$25 million federal defense grant funds anesthesia innovation

A new $25 million grant from the research and development agency of the United States Department of Defense is bringing together researchers from the School of Pharmacy to develop safe, battlefield-ready anesthetics.

The cooperative agreement with the Anesthetics for Battlefield Care program of the Defense Advanced Research Projects Agency (DARPA) envisions an anesthetic that general forces could administer—without specialized training—to casualties on the battlefield with traumatic injuries.

Two fundamental discovery techniques are being applied in the drive to develop the new anesthetics. The first is phenotypic screening in fish. “We have large libraries of compounds whose biology is completely unknown, and now with DARPA, the objective is to test in excess of 100,000 unique chemicals,” said Jason Sello, PhD, co-principal investigator and Department of Pharmaceutical Chemistry faculty member. “We’ve had success with a 12,000-compound screening and we’ve already discovered a remarkable anesthetic. There’s a good chance we may discover 10 molecules, and to discover 10 new anesthetics in a five-year period is just an incredible possibility.”

The second type of discovery technique is computational docking, in which 6 billion molecules are computationally screened for those that fit into pockets in anesthetic receptors. Several hundred of the best-fitting molecules in the computational simulation are synthesized and tested in vitro against known anesthetic receptors in cells. Promising molecules are then re-optimized––using computer-guided design and synthesis—and promoted to testing.

In alignment with the cross-disciplinary collaboration outlined in the School’s strategic plan, the team working to form this pipeline includes Sello and:

• Department of Pharmaceutical Chemistry faculty members Brian Shoichet, PhD; Aashish Manglik, MD, PhD; and John Irwin, PhD; and research assistant Matt McCarroll, PhD;

• UCSF School of Medicine Anatomy Chair Allan Basbaum, PhD;

• UC San Diego Department of Neurobiology Vice Chair Ryan Hibbs, PhD.

Curiosity and serendipity in discovery

“Anesthetics are these really mysterious medicines,” said Sello. “When we started this project, I think it was more curiosity about how anesthetics work, and this radical idea of whether we could discover new ones. It’s hard to imagine who is going to fund that particular type of work.”

In general, anesthetics are highly understudied. “The current anesthetics have major liabilities. That’s why, when you go under anesthesia, there’s a team there—in case the anesthetics start to kill you,” said Shoichet, also a principal investigator. “The therapeutic index isn’t very good.”

Shoichet and Sello said what is most exciting about the grant is that the researchers are united on their desired outcome. “Historically, anesthetics have been discovered just by serendipity,” said Sello. “But historically, we haven’t had insights into the phenomenon of how anesthesia works to the extent we can rationally design drugs.”

Transformational change

Shoichet said the grant from DARPA, which oversees emerging technologies for use by the military, is different from an NIH grant, both in the application process and the level of engagement it requires from principal investigators.

“We had a previous DARPA grant on analgesia and new treatments for pain that is still ongoing, and it has worked really well. We got a lot done scientifically, and some great papers came out of it,” Shoichet said. “They are taskmasters, but they are very supportive of innovative ideas. They want to fund risky stuff.”

DARPA said the agency “explicitly reaches for transformational change instead of incremental advances,” and “does not perform its engineering alchemy in isolation.”

Science as a team sport

The DARPA grant is advancing a new strategy for discovering anesthetics computation while giving trainees the opportunity to see team science in action, Shoichet and Sello said. The relationships formed among the researchers, they added, allow science to meet opportunity and enable research to be conducted on a much larger scale.

“DARPA has been a phenomenal opportunity because I don’t think the pharmaceutical industry was clamoring for new anesthetics,” said Sello. “What makes DARPA unique is bridging the basic science to actual applications.”

Image credit: Shoichet: Elisabeth Fall.