Heads of Laboratories
As large amounts of genetic data, such as genome sequences, have been generated, the field of bioinformatics has become essential for processing and analyzing biological information. Dr. Siggia’s laboratory uses the bioinformatics approach to study gene control in bacteria, yeast and flies, inventing probability-based models to discern the regulatory patterns involved in gene expression.
The genome is more than a parts list — it functions as an assembly manual that directs when and where genes are to be expressed in response to signals conveyed by proteins. Although new technologies have been perfected that provide a genome-wide view of the expression of messenger RNA, the blueprint for proteins, it has still not become clear how regulatory DNA codes for messenger RNA’s expression. Decoding the regulatory part of the genome is challenging; however, as more genomes are sequenced, it becomes possible to compare regions of regulatory DNA and infer functional units.
Dr. Siggia’s lab has developed multiple algorithms, including one called Stubb, to identify regulatory modules computationally. Using Stubb, his lab has scanned the genome of the fruit fly Drosophila melanogaster to calculate the number and location of clusters of binding sites. Fruitful tests include the segmentation gene hierarchy, which patterns the developing embryo through a genetic cascade. Dr. Siggia’s lab is using this signaling pathway as a prototype of combinatorial control to determine new blastoderm patterned genes as well as new regulatory modules. The Stubb algorithm also can examine related genomes and score regulatory regions by their degree of functional variation. By computationally screening the large set of blastoderm modules, Dr. Siggia has found modules that disappeared or moved to nonhomologous but adjacent regions of the genome.
As the cost of resequencing entire genomes decreases, new kinds of bioinformatics experiments have become possible. In collaboration with Rockefeller’s Alexander Tomasz, Dr. Siggia has examined the microevolution of b-lactam resistance in Staphylococcus aureus with the goal of elucidating the genes responsible for this elusive phenomena.
Evolution explains the relationships among organisms by common descent, but the process itself is commonly understood to be too random or contingent to allow the prediction of outcomes. Convergent evolution, however, argues that evolution replayed from different starting points may lead to a common outcome. Dr. Siggia and his colleagues propose to calculate gene networks that pattern the embryo from the principle that they can be evolved quickly through a series of intermediate steps all driven by positive selection. In favorable examples such as vertebrate somitogenesis, they have shown that a plausible network can arise by positive selection and thus show mathematically that the outcome is substantially model independent. A topological model for the interaction of the two signaling pathways that pattern the vulva in C. elegans provided the first quantitative account of that system. They hope to use the insights gained to develop “topological” models for the early events in patterning the vertebrate embryo, in which there is such a plethora of redundant ligands and signaling pathways that assigning numbers to all the components is hopeless. Experiments are under way with Ali H. Brivanlou’s lab to test these ideas.
Another area of interest for the Siggia lab is in modeling cell division. The cell cycle in budding yeast is a network for which most of the parts are known, yet predicting how they will work together remains a challenge. Together with Rockefeller’s Frederick R. Cross, Dr. Siggia is making movies of growing yeast colonies over five or more divisions while following various markers. The analysis of these movies using custom software has led to several new insights into the transitions between phases of the cell cycle, the effects of various feedbacks and the function of “well-studied” genes. Using a new flow cell technology, he and his colleagues have recently been able to phase lock the cell cycle to an external clock in much the same way that circadian oscillators are locked in phase to light.
Dr. Siggia received his A.B. in physics in 1971 and his Ph.D. in physics in 1972, both from Harvard University. He was a junior fellow at Harvard from 1972 to 1975 and then was assistant professor at the University of Pennsylvania for two years before moving to Cornell University, where he became professor of physics in 1985. He has been a long-term visitor or consultant at the University of Paris in Orsay, the École Normale Supérieure in Paris, the Santa Barbara Institute for Theoretical Physics, Bell Labs and Los Alamos National Laboratory. Dr. Siggia came to Rockefeller in 1997.
Dr. Siggia was elected to the United States National Academy of Sciences in 2009. He received a John Simon Guggenheim Fellowship in 1988 and was an Alfred P. Sloan Research Fellow from 1980 to 1982.
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