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A peer-reviewed electronic journal
published by the Institute for Ethics and ISSN 1541-0099 16(1) – June 2007 |
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Xenotransplantation and the
harm principle: Factoring out foreseen risk An Ravelingien, PhD Research Assistant, Department of
Philosophy, Journal
of Evolution and Technology - Vol.
16 Issue 1 - June 2007 - pgs 127-149 Abstract Xenotransplantation
– the transplantation, implantation, or infusion of live cells, tissues or
organs from a nonhuman animal source into humans – has been suggested as the
most imminent strategy to alleviate the shortage of human grafts. The pursuit
of this technology is nonetheless restricted by an unquantifiable risk that
the use of animal grafts will unleash new zoonoses
that may affect the public at large. This paper is concerned with what the
proper response to this public health threat should be. We will demonstrate
that the regulatory measures taken to prevent secondary infections currently
do not warrant full-blown protection of public health. That reality forces us
to reconsider the extent to which the public should be guaranteed protection
from a xenotransplant-related health hazard. In
pondering that question, we will suggest that the permissibility of health
hazards posed by emerging (bio)technologies is
dependent on the perception that the benefits are both substantive and
attainable and on the duty to account for foreseeable risks. In that sense,
there is both good and bad news for the acceptability of xenotransplantation.
An increased understanding of the infectious agents that are known to pose a
health risk, relates the man-made health threat to risks that have a natural
origin. 1 The risk of a xenogeneic pandemic On
18 January 2006, 90,628 patients were enlisted on waiting lists for an organ
transplant across the Researchers
are developing new technologies that yield the outlook of virtually limitless
supplies of transplantable grafts. One of those possibilities is the use of
organs, cells and tissues from specially bred, genetically modified pigs, a
procedure named xenotransplantation. According to
the proponents of this emerging biotechnology, the use of porcine grafts will
alleviate the burden of organ disease sooner than alternative strategies,
such as the use of artificial replacements or regenerative medicine (Cascalho and Platt, 2005). Specially engineered pigs
could also provide suitable organs for infants, for whom the organ shortage
is the most devastating, and for individuals who do not accept human organ
donation for ethical or cultural reasons. Moreover, safe and effective xenotransplantation should annul many of the practical
and emotional burdens related to the long waiting times for an available cadaveric donor organ (Groth
2005). With a source of grafts readily available, the transplantation
procedure can be scheduled and prepared well in advance. Recipient
pre-treatment can be conducted and the quality of organs can be screened in
detail. Xenotransplantation may also widen the
indications for transplantation. Applications of unlimited sources of
animal-derived cells and tissues could potentially address currently unmet
medical needs such as incurable neurological diseases, epilepsy, chronic
intractable pain syndromes, paraplegia due to spinal cord lesions and insulin
dependent diabetes. The
development of xenotransplantation over the past
century has defined many challenges in terms of cross-species immunology and physiology that remain to be met before xenotransplantation, of organs in particular, will be a
viable routine therapy. However, the major brake on clinical use of xenotransplantation procedures relates to the possibility
that the use of animal grafts may facilitate adverse effects to third parties
not involved with the potential clinical benefits. Theoretically, xenotransplantation could allow transmission of either
recognized or novel infectious agents along with the xenograft
and contaminate the xenotransplant recipient,
his/or her intimate contacts and health care workers, and, at worse, the
public at large. It
is well established – and topically illustrated by the recent outbreak of
H5N1 Avian Influenza – that most of the infectious diseases that have emerged
over the past decades can be traced to animal-derived viruses, bacteria, or prions that have passed onto or adapted in human hosts (Murphy 2002, 2). Xenotransplantation appears to pose a particularly
pertinent health hazard. That is due to the fact that transplantation
bypasses most of the patient’s usual protective physical and immunological
barriers. There is also lack of knowledge about the behavior
of source animal-derived infectious agents in immunosuppressed
humans. Moreover, the risk of xenogeneic virus
transfer materialized with evidence that a family of porcine endogenous
retroviruses (PERVs) can infect human primary cells
and cell lines in vitro and can adapt to those cells by serial
transmission on uninfected cells (Patience et. al. 1997; Le Tissier et. al. 1997). In contrast to exogenous
retroviruses, endogenous retroviruses are deemed particularly problematic
because they are resident as proviruses in the DNA
of the host, and thus difficult to exclude. This paper is concerned with what
the proper response to this public health threat should be. 2 Xenotransplant
regulation In a
cautious, initial attempt to define and determine the seriousness of the risk
posed by use of pigs as xenograft source animals, Patience
et. al. (1998a, 539) identified several questions that needed answering
before we can decide whether xenotransplantation
experiments on humans should proceed. More knowledge was required in terms of
the micro-organisms present in the donor animals, the likeliness of
cross-species microbe transfer to cause disease in humans, and the likeliness
of and capacity for potential cross-species microbe transfer to elicit a
human pandemic. In the absence of full scientific certainty, several pleas
for a moratorium were made (Bach et. al. 1998; Butler 1998; COECM 1999),
preferring to circumvent the risk altogether. In most regulatory authorities,
however, de facto moratoria in name of the Precautionary Principle
were soon replaced by stringent national oversight of adherence to detailed
safety protocols for xenotransplantation research
and clinical trials. The
suggested protocols (see for instance US FDA 1999; US PHS 2001; UKXIRA 1999; COECM 1999,
2003; EMEA 2003; OECD 1999, Working Party on Biotechnology 2001; WHO 2001,
2004a) apply to the procurement and screening of source animals, the clinical
and pre-clinical testing of xenotransplantation
products and the post-xenotransplant monitoring of
recipients. Perhaps the most essential, and certainly the most problematic
aspect of the recommended safety measures is the requirement of long-term
(possibly lifelong) surveillance of the prospective recipients. In order for
a clinical trial to be accepted, xenotransplant
guidelines require ensured traceability of the prospective recipients’
whereabouts. To facilitate the tracking process in event of an infection,
various nations are developing computerized registers for all xenotransplant product recipients. Prospective recipients
must also consent to the potential need for confinement or specialized
medical housing. The recipients’ current and future close contacts, too, must
be notified of the infection risk and asked to take appropriate measures to
restrict exposure to others. The prospective recipients will be responsible
for taking appropriate precautions for sexual and non-sexual contact. Among
the more stringent requirements, it has been suggested that the prospective
trial recipients should refrain from having children. These monitoring
requirements will be applicable even if the clinical trial fails to obtain
sufficient graft survival (‘imposed extended compliance’). It
is highly questionable whether such recommendations are the appropriate
response to the threat of xenogeneic infectious
diseases. The need for long-term monitoring will undoubtedly have an effect
on the freedom and privacy of prospective xenograft
recipients (and their close contacts). It is particularly unclear whether
that is something we may demand from patients who aim to improve their
quality of life (Ravelingien and Braeckman 2005).
Moreover, and given the high rates of non-compliance to health
recommendations after an allotransplantation (Hilbrands et. al. 1995), it is unclear whether the
consenting recipients would be continuously willing and able to adhere to the
extensive and stringent supervision. In order to protect public health, then,
it will be necessary to enforce adherence to a person’s prior consent
against his or her later wishes. Most crucially, however, even if it can be
argued that such enforcement is ethical, the legal means by which compliance
can (and should) be enforced prior to a demonstrable state of public
health emergency have not yet been set in place (Florencio and Ramanathan 2001; Florencio and Ramanathan
2004). Although forcible isolation of infected individuals goes back (at
least) to cases of leprosy in the Middle Ages (Lachmann
1998, 297),
enforcement of public health measures is dependent on evidence
that the individual has in fact contracted an infectious disease and poses a
public health hazard. Current public health law provisions cannot enforce
long-term surveillance when the recipients are asymptomatic and the nature
and communicability of possible pathogens are undetermined. Another
problem for current xenotransplant regulation is
the difficulty of ensuring adherence to the (costly) surveillance measures by
the transplant centers themselves, particularly in
nations that do not have appropriate national oversight in place. In the
understanding that the risks of xenogeneic virus
are not confined to the nation in which an outbreak initially occurs, great
effort has been put to establish international cooperation for the protection
of public health on a global scale. The Council of Europe Committee of
Ministers (COECM 2003), the Organization for Economic Co-operation and
Development (OECD 1999, 46), the World Health Organization (WHO 2004a, 2),
the European Agency for the Evaluation of Medical Products (EAEM 2003) and
the International Xenotransplantation Association
(Sykes et. al. 2003, 194) have urged international collaboration to develop
universal standards of good practice. Those institutes recommend that
clinical applications of xenotransplantation should
not be carried out without effective national regulatory control and
surveillance mechanisms and/or without specific authorization. Nonetheless,
there are verbal reports that pig-to-human transplant experiments are
currently being conducted in countries without proper oversight (Cooper 2005;
Rood and Cooper 2006). Those reports indicate that at least 400 islet
transplants and 2,000 bovine cell transplants for pain relief have been
conducted in In
light of these difficulties in preventing xenozoonosis,
the current regulations can be regarded as flawed attempts to address the
Precautionary Principle. They raise false expectations that the risks will be
eliminated altogether. That reality forces us to reconsider to what
extent the public should be guaranteed protection from a xenotransplant-related
health hazard. As a response, we will suggest that a more feasible and
acceptable control of xenotransplantation research
and trials is attainable when a distinction is made between the relevant
social norms for different types of risk. 3 Do as you wish, but do not make a nuisance of
yourself to others
Xenotransplantation involves the conflict of two
intuitively felt moral duties. By not pursuing xenotransplantation
trials, we are refraining from helping waiting-list patients who currently
have no alternative to life-saving treatment. In other words, we are
potentially allowing preventable deaths. By pursuing xenotransplantation
trials, on the other hand, we could help some individuals at the cost of
harming (possibly many) others, with harm broadly defined as affecting
someone’s interests adversely. The
above-mentioned xenotransplant protocols suggest
that the duty not to harm others is the weightiest principle. This appears to
be in keeping with the maxim “Above all [or first] do no harm” (Primum non nocere),
which is sometimes (although incorrectly) deemed the essential principle
underlying the Hippocratic tradition of medical ethics (Beauchamp and
Childress 2001, 113). Within a purely medical ethics context, however, the
duty not to harm would not necessarily enjoy priority over the duty to
provide benefit. The principles serve as a guide for good clinical practice
to patients and have a prima facie character rather than a definite
hierarchy. Whether or not in a given situation the principle of nonmaleficence overrules the principle of beneficence is
co-dependent upon two other principles: respect for persons and equitable
distribution of benefits and burdens. In considering the role of those
principles, it seems to matter whether the person to be harmed is the very
same person who is to be the beneficiary or some other person. In
Kantian ethics, acknowledging a person’s autonomy implies viewing persons as
ends in themselves and not merely as a means to the ends of others. Each
person merits respect for his or her ‘private sphere’, in which he or she is
sovereign and free to determine his or her own destiny. As a moral notion to guide
our acts, that implies that an individual with the necessary critical mental
capacities to act as an autonomous agent may not be restrained by controlling
interferences from others. Strong defense of
personal sovereignty will grant autonomous beings the right to act in such a
way that is of harm to them – even when the decisions are unreasonable or
when they imply an alienation rather than fulfillment
of autonomy – as long as the act is done voluntarily and knowingly of the
effects (Feinberg 1986, 52-97). Within the medical ethical context, milder
trends towards anti-paternalism are more prevalent. As such, a patient is
generally assigned a right to consent to medical research or therapies that
are potentially harmful to his or her health on the additionally specified
condition that the risks are reasonable in relation to the potential
benefits. From that perspective, we can imagine that a recipient will be
willing to accept a xenotransplant, fully knowing
of the potential of xenogeneic virus transmission.
For the patient, that risk may to a certain extent and in severe cases be
counterbalanced by the potential benefits. Nevertheless, the least stringent
and most basic limit of personal sovereignty is set to those harms that are
also other-regarding (Ibid., 58). This is the ‘harm
principle’ as introduced by John Stuart Mill: The only part of the conduct of any one, for which he is
amenable to society, is that which concerns others. In the part which merely
concerns himself, his independence is, of right,
absolute. (Mill 1859) The
duty to respect the autonomy of others makes a strong case against the moral
permissibility of secondary xenogeneic virus
transfer. The case could also be made in reference to the fact that, for the
general population, the harm of a xenogeneic
epidemic will not be counterbalanced by the benefits. That is particularly
compelling when placing the notion of just health distribution in a global
context. The developing world, most parts of which lack even the most minimal
health care, will not have access to the benefits of that expensive
technology (in effect, a critique against most high-tech medical therapies)
but will rather be confronted with yet another health burden. In principle, the conflict between the autonomy of
the beneficiary and the autonomy of others could be resolved if those others
were to consent to the acceptability of the harm involved in xenotransplantation (perhaps, in the belief that they
themselves may one day benefit from the therapy). However, consent of all
those potentially involved in the harm at stake is virtually impossible. In
practice, seeking collective consent would apply to public consultations on a
national level. The important role of public input in the decision whether or
not to proceed with xenotransplantation has indeed
been emphasized (Bach et. al. 1998, 141; Sykes et. al. 2003, 198), but so
far, the various national efforts have not yielded unanimously positive
acceptance rates. Rather to the contrary: public consultations in Canada, the
Netherlands and Australia rendered overall recommendations not to proceed
with clinical trials until the risks were better understood and could be
better managed (Einsiedel 2004, 1110-1). However,
when such nations decide not to engage in further trials, they have no
assurance that they will be protected from the harm they do not wish to
accept. The harms of infectious disease will not be restricted to the country
in which the transplant is performed. With an imperfect guarantee of
recipient compliance to the safety measures, the chance that they can be
identified and confined at those nation’s borders are inherently uncertain. The
moral weight of the harm principle is deeply engrained in our common sense
morality. In fact, we will generally conclude that duties not to injure
others are more compelling than duties to prevent harm or to provide benefit.
A classic thought experiment often used to illustrate this is one in which we
are asked to consider saving the lives of five patients on the waiting list
by killing an innocent person in order to retrieve his or her vital organs (Kagan 1998, 70). While that act would bring about the
best consequences in terms of lives saved, most of us would object to the
means by which the lives are saved. The moral impermissibility of such harm
is not necessarily grounded in deontological principles: it can be supported
on consequentialist grounds as well. The consequentialist could maintain that, although initially
most lives are saved, killing a person for his or her organs would render the
results worse overall. For instance, if the transplants were unsuccessful,
the lives of all six people rather than five would go lost. Alternatively, if
the killing were brought to light, the distress that could cause among the
public would diminish the overall welfare. Moreover, if the public were to
lose trust in the medical community and refrain from seeking medical help, that could result in the unnecessary loss of many
more lives. Notwithstanding
this, even the duty not to harm others is not a moral absolute. Where the
outcomes are clearly favorable in terms of overall
results, this is a consideration to which even some deontic
theories would not be entirely insensitive (Ibid.,
79). In other words, the constraint against doing harm has a threshold at
which point the harm can be outweighed. The problem, however, is that
opinions may vary regarding the level of that threshold. There is no clear
amount of benefit that must be at stake before the constraint against doing
harm can be forsaken. Kagan indicates that the
threshold is rather a function of the size and nature of the harm that has to
be done to bring about the good results (Ibid., 82).
The difficulty of balancing benefit and harm is further complicated in those
cases in which we are not asked to consider the permissibility of doing harm,
but only a risk of doing harm. The nature of the problem is
highlighted by the fact that few of our everyday acts involve no risk
of harming someone else. Some of those everyday acts – Kagan
gives the example of driving cars (Ibid.) – imply risks of serious,
life-threatening harm. That suggests that the permissibility of imposing risk
of harm to others is not solely dependent on the nature and size of harm at
risk; the probability that the harm will occur is also taken into account.
The higher the risk, so it would seem, the higher the threshold. Establishing
the permissibility of risk seems all the more intangible in the case of xenotransplantation. The number of people at stake in
both the benefits and harms is potentially large-scale, while the size and
nature of the harm – whether it be a harmless influenza or a fatal pandemic,
the range in between, or neither – and the probability that any of those
scenarios will occur are essentially uncertain and unquantifiable.
Given that the ‘scientific-descriptive’ component of risk assessment is
thereby lacking, we are compelled to make do with a second component, which
involves an individual and social normative basis (Engels 2000, 185). In what
follows, we borrow two analogies in an attempt to provide additional factors
which play a role in the perception and acceptance of xenotransplant
public health hazards. 4 The ethics of man-made public health hazards
4.1 Analogies
In
her account of the conflict of individual and public interests inherent in xenotransplantation, Martine Rothblatt compares the
situation to the prior development of two similarly risky biotechnologies
(Rothblatt 2004). In both cases, the technologies harbored
a great potential benefit and imposed risks of equally grave harm to the
public. Nevertheless, the situations deviate in terms of tolerance of the
risks. In what follows, we hope to shed light upon the permissibility of the
risk of xenogeneic infections by investigating the
factors that might have led to the different risk perceptions. The
first analogy is drawn in reference to the emergence of antibiotics, which
became a treatment option for a range of bacterial infections in the 1940s (Ibid., 115-122). Rothblatt notes that the antibiotics were
administered with knowledge that improper use could lead to a generation of
resistant forms of bacteria, which in turn could form a major public health
hazard. Indeed, within a few decades, excessive use of antibiotics has
rendered entire new species of antibiotic resistant bacteria which cause an
increasing death toll. The widespread use of antibiotics in both animals and
humans has given rise to new human-borne pathogens as well as new
antibiotic-resistant zoonoses and constitutes an
enduring risk of creating an antibiotic-resistant pandemic. Rothblatt
observes that, in contrast to the current attitude towards xenotransplantation, there is no mention of banning or
severely restricting the practice. The public is willing to accept the risks,
as well as the existing harms, in light of the life-saving benefits provided
and in the confidence that public health regulations can timely manage the
severe harms. The
second analogy is drawn in reference to the development and study of
recombinant DNA technology (Ibid., 122-133). In that
case, the potential scientific and social benefits were not a sufficient
justification and the development of the research went hand-in-hand with
efforts to control and contain public health hazards. Here too, the potential
hazards related to infections from bacteria and viruses. They were taken
seriously from the start and some of the world’s prime molecular biologists
voluntarily implemented a temporary moratorium on the research. In February
1975 stringent requirements were set for the continuation of genetic
experimentation. During the Asilomar meeting, the
scientific expert invitees were confronted with ultimate uncertainty whether
or not cancers or new infectious diseases could result from the splicing of
genes and transfer of chromosomes. Consequently, they decided rather to be on
the safe side and protective measures were established in accordance with a
classification of risk. Experiments that were clearly safe were permitted on the
bench top; (possibly) dangerous experiments were restricted to confined
areas. Those recommendations have since been adopted by governmental agencies
worldwide. Rothblatt
uses the above-mentioned analogies to demonstrate the way forward for xenotransplantation experimentation and clinical
practice. The antibiotics analogy highlights certain conditions, which render
public health hazards acceptable. The permissibility is a function of the
perception that the potential benefits are both significant and attainable
and of the trust that the harm can be effectively controlled once it occurs (Ibid., 120). The emergence of recombinant DNA research
regulation teaches us that mechanisms can be put in place beforehand to
constrain the risks to public health while not necessarily quashing the
potentially beneficial research itself (Ibid., 123).
Rothblatt concludes that xenotransplantation can be
ethically pursued if similar measures are put in place in advance to detect
and restrict related infectious outbreaks globally (Ibid.,
129). Her suggestion is to halt xenotransplant
trials until the detection, treatment and follow-up measures as proposed by xenotransplant regulation authorities are ‘geoethically’ implemented in all nations. This requires a
global buy-in to ensure that even those parts of the developing world are
given the resources to perform effective xenozoonosis
surveillance. The buy-in should include establishing basic health care
support in exchange for randomized blood sampling. The
focus of Rothblatt is on a just distribution of health benefits and burdens
and on means to enhance global security. Again, however, this conclusion is a
flawed response to the Precautionary Principle. She cannot ensure that the
global safety measures will be universally adhered to. Nonetheless, the
analogies she brings forward are useful. In our view, the distinctions
between the two case studies reveal extra factors that are relevant when
questioning the permissibility of man-made public health hazards. These extra
factors do not necessarily require full-proof adherence to xenotransplant regulation. 4.2 Foreseeable risk
A
first relevant distinction between the analogies relates to the perception
that the potential benefits are significant and attainable. Arguably, such a
perception was more apparent in the advent of antibiotics than in the
emergence of recombinant DNA technology. The potency of antibiotics to
decrease the high percentages of mortality and complications due to
infectious diseases was apparent upon its discovery in 1928: pre-clinical
data demonstrated the ability to destroy a common bacterium that was
associated with sometimes fatal infections (Staphylococcus aureus) (Bass et. al. 2001). A decade after that
discovery, during which diverse technical difficulties were overcome, Howard
Florey, Ernst Chain and Norman Heatley were able to
show penicillin’s capability to provide cures for a wide variety of
conditions. By contrast, the advances in therapeutic applications of
recombinant DNA technology have been slower and the importance of its
potential much more contested. The
recombinant DNA analogy also shows evidence of less public trust that the
risks will be manageable at the moment they occur. Instead, it is indicative
of an increased demand to prevent the risks beforehand. That may very well be
a partial effect of the various time frames. Rothblatt indicates that the
invention of new antibiotics in the 1950s and 1960s convinced society that
the emergence of sub-types of antibiotic-resistant bacteria should not pose a
great problem (Rothblatt 2004, 116). Arguably, that trust echoed the
confidence and public support of medical and other scientific research at a
time when laboratory efforts had successfully been mobilized for war
(Frederickson 1991, 259-260). The fruits of those experiments were reaped in
the scientific boom years of the 1950s. Asilomar,
by contrast, is indicative of a turning point in the ethics of science. It
marked the first time that scientists engaged a social contract with society.
The moral impermissibility of knowingly exposing a population to
manufactured risks appears to have increased in significance during the past
century. That may relate to the fact that many risks associated with
contemporary technology transgress former spatial and temporary limits (Welsh
and Evans 1999; 202). The greater focus on accounting for foreseeable adverse
effects in recombinant DNA research may also partly be due to a greater
advance in indications of the risks. In the case of antibiotics, the first
warnings of the risks arose well after applications on soldiers and only one
year prior to widespread clinical use. Antibiotic resistance was marked as a
real threat only after two cases of lethal resistant bacterial infections in
patients occurred in the 1970s (Bass et. al. 2001). That was well after the
scientists were in the position to exclude that kind of harm beforehand. By
contrast, the controversy surrounding recombinant DNA started with evidence
of successful insertion of hybrid genes into E. coli (Rothblatt 2004,
125), of which the adverse effects were evident before they occurred. In that
case, the scientists were in the position to exclude them from occurring
altogether. In
our view, the increased significance of accounting for foreseeable adverse
effects is particularly relevant in understanding the reluctance to accept
the public hazard posed by xenotransplantation. The
case can be further clarified in reference to HIV. Although the current, real
impact of the HIV pandemic relates to the worst-case harms of xenotransplantation, much more stringent monitoring and
surveillance measures are imposed on the xenograft
recipient than on a patient affected by HIV. It has been proposed that the
crucial distinction lies in the fact that xenotransplantation
will be introduced purposely as a clinical experiment, whereas HIV is
an ‘experiment’ of nature (Cooper and Lanza 2000,
216). It appears to make a difference to us whether harm was due to natural
causes or knowingly brought about by the action of another person. That
difference is tied to notions of individual responsibility and human agency (Teuber 1990). This is not to say that moral
responsibility is attributed to only those effects that were purposely
pursued. Rather, the underlying reasoning would seem to be that we are in the
position now to annul foreseeable adverse consequences and thus have a
particular moral responsibility to do so. Indeed, the freedom and autonomy of
HIV/AIDS subjects is respected to the extent that their acts exclude
foreseeable events of virus transmission. If
the permissibility of health hazards posed by emerging (bio)technologies
is dependent on (1) a favorable perception of the
feasibility and significance of the potential benefits and (2) on the duty to
account for foreseeable risks, there is both good and bad news with regard to
the development of xenotransplantation. 5 Foreseen risk and benefit
5.1 The bad news
Proponents
of xenotransplantation have long defended the added
values of applying solid organ xenotransplants to resolve
the organ shortage problem. An unlimited source of animal grafts could help
not only those patients who currently die while on the waiting lists, but
also the individuals who are not enlisted on the transplant waiting lists,
who are withdrawn from a list prior to their death or who have not accepted
human organ donation for ethical or cultural reasons. Moreover, if a
sufficient supply of xenografts were readily
available, the transplant procedure could be precisely scheduled and
preparatory measures could be facilitated (Groth
2000, 833). As such, both the graft and the recipient could be thoroughly
screened prior to the transplant and the diverse patho-physiological
effects of brain death on the organ quality could be avoided. Nevertheless,
xenotransplantation is not a heaven-sent timely
solution to the limits of allotransplantation.
While attempts to transplant nonhuman animal organs to humans go back to the
beginning of last century, xenotransplantation has
not been able to live up to its promises to this day (Deschamps
et. al. 2005). After the failures of early experiments, interest in xenotransplantation was rekindled in the 1960s, motivated
by a first wave of human donor shortages (prior to the implementation of the
brain death criterion) and by increased knowledge of immunology. During that
period, several xenotransplant trials were
conducted parallel to some of the first non-related human-to-human allotransplants. In terms of the results achieved within
both experimental fields at that time, Keith Reemtsma
achieved outstanding survival rates of 63 days and 9 months after the xenotransplantation of nonhuman primate kidneys (Reemstma et. al. 1964). Those survival rates remain by
far the longest ever achieved in animal-to-human organ transplantation,
whereas allotransplantation has since made great
strides forward. It
appears unlikely that xenogeneic organs will
survive and function in humans for prolonged periods in the near future. Sir
Roy Calne, one of the pioneers of the xenotransplantation enterprise, recently pictured that
negative outlook. In a commentary entitled ‘Xenografting
– the future of transplantation, and always will be?’,
Calne doubts that therapeutic xenografts
will be obtained within the next five to ten years (Calne
2005, 6). The prospect of using xenotransplantation
as the medium to avert the waiting list death toll is currently based more on
rhetorical promise than on feasible potential. Indeed, due to the failure to
materialize significant progress to the clinic, private industry has
increasingly withdrawn or suspended commitment in this area (Pierson 2004,
391). The success of xenotransplantation is
obstructed mainly by immunological incompatibilities. Due to the short
survival rates obtained to date, the impact of subsequent rejection phases is
not yet entirely manifest. The many physiological and biochemical
incompatibilities between swine and humans form yet another source of factors
that stand in the way of effective and successful use of xenogeneic
organs. Currently,
most hope and effort are dedicated to various cellular xenotransplants
and extracorporeal perfusion therapies. The transplantation of animal-derived
cells is also very promising in terms of treating a wide variety of diseases,
among which are: diabetes, liver failure, neurodegenerative disease, anaemia,
spinal cord injuries, haemophilia, amyotrophic lateral sclerosis, AIDS,
hypocalcaemia, hypercholesterolernia, lyposomal storage disease and dwarfism (Lanza and Cooper 1998, 40). Nevertheless, many of the
cellular therapies differ in terms of urgency and life-sustaining benefit
when compared to the need for whole organ replacement. Furthermore, the
results of most cellular xenotransplants have thus
far not provided compelling indications of progress in graft survival and
clinical utility. A review of the clinical experience with both
extracorporeal pig liver perfusion and bioartificial
devices containing pig hepatocytes does not
demonstrate a significant benefit for hepatic assist in acute liver failure (Pascher et. al. 2002; Wigg and Padbury 2005). The most imminent contribution of xenotransplantation to the clinic is likely to lie in the
transplantation of porcine islets of Langerhans.
That could provide an alternative to injections of human or porcine insulin,
which are ineffective in fully restoring proper glucose homeostasis. Islet
cell xenotransplantation may eliminate the need for
daily insulin injections and obtain better glucose control. It could thereby
avoid or retard development of the various ills and co-morbidity related to
deficient treatment of chronic diabetes. Islet cells from cadaveric
sources have been shown to provide at least 1-year insulin-independence in
patients with very unstable diabetes (n=7) (Shapiro et. al. 2000). Two recent
reports of more than 6 months of insulin independence in pig-to-monkey
transplants provided promising indications of the feasibility of using islets
from porcine sources too (Hering et. al. 2006;
Cardona et. al. 2006). A recent report of a islet xenotransplant trial in humans suggests that combining
porcine islet cells with Sertoli cells and encasing
them in a semi-permeable encapsulation device is a promising means to
eliminate the immune barrier to cell xenotransplants
(Valdes-Gonzalez et. al. 2005). Although
the latter study is encouraging, the fact remains that xenotransplantation
is overall still “very much in its infancy” (SACX 2004, 2). It is likely that
there will be a long lead time between clinical trials and the commercial
availability of significant numbers of transplantable genetically modified
organs (Welsh and Evans 1999, 210). In effect, given the high costs and
difficulties of breeding appropriate source animals, the question is whether xenotransplantation will ever be able to alleviate
the waiting list death toll considerably. Aside
of these concerns, it is also questionable whether the potential benefits of xenotransplantation are perceived as significant enough
to be regarded a health care delivery priority. Currently, there is reason to
be skeptical about the favorable
attitude of the public in this regard. In 5.2 The good news
In
questioning the attainability of xenotransplant
benefits, we must also take note of the progress that has been made in the
understanding of the level of infectious risk during the past decade. Indeed,
we currently seem relatively well equipped to identify and define the
infectious potential of most known porcine pathogens (Fishman and Patience
2004). Broad
exclusion lists have been generated which provide guidance to breeding out
organisms particular to the source animal species, organisms that commonly
cause infection in transplant recipients and organisms that have a high
inclination for recombination. Those lists also facilitate the screening and
studying of those organisms and the development of possible
infection-suppressive measures. Various potential human pathogens can now be
identified in advance, including porcine circovirus
types 1 and 2, porcine reproductive and respiratory syndrome virus, porcine encephalomyocarditis virus, hepatitis E-like virus, pseudorabies virus, parvovirus and polyomaviruses
of swine (Ibid., 1386). None of these have been shown to cause disease in
humans. Recent research suggests that porcine cytomegalovirus, which has been
shown to cause severe disease even in immunosuppressed
host pigs (Mueller et. al. 2002), can be screened and excluded from herds of
swine by early weaning of newborns (SACX 2004, 22). Conversely, failed
attempts to wean out porcine lymphotropic virus
(Mueller et. al. 2005) and the recent identification of hepatitis E virus
(Van der Poel et. al.
2001) subject those viruses to further risk defining. Significant
progress has also been made in identifying and excluding the infection or
recombination potential of PERV. Archived samples from past recipients of
porcine insulin and clotting factors, temporary skin grafts, islet and neural
cell xenotransplants, and extracorporeal porcine
liver or spleen support have not shown any transmission of PERV or other
porcine virus in patients treated with pig tissues thus far (Heneine et. al. 1998; Patience et. al. 1998b; Paradis et. al. 1999; Dinsmore
et. al. 2000; Levy et. al. 2000; Cunningham 2001). Nor is there a clear
relation between PERV production and illness in pigs, although PERV-C was
originally cloned from a malignant lymphoma cell line (Suzuka
et. al. 1986). Some authors have expressed concern that the promising results
merely reflect the small numbers of patients studied so far, their brief
exposure to the porcine grafts, the poor graft survival and an exclusive
focus on known PERV strains during follow-up. Although the large-scale
follow-up study of 160 patients after transplantation or exposure to pig
tissue (Paradis et. al. 1999) is generally viewed
as the most compelling demonstration of absence of PERV transmission, Collignon and Purdy drew attention to the more negative
outcomes of the study (Collignon and Purdy 2001,
342-3). PERV was in effect detected in the blood of 30 patients. In 23
patients, pig cells were still detected up to 8.5 years after exposure. The
authors suggest that at least the first two of four crucial conditions in
terms of the potential for secondary infection have been fulfilled: the virus
(or its genome) was present in the animal’s cells or tissue and remained
viable in people after transmission of the virus. Furthermore, studies have
recently established the presence of natural immunity against PERV in human
serum, showing that human serum with anti-Gal antibody can inhibit human cell
infectivity of PERV in vitro and in vivo (Bucher et. al. 2005).
That implies that the use of ‘knockout’ pigs that lack the anti-Gal antibody
would entail additional risks. Notwithstanding
this, significant knowledge has been gained on PERV infectivity. Previous
findings had already suggested that only PERV-A and -B can infect human and
pig cells in vitro, while the third subgroup, PERV-C, only infects
porcine cells (Takeuchi et. al. 1998). The other PERV families are unlikely
to encode infectious virus owing to disruptions in open-reading frames. Certain
inbred lines of miniature swine appear to be incapable of producing
replication-competent PERV (Oldmixon et. al. 2002,
3045), and progress in the science of PERV infection of human cells raises
the possibility that the relevant PERV could be genetically engineered out of
a source animal herd (Secretary’s Advisory Committee on Xenotransplantation
2004, 21). Moreover, evidence suggests that PERV is susceptible to currently
available antiviral agents (Wilhelm et. al. 2002). More worrisome are
indications suggesting that, while PERV-C does not infect human cells, it is
involved in extra harmful human-tropic PERV recombinants (Bartosch
et. al. 2004). A recombinant isolate, PERV-A 14/220, has been shown to infect
human cells with a significantly higher titer than
previous PERV-A and –B families. Studies of its genome suggest that it is an
A/C recombinant PERV and that therefore replication-competent PERV-C should
best be excluded from the source animal’s genome. Breeds of miniature swine
have been identified which do not possess replication-competent PERV-C (Wood
et. al. 2004). Alongside
the growing potency to recognize and exclude infection risks, a significant
distinction must be made with regard to the different types of porcine grafts
(Aebischer et. al. 1999, 852). The infection risk
is directly related to the degree of recipient immunosuppression
and the nature and intensity of the epidemiological exposure of the
recipient. Cell-based xenotransplantation products
imply a significantly smaller risk of virus transmission than xenotransplants of vascularized
organs (although at this stage, it could be maintained that vascularized xenogeneic organ
grafts pose the least public health threat due to the limited survival rates
of the recipients (Allan 1999, 63)). Cells can also be best screened for a
spectrum of infectious agents in advance. Moreover, xenogeneic
cell transplant barriers to immunology, such as the above mentioned
encapsulation techniques, may control viral transmission as well. Finally,
it should not be left unsaid that immunosuppressed
allograft recipients too bear a significant, well-documented virus risk,
often with an accelerated course of accidentally-transmitted infection (for
instance, transmission of HIV-1 has been shown to manifest AIDS within six
months (Fishman 2003a)). Over the past two years, six organ transplant
recipients were reported to have died after graft-mediated infection of lymphocytic choriomeningitis
virus, a zoonosis transmitted by rodents (Anonymous
2005, 340). Use of xenografts may be advantageous
in this respect if resistant to human pathogens such as HIV, HTLV, hepatitis
and herpes viruses. Moreover, if a ready source of xenografts
allows scheduling the transplants at the time of greatest clinical need,
exposure to pathogens related to lengthy hospitalizations of donor and
recipient will be reduced (Fishman and Patience 2004, 1388). 6 Implications of revised risk: an optimistic note
In
the following, we wish to interpret the development of findings related to the
virus risk in an optimistic note. We will consider the possibility that all
foreseeable factors that contribute to the risks of a xenogeneic
epidemic can be excluded via current pre-clinical methods of porcine
infectious agent detection and exclusion. 6.1 Theoretical risk
While
the advanced xenogeneic virus research suggests
that the probability of harm is less great than once feared, it does nothing
to change concerns regarding the nature of the risk. Various screening
methods may eventually exclude all pathogens identifiable in pre-clinical
models. Caesarian section and suitable containment
of the source animals may even help to exclude the unknown (Takeuchi and
Weiss 2000, 504). Nonetheless, none of those approaches guarantee that the
theoretical possibility of latent, asymptomatic infection by unknown or
recombined exogenous and endogenous agents is eliminated. Indeed,
undetectable organisms constitute the greatest concern of all, particularly
if they can remain in a latent state within the source animal and recipient
for indefinite time. In contrast to viruses that induce acute symptomatic
viral infections, latent viruses can potentially spread easily between immunocompetent individuals and manifest long after the
initial recipient is released from hospital containment practices. In
questioning the permissibility of risky technologies, the moral duty to
account for foreseeable adverse effects is left undoubted. That moral duty
explains why less stringent control measures are required to preclude risks
from ‘natural’ causes, such as AIDS, in comparison with risks from man-made
causes, such as xenotransplantation and recombinant
DNA research. Nevertheless, a focus on optimal risk assessment to cover all
theoretical consequences provokes the reproach that ‘one cannot prove
something that is not there’. Granted that sufficient pre-clinical detection
and exclusion of known viruses and mutations in the source animals may one
day be feasible, it would be asking too much of those involved in developing
a new technology to guarantee the exclusion of all risks. Indeed, in
comparison with the rationale that underlies our attitude towards the
emergence of other theoretical epidemics/pandemics, it is questionable why
the xenotransplantation enterprise should be answerable
to risks of introducing a novel epidemic or pandemic beyond the degree to
which such risks are constituted by predictable factors. 6.2 Natural and man-made pandemics
If
we were able to reduce the infectious risks related to xenotransplantation
to a merely theoretical risk – one in which all predicable effects
have been eliminated – it would be ambiguous whether we should persist in
treating xenotransplantation as a ‘special case’
and in subjecting it to severe advance public health protection measures. The
only thing that would distinguish the risk of xenogeneic
virus contamination from the contamination of a nature-borne virus, would be the fact that the xenogeneic
virus resulted from human agency. It is not clear why the fact that the harm
results from a man-made technology demands for unequal consideration over
nature-derived harm. The argument works both as a means to put the ‘unique
harm’ of this man-made technology into perspective and as a reminder of our
duty to take ‘natural’ health hazards at least as seriously. First,
the distinction between a natural epidemic/pandemic and a man-made one is not
a relevant factor for those in the medical community concerned with treating
the effects (Fishman 2003b, 911). Also, that distinction is not always
clear-cut. In the emergence of certain pandemics of so-called natural origin,
humans have also played an inflicting role. Notions of moral responsibility
and blame do not apply in such cases, because the effects were unforeseen.
Explanations for the spread of Human Immunodeficiency Virus (HIV) are
illustrative in that respect. There is compelling evidence that HIV (-2 and
some types of -1) is a derivative of Simian Immunodeficiency Virus (SIV) and
was transferred to the human population from sooty mangabeys
and chimpanzees in Most
of the contemporary naturally-caused infections, such as the annual variants
of type A and B influenza, also arise at least in part due to human agency.
The ways we alter the ecology of the world in which we live – through
technology, industry, agriculture, international travel, etc – and the interdependence of humans
and animals are particularly conducive to the emergence of new zoonotic pathogens (Fishman 2003, 910; Lederberg 2002,
114). In a cautious approach to xenotransplantation, the claim is made that: Of course, animals have transmitted viruses and other infectious
pathogens to humans ever since we learnt to hunt or husband them, yet we
continue to meet nasty surprises. (Weiss et.al.
2000, 21) This
does not necessarily serve to demonstrate the unacceptability of the theoretical
risk of xenogeneic infections that are beyond our
control beforehand. Rather, it shows us the urgency to deal with the
persistent manifestation of new epidemics, regardless of their cause. We are
constantly confronted with theoretical risks of epidemics, and xenotransplantation is not per se our greatest concern.
If the risk of xenozoonosis is merely theoretical,
we should rather invest our energy and resources in the battle against all
types of zoonosis, rather than focus on ways to
eliminate just this one, man-made xenozoonosis. Against
that, it may be argued that xenotransplantation
would not be accessible for all those in need of it and could still increase
the health burden of those who are arguably the worst-off in terms of health
care. The worst-off are indeed those in the developing world, which bears
more than 90 per cent of the global disease burden (Benatar
2001, 333) and has neither the financial means nor the infrastructure to
provide large-scale basic health care, let alone expensive technologies to
alleviate organ shortage. Nevertheless, an unjust distribution of the health
burdens would not be alleviated significantly by avoiding the risks of xenogeneic infections altogether. A much greater balance
of health benefits over burdens would be achieved if theoretical xenogeneic infections were regarded as one of the many global
pandemic threats that face all of us today – and in the future – and that
call for rapid response. In thinking of those who are amongst the most
disadvantaged in terms of basic health care, a strong emphasis should be
placed on an estimated 34 to 46 million people affected with HIV/AIDS (WHO
2004b, xii), and on many other infections, such as malaria, which are among
the leading causes of death worldwide. AIDS is particularly illustrative of
the gross discrepancies between the industrialized and the developing world
in terms of infectious health burdens (Boyd et. al. 2000, 68). Sub-Saharan In
any case, the optimistic account of the permissibility of a xenogeneic virus risk is dependent on whether or not we
can exclude predictable factors of the infectious risk beforehand. Even if
that is feasible, still other factors may impede permissibility of xenotransplantation. On the societal level, the question
remains whether this biotechnology must be granted a priority in the
distribution of health care funding. On the individual level, the onus for
those wishing to implement the various xenotransplantation
procedures in the clinic still lies in demonstrating greater proof of the
benefits they promise to provide. That is of importance in terms of
outweighing the remaining risks of physical harm to the future recipients. 7 Conclusion
In
attempts to balance the benefits and harms potentially involved in xenotransplantation, the benefits for the prospective
patients have been subordinated to the risks of unleashing a xenogeneic pandemic. National and international restrictions
on clinical research and trials have been set in place in order to exclude
the risks for the public. However, for both practical and ethical reasons,
these restrictions are inadequate. Indeed, they are a flawed response to the
Precautionary Principle. In this paper, we suggested a different approach,
which does not require that the risk for others is entirely eliminated.
Rather, the most pressing condition for enhancing the permissibility of xenotransplant public health hazards is further identification
and exclusion of the infection or recombination potential of detectable
organisms. Of equal importance is the public perception that the promised
benefits of this biotechnology are both attainable and significant. The
permissibility of harm-doing is then rendered an issue of medical ethics, in
which doctor and patient can consider a weighing of harms against the
benefits of the procedure. While this is the proper direction for further xenotransplant research, the road ahead is still long. Acknowledgements
The
author wishes to thank the Flemish Fund for Scientific Research for the
financial support of this research project. Thanks also to David KC Cooper
and Mike Legge for their valuable comments on an earlier
draft and for their help in reviewing the current state of science. Any
inaccuracies are however the direct responsibility of the author. References
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