The League of Extraordinary Biologists
What it’s like to be young, brilliant, fawned over by multimillionaire investors, courted by universities and corporations around the world, and forever racing—sometimes as teammates, sometimes as rivals—to change medicine as we know it.
The Squealing Pig, on Smith Street in Mission Hill, is an Irish pub and sometime metal bar that shows kung fu ﬂicks. It is also, on certain nights, a place where medicine’s biggest problems are solved.
Three scientists from the Harvard Stem Cell Institute come to the Pig when they need to talk about their jobs. They are not your average scientists; they are freaks of overachievement, young and attractive and supremely ambitious. The goal of their research is nothing less than curing mankind’s last intractable diseases. That they are inching ever closer to that goal is only part of what makes them such a very big deal.
Amy Wagers, who works with the stem cells that form blood cells, learned to fly on trapeze bars while studying at Stanford. At the Pig, the petite blond 35-year-old could be mistaken for a teacher from the nearby Winsor School, and tends to talk with her hands, a demure smile breaking across her lips. Kevin Eggan, also 35, does stem cell research tied to ALS, lives in a Leather District bachelor pad, and rock-climbs in his spare time; his square jaw and chiseled build elicit stares from the women at the Pig. Konrad Hochedlinger, 33 and arguably even more handsome—high cheekbones, gray-blue eyes, and an olive complexion that belies his Austrian roots—skis the Alps when he’s home. His specialty is something called IPS cells, which might prove the biggest game-changer of them all, since they derive their healing powers not from nature, but from science.
On their own, Wagers, Eggan, and Hochedlinger have pulled off things in their labs that have never been done before, advances that have fueled the field’s headline-generating momentum. Collectively, the trio, along with their idiosyncratic bosses, have put Boston at the epicenter of a movement that proponents believe will be no less transformative than the Renaissance. But stem cell research is highly competitive, even when the scientists work for the same institution. As such, Florence in the 1500s may not be its best analogy; instead, think Houston in the early 1960s, when a generation of upstart scientists raced to be the first to the moon. Like John Glenn and company, Wagers, Eggan, and Hochedlinger all have a self-regard proportional to their talent. And like those young Mercury astronauts, the young stem cell researchers all want to put their stamp on history in a field that is advancing by the week.
The best way for them to do it—ironically, the only way—just happens to be in concert with one another, one drink at a time if necessary. Which means the biggest breakthrough may have already happened. Building this team was its own kind of miracle, requiring leaps of faith, back-channel overtures, massaging of considerable egos, and, in one case, the gumption necessary for a protégé to break with and then compete against a mentor who is more like a father to him.
The trick ever since has been keeping the trio together. The sessions at the Pig go a long way toward that. But it’s the thrill of the chase that provides the deeper bond.
To understand the hype around stem cells, it helps to first understand how they work. Crudely put, stem cells are like clay. Crudely, because clay cannot regenerate, cannot make more of itself, but also because the core of the analogy—the shared pliability—sells stem cells short. There are only so many things you can make out of clay, whereas stem cells can grow, or be grown by researchers, into brain cells, bone marrow cells, muscle cells, and so on. You can study how stem cells make more stem cells through cell division and gain insights into cancer, whose tumors are thought to form when cell division goes awry. You can manipulate stem cells to carry a disease, then test a potential therapy directly on them, supercharging the typical drug-discovery process and opening the door to entirely new medicines to fight the ravages of Alzheimer’s, Parkinson’s, and diabetes. All this is why stem cells are the source of such excitement, and of the kinds of hopes and pressures that rest on stem cell scientists like Wagers, Eggan, and Hochedlinger.
Modern stem cell research has its foundation in cell cloning, which scientists have been experimenting with for roughly 50 years. In the late 1990s one of the biggest names in cloning—and therefore the nascent stem cell field—was Rudolf Jaenisch, a curly-haired German who looks like a cross between Einstein and Mark Twain. Scottish researchers had just cloned Dolly the sheep, but Jaenisch, cofounder of MIT biomedical research collective the Whitehead Institute, soon advanced the miracle of Dolly through something called nuclear transfer. The process involved microscopically inserting the nucleus of an adult cell into a “denucleated” egg cell; this in turn allowed for the cloning of new cells. With the tools available at the time, nuclear transfer demanded more than mere brilliance. It required such manual dexterity that only a handful of people in the world could perform it, and none as well as Jaenisch. That gave him a virtual monopoly on cloning that lasted nearly a decade.
In 1998, Jaenisch came to the National Institutes of Health to give a lecture. Sitting in the audience was Kevin Eggan, then working at NIH. Jaenisch’s presentation blew him away. He reached out to Jaenisch afterward, and soon decided to give up his job to pursue a Ph.D. in biology at MIT.
Eggan grew up in Normal, Illinois. “I am, of the men in my family, the soft scientist, the weak intellectual link,” he says. “My dad’s a number theorist, and my brother works for the Aerospace Corporation now and can’t tell me what he does.” At the University of Illinois, Eggan got as far as abstract linear algebra before turning to biology and eventually microbiology. He had been headed to medical school when he had second thoughts, and deferred for the opportunity at NIH.
At MIT, Eggan quickly became known for the same thing at which Jaenisch excelled: nuclear transfer (or as Eggan describes it, “the hardest video game you’ve ever played”). His work required him to spend full days bent over a powerful microscope, using joysticks and foot pedals to zoom in and out on cells that—even under magnification—appeared no larger than the tip of a strand of hair. Eggan hunched over these cells so long and so intensely that he developed trucker’s sciatica. Worse, the smallest mistake would send him back to square one. “You have to ask yourself, are you the sort of person that when you got your Nintendo 64 and you started playing Mario Brothers, and you got to that really hard part, could you die a thousand times over and over and over again, and still be motivated to try again?” He was. Eggan mastered nuclear transfer at the age of 26.
In 1999 Jaenisch gave another lecture, at the Research Institute of Molecular Pathology in Vienna. This time 23-year-old Konrad Hochedlinger was in the crowd. As Jaenisch talked about what stem cell scientists were accomplishing, Hochedlinger sat enraptured. He was studying embryo development at the institute, where he’d received his master’s the year before, but wasn’t satisfied with the work. It didn’t feel big enough. A few days later he e-mailed Jaenisch, saying he would be visiting Boston soon, and asked whether Jaenisch would have half an hour to meet.
Neither of Hochedlinger’s parents had any interest in science. And neither did he, at first—he was into art and architecture. But when his older sister began to study biology, she encouraged him to follow in her footsteps.
Several weeks after his e-mail, Hochedlinger did indeed meet up with Jaenisch in Cambridge. Jaenisch was taken with the young man’s impatience for modest gains. He offered a spot in his lab to Hochedlinger, who gladly accepted. If in Eggan Jaenisch had found a protégé, in Hochedlinger he found something closer to a son.
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.
In August 2006, shortly after Hochedlinger opened his new lab at MGH, a startling paper appeared. A Japanese scientist named Shinya Yamanaka believed he’d found the Holy Grail: a way to take adult cells and reprogram them into any other kind of cell whatsoever. The implications were huge. Up to that point, only embryonic stem cells were proven to have this prized malleability. Politically, though, the use of embryonic stem cells was problematic, decried by religious conservatives on pro-life grounds and, not coincidentally, subjected to a moratorium by the Bush White House. If Yamanaka was right, scientists would be able to skirt that minefield entirely.
Though now settled in at Harvard, Hochedlinger was still in close touch with Jaenisch. After reading Yamanaka’s paper, “I talked to my old boss,” Hochedlinger says, “and he said, ‘Nay, this is bullshit.'” Yet as time went by, both men wondered, Could Yamanaka be right?
Out of loyalty, Hochedlinger had thus far focused his efforts on areas unrelated to Jaenisch’s. But they both sensed that Yamanaka’s work might pave the way for the biggest stem cell discovery yet. The Japanese researcher’s experiment had yielded cells that developed to a point somewhere between the adult skin cells he’d started with and the embryonic cells he wanted to end up with. While they showed the promise of transforming into any other cell—of possessing “pluripotency”—Yamanaka hadn’t been able to demonstrate anything beyond that.
Hochedlinger first asked his most gifted Ph.D. student, Nimet Maherali, to try to reproduce Yamanaka’s results. A few weeks later, Hochedlinger got an e-mail from her: She had succeeded. His eyes lit up. He realized he could greatly improve on what Yamanaka had done. He could take a skin cell and not just turn it into a fully pluripotent cell (also known as an induced pluripotent stem, or IPS, cell), but also coax that same cell to become any of the 220 mature tissue types that make up the human body—all without using a single embryonic cell.
Hochedlinger believed he could do this because the creation of IPS cells was directly related to the nuclear transfer work he had learned at MIT. But he was painfully aware that Jaenisch, as the godfather of nuclear transfer, had to be thinking just as he was, and in all likelihood working toward the same end. What’s more, if IPS cells succeeded it would democratize the field, allowing the reprogramming of cells through far easier techniques and ending Jaenisch’s long reign. Hochedlinger spent several sleepless nights before making his decision: The advancement he had in mind was too important not to directly challenge his mentor.
Both Hochedlinger and Jaenisch were careful to keep their research under wraps before publication. They knew what was at stake. As the 2006 holidays rolled around, they ordered their respective teams to drop everything to work on IPS cells. “Rudolf and Konrad became like the heavyweight prizefighter standing in against his protégé,” Eggan says. “It’s pretty intense. I’m really glad not to be a part of it.” Hochedlinger told the seven people in his Cambridge Street lab they would have to stay at it round the clock; one student brought in a sleeping bag.
On June 6, 2007, Hochedlinger published his findings in the academic journal Cell: Stem Cell. It was a momentous achievement. It was also one, it turned out, he’d have to share—that same day, Jaenisch and Yamanaka published their respective work on IPS cells in Nature. All had found separate ways to reach the same conclusion. As much as he’d wanted to stand alone, Hochedlinger was in part relieved. His mentor had adapted. And their discoveries had even more impact for having arrived together.
Jaenisch is fiercely competitive, but he glows when talking of Hochedlinger. To him, Hochedlinger is still the young man who sent a tentative e-mail from Austria 10 years ago. His accomplishments leave Jaenisch as proud as any father, even as Hochedlinger has become Frazier to his Ali. “It’s an interesting tension,” Jaenisch says. “But I think there’s openness to try not to make this come into an unpleasant relation.”
Harvard’s stem cell team was to be one of the marquee tenants in the 589,000-square-foot life sciences complex the school had slated as the first building on its decade-in-the-making Allston campus. But now five cranes hover over the giant hole where the foundation has been dug, halted by the blow to Harvard’s endowment when the market crashed. So the scientists are making do. The old Harvard labs that were to have been repurposed upon the stem cell institute’s move across the Charles are instead undergoing an accelerated $50 million renovation. At the moment, Eggan’s office looks out on cardboard boxes and a torn-up industrial space.
Meanwhile, the stem cell institute has had to aggressively raise funds to fuel its own unbowed agenda. For Eggan, Wagers, and particularly Hochedlinger, this means participating in a kind of traveling revue.
This past February, 40 handpicked guests arrived at Tashun Estate in Boca Raton, Florida, the mansion of Red Sox owner John Henry. They proceeded upstairs to a massive home cinema, where they were greeted by Henry, sporting a suit and bright yellow tie. MGH president Peter Slavin and David Scadden were similarly attired. Practically the only man in the room without a tie was Hochedlinger. Though the swarthy Austrian had shaved for the event—”which I hate,” Hochedlinger says—and left his jeans at home for once, the young scientist wore his white shirt unbuttoned, revealing his chest hair. Scadden couldn’t help remarking later that Hochedlinger looked as if he had “a touch of Springsteen” about him.
After being introduced by Scadden, Hochedlinger cued up a film he’d prepared for the evening’s presentation, about a type of aquatic salamander and its ability to regrow its organs. When the film ended, Hochedlinger asked the audience, “Why can’t we do this?” He then went on to describe how he and his colleagues were performing the same kind of magic at the cellular level.
He talked about the monumental day in 2007 when he’d created stem cells without using embryos. He also talked about how he had since improved the technique. Previously, for IPS cells to work, researchers had to rely on a retrovirus that, unfortunately, could also potentially lead to tumors in the new cells. Like a crack computer programmer, Hochedlinger had fixed the bug in the IPS code by swapping out the retrovirus for a common-cold virus. Presto—no more tumors.
Before Hochedlinger finished, he made sure to hype his employer. “By creating the diseased tissue in isolation to allow for rapid drug trials”—part of the work for which Eggan had been awarded the MacArthur—”we at the stem cell institute have been able to greatly accelerate research into the treatment of Alzheimer’s, Parkinson’s, diabetes, and ALS, among many others,” he told the crowd.
When Hochedlinger was done, an impressed-looking Henry stood to thank him, then turned to address his guests. “It’s up to all of us here to make sure the things Konrad has discussed are possible,” he said. No checks would be signed that night, but the message was clear: Henry would continue to give generously to MGH, and he expected everyone in the room to do the same. Off to his side was Hochedlinger, rakish in his unbuttoned shirt, the rock-star comparison now even more apt.
Doug Melton doesn’t deny that, to some degree, his team vies for the acclaim that accompanies breakthroughs. “It’s like athletics, where it brings the best out in you, challenging you to do something differently or try harder,” he says. It is very much a team at the Harvard Stem Cell Institute, a yin and yang of competing interests: each member wanting his or her work to stand on its own; each member benefiting from the vigor and sometimes the direct help of the others to propel that same work forward.
And the truth is that all the young scientists would suffer if any one of them left. They’ve had their chances to do that, certainly. After Hochedlinger’s IPS cell breakthrough, he received a lucrative offer from his native Vienna’s Research Institute of Molecular Pathology. It wanted him to head home, to serve as its new director. Cambridge didn’t come anywhere close to the enticements Vienna offered, yet Hochedlinger stayed. He knew that only here, among his peers and the men who had taught him, could he do his best work.
The team’s advances—and with them the motivation to stick together
—keep coming. Indeed, nearly every day the importance of the stem cell institute is reaffirmed. In March, for instance, that affirmation came from the Howard Hughes Medical Institute, based in Chevy Chase, Maryland. Last year it had announced a new award for the nation’s 50 best scientists, one that would pay each winner’s salary and benefits for six years. In addition, each would get $1.5 million of research money—a scientific-funding grand slam. Wagers, Hochedlinger, and Eggan had been among the 2,000 applicants, and Melton and Scadden figured they’d do well if one came home with the money. Instead, all three won the prize.
Quickly, the e-mail traffic turned from stem cell research to Where should we go to celebrate? The three decided that the honor was too great an occasion for the Squealing Pig, that the $1.5 million prize shouldn’t be honored by downing IPAs. They headed to Fort Point hot spot Drink instead.
“We’ll have three ‘bone crushers,'” Wagers told the waitress. When the toxic concoctions arrived—a mix of tequila, Tabasco, sugar syrup, and lime—she raised her glass to her teammates and rivals. The toasts continued well into the night.
The next morning Hochedlinger woke up hung over. He looked at his phone and saw a text from Eggan: “Dude, the bone crusher turned out to be a head crusher.” Soon after, Eggan sent another message: “Let’s have reason to do that again soon. Get back to work!”
A freelance author living in Brookline, Tom Matlack wrote about UMass researchers’ discovery of a microbe that could fuel a clean-energy revolution for the November 2008 issue. Read “Q to the Rescue.”