The League of Extraordinary Biologists
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.”