About

Stephen C. Harrison is a Professor of Biological Chemistry and Molecular Pharmacology who has played a central role in guiding Harvard’s 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, rather than just absorbing facts about biology. Harrison has been involved in the program's development, which focuses on small-group discussions, close mentorship, and engagement with primary scientific literature, fostering an environment where students develop an intellectual relationship with practicing scientists. His work has helped shape the tutorial’s focus on scientific thinking, evidence interpretation, and mentorship, contributing to Harvard’s undergraduate training in the life sciences.

Research topics

• Biochemistry
• Computer Science
• Virology
• Medicine
• Cell biology
• Biology
• Chemistry
• Biophysics

Selected publications

• Mycobacteriophage-mediated gene transfer enables in vitro drug screening and in vivo tracking of <i>Mycobacterium leprae</i>

  Proceedings of the National Academy of Sciences · 2025-06-11 · 2 citations

  articleOpen access

  Mycobacterium leprae , the causative agent of leprosy, has never been cultured in vitro, posing significant challenges for genetic manipulation and drug discovery. Current antileprosy drug screening methods relying on microscopic count, radiorespirometry, and qPCR are time consuming and require the use of radioactive elements. We demonstrate mycobacteriophage-mediated introduction of foreign DNA using the broad-host range mycobacteriophage TM4 and the application of the luciferase reporter mycobacteriophage (LRM) for drug screening. Mycobacteriophage infection of M. leprae was shown using TM4 expressing the highly sensitive BRET-nanoluciferase-based reporter, GeNL (TM4 ::GeNL ), which enables luminescence measurement for over 72 h. When M. leprae was exposed to rifampicin, dapsone, and Q203 for 24 and 48 h, followed by TM4 ::GeNL infection, the luminescence output decreased in a dose-dependent manner, establishing an in vitro two-day screening assay for drugs. We have also electroporated M. leprae with a ColE1 -integration proficient plasmid expressing GeNL and shown that the transformed leprosy bacilli could be propagated in mice footpads and detected using an in vivo imaging system (IVIS). These findings introduce powerful genetic tools for M. leprae research enabling in vivo tracking and in vitro viability testing.

  PublisherDOI

• The structural diversity of xanthomonadin aryl polyenes and functional analysis of the genes required for their synthesis by Xanthomonas phytopathogens

  Phytopathology Research · 2025-04-28

  articleOpen access

  Abstract Xanthomonas is a genus of plant-associated Gram-negative bacteria which infect more than 400 plant species. A characteristic feature of Xanthomonas bacteria is the production of yellow membrane-bound pigments called xanthomonadins. Xanthomonadins are phospholipid-like bio-macromolecules located at the outer membrane. The chemical structure and biosynthetic mechanism of xanthomonadin production remain to be fully elucidated. In this study, a total of 24 Xanthomonas strains from five different species were collected for methylated ester of aryl polyene (MEAP) preparation. High-Performance Liquid Chromatography (HPLC) and Quadrupole Time-of-Flight Mass Spectrometry (Q-TOF–MS) analysis identified three dominant MEAPs, methylated di-brominated MEAP-1, di-brominated MEAP-2, and mono-brominated MEAP-3. MEAP-1 corresponded to the previously reported aryl polyene in Xanthomonas juglandis XJ103. The 24 Xanthomonas strains could be grouped into three categories based on their MEAP profiles. Further, bacterial ooze was collected from X . oryzae pv. oryzae ( Xoo )-infected rice leaves and MEAP was prepared. The dominant MEAP in the Xoo ooze was MEAP-2. This is the first demonstration of in-planta MEAP production during plant infection of any Xanthomonas pathogen. In addition, a xan biosynthetic cluster, which is responsible for xanthomonadin biosynthesis, and the roles of the individual xan genes in MEAP biosynthesis were studied via deletion and subsequent complementation analysis. HPLC and Q-TOF–MS analysis identified the essential genes for MEAP biosynthesis, as well as the genes associated with methylation and bromination. These results provide new insights into the structural diversity of Xanthomona s MEAPs and xanthomonadin biosynthetic mechanisms.

  PublisherOA PDFDOI

• Affinity Maturation and Light-Chain-Mediated Paratope Diversification Anticipate Viral Evolution

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-28

  preprintOpen access

  A key goal of vaccinology is to train the immune system to combat current pathogens while simultaneously preparing it for future evolved variants. Understanding factors contributing to anticipatory breadth, wherein affinity maturation against an ancestral strain yields neutralization capacity against evolved variants, is therefore of great importance. Here, we investigated the mechanism of anticipatory breadth development in a public antibody family targeting the functionally restricted ACE2 binding site on SARS-CoV-2. IGHV3-53/66 antibodies isolated from memory B cells of infection-naïve individuals vaccinated with the ancestral Wuhan-strain mRNA vaccine frequently neutralized evolved Omicron variants and contained several hallmark mutations previously shown to enhance neutralization breadth. Comparative analyses with antibodies from Omicron breakthrough infections revealed that breadth-associated patterns of somatic hypermutation emerged independently of variant exposure. However, Omicron infection had a marked impact on light chain pairing frequencies, suggestive of variant-imposed selection of favorable light chains. Analysis of available IGHV3-53/66 antibody structures complexed with SARS-CoV-2 receptor binding domain (RBD) clarified these findings; convergent somatic mutations on the heavy chain largely refined contacts with invariant RBD residues, while light chain pairings shifted epitopes to avoid steric challenges posed by Omicron mutations. These findings support a model of anticipatory breadth with three key elements: (1) targeting of a functionally restricted epitope, (2) affinity maturation to establish an affinity buffer, and (3) variable chain pairing to generate paratope diversity. These elements each serve to compensate for a distinct consequence of viral mutagenesis, offering a mechanistic framework for anticipating viral evolution.

  PublisherOA PDFDOI

• Specific Interactions between HIV-1 Env Cytoplasmic Tail and Gag Matrix Domain Probed by NMR

  Journal of the American Chemical Society · 2025-05-14

  articleCorresponding

  HIV-1 envelope glycoprotein (Env) is a transmembrane protein that mediates membrane fusion during viral entry. Incorporation of a sufficient number of Envs during viral assembly is critical for viral infectivity. It has long been suggested that the interaction between Env and the matrix domain (MA) of the Gag polyprotein plays an important role in recruiting Envs to the site of viral assembly on the plasma membrane, but direct biochemical and structural evidence is lacking for such an interaction in the context of a membrane-like environment. Here, we report specific structural contacts between the cytoplasmic tail (CT) of the trimeric HIV-1 Env in bicelles and the trimeric MA. Using a combination of measurements of NMR chemical shift perturbation, intermolecular paramagnetic relaxation enhancements, and microscale thermophoresis, we found that, in DMPC-DHPC bicelles that mimic a lipid bilayer, the trimeric baseplate formed by the CT specifically interacted with the trimeric MA via mostly electrostatic interactions involving acidic residues of the CT and positively charged patches of the MA. Nonconservative substitution of these previously unrecognized acidic residues in Env resulted in drastically reduced viral infectivity. Our findings, together with early genetic and biochemical studies, indicate that specific interactions between the CT of Env and MA play a structural role during HIV-1 assembly.

  PublisherDOI

• EefR mutations drive sanguinarine resistance by activating cryptic multidrug efflux pumps in AcrB-Null <i>Escherichia coli</i>

  Virulence · 2025-09-29 · 1 citations

  articleOpen access

  isolates, indicating a significant risk for the rapid spread of this multidrug resistance mechanism.

  PublisherDOI

• Estimation Model for Cotton Canopy Structure Parameters Based on Spectral Vegetation Index

  Life · 2025-01-07 · 5 citations

  articleOpen accessCorresponding

  The spectral vegetation indices derived from remote sensing data provide a detailed spectral analysis for assessing vegetation characteristics. This study investigated the relationship between cotton yield and canopy spectral indices to develop yield estimation models. Spectral reflectance data were collected at various growth stages using an ASD FieldSpec Pro VNIR 2500 spectrometer. Six prediction models were developed using spectral vegetation indices, including the Normalized Difference Vegetation Index (NDVI) and Ratio Vegetation Index (RVI), to estimate the Leaf Area Index (LAI) and above-ground biomass. For LAI estimation using the NDVI, the power function model (y = 10.083x11.298) demonstrated higher precision, with a multiple correlation coefficient of R2 = 0.8184 and the smallest root mean square error (RMSE = 0.3613). These results confirm the strong predictive capacity of NDVI for LAI, with the power function model offering the best estimation accuracy. In estimating above-ground biomass using RVI, the power function model of y = 6.5218x1.33917 achieved the higher correlation (R2 = 0.8851) for fresh biomass with an RMSE of 0.1033, making it the most accurate. For dry biomass, the exponential function model (y = 9.1565 × 10−5∙exp(1.1146x)) was the most precise, achieving an R2 value of 0.8456 and the lowest RMSE value of 0.0076. These findings highlight the potential of spectral remote sensing for accurately predicting cotton canopy structural parameters and biomass weights. By integrating spectral analysis techniques with remote sensing, this research offers valuable insights for precision cotton planting and field management, enabling optimized agricultural practices and enhanced vegetation health monitoring.

  PublisherOA PDFDOI

• Prediction of traumatic hemorrhagic shock using a Multi-scale exogenous variable model (MS-TimeXer-MoE)

  European Journal of Trauma and Emergency Surgery · 2025-06-05

  article
  PublisherDOI

• Effect of the S2’ site cleavage on SARS-CoV-2 spike

  Nature Communications · 2025-11-27 · 5 citations

  articleOpen accessSenior author

  SARS-CoV-2 initiates infection of host cells by fusing its envelope lipid bilayer with the cell membrane. To overcome kinetic barriers for membrane fusion, the virus-encoded spike (S) protein refolds from a metastable prefusion state to a lower energy, stable postfusion conformation. The protein is first split into S1 and S2 fragments at a proteolytic site after synthesis, and presumably further cleaved at a second site, known as the S2’ site, before membrane fusion can occur. Here, we report a cryo-EM structure of S2 fragment after the S2’ cleavage, possibly representing a late fusion intermediate conformation, in which the fusion peptide and transmembrane segment have yet to pack together, distinct from the final, postfusion state. Functional assays demonstrate that the S2’ cleavage accelerates membrane fusion, probably by stabilizing membrane fusion intermediates. These results advance our understanding of SARS-CoV-2 entry and may guide intervention strategies against pathogenetic coronaviruses. SARS-CoV-2 spike protein mediates viral entry into host cells. Shi et al. report a cryoEM structure of a proteolytically processed spike, possibly representing a functional intermediate state, with important implications for intervention strategies.

  PublisherOA PDFDOI

• Evaluation of Leaf Water Content in Watermelon Based on Hyperspectral Reflectance

  Water · 2025-04-10 · 2 citations

  articleOpen access

  Water is a crucial element for the growth of watermelon plants, making rapid and non-destructive monitoring of plant water content vital for precision irrigation in watermelon farming. While previous research has demonstrated the sensitivity of short-wave infrared (SWIR) bands to plant water content, their high costs limit widespread application. In contrast, visible and near-infrared (VNIR) spectral instruments offer significant advantages in terms of affordability, compactness, and spectral resolution. However, their potential for predicting the leaf water content (LWC) of watermelon plants has yet to be fully investigated. This study aims to assess the efficacy of hyperspectral reflectance measured with VNIR spectral instruments in estimating the LWC of watermelon plants at various leaf layers. Hyperspectral reflectance data (350−1100 nm) were collected from three leaf layers (upper, middle, and lower) under various drought treatments. Models for estimating LWC were developed using both spectral indices and full wavelength data. The results indicated that the middle leaf layer was the most effective for estimating LWC, and using full wavelength data achieved higher accuracy in LWC estimation. Furthermore, compared to the simple regression model, the AdaBoost-based machine learning model demonstrated superior performance, achieving an R2 of 0.9636 in estimating LWC through five-fold cross-validation, which indicates high predictive accuracy. Ensemble learning significantly outperforms traditional methods, providing a substantial improvement in model accuracy. The findings offer important technical assistance for the spectral monitoring of LWC and precision irrigation in watermelon cultivation.

  PublisherOA PDFDOI

• Effect of the S2’ site cleavage on SARS-CoV-2 spike

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-03

  preprintOpen accessSenior authorCorresponding

  Abstract SARS-CoV-2 initiates infection of host cells by fusing its envelope lipid bilayer with the cell membrane. To overcome kinetic barriers for membrane fusion, the virus-encoded spike (S) protein refolds from a metastable prefusion state to a lower energy, stable postfusion conformation. The protein is first split into S1 and S2 fragments at a proteolytic site after synthesis, and presumably further cleaved at a second site, known as the S2’ site, before membrane fusion can occur. We report here a cryo-EM structure of S2 fragment after the S2’ cleavage, possibly representing a late fusion intermediate conformation, in which the fusion peptide and transmembrane segment have yet to pack together, distinct from the final, postfusion state. Functional assays demonstrate that the S2’ cleavage accelerates membrane fusion, probably by stabilizing fusion intermediates. These results advance our understanding of SARS-CoV-2 entry and may guide intervention strategies against pathogenetic coronaviruses.

  PublisherOA PDFDOI

Recent grants

• Structure-function studies of the membrane-interacting domains of HIV-1 Env spike

  NIH · $8.4M · 2016–2026

• NIH Grant R01GM083680

  NIH · $1.8M · 2015

• NIH Grant R56AI129721

  NIH · $674k · 2019

• NIH Grant R21AI069972

  NIH · $500k · 2008

• Structure of HIV-1 envelope spike in the context of membrane

  NIH · $531k · 2020–2020

Frequent coauthors

• Yongfei Cai

  Boston Children's Hospital

  121 shared

• Hanqin Peng

  Boston Children's Hospital

  77 shared

• Tianshu Xiao

  Nanyang Technological University

  75 shared

• Sophia Rits‐Volloch

  Harvard University

  74 shared

• Duane R. Wesemann

  Harvard University

  68 shared

• Jun Zhang

  67 shared

• Stephen C. Harrison

  Queen's University

  66 shared

• William R. Jacobs

  Albert Einstein College of Medicine

  59 shared

Labs

• Harvard's Biochemical Sciences Tutorial ProgramPI