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An individual who has a seemingly never-ending supply of creative ideas about how to navigate the combinatorial shoals is Peter G. Schultz, director of the Genomics Institute of the Novartis Research Foundation (GNF) , San Diego, and chemistry professor at Scripps Research Institute, La Jolla, Calif. At the meeting, he gave a stimulating keynote presentation on a wide range of combinatorial applications he has been involved in, from identifying new disease targets to the concept of "taking combinatorial chemistry to the next level"--to whole animals. DuPont Pharmaceuticals researcher operates parallel synthesizer that handles up to 20 simultaneous reactions. "Can you actually make a mutation in every gene of the mouse and screen for interesting phenotypes?" Schultz asks. Indeed, GNF and Scripps researchers are planning to do just that. Using tens of thousands of mice, they will mutate every gene in the mouse, one gene at a time, and screen the mutant mice for interesting phenotypes--characteristics that stem from the genetic changes. "Once you've made all these mutants, what can you look for?" Schultz asks. "You can actually look for interesting neurological effects. Our engineers are building mouse cages that monitor mouse movement. You can do learning paradigms, so you can look for smart mice and dumb mice. You can also look for genes that affect addiction, allograft rejection, body temperature control, etc. Such mutants might reveal fundamental biology as well as targets for therapeutic interventions, such as [drugs for] organ transplants. This is the next higher level of diversity." GNF is currently developing a system for microcrystallization, cloning, expression, and purification of proteins. "Our hope is to be able to clone 60,000 gene targets a year, attempt crystallization of 20,000 targets a year, and solve probably on the order of thousands of structures a year," Schultz says. "We're also building supercomputers to try to virtually [screen] large libraries against these structures. We want in theory to put protein structure determination on the same level as high-throughput screening, combichem, and DNA sequencing." Schultz and his colleagues at GNF are also taking stem cells "and throwing libraries of molecules at them to see if we can differentiate them into specific phenotypes--for example, cartilage versus bone," he says. "We really want to do this on a large scale. So at the institute we're actually building a system now, to be operational this summer, that will allow us to do 200,000 screens a day." If one wants to find compounds with active molecular functions, he says, "I come back to the idea that nature's been doing this for about a billion years and has figured out how to do it quite effectively. The idea is that we can take inspiration from the way nature solves these problems." Protein-protein interactions Another combinatorial application GNF scientists are looking at is functional regulation at protein interfaces. "So much of cellular signaling is controlled by protein-protein interactions," Schultz says. In a study in press in Science, he and his coworkers report having perturbed the interface between human growth hormone (hGH) and its cellular receptor by knocking out a tryptophan residue in hGH. They then screened a bacteriophage expression library for compounds that bound to the interface and that restored the interaction. "When you put the mutated hGH into a cell line with the hGH receptor, you get no signal transduction," Schultz explains. "If you add the small molecule, and only if you add the small molecule, you actually get some activation of the pathway. So the small molecule acts as an agonist." It may also be possible to selectively activate mutated versions of other proteins, like insulin, erythropoietin, and transcription factors, in a similar manner, "so we're beginning to look at ways to regulate these interactions with small molecules," he says. |
| UPDATE | 05.00 |
| AUTHOR | Genomics Novartis Foundation's Peter G. Schultz |
| LITERATURE REF. | This data is not available for free |
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