'Genes as merchandise', 'Who owns the genes of the brain?', 'Patenting life', these and other similar headlines have been going around the world for the past few years. One of the first events to cause public concem about genetic engineering was when, in 1988, the world's first patent of a genetically engineered animal was granted to the President and Fellows of Harvard College, the famous American University, for the Oncomouse. The oncomouse is a mouse that has been genetically transformed with an oncogene, a gene that promotes cancer. There are hundreds of oncogenes which are involved in the production of cancer in humans and in animals. The transformed mouse had a certain type of cancer and so did all its descendants. This transformed mouse was useful as model system for the study of that particular cancer. Animals have been used for decades as model systems in pharmaceutical and medicinal research. When a new potential medicine for the treatment of a disease is produced, it is generally tested first on animals to check if it is toxic. If there is a good animal model, the efficacy of the potential medicine against the disease can be tested. If the tests on animals are successful then clinical trials on humans begin. An animal model is therefore needed for every human disease, otherwise the new medicines have to be tested directly on humans, a course of action that raises many ethical problems. The most used animal models are mice and other small mammals. Unfortunately not all human diseases have counterparts in the mouse. Some human cancers are not known in the mouse, nor is there a mouse equivalent of cystic fibrosis, nor AIDS. Genetic engineers started to change the genome of the mouse so that it would have some human diseases. The Harvard Oncomouse was the first example. There was a strong reaction from the general public and the rights of scientists to 'create' animals with diseases was questioned. Some argued that it is part of the human culture to 'have dominion over the fish of the sea, and the fowl of the air, and over every living thing that moveth upon the earth' (Genesis 1: 28). But where do we draw the line? What worries many people is that if it is possible to transform mice, it will also be possible to transform humans. Transformed living organisms have been patented before, the very first patent being the one given for a transformed bacterium in 1981. This bacterium was changed genetically in such a way that it was possible to use it to clear up oil spills. The transformed bacterium could use petroleum as food, changing it into water and carbon dioxide. The big rush to patent human genes started soon after the patenting of the oncomouse. Table 4 in Chapter 9, shows some medical products made by genetic engineering, starting with insulin in 1982, for the treatment of diabetes and finishing in 1993 with Factor VIII, for the treatment of haemophilia. Many of these products are just proteins made normally by humans. The lack of this protein results in a disease that can be cured by injecting the protein into the blood of the patients. The proteins are made by E. coli which have been transformed by the relevant human gene. This human gene had first to be isolated by someone and when this was achieved, the gene sequence was patented because of its potential usefulness to the phan-naceutical industry. There are three main ways in which a cloned human gene can eam money for the patent holder. The gene can be used to make medical products such as insulin, or it can be used for diagnosis of a disease caused by a single defective gene, or it can be used by gene therapy.
In 1993, the US National Insitutes of Health and the UK Medical Research Council tried to patent thousands of human genes. They did not know what those genes were good for but they gambled that some could eam money in one way or another. The patent applications were refused, however, on the grounds that the function of the genes was not known. The greatest controversy so far triggered by patenting and genetic engineering began in 1994 when scientists at the veterinary school of the University of Pennsylvania, Philadelphia, found a way to change a gene in the germ line of a mammal. Changing a gene in the germ line of an animal means that the gene will be inherited. The technique requires isolation of a testis from the male animal, eliminating all the cells which make sperm, replacing them with cells that have been genetically manipulated in the laboratory, and then putting the testis back into the animal. The animal can now pass on the engineered gene to its descendants. Although the experiments were done with mice, the hope was that the technique could be used to 'create' new domestic animals, pigs which make better salami, cows which give more milk, and sheep with better wool. There was deep public concem, because the technique, as the authors say themselves in their patent submission, could also be used for humans. The patent has not yet been granted. Is this the beginning of scientifically planned eugenics or is it a leap forward toward effective gene therapy?
Scientists in Race to Map Mankind June 98 NZ Herald
It's pure research versus powerful business Interests In the rush to unlock the secrets of DNA, writes RANA DOGAR.
On the sprawling Cainbridgeshire campus of the Welcome Trust, the world's richest medical charity, 300 scientists are plotting the map of life. They are part of the Human Genome Project. Its lofty goal: to decipher all ihe information stored in human DNA by the year 2005 to create, in essence, a recipe book for man. A staircase in the main building, the Sanger Centre, twists upward in the double-helix pattern of a DNA molecule. The $NZ330m campus is a monument to international collaboration. The multibillion-dollar project links laboratories in countries such as France, Germany, the United States, Japan and Britain. Scientists are decoding the three billion letters of the human genome. Although the project's backers, especially governments, look forward to the new drugs, companies and jobs they may spawn, the emphasis is on pure science.. Last month, American scientist J. Craig Venter disturbed the quiet at the Sanger Centre by launching his private rival venture, which he claims will decode the human genome in three years, for under $600 million. The new company will be a collaboration between Dr Venter and Perkin-Elmer, a firm that makes DNA sequencing instruments. And its results will not be only for the good of mankind "This is not a charity project," says Dr Venter. "It's a business on the frontiers of science and medicine." Biotech companies have been seeking out human genes for years and patenting them in the hopes of producing money-making drugs. But the 100,000 or so human genes that are believed to exist account for only a fraction of the genome; in between are millions of letters of unknown value, what some scientists call "junk." Public researchers believe it is important to decode the entire genome, junk and all, because it may provide clues to common ailments like diabetes.
Though Dr Venter says he will do just that faster and cheaper than the public sector, some say his techniques are more geared toward finding cormercially viable genes than detailing the big picture. Until 1992, Dr Venter was a research scientist at the National Institute for Health. Then he was wooed away by Human Genome Science, a biotech firm. The lure: $85 million over 10 years to create his own centre, the Institute for Genomic Research. Many scientists are skeptical of Dr Venter's "shotgun" approach to decoding the genome. Robert Waterston, working on the project in America, says that Dr Venter is using "very untested technology." Francis Collins, head of the NIH's Human Genome Project, says that Dr Venter's product is likely to be "a different product than what the Human Genome Project signed up for." There is little doubt that Dr Venter's technique is capable of deciphering the 100, to 300 genes in the human genome that may be used to make the most valuable drugs. He has made it plain that he intends to seek out the juicy bits of the genome. But obtaining a patent requires much more than simply showing that genes or gene fragments exist. You have to show what they can be used to do (namely, create a drug like insulin). This takes a great deal of money and time. Within days of Dr Venter's announcement, Wellcome announced it would add $181 million to the project. And Dr Collins stresses that "the strong message from the scientific community is that we should stay the course and accelerate our efforts to get the sequencing done." NEWSWEEK
Sulston and Ventner
On your marks ... NS 23 May 98 4
THE international effort to sequence the human genome is shaping up into a race between a company and a loose coalition of organisations funded by gqvemments and charities. With efforts to decode the human genetic blueprint accelerating in both camps, tensions are starting to rise over how openlv the data will be made available, and whether patents on genes will obstruct progress in developing new drugs. The stakes rose last week when the Wellcome Trust, the world's largest medical charity, raised its contribution to the project by £110 million to £205 million. The trust's team at the Sanger Centre near Cambridge plans to sequence one third of the genome instead of a sixth, as was planned. A week earner, a company in the US was formed to sequence the entire genome by 2001, four vears earlier than the target date set by the'Human Genome Project. Formed by Craig Venter, who founded TIGR, The Institute for Genomic Research in Rockville, Maryland, the new company will deploy sequencing machines developed by Perkin-Elmer of Norwalk, Connecticut. The Wellcome Trust denies that its announcement was a tit-for-tat response. "I can sav hand-on-heart most of the groundwork had been done," says John Sulston, director of the Sanger Centre and spokesman for the trust's project. "But I can't say it didn't sharpen people's minds." Venter has pledged to make the sequence data gathered by his company publicly available. But Sulston remains suspicious. Two years ago, the major plavers in the Human Genome Project-including the US National Institutes of Health (NIH) and Britain's Medical Research Councilagreed at a meeting in Bermuda to release sequence data immediately into public databases. They also vowed not to patent genes on a wholesale basis. But companies such as Venter's mav not uphold the spirit of the Bermuda agreement, Sulston fears. "They said they would patent some interesting genes, maybe 100 to 200 in total," he says. "The point is that if they were to get sole rights to lots of genome, they don't have to limit themselves to that." Sulston also complains that Venter's company says it will release data quarterly instead of instantly. But Venter says this is for logistic reasons, not to allow the company to pick the most interesting data before other researchers get a look. Venter is an,,ered by Sulston's comments. "We're going to give the genome to the public for free," he says. "All thev do is complain we're giving it to them on a quarterly basis rather than a daily basis." There are also doubts about the completeness of the data that venter will produce. He is proposing to use a "shotgun" method, in which DNA is broken randomly into thousands of fragments. The sequences of each are determined, then computers work out which fragments overlap. Even Venter admits that the process can leave gaps, although he is confident that they will not be large: "I wouldn't put my career on the line if I and my team didn't think it was achievable." Francis Collins, who heads the NIH genome project, has O'iven Venter's plan a cautious welcome. But he predicts that Venter's estimate of sequencing the genome at a cost of 10 cents per base pair will rise to the 50 cents budgeted by most other labs, once you include the cost of filling in all the gaps. The Sanger Centre and labs funded bv the NIH are taking a more thorough approach, checking and rechecking sequences from individual DNA fragments cloned into bacteria. Andy Coghlan and Kurt Kleiner
PROFILE An Express Route to the Genome? Sci Am Aug 98 14
In his race to beat the Human Genome Project, J. Craig Venter bas riled geneticists everywhere
Craig Venter, the voluble director of the Institute for Genomic Research (TIGR) in Rockville, Md., is much in demand these days. A tireless self-promoter, Venter set off shock waves in the world of human genetics in May by announcing, via the front page of the New York Times, a privately funded $300-million, three-year initiative to determine the sequence of almost all the three billion chemical units that make up human DNA, otherwise known as the genome. The audacious claim prompted incredulous responses from mainstream scientists engaged in the international Human Genome Project, which was started in 1990 and aims to learn the complete sequence by the year 2005. This publicly funded effort would cost about IO times as much as Venter's scheme. But Venter's credentials mean that genome scientists have to take his plan seriously. In 1995 Venter surprised geneticists by publishing the first complete DNA sequence of a free-living organism, the bacterium Haemophilus influenzae, which can cause meningitis and deafness. This achievement made use of a then novel technique known as wholegenome shotgun cloning and "changed all the concepts" in the field, Venter declares: "You could see the power of having 1 00 percent of every gene. It's going to be the future of biology and medicine and our species." He followed up over the next two and a half years with complete or partial DNA sequences of several more microbes, including agents that cause Lyme disease, stomach ulcers and malaria. The new private human genome initiative will be conducted by a company (yet to be named) that will be owned by TIGR, Perkin-Elmer Corporation (the leading manufacturer of DNA sequencers) and Venter himself, who will be its president. He plans to warm up for the human sequence next year by knocking off the genome of the fruit fly Drosopbila melanogaster, an organism used widely for research in genetics. Venter, 51, has a history of lurching into controversy. As an employee of the National Institutes of Health in the early 1990s, he became embroiled in a dispute over an ultimately unsuccessful attempt by the agency to patent hundreds of partial human gene sequences. Venter liad uncovered the partial sequences, which he called expressed sequence tags (ESTs), with a technique hc developed in his NIH laboratory for identifying active genes in hard-to-interpret DNA. "The realization I had was that each of our cells can do that better than the best supercomputers can," Venter states. Many prominent scientists, including the head of the NIH's human genome program at the time, James D. Watson, opposed the attempt to patent ESTs, saying it could imperil cooperation among researchers. (Venter says the NIH talked him into seeking the patents only with difficulty.) And at a con e gressional hearing, Watson memorably described Venter's automated gene-hunting technique as something that could be "run by monkeys." An NIH colleague of Venter's responded later by publicly t donning a monkey suit. Venter left the NIH in 1992 feeling that he was being treated "like a pariah." And he does not conceal his irritation that his peers were slow to recognize the merits of his proposal to sequence H. influenzae. After failing to secure NIH funding for the project, Venter says he turned down several tempting invitations to head biotechnology companies before finally accepting a $70-million grant from HealthCare Investment Corporation to establish TIGR, where he continued his sequencing work. Today, when not dreaming up audacious research projects, Venter is able to relax by sailing his ocean-going yacht, the Sorcerer His assault on the human genome will employ the whole-genome shotgun cloning technique he used on H. influenzae and other microbes. The scheme almost seems designed to make the Human Genome Project took slow by comparison. To date, that effort has devoted most of its resources to "mapping" the genome-defining molecular landmarks that will allow sequence data to be assembled correctly. But wholegenome shotgun cloning ignores mapping. Instead it breaks up the genome into millions of overlapping random fragments, then determines part of the sequence of chemical units within each fragment. Finally, the technique employs powerful computers to piece together the resulting morass of data to re-create the sequence of the genome. Predictably, Venter's move prompted some members of Congress to question why government funding of a genome program was needed if the job could be done with private money. Yet if the goal of the Human Genome Project is to produce a complete and reliable sequence of all human DNA, says Francis S. Collins, director of the U.S. part of the project, Venter's techniques alone cannot meet it. Researchers insist that his "cream-skimming" approach will furnish information containing thousands of gaps and errors, even though it will have short-term value. Venter accepts that there will be some gaps but expects accuracy to meet the 99.99 per cent target of the existing genome program. Shortly after Venter's proposed scheme hit the head-lines, publicly funded researchers started discussing a plan to speed up their own sequencing timetable in order to provide a "rough draft" of the hunian genome sooner than originally planned. Collins says this proposal, would require additional funding, would proceed even without the new competition. Other scientists think Venter's plan will spur the public research ers forward. Venter has always had an iconoclastic bent. He barely graduated from high school and in the 1960s was happily surfing in southern California until he was drafted. Early hopes of training for the Olympics on the navy swim team were dashed when President Lyndon B. Johnson escalated the war in Vietnam. But Venter says he scored top marks out of 35,000 of his navy peers in an intelligence test, which enabled him to pursue an interest in medicine. He patched up casualties for five days and nights without a break in the main receiving hospital at Da Nang during the Tet offensive, and he also worked with children in a Vietnamese orphanage. Working near so much needless death, Venter says, prompted him to pursue Third World medicine. Then, while taking premed classes at the University of California at San Diego, he was bitten by the research bug and took up biochemistry. He met his wife, Claire M. Fraser, now a TIGR board member, during a stint at the Roswell Park Cancer Institute in Buffalo, N.Y., and took his research group to the NIH in 1984. His painstaking attempts to isolate and sequence genes for proteins in the brain known as receptors started to move more quickly after he volunteered his cramped laboratory as the first test site for aii automated DNA sequencer iii-,i(le by Applied Biosystelils Iliterna tional, now a division within Perkin Elmer. Until then, he had sequenced just one receptor getie in more than a decade of work, so he felt he had to be "far more clever" than scientists with bigger laboratories. Venter was soon employ mg automated sequencers to find inore genes; he then turned to testing proto cols for the Human Genome Project, which was in the discussion phase. After leaving the government and moving to TIGR, Venter entered a con troversial partnership with Human Ge nonie Sciences, a biotechnology compa tiy in Rockville established to exploit ESTs for finding genes. The relationship, never easy, foundered last year. Accord itig to Venter, William A. Haseltine, the company's chief executive, became in creasingly reluctant to let him publish data promptly. Haseltine replies that he often waived delays he could have required. The divorce from Human Genome Sciences cost TIGR $38 inilil'on in guar anteed funding. I'lie day after the split was announced, however, TIGR started to rehabilitate itself with a suspicious scientific community by posting on its World Wide Web site data on thousands of bacterial gene sequences. The sequencing building for Venter's new human genome company, now un der construction ad-acent to TIGR, should be a technological mecca. The firm will produce more DNA data than the rest of the world's output combined, employing 230 Perkin-Elmer Applied Biosystems 3700 machines, which are now in final develop ment. These sophisticat ed robots, which will sell for $300,000 apiece, t should require much less human intervention than state-of-the-art devices. Venter says the new ven ture will release all the hutilan genome sequence data it obtains, at three month intervals. It plans to make a profit by selling access to a database that will interpret the raw sequence data as well as crucial information on variations between individuals that in principle should allow physicians to tailor treatments to patients' individual genetic makeups. Most of the federal sequencmg centers do not look at the data they produce, Venter thinks, but just put it out as if they were "making candy bars or auto parts." The unnaiyied new TIGR-Perkin-Elmer operation will also patent several hundred of the interesting genes it expects to find embedded within the human genome sequence. Venter defends patents on genes, saying they pose no threat to scientific progress. Rather, he notes, they guarantee that data are available to other researchers, because patents are public documents. His new venture will not patent the human genome sequence itself, Venter states. The plan, if it comes to pass, should I)e a booti for biomedical research. Yet more than loo scientists who met recently to decide on further plans for the existing, more complete and thorough international Human Genome Project were unanimous that it, too, should go forward. Collins wonders whether the entrepreneur at TIGR will in fact be able to stick to his stated policy of releasing all data, given financial exigencies. But he and Venter have both pledged to cooperate. Venter is unfazed "We will make the human genome unpatentable" by placing it in the public domain, he proclaims. For the next three years, all eyes will be on Venter to see how closely he can approach that goal. -Tim Beardsley in Washington, D.C.
DNA profiles from a sequencer.