The Thrill of Defeat

The photograph also offers a glimpse of what motivates Oates and his colleagues: the sheer intellectual challenge of this pursuit. With his wire-rimmed glasses and starched white lab coat, and his talk of finding his life's calling in the cytoplasm of a cell, Oates is every inch the pure scientist. His world revolves around the lab and the lab bench--"holy spaces," he calls them, "and I have to breathe that holy air to fully stay alive." He has come to accept that his work may never produce a marketable product, but the scientific insights gained in the holy spaces are enough. "When you look at a glowing cell under a microscope, you're looking at life itself," he says. "It's a mystical experience. That stuff transports me."

For nearly 10 years, Oates and a colleague kept the aldose-reductase program barely alive. It was a classic skunk-works project--offline and largely unfunded. "Their work was an open secret, but we didn't flaunt it," recalls John LaMattina, chief of Pfizer's worldwide R&D operations (and Hutson's boss). "Some people would have been less than thrilled to learn that we were still going forward with this effort."

As he worked through the data, Oates began to build the case that high sugar levels inside the cells of diabetics cause damage primarily because of increased oxidant stress. What's really needed, he concluded, is a new generation of superpotent inhibitors that can block the sugar-linked production of oxidants and so slow the ravages of diabetes on sensitive tissues.

In 1993, Oates, working with other scientists and robot scanners, screened Groton's entire library--at the time, more than 250,000 compounds--against the new target. They found a single compound, CP-131337, that showed a glint of promise. After still more years of testing, Oates was convinced they had come up with a powerful agent that should be declared a candidate for a medicine. Once again, Pfizer would have to decide whether to commit to another antidiabetes drug-development program that would take years and millions. "Declaring a new-drug candidate is a pretty big deal," says Oates. "Some powerful people didn't want to move forward."

In the end, Oates's team prevailed. Despite all the years of failed tests and trials and accumulated data, Pfizer was swayed by a question that has thus far proved to be irresistible--as well as unanswerable: What if this one is the winner? To find out, the compound, known as CAN (for "candidate") 809, is now in early development.

Small Victories

Will CAN 809 finally be the brass ring for Pfizer's diabetes research? Hutson and Oates have long ago stopped investing themselves in such hopes. Sure, he'd like to develop a product that ultimately makes it to market, Oates says, "but that's beyond success. That's supersuccess. That's winning the lottery." Instead, they live for the small victories, the incremental steps that may, someday, pile up one on top of the other to put the ultimate prize within reach. Hutson, for example, has made sure that when a researcher publishes a paper, or when a lab gets some positive results on a new therapy, it's trumpeted throughout the organization. "Science folks don't live for the big day when a drug makes it to market," she says. "They live for the small moments when you see exciting results in journals. Small victories help them to deal with the reality that, in all likelihood, there will be no big victory."

There's another fact of scientific life that helps researchers endure so many failures: Ultimately, theirs is a collective effort. A global village of scientific colleagues is dedicated to the effort to unlock the secrets of diabetes. And as the years have passed, the researchers at Pfizer have come to take comfort in the sense of scientific fraternity. "We all know that diabetes is such a tough problem, we can solve it only by cooperating," Oates says. "Even though a colleague or I may disagree strongly over an interpretation of scientific data, each of us knows that the other individual has also committed his or her life to achieving the same objective. Over time, you grow to love and respect these dedicated, hardworking brothers and sisters in arms." It would be great, Oates says, if Pfizer is the one to solve the problem. "But we would be happy if anyone succeeds, because it hasn't been done yet."

It's unlikely, Hutson points out, that their CEO shares the same magnanimous point of view. And she's right, of course. Three years ago, in an effort to stanch the alarming flow of failed R&D projects, Pfizer dispatched 600 of its top scientists to determine why so many compounds flunked in clinical trials. This Attrition Task Force fanned out across Pfizer's worldwide labs, interviewing researchers and compiling their findings in a vast database of doomed projects. The goal, then and now, is to cut the labs' failure rate to 92%. While that number still seems wildly excessive, it represents a doubling of Pfizer's R&D survival rate, from 4% to 8%.