In the “Research Matters” series, we visit labs across campus to hear directly from Stanford scientists about what they’re working on, how it could advance human health and well-being, and why universities are critical players in the nation’s innovation ecosystem. The following are the researchers’ own words, edited and condensed for clarity.
When I was 30, I began forgetting my friends’ names, calling them the wrong ones. Soon after, I was diagnosed with breast cancer. Brain fog is a very common first sign of cancer.
That diagnosis changed everything. That’s when I started sharply focusing on cancer research. Immunotherapy – which supercharges T cells, the immune system’s main cancer-killing force – had just come online at Dana-Farber, where I was being treated. I was excited about its potential, but my oncologist told me it didn’t work for breast cancer.
I thought, “Okay. I have 10 years to figure out something that might help – if not for me, then for others.” Most cancer therapies buy time in stages: first remission, then recurrence, then a second-line treatment. I saw those years as my first runway.
At the time, I was a postdoctoral fellow at Harvard. I had joined Tim Mitchison’s lab, and he suggested I study DMXAA, a molecule that triggered a strong anti-tumor response in mice but had failed in humans. I pushed back at first – I wanted to study something successful. But Tim believed we should investigate failure, do a “plane crash” analysis. That philosophy stayed with me. Every failure teaches us something.
He was right. We found that DMXAA activated what’s known as the STING pathway in mice, but not in humans. STING is part of the innate immune system, our body’s early warning system. When activated, it helps mobilize immune cells to train T cells to recognize and destroy cancer cells, wherever they’ve spread. Combining STING activation with immunotherapy offers the possibility of cures – not just remission or a prolonged waiting game.
That discovery triggered a race to identify a molecule that could activate human STING. That molecule turned out to be cGAMP. My lab has been studying this miracle molecule for the past 10 years.
cGAMP is produced when a cell detects damaged DNA. It acts like a signal flare, alerting the immune system that something is wrong. What fascinated me as a chemist was its instability, caused by a very rare chemical bond. I developed the first stable version by replacing two oxygen atoms with sulfur atoms. That subtle tweak made cGAMP more stable and became the precursor to compounds that are now in clinical trials at Merck and Novartis.
Based on insights from these trials, Merck developed a new STING activator to combine with immunotherapy. In a recent trial, it cured four out of 140 patients – one of whom had failed eight previous therapies. These rare success stories are what keep me going. Still, most patients don’t respond. We now think certain chemical tweaks of cGAMP unintentionally kill T cells even as they try to activate the immune response.
That’s why we started studying how natural cGAMP is regulated. We found cancer cells produce enzymes that chew up cGAMP to avoid detection. We also identified transporters – gates that let cGAMP into cells – and discovered that different cell types have different gates.
If this research had been done in industry, we wouldn’t have been able to share our results so freely. We want people to take these findings and run with them – even fail with them – because that accelerates progress.”
My lab now focuses on understanding how cGAMP is regulated in the body. We identified two enzymes, called hydrolases, that cancer cells use to destroy cGAMP and hide from the immune system. We also mapped the transporters that shuttle cGAMP between cells. These findings are helping researchers design more precise therapies that prime immunity without killing off the T cells.
Understanding the STING pathway might one day help with more than cancer. There’s growing evidence it plays a role in autoimmunity, aging, and neurodegenerative diseases like Alzheimer’s and ALS.
Much of this work was supported by NIH grants, especially a High-Risk, High-Reward award. If this research had been done in industry, we wouldn’t have been able to share our results so freely. We want people to take these findings and run with them – even fail with them – because that accelerates progress. Every failed experiment is a chance to learn faster.
I am extremely fortunate to be part of the Arc Institute, a non-profit that gives its Core Investigators guaranteed funding to pursue high-risk research, but I still rely on Stanford’s ecosystem for recruiting students and collaborations with chemists, structural biologists, and others.
Philanthropy like Arc’s expedites specific areas of research, but it doesn’t operate at the same scale – and can’t replace – federal funding. Science isn’t a straight path; it’s full of switchbacks. You have to fund broad areas of inquiry, even when the connection to human health isn’t obvious – because one day, they might just come together.
Photographer
Andrew Brodhead
