Whose Genome Project?

Journal: Bioethics 5 (1991), 183-211.
Author: Darryl R. J. Macer
The human genome project is a multinational project aimed at obtaining a detailed map and a complete DNA sequence of the human genome. It will have many scientific, medical, economic, ethical, legal and social implications. A fundamental question to answer before considering these is to ask whose genome project is it? We can answer this question from different perspectives, and this aids our thinking about the issues that arise from the project. We can think of who proposed the idea, who should fund the research, who should perform the research, whose genome is mapped and sequenced, who should own the data, who should benefit from the results, and who should make these decisions. We can also compare the answers to these ethical questions with what is occuring in practise.

By September 1990 we possessed the gene sequences of over 5,000 human genes, and the location of 1,900 genes to areas of specific chromosomes (1). The number is growing exponentially, but the total number of human genes is thought to be about 100,000. This compromises only 5-10% of the total DNA in the human genome. The rest of the DNA is of unknown function, and much is thought to be nonfunctional. The total sequence is about 2.8 billion linear bases on 23 chromosomes. The total length of human gene sequences known today is about 40 million base pairs (2).

Who began the Genome Project?

The genome project is often compared to the Apollo project. The analogy highlights the glamour of the project, and may represent the importance of both projects to human pride. The genome project should have many more practical benefits, because not only will the genome project lead to the development of useful new technology, but unlike the Apollo project, the goal itself is also of immense direct practical use. The importance of the project initiation to reaching the goal is also different, people would not have gone to the moon if a positive decision had not been made, but the human genome map will be obtained, with or without a positive effort, though over a longer time scale if undirected. Mapping of the human genome has been progressing for decades (3). The beginnings of the genome project can be at least traced back to Mendel's genetics on peas, the mapping of the trait for colour blindness to the X-chromosome of Drosophila by T.H. Morgan and workers, to Avery and colleagues that found DNA was the physical substance of genes, to Crick, Franklin, Watson and Wilkins who determined the structure of DNA, to those who discovered the genetic code, to Sanger and others who developed DNA sequencing, and to many others who contributed to our knowledge of genetics and molecular biology. In this respect, no single group of persons can claim to have initiated the goals of the genome project.

There were several people in the USA who saw the goals of the genome project as ideal for initiating the first large scale biological research project with a definite endpoint (4). The Human Genome Project or Human Genome Initiative is the collective name for several projects begun in the late 1980's in several countries, following the USA Department of Energy (DOE) decision to create an ordered set of DNA segments from known chromosomal locations, to develop new computational methods for analyzing genetic map and DNA sequence data, and to develop new techniques and instruments for detecting and analyzing DNA (5). Whether the motive was to fill vacant DOE Laboratories; to provide renewed emphasis for science; or to put US biotechnology companies in a better international position (6), the idea itself was sure to catch the imagination of politicians. Some biologists commented that they do not think physicists can do good biology, so the project should not be left to the DOE, and because the NIH is the major funder of U.S. biomedical research, the NIH joined the project.

The goal of discovering the genetic makeup of ourselves, will remain one of the pinacles of human endeavor. We may pursue the exploration of space without limit, ever increasing, but once we have obtained the complete DNA sequence of ourselves we have in one sense reached a pinacle. It will in no way mean that we have come close to understanding ourselves, but we will understand one part of us. Understanding ourselves, one of the dreams, or nightmares, that many people share, will have come closer.

There have been numerous scientists who have contributed to our knowledge, and it will also be fitting that to complete this project will require the joint collaborate work of innumerous scientists, internationally. In the perspective of who initiated the project, who does the work, and whose knowledge is needed, the answer is clearly that many people are, and will be, directly responsible for the mapping and sequencing, and the later intepretation of the data.

Whose DNA is being sequenced?

The actual DNA that will be sequenced will be a composite of different human tissue cell lines, it will not be the DNA of a particular person, but of the species in general. Geneticists estimate that any two people are about 99% similar in their genetic makeup. To put it a different way, about 0.3-0.5% of the nucleotides in our DNA vary between different people. These differences vary from person to person, therefore it does not matter whose genome is actually sequenced (7). Different laboratories often use different human tissue culture cell lines, which are derived from different people. Therefore, the DNA sequences will be different. However, by the characterisation of standardised marker regions the DNA between different individuals will be able to be compared, and a single general map, and eventually sequence, produced (8). Most of the cell lines derived from patients are given for the benefit of research, and a large number of patients will have direct claims to parts of the final sequence. However, all people can say that the sequence is 99% similar to their own. The answer to the question whose genome is being sequenced, is everyone's genome. This is a key point for consideration of the project, it is of direct relevance to all human beings.

We can ask whose DNA should be sequenced? Should a DNA closest to those who are funding the project, or one closest to the most universal in the world be used. In practise, because the amount of individual variation in DNA sequence is greater than the inter-racial DNA differences, this is unimportant. The mapping and sequence information will be, on average, of similar use to all peoples. There are some impossible questions however, for example, if one nation decided that their DNA should not be sequenced, could they stop the sequencing? The same sequence is shared by others, who want to know. Which is the strongest claim, the right to know or the right not to know? This question has been avoided, and for practical purposes we can expect it to be ignored. This avoidance however, may be unethical, and those who command the project should ask the general population whether they want the sequence known or not, rather than just progressing in their belief that the sequence should be known.

While those who object to the sequence being known may be unable to prevent other people from characterising their own DNA, it is a different question whether those who do the sequencing have the right of control over the use of such information. In the United Nations Declaration of Human Rights, Article 27 there are two basic commitments that many countries in the world have agreed to observe (in their regional versions of this declaration). These are (italics added for emphasis) (1) Everyone has the right freely to participate in the cultural life of the community, to enjoy the arts and to share in scientific advancement and its benefits. (2) Everyone has the right to the protection of the moral and material interests resulting from any scientific, literary or artistic production of which he is the author (9). An important question arising from section (2) is whether all people are the author of information that is shared by all people? The writers of this declaration may not have considered DNA, but it would certainly be in the spirit of the Declaration to intepret the DNA sequence as something of shared ownership. On a more general note in section (1), everyone has the right to freely share in scientific advancement. This article expresses two important and relevant guiding statements of law that reflect a strong body of philosophical support from the principles of justice and beneficence, and from the idea of legal property rights. A further discussion of property rights is in a later section discussing data-sharing. The common claims for authorship of the genome should be considered in all aspects of the genome project, especially in the questions of who should make the decisions in the project and the use of data.

Who is funding the Genome Project?

Biomedical research is performed and funded in many countries. There are several reasons why research funding should be shared. The basic ethical reason is the principle of justice, that we should all contribute to shared knowledge that people can benefit from. People from every country will be able to benefit from the information, though to different degrees. Many people also believe that the pursuit of knowledge itself is a good, but this is not a ethical reason but a philosophical one, notably the currently popular philosophy of science. There is also the connection between basic research and the standard of University teaching, and if we consider education to be a basic moral good we can claim that to perform research has a positive effect on the teaching standard which may be a more significant benefit in small countries than the direct results of research. Another argument people give to promote research is that of national pride, that people want those of other countries to have a high opinion of their country.

There is another important reason given to justify research, that of economic profit. For many years science has not only been the individual pursuit of people with unusual ideas, but rather it involves the funding of research by public or private money, consisting of taxes, charities and business investments. We should not be surprised therefore to hear the justifications for the funding of the project in terms of the business opportunities. The US Congress was partly convinced of the usefulness of funding the project by the opportunity to boost US biotechnology.

The U.S. portion of the project (possibly 50% of the total) is estimated to cost US$3 billion over the next 15 years, to the intended completion date in 2005 A.D. The total cost is unknown because the project is being broadened to include other organisms as models, and many countries are contributing additional money to it. Data handling will be an important portion of the total. The 1991 government funding in the USA specifically for the human genome project (not including other indirect research on genetic mapping) is US$136 million (NIH $US90 million/DOE US$46 million) (10), and this figure is increasing. However, when one compares this with the cost of the development of a single drug, at US$ 50-100 million, or the annual U.S. health care expenditure of over US$ 500 billion, it is a small price to pay for such a large amount of information. It is a similar price to less than one week's costs for the recent Gulf war. Biotechnology is very big business, and the projected average US$200 million annually for the human genome project in the USA (11) is minor. The scientific methodology for sequencing DNA is routine, but the cost of US$3-5 for each nucleotide must be reduced by a tenth before the major sequencing effort. This should occur as automatic DNA sequencing methods are improved.

In the USA, James Watson leads the NIH Genome Center's initiative. The powerful advocacy of the project has obtained funding, but the style in which it has been done has resulted in some criticism (12). The initial fear of scientists was that the money would come from other biological research, which traditionally involves many small projects encouraging many individual scientists (13). Critics would prefer the project to stop after generating a general genetic map of the chromosomes, from which the DNA in which more interesting genes are located could be isolated and sequenced. Identifying a particular disease-causing gene can take several years of intense investigation, as seen in the tracing of the cystic fibrosis gene. A more detailed map would decrease the amount of DNA that must be searched through for each gene. Various leading scientists have called for an evaluation of the project priorities after the map is completed, to use the money in the best way to encourage research (14). In the initial phase some of the funds for the DOE and NIH projects came from exisiting research funding. The NIH is spending equivalent to 2-3% of its total budget on the genome project, which in view of the importance of a coordinated mapping project, is worth the cost (15). During 1990 the NIH announced the recipients of special genome research centre grants, which rather than creating new big institutions, will give accountability to expansions of existing research teams. They will be required to produce definite results, such as maps of the mouse genome, and maps of specific human chromosomes, and the sequence of the yeast genome (16). Since the original idea the project has expanded to include other organisms, and is even closer to what people would be doing anyway, except for the centralised planning and funding. The project now aims to understand how the human genome functions and its relationships with genomes of other organisms. In late 1990, the US DOE announced that it would first attempt to sequence all the expressed human genes (cDNA) before sequencing all the human DNA (17).

Given the potential direct medical benefits of the project, the research money that is being spent on this project, and possibly more, can be ethically justified from the principle of beneficence. From the ethical principle of justice, other countries who can afford to pay and will benefit should share the cost of the project. This is because all countries will benefit from the knowledge, and from the spirit of the declaration of human rights, article 27 (1), all people should benefit. There are multi-million dollar projects in Europe, Japan and Australia. The 1990 funding in Japan was the order of US$10 million, but is expanding. France is spending US$40 million in 1991, and US$50 million in 1992 (18). The U.K. government is providing 11 million pounds over the next three years, and has stated that it hopes this is enough to buy its stake in the use of the information. The reasons for other countries to join in the project is not entirely because of their recognition of the principle of justice, but includes more the elements of potential economic benefit, and the element of fear of being denied access to the USA-based databases. The answer to the question who should fund the project on a national level, within the international community, is that every country who can afford to pay, which is close to the current situation and trends. This is based on the assumption that all will benefit, which in practise will be more easily and rapidly assured if countries have contributed money and developed their genetic research capabilities over the course of the project.

Who should do the work?

The distance unit used in gene mapping is called a centi-Morgan (cM), and one cM is equivalent to two markers being separated from each other in chromosome crossing over in normal reproduction 1% of the time. The actual physical length of 1cM varies, being approximately 1 million base pairs. The use of restriction fragment linkage patterns (RFLPs) in combination with genetic linkage analysis allowed the construction of linkage maps for each chromosome with an average spacing of 10-15cM (19). Other techniques are being developed to give finer resolution such as radiation hybrid mapping, and the current map has an average of about 6 cM spacing. Different researchers have published maps of the same chromosomes using different markers, so that a combined total map is impossible to draw. The initial target is to construct a linkage map with an average spacing of 2cM, and maximum gaps of 5cM. Some chromosomes are already covered by markers at 1-5cM intervals (20).

The current mapping paradigm is based on a proposal in 1989 to use physical sequence-tagged sites (STS) as the map labels (21). Different researchers use different cloning vectors for gene analysis, so the exchange of DNA pieces in these different vectors, or DNA clones, is not possible. What is possible using the DNA polymerase chain reaction (PCR) is to generate DNA sequences for any DNA if short sequences are known, from which primers for the PCR can be made. Therefore, the ends of large DNA fragments should be sequenced, and the data combined to make a STS map of each chromosome. This approach means that researchers can continue to use different methods, and develop better procedures, while the information obtained can be integrated to progress the actual physical map. This will avoid the need to exchange different clones of DNA between laboratories, because each laboratory can use the marker sequence as a starting point (22).

In two major U.S. Reports on this project, one by the Office of Technology Assessment (5), and another by the National Research Council of the National Academy of Sciences (11), it was recommended that a map of the human genome be made prior to full scale sequencing. While mapping will benefit from improved methods, sequencing requires much improved and cheaper technology. A map is also essential to efficient sequencing so that a library of DNA fragments can be systematically sequenced. Different research groups have begun to concentrate on different chromosomes in order that they can all have the complete map in a shorter time. There are actually 24 chromosomes to be sequenced, 22 autosomes and the X and Y chromosomes. The five year goal of the NIH program is to construct a map with STS markers spaced at about 100,000 base pairs, and to assemble overlapping contiguous cloned sequences (called contigs) of about 2 million base pairs length. From this physical and informational library system, the sequencing can be started. For chromosomes 16, 19 and 21 the contig maps are over 60% complete (23). Data management technology must also improve, such as programmes to search the DNA sequence libraries, using advanced computing technology (24). Even such seemingly basic tasks as selecting the correct tube from the DNA clone library is being automated by robotics (25).

Using the STS approach allows small teams of researchers to contribute results. There are worldwide efforts, although the major international effort is centred around the USA, Europe and Japan. There are many people from Latin America who are involved in work, though they may still be lacking access to international DNA databanks (26). There are also projects in Australia, Canada, and there will be contributions from many other countries. Most countries fund research in their own country, so the question of who funds research and who performs the research are overlapping. Because of the acknowledged shortage of trained biologists it would be an advantage to the project to provide funds for use in the places where there are personnel but no funds, in any country. This would also aid the internationalisation of the project. However, until now most of the funds are distributed in accord with nationalistic boundaries. There are clearly some countries that lack sufficient funds in view of the more pressing economic problems, but support of UN or other internationally based research centres would aid the internationalisation of the project.

There does not need to be any repository of DNA pieces, what is required is a computer data bank of the sequence. The project requires the establishment and constant improvement of databases containing the sequences of genes, and their location. There are several international databases, and the information should be openly shared among them to make the best and most up-to-date database possible.

The question must be asked whether private companies should do the work. If we are only interested in the goal, the sequence, then it does not matter who does it. If a company can develop a cheap method of sequencing than it should be used, and some suggest that we use a free market approach to select out the cheapest approach for sequencing. Some of the mapping and sequencing could be performed by contract research. This has the advantage that more diverse but risky approaches may be tested than government funded laboratories are likely to pursue. Methods such as direct reading of the sequence by advanced microscopy are possible alternatives to current methods (27). We must address the data-sharing and ownership questions before answering this question.

Coordinated Data-Sharing is Required

The international mapping and sequencing is being coordinated by the Human Genome Organisation (HUGO). Coordination of the international effort is needed to avoid duplicity of effort which could slow overall progress. The European Commission is also coordinating research in Western Europe. There had been talk of giving different countries the tasks of sequencing different chromosomes to avoid duplication, however, such a system was considered impractical given the way scientists work. What may be possible is for different researchers to take responsibility for coordinating the maps for each chromosome. However, many researchers remain more interested in pursuing specific disease-causing genes. Therefore there are only a few chromosomes that are being extensively mapped at the moment, these include chromosomes 21, 7, and X. Other chromosomes, such as number 8, which have few known genetic diseases linked to it, are poorly known. In this way HUGO can play a very useful coordinating role, pointing out the number of existing projects on each chromosome to those who submit research proposals mapping such chromosomes. National medical research funding bodies can reject funding applications that are overlapping. To duplicate work is important for verification, but certain regions may have a dozen teams working for the same goal which is a waste of effort.

There are special needs for the information to be freely shared, though the director of the U.S. NIH genome project, Dr. James Watson, earlier threatened that countries that do not contribute funds may not get the information immediately (28). This remark was targetted at encouraging the Japanese Government to provide funds to HUGO. However, this has been widely criticised by those who believe the information resource belongs to no country, but to the world for its use in medicine. The idea of introducing secrecy would defeat the purposes of coordinating international efforts. The idea is that unless they contribute money, governments will lose control of the decisions about how to use the information. There are already some examples of US-based databases restricting access to outside. Chemical abstracts obtains data worldwide, but restricts full availability to certain US computers. The National Library of Medicine runs Medline and has taken over GENBANK (the DNA data bank) and PIR (the protein sequence database). During the Afghanistan conflict it denied access to Soviet users. In view of this, Europe is combining public and commercial databases to improve the European based EMBL DNA database (29). Recently the US moved the GENBANK database from Yale, which required completely free access for researchers, to Baltimore which may not, and some scientists are suspicious of the motives for this. The first round of threats has resulted in wider international funding, the real test will come with the actual results. The most rapid progress will be obtained if data is shared between all researchers. The full value of one part of the sequence is only known when compared to the rest. Even if one government declines to support such a project, the information still belongs to all people of that country and it is ethical for other countries to share it with them.

There is the already existing problem of data-sharing from the viewpoint of individual competing scientists. The new technology, for example automated DNA synthesisers and the PCR, makes replication of results very rapid, which could encourage researchers to delay publication while they get more of a head start in the next stage of the research. In a system where academic jobs depend on the number of publications everyone wants to get papers published. The self-interests must be considered for the sake of the researchers' autonomy and their future work. Researchers may not reply to letters requesting data, or just reply within a selected peer group. The U.S. DOE has drafted guidelines that stipulate that data and materials must be made publicly available within 6 months of generation, but their is considerable pressure among scientists that this should be lowered to 3 months maximum. The NIH is not in favour of rules, but encourages researchers to share information, to avoid bureaucracy. However, the results of discovering a disease-causing gene, or a detailed map which advances the discovery of such genes by many years must outweigh the short-term interests of individual scientists. A recent example of the collaboration is between the 30 research teams working on chromosome 21 (it contains the Down's syndrome and Alzheimer genes) (30). In this respect the genome map may be the ultimate collaborative research project. The most rapid progress will come from immediate data-sharing, and it is a chance for "scientific altruism" on a global scale. There is an ethical obligation on researchers, especially those using public money, to share data as soon as it is available. If the scientists cannot do this on their own initiative, which is by far the best option, than regulations need to be enforced. It will be possible to make all users of the database first submit their sequence before using the other sequences. Secrecy will undermine the enthusiasm of scientists to participate in the project if they think that other researchers will hide information. Perhaps, there is even a chance for scientists to restore confidence in the section of the population that has lost faith in science.

Who should own the results?

The question of who legally owns the data is very topical because some of the work will be funded by businesses. The question of patenting of genetic material is a potentially contentious issue. The U.S. Congress wants publicly funded science to be commercialised, and during the 1980's intellectual property rights were decentralised from government to research institutions to create commercial incentices (15). The usefulness of map and sequence databases will be determined by how much data they have. If privately run databases have more, or important information in them, which is withheld from public databases, researchers will need to use them.

The information arising from the human genome project could be classified in the category of biotechnology. There are two basic approaches to applying patent law to biotechnology inventions. In the USA, Australia, and many other countries, the normal patentibility criteria shall apply, that is, the invention has the attributes of novelty, non-obviousness, and utility, and the invention should be deposited in a recognised depository. While a country may accept the first type of criteria, some countries have specifically excluded certain types of invention. What is ethical is not the same as what is legal, though we can attempt to reduce the difference. Concerns over ethics have affected patent laws, for example European countries who joined the European Patent Convention have barred the patenting of plants or animals. Denmark has an even stronger worded exclusion in its national law. There is public rejection of the idea of patenting animals in some countries, and the patenting of human genetic material is potentially more contentious.

The public attitudes to the patenting of different types of things, including living organisms was measured in New Zealand in mid 1990. 90% of the public had heard of inventors being able to obtain a financial reward through patents or copyright. Those who had heard of patents or copyrights were asked if they agreed whether patents should be obtainable for different subject matter. 93% thought that the patenting of new inventions is acceptable, and 85% thought information could be patented, but there was less acceptance of patenting new plant or animal varieties, 71% and 60% respectively, and only 51% agreed with patenting of "genetic material extracted from plants and animals" (31). There was more acceptance of the patenting of genetic material among those who thought there were benefits to New Zealand from genetic engineering, and by farmers. There was less acceptance of patenting among the age group 15-24 years old and among scientists and high school science teachers (in separate surveys). The negative reaction reflects the general feeling that genetic material is special, and should be different to other types of information. If the question had been asked regarding the acceptance of patents on "genetic material extracted from humans" we can safely assume there would have been an even lower public agreement.

Some of the ethical arguments that are commonly expressed when talking about patenting of animals are also relevant to the question of the patentability of genetic material. The major arguments for patenting genetic material include;

* Patent law regulates inventiveness, not commercial uses of inventions
* Patenting promises useful consequences (e.g. new products/research)
* Other countries support patents, so our country needs to if the biotechnology industry is to compete
* If patenting is not permitted, useful information will become trade secrets
* Patenting rewards innovation
The arguments against patenting include;
* Metaphysical concerns about promoting a materialistic conception of life
* Patenting promotes inappropriate human control over information that is common heritage
* Some countries do not permit similar patents
* Patenting produces excessive burdens on medicine (increased costs to consumers, payment of royalties for succeeding generations)

Most of these issues will not be affected by permitting patents, as the issues are similar to those existing prior to the patenting debate (e.g. the distribution of wealth, international competitiveness) (32). This issue remains contentious and the fact that different countries have conflicting policy reflects this. The issue is closely related to the commercialisation of genetic engineering, but some sort of information protection is already accepted as an incentive to invest in research of benefit to society. Ethically, we can apply the principle of beneficence. Does commercialisation of the genome project give more benefits than a ban? The benefits should be in terms of general medical or agricultural development, rather than economic prosperity of one company or country over another. Until now there have been very few medical procedures that have been patented, despite their suitability. Only instruments and products used in diagnosis or treatment have been patented, actual procedures have been left open for all to use free of patent liability in accord with the principle of beneficience.

We can rephrase this question by asking do the ends justify the means? The end is the map or sequence, which is open to all. However, by pursing certain means of acheiving this end we may not obtain the same specific end. If we allow more privately funded research there may be more restrictions on the end information, in order to encourage private funding. If restrictions are applied to the general access to information than it is clear that we will have a different shortterm end when we use a shared ownership approach compared to that from a private market approach allowing private ownership. After the period of patent exclusion than the direct result is the same, i.e. the full sequence. The indirect results will be affected by factors such as whether during the period of patent exclusion certain companies have been well established and are able to provide beneficial services or monopolies, and the relative advantages of the open knowledge after patenting compared to industrial secrecy that could occur if patenting was difficult to obtain. More significantly, there may be a greater amount of total knowledge and a more rapid completion date using the approach involving private companies. The means by which these approaches are pursued differs. In one approach the government laboratories spend their resources on the project, at the expense of other projects, but with the cumulative results being openly available to all. In the other approach, the private companies do the research, which would create more total biomedical research knowledge, but certain parts of this would be tied up in patents, though the knowledge would also be available with a small delay.

Other arguments used to support patenting are not so compelling. The claim that the function of patents is to regulate inventiveness rather than to regulate commercial uses of inventions is minor in practice. There have been some recent controversies regarding the commercial monopoly held by the company which was able to patent AZT, the current HIV/AIDS treatment, which has been reaping large profits in view of its monopoly. It is all the more questionable whether this should be allowed because of the key roles that government funded research played in developing AZT and showing it was active against AIDS. There are other examples where the commercial monopolies obtained can not be said to be in the best public good, and the existence of patent laws is certainly relevant to the later commercial uses of inventions. Patenting is said to reward innovation, which is a basis of the successful modern democratic and Asian economic systems. They do recognise property rights in inventions. However, there is an existing difference in the protection of property rights compared with other rights in international law and declarations of human rights. Property rights are not absolutely protected in any society because of the principle of justice, for the sake of "public interest", "social need", and "public utility", societies can confiscate property (33). Therefore there is an existing precedent for exemption from property ownership, which is the point of the exclusiveness of patents, when some property is of great benefit to the public. As for the argument that we should support patents because other countries do, there are certainly many countries that have exemptions for patent protection (34). The exemption because of social need would apply if there would be more benefit from patent exclusion, which is not necessarily so. It depends on the way information is used. Therefore one answer to the question who should own the results of the genome project is no one in particular.

Using a more positive argument, the knowledge gained should be considered as the common property of humanity. There is an existing legal concept that things which are of international interest of such a scale should become the cultural property of all humanity. It can be argued that the genome, being common to all people, has shared ownership, is a shared asset, and therefore the maps and sequence should be open to all. Some of the common factors that derive from the shared ownership are that the utilisation must be peaceful, access should be equally open to all while respecting the rights of others, and the common welfare should be promoted (35). As discussed earlier there are existing legal principles from the Universal Declaration of Human Rights (9). The authorship of the genome can be answered in two ways. The DNA could be viewed as a random sequence of bases, and the author is the sequencer, but this is not what we would normally talk of as an author or inventor, rather the sequencers are discoverers. In the days of colonial rule a discoverer could claim a land as their property, but later it was recognised that the preexisting people had claims to the property no matter how it was developed by the colonisers. The sequencers of DNA are not sequencing un-owned land but rather they are sequencing un-characterised land, the name of mappers is rather suitable for this analogy. Some critics of ownership could go as far as to call those who seek to profit and to control the decisions concerning the human genome project without general consultation, a type of "genomic imperialist". The DNA is not random, it is merely unknown. This is an important difference, in addition to the common possession of the DNA sequence by every member of humanity, the sequencers are not authors. While it may also be unconventional to call the possesser of information the author, they have more claims to that title than the sequencers, in addition they can be called the owners (only in this general way the human sequencers are shared owners because they also possess DNA). The method for sequencing, or mapping, can be invented and patented, and whether that side of the project can be ethically patented lies more with the question of benefit and utility as discussed above.

If these arguments are insufficent to dissuade the private ownership of genome data, in addition to the precedents for exclusion of patents, public opinion could force a policy change regarding the patenting of such genetic material. It could be excluded as for animal and plant patents in Europe. In the broader context, in the USA the commercialisation of human cells and tissues is generally permissible unless it represents a strong offense to public sensitivity (36). The sale of the human genome map and sequence data may be a strong offence to many and incite adverse public reaction forcing legislators to exclude it from patenting. As education about the project and whose property it is grows, we may hope for the exclusion of major profit making from this project. The law should exist to benefit humanity. The debate will continue, as companies will naturally desire to obtain some information protection for their investment, but they will have to be sensitive to strong public feelings that could easily be aroused, which as argued, has an ethical backdrop. The idea that the human genome sequence should be public trust and therefore not subjected to copyright was also the conclusion of the U.S. National Research Council (11), and by the American Society of Human Genetics (37). The European Parliament "Human Genome Analysis" program limits contracting parties' commercial gains with the phrase "there shall be no right to exploit on an exclusive basis any property rights in respect of human DNA" (38). This idea would also include the option that the donor of genetic information, in terms of a cell line, should be able to make that information publicly available, which is usually a reasonable interpretation of the motives for patients to provide material for medical research, the motive to aid humanity in general rather than a commercial interest.

There are not just ethical problems with the patenting of genetic material, there are further legal issues. To qualify for a patent an invention must be novel, non-obvious and useful. If the claimed invention is the next, most logical step which is clear to workers in that field, than it cannot be inventive in the patent sense. If a protein sequence is known, than the DNA sequences that code for it will not in general be patentable, unless there is a sequence which is particularly advantageous, and there is no obvious reason to have selected this sequence from the other sequences that code for the protein (39). In the case of natural products there are often difficulties because many groups may have published progressive details of a molecule or sequence, so it may have lost its novelty and nonobviousness. These are essentially short pieces of the human genome. There are also patents on protein molecules which have medical uses. In this case the protein structure is patentable if it, or the useful activity, was novel when the patent was applied for. The invention must also be commercially useful. There are patents on short oligonucleotide probes used in genetic screening. If someone can demonstrate a use for a larger piece of DNA than they can theoretically obtain a patent on it. An example of a larger patentable section of genetic material would be a series of genetic markers spread at convenient locations along a chromosome (40). Another set of genetic markers on the same chromosome can be separately patented if they also meet those criteria. The direct use of products, such as therapeutic proteins, is well established. The information may also be used in the study of a particular disease, for example, by the introduction of a gene into an animal to make a model of a particular human disease, and it was for this reason "Oncomouse" was patented. The genetic information can also be used to cure a disease, for example using the technique of gene therapy with a specific gene vector.

With the completion of the genome sequence of many organisms, including humans, any new genetic material will no longer be novel as it will be available in a database. If researchers decided to apply for patents on every new protein sequence prior to making it public, they may also fail because of the lack of fulfilling the usefulness criteria. It is therefore likely that in the near future patents will be difficult to obtain on gene products, though it is expected that prior to the sequence determination there will be many applications for these different types of patent. The completion of the genome maps and sequences of many organisms will have many implications for the future of biotechnology patents.

There are private companies embarking on the project (41), and they may be able to patent ways of expressing the genome, or genetic maps, but not the genes themselves. The company Genome Cooperation has been created by Walter Gilbert, with the intention of selling databases that contain sequences of key segments of the genome (42). Companies may undertake contracts for research and development with respect to the technical aspects, but the final product, the sequence, should not be used for profit. Others will be able to obtain the same genes, however it may be cheaper to buy the genes off companies who have found them first, or to use commercially patented genome maps. Perhaps such companies could be rewarded with some funds to reimburse their costs, but it may end up being another case of commercial companies making profits out of human disease. In fact, one commonly voiced aim of the U.S. genome project is to promote the U.S. biotechnology industry, for example, they can sell genetic probes that are made from the gene sequences, and new technology. The political aim is to try to put the U.S. Biotechnology industry above that of other countries, especially Japan. We should shift our attention to the potential for uniting people, and consider it in the so-called "new spirit of international cooperation and understanding".

In answer to the ethical question of whether private companies should perform such research we can say yes, but not in order to make large profits, but they should be able to recover costs if they are still more economical than government research, providing the results of mapping and sequencing are openly accessible. In practise much of the project will be publicly funded, but contracts to do the work may be awarded to whoever is the most competitive. In France two private nonprofit groups (Centre d'Etude des Polymorphismes Humain and Genethon) are spending more money than the French Government on genome mapping, in pursuit of genes for humanitarian reasons, not economic. The role of nonprofit private organisations is also very important in biomedical research, leaving less room for economically motivated private companies.

Who benefits from the results?

There are major applications and implications of such work. It will be a huge resource of information for medicine in the next century (43). There will be much useful information arising prior to the completion of the project, as growing numbers of disease causing and susceptability genes are sequenced and the mutations characterised. Most of the major single gene disorders and some of the genes involved in complex diseases should be known within the decade (44). It will be possible to develop DNA probes to diagnose any known genetic disorder, and also will be easier to characterise new disorders. It will expand the number of human proteins that can be made by genetically-modified organisms, which would allow conventional symptomatic therapy for many more diseases, which could be supplemented by somatic cell gene therapy when appropriate. It would also expand our basic knowledge of human biology, which allows medical treatments to be developed. We may not be able to predict when therapies will emerge after the genes are discovered, because there can still be a long delay in clinical applications following biochemical understanding (45). It is obvious that within the next few decades medicine will undergo a major change, this is the beneficial side of the extra knowledge. The amount of new knowledge is hard for us to comprehend, it will take decades to process it all, but it offers the potential understanding of all genetic diseases sometime during the next century.

The time is right for much discussion regarding how we use the information. It is proposed that in the USA from 1991, town meetings may be held to inform the general public about the human genome initiative, and to solicit opinions on the ethical, social and legal issues that it raises (46). The human genome project has even found its way into French school books. It is essential for widespread education to be available in a way that the public can understand it, and they can be involved in decisions about their project. An adequately prepared lay community is the best way to ensure that misuse of genetics does not reoccur. There should also be education to show that despite all the information, we should not expect disease to be cured within twenty years, and it will not be a panacea for the world's woes. The relatively low cost of ethical and legal studies of the implications of the project compared to the biological research should encourage funding bodies to provide some funding (at least 1%) to ensure society is more prepared for the data (47). In the USA the NIH and DOE have awarded research funds for study of these issues, and have established a joint working group (48). 3% of the NIH and the DOE genome project's budgets is said to be for ethical, social and legal studies, and the preparation of educational material for the public. The European Commission emphasised more consideration of these issues before it will fund much scientific research (49).

The ethical debate must focus on how to use the new information, rather than on whether to discover it, if for no other reason than inevitability. It is pointless to bury our heads in the sand, as the knowledge will come. Most religious approaches support the rationale for obtaining better genetic information, which can be used to alleviate human suffering (50). The question is how to use it properly. There are dangers in any large scientific projects, that they take control of the people, in becoming the sole ideal for progress. We have seen this in the past with the Manhattan project, and the Apollo project. From the initial response to the human genome project, this is also happening here (51). The possibility of mastery and control over the human DNA raises the issue of genetic selection. Ideas of eugenics could be explored. We need to maintain a distinction between diagnosis and treatment of disease, and selection for desirability.

Most importantly we need to elevate the importance of individual autonomy, especially in reproduction. The human genome project raises similar ethical and legal issues to those in current genetic screening, such as confidentiality of the results. However, it will lead to screening on a huge scale, for many disease traits and susceptability to disease. It is important that we deal satisfactorily with the test cases, before we are faced with all these new information. The technology may change the way we think. The amount of information obtained will overwhelm existing genetics services, and geneticists. The ownership and control of genetic information, and the consent to use such information must be addressed. More training of genetics (as well as ethics) will be required for health care workers, scientists, and the general public (52).

The question of fairness in the use of genetic information with respect to insurance, employment, criminal law, adoptions, the educational system and other areas must be addressed. In those countries with private medical insurance, some people may be put into high risk or uninsurable groups because of genetic factors (for example, high blood cholesterol, or family history of diseases). Some insurance companies and employers perform screening in the USA (53). Some legislation has been passed in the USA, such as the Americans with Disabilities Act in 1990, or the proposed Human Genome Privacy Act, to be considered in spring 1991. However, there is only one solution, that is a national health insurance system with equal access to all. These developments are not only desirable, but inevitable, and the sooner governments realise this the less problems will have accumulated when the time comes to switch to nationalised health schemes. The injustice of private health care schemes will be accentuated. We must constantly focus on the question of whose project it is. The neglect of the principle of justice with regard to health care is bad enough, the neglect is even worse when we regard the common ownership of the information in human genome together with the shared taxes that continue to fund biomedical research.

The impact of the information on the individual is one perspective. From justice and the shared sequence, we can say that all people should benefit from the results of the genome project, but we must ask whether they will? In order to do this we must avoid stigmatisation or ostracism, and labelling in general, and look at the individual psychological responses. Some people hope that the knowledge that we are all equal in our genetic differences might end discrimination (38). However, this will require much education and laws to ensure the equality is respected. There will be a change in attitudes to ourselves also, and genetic determinism might become popular. A danger with simple-minded adherence to genetic hypotheses for behaviour is that it oversimplifies the complex interaction of genetics and environment. In the extreme, determinism eliminates the idea of genuine choice, leaving no room for the belief that we can create, or modify ourselves, or that we can make moral choices. The question whether higher human attributes are reducible to molecular sequences is a controversy in the philosophy of biology. The knowledge of human genetics will make scientific understanding of human life much more sophisticated. There may be alteration in social customs, especially if the genetic information is misunderstood by the public as occured at the beginning of this century.

We must examine how to ensure that all benefit from the results. In order to achieve this there will need to be control of the use of the results, not just the discovery of them. If we include the use of the results in the broad meaning of the "genome project", then it is appropriate to briefly discuss options on the use of results. In this perspective we need to predict the conditions, let us assume that the full gene sequence is available (probably within ten years). Let us also assume that technology has allowed the production of cheap and very simple, for example colorimetric, genetic screening testkits. Should these be available to the public, such as do-it-yourself pregnancy tests are today in the USA? There has to be serious concern about such an approach despite the common ownership claims that people can make to the sequence data. There will need to be more serious consideration given to personal reproductive decisions in the future, making life more complicated while hopefully improving its quality. While the people who can make decisions regarding the availability of such kits cannot claim to understand the social consequences of such a move, the general public also cannot understand the broader consequences of their combined individual actions. In this case there is a case for control of public property in order to avoid doing harm. While it may be possible to regulate the use of such kits via the intermediatory control, by the health care workers, there could be particular testkits which may not even be made because of the fear of misuse. A contemporary example of the regulation of a technique with the potential for abuse is the use of sex as a marker for muscular dystrophy genes; in Japan the fears of misuse of this test have meant that sex-linked gene selection is officially unavailable even for medical reasons. Some other countries allow the use of sex selection itself, and in most countries it is condemned but not illegal. There is a case for making it illegal but many physicians want to resist the imposition of laws in medicine. When a technique requires a specialised kit, as in genetic diagnosis for the general physician, the use of the selection can be controlled by production of the kits, though it will be stronger with the outlawing of the selection.

There does need to be control over the use of cosmetic screening and therapy (that has no compelling medical reason) that affects children. However, an important question in ethics and public policy is how will this control be effected? In the 1990 German Embryo Protection Law there is specific mention of Duchenne muscular dystrophy as a serious genetic disease that genetic screening (for preimplanatation diagnosis) can be performed for (54). There has been criticism of this approach because of possible increasing discrimination towards the handicapped who suffer from the legally designated "serious" diseases in which embryos suffering from such diseases can be discarded. It is certainly a sensitive issue, but some control will be required to prevent future abuses, and walking down the slippery slope to cosmetic screening. The production of a list of diseases is one question that needs to be sensitively investigated as a possible means of control. It may be better not to mention the disease in the law but have a list to be used by the regulatory committee. Life will get complicated, but that is the price of such powerful information and technology. It will be further complicated by combinations of various diseases which may be "judged" permissible for parental selection after genetic screening or for treatment using gene therapy. The extremes of a free market approach or a total ban on genetic testing are both strongly undesirable, but attention on the method of control must be made. The question of who decides the application of technology in individual cases must be addressed, whether individual genetic counsellors, codes of practise, legally established regulatory committees, parents, and whether it is freely available to all or only to those who can pay, or only to those judged to be at "significant" risk.

We could ask the question who will really benefit from the project? Will the next generation benefit from being genetically selected? We can ask current questions such as whether a life suffering from serious disease is better than no life? As is the case today, these questions need to be answered by individual parents, but they will become much more apparent with the number of conditions and ease of screening. It may be easier to try to answer the question whether the parents who use such screening on their gametes, embryos and fetuses will benefit from it? They do have benefits of avoiding problems of the extra time that they may need to spend with children, and the extra costs, but they also change themselves by using such screening, by making presumed health a condition of acceptance of children. It is also quite debatable whether the extra time parents spend with children and the potentially greater opportunity to give love, is time better spent than pursuing previous life goals such as time with other children or careers. When people debate these issues there are arguments on both sides, what society really does need is some harder data on the real effects. Rather than presuming outcomes based on incomplete psychological and sociological knowledge, there needs to be detailed study of the effects of genetic screening. While we should not be afraid for society to change, we should be wary of change when there may be adverse social attitude changes. There is a case for limiting the introduction of any population scale use of genetic screening until the effects of the current genetic screening policies are characterised. We will have much data over the course of the next decade, if people are prepared to fund research on this subject. Rather than speculating about the outcomes, there needs to be rigorous study of what data we have before embracing all that new technology can provide. Such study could followup cases where parents sought genetic counseling, and cases where they didn't, and also those who accept or reject selective abortion, for example. The major issues that philosophy can contribute is to say that we need to consider the autonomy of the parents who are all different people, the status of the fetus, and society should not enforce genetic screening. However, we need data to measure the effects on personal, family and social attitudes.

There is less experience with presymptomatic genetic testing of disease risk, such as for Huntington's disease. This is another area where the data needs to accumulate before we will be able to make reasonable predictions about the more widespread use of such testing. The other questions arising from the screening of children or adults for disease susceptability is somewhat easier to address. As mentioned above, from the principle of justice we should work against genetic discrimination, and establish national health schemes, and equal access to employment (except when there is an actual, current, risk of third party harm). There should be a right to privacy of genetic information. Some employment performance based testing can be used, when there is a reasonable and potential risk of harm, but not mandatory genetic tests. There needs to be guidance over the storage of genetic information for legal purposes, in immigration and in crime. There are already some committees which oversee police records with regard to protecting privacy, for example the Supervisory Board of Interpol's computer records (55). We know in general what is required, what is needed is translation of ideas into practise.

There are important questions about who has the right to know our individual genetic makeup? (56) Of course, our general genetic makeup will be common knowledge. It could be argued that because we all share in the information to be made public, we all have a say in the discovery and presentation of it. The sequence must be protected from abuse, it will be the most detailed common knowledge about every individual, and will provide many opportunities for abuse. Though it is not unique in this, for example, psychologists have understood common complicated features of the human mind for many years, and such knowledge is of similar risk to that being unravelled by geneticists.

In existing genetic services we recognise a right not to know our genes. Could this right be extended to general genome sequencing? We may have a right not to know that we will develop Huntington's disease, but what about the right not to know we are at high risk for schizoprenia, alcoholism, or a life in academia? Do we have a right not to know that the common human DNA sequence "programs" us to die at 85 years of age? The difference seems to be in features that distinguish us from the norm in our society, common knowledge such as general life expectancy are not hidden, though death may be a taboo topic in most countries. Are people still afraid of being different, even in the supposedly individualistic Western societies? This is another question that needs answering before we can work out appropriate means of regulation.

We do not know the effects of these different options, and research is required. Heathcare should be equally available to all people, and there should be more medical care given to those with greater medical need. Society does discriminate against the apparently "unusual" including handicapped persons, and laws have been enacted to attempt to lessen this discrimination. More laws will be required, but social attitude and education changes are necessary to change this behaviour. The words unusual, abnormal, disabled and handicapped can all have negative connotations, a more appropriate word may be required. In Japan, recent law has required that the words used in the media to describe a blind or deaf person cannot be "blind" or "deaf", but rather "people that have difficulty hearing, or seeing", so that if you listen to an old movie the former words are censored. While this is an attempt to address some of the discrimination that such words can carry, society requires more than word changes to end discrimination. Most people have a poor knowledge of genetics, which must be improved before they will be able to understand the new knowledge. Incomplete knowledge can be very dangerous when combined with exisiting discrimination, as seen with eugenic programmes earlier this century. We should all realise that we are genetically different, and normality is very culturally defined, perhaps as those who can live comfortably, or anonymously, in a given society? Education of social attitude together with science is required.

Universal laws, for example Article 23 of the International Covenant on Civil and Political Rights (57), states that "the right of men and women of marriagable age to marry and found a family shall be recognised", that has been signed by over 75 countries, and should guarantee that compulsory eugenics is not introduced. It is a very strong statement based on the ethical principle of respect for human autonomy. However, social pressues are very difficult to control. Such a law needs to be supported by equal access to social and health services in order to make it effective. In the same covenant there is also supposed recognition of equal access to healthcare, but what is required is wording such as "equal access to equal health care". This is one avenue that action could be taken from well accepted ethical principles, but education about technology and how to make decisions in an ethical way is also necessary.

For our generation or future generations?

Will society allow individuals to have free choice over the use of genetic manipulation and screening when there is no medical reason for it. Ironically such screening can be used both to reduce individual differences to others, and to highlight differences in ability. There are various arguments used against genetic intervention which has no therapeutic value. It would be a waste of resources, may present risks to offspring, it will promote a bad family attitude, will be harmful support of society's prejudices and may reduce social variability. It will probably not have any significant affect on genetic variability as there will be plenty of alternative healthy alleles. There could also be the idea of a natural genetic autonomy, that we should let the genes come together naturally, and let the individuals develop their genetic potential without unnecessary interference by parents or society.58 A criteria for transgenerational ethics is that not only must a gene alteration be safe, but it must be good therapeutic sense over many generations. There must be unquestionable objectives and benefits, for many generations.

A common feature of many issues raised by the human genome project data is that we need to consider the effects of knowledge and technology on future generations. We have a responsibility to future generations. The beneficiaries and those at risk may not yet be existing. In the sense of benefits and risks, it is their genome project more than ours. We have an obligation to the future from the principle of justice (59). Our traditional view of morality only involves short term consequences. Human action is seen as only having a small effective action range. Moral liability is limited by what is unenforcible. If another agent intervenes, or something unexpected happens, it is not considered our fault. Genetic engineering changes our moral horizon. For that we should be very grateful, as for too long we only examined short range effects (60).

The ethics of long range responsibility are needed. It implies that there is a moral imperative to obtain predictive knowledge and data about the wide-ranging possibilities of some action. Secondary consequences may be sufficient to prevent the primary action, even when the primary action may be good. This imposes a restraint on the use of technology. This is important in making public policy decisions, beyond the physicians concerns with each patient, or the scientists concerns with increasing knowledge of genetics. It means that researchers may be held accountable for secondary consequences of their research. Of course it may be very difficult to predict what will happen in the future, the social pressures and thinking are already very distinct between different countries. If social ideas change, then so may the pressures, such as the desire to use genetic enhancement. We need to ensure future generations retain the same power over their destiny as we do, while benefiting from the culture and technology we have developed.

International management of common knowledge

It would be unethical to withhold information that could provide medical therapy if released. The genetic information of the human being, belongs to all humanity, as previously discussed. It should be available to all at an affordable price, and without discrimination. The benefits that come from its discovery and use should show us how all humanity is one. We will see how the genetic constitution of all humans from all races is the same. We will see how all of us have mutations, no one is perfect in their genetic structure, or should we say perfectly normal. Decisions on the use of genetic manipulation in one country will affect other countries, because people move, change their countries. It is therefore imperative that the decisions about any future germline genetic manipulation, especially of humans, take into account people's opinions worldwide. This may be best handled by an international forum, which national committees should interact with. The coordination needed for the genome project may aid this process, but the developing countries need to be adequately represented, especially because they represent such a large proportion of the world's population.

The answer to the question "whose genome project?", is that it is everyone's. Because of that, the answer to the question who should make the decisions is also everyone. Practically this means that the legal representatives of the people of the world, and the representatives of the various viewpoints of people's of the world (these may be different) need to join together to make decisions. This is the ethical answer. What will happen in practice has so far differed from this approach, rather it has been assumed that who pays for the research can control the project, and it has been suggested that who pays for the research may also be able to control the information arising. There should be increasing awareness that the international nature of human DNA makes the decisions regarding it to be of international common interest. Even if people do not accept international ownership, they should be convinced by the "international interest" and "utility" argument that such information should be openly and equally available.

The international nature of the project and its universally applicable results, as discussed in this paper, make it a project of all humanity. It is essential to have international organisations such as HUGO and the UN bodies taking an active part in the work and considerations of the ethical, legal and social issues and solutions. Many countries are unable to significantly contribute material resources to the scientific project, but they share in the material that is being sequenced, their genes and must be involved in the project's benefits and decisions. By intensifying international coordination at this stage when we are shifting from asking questions to working out solutions, we will be better able to ensure that more people can benefit from the project. People in developing countries will also indirectly benefit from the technology, which will be applicable to many pathogenic diseases which are currently more important diseases in those countries than genetic diseases. There are fundamental ethical questions to be answered from an international perspective, which should certainly be broader than local groups such as the Ethical Committees within the USA, Denmark, France, or even the Council of Europe, rather organisations such as the International Association of Bioethics, and UN-bodies like the C.I.O.M.S., should attempt to develop international approaches to managing the way the project is performed and the results distributed and applied. From these ethical approaches the appropriate intepretations of international law should be applied, and if necessary new articles added. Society's interests not only should transcend propietary rights, but the special nature of the genome project and the claims that we can all make upon the genome should make the shared authorship and ownership legally compelling. Humanity does have a chance to build on the supposely improved international climate, in a very fitting way. We should take this appropriate opportunity to move beyond the influence of our "selfish genes" in our combined efforts to sequence them.


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59. John Rawls, A Theory of Justice (1971; 8th impression Oxford: Oxford University Press 1988).
60. pp. 308-313, 323-324, 345-347, note 52.

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