Editors: Michio Okamoto, M.D., Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.
Fukui Session: Fourth International Bioethics Seminar in Fukui
Editor, Nature Genetics
With this remarkable progress, there is, of course, the prospect that some of this knowledge could be misused. Many are worried about the lack of privacy of this rapidly growing body of genetic information, knowledge that could be used - indeed has been used in isolated cases in the past - to deny citizens insurance, and even employment. There are also deep ethical concerns that if the speed of current discoveries does not go unchecked, then scientists might abuse their newfound powers. Surprisingly, however, one of the most commonly expressed fears of genetic technology - namely, the potential to correct a person's germ cells using gene therapy, thereby allowing that individual to pass the corrected gene onto his or her children - does not arouse any particular concern among the general public, according to a recent opinion poll in the United States.
Success of the Genome Project
The dramatic increase in genetic discovery over the past few years owes much to the Human Genome Project, the 15-year, $3 billion effort to map and sequence the entire 3 billion bases of human DNA. According to recent estimates by leading geneticists in the United Kingdom and the United States, the ability to complete the sequence ahead of schedule is within our grasp, so long as modest increases in funding are available. Dr John Sulston, who has been leading the nematode genome project, estimates that the full human sequence could be achieved shortly after the year 2000.
It must be remembered, of course, that sequencing the human genome, and those of model organisms such as bacteria, yeast, fruit flies and mice, is simply a means to an end, and not an end in itself. In other words, the point of investing so many financial and human resources into these projects is to identify the 60,000 to 70,000 genes that comprise the human genome, affording scientists an unimaginable insight into human biology. With this knowledge will come further spectacular insights into human disease, especially the most common disorders affecting human beings, including diabetes, heart disease, and cancer.
Of course, the full sequence of the 24 different human chromosomes will also teach us much about the inner workings of the cell, and the exquisite programming of gene expression during development. But I think that Dr Francis Collins, the Director of the Genome Center in the United States, was quite correct in emphasizing the potential of the genome project for understanding and treating genetic disease as the most compelling reason for increasing funding for the genome project. Quite apart from the incalculable benefits for human health, it is the only realistic way that the project can be "sold" to the US Congress, which is paying the lion's share of the bill. Before sequencing really begins, however, scientists are building better and better maps of the human chromosomes, thereby allowing them to localize the positions of important disease or cancer-causing genes, and subsequently to enable them to identify these genes. Let me give you some recent examples of these exciting discoveries.
A few months ago, a large team of scientists identified the gene for ataxia telangiectasia on chromosome 11. This was exciting not only for the insights that this gene will provide researchers in understanding how DNA is repaired in cells, but also for more clinical reasons. The proportion of people who carry one defective copy of the ataxia telangiectasia gene, called ATM, is thought to be very high, and these people are suspected to be at far greater risk of developing cancer. It will be immensely important to identify carriers of the ATM gene when technology permits, and perhaps to advise them to change their lifestyle, for example to avoid exposure to X-rays such as they might receive in taking simple mammograms to detect lumps in their breast.
Earlier this month, in our journal Nature Genetics, scientists at Stanford and Duke Universities in the United States, announced that they had finally discovered the 'weaver' gene. Weaver is the name of a strain of mice that have been studied intensely for more than 30 years, because these mice show degeneration of specific types of nerve cells in the brain that, interestingly, are very similar to the nerves that are lost in Parkinson's disease. The gene turns out to encode a potassium channel, which is surprising in itself, as ion channels were not thought to be involved in neuronal development. It might also be noted that this important mouse gene was found as a result of the human genome project, for the researchers were primarily studying human chromosome 21 because of its relevance for Down syndrome. Finally, this kind of success emphasizes the vital role that studies on mice and other model organisms is playing in improving our understanding of human development. The greatest excitement, especially in the United States, has probably been reserved for the discovery last December of the 'obese' gene in mice, by Dr Jeffrey Friedman's group at The Rockefeller University in New York. Friedman and two other groups have shown that injecting the purified protein made by this gene, called 'leptin', into overweight mice leads to a rapid reduction in body fat.
One other gene discovery in the past 12 months has ranked with that of the obese gene, and that is the isolation of the hereditary breast and ovarian cancer gene, called BRCA1. After an intense race lasting four years, the gene was finally isolated by Dr Mark Skolnick and his colleagues at Myriad Genetics, a young biotechnology company founded by Skolnick and Nobel Laureate Dr Walter Gilbert, in Salt Lake City, Utah. Skolnick had been interested in the genetics of breast cancer for 20 years, and about five years ago, he realized that the only way he was going to have a chance to find the gene himself was to launch his own private company, dedicated to finding genes involved in cancer, as well as heart disease, asthma and other common human traits.
Breast cancer is far more common in the United States and Europe than it is in Japan; indeed, it is interesting that Asian women who move to the United States quickly assume the same risk of breast cancer as faced by American women - a lifetime risk of 1 in 8. This suggests that dietary and lifestyle factors common in the West are responsible for the rising risks of developing breast cancer. But whereas progress in identifying the nature of these putative environmental factors is very slow, the scientific and media interest surrounding the discovery of BRCA1 has been extraordinary. About 10% of breast cancers are thought to be hereditary in origin, with half of those attributable to BRCA1, and most of the remainder to BRCA2, which is expected to be isolated very shortly.
In the 12 months that have passed since BRCA1 was found, more than 50 different mutations have been found in families with breast and ovarian cancer, but although there is some evidence that the BRCA1 protein might be involved in controlling cell growth at certain stages of development, that is about all we can say at the moment. American researchers have made one surprising discovery worth mentioning, however. A team of scientists at the National Institutes of Health (NIH) recently reported in Nature Genetics that the carrier frequency of a specific BRCA1 mutation among Ashkenazi Jews is approximately 1 in 100 (or 1%). This dramatic result, if confirmed, is likely to heighten the demand among segments of the American population for genetic testing for the BRCA1 mutation.
In the past few years, the stakes in the human genome project have grown enormously. In the United States, a number of new biotechnology companies are devoted to mining the human genome for important disease-causing genes. Myriad Genetics is arguably the most successful so far: in addition to BRCA1, they have shown that the p16 gene is involved in many forms of cancer, including familial melanoma, and are thought to be very close to isolating BRCA2. Partly as a result of this early success, they have secured multi-million dollar deals from major pharmaceutical companies including Eli Lilly and Bayer Corporation. Other young genetics companies have also formed powerful alliances: Sequana Therapeutics, in San Diego, with Glaxo; Millennium Pharmaceuticals, in Cambridge, Massachusetts, with Hoffmann-La Roche; and Human Genome Sciences, near Washington DC, with SmithKline-Beecham - a deal worth more than $100 million.
These big companies are, of course, competing intensely with each other to discover new drugs and therapies for some of mankind's most common ailments, such as heart disease and cancer. But they do have one thing in common - a growing realization that the next generation of drugs will feature a growing number of products derived from genes identified through the genome project. We can expect important genes for obesity, asthma and probably mental illnesses such as schizophrenia to be found in the next few months and years.
The financial stakes are truly incredible, as illustrated by the following example: Amgen, the most successful and profitable biotechnology company in the United States, has paid The Rockefeller University and Dr Friedman $20 million for the rights to license the obese gene, and promised four times that amount if various research targets and incentives are met in the next few years. The size of this award has shocked many observers, who think that the obese gene may not result in human therapeutics, and that other obesity genes in mice might prove to be more effective.
The Patent Issue
With hundreds of millions of dollars being invested in new companies and licensing fees, and with billions more potentially at stake, researchers in industry and academia are desperate to protect the fruits of their investment, by seeking patent protection on the genes they work so hard to discover. The purpose of patenting is to encourage disclosure of inventions by allowing inventors to enjoy a monopoly on the use of that research for a limited time in return for publication of that invention. Such inventions can include acts of nature, and in the United States and Japan, that can include genes. Some people object to the patenting of DNA on religious, moral and ethical grounds, saying that it reduces human beings to some sort of biological machine. Others counter by saying that a gene could not produce life except in the context of a living organism.
In the United States, the right of researchers to patent genes as "inventions" is widely appreciated and there is not much controversy (at least from the business community). The main requirements are that the invention be "novel", not obvious to a person trained in the appropriate technology, and of "utility" (in the US).
Take BRCA1, for example. Few people in the United States, at least, denied Mark Skolnick and colleagues the right to seek a patent on the hereditary breast cancer gene. Skolnick's company duly filed for a patent before the results were published last October. There was a complication, however. Among Skolnick's senior collaborators were members of a group from the US government's National Institute of Environmental Health Sciences (NIEHS), in North Carolina. This small group had been isolating small fragments of genes in the area of chromosome 17 known to contain the BRCA1 gene. The first fragment of what eventually turned out to be BRCA1 was identified in this government laboratory using a technique called 'hybrid selection', which Dr Roger Wiseman, the leader of this group, has called "The closest thing to magic I have ever seen!"
Initially, Skolnick and his Myriad advisors did not want Dr Wiseman, or his colleague Dr Andy Futreal, to be included on the BRCA1 patent, on the grounds that the presence of government scientists on the application would enable the NIH to control the way in which BRCA1 might be used in screening tests, and so on. Naturally, the NIH saw it differently, and decided to submit their own patent application, on behalf of their scientists. The Director of the NIH, Harold Varmus, said "We have taken all necessary measures to ensure that [our] contribution is recognized and to maximize the public benefit."
In the months that followed, the two sides argued about the precise make-up of the application: The Myriad team believed that the NIH scientists had played an important role in the discovery of BRCA1, but that it was not sufficient to be classified as a 'unique' contribution. The NIH countered by pointing out that Skolnick had received millions of dollars in funding from the government, including the National Cancer Institute. In February this year, both sides finally agreed that Wiseman and Futreal did indeed qualify as 'legal inventors' of the gene, and that their names should be present on the patent application.
As discussed in a book that Michael White and I have just had published in the United Kingdom, entitled "BREAKTHROUGH: The quest to isolate the gene for hereditary breast cancer" (Macmillan, 1995), should the patent be awarded, it would guarantee a 17-year monopoly on the sale of BRCA1-based diagnostic tests and new therapies derived from the gene. There have been some dissenting voices, however. Fran Visco is a well-known breast cancer survivor and advocate in Washington DC. She says "Women gave their blood for this research ... I know many of these women, and they didn't give blood so some company could make millions of dollars."
However, Skolnick, Varmus and most scientists involved in the work think it only fair that Myriad's investment should be rewarded by patent protection. Skolnick said that he would not mind if the government scientists were eventually included in the application, so long as the application went ahead and was successful. Skolnick offers two examples of why patent protection is so important for cases such as BRCA1. First, he points out that penicillin was not patented, so drug companies would not work on it. The US government had to create certain incentives in order to persuade industry to do more research on the antibiotic.
The other example Skolnick gives is that of cystic fibrosis, which is a fatal and very common lung disease affecting about 1 in 2,000 newborns of European decent. Skolnick believes that it would have been more cost effective to have one licensee to enable it to acquire enough money to invest into developing a screening kit. "Consequently," he says, "there is no CF kit because nobody has incentive to spend $30 million to put a kit through the Food and Drug Administration if they know that without patent protection ... others can go in afterward and have a similar kit approved without the associated cost."
Views in Europe towards patenting specific genes like BRCA1 are much more suspicious, however. Here are the views of two prominent British cancer researchers: Dr Michael Stratton, who led the effort to localize BRCA2, says "We do not believe pieces of the human genome are inventions: we feel it is a form of colonization to patent them. I don't think it is appropriate for [BRCA1] to be owned by a commercial company ... because there is inevitably a demand for profit." Dr Bruce Ponder, one of Britain's most respected cancer researchers, argues that "Myriad Genetics could end up in a monopoly position. This could make the [BRCA1 screening] test more expensive than is necessary."
It will probably take a few years before these issues are resolved. There are two major uncertainties that have to be resolved. First, there is no current technology that allows for simple screening of BRCA1, because of the quantity and diversity of mutations that have been discovered. The problem is similar for cystic fibrosis, where there are more than 500 different mutations, and even the best test offered by a company such as Integrated Genetics in Massachusetts, can only detect a mutation 90-95% of the time. This is paving the way for other companies, like Affymetrix in California, to research novel screening methods using new and untried technologies. The other factor yet to be fully resolved is the role of BRCA1 in combination with other genetic factors, such as BRCA2 and ataxia telangiectasia. BRCA1 appears to play only a small role in sporadic ovarian cancers, suggesting that other unknown genes will be of greater importance in screening for breast cancer in the general population.
Who Owns the Genome?
The question of patenting individual genes almost pales into insignificance when compared with the much larger question of patenting huge chunks of the human genome. But that has been a major issue over the past few years thanks to the pioneering work of several groups, most notably Dr Craig Venter's team at The Institute for Genomic Research (TIGR) in the United States, who have been characterizing fragments of expressed genes, or cDNAs, known as "Expressed Sequence Tags" (ESTs). Dr Venter, a former researcher at the NIH, had decided to sequence random cDNAs from brain and other human tissues, as a more rapid and effective means of characterizing important human genes. Dr Venter had spent years of his life, and millions of grant dollars, trying to clone specific neurotransmitter receptors. There had to be a better way, he thought.
While at the NIH, Dr Venter's group sequenced a few thousand genes, isolating many new ones in the process. When he realized the potential of this approach, and that he was not likely to receive the necessary support at the NIH to let him realize his dreams, Venter founded TIGR, a not-for-profit institute with a $70 million, ten-year grant from Human Genome Sciences (HGS). With more than 30 automated DNA sequencers working constantly, Venter's team analyzed more than 100,000 gene sequences from some 200 different tissue libraries, generating more than 80 million bases of DNA sequence. The results of that work have just been published in a special supplement of Nature, called "The Genome Directory."
Although both the NIH, when Venter was a researcher there a few years ago, and the Medical Research Council in the UK, at first decided to seek patents on their collections of ESTs, these applications drew widespread criticism from the academic community, and skepticism from the legal establishment about their authenticity. They were subsequently withdrawn.
However, the release of this information to the academic community has been extremely slow. HGS and its chief, Bill Haseltine, argue that they must protect their investment. They have allowed investigators to screen their vast collections of gene sequences, but on condition that the rights to any genes identified belong to HGS. The power of these collections of genes is already evident. When Dr Bert Vogelstein, at Johns Hopkins University, sought to identify a gene for a rare form of colon cancer, he knew that the gene he was looking for probably resembled a known yeast gene involved in DNA repair. He was granted access to the HGS catalogue, and by looking for similarities between their human genes and other genes, detected what proved to be the first gene for hereditary non-polyposis colon cancer.
By contrast, Britain's Medical Research Council forbade its researchers to enter into collaborative agreements with HGS, and eventually reached an agreement with SmithKline Beecham to gain access to the TIGR databases. The MRC believes that sequence data should be unrestricted and in the public domain, although in that case, it would hardly make sense for a company to invest upwards of $100 million to generate the sequence in the first place, unless it expected some return on its investment.
Because of the criticism leveled at HGS and SmithKline Beecham, another large pharmaceutical company, Merck, announced that it would produce the "Merck Gene Index" - a rival compilation of ESTs that would be made freely available to the scientific community. Already, many thousands of gene sequences have been deposited by Merck into public databases. Although there have been suggestions that these data lack the quality control of other EST sources, the Merck initiative was warmly welcomed by the scientific community, and has certainly boosted the company's image.
Earlier this year, a panel of British Members of Parliament issued a report on "Human Genetics: The Science and its Consequences." The report acknowledged that patenting has an important role in the application of the results of genetic research. However, fragments of genes, or genes of no known function, should not be patentable. The panel recommended that only a combination of a gene and a known utility which is novel and not obvious should be patentable in the context of that utility. In other words, unless the function of a gene has been established, it would be unfair to reward the discoverer of the gene with a monopoly. Moreover, a combination of the same gene and a further novel utility should also be patentable. There was also concern that patent examiners were applying the criteria of novelty and utility too loosely. Indeed, many were shocked when earlier this year, the NIH won a very broad patent for a form of gene therapy called ex vivo gene therapy, in which cells from a patient are removed from the body, genetically modified and then replaced.
In conclusion, although rapid advances in science and technology can occasionally threaten to overturn the patenting system, most politicians, scientists and legal scholars believe that the current system, which has been around since the 17th century, has and will continue to serve society well. In the United States, which is not only the leader in biomedical research but which is increasingly seeing its more and more discoveries made in private companies and not the halls of academia, patent protection must exist in order to ensure that this massive investment continues and grows, and that mankind will benefit from the marvelous discoveries that are being made, and those that are still in store for us.