Lucy Shapiro & Harley McAdams

Lucy Shapiro is a developmental biologist who chose Caulobacter crescentus to ask how a one-dimensional genetic code is translated into the three-dimensional organization of a cell. She was the founding chair of Stanford's Department of Developmental Biology in 1989 and is the Virginia and D. K. Ludwig Professor, Emerita, and director of the Beckman Center for Molecular and Genetic Medicine. Her honors include the 2011 National Medal of Science and the 2025 Lasker~Koshland Special Achievement Award in Medical Science.

Contributions

• Developed Caulobacter crescentus as a model for bacterial differentiation, using synchronized cultures to study a cell cycle that yields a stalked cell and a flagellated swarmer cell. Shapiro et al. 1971
• Showed that bacterial proteins have specific subcellular addresses: newly made chemoreceptors localize to the nascent swarmer pole and are degraded in a temporally and spatially restricted way; chemoreceptor complexes cluster at the poles of E. coli. Alley et al. 1993; Maddock & Shapiro 1993
• Identified the essential response regulator CtrA and showed that its phosphorylation and cell type-specific proteolysis control the G1-to-S transition. Quon et al. 1996; Domian et al. 1997
• Identified the cell cycle-regulated DNA methyltransferase CcrM, linking the methylation state of the chromosome to cell-cycle progression. Zweiger et al. 1994; Kozdon et al. 2013
• With McAdams and colleagues, mapped the cell-cycle transcriptome and the oscillating CtrA/GcrA master-regulator circuit, and co-authored the Caulobacter genome sequence. Laub et al. 2000; Nierman et al. 2001; Holtzendorff et al. 2004
• Showed that chromosomal loci have specific subcellular positions and are moved in order as they are replicated, and that MipZ couples chromosome segregation to placement of the FtsZ division ring. Viollier et al. 2004; Thanbichler & Shapiro 2006
• Identified the polar organizer PopZ and, with W. E. Moerner and others, characterized PopZ as a biomolecular condensate that selectively sequesters signaling proteins at the cell pole. Bowman et al. 2008; Lasker et al. 2020; Lasker et al. 2022
• Translated this work outside the lab through boron-based anti-infectives (Anacor Pharmaceuticals, with Stephen Benkovic) and long-running advice to U.S. administrations on bioterrorism, antibiotic resistance and emerging infections.

Career

• A.B., cum laude, Brooklyn College (1962); Ph.D. in Molecular Biology, Albert Einstein College of Medicine (1966). source
• Faculty member at Albert Einstein College of Medicine 1967–1986, rising to Professor and Chairman of Molecular Biology (1977–1986) and Director of the Division of Biological Sciences (1981–1986). source
• Professor and Chairman of Microbiology at Columbia University's College of Physicians & Surgeons, 1986–1989. source
• Moved to Stanford in 1989 as Professor of Developmental Biology and founding chairman of the Department of Developmental Biology (chair 1989–1997). source
• Virginia and D. K. Ludwig Professor, Emerita, and Director of the Beckman Center for Molecular and Genetic Medicine at Stanford. source
• Senior Fellow at Stanford's Freeman Spogli Institute for International Studies (Center for International Security and Cooperation) since 1999. source
• In 1998 she was invited to speak to President Clinton's cabinet about biological warfare, and later advised the George W. Bush administration on bioterrorism and emerging infectious disease. source
• With chemist Stephen Benkovic she established Anacor Pharmaceuticals in 2002 to develop boron-based anti-infectives; the company produced two FDA-approved topical drugs and was sold to Pfizer in 2016. She later co-founded Boragen (now 5Metis), focused on agricultural antifungals. source
• Trained 71 graduate students and postdoctoral fellows, more than 30 of whom became faculty members; the Lasker Foundation notes two dozen of them run Caulobacter labs. source

Honours

1991

Elected to the Institute of Medicine of the National Academy of Sciences source

1992

American Academy of Arts and Sciences source

1993

American Academy of Microbiology source

1994

Elected to the U.S. National Academy of Sciences source

1994

FASEB Excellence in Science Award source

2003

Elected to the American Philosophical Society source

2005

Selman A. Waksman Award in Microbiology, National Academy of Sciences source

2009

Canada Gairdner International Award source

2009

John Scott Legacy Medal and Premium (shared with Harley McAdams) source

2010

ASM Abbott Lifetime Achievement Award source

2011

National Medal of Science (Biology; presented February 1, 2013) source

2012

Louisa Gross Horwitz Prize, Columbia University (shared with Richard Losick and Joe Lutkenhaus) source

2013

ASCB Women in Cell Biology Lifetime Achievement Award source

2014

Pearl Meister Greengard Prize, Rockefeller University source

2020

Dickson Prize in Science, Carnegie Mellon University source

2025

Lasker~Koshland Special Achievement Award in Medical Science source

I found the simplest organism I could, and set out to learn how the multiple components of a living cell work together.

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I wanted to know how the genetic code, or DNA, that exists in one dimension, is somehow translated into organisms like you and I that occupy space in three dimensions.

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Our labs are totally integrated. … His students are physicists and engineers, and mine are developmental biologists and microbial geneticists. They work side by side.

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In the bibliography

• Bacterial differentiation Science 1971
• Isolation of a Caulobacter gene cluster specifying flagellum production by using nonmotile Tn5 insertion mutants Proc Natl Acad Sci U S A 1982
• Cascade regulation of Caulobacter flagellar and chemotaxis genes J Mol Biol 1987
• Cell-cycle control of a cloned chromosomal origin of replication from Caulobacter crescentus J Mol Biol 1992
• A temporally controlled sigma-factor is required for polar morphogenesis and normal cell division in Caulobacter Genes Dev 1992
• A Caulobacter DNA methyltransferase that functions only in the predivisional cell J Mol Biol 1994
• Circuit simulation of genetic networks Science 1995
• Cell cycle control by an essential bacterial two-component signal transduction protein Cell 1996
• Cell type-specific phosphorylation and proteolysis of a transcriptional regulator controls the G1-to-S transition in a bacterial cell cycle Cell 1997
• Protein localization and cell fate in bacteria Science 1997
• Negative control of bacterial DNA replication by a cell cycle regulatory protein that binds at the chromosome origin Proc Natl Acad Sci U S A 1998
• Cell cycle-dependent polar localization of an essential bacterial histidine kinase that controls DNA replication and cell division Cell 1999
• Differential localization of two histidine kinases controlling bacterial cell differentiation Mol Cell 1999
• Global analysis of the genetic network controlling a bacterial cell cycle Science 2000
• Identification and cell cycle control of a novel pilus system in Caulobacter crescentus EMBO J 2000
• Complete genome sequence of Caulobacter crescentus Proc Natl Acad Sci U S A 2001
• Genes directly controlled by CtrA, a master regulator of the Caulobacter cell cycle Proc Natl Acad Sci U S A 2002
• Generating and exploiting polarity in bacteria Science 2002
• A bacterial cell-cycle regulatory network operating in time and space Science 2003
• Oscillating global regulators control the genetic circuit driving a bacterial cell cycle Science 2004
• Rapid and sequential movement of individual chromosomal loci to specific subcellular locations during bacterial DNA replication Proc Natl Acad Sci U S A 2004
• DnaA coordinates replication initiation and cell cycle transcription in Caulobacter crescentus Mol Microbiol 2005
• DnaA couples DNA replication and the expression of two cell cycle master regulators EMBO J 2006
• A phospho-signaling pathway controls the localization and activity of a protease complex critical for bacterial cell cycle progression Proc Natl Acad Sci U S A 2006
• A dynamically localized protease complex and a polar specificity factor control a cell cycle master regulator Cell 2006
• MipZ, a spatial regulator coordinating chromosome segregation with cell division in Caulobacter Cell 2006
• A DNA methylation ratchet governs progression through a bacterial cell cycle Proc Natl Acad Sci U S A 2007
• High-throughput identification of transcription start sites, conserved promoter motifs and predicted regulons Nat Biotechnol 2007
• Caulobacter crescentus as a whole-cell uranium biosensor Appl Environ Microbiol 2007
• A comprehensive set of plasmids for vanillate- and xylose-inducible gene expression in Caulobacter crescentus Nucleic Acids Res 2007
• Systems biology of Caulobacter Annu Rev Genet 2007
• Caulobacter requires a dedicated mechanism to initiate chromosome segregation Proc Natl Acad Sci U S A 2008
• A polymeric protein anchors the chromosomal origin/ParB complex at a bacterial cell pole Cell 2008
• Architecture and inherent robustness of a bacterial cell-cycle control system Proc Natl Acad Sci U S A 2008
• SpoT regulates DnaA stability and initiation of DNA replication in carbon-starved Caulobacter crescentus J Bacteriol 2008
• Why and how bacteria localize proteins Science 2009
• An essential transcription factor, SciP, enhances robustness of Caulobacter cell cycle regulation Proc Natl Acad Sci U S A 2010
• A spindle-like apparatus guides bacterial chromosome segregation Nat Cell Biol 2010
• High-throughput identification of protein localization dependency networks Proc Natl Acad Sci U S A 2010
• Assembly of the Caulobacter cell division machine Mol Microbiol 2011
• The essential genome of a bacterium Mol Syst Biol 2011
• The architecture and conservation pattern of whole-cell control circuitry J Mol Biol 2011
• Global methylation state at base-pair resolution of the Caulobacter genome throughout the cell cycle Proc Natl Acad Sci U S A 2013
• Cell fate regulation governed by a repurposed bacterial histidine kinase PLoS Biol 2014
• The coding and noncoding architecture of the Caulobacter crescentus genome PLoS Genet 2014
• The global regulatory architecture of transcription during the Caulobacter cell cycle PLoS Genet 2015
• CauloBrowser: A systems biology resource for Caulobacter crescentus Nucleic Acids Res 2016
• Selective sequestration of signalling proteins in a membraneless organelle reinforces the spatial regulation of asymmetry in Caulobacter crescentus Nat Microbiol 2020

Harley H. McAdams is a physicist (Ph.D., Rice University, 1967) who was a department head of systems engineering at Bell Labs before moving to Stanford in 1989, where he became Professor (Research) of Developmental Biology, now emeritus. Starting with a 1995 Science paper with Lucy Shapiro, he brought circuit analysis and simulation to genetic networks, and with Adam Arkin analyzed the stochastic nature of gene expression; he and Shapiro shared the 2009 John Scott Award.

Contributions

• Proposed modeling genetic networks as circuits, integrating biochemical kinetics within a circuit-simulation framework (demonstrated on the phage lambda lysis-lysogeny decision). McAdams & Shapiro 1995
• With Adam Arkin, showed by simulation that proteins are produced in random bursts, so genetic switches can have probabilistic outcomes; extended to the lambda developmental decision. McAdams & Arkin 1997; Arkin et al. 1998; McAdams & Arkin 1999
• Co-led genome-scale analyses of the Caulobacter cell cycle: the cell-cycle transcriptome and the direct CtrA regulon. Laub et al. 2000; Laub et al. 2002
• Described the architecture of Caulobacter cell-cycle control as a small set of master regulators operating in time and space, and built a hybrid simulation and digital-circuit model showing its robustness. McAdams & Shapiro 2003; Shen et al. 2008; McAdams & Shapiro 2011
• Co-authored genome-wide resources including the essential genome by Tn-seq, the base-pair methylome, transcript and coding maps, and the CauloBrowser database. Christen et al. 2011; Kozdon et al. 2013; Schrader et al. 2014; Lasker et al. 2016
• Studied the physical organization of the chromosome, including models of the Caulobacter chromosome as a supercoiled polymer in cell-like confinement. Umbarger et al. 2011; Hong et al. 2013

Career

• B.S. in Physics, Texas A&M (1960); M.S. in Physics, University of Illinois at Urbana (1962); M.A. (1965) and Ph.D. (1967) in Physics, Rice University. source
• Former department head of systems engineering at Bell Labs; he moved with Lucy Shapiro to Stanford in 1989 when she was recruited to found the Department of Developmental Biology. source
• According to Shapiro, after the move he worked in the aerospace industry on signaling between Earth and satellites before turning to genetic circuitry. source
• Professor (Research) of Developmental Biology, Emeritus, at Stanford, and a member of Stanford Bio-X. source
• His and Shapiro's groups began in a spare bedroom of their campus home and later became side-by-side, integrated labs of biologists, geneticists, physicists and electrical engineers. source
• Co-inventor, with Adam Arkin and Lucy Shapiro, of U.S. Patent 5,914,891, 'Simulation Tool for Cellular Regulatory Networks' (issued June 22, 1999). source
• Collaborated with Shapiro and chemist Stephen Benkovic to launch Anacor Pharmaceuticals in Palo Alto. source
• Married to Lucy Shapiro, with whom he collaborated for decades. source

Honours

2006

Fellow, American Academy of Microbiology source

2009

John Scott Legacy Medal and Premium, City of Philadelphia (shared with Lucy Shapiro; the first married couple to share it) source

Our research in previous years produced seminal papers that pointed out the stochastic nature of gene transcription and then showed through modeling and analysis the biological consequences of these phenomena. In collaboration with Lucy Shapiro's group we brought a multi-disciplinary approach to analysis of bacterial cell cycle regulation and control.

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In the bibliography

• Circuit simulation of genetic networks Science 1995
• Stochastic mechanisms in gene expression Proc Natl Acad Sci U S A 1997
• Simulation of prokaryotic genetic circuits Annu Rev Biophys Biomol Struct 1998
• Global analysis of the genetic network controlling a bacterial cell cycle Science 2000
• Genes directly controlled by CtrA, a master regulator of the Caulobacter cell cycle Proc Natl Acad Sci U S A 2002
• Generating and exploiting polarity in bacteria Science 2002
• A bacterial cell-cycle regulatory network operating in time and space Science 2003
• Oscillating global regulators control the genetic circuit driving a bacterial cell cycle Science 2004
• Rapid and sequential movement of individual chromosomal loci to specific subcellular locations during bacterial DNA replication Proc Natl Acad Sci U S A 2004
• DnaA coordinates replication initiation and cell cycle transcription in Caulobacter crescentus Mol Microbiol 2005
• Whole-genome transcriptional analysis of heavy metal stresses in Caulobacter crescentus J Bacteriol 2005
• A phospho-signaling pathway controls the localization and activity of a protease complex critical for bacterial cell cycle progression Proc Natl Acad Sci U S A 2006
• A dynamically localized protease complex and a polar specificity factor control a cell cycle master regulator Cell 2006
• A DNA methylation ratchet governs progression through a bacterial cell cycle Proc Natl Acad Sci U S A 2007
• High-throughput identification of transcription start sites, conserved promoter motifs and predicted regulons Nat Biotechnol 2007
• Systems biology of Caulobacter Annu Rev Genet 2007
• Caulobacter requires a dedicated mechanism to initiate chromosome segregation Proc Natl Acad Sci U S A 2008
• Architecture and inherent robustness of a bacterial cell-cycle control system Proc Natl Acad Sci U S A 2008
• Why and how bacteria localize proteins Science 2009
• An essential transcription factor, SciP, enhances robustness of Caulobacter cell cycle regulation Proc Natl Acad Sci U S A 2010
• High-throughput identification of protein localization dependency networks Proc Natl Acad Sci U S A 2010
• Assembly of the Caulobacter cell division machine Mol Microbiol 2011
• The essential genome of a bacterium Mol Syst Biol 2011
• The architecture and conservation pattern of whole-cell control circuitry J Mol Biol 2011
• Global methylation state at base-pair resolution of the Caulobacter genome throughout the cell cycle Proc Natl Acad Sci U S A 2013
• The coding and noncoding architecture of the Caulobacter crescentus genome PLoS Genet 2014
• The global regulatory architecture of transcription during the Caulobacter cell cycle PLoS Genet 2015
• CauloBrowser: A systems biology resource for Caulobacter crescentus Nucleic Acids Res 2016