"This is an Accepted Manuscript of an article published by Taylor & Francis in American Journal of

Bioethics August 2007, available online: http://dx.doi.org/10.1080/15265160701462426

Towards a Global Human Embryonic Stem Cell Bank

Jason P. Lott, University of Pennsylvania

Julian Savulescu, Uehiro Centre for Practical Ethics, Oxford University

Keywords: stem cells, banking, immunology, bioethics, organs, transplantation

An increasingly unbridgeable gap exists between the supply and demand of transplantable organs.

Human embryonic stem cell technology could solve the organ shortage problem by restoring

diseased or damaged tissue across a range of common conditions. However, such technology faces

several largely ignored immunological challenges in delivering cell lines to large populations. We

address some of these challenges and argue in favour of encouraging contribution or intentional

creation of embryos from which widely immunocompatible stem cell lines could be derived. Further,

we argue that current immunological constraints in tissue transplantation demand the creation of a

global stem cell bank, which may hold particular promise for minority populations and other sub-

groups currently marginalized from organ procurement and allocation systems. Finally, we conclude

by offering a number of practical and ethically oriented recommendations for constructing a human

embryonic stem cell bank that we hope will help solve the ongoing organ shortage problem.

The global organ shortage grows daily despite intensifying efforts to increase the number of

transplantable organs. Conventional methods aimed at increasing the pool of potential donors have

proved largely unsuccessful, and researchers are now considering alternatives to narrow the supply–

demand gap. Human embryonic stem cells (hESCs) in particular have received considerable attention

for their potential to generate specific tissues and grow entire organs. Unfortunately,

transplantation of hESC-derived tissues remains subject to immunological barriers between recipient

and donor that limit the applicability of stem cell technologies.

We believe creating a repository of hESCs is the most immediate way to overcome these constraints,

although the ethical issues surrounding the foundation of such a bank have yet to be fully explored.

In this article we examine some of the more pressing concerns and argue in favor of establishing a

global hESC bank as a partial, yet promising, solution to the organ shortage problem.

Probably the first stem cell bank in the world opened in the United Kingdom (UK) on May 19, 2004

(Healy et al. 2005). This bank, initially announced in September 2002, has been primarily construed

as a resource for basic research rather than a proximate means to achieve the urgent clinical goals

that concern us here. If this research proves fruitful, however, stem cell banks may become the

blood banks of tomorrow, providing transplantable human tissues for the treatment of a wide range

of common diseases and injuries. Whereas today’s stem cell banks are far from achieving such

panaceas, we will argue that solving the global organ shortage problem is currently well within their

reach.

ORGAN SHORTAGE PROBLEM

The shortage of donor organs and tissues for transplantation costs hundreds of thousands of

unnecessary deaths each year. Approximately one million patients are on dialysis worldwide (Dirks

2005), and in India alone more than 7.5 million people experience chronic renal failure (Dash and

Agarwal 2006). Almost “3 million Americans suffer from congestive heart failure ... deaths related to

this condition are estimated at 250,000 each year ... 27,000 patients die annually from liver disease

... In Western Europe as a whole 40,000 patients await a kidney” (Cooper and Lanza 2000), but only

approximately 10,000 kidneys or so become available each year.

It is unknown how many people fail to make it onto transplant waiting lists or fail to register in

official morbidity and mortality statistics and reports. In addition to donor shortages,

underdeveloped transplantation infrastructures also contribute to the organ shortage problem.

Intensive care beds, skilled transplant teams, quality control mechanisms, and extensive

coordination efforts each demand significant financial, professional, and personal investments,

which are frequently lacking in many countries, especially in the developing world. However,

without increases in the supply of transplantable organs, incentives or attempts to improve existing

infrastructures are unlikely to surface (Erin and Harris 2003; Harris 2003a).

HUMAN EMBRYONIC STEM CELLS

hESCs could help relieve the current dependency on donated organs and reduce the number of

transplant-related deaths. Undifferentiated pluripotent hESCs could be used to repair diseased and

damaged tissue in vivo or grow transplantable tissue grafts and organs in vitro. Combination of both

techniques could significantly narrow the supplydemand gap without causing the negative

externalities usually associated with xenotransplantation, organ markets, paid organ donation

programs, and other strategies that have been previously proposed for improving organ

procurement.

Human stem cells can be classified into adult or embryonic types. Adult stem cells are more

specialized than their completely undifferentiated embryonic counterparts, although both can give

rise to a variety of differentiated cell lines. Current research, however, suggests that the

pluripotency of transplanted adult stem cells significantly diminishes across generations;

additionally, these cells may be exceedingly difficult to propagate in culture (Jiang et al. 2002). By

contrast, hESCs derived from the inner mass of early blastocysts are not subject to these obstacles

and may thus hold the most promise for advancing de novo organ growth and tissue renewal.

IMMUNOCOMPATIBILITY

As with conventional organ transplants and tissue grafts, hESC-derived tissues must be

immunocompatible with the intended recipient. Several immunological constraints must be satisfied

to avoid acute rejection and maximize long-term survival rates. Among the most important criteria

are ABO blood-group antigen-matching and minimization of human leukocyte antigen (HLA)

disparities between donor and recipient.

HLA molecules are proteins normally found on the surface of leukocytes and other cells. These

antigens are known to provoke profound immune responses leading to organ rejection among

transplant recipients receiving tissue expressing different HLA molecules than their own tissue

expresses, similar, in principle, to the immune reactions that result from receiving unmatched blood.

HLA molecules are encoded by a highly polymorphic series of genes found at various loci on the

short arm of chromosome 6. HLA genes found at these loci are generally categorized into two

groups, class I and class II. HLA class I is comprised of genes found at HLA-A, HLA-B and HLA-C loci,

whereas HLA class II is comprised of genes found at many loci, although HLA-DP, HLA-DQ and HLA-

DR loci are the usually considered the most important for transplantation purposes.

There are many different versions of the same gene, called alleles, found at each HLA class I and

class II loci. For example, more than 25 different alleles can be found at the HLA-A locus and are

designated as HLA-A1, HLAA2, for example. Similarly, many different alleles can be found at the

other loci. HLA class I and class II alleles are inherited together as a group from each parent and thus

constitute a haplotype. An example of a haplotype is the set of HLA alleles

A14;B12;C2;DR1;DP3;DQ5. Because healthy individuals have two versions of every chromosome,

including chromosome 6, every healthy person has two HLA haplotypes, only one of which they can

pass on to their offspring.

Whereas ABO incompatibility is an absolute contraindication for transplantation of any organ, the

degree of HLA immunocompatibility depends on the number of matched HLA alleles between the

organ donor and recipient (Thorsby, Pfeffer, and Leivestad 2004). Two individuals are considered

haplotypically identical if they each possess the same two HLA haplotypes. Siblings of the same

parents, for example, have a one in four chance of being haplotypically identical with respect to their

HLA haplotypes.

One way to avoid immunological incompatibility between donors and recipients is by use of genomic

replacement through somatic cell nuclear transfer (SCNT), so-called therapeutic cloning, which could

allow researchers to overcome HLA incompatibility without resorting to toxic and expensive

immunosuppressive drug therapies. SCNT entails removal of the genetic material from a human

oocyte and replacing it with the nucleus of a donor somatic cell. The resulting blastocyst and

subsequent hESC lines are genetically identical to the donor (except for minor differences in

mitochondrial DNA) and are therefore optimally immunocompatible.

In this manner, SCNT could be theoretically be used to create unlimited quantities of perfectly

immunocompatible tissues and organs that would not require the concomitant lifelong use of toxic,

expensive immunosuppressive drug therapy to prevent rejection. This solution to the organ shortage

problem might appear ideal because those currently on waiting lists would need only to undergo

SCNT in order to create their own individualized transplantable organs. Unfortunately, however, the

state of SCNT science is still in its infancy with many barriers left to overcome, as evidenced by the

human SCNT scandal and scientific fraud that recently took place in South Korea, and to date,

derivation of hESC lines from somatic cell reprogramming has not yet been accomplished.

If or when such technological barriers are overcome, however, the practical costs of developing hESC

lines in this manner might be substantial and may limit its immediate applicability. A unique stem

cell line would have to be grown for each patient and then differentiated into the desired tissue, a

process that would arguably require intensive use of medical resources in addition to considerable

time and money. It should be kept in mind, however, that these increased costs must be balanced

against the savings accrued from eliminating the need for immunosuppressive therapy status post

transplantation. Even if SCNT proved to be a more attractive financial option for a given patient

because of the latter, widespread implementation of the technique would likely prove to be beyond

the capacities of most countries’ healthcare systems to offer as an alternative to standard organ

donation and allocation.

Producing large quantities of made-to-order, individualized hESC lines of sufficient purity,

pluripotency, and viability for clinical use is also unlikely to be technically feasible in the foreseeable

future. Human embryos created from SNCT often undergo poor embryological development and are

often unable to reach the blastocyst stage or beyond (Bradley, Bolton, and Pedersen 2002). For now,

further work is needed before genomic replacement can become a reliable source of healthy tissue

for personalized treatment protocols. Aside perhaps from the extremely wealthy, most patients

would likely be pursuing traditional waiting lists and organ allocation programs rather than buying

the chance to receive tailor-made tissues from individualized SCNT, given the considerable risks of

failure or delay.

PROPOSAL: ESTABLISHING A THERAPEUTIC HUMAN EMBRYONIC STEM CELL BANK

An hESC bank is a more proximate and feasible alternative for bridging the donor-recipient

immunological divide. An hESC bank is, in principle, no different than a blood bank. Whereas the

latter collects and stores blood of different types to guarantee a steady supply for patients in need

of transfusions, an hESC bank would collect and store stem cell lines for growing and maintaining

supplies of transplantable organs and tissues. An extensive collection of blood-group O, Rh-negative

(universal donor) hESC lines representing a large number of HLA haplotype combinations could

provide an immediate and persistent source of sufficiently compatible HLA-matched cells for tissue

growth and transplantation. Accordingly, an hESC bank could relieve pressure on current organ

procurement and allocation programs, thereby increasing the relative availability of donated organs

and improving organ transplantation-related health outcomes.

Additionally, by ensuring that an hESC bank contains the most frequently observed haplotype

combinations, a significant percentage of transplant patients could potentially obtain compatible

hESC lines for direct implantation—or tissues and organs grown from these cells—without waiting

for suitable organ donors or enduring the pitfalls predicted for individualized SCNT therapy. The idea

is to populate the hESC bank with a sufficient number of cell lines representing various HLA

haplotype combinations so that a given individual would have a relatively high probability of finding

perfect or nearly perfect HLA-matched hESCs and tissues. Importantly, certain hESC lines, depending

on the various combinations of HLA haplotypes they represent, could possibly serve the transplant

needs of many people indefinitely, reflecting both the immortality of these cell lines as well as the

fact that certain HLA haplotype combinations are more prevalent than others in a given population

of individuals.

In this manner, hESC banking may be able to capitalize on economies of scale and avoid the

redundancy inherent in individually oriented SCNT protocols. However, a major difference between

HLA-matched and SCNT-derived tissues, briefly and previously alluded to, is that only the latter

avoids the need for use of lifelong immunosuppressive drug therapy. The reason for this avoidance is

that HLA matching ignores the question of whether other, less immunologically relevant antigens are

matched between donor and recipient. Despite the fact that these other antigens play a

comparatively less important role in determining tissue compatibility, immunosuppressive therapy is

still required for all HLA-matched tissues, regardless of whether these tissues are perfectly HLA-

matched or not (with the obvious exception of tissue shared between identical twins or triplets, for

example, which is antigenically identical for all expressed proteins).

But if immunosuppressive therapy is always required for HLA-matched tissues, then why worry

about HLA haplotypes at all when building an hESC bank? The answer is that the amount of

immunosuppression needed after transplantation varies directly with the degree of HLA matching

between donor and recipient. Patients who receive tissues with higher degrees of HLA matching

require lower doses of immunosuppressive drug therapy and have a relatively higher likelihood of

avoiding transplant rejection or the complications of high-dose immunosuppressive therapy, such as

infection. Recognizing the importance of HLA matching matters when building an hESC bank in order

to offer patients a greater chance of obtaining better HLAmatched tissues than they might otherwise

receive from traditional organ allocation programs in order to reduce subsequent

immunosuppressive drug therapy requirements and minimize the financial burdens, as well as the

morbidities and mortality, these drug regimens typically entail.

An initial source of hESC lines could be obtained from in vitro fertilization (IVF) clinics that freeze

extra embryos following fertility treatment and implantation. Although the exact number of such

“spare” embryos is unknown, more than 60,000 couples undergo IVF treatment each year in the

United States (US) alone, and more than 400,000 embryos are frozen for possible future use

(Hoffman et al. 2003; Schieve et al. 1999) Although a recent study concludes that only 11,000 of

these frozen embryos are explicitly available for research (even fewer are of sufficient quality to

develop into hESC lines), the potential supply is much larger if excess frozen embryos—which are

routinely discarded following successful implantation of their siblings—are included (Hoffman et al.

2003). If similar estimates hold for other countries pursuing IVF, and if roughly as many viable

embryos are destroyed as frozen, then nearly one million spare embryos could be presently available

for hESC banking worldwide.

POTENTIAL PROBLEMS AND POSSIBLE SOLUTIONS

Establishing a hESC bank raises particular ethical issues distinct from broader questions regarding

the moral status of the embryo, informed consent, human dignity, and other much-argued questions

surrounding hESC research. We believe that spare blastocyst embryos lacking neural organization

and cognitive activities are best considered non-persons with no moral status, and thousands of

embryos in many countries (more than 300,000 in the U.K. in the past 10 years alone (Hoffman et al.

2003)) are intentionally destroyed each year as required by domestic laws or due to the wishes of

embryo-donating couples. Accordingly, we believe that using stem cells from embryos that would be

otherwise destroyed is analogous to using organs from individuals that die from car accidents, a

practice which is largely uncontroversial and accepted throughout the world. Likewise, we believe

that there is no outright ethical dilemma in using stem cells from such embryos for hESC banking and

that informed consent to derive hESC lines for this purpose could be reasonably obtained from many

couples, especially given that informed consent is already routinely obtained for intentionally

terminating or indefinitely freezing most spare embryos. Indeed, how could one rationally prefer to

discard one’s embryo than to use it save people’s lives?

Moreover, we believe an even stronger argument can be made that the current needs of transplant

patients outweigh the rights of couples, clinics or disinterested governments to determine the fate

of unwanted embryos. If so, then mandatory hESC banking for the purposes of organ and tissue

development as described previously is preferable to today’s status quo policies of voluntary embryo

destruction or indefinite embryo storage. In the US, for example, hundreds of thousands of embryos

are frozen in storage because fertility clinics are reluctant to destroy them for either fear of litigation

in the absence of legislation or because of explicit requests by donor couples. A modest proposal

would be to use such embryos for hESC banking if donor couples do not expressly determine their

fate, say, five or 10 years after they were placed in storage.

However, hESC banking poses other, more interesting ethical problems that have received less

consideration. These challenges follow from the immunological constraints on tissue transplantation

discussed previously, and their ethical implications for hESC banking cannot be ignored.

Problems

Small Pool of Desirable Donors

Differential frequencies of HLA haplotypes across populations necessarily mean that some blood

group O, Rhnegative cell lines will be more useful than others depending on their HLA compatibility.

For example, hESC lines homozygous for the HLA haplotype A1;B8;DR3 would provide a zero HLA

mismatch for approximately 10% of renal patients at the UK Cambridge Transplant Center, whereas

homozygosity for HLA haplotype A2;B44;DR4 would be maximally compatible with 7% of recipients

(Bradley et al. 2002). Unfortunately these haplotypes occur in less than 1% of the Caucasian

population, so that it may be exceedingly difficult to find the requisite embryos for development of

hESC lines.

Discrimination Against Minorities

Other transplant patients with uncommon HLA haplotypes, especially ethnic minorities, may be less

likely to find compatible embryos within the pool of potential donors (Bok et al. 2004) Such

individuals who are already waiting for organs and are currently marginalized from organ allocation

systems because of similar immunocompatibility problems could potentially receive little or no

benefit from hESC banking initiatives that rely primarily on embryo donations by dominant, non-

minority national populations, despite the fact that in many countries minorities stand to benefit the

most from hESC banking (i.e., from relief of such disproportionately prevalent diseases as type II

diabetes, metabolic syndromes, heart disease, and other related disorders) for which hESC therapies

hold particular promise (Faden et al. 2003; Hussain and Theise 2004; St. John and Alderson 2005). In

fact, their situation could worsen if hESC banking causes a decrease in the total number of organ

donors; incentives to donate could decline and leave these patients with fewer compatible organs

and reduced chances of transplantation success.

Cost of Developing a Complete Bank

Furthermore, no matter what HLA haplotypes are sought, there would soon be diminishing marginal

returns as the number of banked hESC lines grows larger—each additional embryo donation would

increase the number of redundant or unneeded haplotypes. A recent study conducted in the UK

found that a hypothetical hESC bank consisting of 150 cell lines procured at random would provide a

adequate match for 20% of patients waiting for transplantation but that expanding the bank beyond

150 donors conferred little additional benefit with respect to HLA matching and

immunocompatibility (Taylor et al. 2005).

A broad, unfocused search to acquire as many embryos as possible would quickly become more

costly than productive, limiting the overall size of the bank, and leaving only some lucky transplant

patients better off than they were before. These costs have to be considered when allocating scarce

medical resources and must be balanced against other potential methods for increasing organ

supplies, such increasing funding for organ shortage awareness programs and subsidizing the

development of new immunosuppressive gene and drug therapies.

Solutions

Paying for Embryo Donation

Offering incentives to donate embryos with the most broadly immunocompatible HLA haplotypes

could be an effective method of building an hESC bank. These incentives could take a variety of

forms. Suppose, for example, that a couple undergoing IVF treatment has the choice of implanting

several embryos of different HLA haplotypes, some of which are more widely immunocompatible

than others. Financial subsidies could then be offered to partially offset the cost of the IVF

procedure if the couple chose to implant embryos that were not of the desired haplotype and

donated those that were.

Because no characteristic of the potential child’s health or mental abilities ostensibly depends on his

or her specific HLA makeup, one might argue that couples could simply regard this as another

morally relevant issue when picking one embryo for implantation over the next. However, a stronger

case can be made that couples would likely have an interest in choosing embryos with the

haplotypes most likely to be able receive donated organs in the case that the later child would need

a transplant. If haplotyping is performed, couples could then select the “best” haplotype for their

child, according to whatever medical criteria are being employed, following a principle of

“procreative beneficence” (Savulescu 2001a). Regardless, there would be embryos created in the

pool with valuable haplotypes for transplantation purposes, even if parents selected the “best”

haplotype embryo for transfer and this haplotype happened to be the most desirable for banking

purposes.

Subsidies could also be paid to couples considering IVF treatment who could produce embryos of

needed HLA haplotypes but who are unable to afford the procedure. Minority ethnic couples, a

disproportionate percentage of whom are poor, could especially benefit from such incentives,

enabling them to become pregnant and fulfill an important life goal (Jain 2006). In addition, the hESC

lines derived from these embryos could potentially save the lives of thousands of minority transplant

patients, who compete for an extraordinarily limited supply of compatible organs and who are more

likely to die waiting for suitable donors (Foster et al. 2002).

More generally, financial incentives could be offered to all couples who are healthy candidates for

IVF, even if they have no fertility problems and have no need to seek IVF treatment. IVF techniques

have been successfully used for more than 30 years and have proven to be overwhelmingly safe

procedures. Today, for example, IVF enables healthy women to donate their eggs to infertile couples

who can then become pregnant. If we should encourage altruistic or financially compensated

donation of eggs for infertile women in this manner, we should also be comfortable encouraging

couples to produce embryos with much needed HLA haplotypes that could save human lives.

Before proceeding, we wish to pause and acknowledge that inducements or incentives for obtaining

human tissues—be they eggs, embryos, hESC lines, or organs—are not without controversy. Many

research ethics protocols and guidelines, for example, are antipathetic to inducements. In particular,

the Council for International Organizations of Medical Sciences (CIOMS) (Geneva, Switzerland)

guidelines, which carry a good deal of moral weight in many countries, prohibit so-called “undue

inducements” (CIOMS 2002). However, the wording of the CIOMS guidelines is illuminating. They

permit payments in cash or kind but state, “the payments should not be so large or the medical

services so extensive as to induce prospective subjects to consent to participate in the research

against their better judgment” (CIOMS 2002, 18). The qualifying gloss that the CIOMS document

offers on this recommendation is perhaps inconsistent. It states, “Someone without access to

medical care may or may not be unduly influenced to participate in research simply to receive such

care” (CIOMS 2002, 18).

The nub of the problem with the CIOMS and similarly minded guidelines is the question of what,

exactly, makes inducements undue? If an inducement is undue when it undermines “better

judgment,” then neither the existence of nor the level of the inducement per se is morally relevant.

If this definition were true, all jobs, for example, with attractive remuneration packages—not just

financiallyincentivized hESC procurement policies—would constitute “undue” interference with the

liberties of subjects. Anyone who, say, used his or her better judgment to decide whether a

prospective employment remuneration package was attractive would necessarily be unduly

influenced. The CIOMS gloss on their internal guidelines creates a “Catch 22” situation, which is

surely unreasonable and unwarranted. In particular, whenever the best-proven diagnostic and

therapeutic methods are guaranteed by a study for a population who would not normally expect to

receive and derive such benefits from them, this guideline would be broken.

Surely, it is only if the situation is very different that inducements become undue. If, for example, it

were true that no sane person would donate and that only incentives would induce them to

disregard “better judgment” or “rationality”, or if the donations themselves were somehow

immoral, or if participation was grossly undignified, then there would be a legitimate presumption of

undue influence. However, we are talking here about life-saving donations for which the risk-benefit

ratio is highly favorable to donors. Here the balance of protection is reversed—if it is both ethical

and indeed minimally decent to do substantial good at negligible risk, then what objection could

there be to inducing people to do that which they should be willing to do without inducement?

Already, infertility treatment is subsidized in the UK to couples willing to donate eggs under so-called

“paid egg sharing programs” to other infertile couples (Blyth 2002). If subsidy can morally be offered

for the sake of giving people the chance to have a child, it can morally be offered to give people the

chance to live.

Creating Embryos

Why restrict hESC banking to spare embryos that have been donated by IVF clinics and couples? If

human embryos are strictly non-persons lacking moral status, then there is no reason why embryos

should not be created specifically for stem cell development and banking. This line of reasoning

becomes even more compelling if one considers again that most embryos created for IVF use will

never become actual persons and will probably be destroyed. If it is acceptable to intentionally

create and destroy embryos while providing no benefit to anyone—including the embryos

themselves—then surely it is also acceptable to create and destroy embryos to derive hESC lines,

which have the potential to provide enormous benefits for countless transplant patients (Savulescu

and Harris 2004).

Embryos could be selected from combinations of genetically screened sperm and eggs donated by

existing banks or individuals. Offering financial rewards to increase donation rates would once more

be appropriate, especially since such incentives are already in place. Highly sought-after HLA

haplotypes could then be more easily targeted without relying exclusively on spare embryos

supplied by IVF clinics. In countries such as the UK, where the government explicitly endorses hESC

research and where numerous ethnic and racial sub-populations co-reside, HLA screening of

embryos created from sperm and egg donors could potentially contribute a variety of desirable

haplotypes for hESC banking.

Globalizing Stem Cell Banking

hESC banking should be an international endeavor and not isolated across individual countries.

Obtaining embryos from as many distinct regions as possible and allowing global access to derived

hESC lines would increase the diversity of banked cells and improve access to HLA haplotypes that

may be underrepresented among donated embryos or those selectively created from certain

populations.

For example, African Americans in the US rarely seek IVF treatment and therefore would potentially

donate very few embryos to an hESC bank. Because African Americans are mostly HLA incompatible

with Caucasians donors and other ethnic groups in the US, they would be placed at a significant

disadvantage when seeking HLA-matched stem cells. Again, financial incentives could be used to

subsidize IVF treatments, improve egg/sperm/embryo donation rates, and create specific stem cell

lines, but these alone may be only partly successful in securing adequate numbers of compatible

cells within any localized area.

Globalizing embryo procurement would give African Americans access to a broader range of hESC

lines and yield a higher probability of finding HLA compatible tissues while simultaneously abating

problems of distributional inequity that consistently plague organ and tissue allocation programs in

the US These social welfare advantages would extend easily to other racial groups in the US and

wherever else organ-tissue rationing remains biased against ethnic minorities. Insofar as globalized

hESC banking would also capture a multiplicity of non-minority HLA haplotypes that would otherwise

be unobtainable, the practice would be favorable for Caucasians and other majority groups as well.

New Immunocompatibility Standards

Finally, it is worth considering another measure of immunocompatibility that differs somewhat from

HLA-matching and which may weaken the need for haplotypic diversity among banked hESC lines.

Cross-reactive epitope group (CREG)-matching is an alternative approach to donor tissue and organ

compatibility that classifies HLA-A and HLA-B molecules according to their molecular topology, which

is in turn directly correlated with immunoreactivity to recipient HLA antigens (McKenna and

Takemoto 2000). Polymorphisms of both molecules can be collapsed into 10 major CREG categories

so that immunocompatibility becomes a matter of matching CREGs and not individual HLA

haplotypes.

Consider, for example, two individuals, one homozygous (that is, having two identical copies of the

allele) for HLA haplotype HLA-A1, HLA-B8 and HLA-DR2, and the other homozygous for HLA

haplotype HLA-A3, HLA-B35 and HLA-DR2. According to standard immunocompatibility criteria these

two individuals are HLA mismatched and would be hindered in sharing tissues and organs. However,

because both HLA-A and HLA-B alleles belong to the same CREGs (CREG A1C and CREG BW6,

respectively), these individuals would be perfectly CREG matched and entirely immunocompatible

(McKenna and Takemoto 2000).

Why does each matching standard yield different conclusions? HLA-matching ignores similarities in

shape between HLA antigens and only evaluates identical alleles as immunocompatible. CREG-

matching, on the other hand, recognizes these similarities and allows for more inclusive tissue and

organ sharing across HLA haplotypes. Several studies have confirmed that CREG-matching is at least

as good and in some cases better at minimizing acute tissue rejection after transplantation and

should therefore be regarded as a serious alternative to HLA-matching (McKenna et al. 1998;

Takemoto et al. 1994).

Fewer hESC lines would subsequently be needed if CREGs were matched instead of HLA molecules,

which would mean that fewer embryos would then have to be secured to meet transplantation

demands. This approach could have important consequences in the short run because a greater

percentage of transplant patients could be helped with a smaller initial number of hESC lines. Many

minority ethnic groups could also benefit from adopting this standard because HLA alleles commonly

found among racial minorities and Caucasians are often included in the same CREG category,

implying that both could benefit from the same stem cells. Consequently, an hESC bank built around

CREG-matching might be a much fairer way of improving transplant outcomes while minimizing

expenditures on increasing the diversity of banked HLA haplotypes.

Therapeutic Cloning of Desired Haplotypes

The intrinsic financial and technical problems of therapeutic cloning previously mentioned

notwithstanding, another alternative is to take cells from people who have the most desirable

haplotypes for banking and clone these as a source of hESCs. This harvesting could be performed

voluntarily or non-voluntarily, altruistically or commercially. Although all of these alternatives may

be justifiable in terms of the urgent need to save lives, there are good reasons to avoid if possible

“cellular conscription” and using non-voluntary methods. One possibility is to use leukocytes from

donated blood that is no longer required for transfusion purposes. This could be accomplished if

blood donors are informed and their consent sought if their blood is no longer needed. Alternatively,

this approach could be used for all donated blood destined to be discarded—according to the

common principle of waste avoidance—without the consent of donors. This widely shared principle

assumes that it is right to benefit people when we can and wrong to harm them otherwise and

states that, when faced with the choice between using resources for a beneficial purpose versus an

alternative use in which those resources are wasted, we have powerful moral reasons to avoid waste

and do good instead (Harris 2003b).

CONCLUSION

hESC medicine has the potential to cure many transplantrelated diseases and prolong the life of

transplant patients. However, immunological restrictions between donor and recipient apply equally

to organs and tissues derived from hESC lines, signaling the need for an amassment of embryos with

highly compatible HLA haplotypes. Debate is needed in advance of impassioned calls for treatment

on the most appropriate supply of embryos. We have argued that proper ethical consideration of

patient interests, fairness, and practical constraints indicate this is best achieved via establishment a

global, centralized hESC bank. We have therefore advocated measures to increase embryo

acquisition and hESC development toward this end, offering a number of immunologically oriented

considerations that have so far received little attention but which nevertheless deserve to be at the

center of any informed hESC banking debate.

ADDENDUM

Faden and her colleagues (2003) published the landmark article on establishing a public stem-cell

bank in 2003. That article was not given the prominence it deserves in our current paper. Faden and

her colleagues (2003) gave a meticulous analysis of the problem of “biological access” and supported

four strategies to reduce rejection: immunosuppression, induced tolerance (e.g., by mixed

chimerism), HLA matching, and genetic modification of cell lines to reduce the tendency to provoke

an immune response. To deal with the problems of the small pool of donors, discrimination and cost,

Faden and her colleagues (2003) argued that HLA haplotyping could be used according three

strategies: the coveragemaximizing approach, the equal-chances approach, and the ethnic-

representation approach. The coverage-maximizing approach aims to provide matches for the

greatest number of people in the population, which would favor Caucasian Americans. The equal-

chances approach promotes “fairness by giving all persons with haplotypes that can feasibly be

represented in the bank the same chance at biological access to stem cell-based therapies.” The

ethnic-representation approach, favored by most of the authors in Faden et al. (2003) and Bok,

Schill, and Faden (2004), would “select the most common haplotypes from each of the major

ancestral/ethnic groups in the United States in order to make the hank useful to the same

percentage of patients from each ethnic category” (21).

Our solution to these problems of small pool of donors, discrimination, and cost is to increase

donation of all the appropriate cell lines, without commitment to any theory of justice by:

(1) Paying for “donation”: Faden and her colleagues (2003) explicitly reject this approach, and we

defend this approach. One of us (Savulescu) has defended elsewhere the payment of volunteers to

take part in risky research (Savulescu 2001b) and the same arguments apply here. Whereas risk is

involved in generating hESC lines, the only ethical issue is ensuring that donors are fairly

compensated for risk and a minimum price set for providing hESCs to prevent exploitation. Just as

we have a minimum wage to prevent exploitation in labor markets, we should set a minimum price

for providing biological material for the derivation of valuable hESC lines. We do not restrict this

approach to a proposal for paying people already undergoing IVF for their spare embryos. We also

tie this approach to a proposal to pay or subsidize healthy people or infertile people with desirable

haplotypes to have IVF when they would not otherwise have this procedure.

(2) Creating embryos with the desired haplotypes, with fi- nancial incentives.

(3) Creating a global stem cell bank: Faden and her colleagues (2003) support a public stem cell bank

in the U.S. However, because this tissue is immortal, material could be exported all around the world

without diminishing supply in the host country.

(4) Setting new immunocompatibility standards, using CREG rather than HLA typing.

(5) Therapeutic cloning of valuable haplotypes: We canvass the possibility of therapeutic cloning

non-voluntarily or using leukocytes from blood that is no longer required.

(6) Finally, we argue for mandatory hESC banking for organ and tissue development, as opposed to

voluntary or collaborative stem cell banking proposals.

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