About

Stephen C. Harrison, Professor of Biological Chemistry and Molecular Pharmacology, played a central role in guiding the Harvard Biochemical Sciences Tutorial program for decades, including serving as Head Tutor from 1972-1996. His contributions emphasize that students should learn how to think about scientific problems and how discoveries emerge from evidence, fostering an understanding of scientific thinking beyond mere fact absorption. Harrison's work has been integral to the development of the tutorial's focus on reading research papers, discussing experiments, and interpreting scientific evidence, thereby shaping undergraduate education in the life sciences at Harvard.

Research topics

• Biology
• Microbiology
• Genetics
• Cell biology
• Computational biology
• Biochemistry
• Ecology

Selected publications

• Revisiting a Breathtaking Publication in the History of Molecular Biology

  Journal of Molecular Biology · 2025-09-03

  article1st authorCorresponding
  PublisherDOI

• Biofilm formation by <i>Staphylococcus aureus</i> is triggered by a drop in the levels of a cyclic dinucleotide

  Proceedings of the National Academy of Sciences · 2024-12-16 · 5 citations

  articleOpen accessCorresponding

  The bacterial pathogen Staphylococcus aureus forms multicellular communities known as biofilms in which cells are held together by an extracellular matrix principally composed of repurposed cytoplasmic proteins and extracellular DNA. These biofilms assemble during infections or under laboratory conditions by growth on medium containing glucose, but the intracellular signal for biofilm formation and its downstream targets were unknown. Here, we present evidence that biofilm formation is triggered by a drop in the levels of the second messenger cyclic-di-AMP. Previous work identified genes needed for the release of extracellular DNA, including genes for the cyclic-di-AMP phosphodiesterase GdpP, the transcriptional regulator XdrA, and the purine salvage enzyme Apt. Using a cyclic-di-AMP riboswitch biosensor and mass spectrometry, we show that the second messenger drops in abundance during biofilm formation in a glucose-dependent manner. Mutation of these three genes elevates cyclic-di-AMP and prevents biofilm formation in a murine catheter model. Supporting the generality of this mechanism, we found that gdpP was required for biofilm formation by diverse strains of S. aureus . We additionally show that the downstream consequence of the drop in cyclic-di-AMP is inhibition of the “accessory gene regulator” operon agr , which is known to suppress biofilm formation through phosphorylation of the transcriptional regulator AgrA by the histidine kinase AgrC. Consistent with this, an agr mutation bypasses the block in biofilm formation and eDNA release caused by a gdpP mutation. Finally, we report the unexpected observation that GdpP inhibits phosphotransfer from AgrC to AgrA, revealing a direct connection between the phosphodiesterase and agr .

  PublisherOA PDFDOI

• Richard Losick

  Current Biology · 2022-04-01

  articleOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Delivering the message: How a novel technology enabled the rapid development of effective vaccines

  Cell · 2021-09-24 · 15 citations

  articleOpen accessSenior authorCorresponding
  PublisherOA PDFDOI

• Bacillus subtilis: a bacterium for all seasons

  Current Biology · 2020 · 35 citations

  1st authorCorresponding
  • Biology
  • Microbiology
  • Genetics
  PublisherOA PDFDOI

• Concerns about Continuing Claims that a Protein Complex Interacts with the Phosphorelay

  mBio · 2020-03-09 · 1 citations

  letterOpen access1st authorCorresponding

  The major endonuclease for mRNA decay in Bacillus subtilis is the integral membrane protein RNase Y. We have shown that RNase Y interacts directly with a widely conserved, three-protein complex, the Y-complex, that is required for the majority of RNase Y-mediated mRNA cleavage events in B. subtilis (1, 2). This letter raises concerns about a recent paper in mBio (3) and three preceding publications (4–6) that argue that the Y-complex has an additional, add-on function in which it directly interacts with two proteins (Spo0F and Spo0B) in a phosphorelay that is responsible for phosphorylating the master regulatory protein Spo0A. That the Y-complex interacts with RNase Y is based on robust two-hybrid data with multiple positive and negative controls (1), pulldown experiments done independently …

  PublisherDOI

• The Length of Lipoteichoic Acid Polymers Controls Staphylococcus aureus Cell Size and Envelope Integrity

  Journal of Bacteriology · 2020 · 64 citations

  • Biology
  • Microbiology
  • Biochemistry

  cell size and cell envelope integrity. We also show that genes involved in LTA length regulation are required for resistance to beta-lactam antibiotics in MRSA. The proteins encoded by these genes may be targets for combination therapy with an appropriate beta-lactam.

  PublisherOA PDFDOI

• A protein phosphorylation module patterns the <i>Bacillus subtilis</i> spore outer coat

  Molecular Microbiology · 2020 · 31 citations

  • Biology
  • Microbiology
  • Computational biology

  region, has no major impact on outer coat structure. Thus, phosphorylation of CotG by CotH is a key factor establishing the structure of the outer coat. The presence of the cotB/cotH/cotG cluster in several species closely related to B. subtilis hints at the importance of this protein phosphorylation module in the morphogenesis of the spore surface layers.

  PublisherOA PDFDOI

• The length of lipoteichoic acid polymers controls <i>Staphylococcus aureus</i> cell size and envelope integrity

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-03-25 · 3 citations

  preprintOpen access

  ABSTRACT The opportunistic pathogen Staphylococcus aureus is protected by a cell envelope that is crucial for viability. In addition to peptidoglycan, lipoteichoic acid (LTA) is an especially important component of the S. aureus cell envelope. LTA is an anionic polymer anchored to a glycolipid in the outer leaflet of the cell membrane. It was known that deleting the gene for UgtP, the enzyme that makes this glycolipid anchor, causes cell growth and division defects. In Bacillus subtilis , growth abnormalities from the loss of ugtP have been attributed to the absence of the encoded protein, not to loss of its enzymatic activity. Here, we show that growth defects in S. aureus ugtP deletion mutants are due to the long, abnormal LTA polymer that is produced when the glycolipid anchor is missing from the outer leaflet of the membrane. Dysregulated cell growth leads to defective cell division, and these phenotypes are corrected by mutations in the LTA polymerase, ltaS , that reduce polymer length. We also show that S. aureus mutants with long LTA are sensitized to cell wall hydrolases, beta-lactam antibiotics, and compounds that target other cell envelope pathways. We conclude that control of LTA polymer length is important for S. aureus physiology and promotes survival under stressful conditions, including antibiotic stress. IMPORTANCE Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of community- and hospital-acquired infections and is responsible for a large fraction of deaths caused by antibiotic-resistant bacteria. S. aureus is surrounded by a complex cell envelope that protects it from antimicrobial compounds and other stresses. Here we show that controlling the length of an essential cell envelope polymer, lipoteichoic acid, is critical for controlling S. aureus cell size and cell envelope integrity. We also show that genes involved in LTA length regulation are required for resistance to beta-lactam antibiotics in MRSA. The proteins encoded by these genes may be targets for combination therapy with an appropriate beta-lactam.

  PublisherOA PDFDOI

• Biofilm Formation by <i>Staphylococcus aureus</i> is Triggered by a Drop in the Levels of the Second Messenger cyclic-di-AMP

  bioRxiv (Cold Spring Harbor Laboratory) · 2020-02-02 · 4 citations

  preprintOpen accessSenior authorCorresponding

  Abstract The bacterial pathogen Staphylococcus aureus forms multicellular communities known as biofilms in which cells are held together by an extracellular matrix. The matrix consists of repurposed cytoplasmic proteins and extracellular DNA. These communities assemble during growth on medium containing glucose, but the intracellular signal for biofilm formation was unknown. Here we present evidence that biofilm formation is triggered by a drop in the levels of the second messenger cyclic-di-AMP. Previous work identified genes needed for the release of extracellular DNA, including genes for the cyclic-di-AMP phosphodiesterase GdpP, the transcriptional regulator XdrA, and the purine salvage enzyme Apt. Using a cyclic-di-AMP riboswitch biosensor and mass spectrometry, we show that the levels of the second messenger drop during biofilm formation in a glucose-dependent manner and that the drop is prevented in mutants of all three genes. Importantly, we also show that expression of the “accessory gene regulator” operon agr is under the positive control of cyclic-di-AMP and that an agr mutation, which is known to promote biofilm formation, bypasses the block in biofilm formation and eDNA release caused by a gdpP mutation. We conclude that the effect of the glucose-dependent drop in c-di-AMP levels is principally mediated by a reduction in agr expression, which in turn promotes biofilm formation.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01GM01856841

  NIH · $649k · 2016

• NIH Grant T32GM007598

  NIH · $25.9M · 2020

• NIH Grant R01GM018568

  NIH · $12.5M · 2020

• NIH Grant R37GM018568

  NIH · $4.4M · 2000

• Subproject 2: Identification of Pathways that Can be Targeted for the Development of Novel Therapies for MRSA

  NIH · $69.5M · 2009–2027

Frequent coauthors

• Roberto Kolter

  Harvard University

  46 shared

• Abraham L. Sonenshein

  Tufts University

  27 shared

• Charles P. Moran

  Emory University

  23 shared

• Philip Youngman

  University of Georgia

  22 shared

• Patrick Eichenberger

  New York University

  21 shared

• Janice Pero

  20 shared

• Patrick Stragier

  Université Paris Cité

  19 shared

• Yunrong Chai

  Northeastern University

  19 shared

Labs

• Harvard's Biochemical Sciences Tutorial ProgramPI

Education

• B.S., Biology

  University of California, Berkeley

  1965

• Ph.D., Microbiology

  California Institute of Technology

  1970

Awards & honors

• Junior Fellow of the Society of Fellows