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Human Genome Project: Legal, Ethical and Social Implications
In this dissertation we consider the human genome project in its wider context. We take a brief overview of the aims, the working and the sequencing techniques used together with the timeline achieved.
The ability to sequence genes has given a greater understanding of the human genome. This understanding has thrown up a great many legal, social medical and ethical problems and dilemmas which clearly need tube both addressed and solved. This dissertation looks at many of the issues, analyses them, and considers some of the possible solutions.
We primarily consider the situation in the UK, but comparisons are drawn with the arguably more litigious society in the USA, particularly in consideration of the legal implications of the subject.
We make a consideration of the ethical position of researchers, medical professionals and also individuals whether they are considered as research subjects or simply as private citizens.
We draw conclusions from our findings and present them.
The Human Genome Project (HGP) was a vast and ambitious concept which was conceived in the 1980s and formally started in 1990, the main stated aim of which was to achieve the mapping of the entire human genome. It was originally anticipated that the process would take approximately 15 years and was therefore scheduled to be complete in2005/6 but the advances in technological hard and software improved sequencing ability to the extent that the entire undertaking was actually completed in 2003.
The project itself involved over 1,000 principal scientists in over 200Universities, Government laboratories and private facilities.
The stated and defined primary goals of the project were to:
• identify all the approximately 20,000-25,000 genes in human DNA,
• determine the sequences of the 3 billion chemical base pairs that make up human DNA,
• store this information in databases,
• improve tools for data analysis,
• transfer related technologies to the private sector, and
• address the ethical, legal, and social issues that may arise from the project.
(after Collins FS et al 1998),
Although the project was primarily about the sequencing of the human genome, part of the intrinsic preparatory work was carried out in the sequencing techniques of other organisms such as E Coli and Drosophila(the fruit fly)
Brief description of the genome
The genome of an organism is a term which relates to the sum total of the DNA of the organism. This is replicated in virtually every cell in the organism and it should be noted that it includes not only the nuclear DNA but the extra-nuclear DNA as well. It is the basic code for making all of the constituent proteins and thereby it is the ultimate determinant of the various processes that occur within the organism. The human genome has approximately 3 billion base pairs (abbreviated as A T G & C).
These are arranged in sequential style in the DNA double helix and are unique to an individual. There are large areas of repetition and large areas which appear to be “biologically silent” but we shall discuss this in rather greater detail later in this dissertation. (Nichols, E.K. 1998)
Sequencing techniques used
The eventual sequence derived in the human genome project does not represent anyone individual’s genome. The original samples were taken from multiple sperm and blood (from females) donations which were mixed and sent to labs across the world. The differences were comparatively insignificant as the vast majority (99.7+%) of the genomic sequence is identical in every individual.(Collins et al 2001)
Sperm is used, as the DNA : protein ratio is higher in sperm than for other cells and is therefore easier to prepare. It should be noted that sperm contains both the male and female sex chromosomes (X & Y) so equal numbers of each were added to the samples and the blood DNA was added to ensure that female derived DNA was also present.
The original sequencing techniques (in the 1990s) were primarily those of gel electrophoresis, which is slow, labour intensive and expensive. It was reported that the entire human genome project team managed to sequence 200Mb of gene in 1998. Advances in technology and automotive processing allowed one participant (DOE Joint genome institute) to sequence 1.5 billion bases in one month in January 2003. (Soga, Kakazuet al 2004)
It was the discovery and large-scale implementation of the capillary gel electrophoresis technique that was mainly responsible for these advances. One of the major advantages of the capillary tube method is that the comparatively larger surface area of the capillary tube allows for greater heat dissipation which was the rate limiting step for the older models as too much heat would melt the gel carrier. (Tsai et al.2004)
The actual mechanism for sequencing is extremely complex but in essence each chromosome, which comprises between 50 and 250 million base pairs, is fragmented into more manageable size pieces. (the sub cloning step).Each piece is then set up as a template from which a set of smaller fragments are generated, each one is a base pair shorter than the parent (the template preparation and sequencing reaction steps). (Marsha et al 2004)
The resulting fragments are separated by electrophoresis which is an ideal method because of their differing size (separation step). The end base of each fragment is then identified (base-calling step). Automated sequencers then can analyse the resulting patterns which will give representation of the base order which is then “reassembled” into blocks of about 500 bases each (for ease of handling the data) . Number of very sophisticated computer programmes then analyse the raw data for potential errors and can identify specific genes and silent areas (Krill P et al 2000)
Once sequenced, the final details are placed in the public domain such as Embank for open access to all.
We have made several references to the draft and final sequences. The explanation of the difference lies in the fact that there are both intrinsic errors in the processing and also in the variability of the genetic material used. The original draft sequence was published in June 2000. This was the result of each area being analysed at least 4-5times to minimise the errors. This original data was presented inspections of about 10,000 base pairs and the chromosomal locations of the genes were known at this stage.
A higher quality “final” reference sequence was published in April 2003which represented a 8-9 fold sequencing of every chromosome to fill in gaps and to minimise errors which were quoted as being no more than one in 10,000 bases (Kaiser et al 2004)
Human genome project timeline
1990 Official commencement of HGP work
Apr. 1998 HGP passes sequencing midpoint
March 1999 Target completion date for “Human genome Working Draft” accelerated to early 2000
Dec 1999 Human Chromosome 22 sequenced (first human chromosome ever sequenced)
May 2000 Human Chromosome 21 sequenced
March 2000 Drosophila genome completed
April 2000 Draft sequences of Human Chromosome 5, 16 & 19 completed
June 2000 Working draft of DNA sequence achieved
Dec 2001 Human Chromosome 20 sequenced
Dec 2002 Complete Mouse genome draft publication
Jan 2003 Human Chromosome 14 sequenced
June 2003 Human Chromosome Y sequenced
July 2003 Human Chromosome 7 sequenced
Oct 2003 Human Chromosome 6 sequenced
March 2004 Human Chromosome 13 & 19 sequenced
May 2004 Human Chromosome 9 & 10 sequenced
Sept 2004 Human Chromosome 5 sequenced
Oct 2004 Human gene count estimates changed from 20,000 to 25,000
Dec 2004 Human Chromosome 16 sequenced
March 2004 Human Chromosome X sequenced
April 2005 Human Chromosome 2 & 4 sequenced
The whole issue of patenting the genome and the offshoots of the project caused an enormous furore in medical, scientific and pharmaceutical circles. The opposing ends of the spectrum argued that, on the one hand, the benefits of such a fundamentally important piece of work should be freely available for the human race in general and the scientific community in particular, to the other who believed that the money to be made by the commercial exploitation of the genome could be used to finance other related projects. (Nuffield 2002)
The culmination of the argument was that the genome was fragmented and patented piecemeal. In order to fully understand the implications of this we must explore the workings of the patent system. In the UK, patents are issued by the Patent Office. Applications must be received within 18 months of the discovery (it is 3 years in the USA). Once granted, they remain in force for 20 years from the date of issue. In order to be considered suitable for a patent to be issued a product must generally satisfy four criteria, namely:
1) Useful – the patent application must be accompanied by some practical application of the invention (whether it has actually been applied or has been proposed in a purely theoretical sense)
2) Novel – it must be a new, or previously unknown entity.
3) Non-obvious –it must be a significant modification that is not simply a minor adjustment made by someone with appropriate skill and training in that particular area
4) Detailed – the item must be described in sufficient detail to allow person who has appropriate training in the field to use it for the purpose for which it was designed. This is often referred to as the “enablement criterion”
( after Cochran and Cox. 1997)
The academic argument referred to earlier was intensified by the knowledge that raw products of nature are not generally patentable. Special provision had to be made by the agencies on both sides of the Atlantic to allow for patents to be issued for genetic material.
The general guiding principal in issuing patents is that they are issued on a “first to invent” basis.
Where a specific application is not immediately obvious (as is the case with many pharmaceutical and bio-tech products), provisional patents can be applied for and enforced for up to one year after either discovery or publication of the findings. This is a mechanism to allow for the full implications of the finding to be worked out and patented.(Nickols F 2004)
In specific reference to our considerations here, we should note that with bio-tech discoveries in general and DNA patents in particular, coincident with the application for a patent, the applicant is required to deposit a sample of their discovery in any one of 26 designated biological culture repositories which are distributed throughout the world. (Bjorn tad DJ, et al. 2002)
It is a reflection of both the scale and importance of this work to appreciate that to date, there have been over 3 million separate genome-related applications for patents received on file throughout the world.
The legal ramifications of this process are huge. In the UK, USA and Japan (where the bulk of the applications for genome-related patents are filed) the system requires that the details of the applications are kept completely confidential until the full patent is finally issued. As we have discussed, this process can take up to a year. (Brown,2000)
The corollary of this fact is that those scientists and companies who utilise the data ( which is available on the Internet) to evaluate clinical or pharmaceutical applications of gene sequences risk the issuing of a future injunction if it transpires that those particular sequences have been the subject of a previous patent application which has subsequently turned out to be successful. (Morris AH 2002)
The 3 million genome related patents include the genes themselves, gene fragments, tests for specific genes, various proteins and stem cells.
To satisfy the Patent Office the four tests set out above are specifically modified to accommodate genetic material thus:
(1) identify novel genetic sequences,
(2) specify the sequence's product,
(3) specify how the product functions in nature --i.e., its use
(4) enable one skilled in the field to use the sequence for its stated purpose
(after Caulfield 2003)
Even this is not completely sufficient for the current needs of science. If we take the example of gene fragments. Their function is often not known although their structure almost invariably is. The practical applications can be extremely vague. A quoted utility of a gene fragment has been cited as “providing a scientific probe to help find another gene”. Clearly it could cause substantial practical difficulties if a patent were to be issued on such a basis, and the subsequent usage was found to be substantially different, it would not invalidate the patent.
The significance of this can be fully appreciated if we consider that the typical gene fragment, comprising about 500 bases (known as expressed sequence tags or ESTs) actually represent typically about20-30% of the active chromosomal genetic material, the full chromosome may be about 40-60 times larger than this. The active chromosomal genetic material is often referred to as canal and typically only contains its information-rich (or exon) regions. The scientific importance of these gene segments are that they represent very useful tools for research as they can duplicate the actions of genes, can be synthesised in the laboratory, and remove the need for scientists to manipulate the entire gene. (HUGO 2000)
It can therefore be clearly be appreciated that such gene fragments are very useful tools in genetic research and the granting of patents touch entities has sparked off another major controversy in the scientific community. There have been major representations to the various Patent Offices throughout the world not to grant such patents to these universally important entities to applicants who have neither determined the base sequence of the genes nor yet determined their function and possible uses.
As a result of this, the UK and USA Patent Offices decided to issue more stringent guidelines (effective as from 2001) which required that an application for patent of a gene fragment must now specifically state how the fragment functions before a patent can be issued. The wording is "specific and substantial utility that is credible," but is still considered by many to be too indeterminate. (Thompson 1992)
The basis behind the objections stem from the two main arguments already put forward. Firstly the patenting of such a “bottleneck or gatekeeper” product can seriously hinder the eventual development or even the characterisation of more complex molecules. Secondly, scientists are obviously wary of utilising such entities because of the possible financial constraints and penalties that would be imposed if the particular entity that they were using subsequently was found to bathe subject of a provisional (and therefore initially secret) patent application. In essence the patent of the gene fragment could be taken out after a comparatively small amount of scientific work and exert totally disproportionate control over the possible commercial and scientific development of more advanced genome research. (Schwarz D teal 1997),
There are also less obvious, but very practical, implications to this type of patenting. Let us consider the situation where patents have been separately applied for, and granted to gene fragments, the gene and various proteins that the gene expresses. Any scientist wishing to-do research in that area has not only to pay the various license holders for permission to use their patented entity, but there are also hidden costs in the research necessary to determine where (and whether)the patents have been granted. (Short ell SM et al 1998),
Not all research has been hampered or driven by the restrictive practices that the issuing of patents inevitably promotes. Let us consider the case of the Welcome Foundation who, in collaboration with ten other smaller pharmaceutical concerns, agreed to form a non-profitmaking consortium whose stated goal was to find and map out an initial300,000 common single nucleotide polymorphisms (SNPs).
To date they have discovered nearly 2 million. In a truly philanthropic gesture they generated a publicly available SNP map of the human genome in which they patented every SNP found solely for the purpose of preventing others from making financial profit from them and making the information available to the public domain.
The SNP is a single variation in the base sequence in the genome and they are found, on average, about one in every 500 base units. It can occur in an active or in a non-coding region. The effect will clearly vary depending upon the actual site of the variation but they are believed to be a fundamental cause of genetic variation which could give researchers important clues into the genetic basis of disease process or variations in responsiveness to pharmaceuticals. (Russell SJ1997)
In addition it is believed that SNPs are responsible for variations in the way that humans respond to a multitude of potential pathogens and toxins. The SNP is therefore an invaluable tool in the research behind multifactorial disease process where complex environmental and genetic interactions are responsible for the overall phenotypic expression of the clinical disease state. (Santis,G et al 1994).
We have referred in passing to the arguments that are currently raging relating to the issues on patenting genetic material. We should therefore consider the question of why patent at all? Would we be better off if the patent offices did not accept patents of genetic material?
On first examination of the situation one might think that scientific investigation, in general terms, might proceed faster if all scientists had unlimited and free access to all information in the public domain. More careful consideration suggests however, the laws relating to intellectual property are built on the assumption that unless ownership and commercial profits can be reasonably secure (by means such as patents) few organisations would be willing to make the substantial investment that is typically necessary for development and research.
The reasoning behind the mechanism of patenting intellectual property is therefore the marrying together of the need to secure a potential income from one’s work with the ability to allow the transparency of full publication of one’s discoveries which will therefore allow others to consider and utilise the information in their own research. (Berwick. 1996)
Consideration of this point will suggest that the only other effective means of safeguarding the costs of one’s research would be total secrecy which clearly would not be in the general interest of the scientific community. If we add to the general thrust of this argument, the fact that, in general terms, the costs of development(post-invention) far outweigh the costs of research (pre-invention) we can see the economic sense in allowing innovative research-based firms the financial security of development by preserving the profit incentives by means of the Patent. (DGP 2002)
In general terms we could view the patent mechanism as a positive development.(McGregor D 1965). Perhaps it is the breadth and number of the patents allowed in the field of genomic research that is the prime cause of unease in the scientific community.
The arguments presented above can be broadened further if one of the natural extensions of the human genome project is the research into the possibility of cloning. We will not consider the (currently totally illegal) possibility of human cloning per se, but the therapeutic embryo cloning for the purposes of harvesting human stem cells. Such cells have immense potential for the study and therapy of a great number of disease process. As such they have enormous value as both intellectual and commercial property.
The background to our discussion here includes consideration of the fact that courts in both the UK and the USA (Diamond v. Chakrabarty1980) have set precedents that single celled organisms (genetically modified bacteria) were intrinsically patentable. Legal argument then followed and shortly after there were similar rulings in favour of the patentability of simian stem cells.
It logically follows that human stem cells should be afforded the same legal protection. The problem arises then that such a move would offend other legal principles such as technical ownership of another human being.(PGA 2001) Clearly there are enormous, and some would say insurmountable, difficulties in this region. We present this point simply to illustrate the potential difficulties surrounding ownership of the human genome.
Broader legal issues
Matters relating to the legal implications arising from the human genome project already fill countless volumes and we do not propose to make an exhaustive examination of the subject. There are however, number of major issues that arise either directly or indirectly from this project. They are largely interlinked with major social and ethical considerations and society, as a whole, has looked to the law to provide authoritative answers to some of them. (Stripling R et al.1992)
One of the major problems associated with the potential ability to decipher the human genome is what to do with the information that it gives us. The ability to “read genes” brings with it the ability to discriminate with increasing degrees of subtlety. Discrimination is inevitably linked (historically, at least) with varying degrees of injustice.
Whether it is the more obvious forms of discrimination such as insurance loading on the basis of predisposition to disease traits or more insidious and pernicious scenarios such as the ability to discriminate by genetic association with various ethnic groups, the ability is there. Will it become acceptable to refuse a mortgage application on the grounds that a person has been found to have a genetic disposition towards gastric cancer? Could health insurance premiums be based on an interpretation of various aspects of one’s genome?
Some lawyers have already voiced their concerns about the ability of the law to provide genetic defences where it may be possible to challenge prosecutions on the ability to undermine the ethical principle of the validity of individual responsibility. The concept of free-will may be legally challenged in the prospect of discovery of various genetic traits that may predispose the individual to any one oaf number of behaviour patterns such as antisocial or thrill-seeking behaviour or violence. (Laurie G 2004)
We currently accept that some manifestations of the human genome are now routinely enshrined in virtually unchallengeable law. DNA identification in criminal law is commonplace and scarcely questioned. Paternity suits are settled on the basis of genetic make-up. It doesn’t take a quantum leap of intuition to appreciate that there may soon be potential negligence cases brought against physicians and the like who fail to warn patients against the possibility of developing the ever increasing number of disease processes that are thought to have a genetic predisposition or component.
The converse of that dilemma is should we expect physicians to suppress information found by genetic testing if there is no known cure? It follows that if we do not then people could be condemned to live with the knowledge that they are statistically likely to develop any one oaf number of diseases that they may very well, in other circumstances, have chosen to live in ignorance of. (Hyde, SC et al. 1993)
Such cases have already surfaced, unsurprisingly in the USA. The estate of a colonic cancer victim unsuccessfully tried to sue a physician who failed to warn him about a genetic predisposition to colonic cancer from which he subsequently died. (Safer v Estate of Peck 1996)
Some measures have been taken to try to protect exploitation of the genetic status of individuals where it is known. In the USA, some 16states have enacted laws to prevent both health and other insurance companies from using any form of genetic information to load premiums or to refuse cover.
The initial reaction to these moves was one of delight, but it soon became clear that this was only of any potential value when the individual was asymptomatic. There was no bar to premium levels once the symptoms became apparent. To some extent, although the same level of legal prohibition does not apply in the UK, there is little difference. In this country, insurance companies will still load premiums or refuse cover once symptoms are apparent. (Rothstein MR1999)
Social and medical considerations
As we have implied earlier in this piece, the fundamental nature and importance of the human genome project to humanity as a whole means that its impact has great implications for the fields of law, ethics and social considerations. This is hardly surprising as, at the most basic level, all these three considerations are inextricably linked.
Many of the social implications are also tied up with medical considerations and therefore we shall consider both of these elements together.
Humans, as a race, have about 3 million pairs of bases that determine their genetic identity. Interpersonal differences between individual humans however, are determined by only one tenth of one present of our collective DNA. These three million base pairs are ultimately responsible for the physical and perhaps behavioural diversity that we observe in our species. (Erickson 1993)
It is in the nature of inheritance that this variation has accumulated across the generations by small mutations or variations in the base sequences. These small differences are ultimately responsible for all human diversity including many overt disease process and predisposition or resistance to others.
It is clearly important where these mutations take place as some have no functional effect, others may confer some form of advantage or benefit (and thereby the motive factor behind the evolutionary processes) others may cause disease or even be incompatible with life.(Griesenbach U et al 2002),
It can be argued that all disease process have at least a genetic component. It can be completely due to a genetic malfunction such as the defect in the single gene for the cystic fibrosis transmembraneconductance regulator (CFTR) which results in an abnormal expression of one protein (the protein is still expressed, but due to one amino acid irregularity it folds in a different way) which results in the clinical situation of cystic fibrosis. (Piteous DJ et al 1997). Equally it may be due to a variation in the genetic code that modifies how the immune system responds to a particular pathogen (Yoshimura, K et al. 1992).
As we understand how our genome influences literally every aspect of our health we will inevitably discover more ways to combat and tackle the diseases of mankind. Before we move on to discuss overtly social and ethical considerations we should logically extend the appraisal and examination of the medical issues, as they have a pronounced bearing on these other areas.
With the advent of a greater understanding of the human genome and the cellular mechanisms of regulation and disease comes the prospect of gene therapy. On the one hand, the potential benefits for the sufferers of single gene mutation syndromes such as Tay Asch’s disease and Sickle Cell Anaemia are clear and undisputed, and yet the same technology has enormous social and ethical ramifications.
There are thought to be about 4,000 single gene defect syndromes known to medical science at present (Termite, S et al 1998). These are the prime targets for the gene therapy researchers There are also an enormous number of more complex, but still primarily genetically determined disease process, such as Alzheimer's Disease and schizophrenia, together with the commoner Diabetes Mellitus and hypertension variants which, although having a genetic component, are thought to be manifested after a period of interaction with environmental factors. It is quite possible that the techniques of gene therapy could ultimately be applied to these conditions as well.(Sikorski R et al 1998),
Social and medical benefits
The advent of understanding of gene function leads to other developments in the fields of both diagnostics and possibly preventative medicine. There is already considerable debate in pharmaceutical circles about the ability of researchers to utilise genetic information to make predictive assumptions about the ability of individuals to metabolise drugs. (Sailor R et al. 1998).One of the big problems with pharmacology is that, although a normal response to a particular drug can be predicted reasonably accurately, there are variations in genetic make-up which cause marked differences in threat of metabolism and excretion of some drugs. In many cases, these differences are of minor clinical importance, but in anaesthetic and cytotoxic drugs, the differences can be lethal. (Wriggle DJ 2004).
As extension of this thread of argument is that it is known that some malignancies will respond well to some cytotoxic agents while others will show no response at all. The point behind these comments is that there are considerable efforts in the pharmaceutical industry to identify the particular regions of the genome which are ultimately responsible for these differences. If they can be found it follows that they may either be capable of modification (by gene therapy or other mechanism) or their effect can be measured so that the dose (or even the type) of medication can be adjusted with far more confidence in the knowledge of the likely pharmacodynamics of that individual patient.(Spindle et al 2002). It is the ultimate hope and goal of these efforts that the pharmaceutical industry will ultimately be able to speed up the process of drug development, make the drugs faster and more effective while dramatically reducing the number of adverse drug reactions observed.
Social and medical difficulties
Gene tests are currently in the process of being developed as a direct result of the human genome project. Some are already commercially available. the social implications here are huge. Quite apart from the medical implications of being able to predict the likelihood of possibly developing certain disease processes, there are legal and social applications as well. Courts have been presented with the results of gene tests in cases as diverse as medical malpractice, privacy violations, criminal cases and even child custody battles.(Diamond. B. 2001)
The immediate difficulty in this area is, firstly that there is insufficient knowledge to be able to interpret the results of the gene tests with 100% accuracy. This, when combined with the knowledge that many of the conditions that currently can be tested for have no known or successful treatment, leads to enormous social and ethical dilemmas.
While it may be considered quite reasonable to tell a person that they are carrying a defective gene for cystic fibrosis ( as a carrier state, rather than a symptomatic individual) and thereby allow them to make positive decisions with regard to whether they choose to run the risk of passing that particular gene on to future generations. Is it reasonable to tell someone in their 20s that they are likely to develop Alzheimer’s Disease in their 60s? How will that knowledge impinge upon their approach to life? (Douglas C 2002)
Equally how will such knowledge affect the eventual application and acceptance of health insurance policies which are currently worked out on average risks rather than varying degrees of near certainty.
Employment status or even driving status could be determined on one’s genetic make up. If a gene test was available for schizophrenia and this was public knowledge, just how would this affect a person’s standing in society and perhaps more importantly, how would it affect their own management of their lives?
Sadly, the arguments do not just stop there. If one member of a family elects to take such a test, because the genetic information is shared within family units, there are direct implications for the other family members as well. Other members may have elected, for whatever reason, not to be tested. (Casey DK 1999)
For these, and other reasons, there are a number of authorities who are advising caution and careful regulation of research in this particular area We should consider the possibilities presented by gene therapy. If science now gives us the potential to isolate and identify specific anomalous genes in the genome, it is only a small philosophical step to consider ways of replacing defective genes. The difference between the philosophical and the practical in this instance is, in reality, huge. We will spend some time considering the issue as, with many of the other subjects that we have already presented, the initial optimism of positive humanitarian benefit is tinged with the possibility of far more serious issues.
Gene therapy involves exploiting the natural ability of viral (and in some cases non-viral) vectors to infiltrate their own nucleic acid codes into the host DNA. A number of different vectors and mechanisms are currently being explored and a number of trials (currently Phase I trials) are being undertaken. The most promising vectors found to date appear to be the adenoma-associated vectors which are attenuated adenoviruses which have had their own nucleic acid removed and synthetic working copies of the defective gene inserted. The vector is then transferred to the host and the DNA is incorporated into the genome of the host. (Olsen, J. C. 1998).
If, in disease process such as cystic fibrosis, the basic fault is the production of an abnormally folded protein. The new DNA can allow the expression of the normal protein which can help to ameliorate the disease process. The initial trials have proved disappointing but research continues. (Moss RB et al 2004)
The reason that we have included gene therapy in the section of social and medical difficulties is the recognition of the potential down sides to this form of therapy. We can illustrate this by citing a highly publicised case from April 2000. A young boy with a rare single gene defect disease (X-SCID) was apparently successfully treated in what the media hailed as a “major breakthrough in the field of gene therapy”(BBC 2002)
This particular disease process is thought to be caused by a mutation on the gene which codes for the C chain of the cytokine receptors which is situated on the X chromosome only and therefore only presents in boys, and is vital for the functional development of T Killer lymphocytes which are therefore completely absent in the condition. Retroviral vector was utilised to insert a fully functional copy of the gene into bone marrow stem cells which were then re-transfused back into the boy. (Cavazzana-Calvo M et al 2000).
It appeared to be spectacularly successful with the eventual emergence of T Killer lymphocytes into his peripheral blood stream. On the one hand, one might consider this a true breakthrough in the field of genetic engineering, but sadly it was eclipsed shortly afterwards byte news that, of the first ten patients treated in this particular way, two subsequently developed a leukaemia-like illness. Subsequent investigation suggested that the retroviral vector which had been utilised in the transport of the new gene had unexpectedly activated an oncogene LIM-only2 (Lehman S 1999)
This illustrates the fact that the technology is still only incompletely understood. The theoretical risk of insertional mutagenesis had long been recognised, but the practical reality has only just therefore been encountered. Reduction of the risk requires greater specificity of the targeting of the genetic deficit. This may be achieved by a number of different mechanisms that are currently being explored in clinical trials. One method under consideration currently is by directing the expression of the therapeutic genes to various specific tissues utilising both transduction and transcriptional targeting. Other methods being trailed are the use of on-viral vectors. (Reply K et al 2004)
There is considerable interest in the use of cationic lipids as vectors which appear to obviate the risk of insertion mutagenesis. One such lipid GL-67:DOPE (often referred to as lipid 67) is the current subject of clinical trials Zander (J et al 1997)
The major problems encountered in the field at present are the difficulties of producing a high vector titre in the clinical situation and the long term safety considerations, particularly those relating to this point relating to the mutagenesis of oncogenes. It is on this point the Flute research group are optimistic and feel able to make the comment:
The data from our laboratory strongly indicate that the bulk of ravine in the lung, muscle, and liver is episcopal and that rag genomes interact with host cell proteins such as the DNA-dependent protein kinase in the formation of stable high-molecular weight concatemers.
It is the episcopal (extra nuclear) situation of the gene that is currently thought to be the best insurance against inadvertent iatrogenic oncogenes is (Flute et al 2002) but this is clearly no substitute for long term careful and rigorous safety studies.
Other potential downsides that are direct spin-offs from this type of research are currently still theoretical but, in the knowledge of the speed of advancement in this area, may not be too far away in reality. If we accept that it may soon become commonplace to modify and manipulate defective genes in vivo, the same technology could be utilised to modify other features of the genome. Physical attributes such as height and weight have a large genetic component as do strength and stamina. Potentially even factors such as innate intelligence could be influenced by gene manipulation. (Sternberg RJ et al 2004)
While most would agree that the use of gene therapy techniques for reasons of saving lives or modifying disease states is a perfectly ethically acceptable and laudable end in itself, there is little doubt that the overwhelming majority would not be in favour of the latter eventualities. For the perspective of this essay, it clearly opens up enormous difficulties with consideration of ethical, safety and privacy issues. (Sugar man J & Summary 2001)
Let us consider the social implications of another area of genome research. Scientific history was made in 1998 when a conviction was obtained for a man, already dead, in respect of eight previously unsolved rapes in the Washington area of the USA. This was done without any corroborating forensic evidence other that the linking of his DANONE a national database to that found at the various crime scenes.
Clearly few would argue that the use of such technology in this way is anything other than beneficial to society as a whole. Equally one haste accept that even with our current knowledge, DNA has the ability to reveal a great deal more about both an individual and his family than simply a confirmation of their identity. (Halpern SD 2005)
One hears the arguments that databases could only be used for the purposes for which they were set up in defence of the identifications of crime suspects but, with the relentless pace of acceleration in the discovery of new technology who could confidently predict what the future may be able to uncover from specimens that are currently stored.
The potential social impact of such databases is huge. Critics of this type of argument point to the situation in the USA in the 1930s when databases, originally set up to help administer the, then newly set up, retirement programme became expanded to form the basis of a national identity and social security number system and also the use of census records to identify and round up Japanese-Americans prior to shipment to internment camps just after the outbreak of World War II. (HatamiyaLT 1994). It is difficult to have confidence in the current political safeguards that are given about the usage of database material in the light of such experiences. (Casey DK 1999)
Rather like the sections on social, legal and medical considerations, we must begin our consideration of the ethical dimension of this issue with the admission and realisation that there a very large overlap in these various areas.
Given our initial examination of the medical implications of the human genome project, it is perhaps rather appropriate that we begin our examination of the ethical dimension by quoting Hippocrates whose often cited dictum “First do no harm” is arguably central to our considerations here Carrick P 2000)
The first relevant principle of ethics that we must consider comes directly from Hippocrates’ dictum, the principle of Non-maleficence. Literally it means “no malice” it effectively means that, in order to have ethical integrity an action or process must be taken without malice as an intention, even if subsequent uses or interpretations materially affect its consideration. In its broadest medical and scientific interpretation it means that research or investigation should not be the cause of harm to an individual. The legal interpretation is somewhat different. (Kush & Singer 2001). To degree we have already addressed the point (above) but we shall return to it later.
The principle of Beneficence is similar but is commonly defined as the doing of good or the quality of goodness. This is also not quite straightforward as the interpretation of “good” or “goodness” is completely subjective and to a very large extent is dependant not only on the circumstances but also on the civilisation and the culture in which the discussions is taking place. In order to obtain ethical committee approval for research projects one is normally expected to be able to demonstrate both non-maleficence and beneficence before approval is given. (McMillian J 2005)
The third relevant principle here is that of Deontology. This is a rather more recipient directed principle and it requires that, if a person (doctor or researcher) is making decisions relating to another individual then their actions should be based solely on their perception of what is in the best interests of that individual. Another words, their decisions or advice should not be influenced by another considerations (such as profit or kudos etc.). (Tans T 2005)
The principle of autonomy is rather more difficult from an ethical point of view. Many decisions in life are made being influenced bothers. Certainly as far as genetic research is concerned the individual being investigated or treated should be in a position to make a completely autonomous decision with regard to his own wishes and that should clearly be a completely informed decision – as far as current knowledge allows.
Some commentators have added a theoretical confounding factor here and that is that if one accepts that one’s own personality (ego) is primarily genetically preordained at conception then agreement to submit to gene therapy or gene replacement has the potential to change subtle features of one’s personality in any event. (Gallon. R. 1997).
This goes against the original concept of John Stuart Mill who believed that everyone should be allowed to make up their own mind without external coercion from any outside source (Mill JS 1982). Clearly this is a fine point and certainly no more than a theoretical position at the present time and therefore we will not discuss it further.
The ethics of privacy
The one feature that runs through all of these dimensions that we have discussed so far is essentially one of privacy. If we accept that an individual in our society has a right to a certain degree of privacy it would be hard to imagine any more fundamentally basic infringement of one’s privacy that to have knowledge of another individual’s genome.
Safeguarding genetic privacy is :
It will be more complicated than most people imagine, protecting genetic privacy and confidentiality is a worthy goal. Steps taken toward this goal so far, however, are characterised as misguided and simplistic. (Rothstein MR 1999).
There is a certain difficulty with terminology in this discussion. Privacy in its normal context means limited access to a person and the right to keep certain information from disclosure to other individuals. Confidentiality, on the other hand, is usually defined as the right of an individual to prevent disclosure of what they consider to be sensitive information that has already been disclosed in a confidential relationship.
Clearly confidentiality is a different concept to privacy, albeit related. Protecting confidentiality can prove to be difficult because few individuals will have sole access to their own genetic code. In general terms it is in the hands of a few specialised professionals who society has to trust to keep such information from others who think that they have a right to see it.
We have already discussed some of the non-medical uses of genetic information (which by definition, is not covered by the normal rules of medical confidentiality). Other areas where genetic information has been suggested as being of potential use are, personal injury litigation, education and commerce. This is over and above the areas where genetic data is already in the public domain. It is currently generally used for identification purposes. Areas such as immigration, paternity, family membership and in the educational system (in the USA)already use genetic information as part of their routine procedures.
One has to consider the legality of invasion of privacy and potential breaching of confidentiality when it is suggested that defendants impersonal injury cases have the legal power to compel victims to undergo sophisticated genetic testing so that the quantum of damages can be accurately assessed on a more statistically accurate determination of what their life expectancy was likely to have been before they were involved in an accident?
Other potential legal quagmires would include the knowledge of the risk of inherited disease reducing life expectancy when parents were arguing over custody of a child. On the other side of the fence, should any degree of genetic testing be allowed before parents agree to adopt?
We have already discussed the problems of health insurance, but other more mundane issues such as mortgages could be affected by knowledge of the applicant’s genetic make-up.
The principle of Deontology is particularly likely to be offended as commercial pressure, being the force that it , it is very likely that sizeable financial incentives will be invoked in the areas of both health insurance and in employment. Confidentiality will therefore be all the harder to maintain.
In the UK the Equal Opportunities Commission has issued a statement of interpretation which helps us clarify the situation further. It stated that it would find discrimination cases proven if it were found that discrimination occurred on the basis of genetic predisposition. (White et al. 2001). The difficulty arises that this is an ethical and political statement, it does not have any weight in law. It specifically does not apply to unaffected carriers of recessive or-linked disorders.
In the UK employers can request access to prospective employee’s medical records which would, progressively be expected to contain genetic information.
In grasping the issue we have to decide whether genetic information Isa special case or is it to be treated in the same way as other “confidential” information?
Rothstein (Rothstein MR 1999) has put forward a six point plan which comprises arguments for considering genetic information unique and special case. The points are :
1) It reveals health aspects of other family members as well as the individual concerned
2) It reveals parentage
3) It reveals reproductive options
4) It reveals future health risks
5) It is the essence of what and who an individual is
6) It is generally regarded as unique by individuals and third parties.
The converse argument to these points would be that it would be largely impractical to keep genetic information is a separate, but accessible format to “normal” medical records and also that the passing of genetic specific prohibitary legislation is likely to be self-defeating as it will tend to stigmatise people who already have the burden of genetic diseases.
It appears to be positively presumptuous to attempt to draw conclusions when dealing with a project of this magnitude, which some authorities have suggested is on a level with the development of the periodic table in terms of predictive importance to science in general. (Robertson DS2004). It has produced, and is still producing, volumes of data which are completely unprecedented in the field of biology. It is fair to say that that human genome project, although technically complete in terms of its original aims of producing a fully sequenced human genome, is only in reality the first step in a massive undertaking which appears to be set to dwarf the accomplishments of the original project. The work that is now both apparent and available which comes as a direct consequence of the sequencing process, will involve the discovery of the mechanisms of genetic regulation and control of the organism and the expression of the eventual phenotype. The potential consequences for disease process modification are enormous. The task of deriving meaningful and useful knowledge from this data is likely to be the task which will face biological and medical research for the foreseeable future and is likely to require the input from virtually all disciplines of scientific endeavour. (Altria K.D et al 2004)
Rather like the technological advances that were catalysed by the American space programme, the human genome project has provided catalytic impetus to the development of processing technology. The potential profits that were envisaged by the large industrial development corporations and pharmaceutical companies have resulted in injections of capital which have helped to spur on the evolution of sequencing technology which can perform sequencing processes at a rate that could only have been dreamed of a decade ago (Tsai et al 2004).
Although we have set out an overview of the project itself, the thrust of this dissertation is an examination of some of the peripheral issues and consequences of having this information in the public domain. It is accepted that a brief consideration of the literature already available on the subject indicates that the concerns and worries of the scientific community, not to mention the public at large, suggest that the potential consequences of inaction to regulate and control the information that inevitably will arise as a result of the evolution of this process, could have immeasurable squeal for the way that we currently organise our society.
Issues of privacy and confidentiality are addressed in some detail as the ramifications of the inappropriate usage of genetic information is clearly a potentially massive problem. We have made the vitally important point that genetic information is unique insofar as if one person has access to their own genome, it is in the nature of the information contained in it that they also have a great deal of information, by inference, about other members of their family who may wish their right to confidentiality to be respected.
Ethical considerations are a particularly difficult issue to address as although in one sense they are universal, they have a different significance and indeed are to some extent dependent for their interpretation on the circumstance and the culture in which they are being applied. The ethics which we tend to regard as “the norm” in the western world are seen to have different connotations and implications when applied in Asian or African situations. In this dissertation we have therefore tended to restrict ourselves to the more universally applied ethical dimensions of the implications of the human genome project and its offshoots.
The social and medical squeal are perhaps more immediate in their application as medical advances have been apparent from the earliest work in the field. The social consequences have been largely parallel with the advances in medical science. One particular area that we have explored are the difficulties involved in the area of gene therapy. On the one hand is the clear and pressing need for those people who have single gene defects to be given the opportunity to benefit from advances in gene therapy, but this must be clearly weighted against the, already apparent difficulties, found with the phenomenon of iatrogenic insertion oncogenes is.
Such considerations are likely to be typical as reflection on scientific progress in other areas has historically been littered with “blind alleys” of investigation where either expectation is not borne out into reality or the unforeseen consequences of an intervention make it impractical for adoption.
We have seen, and to a degree referred to, a number of “prophets of doom” who have examined and written about the worst case scenarios of the consequences of genetic manipulation. Clearly we cannot dismiss their opinions without comment as again, history shows that it is clearly wrong to view the future of a scientific discovery through rose-coloured glasses. It may be completely appropriate to consider the possibilities that are opened up by the human genome project with optimism and enthusiasm, but that should not stop a reasoned and rational consideration of the potential down-sides that could face society as a whole. It is perhaps only by that consideration that appropriate steps can be considered and instituted before serious and avoidable situations arise.
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