It happens over and over again with new science. A discovery prompts crazy hype and massive investment that the data aren’t ready to support. A crash ensues, backers lose millions, egos are bruised—yet the pioneers slowly trudge forward. They regroup, away from the limelight, and try to learn from failure.
When it comes to synthetic biology—a method of modifying the genes of living organisms to effectively change what they do—James Collins knows this story better than most. He’s an MIT professor who helped found the field nearly two decades ago. He’s seen the hype, when investors placed huge bets on startups aiming to produce clean energy on a large scale; the crash, when many of those companies were wiped out and scientists fled back to academia; and the pivot, when the surviving companies shifted their sights elsewhere.
“I think we’ve recovered now, as a field,” he says.
Gone are the days when a bevy of high-profile startups like Sapphire Energy, Solazyme, and J. Craig Venter’s LS9 offered hopes of renewable, eco-friendly fuels made by engineered algae. In their wake is diversification: Sapphire, for instance, has made a strategic pivot into things like food additives, cosmetics, and nutraceuticals. But from Collins’s vantage point, something else has happened. The “clinical space,” he says, has become a dominant focus for synthetic biologists—meaning tools that could be used for medical research, diagnostics, or even “living” therapeutics like the ones Cambridge, MA-based Synlogic, a startup from Collins’s lab, is trying to develop.
Collins (pictured above) is a New York-New England hybrid. He was born in the Bronx before moving first to Bellerose, in the outskirts of Queens, and later, after he finished elementary school, to New Hampshire. He used to have a strong New York accent and, as a Queens guy, was a fan of the Jets, Mets, and Nets. (Former Nets small forward William “Billy” Schaeffer, who also grew up in Bellerose, would shoot hoops nearby.) Now that Big Apple accent is largely gone (“I joke that I’ve got a New York attitude but not a New York accent,” he says) and Collins shows a fierce allegiance to all teams Boston. He even threw out the first pitch at a Red Sox game in 2008 at Fenway Park.
Collins’s mother was a math teacher; his father an engineer who worked with the aviation industry to develop an altimeter used in the Apollo 11. That naturally led him towards engineering, but biomedical engineering in particular became his passion after both of his grandfathers became disabled—one had a series of strokes, the other went blind. “While I saw this amazing technology that my dad would share with me on shooting stuff into and out of the sky, I was struck by the lack of technology to help restore function to these two guys that I cared for very much,” he says.
Collins graduated from Holy Cross in 1987 and afterwards became a Rhodes scholar who earned a doctorate in medical engineering from the University of Oxford. As a professor at Boston University in the ’90s, he worked to develop a “genetic toggle switch,” effectively launching the field of synthetic biology. By putting such a switch inside a cell, one could program it to sense and respond to elements in its environment.
The work was published in Nature in January 2000, and since that time, synthetic biology has undergone its ups and downs. That journey yielded important an lesson that Collins says he tries to teach his students at MIT, where he is a professor in the school’s bioengineering department. It’s a challenge that Collins says students aren’t well trained for: how to recover from failure. For Collins, the key is to move on quickly, and don’t dwell. “Did your paper get rejected? Well, send it to another journal. Did your grant get rejected? Well fine, get it to another funding agency,” he says. “Be hopeful that you’ve got another possible horizon to go after.”
This is the type of thing Collins has done for years. He claims to have failed “a lot” since starting out as a young academic at Boston University more than two decades ago. Despite winning of numerous scientific awards and a MacArthur fellowship, getting tapped by Eric Lander and Lee Hood to help with the Human Genome Project in the late ’90s, and being one of the more established company creators in synthetic biology—a few recent spinoffs from his lab include Synlogic, Sample6 Technologies, and EnBiotix—he’s keenly aware of what he can’t do.
Business skills, for instance, aren’t one of Collins’s strengths. When he started college at Holy Cross in the ’80s, he thought he might complement his engineering skills with business acumen. Along with friend (and later, Hollywood actor and writer) Mike O’Malley, he “devoured” a business book called In Search of Excellence, which centered on lessons learned from a number of successful companies. The pair was inspired and launched, of all things, a small company called Dance Warehouses, a dance club for kids too young to go to the bars. Safe to say the dream didn’t last. “We poured our heart and soul and much of our money into it and it failed miserably,” he says. “So I returned to campus thinking, business probably isn’t going to be the right spot for me.”
This is why Collins serves as a scientific advisor to his startups, rather than trying to shape their strategy. For example: Atlas Venture, a Boston biotech VC firm, was interested in the work Collins and postdoctoral student Timothy Lu were doing and arranged a meeting. The researchers showed the firm a few ideas, among them a technology for making therapeutic microbes, which grabbed Atlas’s interest and formed the foundation of Synlogic. Collins had been studying the use of these microbes to treat different bacterial infections, but Atlas decided to take Synlogic in a completely different direction. The company is now developing the microbes as treatments for rare metabolic disorders, where the medical need is greater, and the clinical trials are smaller and less costly.
“My forte is not translating a project into a product,” he says. “It’s on the front end of proof-of-concept experiments to validate and demonstrate what the cool new ideas are when they come up in the lab.”
I spoke with Collins recently about his strengths and weaknesses as a scientist and entrepreneur, the ups and downs of synthetic biology, and how to press on after your big idea gets shot down. Below are edited excerpts from our conversation.
Xconomy: So early on in college you try to start a dance company and fail. How’d you go from there to being a professor?
Jim Collins: I thought I might consider entering medicine, and unofficially joined the pre-med program at Holy Cross. I took organic chemistry and really loved it. But I did something quite smart, which was that I had a chance to work at UMass Medical Center and shadow some doctors. I learned a couple of things: I didn’t like interacting with patients, and I didn’t like seeing stuff come out of patients’ bodies. So I crossed that off my list. I also grew up with nuclear war as the major threat, so I was intrigued by what a physicist—or more broadly, a scientist or engineer—could do to come up with a defense system that could shoot nuclear weapons out of the sky. But as I explored that topic, I saw that the physicist/engineers didn’t seem to be having much of an impact on that issue, and decided that probably wouldn’t be the best way I could spend my time.
I really saw that academia would allow me to do very creative work on my own terms. I could get involved with companies, with doctors, and with policy. I jumped at the opportunity when I saw the freedom to create new things, and interact and help train young people.
X: How did you end up going from engineering to synthetic biology?
JC: Tim Gardner, a student of mine, and I had become intrigued about molecular biology. We sat back and began to think about—well, could we tinker in molecular biology? Could we take molecular parts like genes or promoters or other bits of DNA or RNA and build stuff inside a cell? We spent several months thinking through what type of circuit, for, example, might be interesting to build inside a cell. And what we settled on was the notion of a genetic toggle switch [a concept borrowed from electrical engineering, in which a switch can be flipped on or off with a transient electrical signal]. We figured out how you could do this inside a cell, and thereby endow cells with programmable memory, and effectively reprogram them to sense and respond to different elements in their environment.
X: Molecular biology wasn’t your forte, though. What was it like to switch fields on the fly?
JC: it’s not easy to do. What was intimidating was, molecular biology is very, very detail rich and it’s quite challenging to work your way through either a molecular biology paper or textbook if you don’t have a background in it. So it took us awhile to have at least a marginal working knowledge to actually begin to work our way through these papers, and make contributions.
X: Given you weren’t particularly comfortable with business, why did you end up founding companies?
JC: As an undergrad, I saw that I enjoyed the notion of translating work and getting involved with business, but I learned early that I didn’t have the proper skills to run a company. I liked being involved though, and more broadly wanting to have an impact through my work. I’m always excited when we make a new discovery and we impact the academic community, and help change the way people think or inspire new and additional studies.
X: What’s the most important lesson you’ve learned stepping into the entrepreneurial world?
JC: The incredible value of getting the right people involved from the outset. The science and technology is only a very small part of the story. The team is so much more important: Who is your business leadership, and do they have the passion and experience to execute on what your scientific team has created? Who are your investors, and do they have deep pockets and the commitment to bring this company to the level that they can? You have to take your time to find the talent that can add value to the company every day. In many cases we brought on the wrong people at the wrong time. They were incredibly well-meaning and hard working, but they just didn’t have the right skill set or the experience to add value every day to the enterprise.
X: How do you deal with failure, and how do you train your students to deal with it?
JC: We fail a lot in science, and it’s something that I don’t think that students are well trained for in academia. Nobody wants to fail, but I encourage my team to fail quickly—run quick experiments to see if the general notion is going to work—and recognize that most of your ideas aren’t actually very good, and that most of your ideas aren’t going to work, or they’re not the right idea to explain the underlying actual biological mechanism even though they sound right.
X: What do you mean students aren’t well trained for failure?
JC: I think in general, the academic system is set up so that you avoid failure at all costs. If you’re a good student, it’s hard to fail in today’s system, and that’s a problem. Where I learned to fail, and I failed miserably, and repeatedly, was in athletics. In the athletic world, when you’re on the field, you can’t hide from the failure. You miss the shot, or you bounce the ball of your foot, or you don’t run a good race. I was a basketball player and a cross country runner in high school, and I always wanted to be a better athlete than I was—I didn’t run as fast score as many points, or get on the court as much as I wanted. But that was a great spot to learn how to fail and move on. When I became a young academic I was thankful I had those skills, because I failed a lot with the experiments, but I just moved on to the next challenge.
X: How would you characterize where synthetic biology is right now, and where did it go astray?
JC: We need to do a better job of explaining where we’re at, what we can do, and where we’re going. We made a mistake with the strong push toward bioenergy—it was too early, the promise was hyped up more than it should have been, and it was a mistake to think you could go from laboratory bench top demos to industrial scale as quickly as many of the startups and the investors thought they could. Many young people jumped out of academic training into companies thinking this was the next big thing, and we hadn’t even developed the education materials and programs to help train the next group.
I think we’ve recovered now, as a field. Starting about five years ago you saw many of those companies not doing so well, and people came back in academia to focus on developing the foundational platforms for the field and another set of applications.
X: So where is it ready to make an impact now?
JC: Diagnostics, and in parts and platforms. We’re seeing a resurgence in the development of tools that could impact clinical or basic research. I think an area that is incredibly promising is therapeutics—using synthetic biology for example to engineer organisms to address a range of conditions or to produce new drugs. Bio energy is going to be a stretch within the next decade, but in looking out beyond that, I think we could maybe impact that as well. And in agricultural biotechnology, we’re starting to see some intriguing efforts develop as groups are seeing what synthetic biology can do to reengineer plants and other organisms.
X: Have people effectively had to dial down their expectations for synthetic biology?
JC: I don’t think we’ll do everything that people had envisioned, but the field has great potential. We still need to learn a lot of biology. We don’t know enough biology to engineer it with the efficiency and scale that I think we all would like to.
X: So what needs to be done to move the field forward?
JC: We need improved educational materials, and maybe mechanisms that would allow more folks to readily transition into synthetic biology from different [fields]. We need technologies that allow us to engineer biology faster and more efficiently— like cheaper, faster, more error-free DNA synthesis technologies. Improved computational techniques that model and design synthetic circuits.
But the commercial space is going to help. Getting more products on the market, and more diagnostics and research tools out there, and making them available to researchers, consumers, and healthcare workers—those will become the key inflection points for the field. That’s when you really will see folks saying boy, we’ve really executed on the promise.