A fax that Michael Hengartner sent to his mentor helped turn apoptosis into a Nobel Prize–winning pathway.
As an incoming graduate student at MIT in the late 1980s, Michael Hengartner knew he wanted to work with David Baltimore on the transcription factor NF-kappaB. “He’s such a great scientist and NF-kappaB is such a cool protein,” he says. “So I thought, OK, I’ll go to David Baltimore’s lab and work on NF-kappaB.” Back then, first-year students didn’t do rotations, so they got a feel for various labs by sitting in on their group meetings. Although Hengartner was sure he’d be working with Baltimore, one day he tagged along with a fellow student who was headed to a chalk talk in the lab of Robert Horvitz.
“It was completely incomprehensible,” Hengartner laughs. “They talked in alleles—about genetic analysis, double mutants, and ‘n1046 is clearly epistatic.’ I...
Instead, he met with Horvitz, who described what was going on in the lab. “At the end of the discussion, he mentions this little side project he’s been toying with: programmed cell death.” It was the first Hengartner had heard of this phenomenon, by which developing C. elegans embryos would produce—and then destroy—certain cells in its body. “And I thought, ‘What a stupid thing,’” he says. “I mean, I trained as a biochemist and one of the things that annoyed me as an undergraduate was when I learned that my liver could make 38 molecules of ATP from one molecule of glucose, but my muscles only make 36. And I thought, ‘Stupid muscle! You’re wasting two molecules of ATP for every molecule of glucose you burn. It seemed highly inefficient. Now, here I was confronted with an animal that just threw away whole cells. It just sounded weird. So I decided, I’ve got to figure out what’s going on here.”
And he’s been working on the problem ever since. In the Horvitz lab, Hengartner cloned and characterized ced-9, a gene that inhibits apoptosis in worm cells that are destined to live. And he determined that ced-9 is homologous to Bcl-2, a gene that promotes survival in human cells and is involved in some cancers. As an independent investigator, Hengartner has dissected the molecular underpinnings of cell death in the C. elegans germline and explored the mechanisms that mediate the removal of the corpses that apoptosis leaves behind.
“His findings have laid a firm foundation for a lot of the work in programmed cell death,” says former student Tina Gumienny of the Texas A&M Health Science Center. “I’ve seen figures from our papers flashed up on screen during people’s talks at C. elegans meetings. People still come up to me at meetings and say, ‘I loved your work in the Hengartner lab!’”
And Hengartner’s own graduate work—particularly his demonstration that ced-9 is the worm version of Bcl-2—contributed to Horvitz receiving the 2002 Nobel Prize in Physiology or Medicine. “I emailed Michael when I heard the announcement,” says Gumienny. “And he was as delighted as if he’d gotten it himself, because it was his work that helped Bob win.”
As one of only three students working on Horvitz’s pet project, Hengartner quickly made a name for himself by volunteering to give a talk—in place of his mentor—at a special meeting of the American Association of Cancer Research. “I was probably a second-year student and it was my first big meeting,” says Hengartner. “We only had genetics at the time, we had no molecules. So I described this nice genetic pathway and someone in the audience stands up and basically says, ‘Why am I listening to you?’ I said, ‘These pathways are evolutionarily conserved and we think the same genes will function in humans.’ And he said, ‘You have no evidence of that.’ So I decided I’d better start cloning.”
And of course, he kept talking. “He’d present work at Gordon conferences and Keystone meetings and most people assumed he was an up-and-coming faculty member, he had such tremendous poise and phenomenal clarity of thought,” says Genentech’s Vishva Dixit. “He had an encyclopedic knowledge of the field and a deep appreciation of genetics. He really was a most unusual graduate student.”
His work with ced-9, says Hengartner, “was just being at the right place at the right time. I happened to be lucky.” As luck would have it, Ron Ellis—then a senior student in the lab—had isolated worms in which a dominant mutation wiped out all cell death. “That was wonderfully surprising and puzzling to us,” says Ellis, now of the University of Medicine and Dentistry of New Jersey. Because the mutation caused ced-9 to become overactive, even cells that were supposed to die remained alive. To clarify ced-9’s function, Hengartner isolated worms in which the gene was shut down. In these mutants, cells that would normally live, instead committed suicide. “It was a genetic tour de force,” says Junying Yuan of Harvard Medical School, a fellow Horvitz trainee. The resulting article, published in Nature in 1992, “was a spectacular paper,” she says. “Very thorough, very beautifully done. It demonstrated the power of genetics to identify a biologically significant gene.”
When he discovered the homology with the human Bcl-2, Horvitz was traveling. So Hengartner sent him a fax. “On the first page it said, ‘Dear Bob, guess what pops out as a top hit when you use FASTA rather than BLAST with CED-9 as a query? Answer on next page…,’” says Hengartner. Horvitz showed a slide of the fax during his Nobel lecture in Stockholm—and the discovery was described in Cell in 1994.
“So, by the end of my PhD, people actually knew who I was,” says Hengartner. That renown earned him a faculty position straight out of grad school at Cold Spring Harbor, where he took up residence in Barbara McClintock’s old lab. “It was still more or less in the state she left it, so that was pretty cool,” he says. “We collected all the maize kernels we could find. They’re in a jar that we’d shake before mutagenesis for good luck.”
Whether his good fortune came from McClintock’s kernels or not, Hengartner’s tenure at Cold Spring Harbor was productive. He and his team discovered that the CED-9 protein physically interacts with a pro-apoptotic protein called CED-4, preventing CED-4 from activating the cell-death program. That finding, work led by postdoc Mona Spector and published in Nature in 1997, “helped to define the molecular pathway by which apoptosis is induced in cells,” says fellow former postdoc (and coauthor) Serge Desnoyers of the Canadian Institute of Health Research.
He also began to unravel the genes and proteins that trigger cell death in the germline of adult worms—a program that gets rid of germ cells that are not destined to become either sperm or egg. The system has advantages over studying cell death during development, in part because apoptosis in the germline is triggered by a variety of signals, including DNA damage, bacterial infection, or faulty meiosis. “In that way it’s more like the system in mammals,” says Hengartner. Plus, it’s easier to monitor. “Adult worms are bigger than embryos and there’s way more death in the germline than in somatic cells,” he says. He’s even developed fluorescent markers that allow him to spot dead cells at a glance—a skill pretty much anyone could pick up—even high schoolers. “A lot of kids wanted to work in a lab and this was perfect,” says Yuri Lazebnik of the Cold Spring Harbor Laboratory. They’d screen plates of C. elegans for cells that glow and set them aside for someone more senior to check out. “There would be this room full of elves—Michael called them elves—looking at worms and producing data,” laughs Lazebnik. “Everyone was happy.”
“Those were heady days,” says Dixit of cell death in the 1990s. “Everything you touched turned to gold. Editors were calling you, asking you to submit papers. It was an exciting time because the field was breaking open.”
And though the heyday may be over, the discoveries continue to come. “We’re still finding genes that are important for triggering apoptosis in response to DNA damage,” says Hengartner. “Which suggests there’s still quite a bit out there to be found.”
Now, at the University of Zurich—where he is dean of the Faculty of Science—Hengartner continues his exploration of cell death, but is also branching out into proteomics and investigating how protein synthesis is controlled. “I think that’s going to be the next big thing,” says Hengartner. “Worms have hundreds of microRNAs and hundreds of RNA-binding proteins—and I’d like to understand how they control mRNA localization and translation efficiency.” They all bind to the 3´ untranslated region of mRNAs. “But do they synergize? Do they antagonize? Does it depend on the distance between their binding sites? We just don’t know the rules.” And the germline is a good place to start looking. In a routine search for genes involved in controlling apoptosis in the germline, Hengartner and colleagues discovered that the translation of p53—a gene central to the DNA-damage response pathway—is regulated by an RNA-binding protein.
“Michael is one of the leading figures in science here in Zurich,” says colleague Konrad Basler. “And he’s looking around to do something for the university and to move Zurich forward scientifically.” Hengarter was key in establishing a PhD program in molecular life sciences. “We didn’t have a graduate program,” says Basler. Students instead applied to individual labs. “Now we have one of the best programs in Europe. Michael just has endless energy and he gets things done. He moves forward—and leaves a trail of accomplishments behind.”
Hengartner sees his stint in science leadership as a natural part of the scientist’s life cycle. “When you’re a grad student and you’re good at bench work, they say, ‘Why don’t we give you this management job?’”—running a lab staffed by trainees, he says. “And the reason you go for it is you realize that there’s only so much you can do with your own hands. So the way to move your science forward is to recruit a larger group. The same logic applies to being dean. Just as you can get more science done as a PI, you can do more good for science being a dean.”
And as long as the science stays interesting, he’ll keep doing that as well. “Everything in lab now is exciting,” says Hengartner. “If we were doing something boring, I’d say let’s do something else.”