A full picture of life at the molecular level requires new technologies for probing their atomic details.
By Amy Adams
When Soichi Wakatsuki joined the Stanford School of Medicine as a professor of structural biology in 2013, he was the first person there to also have an appointment at nearby SLAC National Accelerator Laboratory, where he is professor of photon science.
This distinction puts Wakatsuki close to his roots as a graduate student in chemistry at Stanford. “At that time I spent most of my time at SLAC,” he said.
Wakatsuki has long had an interest in both probing the structure of biological molecules and improving the technology used to understand them in ever more painstaking detail.
For much of his career, Wakatsuki has explored the relationships between molecules called ubiquitins that latch onto proteins in our cells. The structure of the ubiquitin chains and the places where they attach themselves to a protein control the role that protein plays in the cell.
Regulating these ubiquitin chains is part of the delicate molecular balance within our cells. When they behave irregularly, cancers, neurodegenerative diseases and inflammatory diseases can result.
Wakatsuki has unraveled the structure of ubiquitin chains using powerful X-ray beams to create a molecular snapshot of ubiquitin crystals in all their myriad configurations. Recently, he has grown interested in how proteins in the cell interact with those different ubiquitin configurations to affect cell behavior.
“This is one of the things that I am very much interested in continuing at SLAC,” he said. “We want to understand how these molecules recognize each other and we need to see it with atomic and molecular detail.”
Wakatsuki’s interest in using X-ray crystallography to answer biological questions has led him to develop new technology for probing molecules at increasing detail. He recently led the development of a new technology at SLAC called macromolecular femtosecond crystallography (MFX) that creates atomic level images of molecules in action at femtosecond timescales — or one millionth of a billionth of a second — critical for glimpsing different configurations of the molecule as it morphs. His team is now developing robots that will automate use of the technology to make it more efficient.
Wakatsuki said that answering big questions like how our cells regulate ubiquitin chains, how molecules move around the cell, and how potential drugs enter the cell and interact with molecules within will require combining existing technologies in novel ways as well as developing new ones.
“We have a really interdisciplinary team and I think that makes it very strong,” said Wakatsuki, who is affiliated with both Stanford Bio-X and Stanford ChEM-H, which encourage interdisciplinary collaboration. “When we develop something we know why we are doing it, we know why it is important and needed to solve such a big question.”