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...nonetheless develop gradually. This progressive implementation is the cumulative effect of multitude of discrete individual decision-making processes. Research is initiated into what appears to be a promising line of inquiry or may be a serendipitous by-product of other projects. Investment underwrites this activity, originating in either the public or private sector, for motives of either public health and welfare or profit and return on investment. The end-users of technology, the ostensible intended beneficiaries, accept or reject the applied products of research, either through a considered analysis of the benefits to be gained by adopting a new technology or in the hope that whatever the outcome, it is better than the current alternat ive. Thus, while appearing organic, technological development actually take place within the context of a multitude of decisions at the individual and aggregate levels, from the decision to invest initial resources in research and development, to the decision to commercialize, to the decision to adopt the products of commercialization. Each of these decisions is, at least in part, a reaction to not only a perceived need for technology to address a problem or improve productivity or standard/quality of life, but also to the acceptance of the fundamental changes that will occur as a result of implementation.
While these general thoughts apply to all new technologies, they take on heightened meaning with respect to biotechnology. Research and development in this field along with the concomitant commercialisation of the products of biotechnological innovation, present a unique challenge that we have not had to address in the past technological revolutions that we have weathered. Advancements in biotechnology have the potential to alter not just our environment but our physical embodiment as well. In altering not merely our social, cultural, economic or political environments, but the physical foundations of life itself, the decision to adopt a particular biotechnology may be irrevocable and the results irreversible. There can be no turning back from a decision to alter our biological destiny.
While biotechnology promises to change many aspects of our lives in terms of our relationship with nature and our physical environment, it is in the area of health care that we are most likely to feel the impact of irreversible innovation. To date, this impact has been subtle: we now manufacture, for example, some medications using genetically-modified microorganisms, we provide genetic tests, and we conduct research using our emerging knowledge of the human genome. But the potential of modem biotechnology stretches far beyond these early applications. For example, researchers are working on ways to match medications against a person's genetic make-up in order to reduce adverse reactions and maximize positive ones (pharmacogenetics (1)) and there has been some limited success (but also failure) in inserting non-mutated genes into the bodies of those suffering from genetic diseases (gene therapy). We may also soon have the ability to insert animal organs into human beings in order to replace diseased human org ans. This is called xenotransplantation: the transplantation of an organ or tissues across species.
In each of the above examples, the health benefits to individual recipients of the products of biotechnological innovation are self-evident, although far from uncontroversial. (2) The appropriate balance between the benefits and risks of medical intervention in each individual case is a decision typically made within the confines and confidentiality of a doctor-patient relationship. The appropriate risk management strategies surrounding these decisions are institutionalized in the form of legal rules such as professional ethics, negligence and fiduciary duty. What remains unexamined is the distribution of benefits and burdens amongst various other stakeholders and even the wider population. The outcome of a cost-benefit analysis in relation to a given technological innovation may differ depending upon the unit of analysis. For an individual facing a life-threatening illness, the outcome of adopting innovation under circumstances of scientific uncertainty is likely to be positive, but for the wider population a negative outcome is a distinct possibility. Biotechnological innovation may indeed result in a benefit to the individual recipient, i.e., improvements in the quality or duration of life, but at the expense of increased risk to members of the public in terms of adopting innovation under conditions of scientific uncertainty.
Biotechnological innovation thus raises the question of the appropriate manner in which to reconcile private benefit with public risk. Assuming that a given biotechnological innovation is indeed a viable solution to a given health care problem in a specific instance, and that ethical issues can be addressed in a satisfactory manner, is the risk to the public acceptable? Are there spillover effects in the general population that must be taken into account in balancing the benefits and risks of a given medical innovation applied to individual circumstances? In particular, it should be noted that such spillover effects cannot necessarily be confined to national borders; in a world of increased mobility of both people and goods, an outbreak of infection or disease could easily become an epidemic of global proportions. Given the controversial nature of most innovations in biotechnology in general, and the risk to the greater public in particular, the implementation of biotechnological innovation is not simply an i ssue of consent within a doctorpatient relationship. Instead, a decision must be made within a given community as to whether to even allow the products of innovation to be applied.
Given the varied nature of the risks involved with biotechnology-health, social, and cultural-and the fact that a risk to public health cannot be confined to geopolitical borders, the concept of consent to the introduction of a new technology is difficult to articulate. In order to evaluate whether consent exists, we must address both normative and methodological challenges by defining what we mean by consent in the given context and how to determine whether such consent exists prior to taking any decision to implement new developments in biotechnology. Is consent simply a matter of applying existing principles of representative and deliberative democracy, in that consent may be inferred from the presence of duly enacted legislation? Does consent require the reconciliation
of majority and minority interests through a process of judicial review with reference to constitutional requirements and guarantees? How should we identify a community with the necessary authority to provide consent? When faced with a dil emma in tenns of reconciling private benefit with public risk, how should reconciliation be achieved? (3) Should individual states be permitted to proceed with unilateral implementation efforts, given that the risks of biotechnological innovations cannot be confined to territorial borders?
In this paper, we attempt to construct the necessary analytical framework in which issues such as these can be addressed, thereby bringing order to the difficult task of determining whether a given community has provided the necessary consent to implement controversial innovations in biotechnology. While we focus on one particular biotechnology, xenotransplantation, our general framework is applicable to the introduction of any new biotechnology whether in the health or even agricultural sector.
We begin our analysis with the necessary assumption that in western liberal democracies at least, any decision as to the viability of biotechnological innovation will take into account informed public participation and discussion concerning the identification and assessment of associated benefits and risks. The debate will most likely be framed in terms of whether to proceed with a given technology, and if so, under what circumstances. The necessary public consultation could take any number of forms, including questionnaires, requests for comments, communication through letters, fax or email, or organized public forums. If the end result of the consultation process is a decision to proceed, then institutional design will necessadly follow in order to set into place the necessary regulatory framework and public health infrastructure for implementation.
Our concern is that if either the consultation process or the resulting institutional design is conducted in an ad hoc manner, i.e., without reference to a conceptual framework for the purposes of soliciting and assessing the legitimacy of the public's consent, then any decision to proceed with anew technology is likely to be ambiguous and thus undermine public confidence in the health care system and its administration. Similar difficulties arose when public authorities in Europe ignored the risk of "mad cow" disease and authorities in Ontario failed to ensure that drinking water was properly tested. If we do not know the right questions to ask, the process of collecting answers will at best waste valuable resources and at worst will fail to result in an appropriate (and therefore uncontested) balance between the competing interests involved. Significant deficiencies will not arise until later in the process and will be addressed in a reactive rather than proactive manner.
In an effort to address such concerns before they become problems, we attempt in this paper to provide the necessary guidelines to assist decision-makers in asking the right questions, of the right people, at the right times. We do so by analyzing consent as a function of the nature of the technology in question, the perceived individual benefits and associated collective costs. We have selected xenotransplantation as our case study, based on the timeliness of the issue; the Canadian Public Health Association has recently reported to the federal government on its public consultations designed to determine whether Canada should proceed with xenotransplantation, and if so, under what circumstances.4 The Association concluded that, at present, Canadians are not prepared to proceed with the technology but may be in the future.5
In Part II of this paper, we set out the potential health benefits for recipients of xenotransplants, along with the associated risks to recipients and the wider population, addressing both scientific and ethical concerns. Our objective in this part is to demonstrate that the implementation of xenotransplantation technology cannot proceed in an ad hoc manner, but instead requires a collective decision to implement an institutional risk management structure capable of reconciling private benefits with public risks and potential ethical objections. It is within the design and operation of such an institutional structure that consent plays an important role; given that the risks of xenotransplantation technology cannot be internalized within transplant recipients alone, reconciliation of the costs and benefits of this technology requires consent on the part of others potentially at risk.
In Part III, we set out a conceptual framework for assessing the adequacy of consent within any proposed institutional risk management structure. We divide consent into three related, analytical levels: macro, mezzo and micro; and two contexts: domestic and international. The macro level is concerned primarily with normative definitions of consent, i.e., what consent means within a given community or the factors that must be present before consent is viewed as legitimate. The mezzo level works to formulate public policy within the context of a given biotechnological innovation by recognizing that risk management requires both discrete and continual decision-making. Accordingly, the mezzo level of an analysis of consent demarcates between threshold and process issues. The former entails the necessary consent to proceed with implementation of a given innovation, while the latter envisions a more sophisticated institutional structure for conditional consent that takes account of continual advances in the availabl e store of knowledge. Finally, the micro level exists to operationalize consent by examining various methodologies by which public participation can be solicited and evidence of consent collected and examined.
It is important to note that in developing and articulating a conceptual framework sufficient to address the issue of consent, we are engaging in a process of procedural design rather than advocating for a specific substantive outcome. We are attempting to set out ex ante an appropriate methodology through which issues of consent can be examined for legitimacy, but we do not propose to predict ex poste outcomes concerning the adoption of xenotransplantation technology. Our modest contribution to the debate is to suggest that legitimate consent is more likely to be achieved by understanding consent as a necessary factor in reconciling private benefit and public risk and approaching the process of reconciliation in an organized fashion.
II. Xenotransplantation Technology: Identifying Benefits and Risks
A. Private Benefits: Addressing Organ Donor Shortage Through Xenotransplantation
Between 1988 and 1994, the number of Canadians waiting for solid organ transplants more than doubled. Nearly four percent of those awaiting a kidney transplant currently die before receiving that transplant. Approximately eight percent of those awaiting heart grafts and 11 percent of those awaiting liver grafts similarly die prior to receiving the graft. (6) Other countries face similar scarcity. Japan and the United States report that nearly 5 and 10 people, respectively die every day while waiting for an organ transplant. (7) As waiting lists grow longer, we can only expect these statistics to increase. Given that Canadians lead generally healthy lives, do not frequently die of gunshot wounds, and do not have a high rate of traffic fatalities, we will not soon find an increase in the numbers of organs that are appropriate for transplant. While governments are taking measures to increase the rate at which Canadians donate their organs, (8) we still are unlikely to meet our growing needs.
One alternative for addressing this chronic organ shortage is xenotransplantation, the transfer of living cells, tissues or organs from one species to another, i.e., from animals to humans. This technique has the potential to address a critical worldwide shortage of healthy cells, tissues and organs for medical transplants. By transplanting healthy animal organs into humans, we can provide a sufficient number of organs to overcome the shortfall. Pigs are an especially attractive source for donor organs since their organ size and physiology are in many ways similar to those of humans. Moreover, pigs are relatively easy to breed: they mature early and can be bred in large quantities in highly controlled environments. The perceived benefits to individual recipients are obvious, as individuals on waiting lists for non-existent human organs could be treated instead with xenotransplants.
This is not to say that xenotransplantation does not face significant physiological and immunological barriers. Physiologically, humans and pigs differ in their blood properties and metabolisms. (9) We know, for example, that while porcine insulin can regulate blood sugar levels in humans, primates surviving with porcine kidney transplants have developed anemia. (10) Cross-species compatibility is especially difficult to evaluate given that only a few xenotransplants have survived for any prolonged period. It is reasonable, however, to expect that transplanted complex pig organs will present their human hosts with a number of significant deficiencies. (11) In addition to the physiological differences between pig and human organs, the transplant of porcine organs into a human being will present difficult immunological hurdles. A human body's immune system is very effective at identifying foreign surface proteins so that when an organ is transplanted--no matter how well it is matched to its host--some degree o f rejection will occur. The immunological barriers to xenografts differ from those between members of the same species (allografts) because of the greater molecular incompatibility between host and donor tissue.
Xenotransplantation encounters three distinct types of immunological rejection. The first and most violent form of rejection--called hyperacute rejection--is triggered by the fact that humans and pigs are such different species. Hyperacute rejection results from antibodies in the host attacking antigens on the xenograft. Pigs express a blood group antigen lacking in humans called galactose-[alpha] (1-3)galactose [[alpha]Gal]. (12) Natural human antibodies bind to the [alpha]Gal sugar on the pig organ, destroying it within minutes of exposure to human blood. Second, xenotransplants face acute rejection. It occurs even between species far more similar than pigs and humans, typically within two to three days. (13) Little is known about acute rejection because, while it is similar to hyperacute rejection in that it is caused by antibodies to the [alpha]Gal sugar, it involves a distinctly different process. Third, all transplants, whether from other species or from other humans, must overcome cell-mediated rejecti on to be successful. Because of the differences in species, xenografts face a significantly stronger risk of cell-mediated rejection than do allografts. This form of rejection again arises out of an attack by human T-cells on antigens protruding from the surface of the engrafted cells.
Research aimed at overcoming these immunological reactions continues. While the use of immunosuppresants to control cell-mediated rejection has had some success, it also presents undesirable risks such as drug toxicity and the inability of the recipient to fight off infection normally controlled by T-cell immunity. (14) Other measures being investigated include transplanting a large number of donor cells to overwhelm the human antibody attack (15) and creating transplant tolerance through a mixed bone marrow chimerism approach. (16) A final and more controversial technique to permit xenotransplantation is one based on genetic engineering. By genetically manipulating the donor pigs, we can create transgenic donor pigs whose organs either lack the enzyme that synthesizes aGal or possess human cell membrane proteins that inhibit the chain of events leading to rejection. (17)
Recent scientific developments suggest that we are close to developing technologies to overcome immunological rejection. One study using mice demonstrated that immunization with chimeric peptides blocked the strong T-cell immune response and prolonged the survival of porcine islet grafts in vivo, thus supporting a chimerism approach to immunotherapy. (18) The recent cloning of pigs with the 1,3-galactosyl transferase gene knocked out moves us closer to the possibility of avoiding hyperacute rejection of pig organs in humans. (19) These pigs are genetically modified to not produce the galactose sugar on cell surfaces that is thought to be the principal cause of hyperacute rejection. Nevertheless, even this achievement leads to more questions. Some scientists wonder whether other sugars also trigger hyperacute rejection. (20) Coupled this cloning achievement was the recent report of a cell-grafting approach designed to overcome the immunological problems of xenografting for axonal regeneration of spinal cord in juries. Scientists reported the development of transgenic pigs anned with the gene encoding a human complement-inhibitory protein (hCD59) that shows hope in addressing the problem of natural antibody reactivity. (21) These breakthroughs promise a means to clone genetically modified pigs with great precision. (22)
These recent developments make it not unreasonable to conclude that scientists may soon resolve many of the immunological problems associated with xenotransplantation, making it a genuinely practical treatment. Already, we can measure the survival of xenograft recipients in weeks rather than hours. (23) These individual benefits, however, come with concomitant public risks, not only medical risks beyond the concerns of the individual transplant recipient, but also issues of social and moral acceptability. If xenotransplantation is permitted to proceed in the absence of the consent of those subject to these public risks, then the private benefit to the individual recipient has in effect been underwritten by public costs in terms of the involuntary assumption of risk, notwithstanding that the results of a cost-benefit analysis in the aggregate may have resulted in a negative rather than a positive outcome. In order to understand the magnitude of these costs, it is necessary to examine in greater detail the natu re and extent of public risks associated with xenotransplantation technology.
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