About

Stephen C. Harrison is a Professor of Biological Chemistry and Molecular Pharmacology who 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 the importance of teaching students how to think about scientific problems and how discoveries emerge from evidence. Harrison's work and philosophy have been integral to the program's focus on developing scientific thinking through discussion, mentorship, and engagement with primary scientific literature, fostering an environment where students learn to interpret experiments and understand scientific evidence.

Research topics

• Biology
• Cell biology
• Computer Science
• Computational biology
• Biochemistry
• Chemistry
• Genetics
• Cancer research
• Medicine
• Bioinformatics
• Biotechnology
• Neuroscience
• Business
• Data science
• Pharmacology
• Risk analysis (engineering)
• Botany
• Internal medicine

Selected publications

• A druggable redox switch on SHP1 controls macrophage inflammation

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-20

  articleOpen access

  Immunological proteins are major disease targets, yet most remain undrugged. Post-translational redox modification of cysteine residues has emerged as an important mode of immune cell regulation, particularly in macrophage cytokine responses. Here, we develop a strategy for systematic discovery and small-molecule functionalization of redox-regulated cysteines on immunological proteins. Using deep redox proteomics, we annotate 788 in vivo redox-regulated cysteines across diverse immune-relevant protein domains. We demonstrate how these sites enable cysteine-directed pharmacology through discovery of a novel cysteine activation site on the immune regulator SHP1. Targeting Cys102, we develop a highly selective covalent agonist, SCA, which binds the N-SH2 domain to relieve autoinhibition and activate SHP1. In mouse and human macrophages, SCA selectively engages SHP1 Cys102, antagonizing IRAK signaling and LPS-induced pro-inflammatory cytokine production. Together, this work identifies a druggable cysteine redox switch controlling macrophage cytokine responses and provides a compendium of redox-regulated sites for therapeutic development.

  PublisherDOI

• Degraders of the dengue virus capsid protein exhibit differentiated pharmacology relative to capsid inhibitors

  Nature Communications · 2026-02-10

  articleOpen access

  Abstract Due to the limited size of viral genomes, most viral proteins are multifunctional; yet most direct-acting antivirals are designed as single-function inhibitors. The dengue virus (DENV) capsid protein serves as a building block for new virions while also interacting with multiple host factors to remodel the cellular environment. Using established capsid inhibitor ST148 as a targeting ligand, we develop a DENV capsid degrader, RPG-01-132, that exhibits a broadened spectrum of activity against the four DENV serotypes and an ST148-resistant mutant virus. Using multiple approaches, we show that RPG-01-132’s sub-micromolar antiviral activity is due to CRL4 CRBN -dependent degradation of capsid and that this mechanism disrupts capsid-related pathways required for productive infection, including infectious virus output and capsid-mediated antagonism of the interferon response. This pharmacology is well-differentiated from ST148, which interferes with assembly of new virions, but has no demonstrated effect on the capsid’s nonstructural functions. These findings demonstrate that targeted protein degradation can thus enable antiviral pharmacology not observed with conventional antiviral inhibitors and that is resilient to point mutations that reduce inhibitor potency.

  PublisherOA PDFDOI

• The protocol for a patient-driven online prospective European observational cohort aiming to determine risk factors for the development of psoriatic arthritis among people living with psoriasis: the HIPPOCRATES Prospective Observational Study

  Therapeutic Advances in Musculoskeletal Disease · 2026-03-01

  articleOpen access

  Background: Up to one-third of people living with psoriasis develop psoriatic arthritis (PsA), and the majority have active psoriasis prior to the development of arthritis. Clinical risk factors, such as nail involvement, in conjunction with novel blood biomarkers, could improve PsA risk monitoring and early diagnosis. Objectives: The aim of the HIPPOCRATES Prospective Observational Study (HPOS-www.hpos.study) is to follow a cohort living with psoriasis and identify risk factors for the development of PsA. Design: HPOS is a patient-driven online prospective European observational cohort. Methods: Adult participants with psoriasis but with no prior diagnosis of PsA are eligible. Participants are invited to provide consent and join the study online. They complete a semi-structured questionnaire to collect data on demographics, psoriasis, comorbidities, risk factors for PsA, and the Psoriasis Epidemiology Screening Tool screening questionnaire. Follow-up is conducted through a questionnaire every 6 months. The primary outcome is the new onset of PsA confirmed by a diagnosis from their doctor. The study will also collect peripheral blood samples from a subset of participants for biomarker identification. Ethics: This study follows the principles of the Declaration of Helsinki. To date, ethical approval has been granted by independent ethical committees in 10 countries. Discussion: Studying a cohort of individuals with psoriasis will allow us to identify risk factors for arthritis development and to develop a risk calculator. This can support focused efforts on screening, patient education, and even studies looking to delay or prevent the onset of arthritis. This study, run via remote online data collection, provides an efficient way to recruit a large cohort (25,000) across multiple countries. However, challenges have had to be addressed with some key changes in study design, ethical review, and recruitment strategies required for each individual country. Trial registration: HPOS, Clinicaltrials.gov ID: NCT05858528, IRAS number 325080; https://clinicaltrials.gov/study/NCT05858528?locStr=United%20Kingdom&country=United%20Kingdom&cond=Psoriasis&term=HPOS&aggFilters=status%3Anot%20rec&rank=1.

  PublisherDOI

• A small molecule PTER-selective inhibitor reduces food intake and body weight

  Cell chemical biology · 2026-03-01 · 2 citations

  articleOpen access
  PublisherOA PDFDOI

• A druggable redox switch on SHP1 controls macrophage inflammation

  Nature Chemical Biology · 2026-03-12

  articleOpen access
  PublisherOA PDFDOI

• Design and Development of DNA Damage Chemical Inducers of Proximity for Targeted Cancer Therapy

  Journal of the American Chemical Society · 2026-01-02

  articleSenior authorCorresponding

  Many chemotherapies are effective against cancers that display high levels of genome instability by disrupting or overwhelming the DNA damage response (DDR) to induce cell death. PARP inhibitors (PARPi) exploit this vulnerability by stalling DNA repair, particularly in homologous recombination-deficient cancer cells. Although PARPi are now used to treat BRCA1/2-mutated cancers such as ovarian and breast cancers, they are still limited to a narrow range of clinical indications and are susceptible to acquired resistance. Here, we introduce “DNA damage chemical inducers of proximity” (DD-CIPs), bivalent molecules that rewire the mechanism of action of conventional PARPi. The DD-CIPs function through chemically induced proximity between PARP1/2 and the chromatin remodeling protein, BRD4. From a candidate library of DD-CIPs, we identified DD-CIP1, which induces the DDR and apoptosis in cancer cells at two-digit nanomolar concentrations. Further optimization yielded DD-CIP2, which induces tumor cell death at nanomolar concentrations across diverse blood and solid cancer cells, including cancer types that are insensitive to PARPi. Using small-cell lung cancer (SCLC) as a model, we found that DD-CIP2 triggers DDR, cell cycle arrest, and apoptosis in vitro, leading to antitumor efficacy without substantial toxicity in preclinical SCLC xenograft models at well-tolerated doses. Our findings demonstrate that DD-CIPs may provide an opportunity to address the limitations of traditional PARPi and establish chemical-induced proximity as a strategy for modulating the DDR in cancer.

  PublisherDOI

• Correction: Discovery and optimization of tau targeted protein degraders enabled by patient induced pluripotent stem cells-derived neuronal models of tauopathy

  Frontiers in Cellular Neuroscience · 2026-04-07

  articleOpen access

  There was a mistake in Figure 1G as published. In the originally published figure, the actin loading-control lanes corresponding to QC-01-179 and QC-01-178 were displayed at reduced height and resolution, which compressed the bands and made adjacent lanes appear unusually similar. This presentation artifact created the appearance of potential lane duplication. The figure has now been regenerated from the original high-resolution TIFF files with confirmed correct lane selection and increased display height to improve visibility and distinguishability of the actin bands. This issue did not affect the data quantification or the resulting dose-response curves or text, as all analyses were performed using the original, unedited image files. The corrected Figure 1G (within corrected Figure 1) appears below. The original version of this article has been updated.There was a mistake in Figure 2E as published. In the originally published Figure 2E, the actin loading-control lane corresponding to FMF-06-038 was accidentally duplicated from the sample FMF-06-052 during figure assembly. This error originated from an intermediate file in which the samples were arranged in a different order, leading to an inadvertent copy-paste duplication of the actin lane. The panel has now been reassembled using the original scanned blot images to ensure correct lane assignment. Importantly, all quantifications were performed using the original, unedited image files; therefore, the densitometry analyses, resulting dose-response curves and text were not affected by this mistake. The corrected Figure 2E (within corrected Figure 2) appears below. The original version of this article has been updated.Reminder: Figures, tables, and images will be published under a Creative Commons CC-BY license and permission must be obtained for use of copyrighted material from other sources (including re-published/adapted/modified/partial figures and images from the internet). It is the responsibility of the authors to acquire the licenses, to follow any citation instructions requested by third-party rights holders, and cover any supplementary charges.

  PublisherOA PDFDOI

• Figure S6 from Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex

  2025-12-02

  articleOpen access

  <p>Shows SPR binding analyses of PRLX and analogues to TRIM21 PRYSPRY, and immunoblot verification of TRIM21 expression in knockout cells reconstituted with TRIM21 cDNAs.</p>

  PublisherOA PDFDOI

• Overcoming EGFR resistance by monovalent and bident inhibitors targeting Cys775

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-02

  articleOpen accessCorresponding

  Covalent targeting of EGFR cysteine 797 by osimertinib is one of the most successful breakthroughs in targeted therapy, fundamentally transforming the treatment landscape for non-small cell lung cancer (NSCLC) patients. However, resistance driven by mutation of C797 remains a major clinical challenge. Developing novel covalent strategies beyond C797 targeting presents a compelling opportunity for next-generation EGFR inhibitors. We first demonstrated that cysteine 775, located deep within the ATP-binding pocket, is accessible by a rationally designed covalent molecule ZNL-3, which as the first-in-class covalent cysteine 775 inhibitor exhibited strong efficacy in osimertinib-resistant mouse models. To further enhance resilience to resistance-causing mutations, we developed a dual-warhead, bident compound-YNW-1-which covalently targets both cysteine 775 and 797 simultaneously. YNW-1 is the first intramolecular lock to exhibit balanced reactive efficiency on both cysteines, rendering single-site mutations ineffective to confer resistance. The discovery of ZNL-3 and YNW-1 represents significant advancements in EGFR-targeted drug development, and further optimization toward clinical translation is a worthwhile strategy. SIGNIFICANCE: This study establishes the therapeutic potential of an EGFR covalent inhibitor through unprecedented targeting of cysteine 775 and provides the first demonstration that dual cysteine engagement offers superior efficacy over conventional covalent inhibitors by delaying resistance.

  PublisherDOI

• Figure S5 from Defining the Antitumor Mechanism of Action of a Clinical-stage Compound as a Selective Degrader of the Nuclear Pore Complex

  2025-12-02

  articleOpen access

  <p>Presents a CRISPR/Cas9 base editor mutagenesis screen of TRIM21 using ABE and CBE and shows population doublings, guide z-scores, and comparative analyses for PRLX and JWZ-8-103.</p>

  PublisherOA PDFDOI

Recent grants

• NIH Grant T32CA009361

  NIH · $13.0M · 2017

• Degrading therapeutically important kinases using small molecules

  NIH · $3.9M · 2018–2029

• Development of covalent PIP4K2 inhibitors for the treatment of p53 deficient lung tumors

  NIH · $541k · 2015–2020

• NIH Grant R01CA173469

  NIH · $1.6M · 2016

• The Center for Therapeutic Targeting of EWS-oncoproteins

  NIH · $26.2M · 2022–2024

Frequent coauthors

• Pasi A. Jänne

  469 shared

• Kwok‐Kin Wong

  459 shared

• Tinghu Zhang

  Stanford University

  377 shared

• Nicholas Kwiatkowski

  334 shared

• Jinhua Wang

  307 shared

• Jianming Zhang

  Shanghai Jiao Tong University

  299 shared

• Qingsong Liu

  Chinese Academy of Sciences

  276 shared

• Jarrod A. Marto

  Dana-Farber Cancer Institute

  256 shared

Labs

• Harvard’s Biochemical Sciences Tutorial ProgramPI