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Nonetheless, if there are significant social consequences of enhancement, this is of course a valid objection. But it is not particular to enhancement: there is an old question about how far individuals in society can pursue their own self-interest at a cost to others. It applies to education, health care, and virtually all areas of life.

Not all enhancements will be ethical. The critical issue is that the intervention is expected to bring about more benefits than harms to the individual. It must be safe and there must be a reasonable expectation of improvement. Some of the other features of ethical enhancements are summarized below.

What Is an Ethical Enhancement?

An ethical enhancement:

1.is in the person’s interests;

2.is reasonably safe;

3.increases the opportunity to have the best life;

4.promotes or does not unreasonably restrict the range of possible lives open to that person;

5.does not unreasonably harm others directly through excessive costs in making it freely available;

6.does not place that individual at an unfair competitive advantage with respect to others, e.g. mind-reading;

7.is such that the person retains significant control or responsibility for her achievements and self that cannot be wholly or directly attributed to the enhancement;

8.does not unreasonably reinforce or increase unjust inequality and discrimination — economic inequality, racism.

What Is an Ethical Enhancement for a Child or Incompetent Human Being?

Such an ethical enhancement is all the above, but in addition:

1.the intervention cannot be delayed until the child can make its own decision;

2.the intervention is plausibly in the child’s interests;

3.the intervention is compatible with the development of autonomy.

CONCLUSION

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Enhancement is already occurring. In sport, human erythropoietin boosts red blood cells. Steroids and growth hormone improve muscle strength. Many people seek

cognitive enhancement through nicotine, Ritalin, Modavigil, or caffeine. Prozac, recreational drugs, and alcohol all enhance mood. Viagra is used to improve sexual performance.

And of course mobile phones and aeroplanes are examples of external enhancing technologies. In the future, genetic technology, nanotechnology, and artificial intelligence may profoundly affect our capacities.

Will the future be better or just disease-free? We need to shift our frame of reference from health to life enhancement. What matters is how we live. Technology can now improve that. We have two options:

1.Intervention:

•treating disease;

•preventing disease;

•supra-prevention of disease — preventing disease in a radically unprecedented way;

•protection of well-being;

•enhancement of well-being.

2.No intervention, and to remain in a state of nature — no treatment or prevention of disease, no technological enhancement.

I believe that to be human is to be better. Or, at least, to strive to be better. We should be here for a good time, not just a long time. Enhancement, far from being merely permissible, is something we should aspire to achieve.

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CHEITLIN, M. D., HUTTER, A. M., et al. (1999), ‘ACC/AHA Expert Consensus Document JACC: Use of Sildenafil (Viagra) in Patients with Cardiovascular Disease’, Journal of the American College of Cardiology, 33/1: 273 – 82.

DAVIS, D. (1997) ‘Genetic Dilemmas and the Child’s Right to an Open Future’, Hastings Center Report, 27/2 (Mar. – Apr.), 7 – 15.

DE GRAZIA, D. (2005), ‘Enhancement Technologies and Human Identity’, Journal of Medicine and Philosophy, 30: 261 – 83.

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DE MARCHI, N., DANIELE, F., and RAGONE, M. A. (2001), ‘Fluoxetine in the Treatment of Huntington’s Disease’, Psychopharmacology, 153/2: 264 – 6.

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FEINBERG, J. (1980), ‘The Child’s Right to an Open Future’, in W. Aiken and H. LaFollette (eds.), Whose Child? Parental Rights, Parental Authority and State Power (Totowa, NJ: Rowman and Littlefield), 124 – 53.

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(London: Profile).

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HOLDEN, C. (2003), ‘Don’t Go Off the Prozac’, Science, 301: 760.

(2004), ‘Treatment of Newborn Mice Raises Anxiety’, Science, 306: 792. HOLLOWAY, M. (1999), ‘Flynn’s Effect’, Scientific American, 280/1 ( Jan.), 37.

KAMM, F. (2005), ‘Is There a Problem with Enhancement?’, American Journal of Bioethics, 5/3: 5 – 14.

KASS, L. R. (2002), Life, Liberty and the Defense of Dignity: The Challenge for Bioethics (San Francisco: Encounter Books).

LIM, M. (2004), Nature, 429: 754 – 7.

LIU, Z. J., RICHMOND, B. J. A., et al. (2004), ‘DNA Targeting of Rhinal Cortex D2 Receptor Protein Reversibly Blocks Learning of Cues that Predict Reward’, Proceedings of the National Academy of Sciences, 101/33: 12336 – 41.

MILL, J. S. (1910), On Liberty (London: J. M. Dent).

MISCHEL, W., SHODA, Y., and PEAKE, P. K. (1988), ‘The Nature of Adolescent Competencies Predicted by Preschool Delay of Gratification’, Journal of Personality and Social Psychology, 54/4: 687 – 96.

MORELL, V. (1993), ‘Evidence Found for a Possible ‘‘Aggression Gene’’ ’, Science, 260: 1722 – 3.

PALMA, V., LIM, D., et al. (2005), ‘Sonic Hedgehog Controls Stem Cell Behaviour in the Postnatal and Adult Brain’, Development, 132: 335 – 44.

PERSSON, I. (1997), ‘Genetic Therapy, Person-Regarding Reasons and the Determination of Identity: A Reply to Robert Elliot’, Bioethics, 11/2: 161 – 9.

PRESIDENT’S COUNCIL ON BIOETHICS (2003), Beyond Therapy: Biotechnology and the Pursuit of Happiness (New York: Dana Press).

RIETZE, R., VALCANIS, H., et al. (2001), ‘Purification of a Pluripotent Neural Stem Cell from the Adult Mouse Brain’, Nature, 412: 736 – 9.

SANDEL, M. (2004), ‘The Case Against Perfection’, Atlantic Monthly (Apr. 2004), 51 – 62. SAVULESCU, J. (2002), ‘Deaf Lesbians, ‘‘Designer Disability,’’ and the Future of Medicine’,

British Medical Journal, 325/7367: 771 – 3.

(2003), ‘Human – Animal Transgenesis and Chimeras Might Be an Expression of Our Humanity’, American Journal of Bioethics, 3/3: 22 – 5.

HEMSLEY, M., NEWSON, A., and FODDY, B. (2006), ‘Behavioural Genetics: Why Eugenic Selection Is Preferable to Enhancement’, Journal of Applied Philosophy, 23/2: 157 – 71.

SOCIETY FOR NEUROSCIENCE (2004), ‘Early Life Stress Harms Mental Function and Immune System in Later Years According to New Research’, 26 Oct., <http://apu.sfn.org/content /AboutSFN1/NewsReleases/am2004 early.html>, accessed Feb. 2006.

SPIRES, T., GROTE, H., et al. (2004), ‘Environmental Enrichment Rescues Protein Deficits in a Mouse Model of Huntington’s Disease, Indicating a Possible Disease Mechanism’,

Journal of Neuroscience, 24/9: 2270 – 6.

SULLIVAN, F. R., BIRD, E. D., ALPAY, M., and CHA, J. H. (2001), ‘Remotivation Therapy and Huntington’s Disease’, Journal of Neuroscience Nursing, 33/3: 136 – 42.

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VAN DELLEN, A., BLAKEMORE, C., et al. (2000), ‘Delaying the Onset of Huntington’s in Mice’, Nature, 404: 721 – 2.

c h a p t e r 2 3

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P H A R M AC O G E N O M I C S : E T H I C A L A N D

R E G U L ATO RY

I S S U E S

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M AT T H E W D E C A M P A N D A L L E N

BU C H A NA N

INT RO DUC T I ON

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PHARMACOGENOMICS and pharmacogenetics attempt to elucidate the role of genetic variation in human responses to compounds introduced into the body, such as medications.1 Although the notion of genetic determinants of drug response and toxicity dates to at least the 1950s (Weber 2001), new molecular techniques and the completion of the Human Genome Project promise to reveal genetic variations

1 The difference between pharmacogenomics and pharmacogenetics is not fixed in the literature. For example, some (Lindpainter 2003) suggest that -genomics be limited solely to gene expression analyses, whereas -genetics be used primarily to denote any number of inherited differences in DNA sequences (e.g. single nucleotide polymorphisms, or SNPs) that correlate with differential drug response. In this chapter we use ‘pharmacogenomics’ as a more inclusive term that incorporates pharmacogenetics as well as the genome-wide expression analyses (e.g. DNA microarrays) of pharmacogenomics. Only where necessary will we distinguish the two.

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at an unprecedented rate. Already, some institutions use pharmacogenomic tests to avoid adverse drug effects, via dosing changes, that sometimes result from the anti-coagulant warfarin (Higashi et al. 2002) and the chemotherapeutic drug 6-MP (Marshall 2003). In late 2003 Roche Diagnostics released information on its AmpliChip™ technology, which would test genetic variations of the cytochrome P450 enzymes crucial to drug metabolism (Roche Diagnostics 2003). On the horizon are pharmacogenomic tests to aid cancer therapy (Marsh and McLeod 2004), asthma treatment (Dewar and Hall 2003), and prediction of response to anti-hypertensive agents (Kreutz 2004), among others. The end of ‘one size fits all’ medicine – and the beginning of ‘personalized medicine’ — appears to be near, with pharmacogenomics playing a major role (Langheier and Snyderman 2004).

The potential benefits of pharmacogenomic methodologies are multifarious and could dramatically change the health care system. Adverse reactions resulting from medications are a major cause of morbidity and mortality, as well as a cost for health care systems, as a recent report from the US Institute of Medicine Committee on Quality of Health Care in America has shown (Kohn et al. 2000). Although many adverse reactions result from human error, others are caused by individual differences in drug absorption, distribution, metabolism, and excretion that are the result of genetic variation. A better understanding of these factors may reduce adverse drug reactions (Phillips et al. 2001; O’Kane et al. 2003), as recent research with the HIV drug abacavir suggests (Hughes et al. 2004). In addition, advocates of pharmacogenomics anticipate a streamlined drug development process, both by focusing on specific drug targets (for example, particular receptors) and through the use of smaller clinical trials restricted to individuals whose genotypes make them more likely to respond and less likely to suffer a serious adverse event. Finally, pharmacogenomics might rescue drugs abandoned in the past owing to serious toxic side effects if researchers can show that only a genetic subpopulation suffered the toxic response. These are but a few of the highly publicized benefits of pharmacogenomics.

Not everyone is taken by this excitement, however. Some criticize the pharmacogenomic methodology itself. For example, from a scientific standpoint, van Aken et al. (2003) recognize the impact of pharmacogenomics, specifically on the use of 6-MP, but also note that a larger percentage of adverse reactions could be unrelated to genetic polymorphisms. Why devote so many resources to a small, though important, part of adverse drug reactions if more adverse reactions result from preventable human error? Moreover, one should not ignore the role of multiple mutations (e.g. if a test reveals an individual to be a slow metabolizer of 6-MP, but another, unused test could reveal him or her to also be a fast excretor, thereby compensating for the original variant), polygenic traits, overlapping metabolic pathways, other environmental influences, or concomitant disease status, such as kidney and liver disease (Nebert et al. 2003).

Holtzman (2003) further substantiates this healthy skepticism with an analysis that shows the predictive value of most current pharmacogenomic tests to be

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relatively low. Unfortunately, some findings are nevertheless being prematurely applied via direct-to-consumer Internet marketing of pharmacogenomics, causing some to question the regulation of these tests, or the lack thereof.2

To take these scientific concerns seriously is to acknowledge the speculative nature of some of what follows but does not make the discussion fruitless. Instead, discussion and deliberation may help shape the technological development of pharmacogenomics in a beneficial way (Hedgecoe and Martin 2003). Moreover, it may be more prudent to explore a range of possible issues, some of which may not arise, than to be overtaken by events owing to the failure to think ahead.

It is fruitful to distinguish between concerns about pharmacogenomics as a methodology and concerns arising from the embodiment of the methodology in particular technologies. Some issues may be invariant to the choice of technologies; others may be specific to them.

While acknowledging the potential benefits of pharmacogenomics as a methodology, a number of comprehensive reports in the past several years examine a multitude of ethical, legal, and social factors that may limit the extent to which these benefits are realized — and realized in ethically acceptable ways (Buchanan et al. 2002; Consortium on Pharmacogenetics 2002; Freund and Wilfond 2002; Robertson et al. 2002; Melzer et al. 2003; Nuffield Council on Bioethics 2003; Rothstein 2003). Our purpose in this chapter is to identify and explore the most basic ethical and regulatory issues that are likely to arise if pharmacogenomics becomes widely enough used to have a significant impact on research and clinical practice. First, however, we address the question of whether pharmacogenomic tests are unique when compared to other genetic tests and thus deserving of more or less stringent ethical and regulatory requirements.

IS PHAR MACO GENOMICS UNIQUE?

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In a now frequently cited article, Roses (2000) makes the claim that pharmacogenomic tests are distinct from other genetic tests, specifically those genetic tests that are related to disease genes.3 Roses argues that because pharmacogenomic tests are employed to determine likely medicine response, they do not carry the problematic ethical, legal, and social implications of genetic tests for diseases or predispositions

2 For one example, see <http://www.bankdna.com/index.html>, accessed 5 July 2006.

3 It is interesting to note that this view, which might be called ‘pharmacogenomic exceptionalism’, runs counter to ‘genetic exceptionalism’ more broadly construed. On the latter view, all genetic information is somehow unique and deserves more stringent protections, whereas the pharmacogenomic version seeks to carve pharmacogenomic information out of this circle and place it back with other, ‘less threatening’, medical information. In fact, neither form of exceptionalism is tenable, and for similar reasons. For one argument against genetic exceptionalism, see Green and Botkin (2003).

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to diseases. Freund and Wilfond (2002) add that the uniqueness of pharmacogenomic technologies may be their distinct function: to help identify an appropriate and available intervention. One might conclude from these characterizations that pharmacogenomic tests require less stringent regulatory protections, for example, regarding the confidentiality of pharmacogenomic data, because these data are less likely to result in harm when compared to genetic tests for disease or the risk of genetic disease in one’s offspring. Less stringent regulatory requirements could be advantageous because they might enable research to proceed without being hindered by the many ethical debates that have occurred in other areas of genetics (e.g. the US ethical, legal, and social implications program for the Human Genome Project).

A closer analysis, however, reveals that the supposed bright line distinction between pharmacogenomic tests and other genetic tests is in fact rather blurry (Lindpaintner 2003). Immediately after Freund and Wilfond (2002) make their proposal, they note that regulatory decisions might need to be made on a case-by-case basis, not on the basis of ‘pharmacogenomic’ versus ‘other’ genetic tests. The attempt to draw such a sharp distinction breaks down on several fronts.

First, pharmacogenomic tests will not solely be used to select one intervention from among several equivalent alternatives. Some tests might reveal that no safe intervention is available, whereas others might reveal that a therapeutic intervention is available but at an extremely high price. Both scenarios could raise concerns about discrimination regarding insurance coverage or cost. For example, suppose a pharmacogenomic profile of tissue from an individual with breast cancer reveals that standard therapy will be ineffective at preventing metastasis. This yields information about the type of treatment that will be needed and perhaps about future disease prognosis, both of which might interest an insurance company.

Second, in some cases, pharmacogenomic tests will be associated with ‘disease’ information. For example, the same genetic marker used in a pharmacogenomic test may also indicate a predisposition to a particular disease. Similarly, because the same genes are often involved in drug metabolism and environmental substance detoxification (drugs, after all, are merely a controlled environmental exposure), information from pharmacogenomic tests might also reveal the potential for environmentally mediated disease (Schulte et al. 1999). Were this not the case, one would not expect the US National Institute of Environmental Health Sciences to devote a substantial portion of its initial Environmental Genome Project budget to pharmacogenomics. So it is a mistake to assume either that pharmacogenomic information only conveys likelihood of drug response or that information about the likelihood of drug response is devoid of psychosocial significance.

Lindpainter (2003) goes a step further by noting that pharmacogenomics may in fact be more likely to evoke ethical issues. First, he surmises that because genetic information about drug response will be available to more people in the health care process, from physician to nurse to pharmacist to administrator, the risks of disclosure are greater. Second, he notes that in certain cases an individual might be

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found not only to be at high risk of a particular disease via a ‘disease’ genetic test, but also at high risk not to respond to conventional therapy via a pharmacogenomic test. Under these conditions, the pharmacogenomic test results become even more important from a strictly financial insurance standpoint.

On balance, then, there seems to be no reason to require less or more stringent protections for pharmacogenomic tests as a group. It is more reasonable to remain open-minded as one explores the alternative technologies in which the methodology may come to be employed and the social, legal, and economic context in which these technologies are likely to be utilized.

ETHICAL ISSUES IN TECHNOLO G ICA L

DEVE LOPMENT

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Who Will Develop Pharmacogenomics, and For Whom?

Although it may be unconventional to raise economic incentives as the first ‘ethical’ issue arising in pharmacogenomics, we do so because who receives the eventual benefits of pharmacogenomic advances (and who bears its costs) will be partly determined by economic considerations. Because the economic incentive structure will help determine who benefits and how these benefits are distributed, it is subject to evaluation from the standpoint of justice. Often, ethical analyses conclude with discussions of justice; unfortunately this encourages the false assumption that issues of justice regarding access to and distribution of benefits and costs can be adequately addressed independently of evaluating the production process. To make this assumption is to ignore the possibility that a particular production process, once in place, may seriously limit the possibilities for how its products may be distributed. A widely cited statistic is that 90 per cent of the world’s disease burden receives 10 per cent of the funding for relief of this burden. If this is true, either the ‘distribute later’ approach would need to be of Herculean proportions, or an alternative means is necessary in order to achieve a more just global distribution (Advisory Committee on Health Research 2002). Changing the nature of the production process by modifying the incentives of those who decide which products to try to develop may be a necessary element in any realistic strategy to secure a more equitable distribution of benefits from medical research. As we shall see shortly, one factor that may shape incentives is the nature of the intellectual property rules under which research and development occurs.

One major economic concern of pharmacogenomics is the effect of market segmentation. Market segmentation would occur if drugs that would otherwise be available to everyone with a particular condition became available only to a subset people with a particular genotype. The question is whether such a situation