The basics of what goes on inside a cell have been pretty well known to scientists for some time. The same can be said for the biological structure of organisms—what connects where, and why. But how they get that way—the intermediate steps defining exactly how microscopic busybodies become functional tissues and organs—is still largely a mystery.
Key to solving the mystery is the ability to accurately visualize organisms as they develop, says Philipp Keller, a research fellow at the Howard Hughes Medical Institute (HHMI) Janelia Farm Research Campus in Ashburn, Virginia. His lab spends most of its time developing new microscopy techniques to achieve higher resolution and deeper penetration into developing embryos to give researchers a clearer view of how cellular components interact during development, allowing them to refine their theories based on visual evidence. In coordination with Keller's review article in this week's Science, in which he examines the state of microscopy technology and speculates on the technological advances and computational and mathematical methods that will be necessary to deliver fresh insights into developmental biology, Science Careers spoke with Keller about his career path and ambitions.
Science's Special Issue on Morphogenesis includes reviews on the mechanics of epithelial tissue, self-organizing mini-organs, and the advances in imaging morphogenesis.
Keller never set out to work in a biological field. Growing up near the city of Karlsruhe in Baden-Württemberg, Germany, he was captivated by the hard sciences. "Back in high school, I very much liked physics and math, and also working with computers," he says. "Based on these interests, I decided to study physics."
Keller chose to attend the University of Karlsruhe (now the Karlsruhe Institute of Technology) because it had a strong program in theoretical physics. Then, "Gradually as I went along in my studies, I became interested in a new, emerging area, … [using] physics approaches and methods to understand biological phenomena and processes," he says. He switched to the nearby University of Heidelberg, which had a new biophysics program. "I was hoping it would be more feasible to achieve the most progress during my lifetime" in this field, he says, "that this would be something where I could contribute not just as part of a huge team or a multidecade effort, but as an individual."
He began to study novel microscopy methods at the university and then continued the work as a Ph.D. student at the European Molecular Biology Laboratory (EMBL), also in Heidelberg, Germany, under the direction of Ernst Stelzer and Joachim Wittbrodt. This work, which allowed scientists the most complete and detailed visualization of zebrafish embryos to date, was nominated by Science as a runner-up for Breakthrough of the Year in 2008.
A different path
Keller assumed he was on the path to a traditional research career in Germany, but a series of events led him across the Atlantic to Janelia Farm, the suburban Virginia research campus operated by HHMI. "It was a series of coincidences that led me to Janelia," he says. "I'm really glad that it happened, but tracing it back, it kind of randomly happened."
CREDIT: Kristin Branson
In 2008, Stelzer invited Keller, still a Ph.D. candidate, to accompany him to the United States to attend a bioimaging conference at Janelia Farm. Keller had never heard of the institute before and didn't know what to expect. What he found there was an impressive research facility and a team of dedicated scientists who were interested in the same kinds of cross-disciplinary questions that he was. He spent the next few days chatting with likeminded researchers, and at the end of the conference, a few of them asked him to consider applying for a fellowship at Janelia after finishing his doctorate.
"In fact, it was the only place I applied to," Keller says. As it happened, Janelia's application deadline coincided perfectly with Keller's finishing of his dissertation in 2009. Busy with that project, he simply hadn't given his looming job hunt much thought. "It was not the primary thing on my mind to find a job; I was just finishing up my thesis, but I didn't want to miss the [Janelia] deadline," he says. "I just applied and thought, 'Let's see if this works, and if not, I can still apply to different places later on.' "
He didn't have to. Janelia offered him a research fellowship starting in 2010 and he took it.
The "fellow" position at Janelia is a nonrenewable 5-year independent research appointment that comes with lab space and funding from HHMI. "It's hard to compare it to anything else out there," Keller says. "The thing that comes closest is the assistant professor position, before tenure." After 5 years, fellows can apply to become a "group leader;" these positions are endlessly renewable, but the appointments never become permanent.
Janelia's narrow focus on research appealed to Keller, and he quickly picked up where he'd left off with his microscopy research in Germany. "I can say without exaggeration that it is the perfect framework for starting as a junior lab head," he says. "You can focus entirely on the research. There aren't too many distractions. There's no teaching involved. There's no committees. The grant-writing process is basically eliminated from your day-to-day work because you get internal funding from HHMI."
That's all good—but Keller will end his Janelia fellowship with no teaching experience, little grant-writing experience, and no experience navigating the politics of academic departments. "You could say that's the downside," he says. "Not being distracted by it also means you don't get any experience in it. Once you leave that framework, what are the implications for your future career? It remains to be seen."
Gerald Rubin, vice president of HHMI and Janelia Farm's executive director, says that the young scientist's record of accomplishment at Janelia will more than compensate for a lack of experience in other areas. "From my 25 years on the faculty at UC Berkeley, I can say with confidence that his greater research achievements and proven ability to run an independent research group would far outweigh his lack of experience in other areas in a faculty search," he writes in an e-mail to Science Careers.
For the moment, Keller says, he's singularly attuned to his work. "I'm basically completely focused on the research aspect," he says. "The microscopy technology … is something that could be commercialized, and there are companies interested in it. It's something we support, to some extent. The papers we write up are very detailed to provide all the technical details you'd need to recapitulate the experiment or to build your own imaging technologies," but to do that work himself "would be too much of a distraction from the work I'm doing now," he says.
The next step in his research, Keller says, will be using ever-better microscopy techniques to further explore how functional development emerges from cellular activities, especially within the nervous system. That will require more detailed, higher resolution, real-time imaging, which will aid scientists in their quest to learn how cells form neural circuits and tissue structures with specific functions. "Being able to track the entire developmental history of a system, but then also to map on systematically all the functional aspects that are relevant to its purpose in the animal, I think that would be a very powerful future direction."
Keller has 2 years left in his fellowship, but, like the cellular mysteries he studies, he doesn't really know what the intermediate steps will be between his early development and maturity. For now, he's staying focused on his research and hoping to continue heading his lab for as long as he can. "I think Janelia is a great place," he says. "It's certainly a place I would love to stay for a longer time."
*Top image: Philipp Keller captured this image of a zebrafish embryo using a microscopy technique he has developed to better visualize biological development.