News and Publications

Year In Review - 2000

Molecular Biology

Peter E. Wright, Ph.D., Chairman

cientists in the Department of Molecular Biology use the twin tools of molecular genetics and structural biology to investigate a wide variety of important biological processes. Research continues to make progress toward a better understanding of the fundamental processes of living organisms such as the molecular actions in cell cycle control, tumor development, and even sleep induction. Additionally, the work has led to advances in determining the structural biology of signal transduction, and the molecular basis of protein recognition of nucleic acids. In the related area of biomolecular engineering, researchers have been able to build novel functions into proteins and RNA.

One of the key strengths of the department is the use of x-ray crystallography and NMR spectroscopy to determine three-dimensional structures and dynamics of key biological macromolecules. With a working draft of the human genome now complete, determining the three-dimensional structures of encoded proteins will become a critical factor in exploiting genomic data to obtain insights into biological function for improved drug design. The impact of the post-genomic era opens up new possibilities in molecular and structural biology. While scientists will soon have access to the complete list of all human genes, the determination of detailed structures is needed to accelerate therapeutic drug design. In the near future, scientists will be able to do for protein structure what has already been accomplished for genome sequencing, the next important step in the progress leading to the development of therapeutics and treatments.

Several members of the department are part of a consortium, headed by Ian A. Wilson, D.Phil., awarded a structural genomics pilot grant by National Institutes of Health to develop new technologies for high -- throughput structure determination to enable scientists to obtain better insights into protein functions, their mechanisms of action, and a superior approach for designing new interventions -- creating small molecules that inhibit their actions.

The department is large, with more than 50 full-time faculty members and more than seven times as many supporting staff. In the post-genomic era, the methods for producing gene structures will increase in efficiency. Today, the process of mapping a particular protein to elucidate its structure and function can take from a few days to several months to complete. The power of the new technology will accelerate the research process dramatically, reducing the mapping process from weeks and months to a matter of days.

With all human gene sequences available, and new technologies like gene chips -- thousands of pieces of DNA on a small glass biochip with special fluorescent readers for scanning the genes -- scientists will soon be able to determine precisely which genes are expressed in various cells. One major task that lies ahead will be the mapping of related genes. For example, when a gene is activated, what is the effect? What other genes are activated with it? These maps of interacting genes and proteins will provide a critical understanding of basic human biological function at a much higher level than is currently available. The results will usher in a new era of molecular biology, in which the molecular pathways involved in all biological processes are understood in great detail.

Members of the department have already made considerable progress in the computer modeling of proteins and nucleic acids. A detailed understanding of the forces that not only determine the structure and function of proteins and nucleic acids, but also govern their interactions, can only be achieved through computer simulations. New advances have been made in computational modeling of protein folding pathways, while Charles Brooks, Ph.D., and his colleagues have made exciting progress in understanding the coupling between protein dynamics and enzyme catalysis. Others have made advances in the development of new computational tools for screening compound libraries for promising drug candidates.

Other studies continue to advance scientific understanding of molecular activity in important cellular processes, such as immune response, cellular signaling, and in control of the cell cycle. Future targets for structure determination include proteins and enzymes involved in bacterial and viral infection, antibiotic resistance, and the synthesis of homocysteine, a major risk factor for cardiovascular disease. Research continues on the molecular and biological characterization of feline immunodeficiency virus (FIV), a model for HIV. Scientists have made progress in understanding the regulatory mechanisms controlling FIV expression and mediating cell entry, as well as the development of inhibitors of key viral enzymes.

The tools of molecular genetics and structural biology are being used to build novel functions into particular metalloproteins -- a protein and metal atom combined -- that can specifically target any genome sequence, and that have potential applications in gene therapy. Peiching Sun, Ph.D., a new member of the department, has initiated research aimed at understanding the mechanisms of tumorigenesis. He has developed a novel technology to isolate genes involved in metastasis and tamoxifen resistance in breast cancer.

At the dawn of the new millennium, molecular biology remains a field of enormous opportunity and excitement. The scientists in this department have taken advantage of powerful new technologies to advance their understanding of fundamental biological processes at the molecular level. Their discoveries will ultimately be translated into new advances in biotechnology and medicine.