by Erin T. Strovel and
Miriam G. Blitzer

Researchers in a wide variety of genetic specialties presented their latest work at the 48th Annual Meeting of the American Society of Human Genetics (ASHG). Held October 27-31, 1998, in Denver, Colorado, with over 4,400 scientists in attendance, the conference's several sessions highlighted recent approaches for the treatment of metabolic diseases, the use of microchips for monitoring cancer progression, and the identification of genes involved in dementia and parkinsonism.

As the Human Genome Project progresses, researchers focus on new technologies and strategies for identifying the function of genes. ASHG president Arthur L. Beaudet of Baylor College of Medicine emphasized the theme of genetic individuality and its relevance to medicine, and discussed many of the dilemmas humanity will face as researchers identify genes that lead to genetic predispositions and diseases. "Can the routine use of DNA testing be used to enhance the quality of medical care?" Beaudet asked. He then discussed the impact of new information concerning disease mutations derived from the Human Genome Project, and the potential for population-based DNA screening to identify individuals with a predisposition to develop certain diseases. "This would be appropriate only for those diseases in which effective intervention is available," he said.

One such disorder that Beaudet discussed as a candidate for population-based testing was hemochromatosis, a disease involving iron deposition that causes life-threatening damage to the liver. Individuals with this disease who avoid iron supplements and are treated early can have an excellent outcome. Beaudet speculated that with population-based testing, from 250 to 1,000 lives a year could potentially be saved. But applying new discoveries to the prevention and treatment of genetic diseases will require the integration of genetics, primary care medicine, physiology, and sociology. The benefits of genetics must also be taught to society.

Enzyme Replacement: Advances in Treatment

Will enzyme replacement therapy effectively treat metabolic disorders? To date, the treatments of certain inborn errors of metabolism - diseases that result from the accumulation of undegraded molecules due to the absence of an essential enzyme - have focused on strategies such as manipulation of the diet and cofactor supplementation (e.g., taking biotin or B vitamins). Recently, researchers have made advances in enzyme replacement therapy, in which patients are given the enzyme they do not properly produce.

Emil D. Kakkis discussed enzyme replacement therapy studies on patients with the fatal genetic disorder mucopolysaccharidosis I (MPS-I). [1]. MPS-I results from a deficiency of alpha-L-iduronidase, an enzyme required for the breakdown of carbohydrate materials called glycosaminoglycans in all tissues of the body. The absence of this enzyme results in the accumulation of these complex carbohydrates in cells and organs, resulting in the enlargement of the liver and spleen, joint pain, immobility, neurologic abnormalities, skeletal deformity, and ultimately death around the age of 10. A clinical trial, in which 10 patients were treated over 26 weeks with alpha-L-iduronidase, demonstrated that the therapy improved the patient's physical abilities (endurance and range of motion), reduced fatigue, reduced joint pain, reduced liver size, and improved overall quality of life. "The trial results are very encouraging," Kakkis said. "This clinical trial culminates 30 years of research and marks the first time enzyme replacement therapy has been used effectively with MPS-I patients." Currently, preclinical and clinical trials are underway to investigate the use of enzyme replacement therapy for several other storage disorders.

FISH and Chips

The traditional labor-intensive and time-consuming methods previously used to look at genes in cancer tissues have been replaced by a rapid and efficient screening technique for the examination of DNA, RNA, and protein expression. Microarray technology is a very new method for analyzing large numbers of genes at once. Lukas Bubendorf et al. [2] described the use of this technology to identify genetic factors responsible for human prostate cancer progression. Bubendorf described tissue-microarray technology ("tissue chips") as a "high-throughput tool for the molecular profiling of thousands of tumor types." Tissue chips are microscope slides containing hundreds of different tissue or tumor samples that can be examined for increased or decreased levels of gene expression by comparing the tumors to normal tissue samples.

One way to look at the level of gene expression in a tumor is by fluorescence in situ hybridization (FISH). This technique uses fluorescently tagged DNA segments (probes) that bind to specific genes and "light up" under a microscope equipped to visualize fluorescent signals. Bubendorf's group found several genes, including the androgen receptor, overexpressed in late stage (metastatic) prostate cancer, but not in early-stage or primary tumors. This difference in gene expression levels may provide a means to monitor the disease's progression. This technique represents a major advancement in screening technology. Researchers can now study the expression of specific genes in hundreds of different tumor types, or in different stages of the same cancer, in a remarkably short period of time.

The combination of tissue chips and FISH make this technology an extremely valuable tool for the study of cancer genetics. It will provide invaluable information for understanding the biology of disease, and also will be directly applicable to the management and treatment of these diseases.

Tau and Dementia

The second most common cause of neurodegenerative dementia, after Alzheimer's disease, is frontotemporal dementia and parkinsonism (FTDP). This disease is characterized by behavioral disturbances, reduced speech, memory impairment, and parkinsonism late in the course. Cecile Dumanchin [3] of Laboratoire de Genetique Moleculaire, CHU de Rouen, France, and Peter Heutink [4] of the Departments of Clinical Genetics and Neurology at Erasmus University in Rotterdam, presented their findings identifying a gene involved in familial frontotemporal dementia. These two groups studied families with frontotemporal dementia that showed linkage to chromosome 17. The tau protein, a microtubule binding protein, is located on chromosome 17. It was considered a good candidate to be the gene responsible for this form of dementia because of its known role in the pathology of Alzheimer's disease. The gene was sequenced in these families, and a mutation was found in the tau protein that abolished its ability to bind microtubules, filaments that structurally support axons.

Heutink's group also proposed that when tau does not bind microtubules efficiently, an altered form of the protein accumulates in the cytoplasm of the cell. "It is postulated that it is the formation of tau aggregates that are toxic to the cell and lead to cell death," Heutick said at the end of his presentation. "The tau gene has long been suspected to be involved in neurodegenerative disorders, and the findings that mutations in tau can cause neurodegeneration will have consequences for the understanding of these disorders as well."

In addition to the topics presented here, the meeting featured a variety of great talks, poster presentations, education sessions, and symposia describing a wide spectrum of genetic topics.  Other presentations focused on topics ranging from potential prostrate cancer susceptibility genes to the perils and promises of cloning.  As the Human Genome Project continues and accelerates gene discovery, scientists can look forward to many exciting advances in biomedical research, biotechnology, and therapeutics.

Erin T. Strovel is a senior doctoral candidate in the Program in Human Genetics at the University of Maryland at Baltimore.

Miriam G. Blitzer is an associate professor in human genetics at the University of Maryland School of Medicine.

Caleb Brown is an illustrator and biologist living in Montana. By day he drives a delivery van, and by night he draws pictures with his computer.

Send us your comments and ideas for future articles.

Endlinks

Genomic Medicine - an annotated list of Internet resources related to medical genetics, with sites for the physician, patient, and general public. From the Journal of the American Medical Association.

Online Mendelian Inheritance in Man - an extensive database of inherited disorders that provides information on genetic syndromes, clinical presentation, cytogenetics, mapping, pathogenesis, and population genetics. Maintained by the Johns Hopkins University School of Medicine.

Office of Genetics and Disease Prevention - provides current information on the impact of human genetic research and the Human Genome Project on public health and disease prevention.  From the Centers for Disease Control and Prevention.

U.S. Department of Energy: Human Genome Information Publications - basic information about human genetics, including news, an online genetics primer, and links to other sites.

Related HMS Beagle articles:

Gene Therapy - a Cutting Edge debate addressing the technical and moral issues of gene therapy.

Previous Meeting Briefs

Overhauling the Secretory Pathway

by Tommy Nilsson

(Posted December 11, 1998 · Issue 44)

Pharming the Genome

by Beth Schacter

(Posted October 30, 1998 · Issue 41)

Turn Me On, Turn Me Off: Conditional Genetic Technologies

in the Mouse

by Danielle M. Kerkovich

(Posted October 16, 1998 · Issue 40)

Science? Fiction? How About Both?

by Bill Thomasson

(Posted October 2, 1998 · Issue 39)

Culturing New Connections: Microbial Discovery Workshops

by William H. Coleman and Dennis Opheim

(Posted September 18, 1998 · Issue 38)

Tobacco Road: Avenues of Addiction

by Tabitha M. Powledge

(Posted September 4, 1998 · Issue 37)

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