Ethan Perlstein never planned to be a CEO. Ever since his college research internship in a lab at the National Institutes of Health (NIH), he had dreamed of becoming a professor at a high-powered research institution. After completing his Ph.D. in molecular and cellular biology at Harvard and earning a Lewis-Sigler fellowship at Princeton, he seemed perfectly positioned to take that next step. “I was in the academic 1%,” he says.
Apparently the 1% wasn’t good enough: His 2-year job search yielded zero offers. He was stunned and unprepared. “I was in an existential rut because I hadn’t thought of a plan B,” he says.
[T]he indie label is really more about a spirit than a set of specific practices. It means doing things in an unconventional way and considering and being open to doing things that are not just the standard way of doing things.
Before he founded PLab, though, Perlstein went through some serious soul searching. After finishing his postdoc in 2012, he says, he was “in the wilderness” for about a year as he figured out what to do. He wanted to do research outside academia and industry, so he branded himself as an “indie scientist,” a title he continues to favor even now that he’s a startup founder.
What does it mean to be an indie scientist? “It’s still a very nebulous concept,” he says. To him, “the indie label is really more about a spirit than a set of specific practices. It means doing things in an unconventional way and considering and being open to doing things that are not just the standard way of doing things. There aren’t a lot of examples of people who are outside of the academic and industry monoculture, so just by virtue of not being one of those two things, you kind of fall into this catch-all ‘indie’ label. But there still needs to be more adherents doing it for it to really take shape.”
Perlstein’s early independent pursuits included renting a single bench at a facility in Berkeley, California, where he conducted his own research, which he describes as a hybrid of a legacy project from his postdoc and starting to develop what would eventually become PLab. He brainstormed with his brother, a legal entrepreneur who became a PLab cofounder. He supported himself by consulting for a startup developing a science-crowdfunding platform, and he lived off savings he had been able to put aside during his postdoc.
He also looked to the social media platform Twitter, which he had started using in 2011. Before that, he had “only thought about it in the context of Justin Bieber,” he says, but as he realized that scientists were using it for networking and sharing ideas, it became a big part of his scientific life. When he didn’t get the academic job he wanted, he “turned to Twitter as a source of solace and support—and as an opportunity to learn, … what would a plan B look like?” He commiserated with others who were struggling in the academic market and connected with rare-disease advocates. He found people he could bounce ideas off of as he wrestled with deciding on his next career move. “I really feel like [Twitter] made my transition possible,” he says.
All his research and discussions led him to decide that he should take on the more traditional role of biotech startup founder, but he hasn’t given up on “indie” science. In the long run, he hopes PLab will be successful enough to allow him to “do what I really wanted to do all along, which is to build a truly independent science institution.” He imagines something akin to the Santa Fe Institute, where researchers can go on sabbatical, interact with new people, and engage in interdisciplinary work. “But that’s kind of a long-term fantasy,” he says.
One of Perlstein’s challenges in leaving academia was figuring out how he could do research that both interested him and offered a viable business plan. “I was used to thinking about basic science programs,” he says. “I was never forced to think about how my research would apply in the real world.”
He had started thinking about rare diseases a few years earlier when, while he was doing his postdoc, his stepsister was diagnosed with one. “Having a rare disease in the family definitely made me realize that these are more than just an example that’s convenient for teaching undergrads genetics,” Perlstein says. “Once I had this personal experience it made me think, ‘Geez, what are these things?’”
As he was working to identify a profitable research direction, his thoughts “all crystallized around rare diseases.” This research area seemed to be a sweet spot where he could do intellectually exciting science that would appeal to investors as well.
He also thought he could offer a valuable new perspective. “I had been thinking about model organisms for a very long time in academia, and when I started to realize that there were all these people clamoring for their rare diseases I thought, ‘Why aren’t people using model organisms to study them?’” Most of the published work he found had been conducted in mice, with occasional studies using other standard model organisms such as yeast, nematodes, fruit flies, and zebrafish. “I spent 2013 realizing that there really does seem to be a need to do a systematic model-organism approach in rare disease research,” he says.
His plan is to screen genetic models of a single rare disease in multiple model organisms—some that already exist, others to be created—against a large library of compounds to identify those that could be optimized and refined to become treatments. PLab would then partner with other companies for clinical work. “We really want to be doing lead generation for companies,” Perlstein says. “We would stay very fiercely preclinical and find partner companies to take a candidate compound and advance it in the clinic.”
Investors seem to agree that it’s a worthwhile approach: In 2014, he raised $2.2 million. The company now employs three Ph.D. scientists in addition to Perlstein and a few other research staff.
For now, they are in the proof-of-principle phase of their work. “We wanted to make sure that we were starting with a disease we knew had a high chance of success with,” Perlstein says. They chose Niemann-Pick Type C, a lysosomal storage disease associated with mutations in two ancient genes that are well-conserved in many organisms. It “just screamed that it would be an example that would fit really well with this model organism approach.”
At this point, the Niemann-Pick Type C models have been validated, and the team is beginning the screens. On deck is NGLY1 deficiency, which was first identified in 2012. Like Niemann-Pick Type C, NGLY1—which participates in protein degradation—is present in a wide range of species.
If these two proofs of principle work out, the next question, Perlstein says, is “how do you scale? From two to four? Two to 10 … 20 … 200? The more I think about it, the more I think we jump from two to something like 200,” he says. “The whole value of model organisms is that they are lean and mean,” so once he has established his proofs of principle, ideally he will be able to use a matrix approach to efficiently tackle many rare diseases simultaneously. “The goal that I am trying to get people rallied around is that if we’re successful, we’ll have increased the rate of orphan [or rare disease] drug discovery 10-fold and decreased the cost 10-fold.”
While Perlstein never imagined himself as a startup CEO, now that he’s doing it, “I couldn’t be happier,” he says. “I feel like we’re able to blend the best of basic and applied science. … There are certain parts of academia that I miss, but the parts I miss the most I’ve tried to recreate here: things like journal club, happy hour, places where you can just kind of nerd out and be self-indulgent about the science.”
A model path?
One of the big questions Perlstein’s path presents is whether it will turn out to be rare, like the diseases he studies. “I do appreciate that I have had a lot of luck and fortune and privilege,” he says. “I’m sensitive to the quirks and idiosyncrasies of my story.” Even so, “it doesn’t feel to me like I’m an oddity or fluke. … I’ve seen too many examples of people who start from nothing and are great successes.”
It’s not for everyone, though. “It requires risk tolerance to be founder,” he concedes. “Not everyone has the stomach for that or the luxury and the background to be able to take that kind of risk. But I look around here” —the biotech incubator PLab currently calls home—“and see nothing … preventing people, if they really have the heart and desire, to set up a bench here and get started on something.”
A year in, PLab is not out of the woods. “We’ve survived the birthing process, so at least there’s that.” he says. “We’re showing the first signs that we can stand up on our own two feet.” He’s optimistic about the company’s future but knows he has to hedge his bets—as he once failed to do in his academic career. “Things could sour quickly, but … maybe I’m just saying it, but I think we’re in a tentatively firm position in terms of happiness, subject to contingencies.”