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From Genetics to Cell Communication
From The Biochemistry of Pain to Imaging

SUNY Downstate has been a pioneer in medicine and science since its founding in 1860. Its role as a biomedical research leader was confirmed in 1998 when Dr. Robert F. Furchgott, distinguished professor emeritus, was awarded the Nobel Prize in Physiology or Medicine for his discovery of endothelial-derived relaxing factor and his subsequent discovery that EDRF was the molecule nitric oxide (NO). Dr. Furchgott’s surprising discovery that such a simple molecule could play such an important role in the body has changed how high blood pressure and heart disease are treated. It has led to the creation of Viagra, the impotence drug. And it is being studied by researchers concerned with preventing shock, cancer, and neurological dysfunction.

Well before the turn of the twentieth century, however, researchers at SUNY Downstate were contributing to the growth of scientific knowledge and applying their findings to improving clinical care. Breakthroughs of the last 50 years have ranged from Dr. Clarence Dennis’s development of the first heart-lung machine in 1957, to Dr. Evelyn Witkin’s elucidation of basic DNA repair mechanisms in 1960, to Dr. Raymond Damadian’s producing the first human images using magnetic resonance imaging in 1977.

The research of Dr. Alfred Stracher, another distinguished professor, has focused on the chemistry of muscle proteins, the molecular mechanisms of muscle-wasting diseases, and, most recently, interventions to inhibit deterioration in muscular dystrophy and other disorders. Over the years Dr. Stracher’s work has substantially expanded scientists’ understanding of neuromuscular and neurodegenerative disorders and provided promise for the treatment of conditions ranging from Alzheimer’s disease to spinal cord injury. In studies in a quite different vein, Dr. Mimi Halpern’s investigations of the vomeronasal organ--a poorly understood sensory system in vertebrates--are yielding new insights into such animal behaviors as prey recognition, pheromone detection, and courtship activities. Dr. Gerald Schiffman has developed a pneumococcus vaccine tailored for elderly patients, and SUNY Downstate researchers in the 1980s and 1990s have gained new insights into the transmission of the AIDS virus from mother to unborn child.

Many current biomedical research activities at SUNY Downstate received initial impetus in the mid-1980s, when an influx of New York State and philanthropic funds permitted the development of the Morse Institute for Molecular Biology and Genetics. At that time the departments of pharmacology and anatomy and cell biology expanded through the addition of new faculty talent. Research laboratories were rebuilt and fitted with state-of-the-art equipment needed for DNA synthesis and other sophisticated procedures that now are basic to biomedical research. The 1990s are experiencing a commensurate buildup in neuroscience, funded by grants from government agencies, foundations, and corporations. Currently research funding institution-wide is approximately $40 million annually--double what it was only a few years ago.

One of the largest ongoing studies at SUNY Downstate--also one of the largest research projects ever funded by the National Institutes of Health (NIH)--is the Collaborative Study on the Genetics of Alcoholism, for which Dr. Henri Begleiter, professor of psychiatry and neuroscience, serves as principal investigator. The national, multi-institutional study, part of the 15-year NIH-funded Genome Project, is attempting to identify genetic and other markers of alcoholism. It builds on Dr. Begleiter’s observation some years ago of a remarkable correlation among distinctive abnormal brain wave patterns in alcoholic men and their sons. That discovery led him to focus on the genetic basis of alcoholism and other addictive behaviors, as well as apparently related cognitive deficits affecting the ability to process information efficiently.

Based on the promising results produced in its first five years, the genetics of alcoholism study was refunded in 1994 for an additional five years. Recently Dr. Begleiter and his colleagues announced the identification of several genetic loci related to alcoholism on multiple chromosome sites--work that they reported in Electroencephalography and Clinical Neurophysiology. Of special significance, their findings demonstrate the complexity of inheritance, in that certain genetic loci that have been linked to alcoholism may interact with some neurophysiological factors to produce pathology in one individual, while another individual carrying the same “marker” genes may not manifest the condition. The work contributes new insights into the heritability of behavior, with important implications for the science of genetics.

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From Genetics to Cell Communication
From The Biochemistry of Pain to Imaging

From Genetics to Cell Communication

mcalister.jpgThe work of Dr. William T. McAllister, who has chaired the Department of Microbiology and Immunology since 1986, focuses on a quite different aspect of genetic research. Dr. McAllister and his colleagues are studying the processes through which DNA imparts the instructions that dictate how cells develop and function. Specifically, his research focuses on the use of phage RNA polymerases in nucleic acid probes and in expression systems for cloned genes. Dr. McAllister has recently published his work in the Journal of Molecular Biology and Protein Expression and Purification.

In the simplest terms, RNA (ribonucleic acid) is the subcellular “messenger” that transmits information encoded in the DNA residing in the chromosomes of all cells. The RNA carries instructions (reverse copies of DNA nucleotide patterns) and translates them for the construction of the proteins, or enzymes, that accomplish the work of living organisms, from building tissue to dictating when different cell activities are “turned on.” Understanding exactly how genetic material is transcribed from DNA into RNA is essential to understanding—and ultimately influencing—gene expression.

The enzyme that is responsible for copying the DNA into RNA is called RNA polymerase, and Dr. McAllister and his associates have been using a small RNA polymerase encoded by a virus that infects the common bacterium E. coli as a model. The three-dimensional structure of this enzyme is known, and they have been using computer modeling to understand how the various elements of the polymerase influence enzyme function. The questions they ask concern how polymerase recognizes and utilizes the DNA’s control signals, and then how the RNA disengages from the template. These studies have stimulated much interest among other researchers because T7 RNA polymerase is structurally related to other important polymerases, including the reverse transcriptase utilized by the virus that causes AIDS.

While Dr. McAllister’s work focuses on subcellular processes, the work of Dr. Robert K.S. Wong, chairman of physiology and pharmacology, looks at mechanisms of communication among cells, particularly those of the brain. Dr. Wong pioneered a technique for isolating single neurons in living brain tissue, allowing detailed observation of the molecular and chemical properties of receptors on a cell’s surface. His experiments have focused on the firing patterns and interactions of cells in the hippocampal region of the cerebral cortex--a part of the brain involved in learning, navigation, and memory.

From observations of cell excitation in simulated epileptic seizures, in which cells fire in out-of-control wave patterns, Dr. Wong and his colleagues identified two neurotransmitters, glutamate and gamma-aminobutyric acid (GABA), that are involved, respectively, in stimulating and inhibiting cell firing patterns both in seizures and in such normal brain functions as the laying down of memories (“long-term potentiation”). They have shown that cell receptors for GABA, the inhibitory neurotransmitter, are regulated by intracellular calcium and phosphorylation, and they have discovered a novel excitatory synaptic action of GABA among inhibitory neurons that has yielded new insight into signalling processes in networks of neurons in the hippocampus. This insight could lay the groundwork for developing new drugs to control epileptic seizures, and it offers promise for understanding basic mechanisms of memory and other brain activity. This work was described in recent papers in Science and the Journal of Neurophysiology.

Cells of the hippocampus and related areas of the cerebral cortex are also the research focus of Dr. Robert Muller, professor of physiology. Dr. Muller has been collaborating with Dr. James Ranck in the Department of Physiology and Dr. John Kubie in the Department of Anatomy and Cell Biology to understand brain processes related to navigation: that is, how animals (and humans) form internal maps of their external environments in order to know where they are and how they can get to where they want to go. By implanting electrodes to record the firing of individual hippocampal cells in living rats placed in a variety of environments, Dr. Muller and his colleagues can study identified types of cells (“place cells” and “head direction cells”) that are involved in navigation.

Among other projects that build on these findings is a mathematical model Dr. Muller is developing to translate biological environmental mapping to the practical problem of constructing a mobile robot that can navigate better than any thus far developed. The U.S. Office of Naval Research is funding this work with the goal of constructing an actual robot, in collaboration with robotic engineers at Case Western Reserve University in Cleveland.

Dr. Muller also is pursuing the implications of his group’s discoveries about hippocampal processes in work focused on how memories are created and stored in the brain. Recently, the research team found that place cells formed in a new environment can be destabilized by injecting a drug that interferes with known memory mechanisms in the hippocampus. Dr. Muller has published his work in Science, the Journal of Neuroscience, and Cell.

Dr. Muller, Dr. Wong, and other researchers are now finding multiple convergences of interest, and we are rapidly assembling the critical mass of expertise needed to develop a center of excellence in the field of neuroscience.

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From The Biochemistry of Pain to Imaging

From the Biochemistry of Pain to Imaging

barbour.jpgThe work of our neuroscientists is complemented by the activities of other researchers in related disciplines. Dr. Alan Gintzler, professor of biochemistry, is looking at biochemical events that underlie pain perception and addiction.

In studies of responses to pain during pregnancy, Dr. Gintzler found that women’s pain thresholds vary over time depending on the particular stage of pregnancy. This is related to changes in circulating blood levels of the ovarian steroid hormones estrogen and progesterone. As a result, pain tolerance increases as gestation progresses. He further found that endorphins become activated, under the influence of estrogen and progesterone, and then act as the body’s own pain-attenuating agents. In contrast to commonly used epidural analgesics, these endorphins activate combinations of opioid receptors. This suggests the possibility of new approaches to the pharmacological control of pain.

Dr. Gintzler’s insight that pain is strongly mediated by the body’s hormonal milieu has important implications for pharmaceutical management of pain in women--not only during pregnancy and labor but throughout the menstrual cycle and, in particular, following menopause. His work also demonstrates that pain control is gender-specific, and that the results of studies of the effectiveness of analgesics in men may not apply to women.

Dr. Gintzler also studies the biochemical underpinnings of addiction. His research has identified how some key enzymes active in the body (such as adenyl cyclase) are changed by exposure to addictive substances. His goal is to understand the mechanisms through which such changes take place and lead to addiction, a state in which the body’s biochemical equilibrium is so altered by a drug that a continuing supply is required to maintain the new balance.

The research of Dr. Randall Barbour attacks an entirely different set of challenges, focusing on the development and application of near-infrared technology—a new imaging technology that promises to be more portable, more sensitive, safer for patients, and less expensive than most diagnostic imaging technologies currently in use. It is entirely appropriate that NIR technology should be developed at SUNY Downstate, where the first human images using magnetic resonance imaging were produced in 1977.

Dr. Barbour’s patented approach generates images of internal body structures through computerized analysis of the scatter patterns of refracted light. The technology, which is based on well-understood principles of mathematics and physics, does not require the use of nuclear materials or tissue-damaging types of radiation, and it can be employed either alone or in tandem with other imaging techniques. Because of its precise targeting cap-ability, NIR has potential for therapeutic applications in addition to its advantages in diagnosis.

Already Dr. Barbour and his colleagues have built a first-generation clinical imaging instrument capable of analyzing interior structures to a depth of 15 centimeters. They expect to employ a second-generation instrument in clinical trials before the end of 1998. In the last year alone, they have published 24 articles in such scientific publications as the Journal of Applied Optics and the Journal of Biomedical Imaging.

This brief survey can only touch on a few of the many fascinating studies under way at SUNY Downstate today, as we continue to build on the momentum that has developed in recent years. Our scientists’ rich history of accomplishment is being ably carried forward by the current generation of faculty researchers and the research associates, students, and fellows who contribute so much to their work.