The genome project is a collective name for genetic mapping and sequencing efforts being pursued in various organisms by scientists around the world. These projects, such as the Human Genome Project, arose out of past decades of genetics research, and will result in knowledge of the complete genetic sequence of some bacteria, yeast, plants and animals, and human beings. The data generated is being shared by researchers around the world, but the quantity involved requires advanced genetic and computing technology.
The benefits of this grand project of molecular genetics include the rapid and economical identification of disease-related genes, and the expansion of genetic diagnosis and therapy. There will be numerous benefits for agriculture and industry. However, there are numerous ethical, legal and social impact (ELSI) issues magnified by the enormity of the project. These include privacy and genetic testing, genetic discrimination, eugenics, and genetic determinism issues. The potential economic rewards of utilisation of the gene sequences has led to questions about patenting of cDNA and other genetic data, which are still to be resolved. There has already been a shift in society during the course of this project to focus on the genetic causes of phenotype, and this trend could result in ethical abuses of the information, as well as a different view of humanity. We need to examine the role of molecular and cellular genetics in medicine and society, and educate people how to utilise genetic knowledge for the physical, mental and spiritual health of all people.
THE GENOME PROJECT
The genome project is an international project aimed at obtaining a detailed map and a complete DNA sequence of the genome of a variety organisms, including mycoplasma, the bacteria Escherichia coli, the yeast Saccharomyces cerevisiae, the roundworm Caenorhabditis elegans, the fruitfly Drosophila melanogaster, wheat, rice, the mouse and that of Homo sapiens. It is the Human Genome Project which has captured the public attention, and has been the image responsible for increased funding of genetics research since 1988-1990. It will have many scientific, medical, economic, ethical, legal and social implications. This commentary seeks to trace the historical background, progress, and foreseeable impact of the genome projects in both science and in society.
The number of human genes that have been sequenced is exponentially
growing, and it is impossible to keep a count on the progress.
The expected completion date of the project is around the year
2,000 A.D. and most gene sequences should be known by 1994. The
countries that are involved in the Human Genome Project at the
time of writing include Australia, Canada, The European Community
(especially France and the UK), Japan, Russia, South Korea and
the USA. Genetic analysis of a number of other organisms is
also well underway as part of the Genome Project, and the common
language of genetics and similarity of many genes means that molecular
and cellular genetics is being advanced by studies on all organisms.
ORIGINS OF THE GENOME PROJECT
There have been various accounts written of the origin of the Human Genome Project. The other Genome Projects arose in terminology at the same time or after the phrase "Human Genome Project" had been coined. However, all of these projects involve genetic mapping and sequencing which was underway long before the trendy phrase of "Genome Project" was used, and specific long term projects to entirely sequence some viruses, eucaryote organelle and bacterial genomes have been underway since the late 1970s.
Mapping of the human genome has been progressing for decades (Culliton, 1992). The beginnings of the genome project can be at least traced back to Mendel's genetic studies 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. Therefore, no single person can claim to have initiated the goals of the genome project; and the date of the origin is obscure.
The progress in genetics since the 1960s has been rapid, and by the 1980s the goal of mapping and sequencing the complete genome of particular organisms became a distant goal. The first organisms to have their DNA sequenced were viruses, then the complete mitochondrial DNA of some organisms was sequenced. Projects in Europe, Japan and North America began which were aimed at automating DNA sequencers in preparation for the project. In scientific conferences in the 1980s people discused the idea of a human genome project. In 1988 the Polymerase Chain Reaction (PCR) was devised, which increased the rapidity of DNA manipulation enormously (see chapter 4). By 1992 the project had resulted in physical genetic maps of human chromosomes 21 and Y, a refined complete genetic map of human DNA; and the complete sequence of a yeast chromosome.
The Genome Project has political dimensions as could be expected for any project requiring much funding, with the huge potential rewards for biotechnology industry from the sequencing and future application of genes to medicine and agriculture. The country putting forward the most money for the project is the USA, and some would say that the genome project as a specific image arose in the USA. 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 (Cantor, 1990). The Human Genome Project or Human Genome Initiative is the collective name for several projects begun in the late 1980s 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 (OTA, 1988). The DOE has had a long term interest in assessing the effects of radiation on human health, and sequencing the genome may allow detection of mutations in the DNA. 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 (Lewin, 1990), 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 National Institutes of Health (NIH) is the major funder of U.S. biomedical research, the NIH joined the project. The activities of the NIH and DOE have been coordinated for genome research since they signed a Memorandum of Understanding on October 1, 1988.
The genome project is often compared to the Apollo space project. The analogy shows the glamour of the project. 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 (Macer, 1991). The original time frame was fifteen years, which has since been considerably shortened.
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 interpretation of
The DNA that is being sequenced is a composite of different human tissue cell lines. 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. Different laboratories often use different human tissue culture cell lines, 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 sequence produced.
A detailed genetic map of the human genome is being refined prior to full scale sequencing. A map is essential to efficient sequencing so that a physical library of DNA fragments can be systematically sequenced. 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 (Mb) in humans.
The construction of any map requires markers. The markers of sequence are specific DNA sequences, and the longer the sequence the less copies there will be in any genome. A sequence of 20 nucleotides, for example, is generally unique in a genome. There are two types of maps, maps that are drawn in picture, and physical maps which include a physical collection of sequences of known order and location. Genome analysis involves both types. For short sequences, such as a few genes, convenient markers are the specific nucleotide sequences that are cut by restriction endonuclease enzymes. A sequence of DNA can be cut into smaller specific pieces by digestion with restriction enzymes, and the pattern from digestion with several different enzymes can be used to make a map of that sequence. The use of restriction fragment linkage patterns (RFLPs) in combination with genetic linkage analysis allowed the construction of linkage maps for each human chromosome with an average spacing of 10-15cM in 1987 (Doris-Keller et al., 1987).
The current mapping paradigm is based on a proposal in 1989 to use physical sequence-tagged sites (STS) as the map labels (Olsen et al., 1989). These sequences are longer than those utilised by restriction enzymes, and may be 100-1000 nucleotides long, so that a single tagged site in a genome can be defined by this short nucleotide sequence. 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 for each STS, 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. This approach was used to make a map of the human genome with an average spacing of 5cM in 1992 (NIH/CEPH , 1992; Vaysseix and Lathrop, 1992; Weissenbach et al., 1992). This means that a gene associated with a disease may be linked to one marker, and the amount of DNA which needs to be examined is only about 5 Mb, rather than 15 Mb, as in 1987. As the map progresses, the average spacing will be decreased much more so that the length of sequence between markers will only be 0.1 Mb.
The initial approach was for different research groups to concentrate on different human chromosomes in order that they could 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. An initial goal is a map with STS markers spaced at about 100,000 base pairs, and the assembly of 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. Data management technology must also improve, such as programmes to search the DNA sequence libraries, using advanced computing technology (Watts, 1990).
Physical chromosome maps (overlapping cloned pieces of the complete chromosome) of two chromosomes, 21 (Chumakov et al., 1992), and Y (Foote et al., 1992)) were published in 1992. X-chromosome analysis is also advancing, and 40% was in physical cloned maps in 1992 (Mandel et al., 1992). High resolution physical maps of all chromosomes are expected by 1995. Overlapping pieces of DNA were cloned, and the tags on each piece allowed the pieces to be put into order. This means that once a disease-causing gene is localised to a particular region of the DNA, the appropriate clone can be taken from a freezer and sequenced.
Meanwhile, in 1992, researchers in France describe improved techniques which meant that a whole human genome approach, not individual chromosome approach, could be used to construct a physical library of contigs (Bellanne-Chantelot et al., 1992). A French project, Généthon, took the lead in genome mapping in 1992-3 because it was the world's largest gene mapping lab (Anderson, 1992a). They completed the first physical human genetic map in 1993, using automatic robotic analysis systems. The library of overlapping clones is basically completed using yeast artificial chromosomes (YACs). There are minor gaps where the DNA sequences are difficult to clone. Following its rapid progress the USA began setting up two large genome mapping centers, as the approach begun to be directed at the whole genome rather than just individual chromosomes.
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/Canada, Europe and Japan. There
are many people from Australia, and Latin America who are also
involved in work, via access to international DNA databanks.
There will be contributions from many other countries for particular
genome projects that have regional economic importance also, for
example, China has a rice genome project.
Smaller genomes are useful models for the human genome, and several organisms are models for the sequencing project. Although it is interesting to give the proportion of these sequences that have been sequenced, such figures are constantly increasing, and readers are referred to the pages of journals to read about the completion of sequencing efforts of model organisms. Many viral genomes have been completely sequenced, including the 200 kb cytomegalovirus genome.
By mid-1992 the EMBL databank contained 76% of the 5 Mb Escherichia coli genome sequence, compared to 27% of the 15 Mb S. cerevisiae (yeast) and 0.6% of the 3000 Mb human sequence. The complete sequence of chromosome 3 of yeast (which has 16 chromosomes) was the first chromosome to be completely sequenced (Oliver et al., 1992). It was sequenced by the combined efforts of 35 European laboratories, and was 315 kb of contiguous sequence. By the end of 1993 at least two more chromosomes will be completely sequenced, and many more will follow. It is expected to be the first eucaryote organism to have a fully sequenced genome.
The first multicellular organism that is expected to be fully sequenced is the roundworm Caenorhabditis elegans. This genome project is being undertaken at the MRC Laboratory of Molecular Biology in Cambridge, U.K., and at Washington State University, USA, with other international collaborators. It is being used as a model project as a prelude to the sequencing of the human genome. The total sequence is about 100 Mb. This worm is one of the best characterised animals in the world, with the complete pattern of cell divisions for the whole organism (959 nuclei) and the full connections of the 302 nerve cells known. The life cycle is 3.5 days, which makes it easy to study mutations. The work on the physical map began in the early 1980s, and the genome is arranged in less than 50 contigs (pieces of contiguous cloned DNA sequence) (Coulson et al., 1991). In 1992 about 1 Mb of sequence was produced, and this figure is likely to increase to about 5 Mb of sequence in 1993. The cost of sequencing per nucleotide has fallen to about US 50 cents, a tenth of the cost in 1988 when the genome project began.
The construction of a YAC contig library for the model plant organism, Arabidopsis thaliana, has been made. By 1994 about 2 Mb of sequence is expected, and all the cDNAs will be sequenced by the latest in 1997. Japan and China have rice genome projects, which are still at a mapping stage. Other crops such as wheat, soybean and corn are also being mapped, but their genomes are very large. Similarities in genome organisation aid the progress in all species.
Another model organism that has much historical significance to genetics is the fruitfly, Drosophila. The size of the D. melanogaster genome is estimated to be 165 Mb, with about 5-15,000 genes (Merriam et al., 1991). A physical cloned map has been completed, and the sequence may also be completed before the human sequence. Drosophila has been used in mutation studies of gene function for many decades, and because of a short generation time will continue to be a major research organism for genetics. The genetic sequencing will allow detailed genetic mutation studies at a nucleotide level, which allows studies of the affects of chemical mutagens and ionising radiation.
The mouse genome is the same size as that of humans, yet there
is also a mouse genome project because of the use of mice in genetics
research. Most of the mouse project is underway in the USA, and
a 1 cM resolution genetic map is expected by 1995. There is much
similarity between the mouse and human genomes, so the maps and
sequence markers share many similarities. Cattle breeders have
also begun a cow genome project, pig breeders a pig genome project,
and behavioural geneticists have begun a dog genome mapping project
to examine genes that are linked to the selected behavioural traits
of inbred dog strains.
For many purposes 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. However, the physical cloned genes may be more efficiently obtained from cloned libraries, and such cloned libraries are becoming available from both the public and private sector. For example, the YAC contig library made at Généthon has been copied for several laboratories and is intended to be openly available to all peoples.
The total sequencing project for a genome of 3000 Mb will take a lot of time, however, by sequencing cDNA, which is complementary DNA to mRNA, it is possible to quickly and cheaply sequence a large number of genes. cDNA represents the expressed genes of a tissue or organism that the mRNA was obtained from. Several different cDNA libraries are being robotically sequenced around the world, and the number of genes sequenced from these is so large that by the end of 1993 or 1994 most of the expressed genes in the human genome should have been sequenced. Short sequences of a few hundred nucleotides from a cDNA library are automatically sequenced, and these are called expressed sequence tags (ESTs). The sequences are tags because they can be used to identify a gene sequence, and as a probe from which the full gene can be cloned. Groups in several countries are pursuing this research approach, including a group in the NIH. Until 1992 a group at the NIH sequencing a human brain cDNA library was led by Dr. C. Venter, and patent applications on many of these sequences led to international controversy.
This work is also being pursued by companies. In 1992 the US$70 million Genomic Research Institute was founded in the USA, which is directed by Dr C. Venter (Anderson, 1992b). He estimates that during 1990-1992 at the NIH they identified 8,000 human genes. In April 1993 they reported that they are sequencing about 500 to 1,000 new gene sequences a day, and he estimates that the total in the genome is only 75,000 genes. The facility involves 50 robotic DNA sequencers, and compares to the French genetic mapping approach in its automation. The cost has fallen tremendously because of the large scale, and the cDNA sequencing may be completed by 1994. The representatives of the new institute say that they will not apply for broad patents, but intend only to apply for patents on a few key genes with suggested utility, and will publish results within 6 months of discovery.
The number of genes sequenced is growing exponentially, and estimates
of the total number of human genes range from 75,000 to 150,000.
This compromises only about 5% 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. As of October 1992, the
US-located international GenBank Genetic Sequence Database contained
100 million DNA nucleotides, increased from the 1991 data of 40
million nucleotides. A completion date of 1999-2001 for the
complete sequence is the forecast at the time of writing.
Biomedical research is performed and funded in many countries. 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. However, in France, much of the money for the genome project comes from charity, which has different implications for the way that the data will be shared, as will be discussed later.
The U.S. portion of the project (possibly 50% of the total) was initially estimated to cost US$3 billion over the next 15 years, to the intended completion date in 2005 A.D. However, new technology suggests the date will be the year 2,000, and the cost may be cheaper. The total cost is unknown because the project is being broadened to include other organisms as models, private companies are also spending money, and many countries are contributing additional money to it. Data handling will be another important portion of the total. The 1992 government funding in the USA specifically for the human genome project (not including other indirect research on genetic mapping) was US$164 million (NIH US$105 million/DOE US$59 million), and this figure is increasing. When one compares this with the cost of the development of a single drug, at US$ 50-100 million, or the annual U.S. health care expenditure of over US$ 600 billion, it is a small price to pay for such a large amount of information. Biotechnology is very big business, and the projected average US$200 million annually for the human genome project in the USA (National Research Council, 1988) is minor. The scientific methodology for sequencing DNA is routine, and the costs of US$1-5 for each nucleotide are continually being reduced before the major sequencing effort begins.
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. Critics would prefer the project to stop after generating a general genetic map of the chromosomes, and after the cDNA had been sequenced. Identifying a particular disease-causing gene can take several years of intense investigation, as seen in the tracing of the cystic fibrosis gene. It has been estimated that it cost about US$30 million to trace this gene, yet if a map had existed the cost may have been only US$200,000. A more detailed map decreases 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 (Leder, 1990). This also means that the first regions of the human genome to be sequenced will be ones that are known to have disease-associated genes present. In the initial phase some of the funds for the DOE and NIH projects came from existing 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 (Cook-Deegan, 1990).
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. The 1990 funding in Japan was the order of US$10 million, but is expanding. France spent about US$30 million in 1992, more than half from the charity the French muscular dystrophy association. The U.K. government provided £11 million over 1991-3, and has stated that it hopes this is enough to buy its stake in the use of the information. The Canadian genome research program may be about C$60 million over 5 years. 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 fear of being denied access to the USA-based databases.
The databases are being internationally funded. Japan gave US$600,000 to the Genome Data Base in Baltimore in 1992. This was still less than half of the European contribution, but a sign of the international cooperation. The site of a new European animal and human genome sequence database, the European Molecular Biology Laboratory (EMBL) European Bioinformatics Institute is Cambridge, U.K. Access to these databases, and the U.S. GenBank and EMBL Heidelberg gene sequence databases is possible from other countries. Japan also is host to an international genome database, in communication with these other databases, providing further access for scientists in many countries of the world.
In 1993 the US funding for the human genome project from government agencies was about US$170 million, with about US$80 million from industry. In 1992 eight genome-related companies were established, as the project became more commercial (Anderson, 1993). There are private companies embarking on the project (Kanigel, 1987). 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. Private companies should perform such research and 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 Généthon) are spending more money than
the French Government on genome mapping, in pursuit of genes for
humanitarian reasons, rather than economic ones. The role of
nonprofit private organisations is also very important in biomedical
research in other countries, leaving less room for economically
motivated private companies. Time magazine (8 February,
1993) has said that the French genome project is on higher moral
ground than the US project, because it is donating the results
to the United Nations and is not seeking gene patents.
DATA-SHARING AND PATENTING
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. The European Commission is also coordinating research in Western Europe, and UNESCO has interests in coordination of worldwide research. Although people recognise the importance of mapping, many researchers remain more interested in pursuing specific disease-causing genes. Therefore more attention has been paid to chromosomes 21, 7, and X, which have unknown disease-causing genes.
There are special needs for the information to be freely shared, though the former 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. This remark was aimed 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 first round of threats resulted in wider international funding.
A much stronger threat to data-sharing came following applications by the NIH for patents on cDNA sequences of several thousand genes, before their function was known. The US Patent Office rejected the first cDNA patent applications on all three grounds needed for patents: novelty, non-obviousness, and utility. They said that they could find some partial sequences in existing databases so the application lacked non-obviousness; and they also said it lacked novelty since they used a publicly available cDNA library (Roberts, 1992). However, lawyers suggest it may be possible to overcome the Patent Office objections. Several U.S. companies have also filed patent applications on cDNA fragments (Anderson, 1993), and one Japanese company has applied for patents on 60 partial sequences of full-length cDNA clones which have had their gene function inferred (Swinbanks, 1993).
A secretary of the British MRC has suggested that copyright law might provide researchers with a better way to protect commercial applications while avoiding any obstruction in data flow. But the MRC was not planning to pursue it. However, the UK MRC applied for patents in the UK in 1992 on 1,100 cDNA gene fragments. The ethical arguments against copyright would be similar to those against patenting that are described in the next section, basically the information is naturally occurring, and common property. Following this, the NIH attempted to apply for patents on a further 4,000 genes, but a US lawyer in the Department of Health and Human Sciences blocked the application. Varying points of view have been expressed by patent lawyers (Adler, 1992; Eisenberg, 1992, Kiley, 1992). If the issue is unresolved by 1994, the U.S. Congress may act on a study it has commissioned from the Office of Technology Assessment on the general topic of patenting gene fragments.
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. NIH and DOE guidelines stipulate that data and materials must be made publicly available within 6 months of generation, and earlier if possible. The guidelines are rules for those receiving grants from the NIH or DOE genome project, but encourage researchers to share information, to avoid bureaucracy. 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), who have already produced a physical contig
map (Chumakov et al., 1992). 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. However,
the financial size of the biotechnology industry that stems from
molecular genetics is large enough to have already affected the
way that data is shared. The net effect has probably been positive
to this time, because of the large share of genetics research
that is being performed in biotechnology and pharmaceutical companies.
ETHICS AND LAW OF PATENTING DNA
The question of who legally owns the data is very topical because some of the work is funded by businesses. The question of patenting of genetic material remains a contentious issue with some European researchers delaying data submission to U.K. or US databases following the U.K. and U.S. cDNA patent applications. Behind this is a pressure in many countries towards privatisation of research funding. The U.S. Congress wants publicly funded science to be commercialised, and during the 1980s intellectual property rights were decentralised from government to research institutions to create commercial incentives (Cook-Deegan, 1990).
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 (OTA, 1989). 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 (Macer, 1991). 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.
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 (Carey and Crawley, 1990). 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. 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 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, most genetic material will no longer be novel as it will be available in a database. The completion of the genome maps and sequences of many organisms will have many implications for the future of biotechnology patents.
The public attitudes to the patenting of human genetic material is rather negative (Macer, 1991, 1992a, 1992b). The negative reaction reflects the general feeling that genetic material is special, and should be different to other types of information. 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 (Sieghardt, 1985). 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.
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. All people can say that the sequence is 99% similar to their own. 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 (Sieghart, 1985). 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 interpret the DNA sequence as shared ownership. 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 the ethical principles of justice and beneficence, and the idea of legal property rights.
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 (Macer, 1991). 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 (Knoppers and Laberge, 1990).
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. 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. The DNA is not random, it is merely unknown. Only 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 insufficient to dissuade the private ownership of genome data, in addition to the precedents for exclusion of patents, public opinion could force a policy change over the patenting of such genetic material. In the USA the commercialisation of human cells and tissues is generally permissible unless it represents a strong offence to public sensitivity. 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 (Macer, 1991). 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 is the position of the French government, and was also the conclusion of the U.S. National Research Council (1989), and the American Society of Human Genetics (Short, 1988). 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" (European Parliament, 1989). 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. The European Parliament 1993 patent rule may allow "farmer's privilege", so that farmers pay royalties on a patented gene in a seed or livestock only once, not every time the gene is passed to a descendant. It will also forbid the patenting of cloned "human parts".
Some human genes and proteins that have medical use are patented, and this type of patent has brought about huge profits for some proteins. The annual market for the protein erythropoietin in the world is over US$500 million, and some similarly profitable proteins will be found in the future. Some awards are required for promotion of the biotechnology industry and medicine. However, many people object when a routine medical technique is withheld from people who cannot afford to pay for it. Disease-related genes will be sequenced by the project, and some patents may be issued on screening methods and genes. Patent fees are being requested on the cystic fibrosis gene, even though the patent is not yet awarded. For some researchers, such patent fees may discourage studies. European researchers are challenging these royalties, and we can expect this issue to be as controversial as the cDNA patents discussed above.
The scientist behind the data of the NIH cDNA patents, Dr. C. Venter has since signed a joint letter calling for an end to "patents of naturally occurring gene sequences" in favour of gene patents only on the uses of those patents, which was also approved by participants in the first South-North human genome conference held in Brazil in 1992. Venter left the NIH to begin a non-profit genome research institute, that is funded by a new company 'Human Genome Sciences Inc.' (Anderson, 1992b).
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 are major applications and implications of the genome project for much more than molecular and cellular genetics. It will be a huge resource of information for medicine in the next century. There will be much useful information arising prior to the completion of the project, as growing numbers of disease causing and susceptibility 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. It will be possible to develop DNA probes to diagnose any known genetic disorder (see chapter 13), and also will be easier to characterise new disorders. The list of diseases that have probes is growing (McKusick and Amberger, 1993).
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. 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 rest of this chapter outlines some examples of the benefits,
together with some of the impact of the genetic knowledge. There
are many ethical, legal and social impact (ELSI) issues that need
to be addressed, and some of these are also discussed. The genome
project is also proving to be important for research on these
ELSI issues because of the large level of funding being spent
on bioethics research compared to before the project began. A
combined total of over US$9 million a year was spent annually
for ELSI research on agricultural biotechnology and the HGP in
the USA alone in 1992 and 1993. Other governments are also spending
some proportion of their genome project research funding on ELSI
research and education (Macer, 1992d).
Every person has a different genetic sequence, except for identical twins. Genetic screening involves the use of the binding between the nucleotides A-T and G-C. A sample of DNA is taken from a cell, and then the DNA is split into single chains. The bases in this single-stranded DNA will bind to the complementary bases of a nucleotide probe. The presence or absence of particular DNA sequences that represent different genes or mutations can be screened for.
There are many types of genetic disease, some minor and others untreatable and fatal. One of the most common genetic diseases is inherited forms of cancer. Some genes that increase susceptibility to cancer have been shown to be very common in the population, for example, one inherited breast cancer gene will result in breast cancer in about one in 170 women (Roberts, 1993).
Prenatal genetic screening involves screening of the fetus, inside the mother's womb. There are several safe and commonly used methods to allow samples to be taken from the fetus (Macer, 1990). In addition to noninvasive ultrasound imaging, and the invasive sampling methods of amniocentesis and chorion villi sampling, new methods are being developed. One of the most promising is the sampling of fetal cells from the maternal bloodstream, which has already been practically performed. There are always some fetal cells that enter the mother's blood, and these cells can be separated. When the method is developed to a simpler procedure, this will allow convenient and safe genetic examination of the fetus by a simple blood sample from the mother (Roberts, 1991). We can also screen for genetic disease in embryos before they are transferred after in vitro fertilisation, but less than a hundred babies have been born after preimplantation diagnosis. This technique may only be applicable to a few people because it is expensive and has a low pregnancy rate.
Prenatal genetic screening of the fetus can be used to detect characteristics of the fetus, and should only be performed for serious diseases. These include diseases that would result in serious mental or physical health damage to the fetus. In most cases the fetus is found not to be afflicted, thus removing much anxiety from the parent's mind. Without the use of such tests to confirm the absence of disease, some mothers would have an abortion. In the case that the fetus is found to be afflicted from a disease there are two different possible courses of action. If there is a therapy available and treatment before birth is necessary to avoid health damage, the fetus can be treated for the detected disease. There have been increasing numbers of operations performed on fetuses in the womb (in utero), which have avoided permanent health damage to the fetus. Sometimes the fetus is removed from the womb, operated on, and then replaced to complete normal gestation. If the detected disease is untreatable, and is serious, then the option of selective abortion is available.
There is considerable variability in the abortion laws of different countries around the world, but in general selective abortion of fetuses suffering from a genetic disease is a respected moral choice of the mother. In many European countries routine prenatal diagnosis is offered under national health schemes to all women at high risk of having a fetus with genetic disease or chromosome abnormality. This includes all women older than about 35 years of age, and there is strong support from those women for the provision of these services to screen for serious diseases to all pregnant women.
There is clear public support for prenatal genetic screening in most countries that have been surveyed, and that it also should be available under government funding (Macer, 1992a). One of the most striking results of opinion surveys conducted in Japan is the similarity in the responses of different groups of people; the public, high school teachers, and scientists have very similar mixtures of opinions. This suggests that the results obtained may be close to the real opinion of the Japanese population, and that education does not play the dominant role in determining people's attitudes. In most industrialised countries about two thirds of the population supports prenatal genetic testing and one third does not, or is unsure of their attitude. Despite the support, we should only screen for treatable diseases, or to get a useful medical result for the individual.
We need to elevate the importance of individual autonomy, especially in reproduction. Technology will allow 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 many countries? 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 (Macer, 1990). 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.
There does need to be control over the use of cosmetic screening and therapy (that has no compelling medical reason), especially when it 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 preimplantation diagnosis) can be performed for. There has been criticism of this approach because of possible increased discrimination towards the handicapped who suffer from the legally designated "serious" diseases, for which embryos suffering from such diseases can be discarded. Life 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. 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.
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 susceptibility to disease (Holtzman, 1989; Muller-Hill, 1993). 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. More training of genetics (as well as ethics) will be required for health care workers, scientists, and the general public (Macer, 1990).
Presymptomatic genetic testing is important for some diseases
such as Huntington's disease and polycystic kidney disease, but
it should only be performed with extensive counseling. Huntington's
disease generally afflicts people in their 40's, and is very disturbing.
The disease-causing allele of the gene is dominant, and the children
have a 50% chance of inheriting it. The children, may be close
to marrying age when the parent first shows symptoms, and they
may desire testing before marriage, or testing of their fetus.
It is interesting to see that the level of acceptance is lower
than for genetic testing in general, suggesting that people do
recognise the complexity of knowing whether they will get sick
in the future, or die at a premature age. Such services should
be available, but only where adequate psychological counseling
can be ensured. These diseases are particularly difficult because
the people may experience 40 years of unaffected life (though
often they experience the disease in one of their parents). Should
they alter life plans if they have the gene? On the benefit side,
there is considerable personal relief for people who were at risk
if they learn they do not have the disease-causing allele. In
practice, only about half the people at risk have used the 95%
Huntington's disease genetic test.
PRIVACY AND DISCRIMINATION
The information about whether an individual has a particular DNA sequence and gene, can be very powerful, especially in the diagnosis of genetic disease. It is very important that privacy is respected, because the information in a person's genes identifies some of our risk to disease that medical insurance companies and employers could use to discriminate people (Holtzman, 1989; Macer, 1990; Muller-Hill, 1993). There are already cases of discrimination of individuals after genetic testing in North America (Billings et al., 1992).
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 susceptibility 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 important questions about who has the right to know our individual genetic makeup (Zimmerli, 1990). 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.
DNA sequences can be used to identify individuals, and have been used for forensic cases. When the DNA is specifically cut up by restriction enzymes and the pieces are separated unique patterns are made, called DNA fingerprints. They have been used for hundreds of court cases around the world. In several countries a genetic register of criminals has been established. DNA fingerprints are also used for immigration cases to prove genetic parenthood. There have been disputes about the probability of two individual's DNA fingerprints matching, and calculations have recently been revised, but there is still a low probability of such fingerprints matching (when the size of the fragments of DNA made after digestion with the restriction enzymes, are the same in two individuals).
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 (OTA, 1990). Some legislation has been passed in the USA, such as the Americans with Disabilities Act in 1990, or the proposed Human Genome Privacy Act. However, there is only one solution, that is a national health insurance system with equal access to all and no discrimination based on disease risk factors that people have no choice over.
Privacy is the key ethical issue to protect individuals, and
until we can guarantee privacy and no abuse of the information,
we should not establish genetic registers.
Our genetic information is very important in determining much of our physical character and intellectual capacity. This is especially clear in cases of people suffering from genetic disease. The effect that those people have on a family can be good or bad, some people can cope with it and some can not. Some of the suffering that such people have is the suffering that healthy people have in their own minds, as the handicapped people may not know life to be any different to what they have, that is, others can impose our life goals into their lives; however, some suffering can be real, especially when they suffer much pain all their life. The suffering of the family can also be very real, and preoccupying.
The word eugenics was coined by Sir Francis Galton, and is derived from the Greek word "eugenes" which means "well born" or "hereditarily endowed with noble qualities". Eugenics differs from other human activities in that it is an activity in which we are trying to change ourselves, not the environment or other creatures, and therefore is particularly challenging (Macer, 1990). The idea of some groups of human beings being inferior to others was often based on intelligence, or a method prescribed to define this. The rational was called superior to the animal, thus Aristotle claimed women and slaves were inferior by nature because of diminished reason and being closer to an animal state. The 18th century biologists claimed to prove that Negroes' skulls and physiognomy most clearly resembled those of apes thus justifying slavery. Superiority is often judged by how close people approach to someone's 'ideal' of intelligence and rationality.
Galton defined eugenics as the science of improving the "stock". Eugenics was defined by Galton as the study of agencies under social control that may improve or impair the racial qualities of future generations either physically or mentally. He intended eugenics to extend to any technique that might serve to increase the representation of those with "good genes", in this way accelerating evolution. A major motivation underneath many eugenicists was an idea of human progress, that we must be progressing genetically as well as in our knowledge. This was boosted by the theory of evolution, the survival of the fittest was equated with the survival of the best. The best were the best people to cope with modern life. Galton was a cousin of Charles Darwin. Social Darwinists' tended to equate a person's genetic fitness with their social position. Social Darwinist ideology provided a good climate for eugenic thought, and many qualities such as intelligence, temperament and behaviour were believed to be inherited (Kelves, 1985; Macer, 1990). The eugenicist's concept of the best human was their idea of the "perfect man", which tended to be an intelligent white male of northern European stock, who had been said to have a larger brain. Interestingly, the primary genome sequence used in the genome project will also be of European origin. Some eighteenth century philosophers had believed in the possibility of human perfectibility. There was also a fear that the "stock" was deteriorating. Some twentieth century philosophers and scientists may also share in the dream of perfectibility, but most would argue that the knowledge of genetic variation between individuals already shows that there is no such person ever possible to be called perfect, in all 100,000 genes and regulatory sequences!
A principle concern of the eugenicists was the lower fecundity of family "stocks" from wealthy, and more educated, families. As these people were from this type of family they had fears of their progeny being swamped by large numbers of progeny from uneducated, and thus genetically unfit, classes. These ideas were around before 1900, but people had been ignorant of the process of heredity. Chromosomes were known to be carriers of the genes only around 1900. This gave a rule for the transmission of traits, so instead of relying on ideas from animal breeders, they now had a biological theory. There were eugenic policies in about forty countries, many including sterilisation programs to stop the "unfit" breeding, and immigration policies to select desirable breeding stock into new countries such as the USA. They were particular prevalent in Northern European countries, such as Scandinavia and Germany, and were rejected in Britain, Holland and some central European countries. We can imagine what may result from the knowledge at the year 2,000, of all the genes, if there is a genetically deterministic model of life.
The individual's right to reproduce has been prevented in the past by compulsory sterilisation measures. Because of opposition there has been a growing move to voluntary measures, though these measured may be more enforced by peer group pressure to conform and by financial costs if the State does not provide medical care. If health care becomes centred on private medical insurance companies, there could be more pressure not to bring disabled children into the world, as the insurance companies could insist on prenatal screening.
The major use of eugenic selection occurred together with the move to a more scientific worldview. Recently developed scientific techniques offer more than sterilisation operations or artificial insemination by donor sperm; there is genetic screening to gene therapy in the immediate future. Eugenic measures often end up with racial or social group overtones, more then breeding from the "best genes". The model chosen depends on the society, for instance Spartans wanted good soldiers, geneticists from the middle-class want well-behaved middle-class, the Nazis wanted blonde, blue-eyed, Aryans, and the 1980s Singapore government wanted academically minded parents (Macer, 1990). We must have a clear view of human dignity founded in individuals possessing equal value not dependent on their ability or performance of some task.
For all of history people have preferred to have their children born free of genetic disease. With modern medicine many handicapped people lived much longer, to avoid the need to have these people born, genetic screening is developing. The actual number of people born with genetic disease has decreased in Europe, because of more intercultural marriages which have diluted harmful recessive alleles, and from prenatal screening programs and better nutrition for pregnant women. There will be less severely handicapped newborns if selective abortion is increasingly used, and eugenicists will have new methods. The name has also changed, from eugenics to genetic counseling; we must ensure the focus has also changed, from not just the interests of societies, but to protecting individuals.
The concern's of society are often placed above the rights of individual's when eugenics is developed, and this is the fear held by many today. Eugenic measures have been used in societies under different circumstances, and eugenicists have included both sides of political opinion. We must be aware of our modern medical practise in the light of eugenics and the associated attitudes. The opposition to eugenics may come from the concern for the rights of individuals, both those born, and fetuses; belief that we should not interfere very much with nature or God's purposes or chance; or that it conflicts with some political view, such as the earlier Russian Marxist view that all humans are given equal ability. The Christian opposition is based more on the view that all humans are given equal status or rights, which is not the same as ability.
This is not just to say that the new eugenics is all bad, in fact most people support some genetic counseling. The lesson from history may be that we must be very careful where we draw the line, and that it remains voluntary. There are some important areas of reproductive choice which should be left up to the individual or couples.
The definition of what is a healthy or meaningful life varies widely, and depends on the circumstances people have experienced. Population wide screening among Caucasian people for cystic fibrosis, with the aim of lowering the incidence of children born with this disease, is being considered in North America and Europe. However, in the USA, families whose members suffer from cystic fibrosis appear unwilling to personally use selective abortion (Wertz et al. 1991), though they support the right of others to use prenatal diagnosis and selective abortion. Nowadays the life expectancy of persons with cystic fibrosis is about 40 years of relatively normal life, questioning the "need" for selective abortion of fetuses with this disease. There is a fear, especially by handicapped people groups, that the use of prenatal diagnosis and selective abortion will worsen the discrimination against handicapped adults, therefore they oppose prenatal diagnosis being used at all (Wikler and Palmer, 1992).
However, we should remember that many people become handicapped by accidents or diseases after birth, and these will continue even if some people use selective abortion. The outlook for a handicapped person born in Japan, is like many countries, not always good. Some families are unable to emotionally or financially support a child suffering from serious disease, and these may be the major reasons given for selective abortion. In some opinion surveys some respondents have suggested that they would not support selective abortion if the social services in the country for care and education of afflicted children and families were better. Other families may find the opposite situation, that if they keep the fetus, the child that is born may become a blessing to the family in other ways.
We need to avoid abuses of such screening, for non-disease conditions,
such as sex selection, and for eugenic purposes, by some regulations.
An extra insurance against abuse is to improve social support
services for handicapped people, and to continue to educate people
away from discrimination that is based on any apparent difference.
Such education measures can change social attitudes towards the
"handicapped" (Macer, 1992a).
Many genetic diseases may be able to be treated by correcting the defective genes, by gene therapy. Gene therapy is a therapeutic technique in which a functioning gene is inserted into the somatic cells of a patient to correct an inborn genetic error or to provide a new function to the cell. There are a number of human gene therapy trials currently underway, for several different diseases including several cancers. There have been many human gene transfer or therapy trials approved by the Recombinant DNA Advisory Committee (RAC) in the USA, and also trials approved in China, France, Italy, The Netherlands, and the U.K (Macer, 1992c). It is still an experimental therapy, but if it is safe and effective, it may prove to be a better approach to therapy than many current therapies, because gene therapy cures the cause of the disease rather than merely treating the symptoms of a disease. Also, many diseases are still incurable by other means.
Currently such gene therapy is not inheritable, we need to have much wider discussion about the ethics and social impact before we start inheritable gene therapy (Macer, 1990). However, non inheritable gene therapy to treat patients involves similar issues to any other therapy, and if it is safer and more effective, it should be available to patient's who consent to it. There are many approaches being developed and we can expect rapid introduction of these techniques, because of more than 20 years of preparatory experiments on animals, and the success of some of the current clinical trials.
We can distinguish gene therapy from genetic engineering for
ethical debate, by the therapeutic motive. It is better to leave
the term human genetic engineering for genetic intervention which
is not aimed at direct therapy. However, we may still think of
cases where indirect medical benefit can be given, such as improvement
of the efficiency of the immune system by genetic means or genetic
vaccination. Cosmetic uses of medicine are commonly available
from the private medical sector, and it may be difficult to limit
the cosmetic use of gene therapy in the future when cheap vectors
and delivery systems have been developed. Public opinion supports
the use of gene therapy for treating disease (Macer, 1992a; 1992c).
There is increasing reference made to genetics in popular culture and the media, and a growing sense of genetic determinism and reductionism. Medical problems, both physical and mental are increasingly attributed to genetic causes. The environment also plays a necessary part in shaping the phenotype of an organism, yet genetic explanations are used even when only genetic susceptibilities are involved. We all will be shown to have some increased susceptibility compared to average for particular multigene conditions, such as cancer, or particular mental states. Therefore the difference between a 20% increased risk and the power of a dominant disease-causing gene needs to be emphasized. Additionally, 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. A critical paper by A. Lippman (1992) says that the emphasis placed on the genome project may have negative eugenic effects on society and health care. Genetic explanations are increasingly given as the major causes of disease, and the genome project reinforces this. This restricts the concepts of health and illness.
Most religious approaches support the rationale for obtaining better genetic information, which can be used to alleviate human suffering. 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. 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, while at the same time we need to discuss where molecular biology will take the human species.
All people should benefit from the results of the genome project, but will only do so if we avoid stigmatisation or ostracism. Some people hope that the knowledge that we are all equal in our genetic differences might end discrimination. However, this will require much education and laws to ensure such an 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 behavior 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 occurred at the beginning of this century.
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 schizophrenia, 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.
Genetic mapping of humans is being extended to all races of the world in efforts aimed to complement anthropological studies. This project is called the Human Genome Diversity Project, and is headed by Luca Cavalli Sforza. It involves taking samples from at least 25 unrelated individuals in 400 populations around the world, and analysing their DNA for about 100 loci. It will also mean the generation of numerous cell lines which could be used in future research. Genetic lineages can be drawn to trace the migration of people around the world. Such studies have a potential for racial discrimination if misused, but will answer questions that many scientists want to know. However, people of those tribes may not desire such an answer, and consent may not be asked, raising further ethical questions. The tracing of individual family lineages raises the question of privacy for those individuals, but the privacy issue has yet to be applied to such global studies.
The ability to analyse small quantities of DNA means that ancient DNA can be analysed to trace changes in the DNA that may give useful data about evolution of various species. The oldest DNA to be analysed to date is about 30 million years old, from insects preserved in amber. The technology is expected to be extended, and even within a time frame of a million years would provide valuable insights for molecular genetics. Although this will shed great light on our genetic origins, in recent history political and religious ideals have had a stronger effect on human behavior and history than genes.
The message for health care workers regarding genetic determinism
is more clinical. We must be clear that a pursuit for our lives
to be free of physical suffering is not going to make the ideal
world. Genetic defects have a smaller effect on people than the
moral, spiritual defects and lack of love. The goal of healing
is to benefit the patient - the actual patients are the "ends"
rather than the "means". In this case individuals are
more important than hypothetical individuals (ones as of yet unconceived),
or the human species in general. For example, using gene therapy
to improve the health for sick children is not going to trade
away a part of our humanity that is worth preserving. Love can
be shown in many other ways than through sympathy to people suffering
from genetic disease, and may be shown more by the cured patients.
But the highest type of love is unconditional love, which means
accepting all the people who are different from us in the world.
The act of love may involve genes, but more generally it will
involve social support, diet and a clean and peaceful environment.
As already discussed, there are numerous ELSI issues, and the resolution of these issues will take longer than the physical process of sequencing the human genome. Additionally, the relatively low cost of ethical and legal studies of the implications of the project compared to the biological research has encouraged some funding bodies to provide funding to ensure society is more prepared for the data (Annas and Elias, 1992). In the USA the NIH and DOE have awarded research funds for study of these issues, and have established a joint working group on ethical, legal and social impact (ELSI) issues. In the USA, 5% of the 1992 and 1993 NIH Human Genome Project budget was been allocated to research on ELSI issues and education. In Europe a similar proportion is being spent, and in Canada 7.5% is allocated to this. In Japan less than 1% of the human genome research grants are being spent on these issues (Macer, 1992d). In Europe, a funding program for Human Genome Project scientific research was developed only after establishing a system to allow research funding of the ELSI issues (MacKenzie, 1989). There are also ELSI studies in Australia.
Even with these ELSI studies, it is likely that the implementation of major genetic screening programs will be delayed for ethical reasons until people, both providers and consumers, are educated. Discussion regarding how we use the information has been occurring among the public in several countries, including North America, Europe and Japan. It is essential for widespread education to be available in a way that the public can understand it, so that 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. 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 existing 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, 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 pressures 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.
GENETICS: THE FOUNDATION OF MEDICINE?
Will the next generation benefit from being genetically selected? We can ask 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 increasing number of conditions that can be diagnosed and ease of screening, though the answers may not. 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. While we should not be afraid for society to change, we should be wary of change when adverse social attitude changes may occur. We need data to measure the effects on personal, family and social attitudes.
Will society allow individuals to have free choice over the use of genetic manipulation and screening when there is no medical reason for it? Screening can be used both to reduce individual differences to others, and to highlight differences. The arguments used against genetic intervention which has no therapeutic value include: 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 (Macer, 1990). 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. 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 (Rawls, 1971). Our traditional view of morality only involves short term consequences. The ethics of long range responsibility are needed. 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 (Macer, 1991).
Decisions on the use of genetic manipulation in one country will affect other countries, because people move, changing 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 international nature of the project and its universally applicable results make it a project of all humanity. 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. Society's interests not only should transcend proprietary 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 (Macer, 1991).
Increasingly health care workers will be forced to use genetic solutions to problems which involve genetic factors. For many conditions such genetic therapy represents a better alternative than other treatments, or early death. However, the simplest and most economical therapy for many conditions may be behavioral change in diet and exercise. Changes in lifestyle and diet have increased the incidence of some genetic diseases, including some types of diabetes, cancers, and heart disease. The genome project offers much to molecular genetics and medicine, but good medicine must be much more than this.
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