Research Interests:

Biologists study pathways and networks by perturbing them and observing the result. Whereas these perturbations most often result from mutations in genetic investigations, they can also result from small organic molecules. Numerous examples exist of small molecules being used to explore biology, yet these examples have been brought to light generally on a case-by-case basis. Rather than using small molecules on an ad hoc basis, Stuart Schreiber's laboratory is attempting to use them in a systematic way, so that virtually any area of biology can be examined with small molecules. Key elements of this approach are the use of diversity-oriented organic synthesis of structurally complex and diverse small molecules, phenotypic and proteomic screening of the resulting small molecules, and searchable databases of experiments involving small molecule-based perturbations of biological systems.

Analogous to the most striking, early examples of this approach (for example, Carlsson's use of chlorpromazine to explore the dopamine receptor and Borisy's use of colchicine to discover tubulin), This lab's early efforts used small molecules on an ad hoc basis. Beginning in the mid-1980's, Schreiber and his co-workers studied the molecular mechanisms of the immunosuppressive agents cyclosporin, FK506 and rapamycin, which led to new insights into two signaling networks. Using a synthetic analog of FK506, they were able to show that these immunosuppressants "bridge" two proteins. Both the complex of cyclosporin with its receptor, cyclophilin, and the complex of FK506 with its receptor, FKBP12, bind the same protein, the protein phosphatase calcineurin. This discovery, together with Gerald Crabtree's discovery of NFAT proteins, helped defined the calcium-calcineurin-NFAT signaling pathway, now known to be essential for immune function, heart development, and the acquisition of memory in the hippocampus.

Combining synthetic organic chemistry and cell biology, Schreiber and co-workers co-discovered the mammalian protein FRAP, the target of the complex between FKBP12 and rapamycin, and unraveled its role as a metabolic sensor and a regulator of cell's response to nutrients. FRAP and its yeast orthologs Tor1p/2p are now recognized as the founding members of a family of proteins called the PIK-related kinases (ATM, ATR, DNA-PK), which act as intracellular sensors monitoring a number of different cellular pathways. An analogous approach involving synthetic investigations of trapoxin and depudecin led to the purification and cloning of the histone deacetylases (HDACs). This work coincided with David Allis' discovery of the histone acetytransferases (HATs). Together, these studies strengthened a linkage between chromatin and the transcription regulation apparatus.

A first step towards generalizing this small molecule approach was taken together with Gerald Crabtree. Schreiber and Crabtree developed a method to study the function of cellular proteins for which small molecule partners are not yet known. They synthesize small molecule "dimerizers" that are able to recruit one protein to another (for example an enzyme and its substrate), thereby activating a new cellular signal. This research illuminated the role of proximity effects in biology, and it has been used to probe the pathways activated by a variety of receptors including the T cell receptor, erythropoietin and Fas receptors, and many others. One study illustrated the use of small molecules to achieve spatial and temporal control over a death-inducing (apoptotic) signaling pathway in an animal.

Several years ago, Schreiber and his co-workers undertook an effort to systematize the use of small molecules to explore biology. This approach differs from earlier studies in that it can be used to study virtually any biologic process, and it no longer involves the ad hoc use of small molecules. Using a newly developed planning algorithm for diversity-oriented synthesis, they set in motion several projects, each of which has the potential to generate hundreds of thousands or millions of small molecules having the desirable characteristics of natural products. The promise of this work and a new technique for phenotypic screening of post-translational modifications (the cytoblot assay), led Schreiber, Marc Kirschner, Tim Mitchison and Rebecca Ward to found the Harvard Institute of Chemistry and Cell Biology (ICCB). ICCB's aim has been to develop the field of chemical genetics, where the combination of small molecules made using diversity-oriented organic synthesis and genetic-like (phenotypic and proteomic) screens are used to explore biology. Schreiber and Tim Mitchison (co-directors of ICCB) used a phenotype-based (cytoblot) screening approach to discover an inhibitor of a mitotic motor protein, the first mitosis-specific inhibitor of a protein other than tubulin and a promising lead for cancer. Schreiber and his co-workers used a chemical analog of the genetic concept of synthetic lethality to discover a small molecule that induces premature chromatic condensation (by binding to the PIK-related kinase ATR) preferentially in cells lacking p53, a tumor suppressor often disabled in human cancers. A marriage between chemical genetics and genomics led Schreiber and his co-workers to new insights into nutrient sensing in the pancreas and insulin-responsive tissues, and thereby into the molecular origins of type II diabetes.

Chemical genetics, like genetics, can be used to understand protein function. Although it is important to use small molecules that alter function with the specificity of a gene knockout, the discovery of such molecules allows the instantaneous alteration of function, not possible in classical genetics, even in cells and animals not readily amenable to genetic analysis. Instantaneous alteration of function allows the kinetic time course of events to be determined, which can shed a bright light on complex cellular processes. Perhaps most importantly, in chemical genetics the tools that are used to alter function, small molecules, can be used to control the function of proteins. This promises to build more direct connections between biology and medicine, ones made possible by an integrated use of synthetic organic chemistry, molecular cell biology, and genomics.

Selected Publications:

S. L. Schreiber (1991). "Chemistry and Biology of the Immunophilins and Their Immunosuppressive Ligands". Science, 251, 283-287.

Gerald R. Crabtree and Stuart L. Schreiber (1996). "Three-Part Inventions: Intracellular Signaling and Induced Proximity". TIBS, 21, 418-422.

Stuart L. Schreiber (1998). "Chemical Genetics Resulting from a Passion for Synthetic Organic Chemistry". BioMed Chem., 6, 1127-1152.

S. L. Schreiber (2000). "Target-Oriented & Diversity-Oriented Organic Synthesis". Science, 287, 1964-69.