From the time microscopes and X-ray machines were first used to look inside the human body, medical knowledge has grown in quantum leaps with each new view.

Every advance leaves physicians and researchers thirsting for more. At UC Davis School of Medicine, the development of new imaging technology is an important priority that promises the next generation of UC Davis scientists the tools needed to make discoveries only dreamed of now.

"Better imaging allows doctors to be more accurate in diagnosis and more specific at the site of treatment," says Fitz-Roy Curry, associate dean of research at the UC Davis School of Medicine. "It allows our scientists to better understand how cells operate and diseases progress."

A look over the shoulders of three UC Davis scientists who use advanced imaging technologies offers a tantalizing glimpse into the future of medicine.

Focus on cell membranes

Henning Stahlberg, assistant professor in molecular and cellular biology at UC Davis in the Division of Biological Sciences, comes from a physics background, where high-resolution electron microscopy allows atomic physicists to view metals and crystals down to the level of the atom.

But imaging at this intensity is fraught with difficulty. "Biological materials are fragile," said Stahlberg. "They are either immediately burned up under the illumination of the high-energy electron beam, or they can't survive the vacuum required to generate the beam." Stahlberg's interest is in the proteins that lie within the lipid bilayer of cell membranes throughout the human body. Applying his expertise in physics and computer science to his passion for biology, he uses some ingenious methods to circumvent the problems inherent in studying living systems.

The molecular biologist takes membrane proteins through a series of complex steps that involves extracting them from cells, reconstituting them in artificial membranes and quick-freezing them. He then takes thousands of images from different views to create a three-dimensional picture, and extensively processes the images with a computer. This method, called cryo-electron microscopy, results in high resolution reconstructions of the membrane protein structures.

Stahlberg has elucidated the structure of "aquaporins" — channels that allow water to traverse biological membranes, to an astonishing level of detail. These channels form the basis of many biological processes throughout the body, including blood pressure control, tear formation and cerebrospinal fluid balance, to name just a few.

"Understanding the basic science of aquaporins may have important applications in medicine," said Stahlberg. "With a clear picture of the membrane structure, we can design drugs to fit individual proteins and alter the channels in therapeutic ways."

Visualizing thought processes

Cameron S. Carter, professor of psychiatry and behavioral sciences at the School of Medicine and director of the UC Davis Imaging Research Center, uses imaging techniques to answer some fascinating questions about the workings of the mind: How does the brain work when presented with a challenging mental task? How do people with a thought disorder, such as schizophrenia, use their brains differently from healthy subjects?

Using functional magnetic resonance imaging (fMRI), which detects changes in brain activity as patients perform a mental task, Carter literally watches his subjects think. A typical task may be to name the color of a printed word. If the word reads "yellow" while it's typed in blue, the anterior cingulate cortex, an area of the brain's frontal lobe, becomes much more active than when the word and color match. In subsequent trials, another area of the brain, the prefrontal cortex, lights up immediately afterwards, and subjects tend to perform better.

The anterior cingulate's apparent signaling to the prefrontal cortex may be key to helping us pay attention, Carter speculates, and such observations may help us better understand attention disorders.

This is especially important for people with schizophrenia. While most people think of schizophrenia as a disease of hallucinations and delusions, this aspect of it can be fairly well controlled in most patients with available medications. But poor functional outcome in schizophrenia is actually more associated with deficits in cognition, such as an inability to concentrate well and attend to a conversation or other mentally challenging tasks, an aspect that does not respond as well to treatment.

Carter's studies of people with chronic schizophrenia reveal that the anterior cingulate-prefrontal circuit does not work as well and is associated with less effective adjustments in attention.

"We are going back to first principles to look for treatments," he says. Basic research, involving identifying potential targets for treatment through imaging studies, and correlating findings with other modalities, such as electroencephalogram studies, post-mortem studies of brain organization, and genetic studies of relatives of patients with schizophrenia, play important roles.

"The imaging research center provides scientists with ready access to a wide range of state-of-the-art tools for non-invasively imaging the function, structure and chemistry of the human brain in health and disease," he says. "And its interdisciplinary organization that spans the campus stands out."

The center is housed on the UC Davis Medical Center campus in Sacramento. Carter assumed leadership of the center last fall. It is currently expanding to make room for a new MRI scanner, a new event-related potential laboratory, and new computing and informatics resources to support the analysis and display of imaging data.

Designing the future

Simon Cherry, professor of biomedical engineering at UC Davis College of Engineering, not only takes an innovative approach to imaging technology, he is also at the forefront of creating the machinery for it.

"All the imaging technologies that are so important in diagnostic medicine — magnetic resonance imaging, positron emission tomography and computed tomography — could also be invaluable to further basic medical research," said Cherry. "But fundamental changes are needed to adapt them for that purpose."

Taking sophisticated images of small, living animals, often needed for basic research, is a challenge. Instruments must have better resolution because of the animals' size, as well as better sensitivity to detect the tiny amounts of contrast agents required to avoid disturbing the underlying physiology.

Cherry is particularly interested in PET (positron emission tomography) and optical imaging, which provide a snapshot of a body's activity rather than its anatomy. Using immunofluorescent or radioactive tags, researchers can target specific chemical pathways.

With this technique, researchers can tag glucose molecules to observe highly metabolic cells that actively take up glucose, such as cancer cells. This can be useful for testing new drugs.

"With traditional methods, a researcher would have to see if a tumor has shrunk after several weeks on a new therapy," said Cherry. "With this technique, one can see right after administering a drug whether a tumor's activity has been affected and also observe effects in other tissues." Cherry aims to make his instruments available to most researchers by designing them to be reasonably priced and small enough to fit on a lab bench. He has already developed the smallest PET scanner commercially available, marketed as MicroPET by Concorde Microsystems. UC Davis owns two of them, and they are being used by some 20 different faculty members for a variety of applications, including work by David Amaral, professor of psychiatry, on the reorganization of brain circuits after damage such as from a stroke.

A small animal imaging center, located in the new Genome and Biomedical Sciences building, will open this fall and will house PET, CT and ultrasound scanners as well as a cyclotron to produce radioactive isotopes to tack onto molecules for PET imaging.

Stahlberg is also looking forward to taking a closer look at membrane proteins with the next generation of high-resolution electron microscopy. A special microscope facility is being built for his laboratory to house three state-of-the-art transmission electron microscopes.

"UC Davis is an exciting environment to be in," said Cherry. "We are creating a program that is unmatched anywhere else for its depth and breadth."

Curry concurs. "These new imaging technologies offer whole new windows into the body. The physiological information that research can now provide will give us new ways of practicing medicine."