With a multimillion-dollar electron microscope and computer programs that can pick out the shapes of structures only six atoms wide, Dr. Wah Chiu and his colleagues at Baylor College of Medicine
in Houston are attempting to explain the intricate structures of viruses and proteins.
"What we’re trying to do is understand the architectural design of biological molecules," said Chiu, director of the National Center for Macromolecular Imaging at Baylor and a professor in the department of biochemistry. "Genetics alone is not sufficient, it’s just the beginning. You need both genetics and structures to understand the functions of proteins and protein aggregates."
Chiu has over 50 collaborators around the world who work with him to develop three-dimensional images of the molecules they study in their own labs. These images can help the scientists make hypotheses about the functions of different parts of a protein.
In addition, the shape and organization of a molecule might lead to new ideas for antiviral drugs or vaccines, he said. For example, if a virus consists of five types of molecules arranged repetitively in a sphere, a researcher might think of ways to disrupt this pattern to render the virus harmless, like plug the hole or destabilize the ring.
"Having a structure really can focus their attention on what’s the next best experiment to do," said Chiu. His lab has determined the structure of the herpes simplex virus type 1, LDL cholesterol, and calcium ion channels, among other things.
Visualizing molecules on this scale is not as simple as peering into a microscope, however. First, researchers have to isolate the virus or protein of interest and prepare it specifically for electron microscope viewing. Chiu has three electron microscopes; in the most powerful one the sample is frozen to 4.2 Kelvin (almost –270 °C) with liquid helium.
Once the sample is ready, a skilled microscope scientist takes a picture, which looks to the naked eye like a grainy black and white image. Digital images of the molecule form multiple angles are then sent to Chiu’s computer lab and fed into a computer program that produces a three-dimensional image.
"The first question is ‘What do these molecules look like? Do they look like peanuts or donuts or a steak or spaghetti?’" said Chiu. "By the look, you can make a deduction about how these actually work or what they’re used for."
Scientists in Chiu’s lab can also determine if groups of interconnected proteins change their shape in response to different environmental conditions. If so, they can create three-dimensional animations of this movement.
Chiu and his colleagues are constantly working to improve the image-generating computer programs to be able to visualize the finest possible detail. Even though he can now ‘see’ structures six atoms across, he’s thinking smaller and looking for ways to cut that limit in half. http://www.bcm.tmc.edu