As a precocious 13-year-old growing up in Germany, Peter Baumann had an unusual pastime—taking university courses in ecology. While his friends were out playing after school, Baumann was busy charting the rise and fall of algae, zooplankton, and other microorganisms in ponds. “I was doing it for fun,” he recalls. “I was very interested in becoming a field biologist.”
Metaphase chromosomes stained with DAPI (blue) and a telomeric probe (red). The brightness of the telomere signal correlates with telomere length.
Image: Courtesy of Baumann lab.
By the time Baumann himself was at university, though, first in Germany and then at Cambridge, molecular biology seemed to offer greater rewards and opportunities. So he earned his Ph.D. from the University of London in 1998 working on DNA repair in human cells at the world-renowned Clare Hall Laboratories.
Then he set out to broaden his skills in a post-doctoral fellowship. Searching for a compelling new area of biology, Baumann heard an inspiring talk by Joachim Lingner, a researcher in the University of Colorado laboratory of Nobel Laureate Tom Cech. For years, scientists had known that the ends of every chromosome are protected by strings of repetitive DNA known as telomeres. Researchers also knew that copying the telomeric DNA when cells divide required a special enzyme named telomerase. But they’d been unable to find the gene for the enzyme. Now, Lingner reported, success was in sight. “It was very new and exciting,” Baumann recalls. “People had been stuck for so long and now this lab was close to having the gene in hand.”
Baumann snared a spot in Cech’s lab, and also won a Wellcome Prize Traveling Research Fellowship to fund his work. “The stars aligned perfectly for me to join Tom’s lab,” Baumann says.
The only question: What would he work on? During the interview, Baumann had proposed exploring why DNA repair proteins are found in abundance at chromosome ends. That didn’t seem to make sense. The last thing a cell wants is for its DNA repair machinery to view chromosome ends as broken DNA, and swoop in to join them together. The effect would be disastrous. So why were the repair proteins there?
It was a worthy question, yet Baumann had misgivings. The plan seemed too much like a reprise of his Ph.D. work. He came to Boulder determined to ask for a side project, but Cech was one step ahead of him. Work on whatever you want, Cech told him.
Image: Courtesy of Baumann lab.
Baumann decided to search for the gene encoding a key component of telomerase in S. pombe, or fission yeast. While the protein part of the yeast’s telomerase had been identified, the enzyme’s RNA subunit—the part that binds to telomeres—had not. Baumann narrowed the search to five candidates, then knocked out the gene for the most promising one in yeast cells. Meanwhile, he was pursuing a pet project. A friend in the lab was working on organisms called ciliated protozoa, which have hundreds of thousands of chromosomes—as well as many proteins bound to the chromosome ends. At the time, no one much cared. Ciliated protozoa are so different from human cells that their proteins seemed largely irrelevant.
But what if protozoan proteins did have human counterparts? Every so often, Baumann would compare the sequence of his colleague’s telomere-binding protozoan protein to the latest data from the fission yeast genome project. One day, he got the barest hint of a match. Only twelve of the protein’s many building blocks—amino acids—were actually the same between protozoa and yeast. But eight of the twelve were in key locations. Were the proteins related?
It was a long shot, but Baumann had nothing to lose. “I was still the post-doc in the lab looking for a project that actually worked,” he says. He knocked out the corresponding yeast gene. He then had two knockout strains of yeast, one lacking the possible telomerase RNA subunit, and the other without the unknown gene. If either gene were important, its absence would cause the yeast to lose their telomeres.
When the results came in three weeks later, sure enough, half of the yeast had no telomeres. Baumann figured he’d nailed the RNA subunit gene—except that the sample with no telomeres was labeled as the other knockout strain. “I thought ‘great, I must have flipped the gel,’” he says. But he hadn’t. Instead, he’d made a major discovery: a new protein that was vital for maintaining telomeres. Baumann dubbed it Pot1, for “protection of telomeres.”
The unisexual lizard species Aspidocescelis tesselata
successfully carries on without any males.
Image: Courtesy of Dr. Peter Baumann
When Cech, who’d become president of the Howard Hughes Medical Institute, visited the lab, Baumann showed him the results. “Peter, this is fantastic,” Cech said. “This protein will really make your career.” It did. Baumann published a landmark paper in Science in 2001, and landed a faculty position at the Stowers Institute. The discovery “really changed how people thought,” Baumann explains.
At first, it was a hard act to follow. “It was both a blessing and curse,” Baumann recalls. “It put me on the map, but other labs started working on it.” Those labs scooped him on key follow-on discoveries.
Then Baumann’s lab hit its stride. His team found the S. pompe telomerase RNA subunit gene that had eluded him before. That turned out to be “an incredibly lucky choice,” he says. In studying the precursors to that subunit, he discovered an entirely new and unanticipated pathway for processing RNA. “Not only did that result in a really nice story, it’s providing us with plenty of work figuring out how this works,” he says.
Baumann also answered the question he posed in his Wellcome Fellowship application. It turns out that a complex of two proteins keep the ends of chromosomes from being mistakenly joined together. The work resulted in another surprise: Telomeres as short as 12 DNA repeats are protected by this protein complex.
And he’s even realized his childhood ambition of becoming a field biologist. In what started as a “Saturday afternoon fun project,” Baumann troops out to the New Mexican desert with a fly rod to capture lizards. Not just any lizards, but those that reproduce without sex. Studying how the creatures’ egg cells divide, Baumann has uncovered key details of the mechanism—and has helped explain how the lizards can maintain their genetic diversity (and thus their ability to compete in a changing environment) without the reshuffling of genes that sex brings. The work turned up yet another surprise. Looking for the telomeres in lizard cells, Baumann saw previously undiscovered spheres at the chromosome ends. “Now that we’ve found this novel structure in the nucleus, it raises a lot of questions,” he says. “What is it and what does it do?”