The League of Extraordinary Biologists
Eggan didn’t know what to make of the new guy. He had labored for almost two years, mostly on his own, learning nuclear transfer. And now Jaenisch was telling him to teach Hochedlinger. Eggan did as he was asked—and Hochedlinger picked it up in about four months. Then Jaenisch assigned Hochedlinger the task of solving one of the most important questions of nuclear transfer: whether all kinds of cells, not just the stem cells MIT had been studying, could be reprogrammed to make a cloned animal. A proud man, Eggan would not admit it publicly, but he had met his match in this circumspect, ambitious Austrian. It wasn’t that the two outright disliked each other—they worked side by side, drank together after work—but there was no doubt both were keeping score.
Within a year, Hochedlinger was back in his mentor’s office, claiming he’d done it, he’d proven all cells had the ability to produce a clone. While comprehending the science behind this breakthrough would take an advanced degree or two, the details are simple enough: Taking a special kind of mouse blood cell with a singular DNA arrangement—an arrangement that made it easy to track—Hochedlinger removed its nucleus, then transplanted that into a mouse egg cell. When the egg cell begat a baby mouse, the animal carried in all its cells the telltale DNA arrangement. “All I remember is shouting, ‘Yes!'” Hochedlinger says. His study was published in Nature, less than two years after his arrival in Cambridge.
Until that point, Hochedlinger had harbored doubts about his career path. His former academic colleagues in Vienna, many of them now in industry, were earning very comfortable salaries. Meanwhile, he was learning from a world-famous scientist, spending every waking hour in the lab working on his potentially revolutionary research…and earning so little that he couldn’t afford his own apartment, instead sharing a tiny Somerville hovel with roommates. After his cloning triumph, though, the money would come soon enough.
While Jaenisch’s pupils blossomed at MIT, the stem cell researchers at rival Harvard were making more-incremental gains. The school had stymied itself by spreading its efforts among its departments, medical school, and affiliated hospitals. By contrast, MIT’s team was smaller, but centralized at the Whitehead Institute. If Harvard were to have breakthroughs akin to MIT’s—and it had unparalleled resources to do so—it would need to bring together its disparate entities, harness their power and intellect for a common goal. Two of the school’s scientists set out to do precisely that.
The first was famed biologist Doug Melton. One day in 1991, he had rushed to meet his wife at Children’s Hospital. Their six-month-old son, Sam, had thrown up that morning and begun to hyperventilate. The boy lost consciousness in the ER and still doctors had no idea what was wrong. When Sam came to, a nurse took a urine sample. Soon after, the doctors told his anxious parents that Sam had juvenile diabetes.
Melton threw himself into finding a cure for the disease. A year later, that search led him to stem cells. And that in turn led him to the man who would eventually work alongside him to coordinate Harvard’s stem cell efforts: David Scadden. Scadden taught hematology at Harvard but spent most of his time as a doctor at Massachusetts General Hospital’s cancer center. When Melton met him, Scadden was developing alternative methods to treat the patients he saw ravaged by the disease.
By 2003, Scadden and Melton began talking about creating an ecosystem of sorts for stem cell research at Harvard. The complexities and ever changing nature of the field demanded as much, they believed. Melton had the pedigree to build such an organization, but needed a frontman who could raise money and charm the world outside the lab. Scadden, with his easy bedside manner and innate ability to render advanced scientific concepts understandable, was that man.
Scadden and Melton went to Harvard president Larry Summers and lobbied hard for the money to bring their vision to fruition; in 2004, Summers agreed. But their work was just beginning. They had their stem cell institute. Now they needed some fresh talent.
The first outside recruit pursued by the Harvard Stem Cell Institute was Amy Wagers. She was 30 at the time and based at Stanford, where a pioneering stem-cell biologist named Irv Weissman had accepted her as a postdoc fellow in his lab. The day they met in Palo Alto, Weissman had a pile of fellowship applications on his desk—Wagers had to peer through them to make eye contact—but accepted her on the spot. “It was clear from the moment that she started talking that she was going to be a star in this field,” Weissman remembers. “The clarity of her presentation was astonishing.”
At Stanford, she became known for refuting others’ findings so often, and so thoroughly, that her peers coined a word for it: “Wager-izing.” This sort of work did more than fact-check the field; it informed other stem cell scientists when a lead was not worth pouring precious hours and grant money into. Stem cell research five years ago (and to a certain extent today) was like a vast plot of land presumed to contain oil: Previous findings dictate where you dig. If the hole looks promising, others will soon be digging next to you. Accordingly, it’s to everyone’s benefit to know when there’s no jackpot to be found—that way, the scouring can begin anew, down more promising holes. Wagers was the one pointing out the dry wells.
She scored her biggest debunking while studying how stem cells move in the body. She wanted to see if blood stem cells, in particular, could produce other sorts of cells and thereby help treat diseases unrelated to blood, as was commonly thought. So she resurrected an investigative technique in which she surgically connected the blood systems of two mice to better observe the movement of blood stem cells between them. What she found—what set the stem cell world abuzz—was that blood stem cells could not create heart or liver or lung cells; they produced blood cells exclusively. From that day on, researchers who studied blood diseases like leukemia approached their work thus enlightened.
At the end of her postdoc, Wagers received no shortage of job offers. But when she interviewed at Harvard, “it was the gleam in Doug’s and David’s eyes that convinced me to move all the way across the country,” Wagers says. Less than a month after the Harvard Stem Cell Institute opened its doors in May 2004, Wagers was working at the Longwood medical complex.
Kevin Eggan completed his Ph.D. at MIT in February 2003, and began looking for opportunities outside Jaenisch’s lab. He had liked working with him, but the lab wasn’t really designed to support much more than Jaenisch’s vision.
One day an Israeli postdoctoral student in the MIT lab approached Eggan. “Doug wants to meet you,” he said, referring to Melton. Five or six weeks later, after more back-channel messages, Eggan walked into Melton’s office. The two chatted about how they’d both grown up in Illinois, then got down to business. Melton told Eggan how he believed it would soon be possible to use stem cell technology to create cells that actually carried diseases like ALS or diabetes, then use those cells as a far more efficient way to test new drugs. “I drank the Kool-Aid, 100 percent,” Eggan recalls. He became a junior fellow at Harvard, working in Melton’s lab. After Wagers joined the stem cell institute, so did Eggan, who set about creating the kinds of diseased cells he and Melton had discussed.Within two years, Eggan was testing numerous potential treatments on them—an achievement that earned him a prestigious MacArthur “genius grant.” In the process, he forged the kind of connection with Melton that Hochedlinger had with Jaenisch.
Still at MIT, Hochedlinger had produced his second piece of landmark research: He and a team discovered a way to basically “clone out” genetic defects in mice. With his protégé’s renown swelling, Jaenisch realized it would not be long before he would want to run his own lab.
David Scadden realized that, too, and pounced. Knowing Hochedlinger was also entertaining offers from Sloan-Kettering in New York and Children’s Hospital here, he tried an innovative idea: tying an individual donor—an old-fashioned patron—to this particular scientist. He enlisted Craig Huff, a Harvard Business School alum at Reservoir Capital Group in New York, to contribute a sizable part of the package Harvard would offer Hochedlinger. “Scadden really didn’t have to sell much,” Huff says, “even though that’s something he is pretty good at.” By 2006, Hochedlinger was at the stem cell institute.
The team was now complete. By design, each member was given a research area that would not overlap with the others’: Eggan had diabetes and ALS at Harvard; Wagers had adult stem cells at Longwood; Hochedlinger had embryonic stem cells at MGH. “The problems are so immense that it would be silly to duplicate effort,” Melton says. Truth be told, it was also to ensure harmony among Harvard’s young stars, to keep them from vying with one another. But science doesn’t care about harmony. And soon Hochedlinger would have to go toe to toe with the man he revered: his mentor, Jaenisch.