Craig Crews, Ph.D., does some of his best thinking during early morning jogs along New Haven’s Mill River. The two-mile run along the river that meanders through woods and marshes near his home in the East Rock neighborhood allows Crews’ mind to wander—and to fix on new ideas.

Those ideas feed his work at his lab on Yale’s Science Hill, where his team of 18 researchers is inventing science at the intersection of biology and chemistry. Their goal is to transform medicine with a radically new approach to treating disease.

His morning runs also take him to the earliest days of industry in New Haven, past the Whitney Armory where, in the late 1700s, Eli Whitney produced one of the seminal ideas of the industrial revolution—the notion that things could be manufactured more reliably and efficiently by using interchangeable parts. Crews has always admired the pioneers of industries, including Whitney and Thomas Edison, and he’s proud that his hometown has been at the forefront of one industry after another, from guns and clocks to horse carriages and hardware. “Here in New Haven there’s a long history of practical innovation—embracing technology and having an impact,” he says.

In fact, Crews is cut from the same cloth as Whitney and Edison. He is not only a leading medical science researcher, but also an entrepreneur. Arvinas, the company he started four years ago, uses ideas from his lab to develop therapies for treating cancer. Crews also helps other Yale researchers—and their inventions—make the journey from the lab to the marketplace.

The manufacturing industries of New Haven’s past have faded or disappeared, and today’s primary drivers of the local economy are Yale University and Yale New Haven Hospital. Together, they employ more than 24,000 people. But for years, leaders at Yale and the city have encouraged the rise of a new industry, biotech, to stimulate job growth and economic dynamism. And, since medical science research is the essential ingredient for fostering a biotech industry, and health care is essential for a high quality of life, they see Yale School of Medicine at the center of things. “We want to create a seamless economy of health care, and over a 60-year period the city has had a series of successful strategic plans to accomplish this, to link innovation to commerce, and the city and the medical campus to downtown,” says Matthew Nemerson, M.P.P.M. ’81, New Haven’s economic development administrator who started his career in the city in 1983 as the first head of development for Science Park.

New Haven’s biotech community has seen fits and starts, but today it is achieving critical mass. Upwards of 50 biotech and medical device companies employ more than 5,000 people in greater New Haven. Venture capital firms and large pharmaceutical companies have invested more than $700 million in startups—and these startups have attracted another $5 billion in equity investments. Yale, the state, and the city have established programs aimed at helping student and faculty inventors become entrepreneurs. And New Haven itself has become a more attractive place for young scientists and engineers to live. More than 2,000 housing units have been built or renovated in or near the downtown area in the past decade, so people can walk to the city’s abundant museums, theaters, pubs, cafés, and restaurants.

Optimism is on the rise. More than 300 entrepreneurs, faculty members, students, investors, real estate developers, government officials, and Yale administrators turned out for the Dec. 13 holiday party of Connecticut United for Research Excellence (CURE), the bioscience industry’s advocacy group. CURE president Susan Froshauer, Ph.D., FW ’89, an entrepreneur-in-residence at Yale’s Office of Cooperative Research where she’s working on two Yale startups, later said that “the energy was the best I’ve seen. People were effervescent with hope.”

Challenges remain, however. Growing biotech companies have insatiable appetites for laboratory space. Tweed New Haven Airport needs an upgrade to make it easier for venture capitalists and pharma company executives to get to the city. New Haven still has an image as a crime-ridden city, a reputation that could deter scientists from moving here. And then there’s government funding. If politics and budget pressures reduce funding of basic research at Yale, the biotech engine will sputter.

For New Haven’s biotech industry to grow and prosper, more collaboration is required involving Yale, the state, and city governments, real estate developers, local schools, venture capitalists, and educational leaders, says William Ginsberg, president of the Greater New Haven Foundation and a member of the board of Yale New Haven Hospital. “I’d like to see a very clear leadership strategy for the entire community,” says Ginsberg, who first envisioned a biotech industry emerging here when he was the city’s economic development director in the 1980s.

Nothing embodies the coming of age of New Haven’s biotech industry more than the shiny new 14-story tower at 100 College Street with the name “Alexion” emblazoned across the front. Former faculty member Leonard Bell, M.D. ’84, launched Alexion Pharmaceuticals in Science Park 25 years ago—based on his research at Yale. The company develops drugs for combating very rare diseases. He left the university to become the company’s CEO, and only recently retired. Alexion quit New Haven for Cheshire, a suburb 17 miles to the north, 15 years ago, but when it needed to grow again and was lured by government incentives, it returned to its roots in 2016. Approximately 1,000 people work at the global headquarters in New Haven and Alexion expects to continue to grow in Connecticut. “New Haven is a changed place,” Bell explains. “And we believe our success and our presence here will be great for Yale, for the community, and for people who want to locate here.”

The building at 100 College Street spans Route 34, so it bridges New Haven’s downtown and the medical school and hospital. The crossroads location brings new attention to the shared interests that bind town and gown. No one is more aware of that interplay than Robert J. Alpern, M.D., dean of the School of Medicine and Ensign Professor of Medicine. And while he believes that the most important thing the medical school can provide for New Haven is outstanding medical care, he’s also attuned to the benefits that come from research funneling into local startups.

But rather than abandoning their labs to become entrepreneurs, Alpern says it’s preferable to stay in the lab and advise the biotech companies that license inventions and take them to market.

Craig Crews provides a model for that approach. Like 100 College Street, Crews is a bridge between the university and the business community. He spans the two worlds, but he still lives in the lab.

Focusing on impact

For bioscience innovations to have a major impact on society, there are two essential elements: great ideas and great ambitions. Crews has both.

He joined the Yale faculty in 1995 at a time when deep explorations of the interface between chemistry and biology were just beginning. (He’s now the Lewis B. Cullman Professor of Molecular, Cellular, and Developmental Biology, with appointments in the departments of chemistry and pharmacology.) Soon after he established his lab, Crews hit on the big idea that has shaped much of the work since then. At the time, scientists were exploring the use of chemicals from nature as models for developing cancer-killing therapies. Crews and the team studied natural compounds, and armed with those findings, tweaked the human body’s ubiquitin/protease system to attack diseases at the cellular level. They created synthetic compounds that mimic nature, searching for those that would block harmful proteins or dispose of them with minimal side effects. And they struck gold.

The science harnesses the human body’s system for routinely targeting damaged proteins and breaking them down into small peptides and then into amino acids for reuse. Crews and his team developed a technology they call Proteolysis-Targeting Chimeras (PROTAC), which tags harmful proteins so they will be degraded by the proteasome—the body’s quality control system. Crews calls this a “seek-and-destroy mission.”

These days, Crews says, the most exciting project at the lab is an effort to use PROTAC technology to degrade kinases, enzymes that play a key role in cell growth and metabolism. PROTAC uses the characteristics of kinases to remove disease-causing proteins. As a result, PROTAC-based drugs may well outperform current drugs for attacking a wide range of diseases.

On a Monday morning in March, Crews took his seat at the head of a table for his lab’s weekly meeting in a conference room on the 12th floor of Kline Biology Tower. About 20 students and researchers sat on chairs around the periphery as Saul Jaime-Figueroa, Ph.D., a research associate scientist, discussed the ability of a family of PROTACS to degrade kinases. Crews peppered him with friendly but probing questions. Finally, pleased with the team’s progress, he reminded them of a core belief: “When you do anything with commercial potential, we owe it to you guys and to Yale to file for patents.”

Building companies

In popular mythology, bright young scientists with big ideas raise capital, launch startups, and become the CEO. That’s Leonard Bell’s story. And today, Bell and Alexion provide inspiration for other Yale medical researchers: become an entrepreneur, run a company, and maybe become rich in the process. But because the skills and mindset of research and business are so different, it’s the rare scientist who can make the transition to running a successful startup company.

Fortunately, there are alternative paths for researchers who want to shepherd their discoveries from the lab to the clinic. For one thing, they can launch companies, hand them over to professional managers, and take part-time science advisory roles. That was Crews’ route, first with a company called Proteolix, and now with Arvinas.

In recent years, the business model for developing new therapies has undergone a dramatic upheaval. Previously, most large pharmaceutical firms typically developed drugs from scratch, guided them through regulatory approvals, and took them to market. Now, these companies increasingly leave much of the exploratory work to research-based startups, then buy companies or their intellectual property after ensuring that the drugs have a good chance of passing muster with regulators.

The industry shift makes the relationships between academic inventors and startups even more important. As Arvinas’ chief scientific advisor, Crews participates in a 90-minute review every Tuesday morning, where he gives feedback on new directions for research. (Arvinas, headquartered in Science Park at Yale, is a 10-minute walk from his lab.) Arvinas has two therapies that it hopes to put into clinical trials next year—oral treatments for breast and prostate cancer—but the company is now looking at other diseases.

Crews is also the company’s “storyteller,” according to Sean Cassidy, Arvinas’ chief financial officer. At a biotech industry conference in January 2017, Crews explained PROTAC to potential business partners in speed-dating briefings that lasted from morning until night. According to John Houston, Arvinas’ president of R&D, Crews’ presentations were instrumental in piquing the interest of several large companies, which are now talking to Arvinas about forging partnerships.

The company already has drug development deals with two industry giants, Genentech and Merck, which have committed to investing more than $700 million. Those partnerships prompted Arvinas to boost hiring, and the company considered leaving New Haven. “We were busting at the seams,” says CFO Cassidy. Instead, they expanded into adjacent space in Science Park.

Another alternative to the quit-the-university route for researchers is taking advisory roles with one or more startups. Many biotech companies have advisory boards, but another inventor with close ties to Yale has gone a step further by including academic researchers as key players in the companies he starts.

Jonathan Rothberg, Ph.D. ’91, professor (adjunct) of genetics, was one of the pioneers of next-generation gene sequencing. Last year, Rothberg received the National Medal of Technology and Innovation from President Obama for this achievement. At his Guilford-based startup incubator, 4Catalyzer, each of his four new companies leverages genetics and advances in artificial intelligence to develop drug therapies and medical devices. And each of them benefits from a scientific advisory council that includes faculty from Yale and other elite institutions. The researchers and clinicians help identify new therapies, help design them, and in some cases, help test them in clinical trials.

One of the new companies, LAM Therapeutics, has two drugs in clinical trials. The company was co-founded by Yale geneticist Tian Xu, Ph.D., the C.N.H. Long Professor of Genetics and professor of neuroscience at Yale, and is based on technologies invented in his lab. Xu plays an active role as an advisor.

A support system for entrepreneurs

Qin Yan, Ph.D., associate professor of pathology and director of the pathology department’s epigenetics program, dreams of following in Crews’ footsteps and starting a company to take his ideas into clinical practice. Yan knows biology, but he doesn’t know how to be an entrepreneur. Fortunately, he’s getting a lot of support from Yale—and mentorship from Crews—to help him find his way.

Several years ago the university, with financial backing from the state, established the Yale Center for Molecular Discovery on its West Campus. There, a dozen chemists, biologists, and computer scientists test compounds developed by Yale and University of Connecticut researchers, for their potential as therapies. The idea is that by using this process, researchers can more quickly identify valuable molecules. That way, the researchers can focus on their work and gather the evidence they need to win backing from venture capitalists.

Crews, who was involved in setting up the center, saw that such would-be entrepreneurs as Yan needed more help, so last year he created a companion program, called PITCH, to guide faculty members toward success in biotech. Advisors help researchers draft business plans and craft their pitches to investors.

Yan says PITCH has given him confidence. “If all goes well,” says Yan, “we hope to form the company next year.”

The Center for Molecular Discovery, the PITCH program, and the Blavatnik Fund for Innovation at Yale, a $10 million grant from the Blavatnik Family Foundation aimed at fostering entrepreneurship in the life sciences, are three elements of a broader biotech agenda shared by Yale, the state, and the city. Some real estate developers are deeply involved, too. For instance, Winstanley Enterprises not only developed 100 College Street but also contributed $100,000 toward a new city partnership with Southern Connecticut State University to guide more residents into bioscience careers.

For Yale, the focus on technology transfer and local entrepreneurship began with former Yale President Richard Levin in the mid-1990s. He believed that Yale needed to engage more in the local economy. Between 2006 and 2016, 233 medical school faculty members were awarded patents—many of which have been licensed to businesses. During the past 15 years, Yale’s Office of Cooperative Research (OCR) has helped launch an average of four to five local, venture-backed startups per year. To date, more than 50 startups based on Yale intellectual property have raised more than $700 million in venture capital.

OCR and its companion program, the Yale Entrepreneurial Institute, run a wide variety of programs aimed at helping students and faculty establish companies. They make investments in startups and manage the Blavatnik Fund. They also introduce faculty to venture capitalists. The most recent major success: Lieping Chen, M.D., Ph.D., the United Technologies Corporation Professor in Cancer Research, raised $67 million last year for his startup NextCure. It was the largest initial funding ever for a New Haven-area biotech company. “We’re helping to create a density of interactions—people bumping into each other,” says Jon Soderstrom, Ph.D., managing director of OCR. “You have to have molecules bouncing off each other, because that’s how you create bonds.”

Yale supports other programs aimed at promoting entrepreneurship. For instance, its Center for Biomedical and Interventional Technology, with partial funding from the state, brings together engineers, scientists, clinicians, and entrepreneurs to develop novel approaches to address unmet health care needs. In January, about 200 aspiring entrepreneurs participated in its Healthcare Hackathon. The winner was a smartphone app that reads the facial expressions of military veterans at risk for post-traumatic stress disorder and alerts others if they show distress.

What’s in it for Yale? Not only does the university collect revenues from its patents ($8.3 million last fiscal year), but the potential for faculty researchers to participate in the startup economy is a major plus for recruitment and retention. Also, many students want to explore entrepreneurship in parallel with their studies. Rothberg, the gene-sequencing pioneer, urges the university to brand itself as an incubator for entrepreneurship, which could strengthen both the university and the community. “We have a huge competitive advantage because of the medical school and the life sciences,” he says.

For New Haven, the biotech cluster represents the best opportunity for fostering a startup economy—and creating both scientific and supporting jobs. That’s why the city has made redeveloping the land between downtown and the medical school a top priority. Alexion’s headquarters is part of a much larger initiative, Downtown Crossing, which is aimed at adding new office, residential, and laboratory space, and increasing pedestrian traffic along the Route 34 corridor. The Route 34 highway project in the 1950s cut the city in half. Now government, Yale, and the business community are knitting it back together.

For now, most of the trend lines are positive, and the people who are intent on building a flourishing biotech community in New Haven see a path forward. They speak of making the entire bioscience innovation chain, from lab to marketplace, more “systematic.” The process of inventing in the academic laboratory must become faster—partly with the help of computer simulation, artificial intelligence, and data analytics. Scientists and engineers with great ideas must learn to be entrepreneurs. And ideas, capital, talent, and lab space must be brought together more efficiently.

To Crews, New Haven possesses a historic opportunity to create a competitive advantage over other places. “The process of moving science into the marketplace can’t be ad hoc. You have to fill the pipeline in a systematic way,” he says. “It’s like Eli Whitney and interchangeable parts, or Edison harnessing creativity on an industrial scale. We have to do the same—filling the innovation gap in the pharmaceutical industry and accelerating the founding of biotech companies.”