Researchers
 Ali Brivanlou, Ph.D.
Professor and Head of the Laboratory of Molecular Vertebrate Embryology
How should embryonic stem cells be nourished in laboratory cultures so that the stem cells remain unspecialized?
Many members of the scientific community regard Ali Brivanlou as a leader in the study of embryonic stem (ES) cells. His current studies build upon a decade of basic research with laboratory mice and frogs that has advanced our understanding about the embryonic development of the brain and other components of the nervous system and the formation of other organs.
Several years ago, Brivanlou discovered that early embryonic cells, including ES cells, will develop into nerve cells unless they receive molecular signals directing them to become a heart cell, skin cell or another type of cell in the body. Scientists were surprised that embryonic cells possessed such a “default” mechanism.
A recent research breakthrough in Brivanlou’s lab could have important consequences for ES cell research throughout the world. He and his colleagues discovered that a compound nicknamed BIO could maintain the pluripotency of lab cultures of human ES cells — potentially eliminating the need for mouse cells in these cultures.
In order to be usable for research, human ES cells must retain their active undifferentiated state. Such pluripotent stem cells have not yet differentiated into specialized cells — heart or skin cells, for example. To maintain the pluripotency of the human ES cells, scientists have kept them in lab cultures that include a layer of mouse cells. Although using mouse cells effectively maintains the human ES cells’ pluripotency, scientists are concerned that the mouse cells can contaminate the human cells with toxins. Therefore, such human ES cell cultures are not appropriate for all basic research or any clinical, or patient-oriented studies.
The BIO method, which Brivanlou has shared with scientists throughout the world, is an important early step toward realizing the potential of ES cells for tissue transplant and regenerative medicine.
Brivanlou also recently developed the first atlas, or map, of genes associated with early human development, a guide that will be systematically used to study human development and the potential clinical usefulness of human ES cells.
Elaine Fuchs, Ph.D.
Rebecca C. Lancefield Professor and Head of the Laboratory of Mammalian Cell Biology and Development
Investigator, Howard Hughes Medical Institute
How do stem cells “know” their fate?
Elaine Fuchs studies the cell biology, genetics and development of skin and hair. Her basic research on the molecular mechanics underlying development and differentiation of these tissues addresses one of the fundamental questions underlying stem cell biology: How do stem cells “know” their fate? When scientists understand the factors that determine whether a stem cell develops into a heart cell rather than a skin cell or another type of body cell, they will be better equipped to design cell-based treatments for specific medical conditions.
Unlike stem cells for many other tissues, skin stem cells from an adult human or animal can be cultured easily in the lab (so easily, in fact, that the process is used in treating burn victims). With these cultures Fuchs and her colleagues study how the multipotent (able to differentiate into cells of the same tissue) stem cells of the skin of humans, rodents and other mammals give rise to the epidermis and hair follicles.
Fuchs’ basic research also may elucidate the molecular basis of skin cancers, psoriasis, blistering diseases and other disorders, even ones extending beyond skin. Among her discoveries is the genetic basis of a type of skin tumor that affects the scalp. Because of the extraordinary self-regenerating properties of stem cells, Fuchs hypothesizes that stem cell errors are a likely cause of many types of human cancers. Through research on stem cells, she hopes to understand the genetics of squamous and basal cell carcinomas, the most common types of human cancers in the world.
Scientists led by Fuchs have made several key discoveries about the biology of skin and hair stem cells. In 2003, Fuchs reported that two proteins work in concert to guide a stem cell to become a hair follicle rather than skin. These two proteins help change the stem cell’s shape so that it can separate from adjoining cells and move downward — a developmental step that is essential for a hair follicle to form from a stem cell. One of these proteins, called Wnt, has already been implicated in the spread of some cancers, such as colon and breast cancer. Fuchs believes that the same process that leads to the separation of a stem cell from other cells may shed insight into how a cancer cell metastasizes, or spreads, from its host tumor.
Fuchs and her colleagues also developed a new method to track and isolate skin and hair stem cells, a technique that may also be valuable in searching for stem cells that produce the cells of the heart, pancreas and other specific body tissues.
Peter Mombaerts, M.D., Ph.D.
Professor and Head of the Laboratory of Developmental Biology and Neurogenetics
Can a cell that no longer divides be coaxed into cell division?
Peter Mombaerts is a specialist in genetic manipulation of the mouse, the most prominent experimental mammal in modern biology. He focuses most of his efforts toward understanding the origin and development of the cells of the brain that enable the sense of smell. Basic research on the olfactory system provides a model of how other brain circuits are put together. In recent years his laboratory has mastered the technology of producing a genetic copy of a mouse. This laboratory process, commonly called cloning, was achieved through nuclear transfer — replacing the nucleus of a mouse egg with the nucleus of a cell from an adult mouse. Only a handful of labs in the United States have reported success in cloning mice.
Indeed, through this lab process, Mombaerts and his colleagues have generated 51 mouse ES cell lines — 85 percent of the world’s output of cell lines of this type. Such research with mouse cells may help scientists determine how to produce customized lines of human ES cells to replace, for example, the damaged insulin-producing pancreas cells in people with early-onset or type 1 diabetes.
A great deal of basic research is needed before scientists will be equipped with the knowledge to develop, safely and effectively, customized ES cell lines — ES cells that can then be coaxed to differentiate into specialized cells that can have therapeutic effects when transferred to a patient. Because the specialized cells and ES cells would be genetically identical to the individual, they likely would not be rejected by the patient’s immune system. This promising technology has thus far only been worked out in mouse, and only to a limited extent.
In collaboration with researchers at neighboring Memorial Sloan-Kettering Cancer Center, Mombaerts’ lab at Rockefeller demonstrated that mouse ES cell lines produced through nuclear transfer could be instructed to differentiate into the brain cells that normally produce the chemical messenger dopamine. The brains of people with Parkinson’s disease do not produce sufficient amounts of dopamine, and thus any medication or treatment that could boost the brain’s production of this neurotransmitter potentially could help alleviate the symptoms of the disease.
Anura Rambukkana, Ph.D.
Research Assistant Professor in the Laboratory of Bacterial Pathogenesis and Immunology (headed by Emil Gotschlich, M.D.)
Can adult cells be reprogrammed to become stem cell-like cells?
Anura Rambukkana is investigating the possibility of reprogramming adult cells to make them more like ES cells. He is using a strategy that resulted from many years of his studies at Rockefeller on cell biology of certain nerve cell infection with the microorganism that causes leprosy.
The leprosy bacterium and its components are unique in their biological activities and have a sophisticated ability to turn certain human nervous system cells into highly immature cells whose behavior, function and genetic program is similar to that of ES cells. By studying the molecular basis of this bacteria-induced non-nuclear transfer reprogramming process, Rambukkana and his research team hope to develop a bacteria-free method to turn differentiated adult cells back into stem cells which can then develop into any tissues. Cells reprogrammed in this way to become ES-like cells may have prospects in developing tissue transplant and regenerative therapies.
Since the reprogramming is the reverse process of embryonic development (conversion of adult cells to ES cells), Rambukkana will apply the new knowledge gained from cell reprogramming, particularly the newly identified signaling pathways and genes involved in this process, to understand the basic biology of the development of ES cells to adult cells, which, over time, may provide valuable molecular insights into the functions of human stem cells.
Thomas P. Sakmar, M.D.
Richard M. and Isabel P. Furlaud Professor and Head of the Laboratory of Molecular Biology and Biochemistry
What molecular signals “tell” a stem cell to become specialized?
Thomas Sakmar studies signal transduction, the process by which signals from outside a cell are relayed across the cell’s membrane and into its interior, where they can elicit a response. Much of his research has focused on molecules in the retina, with implications for understanding a variety of serious vision disorders such as macular degeneration and retinitis pigmentosa. The Sakmar lab plans to study signaling in stem cells. The results could have broad applicability in developing human ES cells to treat degenerative diseases and other disorders.
While scientists at many universities are currently at work devising techniques to induce stem cells to differentiate into particular cell types that may have therapeutic value, their efforts sometimes meet with inconsistent or puzzling results. One reason is scientists’ limited knowledge about the mechanism of differentiation of human ES cells and the factors regulating cell development.
Sakmar’s studies may answer several fundamental questions about stem cells: How do stem cells maintain an undifferentiated, self-renewing, pluripotent state? What signals drive the differentiation of stem cells into specialized cells? Sakmar hopes to identify key signaling molecules and pathways that regulate cellular proliferation and differentiation and to analyze how these molecules and pathways function. The results could be vital to giving scientists more precise control over the differentiation of stem cells in lab cultures.
Markus Stoffel, M.D., Ph.D.
Robert and Harriet Heilbrunn Professor and Head of the Robert and Harriet Heilbrunn Laboratory of Metabolic Diseases
Can stem cells be grown in lab to treat type 1 diabetes?
Markus Stoffel is a physician-scientist dedicated to conducting basic research that will offer new insights about the various forms of diabetes. In one promising line of investigation, he applies the tools of genetics and molecular cell biology to probe the beta cells of the pancreas, the body’s sole source of the essential hormone insulin.
These studies may be relevant to developing therapeutic transplants for people with early onset (juvenile) or type 1 diabetes, the most common chronic disease of childhood. It is caused when the immune system of the body mistakenly destroys the insulin-secreting pancreatic beta cells. Stoffel hopes to conduct the research that will enable therapeutic transplants to replace the damaged tissue, with pancreatic islets or insulin-producing beta cells that have been grown from lab cultures of stem cells.
Over the last two years, Stoffel and his research team have obtained proof of principle that ES cells can differentiate into insulin-expressing cells in the test tube. Because the cells produced in this way have not to date been adequate to bring about significant improvement in mouse models of type 1 diabetes, Stoffel and his colleagues have initiated experiments aimed at increasing the numbers and/or potency of insulin-producing cells that arise from the lab cultures of the mouse ES cells. Stoffel already has uncovered several novel factors involved in the proliferation and differentiation of ES cells into pancreatic insulin-producing cells.
Last Modified: 03/15/05 09:44
Text adapted from the development office brochure "Stem Cell Research at The Rockefeller University"
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