Milestone Discoveries
In 1987 Irv Weissman purified the first stem cells and demonstrated that just a dozen or so of these remarkable cells could save a mouse after being lethally irradiated. The ability to purify these cells has opened many new avenues of treatment for malignancies including leukemia, lymphoma and other disease where cancer cells must be eliminated by irradiation followed by transplantation of healthy stem cell populations. In addition the purification of the stem cell lead scientists in other fields to realize that stem cells existed for many types of tissues including skin, brain, liver, and others. These stem cells can also be isolated by techniques similar to those that were developed by Dr Weissman and many groups are working on their isolation and use in a wide range of therapies. When stem cells do become routine in the treatment of disease it is likely that their use will be dictated by principals defined in the laboratory of Minx Fuller whose work is defining the way that these cells are nursed by other cells in their immediate environment. Insights into the specific micro environments needed by stem cells will be essential to understand how they will be used therapeutically.
In 1983 Jerry Crabtree cloned and expressed a gene for a serum protease that is involved in the regulation of the coagulation cascade and inflammation. Scientists at Lilly went on to develop this as a drug and just last year, 17 years later, this protein was approved by the FDA to treat sepsis, a disease for which no other drug is effective. This drug, protein C (now called Xigris by Lilly) is estimated to save 100,000 lives per year (twice as many as died in all the Vietnam war).
David Kingsley's studies of the development of the skeletonal system lead him to discover the cause of a form of arthritis that is independent of the immune response, opening the minds of investigators to new avenues of therapy and a new perspective on this devastating disease.
Work in Matt Scott's lab has lead to the discovery of the basis of the most common malignancy of humans, basal cell carcinoma of the skin. These frequent tumors are related to sun exposure and are produced by mutations in the components of a signaling pathway (Hedgehog) used to translate signaling from the cell membrane to the nucleus. Mutations of the components of this same signaling pathway led to certain types of brain tumors. The identification of the genes that are mutated in these tumors will very likely lead to new and effective treatments of these tumors. This same signaling pathway plays essential roles in the formation of the brain during development.
Breast cancer is one of the most common tumors of women and is clearly the most devastating. Work, by Roel Nusse, while he was a post doc with Harold Varmus and later in his own laboratory lead to the discovery of a signaling pathway (the wnt pathway) that plays a critical role in a wide variety of tumors. Its essential role in the proliferation of tumor cells indicates that it will very likely be an effective avenue of attack against tumor cells that are dependent upon this pathway. Work in Dr Nusse's laboratory is continually leading to new insights into the way that this pathway works and the best strategies to specifically attack it to prevent tumors.
The discovery of stem cells and the ability to manipulate them in the laboratory has opened up new avenues for gene therapy. Thus new genes can be introduced into these cells to cure diseases of a particular class of cell types for which stem cells can be isolated. However the introduction of genes is not sufficient, they must also be regulated in ways that are therapeutically useful. The Crabtree laboratory working with Stuart Schrieber's laboratory and Tom Wandless's laboratory has devised ways of regulating the activity of nearly any protein introduced by gene therapy into a cell. This general technique relies on the ability of small molecules to bring proteins together (proximity) or to produce changes in their shapes (allostery). Several pharmaceutical companies are busy using this approach to make methods of controlling the activity of genes introduced into cells and several of the molecules are presently in clinical trials. The diseases being approached include cancer, heart disease, anemia and others. This approach should allow a new age of gene therapy with precise control of the activities of introduced genes.
The drugs cyclosporin A and FK506 revolutionized transplantation therapy when they were introduced, but their mechanisms of action were unknown for many years until work in the laboratories of Gerald Crabtree and Irv Weissman discovered that they block the immune response by inhibiting communication of information from the cell surface to the nucleus through the calcineurin/NFAT signaling pathway. This pathway relays information from the environment into the nucleus, which in turn coordinates the actions of different cell types in the immune response. This discovery is allowing an understanding of the basis of immunosuppression and the redesign of new classes of immunosuppressants free of the side effects of these drugs. An exploration of the side effects of these immunuosuppressants lead to the discovery that the calcineurin/NFAT pathway controlled the morphogenesis of many different vertebrate organs including the brain, heart, skeleton, kidney as well as others. Work in the Crabtree and Tessier-Lavigne laboratories has shown that Calcineurin/NFAT signaling is critical for making connections between the trillions of neurons during development of the mammalian brain and that defects in this pathway are likely to be responsible for many of the aspects of Down's syndrome.
One of the most common birth defects are abnormalities in the formation of the heart valves. About 1 in 100 children have these birth defects, which are recognized as heart murmurs and often require surgery for correction. The general rules for formation of the heart valves, which are necessary for our moment-to-moment existence was a mystery till the discovery that signaling by calcineurin/NFAT was essential for the production of the delicate valve leaflets and the complicated functional architecture of the valves. This realization should allow new approaches to these common genetic abnormalities.
Recently the entire human genome was sequenced and found to contain about 30 to 40,000 genes. These efforts have opened up the possibility that many of these new genes will be targets for developing treatments for diseases that have been untreatable in the past. But how can one approach such a large number of potential new therapeutic targets? The Crabtree laboratory working with the Wandless laboratory in the Department of Chemistry have come up with a general approach to the development of new drugs. This approach is based on the borrowing of the specificity of protein-protein interactions. It is applicable to virtually any protein target and is presently being used to develop new classes drugs for several different diseases.
