Williams Lab

Williams Lab · Michigan State University · College of Human Medicine

What is a cell saying when a tissue turns acidic?

We read extracellular pH as a signal the body writes on purpose, and build the biosensors, chemistry, and zebrafish models to answer it across cancer, pulmonary, and neurological disease.

Explore the research ↓ Selected discoveries
acidicneutral · extracellular pH
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The premise

Acidity is not exhaust. It is information.

For a century, tissue acidity has been read as a byproduct. Tumors drop to pH 6.0–6.5, wounds to 6.5–6.8, the injured brain below 7.0, and the standard account treats protons as waste.

That is hard to reconcile with what cells do. They deploy proton machinery in organized patterns, hold gradients steep enough to precede cell-fate decisions by minutes, and have conserved proton-sensing receptors tuned to switch on in exactly this range across 500 million years of vertebrate evolution. Why spend energy building something you were trying to throw away? Answering that question is the whole program.

Ratiometric pHluorin2 map of a regenerating amputated zebrafish tail in FIRE LUT: the tissue glows orange and yellow where extracellular pH is most acidic, brightest at the amputation plane, fading to black. A 200 micrometre scale bar is at lower right.
Live extracellular-pH map of a regenerating amputated fin · pHluorin2, FIRE LUT · brighter is more acidic
01

Three ways into one question

The lab runs on one idea read three ways: make acidification visible, find the machinery that writes it, and use chemistry to read and rewrite the signal. Every disease project lives inside one of these.

pHluorin2-GPI reporter The pHluorin2-GPI reporter: a Tol2 construct expressing a ubiquitous pHluorin2 tethered to the outer membrane by a GPI anchor, and a whole zebrafish larva shown in brightfield above its bright green fluorescence.
Pillar i

Make acidification visible

Where, exactly, does a tissue become acidic — and when?

The lab built Tg(ubi:pHluorin2-GPI), a ratiometric biosensor tethered to the outer face of the membrane, and reads extracellular pH at subcellular resolution in a living, transparent vertebrate. Discrete acidic microdomains appear inside the first 72 hours of development, at the notochord, the otic placode, and the myotome.

Developmental pH mapping Wound-margin imaging Brain-injury acidification
See the reporter line →
Proton machinery
Pillar ii

Find the machinery that writes it

Why would a cell spend energy to build an acid gradient?

Wound acidification needs active proton pumping and vesicle release, not metabolic drift. In muscle, disrupting the T-tubule genes bin1b and mtm1 disrupts myotome pH.

Fin regeneration Centronuclear myopathy Evolution of proton sensing
How mechanism is tested →
Ogremorphin · dose response Dose-response curves for ogremorphin: U87 glioblastoma cells lose survival at lower concentrations than HT29 colon cancer cells.
Pillar iii

Read and rewrite the signal

If cells read pH through receptors, can we intervene on that reading?

In an in vivo screen the lab found ogremorphin, the first selective antagonist of the proton sensor GPR68, profiled clean against 158 GPCRs and 442 kinases. Blocking GPR68 pushes glioblastoma into ATF4-dependent ferroptosis; the follow-on series runs past 100 analogs toward two divergent therapeutic profiles.

Glioblastoma Pulmonary fibrosis Lobular breast cancer Acute lung injury
See the chemistry →
02

From observation to therapy

The lab does not only study biology, and does not only screen compounds. It finds a mechanism and uses pharmacology to interrogate it. The same five moves recur across every disease program.

01

Observe

Watch extracellular pH resolve in a living animal, in development and after injury.

02

Discover

Find where acidification is organized, reproducible, and tied to cell fate.

03

Define mechanism

Establish what pumps the protons and which receptor reads them, with genetic and pharmacological tests.

04

Perturb

Build selective small molecules against the sensor and ask what the signal was doing.

05

Translate

Carry the mechanism into disease models, from glioblastoma to fibrosis to breast cancer.

03

Selected discoveries

Ratiometric extracellular-pH maps of zebrafish muscle in control, bin1b morphant, and mtm1 morphant larvae: muscle stays acidic (red) in controls and shifts toward neutral (blue) when the T-tubule genes are knocked down.

Developmental Dynamics · 2025

A zebrafish that lights up exactly where a tissue turns acidic.

A ratiometric reporter tethered to the outside of the cell membrane turns extracellular pH into a live, quantitative readout, and reveals that muscle holds its T-tubule lumen at a pH distinct from the space around it. The line is deposited with ZFIN for any lab to use.

Read the paper →
Panel C: A549 and Panc02 tumor spheroids treated with DMSO, 4 Gy radiation, ogremorphin, or ogremorphin plus 4 Gy; the combination produces the smallest, most disrupted spheroids.

Scientific Reports · 2025

Blocking one proton sensor pushes cancer cells into ferroptosis — and makes radiation hit harder.

Antagonizing GPR68 drives diverse cancer cell types into iron-dependent death and raises their radiosensitivity, pointing to the acidic tumor microenvironment as a liability rather than a shield.

Read the paper →
AlphaFold model of the GPR68 receptor shown as a green surface and ribbon, with ogremorphin docked in the pocket rendered in red.

Experimental Hematology & Oncology · 2024

Glioblastoma survives its own acidity through a GPR68–ATF4 program.

The acidic microenvironment activates a GPR68–ATF4 pro-survival axis that the tumor leans on. Cutting it is the opening for the ferroptosis work, and for combinations with temozolomide and radiation.

Read the paper →
Zebrafish glioblastoma xenograft: engrafted human GBM cells (green) disperse through the larval head in controls but are sharply reduced by ogremorphin treatment and by GPR68 shRNA knockdown, quantified in scatter plots (DMSO vs OGM p = 2.1e-5; control vs GPR68 shRNA p = 1.4e-4 and 1.1e-3).

BMC Research Notes · 2024

Ogremorphin shrinks glioblastoma grafted into a living zebrafish.

Human glioblastoma cells engrafted into zebrafish larvae disseminate through the head. Treating the animals with the GPR68 antagonist ogremorphin cuts that burden sharply (p = 2.1 × 10−5), and silencing GPR68 with shRNA does the same — a fast, imageable test of the target in a whole animal.

Read the paper →
04

How we work

Reading pH the way this question needs took instruments that did not exist. These are the ones the lab built or runs.

Chuck Williams and Kari Sant standing back-to-back in the zebrafish facility, racks of housing tanks behind them.
The zebrafish facility

Co-directed by Chuck Williams and Kari Sant

A renovated, AAALAC-accredited space with capacity near 9,000 adult fish. It runs the in vivo screens, microinjection, and imaging the lab's questions depend on.

In vivo phenotypic screening

Small-molecule screens in living zebrafish. A renovated facility with capacity near 9,000 adult fish.

Ratiometric live pH imaging

Cytation C10 confocal, 405/488 nm for pHluorin2, environmental control for time-lapse.

Co-registered laser injury

The 405 nm line doubles as a calibrated ablation source, so injury and pH land in the same field.

CRISPR knockouts

Targeted knockout generation and microinjection for genetic dissection of the machinery.

Orthotopic larval xenografts

Human tumor cells engrafted in larvae for fast, imageable models of glioblastoma and more.

Virtual screening pipeline

A GPU pre-filter into CNN rescoring on MSU's HPCC, feeding medicinal-chemistry collaborations.

05

Current People

Charles H. Williams III, PhD

Charles H. Williams III, PhD

Principal investigator

Assistant Professor in the Department of Medicine, College of Human Medicine, with a secondary appointment in Pharmacology & Toxicology. Chuck studies extracellular acidification as a druggable signal in development and disease, and builds the tools that premise requires: a zebrafish line that makes extracellular pH visible in a living animal, and ogremorphin, the first selective antagonist of the proton sensor GPR68. His path ran through five years as a research technician and seven as non-tenure-track faculty, thirteen in all before the tenure track, most of it at the bench. The question under it: why an organism would spend energy building a signal it seems to be trying to discard.

Evan Pizzimenti, MS

Evan Pizzimenti, MS

First-year student · Pharmacology & Toxicology

Getting started in the lab, learning the screening and imaging workflows behind the proton-signaling projects.

Alex Pasculle, DO

Alex Pasculle, DO

Clinical collaborator & alumnus · Emergency Medicine

A lab alumnus who still collaborates with us on the clinical side, now an emergency-medicine resident at University of Michigan Health-West. A firefighter and EMT before medical school.

Research staff & undergraduates

Team

Screening, microinjection, imaging, and the day-to-day of the fish facility.

06

Latest from the lab

2026Award Awarded a Falk Medical Research Trust Catalyst Award to optimize GPR68 antagonists for glioblastoma.
2026Paper Novel Wnt potentiators induce iPSC-derived cardiomyocyte proliferation and increase embryonic zebrafish heart size. Journal of Molecular and Cellular Cardiology · DOI ↗
2026Paper A scalable zebrafish platform for new-approach drug discovery. Drug Discovery Today
2026Paper The GPR68 ferroptosis vulnerability extends to DIPG, a childhood brainstem tumor. Frontiers in Oncology
2026People Congratulations to Evan Pizzimenti on completing his master's and matriculating into the PhD program, to Alex Pasculle on earning his DO, and to Veona Cutinho, who begins her PhD at the University of Sydney this fall.
2025Milestone The Williams Lab opens at Michigan State University.
2025People Welcome to Veona Cutinho (technician), Evan Pizzimenti (master's student), Joey Norton (undergraduate), and Alex Pasculle (COM student).
2025Resource The pHluorin2 extracellular-pH reporter line is published and deposited with ZFIN for the community.
2025Patent US 12,194,027 B2 issued: therapeutic targeting of GPR68 to induce ferroptosis.
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Publications

The full record, verified against PubMed. Filter by research pillar.

2026 Novel Wnt potentiators induce iPSC-derived cardiomyocyte proliferation and increase embryonic zebrafish heart size. Journal of Molecular and Cellular Cardiology DOI ↗
2025 A novel transgenic reporter of extracellular acidification in zebrafish elucidates skeletal muscle T-tubule pH regulation. Developmental Dynamicssenior DOI ↗
2026 Zebrafish swimming towards cures: a scalable NAM platform for drug discovery. Drug Discovery Todaysenior DOI ↗
2026 Inhibition of GPR68 induces ferroptosis in diffuse intrinsic pontine gliomas. Frontiers in Oncology DOI ↗
2026 Beyond membrane remodeling: organelle crosstalk and convergent pathology in centronuclear myopathy. Musclessenior DOI ↗
2025 Inhibition of GPR68 induces ferroptosis and radiosensitivity in diverse cancer cell types. Scientific Reports DOI ↗
2025 Ogremorphin inhibits GPR68-mediated MUC5AC expression. microPublication Biologysenior DOI ↗
2025 A novel small-molecule inhibitor of GPR68 attenuates endothelial dysfunction and lung injury from bacterial LPS. Scientific Reports DOI ↗
2024 GPR68-ATF4 signaling is a novel prosurvival pathway in glioblastoma activated by acidic extracellular microenvironment. Experimental Hematology & Oncologyfirst DOI ↗
2024 Inhibition of GPR68 kills glioblastoma in zebrafish xenograft models. BMC Research Notes DOI ↗
2024 GPR68 mediates lung endothelial dysfunction caused by bacterial inflammation and tissue acidification. Cells DOI ↗
2024 Proton-sensing GPCRs: the missing link to Warburg's oncogenic legacy? Journal of Cancer Biology DOI ↗
2019 BMPing up healing capacity with an FKBP12 ligand. Cell Chemical Biologyfirst DOI ↗
2016 Zebrafish small-molecule screens: taking the phenotypic plunge. Computational and Structural Biotechnology Journalfirst DOI ↗
2015 An in vivo chemical genetic screen identifies phosphodiesterase 4 as a pharmacological target for hedgehog signaling inhibition. Cell Reportsfirst DOI ↗

Showing selected records. Full profile on Google Scholar and ORCID.

Recruitment

Come find things with us.

The lab wants people who like building the measurement as much as making it. There are open questions here that reach from a wound margin to a glioblastoma, and reagent requests are always welcome.

Postdocs

Imaging, chemical biology, or in vivo pharmacology.

Currently not looking

Graduate students

Rotations across all three research pillars.

Currently not looking

Undergraduates

Hands-on projects in the fish facility and at the scope.

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Collaborators

Request the reporter line or ogremorphin, or bring a disease model.

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Contact

Email
will4277@msu.edu
Faculty
MSU faculty page
Profiles
Google Scholar · ORCID
Dept
Department of Medicine, College of Human Medicine, MSU · secondary appointment in Pharmacology & Toxicology
Where
East Lansing, Michigan