NEWS RELEASE,10/6//99 UC BERKELEY'S HEALTH SCIENCES INITIATIVE: RESEARCH SUMMARIES & STORY IDEAS

By Robert Sanders, Public Affairs

Alexander Pines, Glenn T. Seaborg Professor of Chemistry and senior scientist, Lawrence Berkeley National Laboratory - Pines, a physical chemist and a pioneer in nuclear magnetic resonance (NMR) spectroscopy - a technique that makes possible the study of molecular structures in materials and biology, and also underlies diagnostic magnetic resonance imaging (MRI) in medicine - is engaged in the improvement of NMR and MRI, seeking to make both as simple and efficient as possible. Working with engineer/physician Thomas Budinger, chair of bioengineering and director of the Center for Functional Imaging at LBNL, he has developed a way to "light up" the contrast of NMR and MRI and thereby extend their usefulness. The patented process, using injectable polarized xenon, has been licensed and will undergo clinical trials for imaging the cardiovascular system in ways that will add to today's MRIs. For the future he envisions specialized MRI instrumentation without the need for bulky superconducting magnets: less expensive, portable devices that may fit into a doctor's office. Collaborating with physics Professor John Clarke, a pioneer in the development of exquisitely sensitive magnetic detectors called SQUIDs (superconducting quantum interference devices), they are combining SQUIDs and laser-polarized gases to develop an imaging instrument that can dispense in some circumstances with the large magnets of traditional MRI machines. James Allison, professor of immunology, Howard Hughes Medical Institute investigator and director of the Cancer Research Laboratory - Immunologist James Allison's basic work on how the cells of the immune system work led him to a new immune therapy that soon will enter clinical trials against prostate cancer and melanoma. Unlike other immune therapies that stimulate the body's immune system to attack tumors, this technique releases a natural brake on the immune system to unleash an assault on the cancer. Though the therapy has so far been tried only in animals with melanoma and prostate cancer, the results were impressive enough that the drug company Medarex, Inc. has licensed it and will spearhead human trials to treat cancer. The drug is an antibody that blocks a receptor called CTLA-4 on T cells, the cancer-killing cells of the immune system. "In terms of immune therapies against cancer, this is the hottest thing going" said Eric Small, an associate professor of urology at UC San Francisco, who plans to conduct preliminary prostate cancer trials. Eva Harris, assistant professor of public health - A 1997 MacArthur "genius" award winner, she spent the past 10 years introducing powerful molecular biology techniques to eager but unseasoned researchers in Nicaragua. The goal was part empowerment - helping scientists in this impoverished country get the tools they need to tackle serious health problems - and part practical - arming a front line that is likely to be the first to encounter emerging diseases. Already this work has paid off in tracking the deadly leishmania parasite in remote villages. "With the level of global interconnectedness today, it takes less than 24 hours for pathogens to get from one place to any other on the planet," Harris said. "If we are to combat these infections before they blanket the globe, we have to train people in the Third World to work with us." With a PhD in molecular biology from UC Berkeley, Harris also is investigating the way parasites like leishmania and the dengue fever virus enter cells, in search of strategies that could lead to new therapies. Dengue fever virus is another serious and growing problem in the tropics, responsible for breakbone fever and the more severe dengue hemorrhagic fever. Spread by mosquitoes, it has the potential to invade the U.S., which makes Harris's studies even more urgent. "We're always trying to understand the mechanisms, but also take what we learn back to the people," she said. Tito Serafini, assistant professor of cell & developmental biology and neurobiology; John Ngai, associate professor of neurobiology - Serafini and Ngai have convinced several UC Berkeley researchers to pool their money to set up a laboratory to make one of the hottest technologies in biology today: gene chips. These tiny devices allow researchers to study 20,000 or more genes at once, creating what are called gene expression profiles. By looking at all the genes active in a cell or tissue or organism, researchers for the first time can reach down to what really distinguishes one cell from another - one normal cell from another, a damaged cell from a normal cell, a diseased or cancerous cell from a healthy one. "Gene expression profiles really give us clues to possible therapies," Serafini says. "Gene chips represent a breakthrough in how biology will be done in the next century." Because gene chips have only recently become available, the labs of Serafini and Ngai, together with a group led by Terence Speed, professor of statistics, will be developing the basic methods for using them to discover new science, thanks to a $1.5 million grant from the National Institutes of Health. These methods will help researchers make the best use of the fruits of the Human Genome Project - a database of all 140,000 genes in the human body. Without gene chips and gene expression profiles, though, the gene database is just a laundry list. "Gene chips give us the ability to see how gene expression changes across the entire genome. It has the same potential as electron microscopy when it was first introduced to enable us to see living things in an entirely new way," Serafini says. Dorian Liepmann, associate professor of bioengineering - Liepmann has applied his expertise in how liquids flow to an important area of medical research today, drug delivery. This quickly led to a novel idea - a microdevice that can mix drugs on a microscopic scale and deliver them to a patient from a credit-card sized packet you can slap on your arm. Insulin for diabetics, antibiotics, pain killers - all are possible candidates for the drug delivery device, which Liepmann hopes soon to demonstrate in a prototype. As a national leader in MEMS (micro-electromechanical systems) technology, UC Berkeley was one of few places such a microdevice could be conceived, let alone manufactured and tested. "With MEMS you could make a million of these and make them cheap," says Liepmann, one of the founding members of the new Department of Bioengineering in the College of Engineering. "BioMEMS brings together a whole lot of biology with engineering." Carolyn Bertozzi, associate professor of chemistry - Bertozzi works at the boundary between biology and chemistry, investigating the role of sugar molecules on the surfaces of cells. Over the past decade, biologists have discovered the important role these complex carbohydrates play in normal biological processes as well as in disease and illness, including viral and bacterial infections. She also has found a trick for getting cells to utilize non-natural sugars. These sugars can be modified with useful molecules, such as probes that assist in the identification of cancerous cells. Earlier this year, Bertozzi, 32, was awarded the prestigious MacArthur Foundation Fellowship, often called the "genius" award. Lee Riley, professor of epidemiology & infectious disease - Riley is probing the tricks bacteria use to invade cells, so he can turn them around to solve some of today's pressing health problems. The tuberculosis bacterium is his particular challenge. Riley has synthesized the protein that helps the tuberculosis bacteria gain entry into human cells, and is now using this protein to facilitate the entry of vaccines into human cells. This technique could improve the efficacy of delivery and even target specific diseased cells. Using the protein to gain entry to cells "opens up a whole new approach for delivering vaccines." Riley said. In fact, in the future we all may swallow a capsule filled with engineered bacteria, and let them carry the vaccine to the proper tissues and cells. Corey S. Goodman, professor of neurobiology and Evan Rauch Chair in Neuroscience, director of the Helen Wills Neuroscience Institute and Howard Hughes Medical Institute investigator - Getting nerve cells to grow when and where you want them is easy for the growing fetus but extremely difficult for adults. Which means that today, spinal cord and brain injuries are permanent. But new findings by Goodman and others hold out hope that such damage might be prevented or reversed. They have found the molecular signposts that nerves follow when growing during early fetal development, and now realize that some tell nerves to stop. If a drug can be developed to cancel that message, spinal cord injury could possibly be reversed. "Getting nerves to regrow in cases of spinal cord injury and neural degeneration will likely require finding drugs to block the molecules that block regeneration," he said. The main goal of his work, however, is to explain how the amazingly complex network of the brain gets wired up. "The human brain has ten trillion nerve cells, and they each make hundreds or more likely thousands of connections with each other. How do the circuits get set up? Where is the genetic blueprint for this brain wiring?" Tom Budinger, chairman of the Department of Bioengineering in the College of Engineering and director of the Center for Functional Imaging at LBNL - To cure disease means first to get the diagnosis right, an effort Budinger furthers with new instrumentation that can probe the body like never before. His laboratory developed and operates the world's highest resolution positron emission tomography (PET) machine. It helps diagnose patients with the rarest medical conditions, from unusual tumors to anomalies in brain function. Budinger also works on making instrumentation cheaper and less intrusive so more people have access to the best tests. In the pipeline are a new "gentler" mammography machine smaller than a laptop computer and a much more accurate probe for prostrate cancer. Chair of the new UC Berkeley/UCSF Department of Bioengineering established last year, Budinger well represents the interdisciplinary nature of the new health initiative. Besides being a bioengineer, he is a medical doctor, professor of electrical engineering and computer sciences, professor of radiology at UCSF and director of the Center for Functional Imaging at LBNL. Suzanne Fleiszig, associate professor of optometry - Fleiszig has discovered that several strains of the bacterium Pseudomonas aeruginosa can infect the healthy eye if they remain in contact with the cornea too long. Such over-exposure is possible with the use of extended-wear lenses, when contacts stay on the eye for 30 days or longer. Infection with this bacterium is of particular concern because experience has shown that it can perforate the cornea within 24 hours. Scientists had believed that healthy corneas were imperious to infection by this agent, but Fleiszig demonstrated that only the topside of the cells were resistant. The cellular underside was vulnerable and became exposed when it peeled off to make way for new cells. The difficulty with extended-wear lenses is that they interfere with tear flow, the eye's natural garbage disposal system. Thus, infected cells could hang around for too long under contact lenses. Robert Tjian, professor of molecular and cell biology and Howard Hughes Medical Institute investigator - Before a cell can make a protein, it must transcribe the correct gene into RNA. Then the cell's machinery takes the RNA and builds a precise protein, or thousands of copies of the protein. Altogether more than 100 different molecules are involved in the seemingly simple step of transcribing a gene into RNA. Tjian identified and cloned some 75 of them. With the steps in transcription now almost completely laid out, drug companies are poised to create drugs that target critical proteins in the machinery - to knock out, enhance or regulate the various molecules that control the process. "I think this approach makes good sense," Tjian said. "But we didn't discover how transcription works in order to develop drugs. We just wanted to get to the heart of this fantastic molecular machine." Daniel E. Koshland Jr., professor of the graduate school, Division of Biochemistry & Molecular Biology - Koshland works on protein chemistry that has implications for various diseases, including Alzheimer's disease. One project involves the protein plaques that form in the brains of those with Alzheimer's. His goal is to find a way to interfere with the process by which they form, and prevent the plaques from clogging the brain. A second project involves receptors that sit on the surface of cells and are turned on by hormones or growth factors. He recently proposed a model for how many such receptors work, based on his study of the aspartate receptor. They are like pistons, he says, moving ever so slightly - the bare width of a hydrogen molecule - yet producing profound effects. He has shown that he can hybridize receptors to make them respond to molecules they normally wouldn't. One day, perhaps, genetically engineered cells will be inserted in the body and turned on - to fight cancer or an infection, for example - by eating a chemical that switches them on. Former editor of Science magazine, Koshland was awarded the Albert Lasker Award for Special Achievement in Medical Science last year. Eva Nogales, assistant professor of molecular and cell biology - Using one of the most powerful electron microscopes around, Nogales is taking detailed pictures of the structures inside cells so that drug designers can target them more precisely. Several years ago she and colleagues determined the structure of tubulin, the molecule that forms chains called microtubules that support and move things around inside the cell. Though her basic interest is how microtubules pull the chromosomes apart when a cell divides, she has found a direct connection to health. Specifically, she used what she has learned to look at an important drug that latches onto tubulin - the anti-cancer drug taxol. Using the relatively new technique of electron crystallography, she is trying to find out how tubulin in cancer cells differs from the tubulin in normal cells, and why some tubulin structures are resistant to taxol. Robert Knight, M.D., professor of psychology - To narrow the huge gap between neuroscience and psychology, UC Berkeley has recently appointed a neurologist as a professor of psychology - believed to be the first such appointment in modern times. Knight has a network of 120 patients with discrete damage in particular parts of the brain who will participate as voluntary subjects in a wide variety of basic brain studies on visual perception, motor function, memory, language and attention. Such brain research will allow new integration of biology and psychology, allowing psychologists at UC Berkeley to test cognitive theories in human patients. Next spring, a new $4 million MRI machine will be delivered that will be dedicated solely to research, one of few such machines not intended also for patient diagnosis. Knight was a professor of neurology at UC Davis Medical School for 18 years and a physician at the Veterans Administration Hospital in Martinez, where many of the patients were diagnosed. Knight's appointment is considered a model for other psychology departments elsewhere in the nation.