Developmental Biology, Neuroscience
Janelia Research Campus
Philipp Keller is a group leader at HHMI's Janelia Research Campus.
Principles of Developmental Building Plans
The process of growing from embryo to complete animal is of staggering complexity. As cells multiply, they migrate from one area of the developing embryo to another, many of them eventually dying, others taking on specialized functions and shapes.
Philipp Keller is fascinated by this cellular dance, but that was not always the case. In high school he was initially drawn to mathematics and physics. Later, as an undergraduate physics student at the University of Heidelberg, three research areas piqued his interest: developing new technologies to overcome the energy crisis, exploring space, and applying physics to biological questions. In the end, the latter topic won out.
"I chose biophysics because I believed that most of the upcoming major scientific breakthroughs would be in this field," recalls Keller. "I find many areas of research exciting but I wanted to work on research topics where it was realistic to hope for spectacular progress within my lifetime."
That decision landed him in 2005 in Ernst Stelzer's laboratory at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany. Stelzer's group had just developed a new type of microscope, called a light sheet–based microscope. Unlike the standard confocal microscope, which views specimens plane per plane while illuminating the entire specimen each time, the new microscope illuminates only that part of the specimen that is observed in the first place. As a result, the specimen is exposed to less light energy. "It is a gentler way of recording information," says Keller. "In biological research you want to minimize any possible disruptions to the specimen you are studying." Another advantage of the light sheet–based microscope, he says, is the considerably higher signal-to-noise ratio, resulting in higher quality data. In addition, the new instrument gathers data much more quickly than confocal and two-photon microscopes, the state-of-the-art technologies used in most biology labs.
At EMBL, Keller combined advanced imaging assays with biophysical modeling and started collaborations with the groups of Michael Knop and Jochen Wittbrodt. He studied meiotic division in yeast, how the architectures of yeast genomes evolved, and how specialized structures, the microtubules, are organized.
Keller next decided to study more complex biological systems. In particular, he wanted to try to record precisely how individual cells move through an entire developing zebrafish embryo. "In a way, it is like going far into space and then looking through a powerful telescope at people on Earth as they go about their business," explains Keller.
For the project Keller worked with Stelzer to design and build a next-generation light sheet–based microscope, called the Digital Scanned Laser Light Sheet Fluorescence Microscope, which he uses to visualize cells that have been tagged with different fluorescent markers. He then was able to observe the zebrafish embryo as it went from a 32-cell "lump" to a 30,000-cell organism with a beating heart. As he observed the growing embryo, Keller recorded the movement and division of every cell.
After gathering a staggering 400,000 images, or 3 terabytes of data, for a single embryo over a 24-hour period, Keller next had to develop computer systems to extract, analyze, and convert the data into what he calls a digital embryo. "With the technologies I developed I could comprehensively analyze cell behavior in an entire zebrafish embryo," says Keller. The press later referred to his work as "Google Earth for Development." However, unlike Google Earth, Keller's reconstructions also comprise "the dynamics of the biological system, continuously from the first few cells up to a stage in which major organs are in a functional state," he explains.
Keller's digital embryo databases and numerous movies are publicly available at http://www.digital-embryo.org/, a site accessed about 50,000 times per month worldwide, according to Keller. "Recently I noticed that one of my movies had actually been uploaded to YouTube, receiving about 180,000 hits so far." Keller's research with zebrafish embryos culminated in a 2008Science article that also made the list of the journal's top ten scientific breakthroughs of 2008.
Given Keller's interest in working at the interface of biology, physics, and computer science, he believes Janelia is the perfect place to do his research. "Janelia is a highly collaborative environment and very strong in all these areas."
This environment will be particularly helpful as Keller ventures into the next stage of his research, examining the development of the nervous system in the fruit fly Drosophila melanogaster. "So far, I have not had a chance to work on neuroscience projects, so this is essentially a new field for me." says Keller. "I am very excited about moving into this fascinating area. Studying how the brain works is clearly one of the most challenging scientific questions I can imagine."
At Janelia, Keller will build a new light sheet–based microscope optimized for his new line of research. "It is simply a lot of fun to use the most advanced technology available to study the core principles of biology," he says. "And if the technology required to address a specific question is not available, it is also a lot of fun to develop your own tools for your projects."