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 and other biological processes.
Genetics and genome sequencing have supplied an extensive parts list for how to create an embryo, yet it is still impossible to construct a precise description of the process from genome scale data. Existing models of signaling pathways have too many parameters to fit experimentally and ignore the complexities of cell biology. Dr. Siggia’s group works to develop mathematical models that apply broadly to biological problems.
Dr. Siggia’s group has recently developed mathematical descriptions for embryonic patterning, which encapsulate how a field of cells can react to an external signal and coordinate among themselves to choose between three discrete fates. The resulting mathematics is geometric and naturally meshes with the phenomenological concepts from the pre-molecular era of embryology.
The Siggia lab has developed a phenotypic model for vulva patterning in C. elegans, which requires a parameter for each new allele, but then can predict the matrix of crosses between all pairs of alleles. Ongoing experiments with Rockefeller’s Shai Shaham aim to test predictions of this theory.
Vertebrate signaling pathways are another area where pathway dynamics in single cells has lagged behind the genetic and biochemical findings. In collaboration with Rockefeller’s Ali Brivanlou, Dr. Siggia’s group has found that the TGF-β pathway is adaptive: in response to a step increase in ligand, the transcriptional response of the pathway turns off. This is not due to the known negative feedbacks that operate at the receptor level since the transcriptional effectors that are phosphorylated by the receptors remain on. By adapting a microfluidic cell, developed at Stanford University, to examine the response of cells to a variety of temporal stimuli, Dr. Siggia and his collaborators have noted an important corollary of adaption in the embryo: that positional information can be conveyed by the rate of ligand changes, not merely its level.
To take a step closer to the embryo, the Siggia lab has begun investigating early differentiation in human embryonic stem cells (hESCs). All three germ layers can be induced by the two classes of TGF-β ligands, and the group has focused on the space-time development of the earliest fates. Because cell communication via secondary signals is an essential part of morphogenesis, stem cell differentiation provides a quantitative assay for this process.
Geometric descriptions of biodynamics are not always evident by inspection. With colleagues at McGill University, Dr. Siggia has developed computational evolutionary methods to discover them. These have led to proposals for how circadian oscillators can both have a temperature-independent period and the ability to entrain and phase lock to a temperature oscillation. Experiments motivated by this theory are in progress with the Rockefeller’s Michael Young. In a related project with Rockefeller’s Fred Cross, Dr. Siggia’s group has demonstrated phase locking of the yeast cell cycle to a periodic cyclin signal. Other problems elucidated by computational network evolution include somitogenesis, Hox patterning and the evolution of blastoderm patterning between fly and mosquito.
The phosphorylation networks in cells have the potential to act as analogue computers. Cells, particularly in the immune system, are often confronted with the task of discovering changes within a temporal stream of noisy data. With colleagues at the Pasteur Institute, Dr. Siggia has recently shown that simple networks can perform close to the mathematical optimum for this problem.
In the recent past Dr. Siggia has also used bioinformatic methods to understand transcriptional regulation in yeast and in the fly blastoderm and, in collaboration with Rockefeller’s Alexander Tomasz, has studied the evolution of antibiotic resistance in samples of Staphylococcus aureus from a single patient undergoing therapy.
Dr. Siggia received his A.B. in 1971 and his Ph.D. in physics in 1972, both from Harvard University. He was a junior fellow at Harvard, assistant professor at the University of Pennsylvania, and then professor of physics at Cornell University. He has been a visitor or consultant at the University of Paris in Orsay, the EÅLcole Normale SupeÅLrieure 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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