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Tiny protein molecules are big players in solving the mystery of brain function

Axel Brunger came to Stanford nine months ago in search of clues to the nuts and bolts of brain function. His quest has led him to study proteins involved in regulating the brain's communication system.

"The goal that we have is to understand the proteins and their functions at the three-dimensional molecular level," says Brunger, who holds faculty appointments in three departments at Stanford.

He points out that communication in the brain is similar to the inner workings of a computer. Both use electrical signals to transmit information. While computers send signals through wires, brains transmit messages through nerve cells called neurons. The brain uses the complex neuron network to relay information to muscles, organs, glands and other neurons. "It's like the electrical links between computer chips," Brunger says.

This intricate messaging system lies at the very base of cognitive processes such as thinking, memory and emotions allowing different parts of the brain to communicate with one another. Scientists have a reasonable understanding of what this communication system is capable of, but how it works at the molecular level remains a mystery.




Brunger's research focuses on the exchange of information at the junctions between neurons, known as synapses. Special proteins are integral parts of the process of neurotransmission across synaptic junctions, and understanding how these proteins work is key to solving the mystery of brain function.

"Some of the proteins of this molecular machinery might be targets for pharmaceutical compounds," Brunger predicts. He hopes the research could lead to new treatments for neurological disorders such as depression and schizophrenia.

To study individual molecules such as proteins, scientists need a way to see them. Ordinary light microscopes will not work because the wavelengths of visible light are longer than the dimensions of the atoms that make up a protein molecule.

Fortunately, the wavelength of X-rays can be just the right size, but the X-ray machine at your doctor's office is not strong enough to observe molecules at the atomic level. For a more powerful source of X-rays, Brunger and other structural biologists on campus use radiation produced at the Stanford Synchrotron Radiation Laboratory (SSRL).

SSRL works by sending electrons zipping around a synchrotron ring 240 feet in diameter. Forcing electrons to move in a circle causes them to produce X-rays. This radiation, coveted by scientists today, was actually considered a nuisance in the 1960s and 1970s when synchrotron rings were used primarily by physicists studying the properties of matter.

"Initially, structural biologists were parasites on these synchrotron X-ray sources," Brunger says. But today, SSRL is dedicated for use by scientists like Brunger who are doing research on the molecular scale. In fact, proximity to SSRL was one of the main reasons Brunger decided to leave the faculty of Yale University last year to come to Stanford.

"SSRL is one of the few places in the world that produces intense X-rays," Brunger says, noting that the university also has attracted one of the highest concentrations of scientists in the world using single molecules to study biological problems.

"There's really a unique opportunity for collaboration here," he observes.


Diffraction patterns


Brunger's research focuses on the reflected light produced by a protein molecule when it is hit by an intense X-ray beam. The pattern of scattered intensities contains clues about the shape of the proteins. Although each molecule contains the information Brunger is after, the scattering produced by a single molecule is too weak to study using current X-ray sources. However, a plan for an even more powerful X-ray source is underway at SSRL, called the Linac Coherent Light Source, which Brunger says could potentially revolutionize structural biology.

In the meantime, Brunger and other scientists use a technique called X-ray crystallography. The idea is to create a lattice of identical molecules that all produce the same scattering pattern, thereby bolstering the strength of the signal. By adding the proteins to mixtures of various liquids, salts, metals, fats, acids and bases, scientists can create crystals made of proteins.

Once he has created protein crystals, Brunger takes the most promising specimens to SSRL and exposes them to X-ray radiation. The diffraction patterns produced by the protein crystals contain information about the shapes of the neurotransmitter proteins. Sophisticated mathematical techniques are used to interpret the diffraction data. Brunger uses this information to create images to represent the three-dimensional structure of the proteins.

"We can't really see proteins with our eyes, so we use computer graphics models to visualize them," he notes.


Groundbreaking research


Brunger's groundbreaking research bridges the gaps between traditional scientific disciplines. He holds appointments in three departments Molecular and Cellular Physiology, Neurology and Neurological Sciences, and SSRL. He also is an investigator at the Howard Hughes Medical Institute.

"My work has always been at the fringes of different disciplines," Brunger says, noting that he was recruited to Stanford last year as part of the Bio-X initiative an interdisciplinary program designed to encourage faculty from different departments to collaborate on innovative bioscience research.

So far, Brunger and his graduate students and postdoctoral fellows have pinned down the structure of more than 10 proteins and protein complexes involved in neurotransmission. Having a picture of these structures will help scientists understand their function.

"Neurotransmission is a very dynamic system of interactions," Brunger says. "It's like an engine with moving pistons. We don't know how they interact with the other components of the engine yet. We really want to understand how these proteins interact, because that will tell us more about how they work."

Brunger and many colleagues think the action of some of the proteins involved in neurotransmission may be a basic biological process that works in other areas of the body as well as the brain. A very similar process takes place in the release of hormones such as insulin. "There are potentially other areas where this research might have an impact," he says. "That's the benefit of working on a really fundamental machinery."



By Betsy Mason

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