The Clinical and Intellectual Implications of Stem Cell Biology
Ronald D.G. McKay
National Institute of Neurological Disorders and Stroke, NIH
About the Lecture
The identification of stem cells in the fetal and adult mammalian brain has many scientific and clinical consequences. The evidence for a common stem cell generating the central and peripheral nervous system (CNS + PNS) will be presented. It is important to determine if stem cells give rise to functional neurons. Experiments will be presented showing that stem cells can generate synaptically active neurons. These results show that the events controlling the birth and death of neurons are increasingly understood. The clinical potential for this technology is now recognized. In our group we have initially focused on clinical models of neurodegenerative diseases. Experiments in tissue culture and in animal models will be used to illustrate how control of the origin of neuronal and glial cells will give new insight into Parkinson's disease, Alzheimer's disease and demyelinating disease. However, it is now clear that this approach has startling implications for many areas of medicine. In the most optimistic setting, these findings may also influence our thinking in cognition and complex systems.
About the Speaker
Dr. McKay's early research in molecular biology led him to describe the first restriction fragment length polymorphism (RLFP) in man and subsequently to develop a quantitative assay to measure the interaction of proteins with specific DNA sequences. He pioneered the field of molecular neuroscience. His research has opened new approaches to understand the molecular and cellular biology of the brain. He is recognized internationally for his work on stem cells. His group has made major contributions to the recognition that stem cell biology will play a major role in medicine. They have demonstrated that embryonic stem cell techniques will be important in neurology, endocrinology, cardiology and oncology. There are no other stem cell researchers whose work has made such a fundamental contribution to biomedical research.
Dr. McKay's published work on his research has been published in Neuron, Cell, Nature, Brain Research, Trends in Biochemical Sciences, Science and the Journals of Comparative Neurology and Neuroscience. His lectures include the Salk Institute, Max Planck Institute, Society of Neuroscience and Harvard Medical School. Among Dr. McKay's numerous panel member and scientific advisory board positions are those in neurobiology with the NIH and the National Science Foundation.
He received a B.Sc. Summa cum Laude in Zoology in 1971 and PhD. in Chromosome Structure and DNA Organization in 1974 from the University of Edinburgh. As a graduate student, Dr. McKay worked in the Medical Research Council Mammalian Genome Unit, Edinburgh, Scotland. He has held positions at Oxford University, Cold Spring Harbor Laboratory, MIT and NIH.
President McDiarmid called the 2134th meeting to order at 8:18 p.m. on October 12, 2001. The Recording Secretary read the minutes of the 2133rd meeting and they were approved.
The speaker for the 2134th meeting was Ronald McKay. The title of his presentation was “The Clinical and Intellectual Implications of Stem Cell Biology”.
Stem cell research and the political discussions surrounding them were briefly front-page news earlier this year. What are stem cells and what is their significance for treating human diseases? In the middle of the last century, it was discovered that radiation death can be rescued by grafting bone marrow. Some cells in the donor bone marrow tissue were able to grow and replace different types of mature blood cells that had been destroyed in the recipient. However, those same types of mature blood cells did not seem to be capable of regenerating when they were transplanted. Cells were found in bone marrow that had the ability to regenerate and mature into different types of cells when they were stimulated by growth factors produced in neighboring cells. These cells with the ability to regenerate and mature into cells of different types are stem cells.
The stem cells found in bone marrow are capable of becoming several different types of blood cells. Later it was discovered that a particular rare form of cancer, teratocarcinoma, contained stem cells that were capable of maturing into a wide variety of cell types. It was also found that when some cells in early embryos were microsurgically moved, neighboring cells in the new location could cause the moved cells to become a different type of cell from what they would have become in their original location. These multipotential stem cells are influenced by neighboring cells in their environment either through growth factors to replicate and differentiate, or through other factors to commit cellular suicide. For a simple organism like the worm C. elegans, we have worked out the replication and differentiation of every cell at each stage of development of the organism. The study of embryonic stem cells will allow us to do the same thing for humans.
Stem cells grown in the laboratory are clones. Clones are not necessarily bad; many domesticated plants, such as roses, are actually highly duplicated clones. Stem cells are surgically removed, then cloned by growing them in culture and artificially stimulating them with growth factors. Bone marrow grafting is necessary because hematopoetic stem cells cannot regenerate and be cultured. However, many embryonic stem cells, like mature skeletal muscle and liver cells, can regenerate and be cultured. If they can be cultured and properly stimulated to mature into insulin producing islet stem cells with the correct physiological responses, pancreatic stem cells may be used to treat diabetes, meaning that potentially 16 million people in the United States might be directly be affected by stem cell research.
Stem cells have been isolated and cultured from fetal and adult mammalian brain tissue. There is evidence for a common stem cell originating from embryonic epithelial cells that generates both the central and peripheral nervous systems (CNS and PNS). The CNS stem cells differentiate into at least three types of cells, oligodendrocytes, astrocytes, and neurons. The fate of cultured CNS stem cells is determined by exposure to protein growth factors known as bFGF, BMP4, DAPI, p75(NGFR), and HNK-1. These cultured neural cells appear not only to differentiate, but also to hook up correctly and form functional synapses. In studying clinical models of neurodegenerative diseases it will be important to determine if these cultured stem cells can give rise to functional neurons.
The clinical potential of this technology for a number of neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and demyelinating disease is obvious. In Parkinson's disease a specific type of CNS cell that makes dopamine dies. Parkinson's disease has been modeled in the mouse by killing these dopamine producing cells. This disease model state can be treated by replacing the killed cells with stimulated stem cells. While undifferentiated stem cells can be cultured, the differentiated stem cells that release dopamine appear to survive but the transformation is not efficient. The survival of the differentiated cells depends on the cellular neighborhood. Especially critical are the oligodendrocyte myelin producing cells. In Parkinson's disease, grafts are effective for 8 to 10 years, but then appear to succumb to whatever is causing the disease.
It is possible that adult stem cells will be beneficial in treating some heart disease models. Very recently, it has been demonstrated that grafted blood marrow stem cells are capable of differentiating into heart tissue cells, cardiomyocytes, and regenerating tissues typically destroyed in heart attacks. [D. Orlic, et al. “Bone marrow cells regenerate infarcted myocardium.” Nature 410, 701-705, 2001 Apr 5, PMID:11287958 .]
Although there has been rapid progress in molecular biology, we have still not learned enough from the genome project to know which genes are important in most disease states. Stem cell technology is important because it links biology at the molecular level where the genome works with biology at the level of the organism, our human patients.
Mr. McKay kindly answered questions from the floor. President McDiarmid thanked Mr. McKay for the society, and welcomed him to its membership. The President made the announcements about the next meeting, parking, refreshments, signing the guest book and the Society nominating committee, and adjourned the 2134th meeting to the social hour at 9:25 p.m.
John S. Garavelli