Richard Mulligan: from skeptic to true believer

For most people, the trip from the Whitehead Institute at MIT (the Massachusetts Institute of Technology) to Harvard Medical School is a two-mile bus ride. For Richard Mulligan, who late last year became the first director of the Harvard Gene Therapy Initiative, it seems like a voyage to a new world. It is daunting enough that Mulligan had to move from the MIT’s ‘research is all that counts’ atmosphere to the ‘it wouldn’t hurt to wear a tie’ corridors of Harvard Medical School and its affiliated hospitals, which are joint sponsors of the initiative. But for Mulligan, who appeared tieless for an interview at an upscale Cambridge restaurant, the move represents an even greater leap — from skeptic about gene therapy to true believer. As a founder member of the RAC — the Recombinant DNA Advisory Committee set up to screen gene therapy protocols for the US National Institutes of Health (NIH) — Mulligan became known as a nitpicking critic of what he saw as premature attempts to conduct human studies of scientifically dubious genetic therapies. He was seen as wanting to have it both ways, saying yes to basic research but no to clinical trials. In his new post, he has assumed responsibility for actually making gene therapy work in humans. Mulligan earned his reputation by developing and testing some of the earliest and most successful vector systems for delivering genes to experimental animals. Shaped by his undergraduate years at MIT and 15 years on the faculty there, Mulligan admits he was a purist about most of the applications that poured in to the RAC. At MIT, he had been trained to critically evaluate data, without allowing any implications of the findings to bias his interpretation. By contrast, he says “some people interpreted their scientific data poorly in order to go forward in the clinic.” Some of gene therapy’s early advocates were clinicians who criticized Mulligan for his hesitation. He remembers them arguing that they had patients dying and needed to move ahead despite not having all the facts. Mulligan also raised some colleagues’ ire by warning that shoddy gene therapy experiments would soil the field. Now, a decade later, Mulligan’s skepticism has been validated at the highest possible level. A 1995 report by an influential NIH-appointed committee slammed prior gene therapy trials as unsuccessful and “oversold,” filled with experiments that suffered from weak design and non-informative outcomes. Worse yet, despite a NIH gene therapy budget of $200 million a year, the report found that there had been a “very low frequency of gene transfer” and that in more than 100 protocols, not a single patient had been definitively helped. Consequently, the report called for a return to basic laboratory science rather than longshot studies of patients. “I could have written that report myself five years earlier,” says Mulligan, who by then was on sabbatical at Somatix, a California biotechnology company he had helped to found. His stint in biotech also confirmed that there was a lot of basic research still to be done before the field would be ready for companies to kick in with the developmental phase. Mulligan’s own laboratory work, which he continued even while working at the company, never strayed from a fundamental rule: “If gene therapy were banned tomorrow, would our science be of intrinsic interest?” At the same time, even as the clinical failures piled up, Mulligan’s confidence grew that someday human gene therapy would succeed — and that the field would proceed without him if he did not find a way to become active in moving the basic science discoveries into the clinic. It would have been easy enough to stay on at Somatix. “They were beginning to work on cancer vaccines, which I had been very interested in,” he recalls, “. . . and they were beginning to succeed,” at least in certain systems. But making gene therapy work at a company is complicated by the fact that even successful techniques may not be applicable to large enough patient groups to be profitable, says MIT molecular biologist and Nobel laureate Phillip Sharp, one of Mulligan’s mentors. On top of that, adds Sharp, “In the long term, Richard would never fit in at a company — he’s too free-spirited.” Meanwhile, Harvard beckoned, beginning with an offer to move his laboratory to the Harvard-affiliated Children’s Hospital. Mulligan would also become a well funded Howard Hughes Medical Institute investigator in making the move. But the recruitment effort went beyond the Children’s Hospital and the Howard Hughes. All the Harvardaffiliated hospitals and the Dean of the Medical School itself, Daniel Tosteson, agreed that Harvard needed an initiative in gene therapy. One of the recruiters told Mulligan that it was the first thing all the hospitals could agree on in about 50 years. All in all, Mulligan got the impression that Harvard Medical School could Magazine R601