Manifold Bio: Gleb Kuznetsov, CEO
“Create the environment where you can move most efficiently for your technology, product or science.”
Nature is the master multitasker. Billions of molecules thrown together in the ancient “primordial soup” led to the assembly of complex biomolecules, and eventually the first primitive forms of life. Over eons, innumerable organisms were evaluated in parallel, with the “fittest” selected to pass on their genetic material.
Classic drug discovery—testing one agent, in one dish or one animal, at one time—stands in stark contrast to the massively parallel nature of evolution. Looking to model nature’s approach, scientists have long sought to develop highly multiplexed methods to increase the efficiency of finding new therapeutic agents. Many of these high-throughput efforts to screen small molecules or biologic agents have occurred in the lab dish—a flat world, which is a highly abstracted version of biology: “How do you go beyond the limitations of in vitro systems and get early feedback [selection] from challenging a drug design with the full complexity of a living organism?” asks Dr. Gleb Kuznetsov, CEO of Manifold Bio. Technology that could evaluate many complex drugs, in parallel and in vivo, would more closely resemble “real biology” and may overcome the pitfalls en route to successful clinical translation. The benefits of such an approach to drug developers, and ultimately patients, would be manifold.
Co-founded in 2018 by Gleb Kuznetsov (CEO), Pierce Ogden (CSO), Shane Lofgren (Head of BD) and George Church, Manifold Bio uses technology developed in Church’s lab to eliminate a key bottleneck in biologic drug development. Their M-Design platform allows for pooled in vivo testing of protein therapeutics. Each protein drug is tagged with a protein barcode called an M-Code that allows simultaneous tracking and quantitation of proteins in different tissue types: "Manifold’s vision was to unlock in vivo screening broadly for proteins and other biologic agents. How do you tell where the protein or the drug is going in a complex living environment?” describes Kuznetsov. With groundbreaking tech in hand, Manifold’s team is now in the early stages of building a pipeline of bespoke protein therapeutics with increased selectivity for target tissues or tumors.
In July 2022, Manifold announced a $40 million Series A financing led by Triatomic Capital and joined by Section 32, FPV Ventures, Horizons Ventures, and Tencent. Existing investors Playground Global, Fifty Years, and FAST by GETTYLAB also participated. The round has enabled Manifold Bio to move into a significantly expanded laboratory where it will grow the team, accelerate its efforts advancing internal drug programs, and advance its protein engineering platform to support expanded indications and partnerships.
A computer scientist originally, Dr. Gleb Kuznetsov (CEO) avoided biology as an undergraduate at MIT. It was not until his Master’s degree in CS that he realized he was missing out: “I had one more credit, and I decided to take Manolis Kellis’ bioinformatics class. Taking that class was like a moment in a video game where you walk into the correct room, and the music starts getting louder, so you know you're doing the right thing.” After a stint as a software engineer at Google, Kuznetsov jumped back into biology—following an “intuition” that technology would soon redefine the field. This gut feeling led him to George Church’s lab where he completed his PhD thesis as part of the Harvard Biophysics program. His work combined computational and experimental approaches to “hack biology”: including projects focused on engineering genomes and proteins.
A true computational and wet-lab hybrid, Kuznetsov is passionate about merging creative experimentation with cutting-edge technology (Q#3). Drawn to industry by the prospect of building a collaborative culture, hiring the most talented scientists and being efficient, Kuznetsov and his team are rising stars in the founder-led biotech movement (Q#2).
Below is an interview with Dr. Gleb Kuznetsov, CEO of Manifold Bio from September 2022:
1. Briefly describe your background, and the moment you decided to jump from academia into entrepreneurship. What different paths did you consider, and what was the deciding factor to make the transition?
I was a computer science major in undergrad [at MIT]. I actually tested out of biology in high school, by taking AP Biology, so I never took a biology course in college. During my master's year at MIT [in CS], I had one more credit, and I decided to take Manolis Kellis’ bioinformatics class. Taking that class was like a moment in a video game where you walk into the correct room, and the music starts getting louder, so you know you're doing the right thing. Looking at DNA sequences and seeing nature through a computational lens… it was a pretty inspiring moment.
[During this class] I happened to work with Adam Marblestone, in George Church’s lab—he and I got to know each other by collaborating on the final project. Fast forward a bit, I had a job already lined up at Google as a software engineer. Outside of Google, I was participating in this DIY hackerspace, called “Bio Curious.” I realized I was super interested in biology, and that I wanted to do science “for real.” The path to do that was to join a company, or join a lab. So, I ended up talking to a bunch of folks at different labs, and left Google to join George Church’s group as a software engineer and research tech.
[The Church lab] is where I was fortunate to have great mentors like Marc Lajoie and Daniel Goodman bring me up to speed. I didn't have a strong thesis of: “I'm here to do academia.” I just thought that biology, especially some of the cutting-edge DNA technologies [sequencing and synthesis], were going to redefine the field. Over time, it became clear that this novel tech had direct connections to therapeutic areas: in reading/writing DNA, and engineering proteins and genomes. So, the connection to what we do now [at Manifold] –engineering protein therapeutics [antibody-like drugs]—it was a pretty natural transition. A combination of factors made industry appealing to me: the focus on building a product addressing real world needs, as well as more flexibility when building a fundamentally interdisciplinary team. Those factors pointed me towards biotech and entrepreneurship, as opposed to academia.
How was the transition from the academic lab to starting your own company?
George Church’s Lab plus the Wyss Institute truly catalyzed the transition. Over the years I had the opportunity to work with a number of talented scientists. One of the most talented was my co-founder Pierce Ogden (CSO of Manifold). We basically worked together since the beginning of grad school, pair-programming and pair-pipetting. We established good practices as far as collaborative experimental design, computational infrastructure, and knowledge management. We also had the chance to mentor a number of graduate and undergraduate students and establish our team culture. It is quite common, at least in George Church’s lab, that people graduate and stay on for another year or two to wrap things up, or in our case, put the pieces together to spin out a company. This extra time gave us a chance to experiment with some new technical approaches and also get out and speak with experts both in academia and industry. By the time we were ready to leave, we had established a framework for doing science, building a team, and testing business hypotheses. We still had to learn a lot, but having the time to lay the foundations and build a strong relationship was key.
Were there any mentors who helped you think about starting a company, or inspired you?
I think a big factor is just seeing your peers successfully start companies, raise money and everything - it was a huge confidence boost. You realize: “wow, that's possible,” and that there's no “magic” to it. It also helps being able to lean on those peers. So, who would [start a Newco] right before us? Dan Mandell [CEO of GRO Bio], Eric Kelsic [CEO of Dyno Therapeutics], Alexis Rovner [CEO of 64x], to name only a few. And then, Marc Lajoie [CEO of Outpace Bio] in parallel, but on a slightly different path early on. So I knew all these people that had done it, which was pretty motivating—and I could ask them how they did it.
2. Nucleate is making waves in the founder-led biotech community. What was your experience in the program, and how did it help Manifold?
As we were wrapping up our PhDs [in 2018], Pierce and I felt there was a lot of potential to apply the kind of technology we were developing to the therapeutics space. At that point [Fall 2018] Nucleate was in its first year– Soufiane Aboulhouda and Marissa Pettit were putting it together. Soufiane kept coming up to our bench and literally saying: “you guys should do this … let us help you bring the company into focus and get the key pieces going.” So that's really the value it played for us: Nucleate got us away from the bench and into thinking about the key steps of what would be our product focus, coming up with a pitch deck, thinking through a basic operational plan, thinking through IP, and then putting us in front of mentors that started asking us hard questions. Nucleate dovetailed into something else that I did, called the Spark I-Corps program [via MIT]. It is a customer development type bootcamp that they do, but focused on biotech and the life sciences. So, all of these activities together—going through the reps with Nucleate and Spark, and then continuing getting out there and talking to folks--were the catalyst for thinking more about business, as opposed to just technology development.
3. What is one book that has influenced the way you think, which you would recommend to fellow scientists or entrepreneurs?
The book that comes to mind right away is called Creativity, Inc, by Edwin Catmull—one of the founders of Pixar. The book describes the cultural evolution of the company. Pixar has this really analogous challenge [to biotech]. Pixar’s product was a creative output of a cartoon or a movie. But, to make that possible, one had to combine high-powered artists and creatives, with cutting-edge technology. And so they also had to push the boundaries, both in terms of storytelling and [the way in which] that story was told. Toy Story is this mind-blowing feat of technology and storytelling. For us [at Manifold]: part of our whole vision is bringing cutting-edge technology to drug discovery, and in doing so challenge current paradigms. We need to bring together really creative and high-powered scientists, often with an academic bent, but also stick to milestones, timelines, and ultimately develop a product. How do we maintain that focus? [Creativity Inc.] talks a lot about the principles of culture building, team building, and finding ways to channel creativity without constraining it too much. To me, it's an inspirational book that I continue to draw upon as we're building Manifold.
4. What was the original vision for Manifold? What is the company’s origin story and how has the vision changed or stayed the same since the company’s inception?
Our vision for in vivo based biologics discovery has existed for quite a long time, even before we figured out exactly how to do it. There are a few pieces [of Manifold’s origin story]. The first is that we were working on antibody discovery technology toward the end of our grad school and right after as postdocs. We went out to talk to a lot of people in pharma, and asked them questions like: “hey, here's how we make antibodies. Isn't that cool? Would you buy these?” The feedback we got was: “there are a lot of ways for us to source antibodies, but ultimately there are really hard questions that come along the way before we make them into drugs.”
Before human testing [of antibodies], there's a point where you have animal tests. How do these antibodies navigate complex mammalian environments? This is a key de-risking step. No matter how cool the antibody discovery technology, it will be bottlenecked by throughput at those key gating steps. So that's one point of motivation. In parallel, Pierce was working on in vivo discovery technology for AAVs. His thesis was on AAV capsid engineering that led to a Science paper that was the foundation of Dyno Therapeutics. Pierce was thinking a lot about in vivo discovery for AAVs—in this case you have DNA present inside of the viruses, which can be used for quantitation in a high throughput screening approach. So, there was this natural question that emerged: can we make a way to track proteins? Because then we could extend to protein therapeutics more broadly, positioning us to effectively solve a much bigger industry bottleneck. In vivo discovery for protein therapeutics would be incredibly enabling. But the question is how do you do it? The technology didn’t exist yet.
I remember when Pierce first proposed the idea, where we didn’t have to solve the general problem of next-generation protein sequencing, but instead engineer a set of trackable barcodes that we could re-use across drug designs. There were a number of hard questions to figure out, and the approach was very far from obvious, but the vision was so powerful and in many ways has remained the same at its core.
At the time, Pierce had the chance to join Dyno as a founder, but we were so excited about building a technology that no one else had and that unlocked an even bigger therapeutic space, so we decided to go all in on Manifold. From the beginning our vision was (and is): how do you unlock in vivo screening for proteins more broadly, but also other delivery mechanisms. How do you tell where the protein or the drug is going in the complex environment of a living organism?
5. What are some broad areas of clinical medicine and science that could benefit from more precisely targeted biologics? [What are some specific case studies that Manifold points to when describing its value prop]
We use this tagline internally of getting drugs to go where they should go and not where they shouldn't. There are so many drugs, you can basically frame as effectively having a targeting component and effector component. Antibody effector components are quite forgiving, quite mature, and they're very potent, whether it's a T cell engager, NK engager, or an antibody drug conjugate. Those effectors can do a lot of damage to the cells that they end up next to. So, the question is: how do you get them only to the cells that you want them to go to?
Oncology is naturally a space where you've got cells expressing targets that also happen to be expressed in healthy tissue. How do you end up with a drug that only goes to the cancerous version of those targets? How do you get that feedback from a complex in vivo system, with a 3D representation of the full organism [versus a 2D in vitro model]. So oncology is a focus. Beyond oncology, we’re excited about the possibility of taking on grand challenges like crossing the blood brain barrier [BBB], and there’s no shortage of approaches to achieve this—whether you are building a shuttle or some other way of getting a targeted antibody across the BBB. Of course, the possibilities extend into the autoimmune space and even into genetic diseases where targeted action at specific tissues or cells is key. The re-framing of clinical problems as targeting or delivery problems actually makes it very clear that an ability to measure and engineer biodistribution in high-throughput can be incredibly enabling. If you have a custom technology basically made from day one [with Manifold approach] to address that issue, you have this unprecedented advantage to ultimately make a useful drug product.
6. What excites you most about working at Manifold? What gets you up in the morning?
The number one thing for me is the people. We have an amazing team with really smart and kind people. That all sources from our hiring and recruitment process. From day one, we've taken it really seriously and made sure that it's a two-way thing, when you're bringing someone on board to a startup, you want to make sure it's a really good fit for them and for the company. One of the key aspects of my role here is to create flow for people, and build an environment to get the smartest people to come here.
7. Briefly discuss Manifold’s team and culture. How did you build that culture, and how do you think about scaling it?
Good culture starts with really aligning with your co-founders: what you care about and what's important. We ended up doing an exercise to formally put down our culture and values about a year into Manifold, when we were at the stage of five or six people. It was entirely unsurprising to me what the top two values were that popped out. One is “scientific boldness” and the other is “team focus.” I think other ones have naturally emerged from a mix of intuition or just our predisposition. One is having a principle of ownership: very clear, who owns what, who's responsible for something. It’s not that everyone has to go after things alone, it's more like avoiding things falling through the gaps. In our work, we make sure it's very clear who owns what, but then share in both the success as well as failures. I think that is really important.
Complementary to our cultural values, a special aspect of our team is how we’ve enriched for wet-lab and computational “hybrids” from early on. Both Pierce and myself are of this phenotype. For a company building technology at the intersection of biology and compute, it’s essential to have folks that deeply understand both sides and can bridge between specialists more on one side or the other. I often describe our scientific culture having a “town square” around experimental design, where the team comes together to design experiments that produce the right data to enable quick decision-making and iteration.
[Building and scaling our culture] starts in our hiring process, where we really define what we're looking for, as far as skills, competencies or cultural points. One very effective thing we’ve done from the beginning is a case study, where we work through a problem together. This gets both the candidate and us to understand what working together is like.
You also need to get lucky—you often hear that the first few people you hire can really define the trajectory of the company and I’ve seen it first-hand. Our first two hires—Kate Nudel and Hoong Chuin Lim—set the scientific and team culture from the beginning and have grown as leaders within the company. This set a strong precedent for the amazing team we’ve built around them.
A common pattern we see for the reason people transition from academia to industry, or at least for the folks that join our team, is because they're looking for more of a team-based approach than academia often offers. In academia, there is inertia to building a big enough team that is all in on a single problem, because each person needs to optimize to have their own papers, etc.… that's just the nature of it. In a company, it's a different game. You're working together to accomplish a big, complex problem. That's the core, and the kinds of people that have joined the team need to care about that: how do we do something big together and combine skills and combine expertise?
8. What has the transition been like from academia to biotech? What have some of the challenges been making this leap?
I often say that the hardest thing about getting into biotech is navigating the idea maze of the actual product, drug or therapeutic indication that you're going after. Because that's something that's generally quite unfamiliar even for scientists. For us, we were very comfortable with technology development. But how do you choose a drug, think about the biology, markets, patients, or the nuances of drug development and clinical trials? That was very unfamiliar. I think Sri Kosuri from Octant used the phrase “idea maze” when I talked to him in the early days. He's another Church Lab alum. That's probably one of the biggest challenges for less experienced founders in the space.
So how do we overcome that? Our co-founder, Shane Lofgren, who's Head of Business Development comes from more of a classic oncology, scientific background. He was a bioinformatician for a number of years, and worked at Stanford and MD Anderson. He also spent a lot of time with the Technology Office at Stanford, and then spun a company out of MD Anderson, working with Atlas Ventures. Most importantly, he’s incredibly generative in his thinking and loves talking to people and stress testing ideas.
This is the story of how he joined our team. We’d known Shane for a couple years and enjoyed brainstorming about science with him. When we were thinking about kicking off a seed fundraise for Manifold, we sent him the early version of our Nucleate deck, and he wrote back: “this technology sounds cool, but there’s a lot of nuance missing in the applications you’re proposing going after.” He wrote this 2000-word email picking apart our plan. So, I wrote back a one liner like, “well, Shane, what would be a better way to think about the application strategy?” And after a weekend, I get back this giant email with lots of ideas. It ended with: “we should get together and brainstorm…I actually have a lot more ideas.” So that was the beginning.
The three of us work really well together while having distinct areas of ownership. I think this speaks to the importance of having a founding team that can cover a lot of surface area. You need someone that can own the scientific roadmap, someone to own the business development strategy, someone to communicate the vision and plan to investors…and so on. Between the founders and the early team, we continue to successfully overcome whatever challenges come our way.
9. What is another biotech (public or private) that you think serves as a paragon of an impactful company? What are the key learnings from this case study?
Maybe a little grandiose, but I look at Genentech as a company that is very inspiring. In the early days, they had a very new technology [mastery of molecular cloning] that they leveraged to start biotech. On top of that technology, they were able to take a human protein, industrialize the production of it and make incredible therapeutics: from insulin through growth hormone, eventually. They were also some of the first to make cancer targeting antibodies. Critically, it wasn’t just “one cool trick” spun out of the lab but an ambitious technology roadmap brought to life by a culture of innovation that revolutionized medicine. Some of the best science in the therapeutic space continues to come out of Genentech. They're still at the forefront, for example recently hiring innovative leaders like Aviv Regev.
Another company I’ve been watching closely is Recursion. If you read their S-1, the CEO [Chris Gibson] has a sentence in there that has this language like: “we are intentionally audacious, expansive and impactful.” It’s hard to actually make a drug. It’s a big promise to come in and bring new technology to drug discovery. But I think that they're really doing a good job of sort of bridging that gap: having a novel screening platform but also doing what's necessary to actually make a drug - they have a number of clinical trials going now. They also have really interesting partnerships, like a creative partnership with Genentech, where my understanding is they’ve found a way to share data, algorithms and models, in the pursuit of therapeutic areas of mutual interest. They're a trailblazer in this movement of “techbio” in the past decade.
10. In today’s climate what is one short piece of advice you would give to prospective biotech entrepreneurs [can be about building a team/culture, raising funding, keeping motivated, pivoting etc.?]
The advice I like to share, which is actually independent of the climate, is an answer to the common question: “When should we spin out?”. We've done two fundraises, a Seed raise and a Series A. Both times have been possibly the worst times to raise in the last few years. Our Seed was right at the beginning of COVID. The pandemic definitely took the wind out of that fundraise process, but we still managed to succeed. We did our Series A as the biotech and tech market were coming down in the Spring . So, we've worked for it both times.
My advice is for people who are thinking about this question, which we also had: “should we stay at Harvard and de-risk our technology more? How long should we stay in academia?” The focus is often on IP, and doing the game theory: “if we stay longer at Harvard, they own more IP, but the forward value of the company is higher.” So that's the first order question that lots of entrepreneurs are trying to optimize. In our experience, we were dabbling with talking to investors vs more de-risking experiments, and then COVID happened so the labs got shut down. At that point, we had nothing to do but talk to investors--we couldn't really go into lab and further de-risk the technology.
As soon as we raised a bit of money, we realized we had so much more flexibility in hiring. There are fewer rules than in academic hiring, and you're more competitive with compensation and equity. Having more flexibility in how you build your team is very big. The question people should ask is: where can you move faster with respect to the technology or science? For some science, I would say you probably can move faster in the lab, perhaps because of expertise or specialty equipment. For us, we’re more of an engineering company, so it made a lot more sense to just get out and raise and build that momentum. And as a startup, you just have more control over crafting your environment. So that's the general advice that is climate independent: Create the environment where you can move most efficiently for your technology, product or science.
In the end, your goal as a venture funded entrepreneur is to grow a very large pie. You can't optimize how exactly it's divided. The university is going to get a piece, investors are going to get different amounts, and of course you want the team to own as much as possible. The key thing is just having a mission on how to efficiently realize value and get the necessary resources. Is this still at the University-level or can it be done with seed funding?
11. What has most impressed you about any experienced or thoughtful investors with which you have interacted? What is one piece of advice you would give to new biotech investors? [Can touch on things investors don’t understand, overemphasize, underemphasize, aren’t aware of entirely]
I've been always impressed with investors who understand the importance of creating optionality, especially early on, for a startup. I think that's sort of a common theme amongst our investors. But it's not just total or broad optionality: our investors didn't want to hear “this could do everything” they wanted to see “here's the focus, here’s plan A that has a lot of value and impact.” But they also want to see how there can be a quick adjustment into a plan B, or a plan A plus plan B.
I‘ve also been attracted to investors who are keen on thinking from first principles together in a collaborative manner with the company. I met folks like this from both the “techbio” and classic “biotech” sides. A common theme of the best discussions was a stream of hard, incisive questions coupled with brainstorming about how to best realize the value of the therapeutics and platform that we are building.
Thinking through the value capture and the collaborative exercise is what I really enjoy. I think it can be tempting for an investor to ask questions that may be interesting, but ultimately may not move the needle on a decision for you, or empower you to bring it back to your partnership. This can be hard, and more often comes from junior folks who are still honing their pattern-matching skills, but I’ve also seen junior investors with great questions, energy, and ability to lobby for the company inside the partnership. As we've gotten better at pitching, we've learned to steer people towards questions that help them gain conviction, whether it's a yes or no, and then be able to sell that to the rest of the partnership.
12. Any recent announcements (hires, abstracts/publications, awards, job openings) or key milestones regarding Manifold that you want the public to be aware of?
We're always looking for really good scientists. I think we’ve built a fun place to innovate, and we're about to move into a beautiful new lab. We’ve made great progress, but we’re still relatively early in realizing the full potential of what a team like ours can do. We’re developing foundational technology that will refactor the entire biologics drug discovery and development process and contribute meaningfully to improving human health. Please reach out or send folks our way. I’d love to meet them.