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June
3, 2002
Fighting
Disease on the Cellular Level
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, 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, 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 (American Association of 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 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
and Edwin Taylor are members of the National Academy of Sciences
and the American Academy of Arts and Sciences.
Lorand,
who joined Northwest-ern in 1955, is one of the world’s leading
experts on blood clotting mechanisms. 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 Goldman, currently have prestigious MERIT
(Method to Extend Research in Time) awards from the NIH for outstanding
records of scientific achievements. The other recipients are Lester
I. (Skip) Binder and Linda Van Eldik for their work on Alzheimer’s
disease. Previous MERIT award recipients in the department include
Lorand, Arthur Veis and Gary Borisy, Leslie B. Arey Professor of
Cell, Molecular and Anatomical Sciences. Borisy is currently the
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.
For
this article, 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 who were featured in an earlier OBSERVER
article.)
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, Robert Laughlin
Rea Professor of Cell and Molecular Biology, 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
Bartles investigates the role of espin, a cytoskeletal protein he
discovered, which 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 also 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
Chisholm, who also is the 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 a wide range of 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.
Yoshio
Fukui’s studies, which employ high-resolution light microscopic
methods including digital fluorescence microscopy, emphasize 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 literally only a supportive role in terms of maintaining
the structure of the cell, 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 Lorand; Veis;
Mary Hunzicker-Dunn; Jonathan Jones; Sharon Stack; and James M.
Kramer.
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 Veis’s
NIH grants have been funded for over 40 years.
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 Levine, Fred Turek and Kelly Mayo;
and Larry Jameson, M.D., 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 Goldman,
Stack and Kathleen Green, Joseph L. Mayberry Professor of Pathology.
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.
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. 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 Adam, Sui Huang, Carolyn L. Jahn and Richard C. Scarpulla.
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
all over 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.
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.
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.
Recently she has also been collaborating with Doug Engel on the
Evanston campus in genetic studies of blood cell development in
the mouse.
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, Binder studies the
neurofibrillary tangles recognized to be a hallmark of Alzheimer’s
disease. Binder was the first to discover that the tangle is made
of the microtubule-associated protein, tau. Working closely with
Binder is Robert Berry, 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, M.D., studies the neurobiological basis of learning and
memory in aging brains.
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, specifically, experiments to determine
whether S100 can act as a biomarker of Alzheimer’s disease
and other disorders. In addition, 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 Vassar 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.
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.
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