Harvard Medical School
Dr. Walz is also a professor of cell biology at Harvard Medical School.
Thomas Walz uses molecular electron microscopy to study how membrane proteins interact with lipids, how membrane channels conduct specific solutes, and how protein complexes can change chromatin structure.
Thomas Walz was a University of Basel undergraduate student in Switzerland when he witnessed electron microscopy pioneer Eduard Kellenberger revealing the sophisticated structure of a virus in what seemed like a clear drop of water.
"It was fascinating to watch a transparent fluid put onto a grid and into a microscope and see this wonderful viral structure," he recalls. "It looked like a moon-landing capsule." Walz, now a structural biologist at Harvard Medical School, was captivated. Since then, he has been pushing the limits of electron microscopy, showing that it can do a great deal more than was once thought, including revealing high-resolution details about the architecture of challenging membrane proteins.
Electron microscopy is an important tool in structural biology because it allows scientists to see images of the structure of proteins, sometimes even revealing the protein's amino acid building blocks and their spatial relationships to one another. "If you want to understand a protein and how it catalyzes reactions, you have to see its structure—that's absolutely essential," says Walz, who is also director of Harvard Medical School's electron microscopy core facility.
By focusing a beam of electrons instead of light, electron microscopy delivers images at extremely high resolution. Walz has solved protein structures down to 1.9 angstroms, the highest resolution yet achieved by electron microscopy (1 angstrom is one ten-millionth of a millimeter). His goal is atomic resolution, and he's getting close, because the distance between two atoms is "only" 1.5 angstroms. "We're almost down to a resolution where we can cleanly separate one atom from the next," he says.
Acclaimed as a scientist whose intuition leads him to problems that are slightly off the beaten path yet that consistently yield insights that are transformative in unexpected ways, Walz used electron microscopy to solve the structure of aquaporin-0, an unusual water channel found in the lens of the eye. Unlike other water channels, aquaporin-0 can act either as a water pore, selectively conducting water molecules into and out of cells, or as a cell adhesion molecule. How it does that was unclear. In 2004 and 2005, Walz's group produced two research articles describing the channel's structure at both 3- and 1.9-angstrom resolution and solving the mystery of the channel's dual role.
In young cells, the full-length aquaporin-0 protein is a normal water channel. As cells age, aquaporin-0 is cleaved, which causes it to begin making membrane junctions, where two cells come together at their membranes, a process called cell adhesion. Upon formation of these membrane junctions, the water channels in the interacting proteins close. "The protein completely changes function: from water pore to cell adhesion molecule," Walz explains.
Aquaporin-0 is just one of several proteins in the eye that play more than one role. It's an evolutionary adaptation that occurs because many of the eye's cells lose their organelles—that is, they become sacks containing only proteins. The cell has to get by on the same complement of proteins for the entire life span of the organism because there are no organelles to generate new proteins. So the lens has adapted and learned to use the same proteins for different purposes, a process called gene sharing. "Aquaporin-0 is the first membrane protein implicated in gene sharing," Walz says.
Walz has begun widening the scope of his investigations in several directions, but he's most excited about protein-lipid interaction, mainly because it's an area he says is unexplored. He uses aquaporin-0 as his model to study how lipids with different chemistry and shapes interact with membrane proteins.
Normally, lipid bilayers are very fluid, posing problems for scientists who want to visualize how membrane proteins sit in a biological membrane. Walz makes two-dimensional crystals by purifying a membrane protein and putting it back into a lipid bilayer in a crystalline array, then imaging those crystals. Because aquaporin-0 crystals have only a single layer of lipid molecules between proteins, the lipids are fairly restrained in movement, enabling Walz's team to observe, for the first time, how lipids make nonspecific contact with the protein.
"What is nice is that lipid bilayers have many different types of lipids. Now we can manipulate that lipid and watch how it changes the membrane's interaction with the protein," Walz says. For example, scientists proposed that proteins in a thicker lipid bilayer could adapt by stretching a bit. With the aquaporin-0 crystals, he can now test if this really happens. His aim is to look systematically at the chemical characteristics of lipids and how these affect their interactions with the protein they surround. "These are fundamental questions that before we could only address by indirect methods or by modeling, and now we can visualize the changes directly."