A Life-Changing Encounter
The first time Stan Crooke helped treat a terminal cancer patient was in 1969—or maybe 1970. The 81-year-old physician and pioneering drug designer can’t quite remember the year. He has, after all, worked with many patients with seemingly incurable diseases over his long career. But in this case, he certainly remembers the feel of it.
Crooke was a third-year student at Baylor College of Medicine at the time, his Ph.D. already behind him, and a young man had been referred to the hematology-oncology unit with an abdominal mass. It turned out to be disseminated testicular cancer. The patient was maybe 25—around the same age as Crooke himself then—and a college grad engaged to be married. Crooke was in the room when the patient received the news, and seeing “the process of telling him that he was going to be dead in six months was impactful for me,” he says. The interaction showed Crooke that a physician would sometimes be in “the most responsible position a human being could be in,” face to face with a patient who has “put his life in your hands.”
From Country Doctor Dream to Drug Development
He could have had a career filled with those moments. He had a classmate who talked about setting up a rural practice somewhere, out in the country’s plains, or maybe a foothill community, and he wanted Crooke to join him. But that wouldn’t work. For years, Crooke’s wife Nancy had been plagued by a mysterious vasculitis, an autoimmune disease of the arteries that physicians couldn’t get a handle on. And they had a young son with a learning disability, who would probably require private schools. Crooke needed a guaranteed, sizable income, more than what a country doctor would make.
But another important thing had happened in that room with the young cancer patient: The medical team had offered to try an experimental drug called bleomycin. Crooke had never heard of it, and when he looked it up, he saw it was a natural product discovered in Japan, not yet approved for clinical use in the United States. It had “a structure that I’d never seen, a mechanism of action that was completely unknown” and a “bizarre toxicity,” he recalls. Returning to his Baylor lab, Crooke began investigating bleomycin, and he realized something else about medicine: The impact he might exert from “making one good drug” could exceed any good he could do as a physician. He was nearing the end of his M.D.-Ph.D. program, so he called Bristol Labs, the company that had the rights to bleomycin in the U.S., asked for a job, and got hired as a clinician.
Career Roller Coaster and the Birth of Antisense Technology
It put Crooke on a career roller coaster, and for decades he fought through—and sometimes with—the drug development world. He would spearhead the effort to introduce a new type of drug therapy into the pharmaceutical arsenal, but the patient was never far from his mind. Now, after more than eight decades on the planet, Crooke finds himself again seeking to treat people suffering from diseases or disorders one-by-one.
The seminal papers in so-called “antisense technology” were two studies published in the Proceedings of the Academy of Sciences in 1978. Those papers reported that a short, single-stranded piece of synthetic DNA, when delivered into stem cells taken from chicken embryos, was able to inhibit the replication of a virus infecting that embryo. The piece of DNA—called an oligonucleotide—bonded to the “sense” strand of messenger RNA in the cells, rendering it unable to produce a protein critical to virus replication. The term “antisense” itself arose from the bonding to this “sense” strand, and the paper suggested that antisense oligonucleotides, or ASOs, might be able to influence protein production elsewhere in the body. That ability had all kinds of tantalizing possibilities for medicine.
Crooke learned about antisense around 1987, when a speaker at a symposium hosted by the pharmaceutical company SmithKline presented his own work in the young field. By then Crooke had left Bristol, was worldwide president of R&D at Philadelphia-based SmithKline, while also running a lab at the University of Pennsylvania. After the talk he dug up those original antisense papers. It was fortuitous timing, because Crooke was at something of a crossroads. Nancy had died of her illness in 1984, leaving Crooke a widower and a single father. He had begun to rebuild his life, in particular by marrying a researcher named Rosanne Snyder, a former grad student at his UPenn lab. But he’d grown unhappy in his career. The pace of innovation at a big pharma company was frustratingly slow, he felt, and SmithKline’s shares had been underperforming. It seemed like the company might be bought, and Crooke was dead set against that. He was “very aggressive” about saying so, he recalls, a stance that left him with few friends in senior management, and he admits that he “should have been a better subordinate.” But also, he thought the drug development world needed a new way to make medicine, and he wanted to investigate antisense on his own terms. After all, he had that pharmacology degree in his background, his M.D. training, all his research work, and now he had spent years actually making drugs. Something told him he was exactly the right person to develop antisense as a drug platform.
So when SmithKline fired him in 1988, he was already halfway to forming a biotech startup. He rounded up a core of talented researchers.