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, now a biochemist at the University of Washington. 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. And by the time he completed his postdoctoral training in the lab of HHMI investigator Thomas Walz at Harvard Medical School, Gonen had already made his mark.

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 channels’ 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. As a result, no one has yet obtained a high-resolution structure of a mammalian facilitative glucose transporter.

Gonen’s lab is trying hard to accomplish this feat with cryoelectron microscopy—a type of electron microscopy that allows for observation of specimens at very cold temperatures, thus preserving their native structures. By combining several static images of glucose transporters in different conformations, Gonen plans to build a movie of a glucose transporter as it shuttles sugar molecules through the cell membrane.

He has already used cryoelectron microscopy to reveal the workings of another, smaller, channel. In 2005, working in the Walz lab, 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.”

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RESEARCH ABSTRACT SUMMARY:

Tamir Gonen uses molecular electron microscopy to study structures of large protein complexes that function as molecular machines.

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Photo: Paul Fetters