1999 Genetics, Law and Society Conference, Saint Paul, Minnesota

Protection of the Genetically Challenged
by Alastair Kent, Director, Genetic Interest Group: UK 
President, European Alliance of Genetic Support Groups
August 1999

A patient's perspective on recent progress in genetics and the promise for improvement in health and well-being that this offers to those with chronic disease.

Introduction

The un-ravelling of the human genome is probably the fastest moving area of bio-medical science in the world today. It is confidently predicted that the first draft of our genetic makeup will be known during the course of the next year, with the quality of the "map" being improved and refined substantially during the next two or three years.

Given the potential that this new information has for improving human health and for tackling the fundamental biological processes that underpin or cause many currently intractable or incurable diseases, the creation of the genetic map of the human species represents a significant and a fitting marker for the new millennium.

But information in itself is not enough. Science without application is sterile and if this new knowledge remains an academic curiosity then we will have failed to respond to the entirely legitimate aspirations of those currently experiencing chronic ill health, disability and premature death to be well. More importantly, those yet unborn will look back at our generation and see that we lacked the vision and the courage to take the necessary steps to ensure that the new genetics was able to fulfill its potential for good, and as a result millions of people throughout the world will continue to suffer from potentially avoidable ill health and to live lives that are qualitatively and quantitatively poorer than might otherwise have been the case.

In the time allowed to me, I would like to consider some of the issues that will have to be addressed if this promise is to be met. I am basing my thoughts on the assumption that science will deliver the knowledge we need to understand the way in which genetic factors work in health and disease and that the complexity of the interrelationship between genes, and between genetic and environmental factors, is not intellectually incomprehensible. If I am wrong and it is just too difficult to understand then that to my mind will represent the only legitimate excuse that we can hold out to future generations as an excuse for our failure to deliver.

From Research to Development

Throughout the developed world the route adopted by governments of all political persuasions for producing new medicines has been the encouragement of private rather than public sector investment. Initially, in European countries at least, much of the initial investment in basic research came from public or from charitable sources, with the private sector stepping in when a commercially viable outcome becomes a possibility, but this artificial distinction between basic and applied research no longer holds good. Private sector bodies are now committed to basic research and academics have to be increasingly aware of downstream commercialisation issues if they want to see their work used to conquer disease.

In essence there is a contract between society, government as the representative of society and private sector bodies that goes something like this:

"In return for your willingness to invest in the development of new medicines we will allow you to make a reasonable profit from curing disease".

Whether or not this relationship is morally right or wrong in an absolute sense seems to me to be an irrelevant question. This is the situation as it exists now, and to wish it were otherwise is a waste of time and energy. Practically, I know of no patient who would refuse to take a medicine that worked on the grounds that it had been developed by a private sector company for profit rather than by the public or charitable sector. Given the reality of the situation, it would seem to me that the best course of action for anyone interested in innovative medicine ought to be to try and ensure that the private sector is as successful as possible, whilst at the same time ensuring that the tax regime was such that the government revenues are able to meet public health needs in areas where science or medicine have yet to deliver.

Central to this relationship is the issue of intellectual property rights - the patent. Patenting in the field of genetics has generated intense debate in recent years - much of it creating heat rather than spreading light, with mis-information and misunderstanding leading to the adoption of entrenched positions from which it is now difficult for the protagonists to move without loosing face.

The morality of patenting gene sequences is a question that has vexed philosophers and ethicists on both sides of the Atlantic greatly. Why this should be so is unclear to me, given that the patenting of other biologically identical molecules such as human enzymes and replacement hormones has not been seen to be problematic and there is no logical distinction between the DNA sequence that codes for a protein and the protein itself in terms of the body's need for the correct substance to be present if it is to work properly.

But even if it were to be demonstrated that there was a moral argument against patenting gene sequences, this is yesterday's argument. If the requirements of patent law are applied strictly, then the elucidation of one more gene sequence can in no way be said to meet the requirements of novelty or non-obviousness and nowhere is there an inventive step given that, if time and money were available any reasonably competent academic geneticist could probably work out the structure and function of any given gene using techniques "well known in the art".

Much more important is the impact of patenting on the opportunity to improve health products for those currently sick. Here the challenge for patent examiners is to ensure that the claims made in applications for patent protection really do hold up to critical scrutiny and that they are worthy of the grant of a patent. This is particularly difficult in a field which is moving forward as fast as genetics and there is always the danger that there will be a lag between the state of the art knowledge of scientists researching the field and patent examiners approving the grant of intellectual property rights. Resolving this is fundamentally an administrative issue, not an insurmountable intellectual problem.

It is sometimes claimed that patenting in genetics will create barriers to research as patent holders will be able to block access to others using their knowledge. Whether or not this is the American experience I cannot say, but I doubt that it is the case. In support of this I would give the example of the gene sequence for cystic fibrosis. This has been the subject of a patent for many years now, but I would hazard a guess that the amount of research into CF and into genetic based therapies for CF has been greater since the grant of the patent than prior to this. This is not to link the patent causally with an upturn in research volumes - it is more an reflection of the new possibilities created by advancing science across the field.

Even if it were to be the case that gene patenting has impaired research in the USA, it would not be so in Europe, where under European Patent Law research is exempt from royalty payments up to the point where commercial application becomes an issue. Attempts to use patents to block competition or to prop up inadequate products can be challenged by using compulsory licensing procedures. At present this is cumbersome and there is a case for simplifying and speeding up the process but again, this is a practical, not an ethical question.

The grant of a patent sometimes appears to reward unfairly the person who puts the last brick in the wall and to deprive those who carry out basic research of the opportunity for commercial benefit. Although there is some justice in this view, there is also the opportunity to create a virtuous circle. If universities, publicly funded institutions and charities are alive to commercial possibilities, then a revenue stream for funding further basic research and moving them nearer the achievement of their primary goal can be created through the judicious application of intellectual property law. Indeed it is arguable that this is not only good economic sense, it is morally right if they are to create the best chance of curing disease sooner rather than later.

The Role of the Market

Left to its own devices, the laws of the market place will never in themselves produce the medicines for treating all genetic diseases. Many, especially those which result from mutations in a single, highly pentrant gene are too rare to attract the necessary investment. Even if research and development programmes were to be successful, the numbers affected are so small as to make the cost/case of treating too great to be considered. Yet people with rare disorders have exactly the same hopes for good health as those with more common ones and whether or not the disorder that affects you is rare or common makes no difference if you are the one who has it. If you've got it, you've got it 100%.

One response of governments to meeting the needs of those with rare disorders for innovative medicines which reflect current scientific understanding has been to alter the rules of the market to bring rare disorders into the frame of economic viability for private sector investment. The route chosen in most developed economies has been by the creation of "orphan drug" legislation. The USA has had this for over a decade and in that time well over one hundred new treatments have been brought to the market for the benefit of those with rare disorders. The US orphan drugs act works by offering a combination of practical and financial incentives, including a period of market exclusivity to prevent competitive products being marketed and tax credits to allow the risks associated with funding Research and Development to be offset to some extent against profits elsewhere in the company now or in the future. This also has the effect of reducing the cost/case treated to the final purchaser, making the product more likely to be affordable.

The European Union is introducing its own set of regulations to promote interest in products for the treatment of rare disease. These are ostensibly modelled on the American model, but there are crucial differences based on the different legislative powers of European and national institutions.

In the USA, the orphan drugs act was passed by government and it applies throughout the nation. The population base of the USA means that absolutely rare conditions can still affect significant numbers of individuals and that a common set of incentives will apply whether the research is undertaken in Boston or in California.

In Europe, no single nation has the population base to act independently. Even Germany with a population of 90 million, cannot realistically adopt across the board measures. In the smaller nations states, which comprise a majority in Europe the needs of those with rare disorders cannot hope to be addressed. At the level of the European Union where the needs of 350 million European citizens can be considered in block. This is both an opportunity and a problem, because the European Institution have no power to vary national tax regimes or to influence national health services. Under the principle of subsidiarity agreed in the treaties of Maastricht and Amsterdam these remain national competences. This means that the tax credits available in the US cannot be legislated for use by the EU. Nor can there be any central pressure to ensure that products developed under the aegis of the European orphan medical products regulations will actually be made available for use by patients in any or all of the 15 member states' health care systems.

Given that orphan medical products will almost certainly be prescription only medicines, over the counter sales will not be an option. It is to be hoped that the EU's proposals will provide the genuine incentive that will stimulate investment in meeting the health care needs of those with rare disorders, and not turn out to be a piece of windy political rhetoric that promises much but delivers little. In my mind at least the jury is still out.

"Embracing Diversity"

Although scientific knowledge in itself is morally neutral, the uses to which it is put are not, and advances in understanding in the field of human genetics carry with them the potential for abuse as well as the opportunity for great good.

We stand on the edge of a world in which may hitherto incurable conditions may be treatable. But the gap between knowing which gene causes a given condition and having an effective treatment for that is an immense one. For many disorders the only option currently open to families at known genetic risk is the possibility of ante-natal diagnosis coupled with the option of termination of pregnancy when a fetal abnormality is detected.

Some, particularly those who are active in the "pro life" movement or those active in the disability rights lobby, claim that over expanding ability to detect an increasing number of genetic abnormalities ante- natally will result in an attempt to eliminate disability through the adoption of either an overt or covert "seek and destroy" policy.

Of course, if this were to happen it would be morally and ethically unjustifiable and it would be totally abhorrent to the majority of people whether lay or professional. However, I believe that this is not only unlikely to happen, but also that to claim that it will is to fly in the face of scientific fact and political probability. There are a number of reasons why I feel confident that the resurgence of state sponsored eugenics is an unlikely prospect and why the attacks on the new genetics that are made by pro-lifers, disability activists and/or environmentalists working separately or together can be resisted. Whether or not they will be is another question. Dietrich Bonheoffer's phrase "For evil to triumph it is first necessary for good men to do nothing" springs to mind.

That disabled people are entitled to full human and civil rights in society goes without saying. The extent to which they have been able to achieve this is an issue for all of us and the tactics adopted to make progress towards this goal has varied between different societies depending on their cultural heritage and their legislative framework. Stereotypically the American approach has been by recourse to law, whereas Europeans have tended to take a more collaborative approach.

(Note by Editor:In the United States there are a substantial number of court decisions that determine under what conditions pregnancies are allowed to continue and under what conditions pregnacies can be terminated. Eugenic considerations f or example have resulted in laws to sterilize the mentally defective. T he United States Supreme Court upheld one such law seven decades ago (Buck v. Bell, 274 U.S. 200 (1927)). Since then, U. S. law has generally supported a citizen's right to reproduce. (See Skinner V. Oklahoma, 316 U.S. 535 (1942)(striking down law imposing sterilization for certain criminal offenses); State v. Brown, 326 S.E. 2d 410 (S.C. 1985)(overturning a sentence offering defendants choice of prison term or surgical castration plus probation); Ill. Ann. Stat. Ch. 730, para. 5/5-5/3(J)(Smith-Hurd Supp. 1994)(statute prohibiting sentences requiring use of birth control). Cf. Relf v. Weinberg, 372 F. Supp. 1196 (D.D.C. 1974)(overturning federal regulations under which minor and incompetent poor persons had been involuntarily sterilized under federally financed family planning programs); Walker v. Pierce, 560 F.2d 609 (4th Cir. 1977) (allowing physician to require that Medicaid patients undergo sterilization as a condition of his delivering their third or subsequent child). For analysis, see Rebecca Dresser, Long-Term Contraceptives in the Criminal Justice System, Hastings Center Rep., Jan.-Feb. 1995 at S15. For a discussion of the use of contraception as a condition of welfare benefits, see David S. Coale, Norplant Bonuses and the Unconstitutional Conditions Doctrine, 71 Tex. L. Rev. 189 (1992).

Of course, the Court has also upheld the right not to have children, see Roe v. Wade (government has important interests that outweighed the rights of the mother only in the last trimester).

The Supreme Court has not yet addressed claims of a right to reproduce involving technological assistance, or involving the services of non-marital partners willing to provide gametes or to gestate a child. See, e.g. In the Matter of Baby M., 537 A.2d 1227 (J.D. 1988) (surrogate motherhood); Johnson v. Calvert, 19 Cal. Rptr. 2d 494, 851 P.2d 776 (Cal. 1993) (non-genetic (gestational only) surrogate motherhood); Davis v. Davis, 842 S.W.2d 588 (Tenn. 1992)(dispute over disposition of frozen embryos between genetic parents asserting conflicting rights to reproduce and to avoid reproducing). For further discussion of procreative freedom and the law, see generally, John Robertson, Children of Choice: Freedom and the New Reproductive Technologies (1994).

More generally, questions to be asked might include questions such as:

How should the scientific validity and clinical utility of genetic tests be established? In particular, are the uncertainties surrounding genetic tests and their interpretation adequately understood by scientists? By the public? By regulators, insurers, judges the media?

How should law exercise its regulatory power over the relevant professions and industries?

What are the relationships between particular technological developments and legislative and regulatory proposals such as DNA data banks and the proposed Genetic Privacy Act?--L.H.)

Which of these ultimately will be more effective is hard to say, but the goal, the end point is clear.

To claim that genetics will somehow reverse the trend and will result in active elimination of disabled people from society or the creation of a de-valued underclass of the "genetically imperfect" is to abuse the integrity of the medical profession, to misunderstand the way in which biology works and to denigrate the experiences of those faced with the decision whether or not to continue with a pregnancy when a severe abnormality is detected.

To put a context on the issue, every year in the UK about 180,000 pregnancies are terminated for non medical reasons. A further 2,000 (approximately 1%) are ended because of the detection of a significant abnormality. The vast majority of these are wanted pregnancies. After all, if a woman does not want to be pregnant she does not have to go through the process of genetic testing to secure an abortion and the process itself is not without risk to the pregnancy even if the fetus is subsequently found to be healthy. To suggest that an increased ability to undertake ante-natal testing will lead to a rush to "designer babies" with pregnancies being terminated for trivial reasons such as hair or eye colour is to fail to appreciate the magnitude of the decision to terminate a wanted pregnancy for the woman who ultimately has to take it.

Nor is it possible to draw up any list of conditions which are either so serious that a pregnancy must be terminated or not serious enough that abortion must be ruled out. What might be a life enhancing experience for one family might prove to be a soul-destroying burden for another and to cede to a third party, be it a benevolent (or otherwise) state, a special interest activist group or any other external agency the right to decide which pregnancies must be allowed to continue or alternatively which should be terminated is to give away an important protection against a return to eugenic policies practised in the past.

To claim that such an approach would result in an elimination of disability in society is also to fly in the face of science. Only a relatively small contribution to the presence of disabled people in the population is a direct consequence of single gene defects detectable ante-natally. Most disability is a result of a series of highly complex gene:gene and gene:environment interactions which impinge on all of us and which would, if they were to be made the target of a "seek and destroy" policy quickly result in the termination of all pregnancies on the grounds that life ultimately is a fatal condition we inherit from our parents and we all carry within our genotype the genetic predisposition to a range of chronic disability and ultimately fatal conditions.

While it is undoubtably true that disabled people make a significant contribution to the diversity of the human condition and that that contribution should be recognised and valued, I would contest that there is an essential difference between recognising diversity that exists, and taking action to reduce the occurrence of avoidable ill health and reducing the incidence of disabling conditions where possible. Few parents to be would see having a child with a disability as a positive goal and even if the social care systems available meant that the handicapping impact of the disability for the affected individual and the wider family were reduced to the maximum possible extent. Most people would not see the choice between a child with a disability and one without as being equal value choice. This is not to deny that parents love, esteem and celebrate their disabled children. Simply it is to affirm the entirely understandable wish of parents to see their offspring have the best possible opportunity they can give them. Indeed it seems to me somewhat bizarre to claim that, because disabled people can teach society something about the nature of the human condition it is somehow necessary for them to exist for the greater good of humanity as a whole. Such a belief is ethically unsustainable if the means to intervene exist. We must be careful to avoid compromising the right of people who are here present (i.e. parents or parents to be) to decide for themselves because of a perception of the assumed views of those as yet unborn about the likely quality of their existence.

Standing the issue on its head may help to bring things into focus. Ask yourself, would it be ethical for a doctor to help a pregnant woman who came to him or her claiming to want to produce a baby with a congenital abnormality achieve her desires for example by prescribing excess alcohol consumption, the exclusion of folic acid from the diet, a regime of illegal narcotics and a daily bath in Agent Orange? Of course it wouldn't! By the same token to fail to take action to ensure that people are able to make informed decisions about the likely future health and well being of their pregnancy, and their ability to provide the circumstances for those chances to be maximised - not only for the individual but for the wider family - even where this may lead to termination on the grounds of fetal abnormality must be seen to be morally culpable.

Hopefully, as science moves on, more and more currently incurable genetic disorders will become treatable so the dilemmas for families will be reduced, but until that happens we must be careful to protected the rights of families not to be put under pressure, whether overt or covert, from third parties to follow a particular course of action, whatever that might be.

One of the ways in which we will close the gap between scientific progress and potential health gain is through the judicious application of intellectual property law to ensure the maximum possible opportunity for investors to see genetic medicine as an exciting prospect for their wealth in the face of a myriad of competing claims on the resources at their disposal.

"Future Proofing" Health

For many genetic conditions the best hope of a really effective cure would seem to lie in the application of gene therapy techniques to switch off a defective mutation, to over-ride its operation or to switch on an inactive process. When these therapeutic interventions involve somatic cells it has been generally concluded that the techniques involved will raise no new ethical questions not already considered in the context of other aspects of medical procedure.

However, many genetic conditions are multi system conditions and the best or even the only way to influence their progress may be in the very early stages of embryo development. This may carry with it the prospect of genetic change affecting the germ line and so being transmitted between generations. There are already signs that this is the direction in which research into some disorders may be taking us, and it would be sensible to consider the issues in advance, so that a balanced and rational outcome is the result, not a response driven by emotion and a failure to consider all the relevant facts.

The possibility of germ line changes, whether intentional or as an concomitant of somatic cell therapies raise issues of safety and the adequacy of our biological knowledge "in the round" regarding the effects of specific genes. These are essentially technical questions and ought to be answered by scientific experiment - assuming of course that it is possible to design experiments that would meet existing criteria for ethical acceptability.

Rather more difficult is the question of inter-generational justice and the right of one generation to interfere with the genetic diversity of future generations. I do not believe that there is as yet any consensus on this issue. There are arguments to be made in both directions. However I would strongly press that the moral high ground does not automatically belong to those who advocate not intervening if it can be done safely. To quote one mother at a recent meeting I attended "I don't see what's so wonderful about biodiversity if it means that I don't have the option to not to pass the gene for Tay Sachs disease to my children". Just as we are taking steps to remove asbestos from the environment because of its effect on the health of the community, might we not also seek to reduce the incidence of genes for serious disease for similar reasons, always respecting the limits of our power to intervene and the freedom of individuals to make informed decisions for themselves.

Conclusion

To conclude. We stand at the edge of a new era. Genetic medicine is likely to be able to deliver substantial gains in our ability to treat or prevent many of the conditions which represent major health scourges in the developed and the developing world. Whether or not this promise is to be realised will depend not only on the ability of scientists and doctors to deliver the knowledge but also of the willingness of all in society to see that systems are created which deliver the benefits to all who need them - and not just those who can pay for them.

For health gain for all to be realised then, as a society and as part of the global community we need to tackle the issues generated by this new knowledge in the round. The ethical and social questions must be addressed and not ducked. Resources need to be generated to move knowledge from the lab to the clinic and to create products which meet the hopes and expectation of those facing chronic ill health, disability, and premature death themselves or in their children. Regulations, legislation and other controls must be structured in such a way to permit the good and prohibit misuse of, genetic data about individuals. At the same time we must guard against the over-rigid application of the precautionary principle. Risk can be managed and reduced but never eliminated completely and if we try to do so then we will never achieve anything. This will result in genetic medicine withering on the vine, leaving future generations to curse us for our timidity, rather than praise us for our vision and boldness should we fail to seize the day.

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