ADVANCED IMAGING TECHNIQUES GIVE MEDICAL RESEARCHERS A
WHOLE NEW OUTLOOK
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
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
"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."