8. “Strand”ed in a pandemic — designing smart mRNA w/ Jake Becraft

In this episode, we interview Dr. Jake Becraft, co-founder of Strand Therapeutics. We talk to Dr. Becraft about running an RNA therapeutics company during the pandemic, the future of synthetic biology and RNA, and advice on converting your graduate school research into a start-up.

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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 in Translation. We're a group of graduate students and postdocs working to bring you conversations with members of the engineering biology community. I'm Catherine Brink, a postdoc in Megan Palmer's group at Stanford. And I'm Ross Jones, a postdoc in Peter Zantras' group at the University of British Columbia. Today we're joined by Jake B. Craft, Jake is CEO and co-founder of Strand Therapeutics, a biotech startup that's working to build next-generation programmable RNA therapeutics. Today is a bit of a reunion since Catherine, Jake, and I all used to be in Ron Weiss's lab at MIT. In fact, Jake sat right behind me. So it's great to be able to have you, and thanks so much for joining us on the show. Thank you guys for having me. Yeah. So to get us started off, can you tell us about your journey to becoming a SYNBIO entrepreneur? Yeah, sure. So I think of my entire career so far, and it hasn't been that long. So I feel like career is a weird word to use at 30 years old. But I think about my entire career kind of as being focused on the idea that almost all disease that's non-infectious has a genetic origin. And so early on when I was an undergraduate at University of Illinois, what I started looking at was, how can we kind of get in the way of the disease progression? How do we deliver a therapeutic gene, a DNA, an RNA, whatever? This is in the late 2000s to the early 2010s. And DNA delivery, synthetic DNA delivery, was pretty much the only option that we had. When I came to MIT, I had been frustrated by the delivery of DNA and sort of the issues that had come with these synthetic DNA delivery technologies. And so I decided to say, I'm not going to mess with the delivery technologies anymore, and I'm going to just look at the synthetic biology side. Right at the time, I had just read this amazing paper from George Church that was all about how you can incorporate DNA origami and gene therapy together to make these really complex, crazy things. And it caught my attention. But when I joined Ron Weiss's lab at MIT, where we all have spent some time, Ron quickly introduced me to this postdoc who was working with him, who was working on messenger RNA. Messenger RNA, the thing that got me about it was it doesn't have to go into the nucleus. And so for all of the DNA work I was doing as an undergraduate, the big problem that we ended up constantly trying to figure out unsuccessfully was how do you get from the cytosol into the nucleus? Getting an endocytosed into the cytoplasm was simple. Getting into the nucleus was hard. And that's why I decided to give up on that and go to the synthetic biology side and make delivery someone else's problem. And when I met Tesuku and Ron facilitated this introduction, it was a very seamless transition because on one side I got to engineer at the gene level, at the actual nucleic acid level, and do synthetic biology and mess with all of the cool genetic circuitry and logic gated systems that had captured my attention as a young scientist. But at the same time, I got to work on a platform that I thought had direct translatability. At the time, Moderna was a company that was, you know, they'd probably raised like a hundred million or two hundred million, which is like nothing for them, right? It was very early on. And BioNTech was just getting started as well. And there was this little seedling of an industry, mRNA industry, that was starting. And so we thought that if we built genetic systems, genetic logic gated systems that were specifically built to layer on top of mRNA therapeutics, which means you can't you can't use things that degrade the mRNA because if you do that, then you lose all of your transcript. You have to have things that are inherently reversible. There's all of these design challenges that mean that you have to pretty much take all of the ethos of synthetic biology, but then in like imagine an entire new toolkit. We created that essentially at MIT. And that had its ups and downs as any like PhD project does. And Ross probably remember plenty of my frustrations sitting next to me for all those years. But the leap to an entrepreneur was just the next step for me in the commercialization of that research. We thought about, you know, could this could this be adapted? Could we sell this to a Moderna? Could we sell this to a BioNTech? Like, how does this technology actually create the change we want to see in the world? The technology was significantly differentiated from what other people were developing, though, in the mRNA space. And that coupled with my want to continue to lead the research and push it forward and our ability to excite other people like investors to get behind us ended up in creation of Strand. So I think of it as, you know, one long journey to here. Been working on this particular technology that Strand has for seven or eight years now. And I'd say it's probably the most exciting time of any point from a research perspective that I've been involved with the work now based on the teams that we've built at Strand now and sort of the direction that we're going. So you alluded to this a little bit earlier, but it seems like you have sort of a specific space carved out at Strand that differentiates you from some of the other companies in this industry. And I was wondering if you could elaborate on that and tell us a little bit more about Strand specifically. So starting the company and what problems you decided to solve. Yeah. So early on, and this goes back to the MIT days as well, our questions were really looking at mRNA, looking at the modified RNA platform, it was pretty clear that messenger RNA vaccines would be the lowest hanging fruit, the easiest kind of to accomplish. The promise that was being laid out for everything else that mRNA could do or believed in it fundamentally, as in I believe that the messenger RNA molecule in some way scientifically has the ability to do those things, to go into new tissues, to do interesting things, to replace genes. But the technology that was being pushed forward with modified RNA specifically was lacking in two areas. So there was the sustainability of expression. With modified RNAs, you're looking at one to two days of expression, and there was the specificity. So all delivery technologies are inherently flawed in one way or the other. You're almost never going to have 100% delivery into a given tissue type just based on the delivery technology. So how do we bring technologies forward that kind of push the boundaries on both those sides? So we started working on a system called replicating RNA. I mean, that's been pretty public now. We've published some papers on it, and what we're able to do with replicating RNA is increase that longevity of expression, and there's all sorts of fun and interesting science that underlies that. And then with the specificity, we started building genetic logic gated systems. And so what those logic gates were able to do is take in biomarkers, things like microRNA signatures, for instance, take those in, process that information through the construction of a genetic logic gate or multiple logic gates, and then the output is, of course, the therapeutic. And what that enables you to do is deliver an mRNA into the body, have the lipid nanoparticle or the carrier vehicle take it kind of wherever the particle will take it. It will never be 100% in anywhere, but take it to, hopefully, a large portion go into your target tissue of interest, and then you have the logic gate take care of the rest of that specificity. And so to me, those were differentiating pieces, and there's down a scientific rabbit hole reasons why it doesn't always plug in exactly, at least to what folks in the mRNA space were doing three or four years ago. I think we've definitely created some excitement in the mRNA synthetic biology space where I've seen others now inherently interested in it as well. Yeah, it's awesome. So you've been building up Strand for a few years now. I'm just curious how Strand has grown, how your vision for it has grown over the last few years. One of, I would say, the coolest things about starting a company based on a PhD work that you spent, let's call it a good four to five years, though I was at MIT for six years, you spent like four or five years building, is that like any PhD student, you have a million different corollaries and things that are in your head. You're like, what if we did it like this? What if I used this mRNA to do this? What if we incorporated machine learning? What if we started to, there's all these different things and collaboration, side projects, different things you think will be beneficial that build up in your head over time, and no one ever completes all of them. And I think that the coolest thing about building Strand, where we are today, having just closed our Series A and starting to really scale and build out both the company side and the research side, has been to see a lot of those side projects now have the attention that they deserve from people who are way better at working on those problems than I am. I was never going to be someone who was going to diligently develop a machine learning platform on it, but we can hire three or four really amazing scientists who can then interface with other scientists who are also better synthetic biologists than me and have those people work together to actually bring all of this tech forward. Having that interdisciplinary approach, like I said, this is the most excited I've ever been about this science in the entire time that we've been working on it. And a big reason for that, I think, is that academic to industry transition that happens where there's a distributed team. Even in Ron's lab, we had an actual team working on this platform. Tasuku, myself, Tyler Wagner, Katie Bodner, other sorts of people were all working on this mRNA technology, but we all had our own projects and we're all moving in a singular direction. But again, it's individual projects and it's academic. Now we have 30 plus scientists all working to diligent research goals and then the side projects have been refitted as features and functions that increase that platform. And that's been phenomenal. It's just been cool to see it happen and start to see some of the research that we're seeing now. Ideas I had as a third or fourth year grad student obviously didn't have the time or expertise to execute on. And now there's four or five people more talented than me working on it and you start to see actual deliverables and you're like, oh my God, this actually works. And that's by far the coolest part. That sounds really awesome. It must be really cool to be able to see your ideas taking shape through the company. Yeah, it is. I think the best advice that people give young entrepreneurs that I completely agree with is hire people that are better than you. And I started out by having a co-founder who's a better scientist than me, Tsutsuku. And then we've grown a team of people who are just better than me and better than us at certain areas who can take on these research problems. And it's been quite phenomenal to see. I think it's also to see people take ownership and at a startup, you give people a big chunk of equity of the company and you hope that the company is financially successful, that everyone will have these great things in the future and you hope you're successful for patients as well because then people have that good feeling of doing something for the world and also builds their own competencies and their careers. But to see people take ownership of Strand at one point for over a year, it was just Tsutsuku and myself. And we were like, Strand's a company we started. And then it's like, what's that mean? It's like, well, we incorporated it and then that was it. It was just us two running around trying to get people to give us money to do our science project. And now to see 30 plus people diligently working and bought in and invested in the company and actually with an ownership over it. We are Strand or people who really identify with it and work at the company. That is, yeah, I don't really know how to explain that. That's just kind of a corollary of the other cool things that are happening with it. Maybe just to follow up on one thing you were talking about with this difference between academic and industry research, especially for a small company. I think a lot of our audience would be kind of interested in going into work at a small company like yours. What are the key things that you sort of have to know going into that situation? And this is going to paint with a broad brush across both what is academia and what is industry and everything. If you work in different labs or whatever, I think that academia and academia's role in the grander research scheme is to essentially boil the ocean of possibilities, to ask questions like, well, what if messenger RNAs also had synthetic biology tools? That's kind of a crazy question that requires just all sorts of fundamental research. Like Ross, I'm sure you saw any number of my lab presentations in grad school that had to do with all of the things that don't work or all of the things that partially work. I always love to present those things because, one, it showed that I was doing work even though I didn't have good data. But also, I think it's good to kind of highlight what has been tried and how it's been tried and to show people that failure can give you a readout. I think that role of academia sort of boiling the ocean of what's possible and getting to proof of concepts is incredibly powerful. But where industry or at least startups kind of intersect into that and take off is when once you have a proof of concept and that concept is fairly big enough to where you say, okay, we've shown that we can do X and we know that X will be important in, let's say, three different verticals within healthcare. Now, can we put a team and dedicated capital behind developing just X? What I think is awesome about startups, about small-scale startups even, because we haven't gotten to the bigger startup stage of Strand yet, so I have no experience there. But what's awesome is that we have essentially one idea or two platforms that we're developing that are spun off of the same singular starting platform that we came into Strand with. We have 20, 30 scientists sitting and they all occupy a different space of this. There's like six people working on manufacturing. How do we increase the purity of this? How do we get this to be – how do we get this mRNA to be more uniform? How do we incorporate it into these nanoparticles and what do those nanoparticle characteristics have to be? Then there's people what should the sequences be and how do we reduce this immunogenicity and how do we increase this expression and how do we increase this efficacy over here and then, oh, what if we incorporated this piece? There's so many people who are all experts in their domain that are now plugging into a singular goal. That sort of power is just – the speed at which you're able to move, it's essentially like putting 30 people on a PhD project and saying, each of you take this small piece of this that you're a world expert in. That speed and diligent and sort of unification – everyone, of course, has their own development goals and things that they want for themselves like everyone does, build their career and do whatever, but the overarching goal and mission of the company to have so many smart and talented people unified behind singular research objectives is just frankly phenomenal. That's what I think is powerful about small and early stage startups. I guess one thing too that might be different is that in academia, your research product doesn't have to be something that sells, but eventually with a startup, you might want to have a product that could sell. Could you speak a little bit about that sort of distinction and how you come up with a product from a research project? This is – now we're going to get me onto my soap box here real quick about some problems that I have with the current state of academic research. That's actually that – I feel like in bio engineering, biotech, synthetic biology, what have you, we have actually pushed academic research very much to that application focused area. Whether that's an application that anyone from industry looks at and is like, that's a bad idea. That's not translatable. Regardless, everyone kind of thirsts for that. They thirst to be relevant. I think my philosophy on academic research is it should enable and we should fund at the NIH level, at the NSF level, at all the major federal sources of funding for research. We should fund science for the sake of science, especially in synthetic biology. I feel like synthetic biology as a field basically exists because we funded science for the sake of science, like a repressilator. The early repressilator paper, like that had – no one would have foreseen the sort of market impact that that early research would then inspire. I think that academic research should have more freedom. Maybe this is just my unique perspective of seeing a lot of professors who are entrepreneurial and wanting to do a lot of sort of spin-out pieces. I think that where we get maybe out in front of our skis is expecting every single research paper in synthetic biology or every single biological engineering paper to have an immediate translatable benefit. Sometimes engineering – honestly, I think Doug Loffenberger at MIT does a fantastic job of this. Sometimes he uses engineering concepts to study biological phenomena. That is amazing. Doug's co-founded a number of companies and he's done translational research too. He's very relevant in the broader biotech ecosystem. At the same time, he's not afraid to do these sorts of exploratory – or just use engineering and engineering tools to interrogate biology, which I really admire about academics. It's not about who starts the most companies. It's not about whose IPO is the most companies or has the most spin-outs or sits on the most SABs. In academia, I feel like it should really be about the pursuit of knowledge. If you want to develop an idea or there is a kernel of something possible in the academic context, there is plenty of capital out there that I think will chase those ambitious ideas. What I would also like to see more schools, especially the big schools with tons of money behind them like MIT. What I'd like to see them backing are more resources for translation. It shouldn't be that you need to be in Bob Langer's lab where there's a lot of money and support for you to really push your technology to that translational level. It shouldn't be that people are faking NIH grants that are really just translational SBIRs. They're like, oh, I have an R01, but really they're just trying to get enough data to get VC funding. I think that universities, especially the bigger universities with money and with benefactors to build these programs, they should do more stuff like Harvard's done with the Wyss Institute. If you want to translate research, then that's an area that you can innovate in. Academic research can be exploratory over here, and industry research or startup research can be taking the ideas once they're fully baked and scaling them out. Now I'm off my soap box. I guess on a more practical level, say you're a scientist, you've been working in academia, you have a research project. You think it's a really cool technology, right? How do you go from having a technology to having a product? What does that process look like of thinking through different options in that realm? It depends on what stage you're thinking about this question. I think that right now where we're at with the funding environment, the investor excitement for platform technologies and disruptive technologies, and really what we're seeing is an intersection of the so-called deep tech philosophy now being applied to biotech, which is inherently deep tech. It's just a little more convoluted because there's also FDA requirements and all of these sorts of things that historically have made it hard for tech and deep tech investors to invest into. Over the last five years, we've seen quite a change, I think, in the investor philosophy. If you just look at all the major West Coast funds, like all the Silicon Valley funds, they're investing in this disruptive platform technology constantly. Almost all of them have biotech funds and they're investing in what I think are really, really cool companies that might not even have 100% product. Everyone has an idea or a platform or a mission and some early science to say that we can figure this out. Then the company's job is to develop the technology and distill it down into how that eventually makes money or how it eventually goes into the market. As a therapeutic company, that's pretty straightforward, but there's also a big push now of what I call cogs in the machine. I mean that whatever the opposite of disparaging is because there's a huge investment potential there. What I mean by that is companies doing manufacturing or innovating on the production side. Look at Ginkgo. It's going to enter the public market at the highest valuation of any biotech company in history. Really, I would categorize Ginkgo as the king of cogs in the machine. They are the production foundry, we can build anything with DNA people. When I think about what do you need from an academic position, I think that you need to have an idea of what the potential of your technology is and a plan for how that would innovate, whether it's as a cog in the machine or whether it's as a therapeutic or whether we're seeing synthetic biology in agritech with PivotBio's recent major funding round. You need to have an idea of what the potential of this technology is, what the market of what it would disrupt is sized at, and you need to be able to present that in a way to investors that will facilitate the coming together of some sort of funding. I don't think you need to come out with this is our first product or this is how we would make money. You need to showcase that you understand a market, you understand what the current top line technology is, and you have something that is fundamentally disruptive. With that, there's a lot of funding out there for people to explore those ideas. It's a different world than it was even five years ago and it's incredibly exciting. Yeah, it is super exciting. Speaking of funders, you haven't really pulled punches on Twitter talking about the startup scene and dealing with funders and whatnot. What recommendations do you have for our audience in dealing with this ecosystem and what things would you like to see change to make the whole startup seem more productive and healthy? Yes, I do talk on Twitter sometimes about what I see as shortcomings in the biotech ecosystem. We'll say that nowadays, and again, this is not the same as it was even five years ago, but nowadays, there are no shortage of, I think, fantastic founder-centered investors, a lot of them coming from the deep tech ecosystem, a lot of them coming from Silicon Valley, but not all of them. There are fantastic investors in basically every major city in the United States. I think a strand we've taken money from people in almost every major city that investors, venture investors and private equity investors locate. I would say that the best advice is to really talk to other founders about who, like if you're a new entrepreneur, if you're wanting to spin out and you have an idea, the best thing to do is to talk to as many other startup CEOs and startup co-founders as you can. Talk to them about who they like. I have any number of investors who I like who have both passed on investing in my company or that I don't even know super personally. There are folks out there that I think just by what I'm seeing them do and just by their reputation by talking to other executives and co-founders who I know that I just know there's a lot of fantastic people out there who want to back young technical founders. I think what's pushing this is really two things. One is that there's a convergence of technology happening at such a rapid rate that no one can even stay on the top of it. If you're a great small molecule drug executive and you really understand screening technologies and how to move screening technologies into pre-clinical and then into a clinical developed pathway and then flip those drugs out to big pharma, that's wonderful, but you might be completely out of your depth in a company that uses AI to do the screening. There's obviously lots of different controversies about how useful the current platforms of AI for drug discovery are, but still I wouldn't say that a PhD in machine learning that also studied biology has any less of an insight than someone who's done this drug screening platforms for 20 years because it's just a fundamentally different model. Building those companies is going to be fundamentally different. That's why you see success from companies like Recursion Pharma, like Atomwise. You see success from them in the markets because they were led differently. They were led by young founders. The second is that there's clearly outsized returns happening in the biotech market and more so than there are in some of the more tried and true cornerstones of what Silicon Valley invested in like social media. What you end up seeing is that people who are maybe not complete subject matter experts who have a history of investing in people who are subject matter experts in deep tech. If you're a deep tech investor, you're not going to understand every single vertical of AI, robotics, space tech, rockets, and everything. Then moving into biotech, you can essentially apply the same logic that you use to invest in all of those places, which is why does this company have an outsized advantage over others around it between IP and knowledge? Why do these founders have an outsized advantage over others? Because they are leaders or they are uniquely positioned with their understanding and background to win in a certain sector, and that's how you underwrite the investment. I think that because of that, because of those factors, it is changing the face of biotech. It is changing the types of executives to the point where now you see some of the more established players, the Boston biotech mafia, if you will, making investments in some of these younger executives, these spun out executives. It's happening more commonly than it used to, and it only took a handful of IPOs. Okay. One thing that some of the people in our audience that might want to start their own companies might wonder is when did they take on the reins of CEO as you did, and when did they look for somebody to bring in as a CEO and then focus themselves maybe more on the science side? That's a fantastic question. One I've actually had with a number of companies that I've mentored as they've spun out. Everything in the company is just going to come down to a personal question. If you're an individual who wants to lead the scientific research, continue to lead the scientific research, then that's what you should do. If you're a person who wants to lead the communication of the company, at the end of the day, once a company gets to a certain stage, a CEO is essentially a chief education officer. Your job is essentially just communication. I think, Ross, you probably remember how obsessed with science communication I was in grad school. That's really the role of the CEO to a certain extent. There's communicating internally leading the vision, landscaping the entire competitive market and trying to figure out where you fit in. You have an entire team that should be influencing that, but as a CEO, you're a very external-facing figure of the company. You're talking to the media, you're talking to investors, you're talking to potential partners, and that's all an education piece. It's bringing someone up to speed with what your technology is, why it matters, what the market is, and educating someone usually in a very quick fashion, too. You need to be quick and concise. You don't have an hour-long platform like you would in a group meeting or something to bring someone up to speed. You have to be very meticulous with how you think about that. I guess the question is, who are you? What I push back on is the older school biotech notion that no one under the age of 45, and usually anyone who's not an older gray-haired white man, can be the CEO of a biotech company. I think that is fundamentally flawed, obviously, and we've seen that happen throughout the history of biotech. It's just something over the past 15 years that Boston Biotech has really dug in about. For someone, I think, ask yourself the question, do you want to lead the research or do you want to lead the company? I guess the leadership is really a communication. It's a rallying cry. Do you want to be a lieutenant who has a very diligent execution list that's the CTO or the VP of research or the head of R&D, whatever it is, and you're running a team of scientists, which is what I think a lot of non-communication-focused scientists are very, very good at? Or do you want to truly represent the company to everything? You're going to have to give up one thing. I touch the science far, far less than my co-founder, Tesuku, does. That bums me out sometimes, to be honest. I like the science. I worked on it for so long. I like thinking critically and having those very discreet problems that you're trying to solve or even open-ended boiling the ocean ones. You need to just be honest with yourself. What do you want to do? I think all of us talk about the general startup ecosystem has been really, really fascinating that we would be remiss in having an RNA technology expert and innovator on our podcast if we didn't spend a little bit of time talking about the current pandemic situation and the role that RNA technologies have played in that. To get us started off, putting RNA technologies aside, you've been growing a company during the pandemic. I know that for me personally, it was disruptive to my research. We weren't allowed to be in lab for a little while and everything. How has the pandemic affected your launch? Yeah, that's a whole can of worms of a question. Early on, the pandemic was, I think, as disruptive to us as it was for pretty much everyone else in the world. At first, we shut down our lab. No one really knew what to expect, but we needed to wind back to protect our employees, to protect everyone's well-being. We shut down for about a month and a half before people started getting mass mandates together and figuring out how we could safely go back to work. As a research and development company, you can't go. Our company is like 90% scientists at this time or 95% scientists at that time. People just can't work remote. We started to move back and got policies into place. And just with everything in life, and I was having this conversation just earlier today, which is we kept hiring people. To the first market crash that happened at the beginning of COVID, Biotech was very resilient because the model for Biotech is you raise money and then you don't make any money and then you get some work done and then hopefully you raise more money. That's the model. We don't need people to be out, to be shopping, to be doing anything. There's no revenue that we're expecting, so we didn't have that sort of an issue. We just had a conversation to say, well, we can't stop research, so we have to keep hiring. We kept hiring people. That was weird at first because you're doing Zoom meetings. I was very big in that I want to meet in person, sit down with every single person we hired. We had I think like 13 or 14 people at the beginning of the pandemic and I had met all but one of them in person before they were hired. The one person I didn't meet, it was just because the schedules just would never work out and I had a nice hour long Zoom call with her to feel good before she was hired. That was a shift. There were people that, our head of formulation, for instance, we brought over this incredibly talented scientist, Alok Shah, to lead our formulation group. I didn't meet it because he was also working half remote and I was starting to, by the summer of last year, I was starting to come in, work in the office just to see people a little bit, keep an ear to the ground on how things are handling, just feel the company really. It was like four or five months until I met him in person. I ran into, we happened to cross paths in the office and I was like, oh, oh, I've never seen you not as a person on a screen. Now that's more the norm and now with vaccines coming out and now with people returning, a return to normalcy like we are. I'm getting to meet more people, spend more time in the office, talking to folks, meeting some of the people I haven't really gotten to speak with that much. Yeah, that was a definite challenge. There's just no way to work remote as a research and development company. Yeah, I can definitely relate to that. Having started my postdoc during the pandemic, took a long time to actually meet everyone. I'm curious how the COVID pandemic has changed your perspective on the medical system and the role that synthetic biology can play to improve medicine, to improve our response to things like pandemics. Do you guys have any plans to help us deal with COVID itself and all the variants that are coming up? I will say that we're not an mRNA vaccine company. We're very much focused on technology that allows us to adapt messenger RNA to a more rigorous therapeutic context outside of vaccines. That's what I believe that our technology is fundamentally different on. I think that personally, I've been now an advisor to the Biden administration, to the White House and OSTP on supply chain mitigation and also future looking strategies. I worked with a number of members of Congress to help understand different bills that are being prepared right now for future pandemic readiness. As an individual and as an mRNA expert who also doesn't have a dog in this fight of mRNA vaccines, I feel like I can make myself available to both the US government and other governments around the world that have come forward to ask for help in understanding this rapidly moving world. I don't think my feelings on synthetic biology and healthcare have changed because I was obviously very bullish on it. What I think is exciting is that the rest of the world is all of a sudden paying attention. I mean, I'm having conversations with my grandmother about mRNA. I don't think we've ever talked about messenger RNA, despite the fact that I did my PhD in it. I don't think we've ever had a conversation about it. Friends of mine who aren't in the sciences are asking me about things even beyond messenger RNA. People are paying attention to the innovation that's happening about CAR T therapies, for instance. I'm having a friend who is just interested in that now. Just in the same way that I think technology, like the technology sector became very in vogue in the public sphere over the past 20 years as different sorts of innovations came forward, I think that biotech is now having what I believe is a very well-deserved time in the limelight. I think that the pace of innovation that we're going to see over the next five to 10 years, especially as technology and biotechnology converge into overlapping Venn diagram-like fields, is going to be very, very exciting. What innovations are you most excited about and looking forward to, either related to RNA or unrelated to RNA and synthetic biology, but within the biotech ecosystem? I'm most interested in the way that synthetic biology will overlay on top of what today's current gene and cell therapies can do, actually. We've had amazing advances in gene and cell therapy, viral-based gene therapies, oncolytic viruses, AAVs, and also cell therapies like CAR T therapies and now even NK cell therapies. Where I think that we have maybe the coolest future is now that synthetic biology has genetic logic gates and other sorts of quote-unquote smart therapeutics are coming forward, where we are now looking, I feel like as a field is, how will we now take the existing synthetic biology technologies, overlay them on top of these platforms that have already shown their ability to be used in different disease contexts, but usually are fundamentally limited in their ability to express certain protein or express in certain areas of the body or be used in certain contexts because they're not safe enough or they're not whatever enough. Now that we see synthetic biology laid on top of the great work that we've already done on those platforms, that is what I am most excited about. We're going to see viruses that can truly target cancer in the body or we're going to see cell therapies that can not just treat cancer, but maybe can treat autoimmune diseases and all sorts of new and exciting areas. We're going to see probably, if everything holds and Strand is working on this, I guess as a statement of conflict of interest, but we're going to see people start to intersect gene and cell therapy together. There's lots of companies now thinking about how do we create platforms that can deliver different payloads into immune cells so that we don't have to do this huge, heavy lifting manufacturing process of taking cells out of the body and modifying them and putting them back in. Can we turn those into off-the-shelf gene therapy approaches essentially? You touched a little bit about what Strand is doing to move to this advanced stage of biotechnology for therapies. I'm wondering if you could talk a little bit more in depth about the RNA technology that you guys are making and how you're pushing things to the next level and where you see your specific technology going in five years and 10 years and so on. Absolutely. Like I said, I fundamentally believe in the mRNA molecule's ability to get into a diversity of tissues and have a therapeutic effect. There's mRNA in every cell in your body and so there's no hard scientific reason as to why you can't get synthetic messenger RNA into any of those cells and be able to have some sort of an effect. In the coming years, we've publicly disclosed what we're focusing on. Solid tumor, immuno-oncology is where we started and now we're also moving into in vivo cell therapy approaches. Disclosing both of those, I think that beyond that sort of area, we can now build the exact same technology or utilize the same technological platforms to move into all sorts of new and exciting areas. Fundamentally, what Strand is doing is we're creating messenger RNA platforms that can express for an extended period of time so their cargo, whatever you encode onto the messenger RNA can be actively produced in the cells for anywhere from one to four weeks. That is enough to have therapeutic intervention in a whole plethora of different diseases. Building on top of that, we're then building so-called smart messenger RNAs. The mRNAs not only have a longer expression duration, but they have the ability to only be active in certain cell types. I'll explain a little bit about how that may be powerful in our first program of solid tumor, immuno-oncology. All of the messenger RNA platforms and really a lot of the gene therapy-based IO approaches currently being worked on for solid tumors are pretty much all intratumoral administration. You need to inject into the tumor directly, and then you elicit a sort of immune reaction against the tumor in some sort of a way. Now, we have an approach for our first drug that will be administered intratumorally that we think is unique and actually incredibly effective compared to all the other options that are in this field for treating these solid tumors. What's more important is the long-ranging vision, which is, can we deliver a therapeutic into the bloodstream of a patient? The nanoparticle will end up in a couple different tissues. It'll end up in the liver. It'll maybe end up in the spleen as well, but then also end up in the tumor and have enough of the drug end up in the tumor such that if you build a sufficient, logic-gated system that is specific to only activate inside of the tumor and not activate when it enters the liver or the spleen, then what you've created is essentially an ability to target tumors throughout the entire body and not just ones that you can inject into. That is a real shift in our ability to think about IO for solid tumors and our ability to get into different sorts of tumors throughout the body. That right there, I think, will be a complete paradigm shift in the way that we treat solid tumors. Then you take that same logic, the same logic that a lipid nanoparticle can deliver a messenger RNA throughout the body in different percentages to different organ systems, and you then utilize synthetic biology to hone in on certain cell types and certain tissue types. That right there essentially opens up your therapeutic modalities to a whole slew of rare diseases, CNS diseases, all sorts of new and interesting areas that we're very interested in going after. It's amazing what Estrand has been doing, and I'm just curious what your thoughts are on the space outside of therapeutics. What are synthetic biologists missing right now, and where should we be looking? That's a fantastic question, Ross. The view of synthetic biology right now, and what I'm hoping that more people get behind in the synthetic biology field is that there are lots of different areas to innovate. Not all synthetic biology innovations have to be in therapeutics. I say that as someone who went into therapeutics, but what I think is really awesome about synthetic biology is that because it's essentially just building with DNA or messenger RNA, building different sorts of call and response systems, is that there's a whole number of different verticals within the healthcare sector that people can go into. What my concern is, and I say this with only a little bit of irony that I did start a therapeutics company, is that I would like synthetic biologists to understand that there is a whole healthcare ecosystem that is also exploding at the exact same time. With new modalities, cell therapies, gene therapies, everything, there are all sorts of new technologies or production means and supply chains that are being taxed or need to be innovated on. Even a couple years ago, the New York Times wrote an article about the supply crunch of AAVs and how CMOs are incredibly taxed. One of the rules that we say in biotech a lot is that if the New York Times is writing about it, then it's a huge problem and has been a problem for a while. By the time that someone identifies that and says, oh my God, there's this huge supply crunch. I guess I would encourage, and I often do encourage other synthetic biologists to take some time plugging into or talking with people in the biotech sector, especially gene and cell therapies, to think about what does the whole ecosystem look like? There are aspects of this entire vertical, this entire sector of our economy that I didn't even realize existed or existed at scale. Just what we have to do to source raw materials and then use those raw materials to produce DNA, then produce mRNA, then to formulate them into lipid nanoparticles. While all of the therapeutic development or helping part of that therapeutic development is very important, also all of that production, I think, will be a huge part of sectors moving forward. I don't feel like there's enough synthetic biologists innovating in that sector. Those are the sorts of things that companies like Ginkgo have started to go after, of course, but I think that there's a lot of room for ... One of my favorite companies right now is this synthetic biology company out of George Church's lab called 64X Bio. What I think is amazing about them is they use synthetic biology to attack manufacturing issues that are different cell lines that are used to produce things. When I look at that sort of an innovation, that innovative idea, I get even happier for the idea that there will be more companies like that, as long as people start paying more attention. Well, I think that's a really inspiring note to end on. Certainly, there's a lot of work that students and post-docs like ourselves could be doing to help improve this sort of ecosystem. One last question for you before we let you go about your busy day. Is there anything in particular that you'd like to promote or plug before we sign off today? This could be things like articles or books or job openings or even other companies or work in this space. I would say to all synthetic biologists in academia right now looking to make the transition to a company that I think embodies academic curiosity at huge amounts of ambition over what we can accomplish from research projects while having the sort of diligent focus of industry, they should check out Strand's website and they should apply for jobs there because we are always looking to hire highly talented synthetic biologists. There are a ton of openings on that site right now and I would love if people would apply. Great. Thanks, Jake. Thanks to all our listeners. This has been another episode of EBRC in Translation, a production of the Engineering Biology Research Consortium's Student and Post-doc 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 Post-doc Association, you can find our membership application on our website. A big thank you to the entire EBRC Spa podcast team, Catherine Brink, Ross Jones, Fatima Anam, Andrew Hunt, Adam Silverman, Kevin Reed, David Mai, and Koksie 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.