Inventing New Drugs to Reverse Cognitive Decline

“We think that ISRIB may uncover an untapped reservoir in the brain that allows damaged memory circuits to be repaired,” Dr. Peter Walter says.

Ask Peter Walter, PhD, about his wonder molecule ISRIB, and he will place in your palm a wee plastic model. It will be long and knobby, like a grub, and spray-painted gold.

“Our gold mine,” he will say, beaming.

Indeed, ISRIB’s impact on human health could be huge: In experiments with mice, ISRIB – short for Integrated Stress Response Inhibitor – completely reversed severe cognitive impairments caused by traumatic brain injury. Even in healthy mice, the molecule significantly improved learning and memory.

“It’s just amazing,” says Walter, professor in the UCSF Department of Biochemistry and Biophysics. “We think that ISRIB may uncover an untapped reservoir in the brain that allows damaged memory circuits to be repaired.” Beyond healing injured brains, he hopes that ISRIB – or molecules like it – will one day treat neurodegenerative disorders like Alzheimer’s and Parkinson’s.

As a young scientist, Walter didn’t set out to cure disease. He immigrated to the US from West Berlin during the Cold War to pursue a career in basic science, and in 1983, set up a lab at UCSF. Here, he devoted decades to uncovering the workings of the “unfolded protein response,” a vital cellular mechanism, for which he won some of biomedicine’s most prestigious awards, including the Lasker Award, the Shaw Prize, and, in 2018, the Breakthrough Prize – the so-called “Oscars of Science.”

The unfolded protein response helps keep cells healthy. Essentially, its job is quality control for the manufacture of proteins, which carry out the business of life, from digesting food to making new memories. If the unfolded protein response goes awry, it can contribute to an array of diseases, including cancer, diabetes, viral infections, and brain disorders.

Biologically, the unfolded protein response is as complex as it sounds, involving numerous cellular pathways. The more Walter learned about these pathways, the more he wondered how he might control them – because if he could control them, then perhaps he could fix the troublesome machinery in diseased cells.  And if he could fix diseased cells, he could cure patients.

The challenge was to find the right tool for the job. But where?

Walter’s team turned to the vast library of molecules in the UCSF School of Pharmacy’s Small Molecule Discovery Center. One by one, the researchers added each molecule to cells in a dish, testing whether it tweaked the unfolded protein response in the way they wanted. “We looked through hundred thousands of molecules, and we found one,” Walter says.

That “one” was ISRIB. In 2015, UCSF licensed the molecule for drug development to the Google-backed biotech company Calico. Carmela Sidrauski, PhD, a former postdoc from Walter’s lab, now leads the Calico team.

It will likely be another year or so before an ISRIB drug is ready to be tested on humans, but Walter is enthusiastic about its clinical potential. “There are so many people suffering,” he says. “If ISRIB works as well in people as it works in animals, that would be revolutionary!”

Your giving inspires a world of good health.

Give to UCSF