Research on Disease Mechanisms in the Department of Developmental Biology

Faculty and students in our department are working to understand the general principals of development and aging. Often this work relates directly to the mechanism of human disease giving molecular insights that open the possibility for development of therapeutic approaches. Some of the areas that are being covered in our work are given below:

Aging: Stuart Kim
Alzeimers Disease: Ben Barres and Gerald Crabtree
Antibiotic Design: Lucy Shapiro
Arthritis: David Kingsley
Birth defects: Anne Villeneuve, Will Talbot, David Kingsley, Seung Kim, Matthew Scott, Roel Nusse, Gerald Crabtree
Congential Heart Disease: Gerald Crabtree
Cancer: Roel Nusse, Matthew Scott, Anne Villeneuve, Margaret Fuller, Irv Weissman, Stuart Kim
Glaucoma: Ben Barres
Diabetes: Seung Kim
Down's Syndrome: Gerald Crabtree
Infertility: Anne Villeneuve, Margaret Fuller
Mental Retardation: Gerald Crabtree
Multiple Sclerosis: Will Talbot, Ben Barres
Stem Cells and Regenerative Medicine: Irv Weissman, Seung Kim, Roel Nusse, Margaret Fuller, James Spudich

Research in Developmental Biology on Mechanisms Underlying Human Disease

Ben Barres:
Regeneration, Spinal cord injury, Multiple Sclerosis, Paralysis, Glaucoma, Alzheimer's disease
Why does the brain fail to regenerate and repair itself after injury? Unlike most of our body parts, when our brain or spinal cord is injured, little regeneration and repair occurs. In our lab we are investigating the basis of this regenerative failure. It has long been known that the developing nervous system has a relatively good abililty to repair itself, but that this ability is lost with maturation to adulthood. The Barres laboratory has developed novel methods to purify brain neurons and to study their behavior in culture. Recently, the Barres group used these methods to compare the ability of young and old neurons to regenerate, and discovered that the old neurons regenerate their axons 10 times more slowly than do young neurons. This was a surprise because it has long been thought that poor growth ability of the old neurons was caused by inhibition by glial cells present in the mature brain. These results show that a major part of the problem is intrinsic to neuron maturation itself. The Barres lab is currently using genomic methods to elucidate the molecular basis of this loss of axon regeneration ability. The answers should provide novel targets to develop drugs that induce rapid regeneration.

Gerald R. Crabtree:
Brain development, Downs’ syndrome, Cardiovascular development and disease, Immunosuppression and autoimmune disease, Allergy and asthma, cancer, Gene therapy
The Crabtree laboratory is investigating the role of intercellular signaling through the Ca2+, calineurin and NFAT pathway in the development of the nervous system, vascular system and immune system. Dr. Crabtree’s group discovered the Ca2+/calineurin/NFAT signaling pathway and has worked out the biochemical details of its function. Dr. Crabtree’s studies with mice in which the genes in the pathway are disrupted has recently revealed that Ca2+/calineurin/NFAT signaling has an essential role in formation of connections between the trillion or more neurons that make up our nervous systems. Mutations of calcineurin and the NFAT genes are also revealing essential roles for this signaling pathway in heart and vascular development, the development of T and B cells, bone and muscle. Signaling by Ca2+, Calcineurin and NFAT is also critical for protection against the development of allergy and asthma. Mice with mutations in the NFATc2 and c3 genes have the highest levels of IgE ever recorded and have severe allergic diseases. Recent studies in the Crabtree laboratory have implicated this pathway in Down's Syndrome, as the gene for DSCR1, a calcineurin inhibitor, is overexpressed in Downs’ syndrome patients. Finally the Ca2+/calineurin/NFAT pathway is the target of the immunosuppressants FK506 and cyclosporin, which revolutionized present day transplant therapy.
An additional area of interest in Dr. Crabtree’s laboratory is the SWI/SNF like BAF complex, the components of which Dr. Crabtree’s group purified and cloned. Dr. Crabtree’s laboratory discovered that the SWI/SNF like BAF complex acts as a tumor suppressor.
Dr. Crabtree’s group is also developing new approaches for regulated gene therapy based on the use of small molecules to regulate the transcription, activity, or secretion of therapeutically useful proteins.

Margaret T. Fuller:
Stem cells, regeneration, cancer, infertility, meiosis, cytokinesis, tissue specific transcription machinery and developmentally regulated gene expression programs.
Dr. Fuller’s laboratory investigates the mechanisms that regulate proliferation, differentiation and self-renewal of adult stem cells in vivo. Understanding the fundamental mechanisms that regulate normal adult stem cell behavior in the body may provide key strategies for growth, amplification and manipulation of adult stem cells in the laboratory in preparation for clinical use for gene therapy and tissue regeneration. Dr. Fuller’s group has recently demonstrated that the microenvironment provided by support cells plays a critical role in regulation of stem self-renewal and maintenance in vivo. Particularly exciting is her laboratory’s identification of the signaling molecules that specify stem cell self-renewal, as these ligands can now be tested for ability to signal stem cell proliferation and expansion of stem cell populations in vitro.
A second focus of Dr. Fuller’s research explores how the developmental program regulates the cell cycle. During development of an embryo, tissue or organ, it is critical that cells divide on schedule and stop dividing when they are supposed to. Failure of precursor cells to stop dividing and initiate differentiation is an early step on the road to cancer. Dr. Fuller’s group studies the molecular mechanisms that regulate cell cycle progression and the defects that lead to cell cycle arrest or precursor cell overproliferation during the developmentally programmed cell cycle of male meiosis. Most strikingly, Dr. Fuller’s group has identified important checkpoint pathways that coordinate cell cycle progression with the expression of terminal differentiation genes. In addition, Dr. Fuller’s laboratory is utilizing a genetic approach to identify key genes and molecular mechanisms that mediate and regulate cytokinesis, the final step in cell division.
Dr. Fuller’s group also uses the laboratory fruitfly Drosophila to investigate the molecular and genetic causes underlying meiosis I arrest male infertility. Dr. Fuller’s work has established as a paradigm that spermatogenesis requires the action of specialized forms of the basic transcription machinery. Similar testis-specific components of the general transcription machinery have now been shown to be utilized for spermatogenesis in man and required for normal male fertility in mouse.

Dale Kaiser:
Organ formation, Birth defects, Skeletal development, Cell-cell communication and morphogenesis
Dr. Kaiser’s laboratory investigates bacterial development to understand basic molecular mechanisms through which cells communicate and cooperate to form and pattern multicellular structures, as in organ formation and embryonic development in higher anamals. How does cell movement build a structure? How are morphogenetic movements coordinated by interactions between cells or cues from extracellular materials? These questions underlie and motivate Dr. Kaiser’s research on Myxobacteria. Masses of myxobacterial cells move in ways that are striking for their organization. Although each cell can move on its own, groups of 5 - 50 cells temporarily associate to move as raft-like units. Also, 100,000 cells assemble in species specific ways to form their fruiting bodies. Different species of myxobacteria give rise to fruiting bodies of characteristically different form, showing that the underlying patterns of cell movement are inherited. Morphogenesis of fruiting bodies is facilitated by gliding motility which permits cells to move over each other and thus to build a complex three-dimensional structure. The fruiting bodies of Stigmatella and Chondromyces, for example, have a tall stalk surmounted by multiple, spore-containing macrocysts. The assembly of motile myxobacterial cells into a fruiting body of particular shape and size, followed by the differentiation of spores, has striking parallels to the early stages of human skeletal development. In skeletal development, cells of the dorsal mesoderm migrate, signal to each other and assemble into concentrates that eventually become pieces of bones, tendons, connective tissue, and muscle. Because of this basic parallel, fruiting body development may yield insights into molecular mechanisms underlying human skeletal abnormalities arising as consequences of abnormal development.

Seung K. Kim:
Diabetes, Stem cells, Birth defects, Tissue regeneration
Dr. Kim’s laboratory investigates the mechanisms that regulate formation and function of the pancreas. Dr. Kim’s studies are identifying key cell-cell signaling pathways and master regulatory genes that control morphogenesis and cell differentiation of the pancreas during embryonic development and growth and function of the pancreas in adults. The molecular pathways that mediate and regulate organ formation during development are the best candidates for strategies that can be harnessed to specify regeneration of damaged or lost tissue. Using this approach, Dr. Kim’s laboratory has become one of the world leaders in the effort to use embryonic stem (ES) cells to develop novel strategies for islet cell replacement in type I diabetes mellitus.
Dr. Kim’s research also employs the powerful genetic and genomic approaches available in the laboratory fruitfly Drosophila to investigate the regulation and function of the insulin pathway in growth regulation, development and homeostasis. As there are many parallels between Drosophila and humans in the role and regulation of the insulin pathway, Dr. Kim’s work is providing important insights into how this critical hormone modulates development, behavior, nutritional homeostasis and aging, and how the production and action of insulin is controlled in the body.

Stuart K. Kim:
Aging, Diabetes, Cancer
Aging is among the most universal of biological processes and perhaps also among the most mysterious. Numerous age-related changes are apparent at the organismic level, but we are only now starting to understand age-related changes at the molecular level. Oxidative damage, replicative senescence, accumulated stress and metabolic rate have each been proposed to specify life span. Dr. Stuart Kim’s laboratory is using functional genomics approaches to uncover the underlying genetic networks that determine longevity in the nematode C. elegans, an excellent model organism in which to study aging. The normal life span for worms is 2 weeks but under poor growth conditions, worms enter the dauer state and have life spans that can be 10 times longer. Powerful genetic screens have been used to identify mutants with increased life span. In particular, loss-of-function mutations in genes in the C. elegans insulin signaling pathway (such as daf-2 insulin receptor and age-1 PI3 kinase) extend life span. These results indicate that insulin signaling plays an important role in specifying life span, probably by regulating rates of cellular metabolism. Although previous genetic experiments have identified upstream regulatory pathways that influence the rate of aging, metabolic processes and genetic pathways that lie downstream of the insulin signaling pathway and that directly influence cellular senescence and organismic longevity are poorly understood.
To identify terminal effector genes that may directly influence life span, Dr. Kim’s group is using DNA microarrays containing nearly every gene in C. elegans to profile gene expression changes during normal life span, during the dauer stage and in mutants with increased longevity. In analyzing these gene expression patterns, Dr. Kim seeks to identify common genetic mechanisms involved in specifying life span. A surprising result is that Dr. Kim’s preliminary studies found only 164 aging-regulated genes from an extensive microarray analysis of gene expression changes during the normal life span. This result indicates that gene expression in old worms is relatively stable. The 164 aging-regulated genes include two insulin-like genes and a sir-2 homolog that increase at the end of life. Previous studies have shown that insulin signaling and sir-2 regulation act to specify life span in C. elegans. Heat shock genes decrease in old age, possibly resulting in increased levels of protein denaturation, decreased cell function and organismal senescence.

David Kingsley:
Arthritis, Bone formation and healing, Skeletal development, Genetic mechanisms of adaptation in evolution
Dr. Kingsley's lab studies the genetic basis of bone and cartilage formation. His studies have identified a key family of secreted signaling molecules used to induce bone and cartilage formation during embryogenesis. These same signals molecules are reactivated in adult animals during repair of bone fractures. This work provides an excellent example of how the pathways used to stimulate tissue formation in embryos are also critical for repair and regeneration of tissues in adults. Dr. Kingsley's work has also identified novel molecules that control both formation and maintenance of synovial joints. These studies have revealed a novel pathway that normally protects the joints of higher animals from mineral deposition and arthritis. Mutations in this pathway lead to hereditary forms of arthritis in both mice and humans. Manipulating the activity or level of this pathway may provide new strategies for preventing some forms of joint disease in humans. Finally, Dr. Kingsley has pioneered the use of new model systems to study the genetic basis of vertebrate biodiversity and response to global climate change. His work with stickleback fish is uncovering the genomic and genetic basis of dramatic changes in both skeletal and physiological characteristics in different species. This work will provide a new understanding of how organisms adapt to changing conditions, and how basic developmental pathways can be modified to obtain useful changes in both structure and function of higher animals.

Harley McAdams:
Bacterial pathogenicity, Design of new antibiotics, Cancer
Dr. McAdams’ group works on fundamental properties of the genetic regulatory circuits that control how cells function. These circuits include switches that respond to signals from the cell's environment and oscillatory circuits that control the cell cycle. Many infective bacteria depend on proper functioning of such switches for success in growing within the bodies of their target hosts, including humans. By understanding the details of these control circuits at the level of their detailed chemistry and physics, Dr. McAdams’s group seeks to identify places where new antibiotics could disrupt the infective process or kill the bacteria. Dr. McAdams pioneered studies that showed how random events in the fundamental chemistry of the genetic machinery of cells could affect the macroscopic behavior and health of cells. Now it is becoming widely recognized that these so called "stochastic mechanisms" are important in many bacterial virulence mechanisms and probably even play a role in early events that start healthy human cells on the path to becoming cancer cells.

Roel Nusse:
Cancer, Stem cells, Birth defects, Neural regeneration
Dr. Nusse’s laboratory studies the role and mechanism of action of the cell signaling molecule wnt in embryonic development, tissue regeneration and cancer. Wnt genes encode secreted signaling proteins that control many of the patterning and growth events during embryonic development. Dr. Nusse was the first to show that misregulation of wnt pathway signaling leads to breast cancer in mammals. Dr. Nusse laboratory has utilized the laboratory fruitfly Drosophila to identify many steps in the regulatory pathway of wnt signaling, including the receptor. Now using biochemically purified functional wnt protein, Dr. Nusse’s group is investigating the role of wnt pathway signaling in stem cell self-renewal, differentiation of embryonic stem (ES) and neuronal stem cells in vitro, and limb regeneration.

Matthew Scott:
Cancer, Birth defects, Brain development, Neural stem cells
Dr. Scott’s laboratory investigates the master regulatory HOX genes and the cell-cell communication pathways responsible for setting up normal body pattern, organ formation, skin and hair development, and brain and heart development in the early embryo. Dr. Scott’s work on the Hedgehog (Hh) signaling pathway has revealed the genetic and molecular basis for the most common form of human cancer, basal cell carcinoma of the skin, as well as the childhood brain cancer meduloblastoma. Dr. Scott’s laboratory is utilizing genetic approaches in the laboratory fruitfly Drosophila to investigate the mechanism of how Hedgehog signaling acts and how this critical signaling pathway is regulated in normal development and in disease. Following up on his discoveries of the role of the critical negative regulator of Hedgehog signaling, Ptc, Dr. Scott’s group is investigating the molecular basis of the human neurodegenerative disease Niemann-Pick type C1 (NPC1), which is caused by defects in a protein related to Ptc. In addition, Dr. Scott’s group is utilizing a combined genomics and genetic approach in mammals and zebrafish to investigate the mechanisms that regulate proliferation and differentiation of neural stem cells in the brain and that specify normal development of the cerebellum.

Lucy Shapiro:
Cell cycle regulation, Asymmetric cell division, Design of novel antibiotics, Gene regulatory networks
Dr. Shapiro’s research investigates the mechanisms that coordinate cell differentiation and the cell cycle using as a model system the bacterium Caulobacter. Dr. Shapiro’s pioneering studies have shown that cyclic phosphorylation cascades and proteolysis regulate cell cycle progression in bacterial cells, and in higher organisms. Dr. Shapiro’s group made the striking discovery that specific regulatory proteins and chromosomal regions undergo dynamic and stereotyped changes in subcellular localization during cell cycle progression. Utilizing the power of facile genetics and genomics available in the bacterial system, Dr. Shapiro’s group is rapidly discovering key regulatory mechanisms that govern asymmetric cell division, cell cycle progression, and the coordination of the cell cycle and cellular differentiation programs. The knowledge of bacterial development and genomics that Dr. Shapiro’s research has generated has allowed her laboratory to develop novel strategies for the design of new antibiotics, an acute medical need to combat the worldwide rise of antibiotic resistant strains of pathogenic microorganisms.

James A. Spudich:
Stem cells, Cardiovascular function and disease
Dr. Spudich’s laboratory utilizes state-of-the art biophysical, structural and molecular techniques to investigate the mechanism by which the motor protein myosin transduces the chemical energy of ATP hydrolysis into mechanical motion. The myosin family of molecular motors generate the force and motions that underlie muscle contraction, cell division, cell movement, and membrane translocations in cells. Defects in myosin motor function have profound effects on heart and vascular physiology, as well many other cellular and organ functions, ranging from secretion to hearing. In a second area of interest, Dr. Spudich’s group is utilizing their in depth knowledge of the cytoskeleton to investigate asymmetric cell division of stem cells, in order to understand the mechanisms that specify stem cell self-renewal and differentiation.

William Talbot:
Multiple Sclerosis, Birth defects, Brain development, Neural degeneration and regeneration
Myelin, the white matter that insulates and protects nerves, is essential for the efficient conduction of nerve impulses. Myelin is damaged by disease processes such as Multiple Sclerosis. At the cellular level, damage to myelin disrupts the conduction of nerve impulses and leads to the loss of nerve fibers. There are still no effective therapies for the recovery of function in regions of the brain and spinal cord that have been damaged by demyelination. Successful treatment of Multiple Sclerosis may require the use of therapies that promote regeneration of myelin. Dr. Talbot’s laboratory uses a combined genetic, cellular, and molecular approach to investigate the genes that govern the formation of myelinated nerves in zebrafish, a vertebrate model organism amenable to large-scale genetic studies. The Talbot group has identified zebrafish mutations that reduce or disrupt myelin production. Dr. Talbot’s laboratory is characterizing these mutants to learn how the mutated genes function to promote the normal development of myelin and mapping the mutations to identify the genes that are responsible. Dr. Talbot’s studies will identify the molecular pathways that trigger myelin formation. The analysis of zebrafish mutants will lead to new animal models of diseases of myelin. Dr. Talbot’s research program on myelination is providing information about basic mechanisms that may lead to the development of new therapies for diseases of myelin, including Multiple Sclerosis.

Anne Villeneuve:
Birth defects, Downs’ syndrome, infertility, Repair of DNA damage, Cancer, Aging
Dr. Villeneuve’s research investigates underlying chromosomal mechanisms that lead to miscarrage, birth defects and Down’s syndrome, cancer and aging. Using the nematode roundworm Caenorhabditis elegans as a powerful genetic model system, Dr. Villeneuve’s group is discovering the mechanisms by which chromosomes reliably pair, recombine and properly segregate during meiosis. These events are of central importance to sexually reproducing organisms, since defects result in embryos that receive an abnormal number of chromosomes. Dr. Villeneuve’s innovative work has been responsible for the emergence of C. elegans as a major model system for investigating the mechanisms underlying meiotic chromosome behavior. Dr. Villeneuve’s laboratory is also investigating how organisms protect themselves from DNA damage. Whether damage is incurred through exposure to environmental mutagens or arises spontaneously, organisms depend on their capacity to recognize DNA damage and either repair it or eliminate the damaged cells. Failure can lead to the development of cancer, and defects in the ability to repair DNA accurately are responsible for several inherited human cancer syndromes. Accumulation of DNA damage is also postulated as a major factor driving the aging process. Dr. Villeneuve’s laboratory is using the genetic and genomics power of the C. elegans system to identify new components of the DNA repair machinery, to investigate the roles of these components in genome maintenance, and to explore the involvement of these DNA repair mechanisms in aging.

Irving Weissman:
Stem cells, cancer, neural regeneration, immune system function
Dr. Weissman’s laboratory investigates the purification, biology, transplantation, and evolution of hematopoietic, germ line and neural stem cells. Dr. Weissman is a world leader in stem cell biology. His group studies mechanisms that regulate and mediate differentiation of blood cell types from hematopoietic stem cells, the mechanisms of homing, competition and colonization by exogenously introduced stem cells, and the role of programmed cell death in leukemia. Dr. Weissman’s work on the immune system and cancer is revealing mechanisms that regulate differentiation of T and B cells, lymphocyte homing, lymphoma invasiveness and metastasis.

Some of the Accomplishments and Discoveries by Members of the Department of

Developmental Biology Relevant to Disease

Since most of our studies are directed at understanding the mysteries of development it often takes many years for our work to be translated into clinically useful results. A few examples of how work in our department is contributing to medicine are given below.

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 50,000 lives per year (more than the number of American lives lost in all the Vietnam war).
David Kingley’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.