think about this? Right. As a, as a society, you know, the, the US government is putting some work into, you know, biosafety for these new biotechnologies, because what you're really asking, I think, is could someone somewhere make something dangerous because they're able to program a cell? There are ways—

38:33 Anton Jackson Smith: Which is always going to be yes, but—

38:34 David Booth: There's bad people out there.

38:35 Anton Jackson Smith: Yeah.

38:36 David Booth: And there's, and we should put work into figuring out how to limit that potential, right? Like whether it's, you know, in the toolbox, the things you can do are, you know, intrinsically safe and the pieces that might be useful for curing the cancer are slightly more controlled as to who who has access to them at first, because, uh, you know, they could also be deployed for some, you know, more nefarious purpose. But I think the other thing that's really important to keep in mind is we had this experience with the pandemic, right? It's like the risk analysis of there are bad people in the world, but our evidence is that there's actually very few of them. Otherwise, even more horrible stuff would be happening all the time. Whereas we did have the experience of not a programmed bioweapon, but a bioweapon that escaped from nature. And killed billions of, or sorry, millions of people. What would the world have been like during the pandemic if we had the ability to detect and respond to that virus much more rapidly? What if more people were enabled to kind of solve the problem? And I think that's the real potential of it.

39:38 Anton Jackson Smith: Yep. Take us back somewhere along the, I mean, we're sort of living in the future here, so somewhere along the journey in the study. Um, there was probably a moment where you said, um, in order to bring this to reality, it's got to be a business. It's got to be a startup. It's got to be actually independently funded and sort of capitalistically motivated as opposed to living within research institutions or being philanthropically funded. How do you think about the fork in the road and others who might be coming along following your footsteps, thinking about how to have the most impact with their research? Why did you choose to start a startup? Decided why should others choose to do so or not?

40:14 David Booth: Yeah, great question. Um, I think for us, there were sort of 3 pieces. One was through our, you know, the years we've been working on this in the academy, there was awesome work being done, but we realized that if we sort of left it to just academic labs, the synthetic cells that I've been describing that solve real problems out in the world that are usable by more people, like, wouldn't happen or they would happen very slowly, just because of the incentives of the way academia is set up, right? You work on your problem. And there was this missing layer, the engineering layer of how do you take this technology and make it really useful and build the tools to make it much more effective to work with that, like, you know, you don't write a grant as a professor to get the money to do.

40:58 Anton Jackson Smith: So, and we really come from like a, where's the money coming from?

41:01 David Booth: Well, yeah, well, the incentive structure, you know, um, so, so that was one. The second was we realized that, yeah, I mean, there's this unbelievable long-term potential for, for synthetic cells. As part of the bioeconomy, you know, to just be hugely valuable. But there's also very real applications for them right now. Like we could be helping people with synthetic cells right now. We should make that happen. And then the third reason was kind of more tactical, which is just like, uh, particularly here in the Bay Area, like a startup is kind of like the API for describing that you're doing a thing. It's very easy to start a company and then, you know, talk to people about it. Whereas there's, there's other sort of more innovative modalities for maybe doing research, but not in a university, uh, something called FROs, like a focused research organization, which if you're in science might be worth looking into, but it's just very complicated. And what you, you know, if you're already innovating on the technology and you're innovating on the business model, you don't also want to have to innovate on like the organizational structure of what you're doing. It's much easier to take the playbook and run with it.

42:05 Anton Jackson Smith: Right. I've, I've been familiar with that in the past. If you're going to be innovative, pick the, choose the vectors in which to be innovative. And in fact, the through cooperation with, uh, grants and, you know, non-dilutive and venture capital funding is, is a well-beaten path at this point in time.

42:20 David Booth: Yeah, exactly.

42:21 Anton Jackson Smith: Um, you have not always, like you said, so you have not always existed within this very deep frontier field of biology today. You started out with computer science, also law. We actually first met each other in law school in Otago, though it was a, you know, a little bit of a passing interaction. Take us back to those days. I mean, if you could meet yourself and I think actually you had a good line about how law was actually sort of a systems of the world. Type of, you know, foundational education coupled with computer science, which is sort of a digital systems of the world foundational education. Um, don't know if you have observations on what you'd do now starting all over again or talking to a young 18, 19, 20-year-old based in New Zealand. What's the advice for them? Here's the trigger. It's, you described a moment, which sounds like an inflection point when you read about the students that had, you know, been pursuing the E. coli Dialysis. Dialysis. This is the one. And that was influential to you. That, that changed your life by setting you on your path. Somebody's listening to this podcast. What do you want to, you know, tell them?

43:22 David Booth: Oh, big question. Um, I mean, I think the key thing is to, yeah, be pursuing something that you really deeply care about and find interesting. Um, and I think also probably have a bit of trust that you'll figure out how to make it work because when you, when you say all those things, I'm like, You know, what would I tell myself to do differently? I don't think anything, because it put me here and it makes sense to me now. And it, it made sense back then in this, in this very specific way, but it took a long time. And there are a lot of parts along that road where I was like, wow, yeah, I've been doing a lot of different things. Does— what's this about? Yeah, it's funny. I, you know, I, I ended up studying law at Otago alongside molecular biotechnology because I, when I was in Vietnam, lived with some people who were lawyers and we talked about it. It sounded interesting. So I just took first year law and I just found it fascinating. And I was like, I kind of knew then, um, cause I've been in the computer world. I thought I really want to do a startup. So this might be a good way of having, you know, learning about more about business and the sort of organizational side of things. But when I started doing it, I just really enjoyed it because as you said, it's just a different kind of engineering system. And I think that's, that's what I really like.

44:28 Anton Jackson Smith: What can we do to support you? What are the things that you want to put out in the world? Are you recruiting? Are you looking for partners? Are you looking for, you know, people to hop aboard or otherwise support? Um, how can we help?

44:42 David Booth: Thank you. Uh, yeah, I'd say, um, yes, yes, and yes. We're, we're looking for partners. We're looking for interesting people to talk to who might have a problem that they believe is, uh, solvable with biotechnology generally, or, you know, so specifically.

44:54 Anton Jackson Smith: If you're in, um, agricultural research, if you're in medical research, if you're thinking about the ways in which, um, you could be developing. And I mean, really the, the whole podcast, the scope is, is, is endless.

45:06 David Booth: Um, yeah, exactly.

45:07 Anton Jackson Smith: What do they do? Do they get in touch with you to talk about it? Do you have a team for sort of early explorative partnerships?

45:12 David Booth: Um, yeah, you can email us build@bnext.bio, um, or contact David and put us in touch. You know, we're, we're fortunate to be, uh, grant funded, um, on the open source side, uh, right now. And that's, that's been really enabling for the, for some of that deeper research we're doing, but we're also, you know, We're sort of raising private seed capital. So if you want to talk about that, please get in touch.

45:35 Anton Jackson Smith: Absolutely.

45:36 David Booth: And we're also, you know, we're consistently not always hiring tomorrow morning, but, but looking for amazing people who care about synthetic cells or have relevant talents that, that would love to work with us. Um, I'd also say if you are either working with synthetic cells right now as a researcher, or you want to be, then get in touch with us on the nuclear side and we can help you get set up to, to, to use them in your research.

45:58 Anton Jackson Smith: Yeah, there'd be academic partnerships, all sorts of labs. I'm sure you know many of them already, but there'd be a great opportunity to throw that to the old Otago crowd and get them involved.

46:05 David Booth: It's a really great—

46:06 Anton Jackson Smith: Strong medical community.

46:08 David Booth: Yeah. And it's a good point because one thing I've thought about, you know, pretty much all the time I've been here is I think, you know, biotechnology is a really powerful, has a lot of potential for New Zealand as a country. Um, and that's something in the long term for me personally, I care deeply about, you know, it's like I read the news from here and, you know, we have some challenges and like, you know, there's always the, like, like, how does our country work kind of energy going on. But, you know, we have some really unique advantages. We have, you know, really awesome universities. We have great people. We have really deep knowledge of actually super relevant things, things like agriculture, right? And like built on our history that could translate into being able to develop really powerful biotechnology. And we also have, you know, I think a pretty unique and positive relationship with with, with actually nature and the land in New Zealand that doesn't necessarily exist everywhere else. So I think if anywhere could make like, you know, ethically grounded, built in concert with society and useful biotechnology, it would be New Zealand. And then the power of that is you can apply, sell it everywhere in the world. You can apply it everywhere in the world and you don't have to ship a shipping container load of it. Because a lot of it is just about information or small tubes. So, so I'd love to see, see more of that for, for us as a country.

47:24 Anton Jackson Smith: It's a really inspiring angle. And do you get back often? I mean, you're obviously based in San Francisco, you have been for some time, but maybe back for summer. Shall we get you out on tour speaking to people? I'd love to help.

47:33 David Booth: Yeah, I would love that. I don't get back as often as I'd like now. The pandemic kind of messed up my schedule and I haven't gone back into it, but I'm trying to get there later this year. Um, and then hopefully a bit more frequently depending on, you know, the demands of doing our startup, which are quite high.

47:47 Anton Jackson Smith: One of the, I mean, one of the reasons we're here and one of the reasons I love doing what I do is that a lot of the people like you leave to pursue the knowledge, the opportunity. I'd say there is no counterfactual in which you stayed in New Zealand and wound up doing what you're doing. You had to be at Stanford for 8 years, or had to be surrounding yourself with the world-class leading, you know, world-leading experts in this field. I mean, how do you personally grapple with that thing in a sense of, you know, the brain drain, we snarkily call it, the talented young Antons that leave. and, you know, how do we solve this one better? Is there a problem? Yeah. A solution for that.

48:22 David Booth: Yeah. I'm not sure whether there is a solution, 'cause I think it's great for Kiwis to go out into the world and, you know, see what it's like, learn how other people do it. And yeah, the opportunity is really high. I think one thing I would like to see is a, yeah, long-term outcome of what we are doing, right? Is, yeah. So right now, one of the reasons I went to Stanford is there realistically only a handful of universities that were where you could even do like this deep synthetic biology research at a high level. But as we make it more accessible by building tools like the synthetic cells, what I'd like to see is that, you know, then I could have, I could have done it in undergraduate at Otago. That would be great. And maybe you could start a company with it. Um, yeah. In, in New Zealand, um, you know, New Zealand will always be home and I'd increasingly like to spend more time there, but for now, yeah, the opportunity, the connections, just honestly the supply chain of like things you need to build it, um, as well as the capital.

49:13 Anton Jackson Smith: I'm going to throw some startup clichés around you at democratizing access to the information or to the capacity to build this kind of startup that was previously only available by studying at Stanford for 8 years.

49:25 David Booth: Yeah.

49:25 Anton Jackson Smith: Is now available through Nucleus and theoretically in many labs around, not every lab, but at many labs around the world. Um, and I think that, I mean, my answer to that question, which is a little bit of a setup, but it's a, we just need to get your brain back. Even if we don't get your body back into the country, we need to get your brain back open and you knew how to send talented people to you, keep this sort of ecosystem really thriving. Because I think I hear the same story every, every time as people who feel like they've had this incredible journey through their early days. They benefited so much. They learned so much. They are who they are because of the upbringing they had. Yeah. And now they're saying, how do I give back? How do I throw down a ladder for those after me? And there's not really an obvious way to do it. So excited to see more of that. It's a great place to wrap Perfect.

50:08 David Booth: Yeah. And I'm grateful you guys are trying to, you know, get the ecosystem going, um, over there as well. Like I might not be there physically, but my brain does live there.

50:16 Anton Jackson Smith: Absolutely. Well, it's a, it's a lot of fun. So we're going to keep doing it and, um, we'll have you back down soon, uh, to visit as well. Anton, thanks so much. Yeah.

50:24 David Booth: Thank you so much.

50:25 Speaker C: Yeah.

50:25 Anton Jackson Smith: Shout out to the Thanos Inky gang for the podcast space up here in Fort Mason, San Francisco. Anton down near the Dogpatch, San Francisco. No, you're down —mission.

50:34 David Booth: Yeah, you're a true dog patch. I feel like a dog right at the interface there.

50:37 Anton Jackson Smith: Right. And with some really cool— you went for a walk around of the biolabs that you have on tap as well. So thank you, sir. And that's a wrap.

50:48 Speaker C: Thanks for listening. As a quick reminder, make sure you hit subscribe over on your favorite podcast player so you can keep getting stories like this landing in your feed every Friday. Help power you through those weekend chores. For my day job, I'm an entrepreneur in residence and an investor at Blackbird Ventures. We're backing best Kiwi and Aussie founders no matter where they are in the world, back home with global ambitions or out there building generational companies. My personal sweet spot is pre-seed and seed. I like to say there's no check too early, so drop me a line anytime. It's dbooth@blackbird.vc. This episode was produced by Day One, the podcast network for founders, operators, and investors, part of the Day One Network. Thanks again. Look forward to seeing you back next week.

51:28 Anton Jackson Smith: Thank you.