William and Mary maintains a comprehensive program in the life sciences, with strong faculty and student scholarship and graduate research in the areas of Biology, Chemistry, Applied Science, and Marine Science. These departments and schools, working independently and in collaboration, have developed a program that advances key fields of research in the life sciences and human health research The quality of William and Mary's research has been consistently recognized through sponsorship by the National Science Foundation, National Institutes of Health, the Howard Hughes Foundation, and several related federal and state agencies, private foundations and companies. NSF reported that William and Mary ranked first among the top twenty-five "Doctoral Universities" in the country in conferring bachelor's degrees to students who went on to earn doctoral degrees in the physical and biological sciences between 1991 and 1995. In the ten years between 1981 and 1992, our faculty produced the highest number of scientific publications of any predominately undergraduate institution in the nation, according to the Institute for Scientific Information.
Chemistry has ranked second in the nation in the total number of bachelor's degrees awarded among institutions without a doctoral program in the field (notwithstanding the size of our student body). The department has also consistently ranked in the top ten (including schools with doctoral programs) in the graduation of students who are certified by the American Chemical Society.
Graduates from Biology - perennially among the largest undergraduate departments within the School of Arts and Sciences, and the department with the most students taking the GRE exam - average in the 76th percentile on the GRE exam. As an average of all students taking the exam, this figure is exceptional, placing the College among the nation's top schools.
Both programs provide the necessary breadth and depth of scientific training while allowing students the maximum flexibility in the development of an academic program consistent with their career interests. Students, for example can study and conduct research in such interdisciplinary areas as biochemistry, molecular biology, biological psychology, and environmental science, as well as in polymer chemistry and exercise physiology. These interdisciplinary opportunities are enhanced by each department's established partnerships with other academic departments as well as with national scientific facilities located within the region. For example, many of our undergraduates conduct research under the guidance of faculty within the College's School of Marine Science/Virginia Institute of Marine Science as well as within the laboratories of our Applied Science graduate program. Locally, students and faculty also conduct research in collaboration with the Department of Energy's Thomas Jefferson National Accelerator Facility (Jefferson Lab) and the NASA Langley Research Center. In addition, the College is one of four university partners establishing a laboratory facility - the Applied Research Center (ARC) - in a new research park adjacent to Jefferson Lab.
Many of William and Mary undergraduates continue on in their scientific careers, and among these a number have received prestigious awards. Since 1990, 15 science graduates have received NSF Predoctoral Fellowships, four have been awarded scholarships from the NIH Medical Scientist Training Program (MSTP), and five have received Howard Hughes Medical Institute (HHMI) Predoctoral Fellowships. Eleven of the 15 NSF predoctoral award winners were biology and/or chemistry majors, and all of the NIH MSTPs and HHMI fellowships were awarded to biology and/or chemistry majors.
A large number of students from both the Biology and Chemistry Departments go on to medical school or graduate school within their respective fields, including such schools as Harvard, MIT, Cornell, University of California-Berkeley, University of Chicago, Stanford, Princeton, Yale, Columbia, Northwestern and Johns Hopkins. For example:
- For the last three classes of chemistry graduates, 44% went on to graduate school in chemistry or a closely related scientific field, and 13% continued on to medical school;
- Within biology, approximately 45% go on to receive a doctoral degree (26% medical, 12% biological sciences, and 7% other, including dental). Another 25% go on to receive a master's or law degree; and
- In 1996, 65% of students who applied to medical school were accepted, as compared to 38% nationwide. (Approximately 66% of these students are biology majors, and 10% chemistry majors.)
After leaving William and Mary, many of our students make significant contributions to their respective fields. Biology alumni Michael Fitch '93, for example, is now a student in Case Western Reserve's M.D./Ph.D. program. Although he is still a student, he has already won a NIH Medical Scientist award and published the cover story in an issue of Experimental Neurology (as the first author of two), a short paper in Nature, a review chapter in a book currently in press, and several other papers.
Conducting hands-on research with faculty mentors is an integral part of William and Mary's science program. Our biology and chemistry students work one-on-one with all of our faculty, including several who have been recipients of national awards. For example, in 1995, President Clinton named biology professor Margaret Saha a Presidential Faculty Fellow-an award which was accompanied by an unrestricted $500,000 grant from NSF which has supported her research efforts in developmental biology and neurobiology. During the 1996-97 academic year, 55 chemistry and 68 biology undergraduates conducted independent research with faculty mentors. The College also conducts an extensive, ten-week summer research program across the disciplines; during summer 1998, 45 chemistry undergraduates and 22 biology undergraduates conducted scientific research on campus. The focus of the research range from molecular biology to pharmaceuticals.
In Vivo Gene Imaging
At present it is virtually impossible to assay gene expression in mammals without sacrificing the organism and performing biochemical or molecular assays. A collaborative group form the College's Biology Department (Drs. Bradley and Saha) and the Jefferson Laboratory Detector Group (Dr. Majewski) are currently engaged in experiments to develop a system using I-125 attached to a specific molecule as the probe and a novel position sensitive photomultiplier tube detector. They are currently using this technique to perform real time imaging of a number of biologically important molecules (including GnRH, melatonin, and a cocaine analog that binds to dopamine transporters) and are successfully obtaining in vivo images of gene products. The ability to monitor gene expression in vivo in real time allows for the possibility of following gene expression under an array of different conditions including monitoring the effects of various drug treatments to tracking potential gene therapies.
In addition, Dr. Eric Bradley is specifically applying this imaging technology to diabetes research (Bradley, Eric L., "Imaging Diabetes: An In Vivo Analysis of the Insulin, Leptin, and TNF Ligand-Receptor Systems," American Diabetes Association). The goal of this project is:
- to develop and provide a new tool to investigate critical research questions within the diabetes field, namely, an in vivo imaging system for critical molecules implicated in the pathogenesis and later clinical complications of diabetes; and
- to apply this imaging technology to test commonly held views in the field that could benefit from rigorous testing via other methodologies, and, should they be warranted by the data, to propose alternate hypotheses or models.
More specifically, Dr. Bradley wishes to test the general hypothesis that receptor abnormalities, particularly that of the insulin receptor, the leptin receptor and the TNFa receptor, are central in the pathogenesis and chronic complications of Type 2 diabetes. This work will involve:
- optimization of the imaging system for the detection and analysis of critical molecules implicated in the pathogenesis of diabetes;
- determination of the "normal" profile of key ligand binding distribution during the lifespan of normal mice;
- determination of the normal distribution of the binding locations for the ligands of interest in a naturally occurring population of genetically variable mice; and
- determination of the profile of these ligands during the induction of diabetes in two model systems for diabetes, namely streptozotocin-induced and feeding-induced.
Genetic and Behavioral Bases of Alcoholism
The age at which alcohol consumption by young adults begins is reported to be ever decreasing with recent surveys indicating that over 10% of 13-year-olds and about 70% of high schoolers consume alcohol. In light of these astonishing statistics, our lack of understanding about the underlying causes of adolescent-onset drinking is surprising as well as disturbing. Most investigations of the genetic bases of alcoholism employ highly inbred strains of rodents as model systems, models that do not accurately reflect the variation present in the human population. The laboratory of Dr. Eric Bradley is using the species Peromyscus leucopus to select for preferrer and avoider phenotypes in a natural population. Following a selected breeding regimen the avoider phenotype has been intensified and shown to be inheritable and linked with defective alcohol metabolism via the alcohol dehydrogenase gene product.
However, it is also recognized that genetics alone cannot account for the prevalence of alcohol abuse. Experiential factors must also act, either alone or in concert with genetic predispositions. Due to the early age of onset of alcohol consumption patterns, it is likely that experiences with alcohol occurring very early in life contribute to later acceptance of this drug. The laboratory of Dr. Pamela Hunt (Psychology) is investigating these experiential factors. The specific aims of this proposal are to examine these types of early experience and how they might contribute to a young organism's learning positive associations between alcohol and affective context. The studies will focus on using the developing rat as a model system. It is anticipated that the detection of respired alcohol in this situation will increase later alcohol intake. Both types of early experience with the odor and taste of ethanol could have a substantial and possibly long-term impact on an animal's willingness to ingest alcohol.
There is a tremendous amount of individual variation in brain structure and function that has important health consequences including adverse drug reactions and inappropriate drug dosages. We know little about the underlying neuroendocrine bases of individual variation, nor do we have anything more than an empirical sense of how to deal with brain variation as a public health issue. The laboratory of Dr. Heideman (Biology) investigates individual variation in a neuroendocrine pathway that is known to contain high levels of genetically based individual variation--the pathway through which photoperiod inhibits reproduction in short days, but stimulates it in long days. In humans, elements of this neuroendocrine pathway are thought to play a role both in reproduction and in some types of depression. Preliminary work on a white-footed mouse, Peromyscus leucopus, model has identified variation in circadian characteristics, putative melatonin receptor abundance, and food intake that are correlated with genetic variation in reproductive inhibition in short days. This work will uncover the genetic basis for this variation, and will provide us with information on the kind of variation we can expect to find in brain pathways in natural populations, including human populations.
The laboratory of Dr. Eric Bradley is using the same genus to investigate the role of the adrenal in the control of reproductive inhibition that occurs in the prairie deermouse (Peromyscus maniculatus). This species has been shown to control numerical population growth via a natural suppression of reproductive maturation in young born into dense populations. The basic mechanism for this appears to involve a failure of at least 90% of these young to pass through puberty. This inhibition is completely reversible if the inhibited animals are removed from the population context. It has been shown that the adrenals of inhibited animals have different cellular morphology; the pubertal transition in terms of adrenal and gonadal cellular development at the light and electron microscopic level as well as the molecular level is currently being investigated. This study should reveal the nature and degree of the relationship between adrenal development and gonad maturation in the normal pubertal transition of deermice and serve as a model for the role of the adrenal in human idiopathic infertility.
Critical in all endocrine processes are nuclear hormone receptors that serve as transcription factors that alter gene activity in response to hormone. Mutant receptors are associated with a variety of endocrine and neoplastic diseases. A challenging direction for the future is to integrate understanding of gene regulation at the level of DNA-protein interactions with the additional levels of control made possible by the compartmentalization of eukaryotic cells. The research of Dr. Liz Allison (Biology) addresses the molecular mechanisms regulating nuclear localization and subnuclear distribution of the thyroid hormone receptor (TR). Factors contributing to nuclear localization are being characterized by a two-fold approach: analysis of the trafficking of native and green fluorescent protein (GFP)-tagged receptors in mammalian cells, and testing the ability of exogenous factors to enhance nuclear retention of TR in Xenopus oocytes. Elucidation of mechanisms that target and retain TR in the nucleus will aid in understanding how failure to appropriately coordinate this process may contribute to abnormal or diseased states.
Cellular Determination and Plasticity
The molecular mechanisms of immunity involve specific transcription factors that determine the differentiation and activation pathways that generate immune responses. The research of Dr Patty Zwollo (Zwollo, Patty, "CAREER: Mechanisms Regulating Activity of the Pax-5 Transcription Factor During B-Cell Development," National Science Foundation.) has focused on the transcription factor Pax-5, which is expressed in mouse B cells, as a key regulator in the differentiation of this cell type. Recent data indicate that alternatively spliced products (isoforms) of this factor are differentially expressed during B cell development. Two of these are particularly interesting because they may have opposite activities: one isoform, Pax-5a, activates transcription of target genes, whereas Pax-5d, which does not possess a transactivating domain, may repress transcription. The generation of monoclonal antibodies may be potentially useful for a variety of practical applications. For example in clinical tests, they may provide a diagnostic marker for tumor growth and leukemias; they may also be applicable for environmental monitoring studies where the stress of anthropogenic pollutants has been shown to be related to increases in the incidence of immunosuppression and tumor development in lower vertebrates.
The research plan of the laboratory of Dr. Michael Deschenes (Kinesiology) is designed to reveal novel information concerning the determination and remodeling of the neuromuscular system as a result of alterations in physical activity in both the young and the aged. These analyses focuses on the morphological adaptations in the neuromuscular junction (NMJ), as well as changes in the expression of synapse specific molecules known to regulate the function of that synapse. Plasticity of the NMJ resulting from varied neuromuscular stimuli will be studied in both Type 1 (slow-twitch) and Type II (fast-twitch) muscles since synaptic structure is specific to muscle fiber type. Another primary objective will be to compare the plasticity of the NMJ vis-a-vis morphological and biochemical remodeling of muscle fibers in response to altered neuromuscular activity and aging. The proposed experiments represent an encompassing investigation into several unexplored areas of activity including senescence related remodeling of the neuromuscular system and the potential mechanisms involved in such plasticity.
The primary focus of the research in Dr. Margaret Saha's laboratory is to elucidate the mechanisms by which cells in the developing vertebrate embryo adopt a particular fate and maintain it throughout their lifespan. The significance of these questions is twofold. First, embryonic cells share many similarities with cancer cells, therefore understanding the biochemical signals by which embryonic cells communicate and grow in a controlled manner may yield important insights about cancer cells and their aberrant growth. Second, embryonic tissues and cells display an amazing degree of plasticity, that is, the ability to adapt to new environments and conditions, even adverse conditions. We are currently addressing these questions by focusing on the biochemical signals that lead to the determination of neural cells and vascular cells and by attempting to decipher the mechanisms by which cells are able to change their fate.
Genetics of Infertility
Approximately 15% of all Virginia couples are infertile, and fully half of the problems are due to male infertility. These problems can be aided by basic biological and applied studies of genetic factors affecting fertility. Researchers in the laboratory of Dr. Diane Shakes (Shakes, Diane C., "Metaphase to Anaphase Transition in Mitosis and Meiosis," National Institutes of Health) are using the model organism. C. elegans, to isolate and identify mutants with defects in meiotic chromosome segregation. Molecular genetic analysis of such mutants is helping them identify and functionally analyze the molecular players in C. elegans meiotic chromosome segregation, many of which will undoubtedly play similar essential roles in human meiotic chromosome segregation. In more applied studies Dr. Stan Hoegerman (Biology) is studying aneuploidy (abnormal chromosome numbers) in sperm from normal and infertile human males using fluorescent in situ hybridization technology. Using this methodology, chromosome-specific DNA sequences are bonded to the studied chromosomes allowing their enumeration.
Dr. John Griffin (Griffin, John D., "CAREER: Physiological Responses and Anatomical Pathways Involved in the Generation of an Immune Response," National Science Foundation) is exploring the generation of immune responses.
Dr. Mark Forsyth (Forsyth, Mark H., "A Comparative Genomic Approach to Genetic Diversity Among Virulent and Avirulent Helicobacter pylori Isolates," The Jeffress Memorial Trust) is exploring issues in genetic diversity.