Whitehead Institute for Biomedical Research
Dr. Sabatini is also a professor of biology at the Massachusetts Institute of Technology, member of the Whitehead Institute for Biomedical Research, member of the Koch Institute for Integrative Cancer Research at MIT, and senior associate member of the Broad Institute.
Regulation of Growth and Metabolism in Normal and Diseased Physiology
Size matters a great deal to biologist David Sabatini, whose research revolves around the fundamental question of how cells, organs, and living creatures grow.
"I think it's one of the most interesting questions out there," he says, "because it's one of the most obvious things to think about. You look at the natural world around you and see such tremendous diversity in size. Yet we actually know relatively little about how size is regulated."
Sabatini has been exploring these questions since his days as a graduate student, when, in 1994, he identified a protein complex in mammalian cells known as mTOR that anchors a master growth-regulating pathway in mammals. mTOR is the mammalian target of rapamycin, a chemical that causes cells to stop dividing and shrink and is a potent immune suppressant used to stifle rejection of transplanted tissues and organs.
"I decided to study it further, and in essence I haven't stopped," says Sabatini, who is a faculty member at the Whitehead Institute for Biomedical Research and the Massachusetts Institute of Technology. "It has led into a number of new and surprising areas." Among these are the liver's involvement in the physiological response to calorie restriction, and the links between energy, nutrient metabolism, and cancer.
"It's also clear that the mTOR pathway, which is regulated by nutrients, is involved in the process by which caloric restriction slows aging and increases life span," Sabatini says—while disavowing any plans to get into the fountain of youth field.
Sabatini was a graduate student in the lab of Johns Hopkins University neuroscientist Solomon Snyder when he identified mTOR. Upon receiving his M.D. and Ph.D. degrees from Hopkins, Sabatini joined the Whitehead Institute as a Whitehead Fellow and began searching for other components of the mTOR pathway. "It was a very frustrating few years," he recalls. "We did a lot of protein purifications, and the protein complexes with which mTOR was interacting were unstable."
Eventually, after adding a chemical to stabilize mTOR's structure, Sabatini purified and identified two mTOR-containing protein complexes (mTORC1 and mTORC2). It turned out, surprisingly, that mTORC2 is a long-sought switch that turns on the PI3K/PTEN/Akt signaling pathway that is perturbed in some forms of cancer. The complex is a hot topic in cancer research, and Sabatini and others are now devising mTORC2 inhibitors as cancer drug candidates.
In an offshoot of the work on mTOR, Sabatini's group has been developing new technologies that will permit researchers to identify the components of signaling networks in mammalian cells. Sabatini and his colleagues have developed "cell-based microarrays"—microscopic slides printed with spots of mammalian cells that over- or underexpress particular gene products. This technology allows researchers to look at the cellular effects of perturbing thousands of genes simultaneously. Sabatini's group is now using the technique to identify candidate genes that underlie phenotypes of interest, such as cell size.
In 2005, the RNAi Consortium, led by Sabatini and colleagues at several Boston-area research institutions, created a library of RNA-interference (RNAi) reagents that researchers can use to block the function of every human gene. Sabatini and his colleagues are using those RNAi tools in a new project that gets him back to his roots in cell growth studies: a systematic effort to identify the metabolic processes that allow tumor cells with common cancer-causing mutations to survive. "Many cancer cells grow and proliferate at rates far higher than most other adult cells, creating a demand for the building blocks of macromolecules that is not shared by most normal cells," Sabatini notes. "For these reasons, it is surprising that the literature contains relatively little information on the metabolic processes, besides glycolysis, that are necessary for tumor cell life."
Sabatini's ambitious goal is to use RNAi technology to identify all of the human metabolic genes necessary for cancer cells to survive in standard tissue-culture conditions and in conditions that mimic oxygen-deprived regions of a tumor. "The results of this screening approach will lay the foundation for a lot of our future work," Sabatini says. "Ultimately we hope it will provide a therapeutically useful connection between the genetic lesions that underlie tumor formation and the metabolic adaptations that allow cancer cells to survive in a tumor."