Biochemistry, Structural Biology
Janelia Research Campus
Dr. Gonen is a group leader at the Janelia Research Campus. Prior to this he was an HHMI early career scientist from 2009 to 2011.
Structural membrane biochemistry and MicroED method development in cryo EM
Tamir Gonen was 15 years old when he immigrated to South Africa from Israel. As Gonen struggled to master English, a teacher suggested he might be best suited for a career in business, rather than pursuing chemistry and biology. "I was told I had absolutely no aptitude for those subjects," recalls Gonen. But after stints as a business and medical student in New Zealand, where his family moved next, Gonen determined that scientific research was his calling.
Today, Gonen's research centers on the exploration of membranes, the two layers of lipids that encapsulate cells. In particular, he is interested in the proteins embedded in membranes that form gateways channeling everything from chemical signals and nutrients to wastes and pathogens. A cell's surface is studded with a dense and diverse array of such structures, each specialized to perform a particular job. "Every cell in the human body is separated from its environment by a membrane," Gonen explains. "And everything that happens between a cell and the outside world happens through these gateways or channels."
Understanding how membrane channels work provides insights into cell function as well as into human disease. For example, people with type 2 diabetes cannot regulate the amount of glucose circulating in the bloodstream. One family of channels on the surface of human cells, known as glucose transporters, is responsible for funneling nutrient sugars from the bloodstream to cells. "Once we know the channel's structure, we could begin to understand its function, and one day it may be possible, for example, to use this information to design drugs to make a channel work faster or slower," he says. "It might be possible to find a way of better controlling circulating blood glucose."
One way to understand how channels function is to see how they are built. To that end, Gonen employs methods in structural biology—some of which require growing crystals of particular molecules and then either bombarding the crystals with x-rays or electrons or visualizing samples with powerful electron microscopes—to tease out the three-dimensional structures of channel proteins.
But obtaining the structure of biological molecules is no easy feat. For one thing, it is often tricky to grow crystals of sufficient size and quality for analysis. Membrane proteins, in particular, resist being dissolved in solution, the first step in growing crystals. To alleviate the crystallization problem, Gonen's group developed MicroED, a method for structure determination from vanishingly small crystals. "The crystals we use for MicroED are a million to a billion times smaller in volume than the crystals needed for x-ray crystallography."
Gonen's lab is now split roughly 50-50 between method development (MicroED) and membrane biochemistry. The proteins Gonen studies are all involved in maintaining the correct ion, water, and nutrient balance in cells. He hopes that if we know how they are built, we can also learn about how they work. "There are still a lot of biological questions we have regarding how membrane proteins help cells maintain homeostasis."
In 2005, Gonen produced an exquisitely detailed portrait of crystals of aquaporin-0, the channel that allows water molecules to pass one at a time through the cell membrane. Gonen was able to crystallize the aquaporin protein in a lipid bilayer, allowing him to visualize the contacts between lipid molecules and protein. The work, hailed as a breakthrough by scientists in the field, gave a first glimpse at how membrane proteins function in their lipid habitat and how the lipids accommodate the embedded protein.
Seeing a biological structure in all its molecular detail for the first time, says Gonen, is a thrill that a career in business would have been unlikely to evoke. "When I take a protein sample, put it in the electron microscope, and crank up the magnification, I feel like an explorer. I'm the first person in the world to see this protein. That's what I think is really cool."