Fighting Disease on the Cellular Level

June 21, 2002

Fighting Disease on the Cellular Level

CHICAGO— Contrary to those static diagrams of a cell you may remember from high school biology, a eukaryotic cell (cell with a nucleus) is actually a dynamic and intricately ordered living creature, complete with its own set of tiny "organs" and empowered by thousands of chemical mechanisms that enable the cell to digest, reproduce, move, and communicate with other cells.

The remarkably complex anatomy of all eukaryotic cells and many of their basic molecular mechanisms are strikingly uniform in the 60 trillion cells comprising the human body. Cell biologists relate these features to cellular functions by determining the molecular mechanisms responsible for fundamental processes ranging from cell division and protein transport to signal transduction and the migratory behavior of cells underlying tissue formation during embryonic development and wound healing.

It follows that an understanding of normal cells paves the way for a greater comprehension of a variety of human diseases, says Robert D. Goldman, PhD, Stephen Walter Ranson Professor and chair of cell and molecular biology at The Feinberg School of Medicine.

"All disease results from failed mechanisms within cells. Analyzing the workings of healthy cells will lead to development of targeted therapies, improved methods for facilitating wound healing, development of artificial tissues, and a better understanding of the potential uses of human stem cells," he said.

Goldman is a highly regarded authority on the structure and function of the cytoskeleton. His other passion in science lies in the area of the public's understanding of science and technology. With Boyce Rensberger, award-winning former science editor of the Washington Post , he directs the Science Writers Fellowship Program at the Marine Biological Laboratory in Woods Hole, Mass., which offers journalists the opportunity to gain hands-on experience with the laboratory techniques used by biomedical researchers.

In his 20 years as chair, Dr. Goldman has overseen the development of a department that now ranks in the top 10 of its peer departments in 126 U.S. medical schools (Association of American Medical Colleges data). This year, CMB faculty were awarded approximately $10 million in grant funding from the National Science Foundation and the National Institutes of Health, including several MERIT (Method to Extend Research in Time) awards and Program Project Grants (PPGs).

The department is home to a number of scientists whose body of research has been honored both nationally and internationally. Laszlo Lorand, PhD, and Edwin W. Taylor, PhD, are members of the National Academy of Sciences and the American Academy of Arts and Sciences.

Dr. Lorand, who joined Northwestern in 1955, is one of the world's leading experts on blood clotting mechanisms. Dr. Taylor, widely acknowledged as one of the "fathers of cytoskeletal research," received the E.B. Wilson Medal, the highest honor awarded by the American Society for Cell Biology. He also is a member of the Royal Society of London.

Three researchers, including Dr. Goldman, have prestigious MERIT awards from the NIH for outstanding records of scientific achievements. The other recipients are Lester I. (Skip) Binder, PhD, and Linda Van Eldik, PhD, for their work on Alzheimer's disease. Previous MERIT award recipients in the department include Dr. Lorand, Arthur Veis, PhD, and Gary G. Borisy, PhD, Leslie B. Arey Professor of Cell, Molecular, and Anatomical Sciences. Dr. Borisy is president of the American Society for Cell Biology.

Department researchers employ a broad range of technological methods, including biochemical, biophysical, and immunological approaches, as well as digital and confocal microscopy, video-enhanced light microscopy, and molecular biological and genetic manipulation of function at both the cellular and organismal level.

The work of these investigators is described by areas of research: cytoskeleton; cell surface/extracellular matrix; molecular mechanisms and the nucleus; and the cellular basis of disease, emphasizing Alzheimer's disease. The department also includes a group of physical anthropologists.

The cytoskeletal group studies one or more of the three major "scaffolding" components of mammalian cells, including actin, microtubules, and intermediate filaments.

The pioneering research of Gunther Albrecht-Buehler, PhD, Robert Laughlin Rea Professor of Anatomy, attempts to integrate all of the cells' cytoskeletal and molecular activities that are responsible for regulating cellular behavior patterns. His work on the role of the centrosome, a structure located near the nucleus and the microtubule organizing center of the cell, suggests that the centrosome is the "brain," or unifying system, that controls cell motility.

The Borisy lab is internationally recognized for groundbreaking studies of the function and organization of microtubules, filamentous structures that course through the cell and act as "tracks" on which protein complexes called molecular motors use energy to move other "molecular cargo" from one part of the cell to another. Borisy's group also studies the organization and dynamics of actin which, in addition to a multitude of its other duties, is essential to processes involved in cell migration and, hence, embryonic development.

James R. Bartles, PhD, investigates the role of espin, a cytoskeletal protein he discovered that is present throughout the nervous system and is a key structural component of the stereocilia of hair cells, the apparatus in the inner ear that detects sound and motion and helps control balance in the body. His research showed that a defect in the espin gene causes abnormal behavior in mice (the animals appear to dance) and renders them deaf. For this work, Bartles recently received a five-year grant from the National Institute on Deafness and Other Communication Disorders of the NIH.

Rex L. Chisholm, PhD, who also is director of the Center for Genetic Medicine, studies the myosins, a class of molecular motors that interact with actin to power cell motility and facilitate processes ranging from intracellular transport to cardiac and skeletal muscle contraction. Myosin motors have been linked to numerous human diseases, including hypertrophic cardiomyopathy, the leading cause of sudden death in otherwise healthy adults. Because of this research, the Chisholm lab has become a training ground for fellows in cardiovascular surgery.

The research of Yoshio Fukui, PhD, which employs high-resolution light microscopic methods including digital fluorescence microscopy, emphasizes the remarkably dynamic activities of the various cytoskeletal systems and their related proteins in living cells.

Although it had been commonly believed that the intermediate filament (IF) system serves only a supportive role in maintaining the structure of the cell, Dr. Goldman's research over the past 15 years has indicated otherwise.

The Goldman lab has shown that the IF system forms a continuous dynamic network linking the nuclear and cell surfaces that performs important functions ranging from maintaining cell shape to regulating nuclear structures involved in regulating gene expression and DNA replication. Abnormally functioning IF have been linked to ALS, Parkinson's disease, and muscular dystrophy.

The cell surface/extracellular matrix group consists of Dr. Lorand; Dr. Veis; Mary Hunzicker-Dunn, PhD; Jonathan C. Jones, PhD; Sharon Stack, PhD; and James M. Kramer, PhD.

Dr. Veis is another of the department's celebrated researchers. He studies the regulation of growth and remodeling processes in the collagen fibril matrix, bone, and dentin. Remarkably, several of Dr. Veis's NIH grants have been funded for over 40 years.

Dr. Hunzincker-Dunn studies the cell surface-mediated signaling pathways by which reproductive hormones induce differentiation of ovarian cells. She also leads an intercampus PPG that focuses on the signaling pathways and actions of follicle-stimulating hormone. Her collaborators in this venture are Weinberg researchers Jon E. Levine, PhD; Fred Turek, PhD; and Kelly E. Mayo, PhD; and J. Larry Jameson, MD, PhD, Irving S. Cutter Professor and chair of medicine.

The Jones lab concentrates on interactions between epithelial cells and the extracellular matrix. They have conducted studies on cell junctions called hemidesmosomes, which Jones believes act as "signal transducers" between the connective tissue and epithelial cell layers, thereby influencing epithelial gene expression. His lab group also studies surface factors that promote endothelial cells to form new blood vessels, and he directs a PPG that is studying cell alterations in oral cancer. The PPG co-investigators are Dr. Goldman, Dr. Stack, and Kathleen J. Green, PhD, Joseph L. Mayberry Professor of Pathology and Toxicology.

Dr. Stack's research focuses on the molecular mechanisms producing oral cancer and the regulatory mechanisms involved in the development of ovarian cancer. In particular, she investigates the mechanisms controlling the transition of normal cells to malignant cells capable of migrating from their normal locations to form tumors in other tissues.

Dr. Kramer studies the functions of collagen, one of the major components of the extracellular matrix. He heads up a team of researchers known affectionately as the "worm group" because they study the nematode Caenorhabditis elegans. The simplicity of this worm's systems makes it a powerful model for molecular genetic studies of extracellular matrix functions. Dr. Kramer has shown that mutations in the genes that code for collagen in C. elegans basement membranes cause embryonic death and are similar to those in humans with Alport's syndrome.

The group focusing on molecular mechanisms and the nucleus includes Stephen A. Adam, PhD; Sui Huang, MD, PhD; Carolyn L. Jahn, PhD; and Richard C. Scarpulla, PhD.

Dr. Adam studies the regulation of the transport of molecules in and out of the nucleus. He developed a biochemical assay for quantifying the movement of materials into the nucleus, now used in laboratories around the world. His most recent studies involve a genetic approach to understanding the function and regulation of nuclear transport proteins known as the importins. These proteins play a critical role in signal transduction and the transport of gene regulators or transcription factors into the nucleus.

Dr. Huang is investigating the nuclear mechanisms underlying the processing of RNA, particularly the perinucleolar compartment — a unique nuclear structure she discovered — which is present primarily in cancer cells. She and her lab group, in collaboration with researchers at the Robert H. Lurie Cancer Comprehensive Cancer Center of Northwestern University, have been studying the prevalence of this structure in breast cancer to determine whether the presence of this nuclear structure can be used as a diagnostic indicator of malignancy.

Dr. Jahn uses several types of ciliated protozoa to study the mechanisms responsible for gene rearrangements, a phenomenon found to be associated with a number of human diseases, including birth defects and cancer. She has also been collaborating with J. Doug Engel, PhD, on the Evanston campus in genetic studies of blood cell development in mouse models.

Dr. Scarpulla's studies center on the molecular interactions and physiological functions of proteins involved in the nuclear control of mitochondrial biogenesis. His research is widely recognized as prerequisite to understanding numerous human disorders ranging from cardiomyopathies to neuromuscular diseases that are linked to mutations in mitochondrial genes.

In the group working on Alzheimer's disease, Dr. Binder studies the neurofibrillary tangles recognized to be a hallmark of Alzheimer's disease. Dr. Binder was the first to discover that the tangle is made of the microtubule-associated protein, tau. Working closely with Binder is Robert Berry, PhD, who carries out biochemical studies of the self-assembly properties of tau protein in a variety of neurodegenerative diseases including Pick's disease. In a related area, Yuri Geinisman, MD, studies the neurobiological basis of learning and memory in aging brains.

Dr. Van Eldik is widely recognized for research on molecular mechanisms and modulation of glial cell activation during the development of Alzheimer's disease. Her lab also studies the function of the brain nerve cell protein S100, focusing on experiments to determine whether S100 can act as a biomarker of Alzheimer's disease and other disorders. In addition, Dr. Van Eldik plays a major role in the Drug Discovery Program and heads an NIH postdoctoral training grant in this area.

The newest member of this group is Robert J. Vassar, PhD, who studies the role of beta-amyloid, another important marker of Alzheimer's disease. He studies an enzyme, BACE1, known to be involved in amyloid production. Dr. Vassar also developed the BACE1 knockout mouse required for studying the biological functions of this enzyme. BACE1 has become a prime drug target for the treatment of Alzheimer's disease.