Human Genome Project Victory for Public Science

The publication of the human genome map has been greeted with the accolades that it deserves. But, for the first time in the history of science, the details of such a pathbreaking event has been published separately by two different sets of scientists in two different journals! An event, possibly as unique as the sequencing of the human genome itself. The two sets of scientists represent, respectively, the public funded Human Genome project, and a private company called Celera Genomics. The former published its results in the journal Nature, and the latter in the journal Science. Most commentators have lauded this as an unique example of collaboration between public and private funded science. Unfortunately, nothing could be further from the truth.

The truth is that Celera made a determined bid to appropriate years of labour put in by scientists of the Human Genome Project. If it had succeeded, there would have been just one publication of the resulsts—by Celera. And Celera would have ensured that access to the data was restricted by commercial concerns. To understand how the challenge was mounted and finally met successfully, a brief recapitulation of the Human Genome Project is in order.

AN IMPOSSIBLE DREAM?

The idea of mapping the human genome was greeted with widespread scepticism when it was first mooted fifteen years ago. It was felt to be impossible to execute, and even worse, grave doubts were raised about the utility of such an exercise. One of the first to grasp that potential was Robert Sinsheimer, a biologist who was then chancellor of the University of California (UC), Santa Cruz. In 1985, Sinsheimer assembled some of the best minds in the nascent field of genome analysis, including Walter Gilbert of Harvard University to discuss the proposal. The collective conclusion was predictable—the idea was seen as bold and exciting but simply not feasible. But the meeting did capture the imagination of Gilbert, who soon became the proposal’s biggest champion. His support meant the idea could no longer be blithely dismissed as a decade earlier, Gilbert and Allan Maxam, also at Harvard University, had invented a technique that enabled scientists for the first time to determine the genetic sequence of an organism. Gilbert went on to share the Nobel Prize later. Probably even more crucial was Gilbert’s ability to persuade another giant of molecular biology—James Watson, who shared a Nobel Prize with Francis Crick and Maurice Wilkins for their 1953 discovery of the double helical structure of DNA—to be interested in the project.

In 1988 the Human Genome Project (HGP) received approval for funding from the US Congress and the US National Institute of Health (NIH) was put in control. Over the years the project became a large collaborative effort involving 20 laboratories in six countries. It was decided that the project should have a dual approach, proceed with the mapping of the whole human genome but also construct smaller maps that would greatly speed the search for disease genes—thus offering immediate medical applications. Full-scale sequencing of the genome was postponed until new technologies made it faster and cheaper. James Watson was chosen to lead the project.

NIH MOOTS PATENTING OF GENES
The project received its first major jolt in June, 1991 from a member of its own team—Craig Venter. Venter derided the idea of proceeding with the mapping of the genome and instead suggested that the focus should be on finding specific genes. Venter and colleague Mark Adams had developed a new technique, called expressed sequence tags, that enabled them to find genes at unprecedented speed. A few weeks later, Venter described his work at a congressional hearing. Venter advocated that patent applications should be allowed on the partial genes he was identifying—at a rate of 1000 a month. Watson denounced the patenting scheme as “sheer lunacy” and said that “virtually any monkey” could do what Venter’s group was doing. Watson argued that Venter and NIH had no clue about the function of the genes from which the fragments (that were proposed to be patented) came. If the patents held, that meant anybody could lay claim to most of the human genes. Later, when applications involving these genes are discovered, the original patentees would be able to make huge profits, without having done any work on the actual applications.

What lay at the core of this controversy was the liberal manner in which the US Patent office examines Patent applications. A gene itself occurs in nature and can’t be patented. But a patentee can glean enough information from the computer analysis and laboratory tests to speculate on ways that a gene could be a future target for medical applications—say a target for a new drug. It is this informed speculation on the gene’s function that can turn a “discovery” into a patentable “invention”. While Patent laws do not allow discoveries to be patented, patentees attempt to convert a discovery (that of the sequence which forms the gene) into an invention, purely on the basis of informed guesswork.

Watson’s concerns were however overruled, and he left in a huff in 1992. Venter, too, left NIH in 1991 when he was offered $70 million from a venture capital company to try out his gene identification strategy at The Institute for Genomic Research (TIGR). After Watson’s departure Francis Collins of the University of Michigan, was chosen to head the project. A physician by training, Collins brought a different perspective to the genome project, placing its medical applications in the forefront.

The issue of public access to the data generated by the HGP (as opposed to restricted access by virtue of granting of Patents) simmered for years. Finally, in February 1996, at a meeting in Bermuda, international partners in the genome project agree to formalise the conditions of data access, including release of sequence data into public databases within 24 hours. These came to be known as the ‘Bermuda principles’.

The project, under Collins’ tutelage, made steady, incremental advances. The project undertook to mapping small fragments of the whole genome and subsequently reassembling these small maps. Even so, reassembling the DNA fragments that were being mapped, in correct order, continued to be difficult.
In 1995, Venter (now at TIGR) announced that he had hit upon a different method of mapping the genome. Venter claimed that much faster results could be achieved by shredding the entire genome into small fragments and using a computer to reassemble the sequenced pieces by looking for overlapping ends.

CELERA ENTERS THE RACE
In May 1998 Venter announced that he had teamed up with Perkin-Elmer Corp., which was about to unveil an advanced, automated sequencing machine, to create a new company that would single-handedly sequence the entire human genome in just 3 years. The company was soon to be named Celera Genomics. This announcement galvanised scientists working with the Human Genome Project, now afraid that after they had spent years laying the groundwork, Venter might just about beat them to the finishing post. They were also concerned that the US Congress might fall for Venter’s ploy and actually stop their funding. Venter’s plan would never work, they countered—the sequence would be riddled with holes and impossible to reassemble.

Collins announced new goals for the Human Genome Project (HGP) in September 1998, just 6 months after Venter’s surprise announcement. The race between HGP and Celera was now on. Venter announced in October 1999 that his crew had sequenced 1 billion bases of the human genome—a claim countered by NIH, which noted that Celera hadn’t released the data for other researchers to check. The HGP announced in November that it had completed 1 billion bases. Venter countered in January 2000 that his crew had compiled DNA sequence covering 90 per cent of the human genome, and the HGP asserted in March that it had completed 2 billion bases. As the battle raged, another battle was also being joined. The HGP denounced Venter for his plan to release his data on the Celera Web site rather than in GenBank, the public database.

Meanwhile, the two sides had begun talking about a possible collaboration in December 1999. But in March 2000, the discussions became acrimonious foundered. Finally, a truce was brokered, under which both groups would announce their drafts at the same time. Venter, however, still refused to deposit his data in GenBank.

The truce held till it collapsed over plans to publish their papers. At issue, again, was Venter’s refusal to deposit his data in GenBank and his insistence on restricted access to his data. These issues remained unresolved till the end and led to the curious spectacle of separate publications of the human genome map in two different journals by the two contending groups.

TRIUMPH OF PRIVATE ENTERPRISE?
Many have projected the late rush to the winning post by Celera Genomics as an example of a small private enterprise successfully taking on the might of a large public funded effort. The facts, however, are quite different. First, Venter did most of his work while still working as part of the project at NIH. He, thus, had access to years of labour put in by the HGP. Even after he left the NIH, he had the advantage of having access to data generated by the HGP that was regularly put in public domain. Finally, Celera Genomics is not a small private enterprise. It had at its command, resources that were—in certain instances—far in excess of what was available to the HGP. The super-computer used by Celera is the largest in civilian use in the world!

In fact, members of the HGP are now arguing that Celera’s genome map, published in Science could not have been completed without drawing heavily on their own work. Eric Lander, director of the genome centre at the Massachusetts Institute of Technology, said “For three years the public project was told that we were inefficient, slow and pointless for proceeding in a careful fashion, … At the end of the day, it has transpired that we have been the ones who have guaranteed that there is a human genome sequence. We have saved the day.” Even Craig Venter grudgingly admitted his debt to the HGP when he said that the company decided to make use of the public data, once it became clear that it would be available in time, “instead of spending six months and [another] $60 million”.

If there is a moral in this story, it lies somewhere else. It lies in the story of James Kent—the man who wrote the computer programme that pieced the data together for the HGP in a matter of a four weeks using an array of simple personal computers! A man who had to ice his wrists at night because of the fury with which he created this complex programme. Kent was later to state that he offered to write the programme for the HGP because of his concern that the genome would be locked up by commercial patents if an assembled sequence was not made publicly available for all scientists to work on. “The U.S. Patent Office is, in my mind, very irresponsible in letting people patent a discovery rather than an invention,” he said. “It’s very upsetting. So we wanted to get a public set of genes out as soon as possible.”

CONFLICTING PERCEPTIONS
The conflicting perceptions of HGP and Celera Genomics are clearly reflected in the introductory remarks in the journals where they were published. Nature (where the HGP published) said, ” … Nature has followed a traditional model in the publishing of extensive scientific data. …. we require the results of genome sequence analyses, as with protein structure co-ordinates, to be immediately available from an appropriate database without restriction. This supports an unwritten contract with our readers that what they see described is what they can use, without obstacles, whether they work in the commercial or academic sector (an increasingly blurred distinction). … And it supports a principle enunciated by the United Nations that the human genome in particular is, in a symbolic sense, humanity’s common heritage.

Since we established our policy on access to genome data in January 1996, Nature has been able to hold the traditional line. The burden of providing proof that the line should be abandoned lies with the companies—either through rational debate or possibly by the sheer scientific significance of their output in the absence of a publicly funded equivalent. With a publicly funded project delivering data, Nature believes that the human genome sequence is not the place for the traditional rules to be broken”.

Science (where Celera published), on the other hand commented, “The technical innovation and drive of Craig Venter and his colleagues made it possible to celebrate this accomplishment far sooner than was believed possible. Thus, we can salute what has become, in the end, not a contest but a marriage (perhaps encouraged by shotgun) between public funding and private entrepreneurship”. Significantly, it goes on to lament the absence of stronger patent protection—”Commercial researchers are producing more and more potentially valuable sequences, yet (at least in the United States) laws governing databases provide scant protection against piracy”.

Many now criticise Science for colluding with Celera—for agreeing to its terms that do not allow full access to its data. In a way it has set an extremely unfortunate precedent. We are fortunate that the HGP allows unrestricted access to its data. We have the likes of Watson and Kent, and many more to thank that the Human Genome map is public property today. But the battle is by no means over. In every field of human endeavour, knowledge is set to be boxed in by restrictions. Science, for its own sake, can only hope that there will be other men of integrity who will rise to the challenge whenever narrow private interest seeks to appropriate the fruits of human intellect.