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MIT Better World

By Leda Zimmerman

“You didn’t want to get off the T at Kendall Square,” she says. “I got lost among the parking lots and gravel pits, and it seemed dead.”

Fast forward 20 years: Kendall Square is one of the hottest stops on the Red Line, a boomtown for biotech and other innovative industries. It’s a transformation spurred not just by pharmaceutical industry giants like Novartis and Pfizer, but by MIT scientists and engineers like Koehler, the Goldblith Career Development Professor in Applied Biology in the Department of Biological Engineering, member of the Koch Institute for Integrative Cancer Research, and associate member of the Broad Institute of MIT and Harvard.

In 2017, Koehler cofounded Kronos Bio, which is developing tools to take on recalcitrant cancer targets. She is among a new wave of MIT faculty and researchers launching spinout companies a stone’s throw from their academic laboratories.

“Kendall Square is the center of the universe when it comes to biomedical research,” says Alec Nielsen PhD ’17, CEO and cofounder of newly launched Asimov, a company designing microprocessor-like biological circuits for applications in food, materials, and therapeutics. The company, like Kronos Bio, is located in LabCentral, a 100,000-square-foot, nonprofit Kendall Square coworking facility that serves as a biotech launch pad. (Among LabCentral’s cofounders is MIT alumnus and Cambridge Innovation Center CEO Tim Rowe MBA ’95.)

“You can feel something special here,” says Nielsen, a research affiliate at the Department of Biological Engineering. “People are incredibly driven, working on ideas that are going to change the world, and they want to be in the middle of this nexus of innovation.”

Even biotech business veterans appreciate the new energy: “Kendall Square feels like the Silicon Valley for biotech, and is certainly the place people and companies want to be,” says David Bartel, professor of biology and member of the Whitehead Institute for Biomedical Research, and cofounder of Alnylam.

Seventeen years after its founding, with 750 employees, Alnylam might be considered middle-aged. “But we still have a startup culture,” says Bartel. With tools based on RNA interference (RNAi), the company has just achieved commercial release of its first drug and is in late-stage trials for medicines to treat hemophilia and high cholesterol.

Alnylam can trace its lineage to Biogen, one of the very first biotechnology firms. Cofounded in 1978 by one of Bartel’s fellow Alnylam cofounders, Institute Professor and Nobel Laureate Phillip A. Sharp, Biogen has focused on therapeutics for such diseases as multiple sclerosis, leukemia, and lymphoma. Today, it is a sprawling multinational with revenue upwards of $12 billion. But it still makes its home on Binney Street in Kendall Square.

Limits of the lab

In an industry where surviving beyond the first year can be a challenge, Biogen’s success might appear a beacon for the latest generation of biotech founders. But according to MIT entrepreneurs, spinning out a startup is less an issue of reward than a matter of driving forward a mission.

“I didn’t have a burning desire to start a company,” says Bartel. “But our research suggested we could use our RNAi technology to block production of disease-causing proteins, and we saw that we couldn’t accomplish this in the context of an academic lab.”

Venture capital groups (VCs) also saw the potential, and encouraged the scientists to start a company, recalls Bartel. “They came to us and made it easy for us to continue our academic research and just focus on the science.”

The basic discoveries that gave rise to Alnylam involved the biochemical mechanisms behind the control of gene expression. In labs at MIT and elsewhere, Alnylam’s principals figured out how to harness a natural, biological pathway in which short RNA molecules target messenger RNAs producing proteins, including proteins that underlie a number of disorders.

“We were hoping this technology could be used to help patients with diseases for which there were no drugs available,” says Bartel, whose cofounders in addition to Sharp include Paul Schimmel PhD ’67, the John D. and Catherine T. MacArthur Professor of Biochemistry and Biophysics Emeritus at MIT, and former MIT postdocs Thomas Tuschl and Phillip Zamore. “And the scientists at Alnylam, who all share this dream, have begun to make it a reality.”

Alnylam’s therapeutics come in the form of synthetic RNA molecules that reduce the production of disease proteins. Designed to find their way into the liver—a production hub for proteins integral to regulating cholesterol, blood pressure, and other physiological processes—some of these drugs under development can knock down a disease-causing gene for three to six months. The company has just released Onpattro (patisiran), a drug that treats a rare disease involving protein buildup in organs—marking the first approval by the US Food and Drug Administration of a therapy based on RNAi.

Map showing MIT-founded companies in Kendall Square

A bolt from the blue

“What I’ve always cared about is coming up with a path to translate ideas and inventions from our group to the wider world via some vehicle,” says Koehler. “We see ourselves as tool builders, running proof-of-concept experiments in an academic environment, and every once in a while, lightning strikes.”

The research that galvanized the launch of Kronos Bio evolved over the course of a decade. Koehler, who is a founding member of the new MIT Center for Precision Cancer Medicine at the Koch Institute, had been working on a technology to help identify compounds that might interact with certain proteins. Using robotics, she could print minute quantities of drug-like compounds, 10 to 20 thousand at a time, on a glass slide, and then analyze swiftly whether any of these compounds interacted with a protein of interest introduced onto the slide. The tool, called a small-molecule microarray (SMM), was essentially a drug screen on a chip.

“With this chemical probe discovery, we could look for pinches of magic dust that would modulate the function of the protein,” she says.

But Koehler found an even neater twist on this technology. She could use her arrays to screen not just for any proteins, but for those most challenging from a drug discovery perspective, such as transcription factors, which determine when genes get turned on and off. A specific target of her work was MYC, a prolific oncoprotein associated with solid cancers and leukemias.

“MYC is like Bruce Banner,” Koehler says. “It regulates normal cellular function but when something goes wrong, it turns into the Hulk, wreaking havoc in cells.”

The platform Koehler designed could deliver high-throughput testing of hundreds of thousands of compounds with the potential to block MYC and other previously intractable targets, such as the androgen receptor, a transcription factor whose dysregulation can lead to prostate cancer. Recognizing the potential of this technology, big pharma companies and VCs came knocking.

Uncertain of the best way to move her research forward toward real-world applications, Koehler applied for a grant from the MIT Deshpande Center for Technological Innovation. “Mentors there gave us critical advice on patents, hiring, the scope of what to commercialize, and what we needed to do on the academic side before discussions with outside funders,” she says. “This kind of granular involvement, advice, and input really enabled me to think about translating my ideas.”

Koehler also found “an MIT guy whose vision aligned with mine,” she says. Chris Wilfong MBA ’12, operating partner at the VC firm Two River, is now chief operating officer at Kronos Bio. Since settling into LabCentral space in late 2017, the company has moved swiftly to develop “hits” from Koehler’s SMM platform into potential anticancer therapeutics.

“It’s amazing to see how Kronos professionals wearing the hat of medicinal chemistry have advanced these compounds,” says Koehler. “In just a couple of months, they’ve reached a stage that an academic lab could never have reached.”

Asimov co-founder Christopher Voigt. Photo: M. Scott Brauer
David Bartel, a co-founder of Alnylam. Photo: Gretchen Ertl/Whitehead Institute
Kronos bio co-founder Angela Koehler. Photo: Maria Nemchuk
From left: Alec Nielsen PhD ’17 and Raja Srinivas PhD ’17 are cofounders with MIT professor Christopher Voigt of biotech startup Asimov. Photo: Monique Brouillette/MIT Technology Review

Ideas that could change the world

For Christopher Voigt, the Daniel I.C. Wang Professor of Biological Engineering and cofounder of Asimov, a spinout can be liberating. “You take what starts as a crazy idea and see it fully implemented, which frees you to pursue higher-risk research,” he says. “What might have been simply an academic paper can turn into something with impact.”

Asimov’s technology is a pathbreaking platform for computer-aided design of genetic circuits for the purpose of creating new biological constructs.

“We’re the first to focus on design automation in biology, and no one else is doing anything like it,” says Voigt. Where other companies might place genes into cells to make one product, or turn a single gene on or off, the Asimov platform “goes after the dynamics of gene expression, turning a sequence of genes on and off at certain times, in certain conditions,” in a process that mirrors the way nature operates “to create complex structures, intricate materials, and delicate organisms,” he explains.

It is a singular, foundational toolkit that will make significant and wide-ranging impacts, predicts Alec Nielsen.

“We could engineer living cellular therapeutics and patrol the body for disease, or make smart plants that sense extreme climate change conditions like drought or cold and respond appropriately, or set up enzymatic assembly lines in cells to create complex molecules,” he says. “Our stance is that 50 years from now, every single new biotechnology will have engineered genetic circuits running.”

As a graduate student, Nielsen accompanied Voigt to MIT from the University of California, San Francisco, to pursue this work. A self-described technological optimist, Nielsen spent six years learning to harness the dynamics of gene expression and devising a programming language for cells much like that used to design circuits for semiconductors.

“On our platform, the cell boots up a sequence like a computer boots up software,” explains Nielsen. “The cell is now imbued with new functionality.”

The Voigt lab made a point of ensuring that the designs would work as expected, where the software could reliably design DNA that would function in the cell as simulations predicted. Having proven the efficacy of the platform, the researchers recognized that they had “reached the point in the life cycle where the idea required implementation,” in Voigt’s words. It was time to start a company.

Nielsen, who had earlier participated in the MIT $100K Entrepreneurship competition, took the leap. “In my mind, the question had always been what would be the best way to make a positive impact in the world through synthetic biology,” says Nielsen. “I had been focused on the academic track, but after a lot of soul searching, I felt confident a company would be the most impactful way to disseminate our ideas in the world.”

With funding and strategic guidance from the legendary Silicon Valley VC firm Andreessen Horowitz, CEO Nielsen, just two years out from receiving his doctorate, is rapidly staffing up and refining the design platform. Having recently inked the company’s first deals, Nielsen expresses near-boundless enthusiasm for Asimov technology.

“One hundred years from now a lot of the most interesting applications of engineered gene circuits will be things we can’t predict, in the same way it was impossible to imagine things like mobile phones or Instagram at the start of the semiconductor era,” says Nielsen. “I think it’s hard to overstate how important biotech will be this century.”

Nielsen already anticipates outgrowing his startup space. “We’ll soon be busting at the seams and will have to find our own headquarters,” he says. “We’re looking at Kendall, because it’s the place to be.”