Answer: The pace of advances in modern genetics is such that techniques and concepts developed in research laboratories are becoming assimilated into the practice of genetic diagnosis and counseling at an ever-increasing rate. One such advance, already alluded to, relates to observations regarding the sizes of fragments of DNA obtained from fetal cells in amniotic fluids. From such observations, and using recombinant DNA technology, clinical geneticists are now able to detect differences between normal individuals and those that have sickle cell disease or thalassemia. Question: What plans do you have for the coming year with regard to coordination with the Bureau of Community Health Services in the area of genetic counseling? Answer: This matter is currently under review by Secretary Schweiker. Once the new Administration's policy has been established, it will be provided to the Subcommittee. BASIC RESEARCH IN GENETICS Question: What progress has been made in the area of basic research in genetics? Answer: Basic research in genetics has been one of the fastest moving fields of research in recent years. The dramatic increase in the pace of genetics research can be attributed to the invention of two powerful new research tools, namely, recombinant DNA technology and rapid methods for determining DNA sequences. Both techniques are considered so important that Nobel prizes have been awarded to the inventors of each. The availability of these new methods has allowed scientists to apply the approaches that were used so successfully, for many years, in studies of bacteria and viruses to research on the much more complex genetic material of higher organisms, including man. Three significant discoveries, with potentially far-reaching implications, have already resulted from research on genes in higher organisms. First, scientists have discovered that many genes exist in pieces rather than continuous stretches of coded information. These pieces are separated by intervening sequences of DNA, called introns, which do not themselves get translated into the proteins essential for the body's growth and functions. However, since these intervening sequences are present during a part of the process by which genetic information leads to protein synthesis, but are cut out at another stage, it seems clear that they play an important role in controlling gene activity. Further research on the nature and fun ction of "introns" may be critical to understanding the control mechanisms of normal development and the loss of such control which results in developmental abnormalities and certain diseases. A second significant discovery is that pieces of genetic information frequently move around or are transposed on the chromosomes. Awareness of the importance of these "transposable elements" or "jumping genes" continues to increase. New evidence suggests that transposition of genetic elements plays a role in mutation (hereditary change) and differentiation or maturation as well as in other phenomena. For example, the genes responsible for the synthesis of antibodies are assembled from several pieces of genetic information which move into close proximity when such synthesis occurs. Evidence suggests that such gene transposition may explain how the human body can make the millions of different kinds of antibodies which are responsible for eliminating invading viruses and bacteria from the body and are involved in such phenomena as allergy and graft rejection. Other significant studies indicate that "transposable elements" or "transposons" may have some bearing on malignancy. Some viruses that can transmit cancer genes in laboratory animals have been found to be specialized "transposons" which carry a normal cellular gene to a new location. This leads to changes in the cell that transform it into a cancer cell. A third significant finding concerns gene amplification, a phenomenon occurring when genes make many copies of themselves in order to respond to a need in the cells for the production of large amounts of certain substances. This normal process can also be called into play in abnormal circumstances. For example, when cancer patients are treated with the chemotherapeutic agent, methotrexate, they may become resistant to the effects of the drug. This resistance is brought about by multiplication of the gene that makes the protein which is inhibited by methotrexate. As a result, the methotrexate becomes less effective in combating the patient's cancer. These are just a few examples of the kind of knowledge being gained through research in basic genetics. We expect that the rapid pace of new discoveries in this area will continue for some time and that the impact on medicine will be profound. Question: Are there any new insights into the genetic components of such diseases, as diabetes, atherosclerosis, hypertension, etc.? Answer: Approximately forty diseases, including such common diseases as certain variants of diabetes and arthritis, as well as other conditions such as psoriasis and celiac disease, have been shown to be strongly associated with one or another variant of a gene complex, known as HLA (Human Leucocyte Antigen). However, relationships between this gene complex and a predisposition to certain diseases are far from clear, and are currently a topic of intensive study in many laboratories. During the past two decades, susceptibility to mental disorders such as mania, depression, and schizophrenia has also been shown to be associated with genetic factors. Question: How much does the Carter budget allow for the continued support of basic research in this field? Answer: The budget amount for this program is currently under discussion within the Reagan Administration. After the revised budget is forwarded to the Congress, we will provide an appropriate answer to this question. Question: How do you interact with the other institutes in terms of sharing the knowledge gained from basic research supported by your Institute? Answer: The Genetics Program, like all of NIGMS, considers itself to be a generator of concepts which often, unexpectedly, become relevant to disease conditions which are of major program interest to the more categorical NIH institutes. Research projects, which because of their fundamental, noncategorical significance originally were supported, are often transferred to categorical institutes when their emergent relevance to conditions such as atherosclerosis, cancer, and infectious disease become apparent. Furthermore, the Genetics Program currently is developing other means of interacting with other NIH institutes. In recent years, we have held workshops in collaboration with other institutes in regard to: (1) common diseases which have strong genetic components such as hypertension, diabetes, and atherosclerosis, (2) how a data bank might be developed to take advantage of the proliferation of information on nucleotide sequences in nucleic acids and to serve the needs of research supported by all institutes, and (3) new possibilities for developing mouse models of human genetic disease, as well as mouse strains for use in research on the mutagenicity of chemicals. Recently, NIGMS has undertaken a survey to determine the extent of the overall support of genetics at NIH. Since nearly all human disease has some genetic component, this determination will lead to an increase of common interests and continued interaction with other NIH components. One activity supported by the NIGMS that has a great effect on the more categorical programs is a Cell Bank which develops and distributes cell lines representing human genetic disease. Such cel1 lines are distributed to grantees of all the institutes, as well as to members of the intramural research staff of NIH. We have received much favorable comment on this cell bank and these cell lines are generally recognized to be of high quality. Furthermore, it is a cost-effective enterprise. Since its existence avoids repetition of the development of particular types of cell lines by individual investigators, research can be performed which would otherwise not be readily possible. Question: What evidence can you provide indicating the effectiveness of your work? Answer: The effectiveness of the NIGMS Genetics Program can be demonstrated in a variety of ways. Most simply, it can be readily measured by the recognition of the work of grantees of the Program by the scientific community. For example, two of the three recipients of the 1980 Nobel Prize in Chemistry were American scientists supported by the Genetics Program: Dr. Paul Berg (supported by NIGMS since 1960) and Dr. Walter Gilbert (supported by NIGMS since 1969.) However, the more intangible effects of the Program are probably even more profound. The NIGMS Genetics Program supported a major portion of the research that led, in the 1970's, to the development of recombinant DNA technology. This technology is now a major tool in biology, and it is being applied successfully to areas as diverse as: (1) cancer research, (2) investigations of organisms infectious for man, (3) research related to the basic cause and the diagnosis of genetic disease, (4) the manufacture of rare and expensive chemicals such as insulin, growth hormones, interferon, and safer vaccines, (5) the improvement of plants which provide food, and (6) research on energy resources. In very specific ways, then, the Genetics Program has provided concepts needed to stimulate several segments of the U. S. economy. CELLULAR AND MOLECULAR BASIS OF DISEASE Question: Has research supported under the Cellular and Molecular Basis of Disease Program yielded any new insight into the cause and possible treatment of cancers or other diseases? Answer: Research supported by the Cellular and Molecular Basis of Disease (CMBD) Program has provided many new insights regarding the cause and possible treatment of cancers and other diseases, while also developing information regarding the structure and function of the cell and its components. Just as the human body is composed of organs--the brain, heart, liver, muscles, and so on--each with its own unique and special function, each of the cells--of which all organs and tissues are composed--also has its own array of tiny organs, or organelles: a nucleus that contains the genetic instructions by which the proteins of each cell are synthesized, microsomes that carry out protein synthesis according to the instructions sent on genetic messages from the nucleus, mitochrondria that provide the energy required for life processes, microtubules and microfilaments that provide structure and motility, membranes that divide the cell into compartments and protect it from its external environment, and so on. One of the most important research areas in modern cell biology, the study of cell membranes, has direct applicability to learning more about cancer. Cancer is clearly a cellular disease, in which growth, motility, and shape of cells, as well as cell-cell interactions are no longer normal. All these properties are intimately tied up with changes in the cell membrane since it is this organelle which must mediate cell-cell interactions, and change shape for any form of cellular motion. The membrane and its underlying cellular skeleton are known to be altered in cancer and what is being learned about normal cell membranes is rapidly being used to elucidate the abnormalities of the membrane of a cancer cell. We now visualize membranes as islands of protein floating in a "sea of lipid." Membranes consist of: Channels for the entry and exit of sodium, potassium, and other ions, and for glucose, amino acids, and other nutrients needed to maintain the life of a cell. Receptors for essential chemicals and hormones such as insulin or growth hormones which send signals into the cell to alter their metabolic activity. Glycoproteins that have on their outer surface complex branching structures made of sugars that serve to communicate with other cells and to give the cell a specific identity--these are important in organ transplantations. Gap junctions that serve as communicating portals between adjacent cells to let small molecules and electrical impulses pass directly from one cell to another. Tight junctions that form tight seals between cells--such as those lining the intestines--so that nothing can pass between. Thus, nutrients absorbed from the gastrointestinal tract must pass through the cells lining the intestines; they cannot go between. This prevents the bacteria in the intestine from invading the body directly through spaces between the cells. Cancer researchers are now studying whether one or more, or all of these parts of the membrane are altered when a cell becomes malignant. They are also trying to understand the fundamental changes in the cell that remove it from its normal state. Is it in the glycoproteins that appear to give the normal cell its identity or through the branching sugar moeities that stand out from the cell surface? Are the glycoproteins normal in cancer, or are they modified in some way so that the cell is no longer identified as belonging to that organ or tissue? Or, is the significant change in the gap functions that normally provide direct portals of communication between the cytoplasm of adjacent cells? Is this communication altered in cancer cells? Whereas normal cells normally remain in place within their respective tissues and carry out their normal function, malignant cancerous cells pry themselves loose from their moorings, become motile, move around, and metastasize to other locations in the body. What are the normal control mechanisms by which cells are prevented from entering the motile state--or on other occasions are instructed to do so? Such studies are possible because work supported by the CMBD Program has clarified so much about the normal cell. Examples of the relationship of NIGMS supported studies to cancer research can be illustrated by the following: 1. Dr. S. Jonathan Singer of the University of California, San Diego, one of the early pioneers in research in membrane structure, proposed the "fluid-mosaic" model for cell membranes in which proteins may be compared to "icebergs floating in a sea of lipids." This is still the predominant theory of membrane structure. Supported for many years by NIGMS for fundamental research on membrane structure and function, he began to receive support from the National Cancer Institute in 1977 for research on mechanisms of transmembrane control in malignant cells contrasted to normal cells. 2. 3. 4. Dr. Werner Loewenstein of the University of Miami is one of Dr. Albert Lehninger of Johns Hopkins University first dis- Dr. Raymond Blakely of the University of Iowa has been supported by the NIGMS for a number of years for his study |