At the dawn of his career, immunologist, biological chemist, molecular pharmacologist and seven-time biomedical entrepreneur Timothy Springer thought science was a bad idea. “I was suspect of the purposes that science had been put to,” he says, “making Agent Orange and napalm.”
It was 1966, and Springer was a Yale undergrad thinking, “What the hell good is this Ivy League education? The best and brightest, the Ivy League-educated people, totally screwed up in getting us into the Vietnam War.”
So he dropped out. For a year, he lived on a Native American reservation in Nevada for Volunteers in Service to America (VISTA). He helped the Tribal Council draft resolutions, launched a 4-H club and lobbied for paved roads so kids could go to school.
Finally, he returned to school at the University of California, Berkeley — trying anthropology, sociology and psychology. Switching to biochemistry his junior year, Springer asked his advisor, scientific visionary Daniel Koshland, Jr., former editor of Science, “Do you think I can do this — graduate with a degree in biochemistry?”
“Of course,” Koshland answered.
A year later, Koshland’s lectures inspired Springer to study how changes in the shape of proteins could alter their function. With that, Springer was cast into a stream of heady graduate and postdoctoral experiences, starting in the Harvard laboratory of Jack Strominger, MD, who later won the Lasker Prize for his work on T cells and immune defense.
Then came postdoctoral work with César Milstein in Cambridge, UK. Milstein had only recently, together with Georges Köhler, developed the hybridoma technique for producing monoclonal antibodies. The work eventually earned them, along with Niels K. Jerne, the 1984 Nobel Prize in Physiology or Medicine.
Landing at Harvard Medical School in 1977, Springer began making monoclonal antibodies to advance his studies of proteins that steer the cells of the human immune system around the body. He had no intention of working with industry.
So industry chose him. His trainees eventually crossed over, and Boehringer Ingelheim and later Biogen offered to sponsor research in his lab. So Springer partnered, and his discoveries led to two drugs for psoriasis, both approved by the Food and Drug Administration in 2003.
Still, he remained wedded to academia. He painstakingly uncovered the complexity of how immune cells, particularly leukocytes, make their way out of blood vessels and into tissues during infection. The three-step model he conceived explained what goes wrong in autoimmune disease, when the body mistakenly attacks itself. Blocking any one of the three steps, Springer proved, could thwart autoimmunity’s damage by stopping the emigration of blood cells out of vessels.
“I thought ‘this is really big biology, a huge new area for drug discovery,” he says. “I needed to do something much bigger than what I could accomplish in my own lab.”
How does a scientist start an enterprise? Springer sought the guidance of someone who knew the drill: biologist, entrepreneur and philanthropist William A. Haseltine, PhD.
Haseltine was then at the Dana-Farber Cancer Institute where Springer was on the faculty and an advisor to an investment firm called Healthcare Ventures. He listened as Springer described his three-step model and how it opened the door to an entirely new class of drugs for autoimmunity.
Impressed with the concept and business plan, Haseltine invited Springer to a Healthcare Ventures board meeting. The formal presentation was non-eventful. But afterwards, standing in front of the firm’s founder, Walter Steinberg, Springer fired up a VCR movie of the three-step process. As the tape played, he yanked out a Silly Putty-like ball, lobbed it at the screen and exclaimed, “See that? That’s how the cell rolls in the circulation.”
Steinberg didn’t understand the ins and outs of leukocyte adhesion, but the silly prop and the unbridled passion of an unconventional scientist-entrepreneur got his attention. He turned to another partner and said, “this guy is really crazy; We have to start this company.”
And so Healthcare Ventures backed Springer’s idea — to the tune of $10 million — and LeukoSite was born in 1993. Confident in the technology, Springer fought hard for a 20 percent stake — valued at $2.5 million dollars.
“Do you think you’re worth that much?” the venture capitalists countered. Springer, whose annual salary at Harvard at the time was $25,000, answered, “Yes, I do.’”
Four years later, the company went public with multiple drugs under development, three of which would be approved by the FDA. In 1999, LeukoSite merged with Millennium Pharmaceuticals and the stock value surged to $10 billion. At the peak, LeukoSite’s portion of Millennium was valued at $3.5 billion.
Although his initial 20 percent stake had been diluted, it was “more money than I’d ever had,” Springer recalls. “I began to wonder: How does this affect what I do in life?”
Springer decided to double down on academics. Recruited by Fred Rosen, MD, as VP of the Center for Blood Research, Springer in turn helped recruit an extraordinary collection of prominent scientists under the umbrella of Harvard Medical School. He entered new fields of structural biology and single-molecule biophysics. (The Center eventually became the Immune Disease Institute (IDI) and later the Program in Cellular and Molecular Medicine (PCMM), merging with Boston Children’s Hospital in 2012.)
Then, one day, he had a visit from IDI immunologist Ulrich von Andrian, MD, PhD. Von Andrian, who Springer had hired, had founded a company that was making vaccines and immunotherapies from self-assembling nanoparticles. He wanted Springer to invest in the second round of funding.
Intrigued by the science and confident in the scientists, Springer agreed. Immediately von Andrian’s co-founder Omid Farokhzad, MD, a leader in drug delivery and targeted nanotechnology, called up other potential investors, saying “Look guys, you can stop doing your due diligence. Tim Springer has decided to invest.”
Next came PCMM investigator Derrick Rossi, PhD, pitching the concept of using modified RNA to make induced pluripotent stem cells, manipulating adult cells back to their quasi-embryonic origins. Again intrigued, Springer became the founding investor in Moderna Therapeutics, which now focuses on using nanoparticles or other vehicles to shuttle messenger RNA into cells, thereby using the body’s own cells to make therapeutic molecules and vaccines.
With $800 million in the bank, an impressive patent portfolio and potential therapeutics in clinical trials, Moderna is today valued at $3.5 billion. “It is hands down the most valuable private biotech company ever formed,” Springer says. In June, Moderna teamed up with Merck to develop personalized cancer vaccines, a deal with an upfront cash payment to Moderna of $200 million.
Springer has since launched or helped launch four more companies: Editas Medicine, Scholar Rock, Morphic Therapeutics and Ab Initio. But finding his greatest passion lies in his idealistic and scientific roots, he recently incorporated a nonprofit dubbed, for now, the “Institute for Protein Innovation.”
The Institute would develop “synthetic” monoclonal antibodies, traditional antibodies with inserted snippets synthesized chemically. In Springer’s vision, researchers would design inserts to create diverse libraries of antibodies, pre-selecting those with the most “developability” as therapeutics.
Ultimately, the antibodies would target the products of each of the tens of thousands of genes revealed by the human genome sequence, helping unveil their action and importance in disease, forging — as Springer puts it —the “missing link” between genomics advances and health care. The Institute would serve as a “foundry for molecular tools” to probe the molecules important in disease. Doled out open-source, these same tools could serve double duty as leads for new drugs.
Beyond its products, the Institute would house a program to incubate the clever ideas and entrepreneurial dreams of young scientists seeking to impact the world with devices and therapeutics — scientists like Springer 40-plus years ago. Through this program, Springer hopes to overturn the view that startups are rare and mercenary and that scientific entrepreneurs must be endowed with special skills and “sell out.”
Meanwhile, Springer is back at the bench at the PCMM and the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, guiding his own team to new frontiers beyond the three-step model of immune-cell exit from blood vessels.
“I love business,” he says. “I’m very excited about all my companies and the Institute. But I still love the science best.”