As a long-time gene therapist, Nicole Paulk was already questioning a core assumption of the field: that every gene therapy needs to be bespoke for each disease. Today, she’s the Founder and CEO of Siren Biotechnology, a company built to make universal gene therapies a reality.
Nicole joined me to talk about turning moonshots into companies, why unpopular ideas are the right ones to pursue, and how biotech has to move faster and cheaper to survive. — Sajith Wickramasekara
* Editor’s note: The conversation has been edited for length and clarity.
How COVID launched an idea
Sajith Wickramasekara: Let's start at the beginning of Siren Biotechnology. You raised $6 million dollars, moved into an incubator space with Bayer, and got your startup running in just a few weeks — in the middle of COVID. How did it happen?
Nicole Paulk: We had this project in my lab that back then we lovingly referred to as the “universal payloads” project — all founded around the idea of making a single AAV gene therapy to treat more than one thing.
When we started, we weren't thinking that this would be a company. It was super academic. Fast forward all these years of work, and it ended up becoming an oncology company.
But the impetus for starting Siren was COVID itself. And it's not because we were a virology lab. It was out of frustration.
Take yourself back to the beginning of COVID, where you just got told to go home and lock yourself up. In that moment, we were just hitting the zenith of this project.
Back then, we were a very in-person lab. Every single person was doing mouse work in the surgical suites, needing to be in the tissue culture room. So the project was completely stalled.
Saji: And you couldn't get permission to go back in?
Nicole: Not unless we pivoted the lab to working on COVID. But I didn't want to pivot the lab because I knew if we did, it would become permanent. I wanted to keep working on the project we were working on.
At UCSF, we were beholden to the state legislative rules and couldn’t come back. But all my friends that had startups in industry could just come back.
So I was like, what if I started a company? If I could raise some money and start a company, could we keep going back to work?
I talked to some folks in the department, and they're like, that's a whole endeavor. You don't just up and do something like that. I said, assume I could — could we come back to work? They said, “We hate this, but yes.”
So I had my marching orders. I pinged a bunch of VCs that I had been doing diligence for already, and we threw together a pitch. We managed to get Founders Fund, Lux Capital, and some of these marquee investors. But they were like, if you do this, you have to leave [academia]. You can’t just take a quarter-long sabbatical or be interim CEO.
So that was the impetus to start Siren. They were only willing to write the checks if I left and really did it. Siren wouldn’t have been here if not for COVID. It’s one good thing that came out of that whole terrible situation.
“Siren wouldn’t have been here if not for COVID.”
The power of a universal gene therapy
Sajith: Let’s talk about this universal gene therapy concept. What is it, and why do we need it for gene therapy to succeed?
Nicole: Every gene therapy on Earth, whether it's in an academic lab, a tiny startup, or big pharma, is bespoke for one disease. Meaning, an AAV gene therapy for hemophilia B can't be used to treat spinal muscular atrophy because the genetic medicine, the payload that goes inside the virus, is specific to that disease.
Sajith: So every company has to do a lot of foundational AAV reengineering from scratch?
Nicole: Exactly. I sit on a lot of scientific advisory boards, and I kept getting asked to sit in the same whiteboard meeting.
Whether it's a public company with 10,000 employees or a tiny startup with two people and a dream, they'd have their foundational IP, like a new capsid or promoter that allows them to target something in an interesting way. And we’d start walking through this process.
Like if they have a new capsid, now they need a promoter or a payload. But they don't want to pay licenses for everything — whether it’s a promoter, backbone, payload, capsid, manufacturing platform, purification platform, or delivery route. They want to own the entire tech stack.
Instead of being two years out from the clinic, now it’s six years. And now they don't need to raise $50 million dollars, it’s $500 million dollars. All of a sudden, it's ballooned into this massive thing, with a categorically different set of needs.
Everyone wanted to build the whole thing from scratch, but it all usually stemmed from the fact that they thought, no matter what, we have to change the payload.
So I thought, what if you didn't have to change the payload?
“What if you could make a gene therapy that could treat 2 or 200 diseases with the exact same drug product? Could that be possible?”
That would short-circuit a lot of the challenges: the amount of time, capital, space, and people needed, plus the regulatory burden. It all stems from this seemingly very simple idea that we have to change the payload every time.
Sajith: So scientifically, how does that work?
Nicole: We took a step back and thought, is there anything you could put inside a virus that could treat more than one thing?
What can modulate cell signaling, cell interactions, cell behavior, and cell states, that can also work in adults and kids, across different developmental time points, tissues, and disease states? We started making a list of things that we're interested in, like transcription factors and cytokines, and just started testing them.
Sajith: Is this still in academia?
Nicole: This is still pre-startup. But very soon, we realized we were interested in cytokines. They’re really interesting because they're very pleiotropic, with activity in oncology, autoimmunity, infectious diseases, and all kinds of things. That’s the moment when we decided to spin out.
We didn't have a named development candidate, but realized that engineered cytokines and oncology were a good place to start. We were heads down for three years, figuring out which one of these would be our first universal asset.
The nice thing about cytokines is they're basically retraining your immune system to fight cancer. As we’re talking right now, we both have a tumor. We've had one every day of our lives. It was an individual cell, and your body is doing basal background cancer immunosurveillance mediated by the healthy cells around that tumor cell, which are sending out little cytokine signals to your immune system to investigate any suspicious cells.
Your immune system gets that little signal — that “siren,” hence the name of the company — and it comes to the site and chews the cell up.
“Basically, we’re using viruses as the “delivery truck” rather than delivering cytokines themselves, which can have a half-life of single-digit minutes. The virus itself has no anti-cancer activity. It's just an engineerable FedEx truck to deliver packages, and the package happens to be the cancer drug.”
Chasing bold (sometimes unpopular) ideas
Sajith: You've built your career chasing bold ideas. In grad school, your PhD adviser warned you not to go into gene therapy. What gave you that conviction to find funding anyway?
Nicole: My undergrad was in medical microbiology. I was already enamored with the idea of using viruses as medicines. I’d read a bit about gene therapy and thought, this seems so cool!
Saji: This is the early 2000s?
Nicole: Timing-wise, there was stuff happening in academia, but there were no commercial gene therapies yet.
I joined Markus Grompe's lab at OHSU, and he was the Director of the Oregon Stem Cell Center. I asked, “What if I did something with viruses?”
Almost as a joke, he said, “If you go find some money, but otherwise I've got all these grants to study stem cells. I need to pay you to study stem cells.”
So I went out and got every last scholarship, fellowship, and grant that you could possibly apply for — including ones that I wasn't even technically eligible for.
Then, because the field wasn't very popular yet, there was all this fundamental stuff to do.
There wasn't a lot of competition. I think I published six papers in three years.
Sajith: Did your advisor like viruses after that?
Nicole: Papers are currency in academia. We were publishing really well, so about halfway through my PhD, he was all in.
It was also right at that moment when everyone heard about gene therapy for the first time. It was in the news: gene therapy companies were starting to infuse humans with viruses, and that was the data from Spark Therapeutics for Luxturna, which became the first FDA-approved AAV gene therapy.
When I started my postdoc and then my academic lab at UCSF, there were maybe a dozen of us who were famous. We got to have an outsized impact, despite the fact that there weren't many of us.
Sajith: A lot of first-year PhD students would probably just do what the lab is doing. What made you keep going on?
Nicole: A combination of stubbornness and being a big, geeky nerd who just thought it was so cool.
Why startups should still write grants
Sajith: You've said that no matter what's happening in the market, grants will always be there. Is pursuing research grants still worth it in your opinion for early-stage startups?
Nicole: Without a doubt, unquestionably.
I can't imagine a world where you aren't writing grants, and I think absolutely everybody should, whether it's a federal grant, state grant, from a disease foundation, vendor, or global entity.
Grants have this amazing ability to force you to laser focus and actually think through your idea before you get started.
Sajith: It forces you to write a narrative.
Nicole: You have to build an entire story around why this is needed, why it’s important, why now, why I’m uniquely suited to this. And then also the exact experiments.
When someone asks me, what's going to be your use of capital? I can tell you down to the dollar, because I've quoted it with the exact vendors we’d use, the exact study designs, and the exact number of tissues that we’d harvest. It gives you a level of granularity that is impossible to do without having done that exercise.
It also allows you to see blind spots, not just in the experiments, but for your company. It's kind of like in academia: the best papers are the ones that you pre-write before you start. Like, what are the figures gonna be?
Everything else is just noise, and I'm not going down that rabbit hole. In this market, no one’s going to give you money to run your cute side experiments.
You have to stay laser-focused on the near-term derisking milestones to keep inching towards the clinic.
“There's no more clarifying thing than writing it all down. So you might as well write a grant and get some non-dilutive money.“
It’s maybe $5 million dollars that we've brought in non-dilutive money already, to date.
Sajith: $5 million is like a series A for most companies.
Nicole: You can do a lot with $5 million.
Crowdfunding for biotech
Sajith: Siren became the first therapeutic company to crowdfund, raising $1 million in the first week. There’s not a huge precedent for this in biotech, and honestly, some people probably have a negative perception of crowdfunding. Why was it so important to you?
Nicole: It happens in tech, but definitely not in biotech. I hadn't even heard about it prior to last January.
A private company can raise up to $5 million dollars every 12 months from non-accredited investors every year. I didn't believe it; I had to call our corporate counsel. They said, it’s not normal, but it is a thing you can do. And I thought, well, we have to run this experiment.
Sajith: Did you feel like there were hundred-dollar bills on the ground? Like, why isn't anyone picking it up?
Nicole: I didn't know if it would work. Could anybody be interested in a therapeutics company given the timelines?
But wouldn't it be cool if we brought a bunch of patients onto the cap table? They personally want this to work in a way that no VC could ever, personally and intimately, have that kind of conviction.
Sajith: Sounds like it was a hit.
Nicole: People really liked it. Now we definitely know that it works. You're still going to need institutional VCs; this is still an expensive business. But this is an additional thing you can do.
Sajith: That's so cool. More biotechs should do this.
Making it in today’s market
Sajith: You've been on a lot of scientific advisory boards. What have you learned about what institutional investors look for in biotech companies, especially as the market's changed?
Nicole: There's how I would have answered that five years ago, and there's how I would answer it right now in this unbelievable market.
Companies are going to have to evolve into ones where you can go from concept to FDA-approved drug in four years. And you're going to have to do it for not $2 billion, but $50-100 million.
Given what's happening with AI, China, and expectations to be competitive, what can you do as a company to get ready for that?
It's a wholesale reimagining. I still get asked to do diligence, and everyone's still doing an NPV [net present value] of $1 million. But by the time a gene therapy is ready to hit the market six years from now, there is no way it’s going to have a list price of $1 million dollars.
Sajith: No one's going to pay for that.
Nicole: The first 20 or 30 gene therapies will get to do that, but the 300th gene therapy will not.
Sajith: It has to get cheaper. That's how technology works.
Nicole: It's not just the founders who haven't accepted it yet. It's all the VCs, bankers, private equity firms, and just the whole industry. All the vendors still assume they can charge X dollars for a bottle of media or a GMP run, because no matter what, the company’s going to raise a billion dollars.
“No one is ready to have the conversation that we all need to alter our expectations. Speed and cost have to change by whole-digit orders of magnitude.”
Heading to the clinic with a team of six
Sajith: You've been super capital efficient. If I understand correctly, you’re almost at the clinic. How many full-time people do you have?
Nicole: Six. I think that's the new normal, though. That's what it's going to need to be.
Sajith: How does one get to the clinic with six people? How can more biotechs do that?
Nicole: Be brutally efficient. We only do things that we’re uniquely qualified to, and must, do in-house at Siren.
Sajith: What's an example of something you outsource that a lot of people would do in-house?
Nicole: We do things in-house that we want to eventually tech transfer. Obviously, any discovery is still happening with us. But for the most part, we want to get it perfect inside Siren and then tech transfer it to a CRO or CDMO as fast as we can.
Sajith: Do you think companies keep stuff in-house too long?
Nicole: Too long. They want to own everything.
They want an in-house capsid engineering team, an in-house promoter engineering team, and their own electronic lab notebook, because they want to own the whole tech stack.
Don't try to be everything. Move as fast as you can in this narrow thing and just get to human data as fast as you can.
“Let the people who are pros do the thing they're pro at. You do the thing that’s special and uniquely you — and only that. Everything else you should be outsourcing, licensing, or collaborating on.”
Sajith: What are the roles on your six-person team?
Nicole: I am the only C-suite.
Sajith: I love that, because that's a ton of burn, typically.
Nicole: For sure. What’s one way that you can tell if a company is gonna succeed or fail? If I get a deck and the first 10 hires are all C-suite — before you have scientists, a space, or even a concept.
How do you need a Chief People Officer on day one? They're super important, but for 10,000-person companies, not 30-person companies. You don't need that.
Sajith: So you're the only C-suite. Is everyone else a scientist?
Nicole: We have a bunch of scientists, and then we've got one person in charge of viruses and one person in charge of animal studies. That's the whole company.
Sajith: Because those are things that you will live or die by, basically.
Nicole: They are unequivocally essential to the company. Everything else is a consultant, vendors, or in collaboration with other groups. We have six full-time people, and that's all we need. Maybe as we start the clinical trial, we'll hire one more person.
The future of gene therapy
Sajith: At SXSW, you predicted that we'll all have a viral gene therapy in our lifetime. What is the biggest bottleneck to making that happen today?
Nicole: The entire field needs to have a “come to Jesus” moment. How are we going to exist in this modern time, where money is not free, and there are folks chasing at your heels, China and otherwise?
Sajith: So it's not even about gene therapy; the whole R&D complex needs to get rebuilt.
Nicole: It's one thing for me to say I'm going to be really capital efficient, but I can't do that if my CDMO and CRO are charging $20 million for IND-enabling animal studies. We need to collectively have this conversation, and I don't think we're having it yet.
“If I could make a wish, it would be getting all the CEOs, VCs, and regulators in a room. We all have to right-size our expectations to something that’s realistic for the moment — but we all have to do it together.”
We also need to come up with a strategy collectively, as the United States. Like, what is our answer for China?
Sajith: When you first started your lab, you specifically were looking for challenges that were too long-term and high-risk for industry. Do you believe that the early concept for universal gene therapy could have only come out of academia?
Nicole: For sure. With this macroeconomic market, there is no way someone would give you money to just tinker around. I don't think that’ll happen anymore in industry. Those types of things have to happen in academia.
“Industry is great for taking an idea and advancing it, like these incremental things. But you need the blessing of time that academia gives you to really tinker.”
The truth about leaving academia
Sajith: Talk to me about leaving academia. How did people react?
Nicole: A lot of people asked, why would you do that? Why wouldn't you just sit on the scientific advisory board and keep spinning things out?
Sajith: Was that ever an option to you? What was the decision-making process?
Nicole: It was a very purposeful decision. Some people can do it well. There are the big famous labs, like David Liu, George Church, and Feng Zhang, that do it well. But I think the vast majority of labs do it poorly.
The average academic lab that spins out companies does it in a horrible way, where you have this conflict of interest. You've got scientists at the company making $130,000 a year, while students make $40,000 and need to publish for their careers. So what do you do if a student discovers something negative for your company? I've seen professors say, let's just not present that. I decided to completely extricate myself because I don't ever want to put a student in that situation.
Sajith: You said that being a CEO is 10x harder than being a professor, but you have no regrets. What surprised you the most about being a CEO?
Nicole: It was surprising how it was exactly the same as being a professor, and also zero percent the same as being a professor, at the exact same time.
The single most important thing is to find money. That is unequivocally your job at both of those roles.
The next most important thing is to find the smartest, best people in the world and convince them to work with you. Once you've got them in your lab or company, make sure that all the roadblocks are out of their way. Is it that they need access to money, equipment, or a sample? Get the roadblocks out of their way so that they can do the best science ever.
Go out and evangelize your story to the world and tell everyone it's the coolest science that has ever existed, and it's the most important thing on the planet. All of that is the same.
I was surprised how well being a professor cued me up for being a CEO, because everyone tells you they're totally different. But there's a lot of overlap.
“There’s a gut reaction that someone coming from academia is inherently going to be a bad Founder or CEO, but I would push back on that.”
Sajith: What’s been surprisingly different or hard?
Nicole: Everyone tells you that industry is faster, but I don't even think I knew how fast I could move.
You get out in industry, and it’s like, “You want me to do it in one-tenth the time? That's not possible.” And then all of a sudden, you realize, it is possible.
Sajith: Could academia speed up?
Nicole: It just needs money. It also takes unrestricted time. In academia, you just have all these distractions. You have to teach courses, sit on committees, and review someone's PhD thesis. When you don't have all this bureaucracy, you can be laser-focused on this one thing.
It's also finally a team sport. Academia is super brutal, cutthroat, and individualized. In industry, we really are a team. It’s just so much more fun.
Sajith: You walked away from a dream job and basically took a leap off a cliff. It’s a superpower of yours from what I can tell. But have you taken any big risks that haven't worked out?
Nicole: My anti-CV is ten times longer than my CV. It’s all things that you didn't win: the papers that you submitted that didn't go anywhere, the grants you didn't get, the awards you didn't get. The number of things I have not gotten is so much longer.
Sajith: It sounds like you’re very comfortable with rejection.
Nicole: You have to be. You have to be okay with people telling you to your face, “This is a terrible idea.” Or, “I do not want to fund this grant.”
Sajith: Maybe that's the lesson that people should have. If they haven't heard that a lot, people are not taking enough risks.
Nicole: You're not taking enough risks if you're not getting told “no” a lot.
The best ideas are unpopular
Sajith: You've talked about how it takes a level of obsession to bring an idea into reality. What advice do you have for a scientist who has an idea that people think is crazy?
Nicole: You have to get comfortable being uncomfortable. The vast majority of people aren't going to like your idea, and that's okay. Because if everybody thinks it's a great idea, it's probably boring and incremental — and something obvious that China’s probably already working on.
Not everyone is going to love your idea. In this market, you probably have to talk to at least a hundred VCs before you get even one term sheet. Just get the money, get to work, and you can worry about valuations later.
And it's okay if it all doesn't work. You can riff on it and start something else. You don't have to wrap up your whole self-worth in this one company. Just lower the stakes, and get cooking.
