Genome Project Planners Vie For Leadership

WASHINGTON—in the three years since it was first proposed, the U.S. effort to map and sequence the human genome has joined the ranks of Big $cience with astonishing speed. Unlike the prospects for such controversial megaprojects as the superconducting supercollider and the space station, funding for the genome project appears to be going nowhere but up. The Bush administration has requested a total of $128 million more than double the current level of $53 million, and Congress appears to. be willing to go along. Even at an eventual cost of some $3 billion, few doubt the value to humanity in knowing the entire sequence of the three billion base pairs that comprise our 100,000 or so genes. But these encouraging signs hide the major hurdles that lie ahead. Next week the NIH’s Human Genome Advisory Committee, headed by Rockefeller University biologist Norton Zinder, will meet to begin drafting a report to Congress on who should lead the effort. The question has always been a divisive one. Among those who would seek to challenge NIH for the genome throne are the Department of Energy (DOE), which feels better suited to coordinate such a technology-driven enterprise and the biotechnology industry, which is expected to provide both short-term technological solutions and long-term products. The U.S. effort now consists of work coordinated by NIH, which this year received about $27 million, and by Doe's national labs, which are spending $18 million on genome research. Meanwhile, scientists in a half-dozen other countries are also embarking on major efforts. Many participants believe that all these projects must soon be organized into a coordinated international effort to avoid redundancy and ensure reliability. But just how to undertake such a major collaboration is an issue that has split the community and generated competing proposals from all corners of the globe. In late April, Nobel laureate James Watson let loose the first of what promises to be many salvos by offering a plan to distribute responsibility for diverse “chromosomes” around the world. Watson, the parttime director of NIH’s Office of the Human Genome, aired the idea at both a Washington meeting cosponsored by the Alliance for Aging Research and the American Medical Association and a later meeting to incorporate the Human Genome Mapping Organization (HUGO). “Fellowship and the other things sound. nice,” Watson said, “but we really just want to get the job done in the fastest time and the lowest cost.” To that end, Watson has suggested that “different countries be responsible not for doing all the research, but just for the coordination of activities on a particular chromosome.” Each participating country would be assigned one or more specific chromosomes to sequence. The approach, he explained, would ensure that all the parts of the genome—even the difficult or uninteresting segments—would be worked on simultaneously. Harsh Criticism The proposal was meant more to kick off debate than as a way to settle the issue, Watson admits. Back at the Cold Spring Harbor Laboratory, which he directs, Watson was quick todefertohis critics. “Alot of people don’t like It,” he told reporters. “But I’d like to find something that will work, so I’m open to anything.” Even so, the harshness of the criticism has caught many by surprise. “I have a great deal of respect for Jim Watson, but I find the whole proposal very cavalier and disturbing,” says Jack McConnell, director of advanced technology at Johnson & Johnson. McConnell, as a corporate scientist, worries that Watson might “take an odyssey around Europe and drop off chromosomes with cronies” at the expense of U.S. industrial scientists. George Bell, who directs Los Alarnos National Lab’s genome program, says that the proposal is “superficially attractive.” But he questions whether the method is the best way to get the job done quickly. The opposition to Watson’s proposal may reflect more than simply the downing of a trial balloon. Many scientists have used the idea as an opportunity to attack not just the proposal, but also the ability of Watson—and, for that matter, NIH—to lead the project. “It’s not a scientific project, it’s an engineering project,” says Charles DeLisi, who directed DOE’s genome program until leaving 18 months ago to head the biomathematics department at the Mount Sinai Medical Center in New York. Du Pont genetics director Mark Pearson adds, “I don’t think the bulk of the sequencing is going to be done in NIH-style labs.” Pearson and others say that the work is more likely to end up at gene “factories” in industry or academia and that the views of that community should be recognized early on. “Watson is treating [the genome effort] like it’s not big science,” says McConnell. Once some basic science questions are answered, he says, the project’s success will depend on developing sequencing machines far faster than those currently available. That challenge, he notes, is comparable to what confronted scientists working on the atomic bomb as part of the military’s Manhattan Project. “The whole program is predicated on a hundredfold improvement in technology,” believes biologist Charles Cantor, who was picked last year by DOE to lead the genome center at Lawrence Berkeley National Lab. For scientists in industry and the DOE labs, there is a growing concern that the Bush administration has handed the genome project to Watson and NIH on a platter. Their suspicions were confirmed when the White House added an unsolicited 50% to NIH’s requested 1990 genome budget, raising the total to $100 million (see The Scientist, May 1, 1989, page 3). Meanwhile, the administration’s request for DOE’s projects totals less than a third of that, at $28 million, although the number is a $10-million increase from current levels. “I believe that the current budget proposal reflects nothing more than the fact that NIH has won a turf battle,” says Sen. Pete Domenici (R-N.M.), the Senate’s leading proponent of a larger role for DOE, in no small part because Los Alamos is located in his state. Speaking at a Senate appropriations subcommittee hearing last month on DOE’s budget, Domenici told DOE energy research director Robert Hunter that “you shouldn’t settle for anything less than leadership in this field.” Those who claim DOE has lost the lead to NIH say the reason may be simply a lack of effort. “Organizationally, nothing at DOE has changed since I left Washington a year and a half ago,” oomplains DeLisi, whose 1986 memo recommending a major DOE genome project is credited by many as having brought the idea to a boil. “I don’t think they’ve gone much beyond my original memo,” he says. A “memorandum of understanding” exists that outlines cooperation between DOE and NIH, but insiders say it has had little impact. Hunter disputes that assessment, claiming that the two agencies “are working together closely” and that the administration’s 1990 budget. proposal reflects its commitment to a major role for DOE. Despite Hunter’s assertion of a real partnership, the perception that NIH is running the genome show has prompted a host of competing proposals. At the Washington meeting last month, Johnson & Johnson’s McConnell proposed a consortium to make the national labs and industry equal partners with NIH. The structure, which is similar to an earlier bill proposed by Domenici would create an advisory panel to set strategy, identify goals, and spot commercial opportunities for gene technology and research. Aides say that Domenici may introduce a new version of his bill that includes the idea of a consortium after he meets this month with Watson. But others say that such a consortium is not likely to be the final solution to the leadership problem. “A consortium is just a code word for better cooperation [between DOE, NIH, and industryl than we’ve had,” says Du Pont’s Pearson. “If they could get their strengths together, we’d have a better overall project.” Los Alamos has already tried to create its own industrial consortium in the last year to speed the development of advanced sequencing tools. Says Bell, ‘We wanted to share the effort equally between the lab and industry. This is abiggame and a lot - of.people can participate.” But industry has been slow to respond, and Bell suspects he will be forced to settle for separate agreements with individual companies. Uncertain Commitments So far, the concerns of most of the participants have focused on coordinating U.S. genome research. Domestic spending on the project this year was greater than that of the rest of the world combined, and the extent of commitments overseas are still uncertain. Japanese involvement appears likely to be modest, and no organized national effort on the U.S. scale is planned. Officials of the European Community recently backed away from plans to spend $16 million to develop common data formats for genome information Although British interest remains strong, with $32 million committed to the project “the leadership is going to have to come from us,” says Lawrence Berkeley’s Cantor. Nevertheless, foreign participation in the project is seen as a crucial element in a unified U.S. program. HUGO. which was officially organized this spring under the direction of Watson and Johns Hopkins geneticist Victor McKusick, is expected to spearhead the drive for a coordinated international effort. Among the issues facing HUGO are data format standards and the free exchange of data. Those issues as well as the larger ones of leadership are likely to give rise to heated debate at next week’s meeting of the NIH advisory committee. Congress has asked for its recommendations by next spring, find it appears as though panelists will have no shortage of options to weigh.

Genome Project Planners Vie For Leadership

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Christopher Anderson

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June 1989

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