Thomas J. Silhavy

Thomas J. Silhavy
Warner-Lambert Parke-Davis Professor of Molecular Biology
Thomas Laboratory, 310

Faculty Assistant

Jennifer Munko


  • B.S., Pharmacy, Ferris State College
  • A.M., Ph.D., Biochemistry, Harvard University

Research Area

Microbiology & Virology

Research Focus

Protein targeting and signal transduction

All cells have subcellular compartments that are bound by lipid bilayers, and this three-dimensional organization is essential for life. If we consider lipid bilayers themselves as compartments, then Gram-negative bacteria, such as Escherichia coli, have four distinct subcellular locations: the cytoplasm, inner membrane (IM), periplasm, and outer membrane (OM). The noncytoplasmic compartments are collectively termed the cell envelope. We wish to understand cellular assembly, in particular, the process of OM biogenesis. The OM is an asymmetric lipid bilayer containing phospholipids in the inner leaflet and lipopolysaccharide (LPS) in the outer leaflet. Membrane spanning outer membrane proteins (OMPs) typically assume a beta-barrel conformation. All OM components are synthesized in the cytoplasm or the IM and therefore, OM biogenesis requires the transport of these molecules across the cell envelope for assembly at their final cellular location. Strikingly, these transport and assembly processes occur in an environment that lacks an obvious energy source such as ATP. We have used a combination of genetics, biochemistry, and bioinformatics to identify the cellular machinery required for the assembly of OMPs and LPS in the OM. Both of these assembly machineries have protein components in every cellular compartment, and this spatial organization suggests the temporal order of component function (Figure 1). Current effort in the lab is directed towards understanding the how these machines function in molecular terms, and how their activities are coordinated.

Stationary phase

When E. coli deplete their environment of essential nutrients they enter a physiological state termed stationary phase in order to survive prolonged starvation and resist various toxic insults. Entry into stationary phase is accompanied by large changes in gene expression, most of which are mediated by sigma-S, the central regulator of the stationary phase response. Sigma-S regulation is complex and occurs at all levels, but regulated proteolysis is of primary importance for carbon starvation. In log phase cells, the two-component response regulator SprE directs sigma-S to the ClpP/ClpX protease, but as cells enter stationary phase this destruction ceases and sigma-S accumulates. SprE belongs to the response regulator family of two-component regulatory proteins. As such it was assumed that the activity of SprE was controlled by phosphorylation. We have shown that this model is not correct. Something else must control SprE activity upon carbon starvation. It was also assumed that starvation for any essential nutrient would increase RpoS levels by the same mechanism that causes RpoS accumulation under carbon starvation. We have shown that this is not the case either. The cellular response to nutrient limitation is much more complex than previously appreciated. We wish to understand the molecular events that signal starvation for various essential nutrients, and the mechanisms employed by the cell to insure survival under these stressful conditions.

Thomas J. Silhavy is the Warner-Lambert Parke-Davis Professor of Molecular Biology at Princeton University. Silhavy is a bacterial geneticist who has made fundamental contributions to several different research fields. He is best known for his work on protein secretion, membrane biogenesis, and signal transduction. Using Escherichia coli as a model system, his lab was the first to isolate signal sequence mutations, to identify a component of cellular protein secretion machinery, and an integral membrane component of the outer membrane assembly machinery, and to identify and characterize a two-component regulatory system. Current work in his lab is focused on the mechanisms of outer membrane biogenesis and the regulatory systems that sense and respond to envelope stress and trigger the developmental pathway that allows cells to survive starvation. He is the author of more than 200 research articles and three books.

Professor Silhavy received his BS in Pharmacy (summa cum laude, 1971) from Ferris State College and his MS (1974) and PhD (1975) in Biological Chemistry from Harvard University. As a graduate student with Winfried Boos he helped characterize the role of periplasmic binding proteins in sugar transport. As a postdoctoral fellow with Jonathan Beckwith at Harvard Medical School he helped establish gene fusions as an experimental tool. He served as an Instructor of Microbiology at Harvard Medical School for two years, and he worked at the NCI Frederick Cancer Research Facility for five years where he was Director of the Laboratory of Genetics and Recombinant DNA. He came to Princeton in 1984 as a founding member of the Department of Molecular Biology.

In recognition of his scientific accomplishments Silhavy was awarded an honorary Doctor of Sciences degree from his alma mater, Ferris State College (1982), was elected Fellow of the American Academy of Microbiology (1994), the American Association for the Advancement of Science (2004), and the American Academy of Arts and Sciences (2005), and he is a member of the National Academy of Sciences (2005) and an associate member of EMBO (2008). In 1999 he received an NIH MERIT award, and he received the Novitski Prize for creativity from the Genetics Society of America in 2008. His commitment to teaching is evidenced by the President’s Award for Distinguished Teaching at Princeton (1993), the Graduate Microbiology Teaching award from the American Society for Microbiology (2002), and the Graduate Advising Award at Princeton (2003).


  • Appointed Editor-in-Chief of the Journal of Bacteriology, American Society for Microbiology
  • Appointed Editor-in-Chief of the Journal of Bacteriology, American Society for Microbiology