Human Embryonic Stem Cell Lines: The Ethics of Derivation

HUMAN EMBRYONIC STEM CELL LINES: THE ETHICS OF DERIVATION Fran~oise

Baylis, PhD

Departments of Bioethics and Philosophy, Dalhousie University, Halifax NS

Abstract: In Canada it is permissible to proceed with stem cell research using human embryos created by in vitro fertilization (IVF) provided: these were originally created for infertility treatment; they are no longer required for such treatment; and there is an appropriate consent for their research use.As such, IVF human embryos in excess of clinical need are a valuable resource for embryonic stem cell researchers. A point often overlooked, however, is that these excess IVF human embryos are also a scarce resource. Their scarcity suggests the need to develop sound policies and procedures, in a timely and coordinated fashion, to ensure that the few human embryos available for embryonic stem cell research are not used in less important research endeavours or used when other biological materials are appropriate. Injudicious use of the few human embryos available for research use may risk the following consequences: no ongoing research in Canada to derive human embryonic stem cell lines; a reliance on the importation of stem cell lines from other countries for any research on the use of embryonic stem cells; and pressure from Canadian researchers to remove the prohibition on the purposeful creation of human embryos for research use. Resume : Au Canada, il est permis de poursuivre la recherche sur les cellules embryonnaires creees par fecondation in vitro (FIV), pourvu que: elles aient ete creees pour un traitement contre I'infecondite; elles ne soient plus utiles pour ce traitement; et qu'on ait obtenu un consentement eclaire permettant leur utilisation pour la recherche. En tant que tels, les embryons humains excedentaires produits par FIV sont une ressource importante pour les chercheurs qui font de la recherche sur les cellules embryonnaires. On oublie souvent, cependant, que ces embryons humains excedentaires crees par FIV sont aussi une ressource rare. Cette rarete temoigne de la necessite de mettre en place des principes et methodes adequats, en temps opportun et de maniere coordonnee, pour s'assurer que les quelques embryons humains pouvant etre utilises pour la recherche sur les cellules embryonnaires ne font pas I'objet de recherches d'une importance moindre ou qu'elles ne sont pas utilisees quand d'autres materiels biologiques pourraient repondre aux besoins. Si les quelques

KeyWords Human embryo research, stem cell research, scientific merit, legislation, regulation Franc;oise Baylis is an Associate Theme Leader for the Stem Cell Network (A Network of Centres of Excellence) and was a member of the CIHR Ad Hoc Working Group on Stem Cell Research. The views expressed herein are her own. JOGe

embryons humains pouvant etre utilises pour la recherche ne sont pas utilises de fac;on judicieuse, nous risquons de voir les consequences suivantes : il n'y aura plus de recherche au Canada visant a deriver des lignees cellulaires des cellules embryonnaires; nous devrons dependre de I'importation de lignees cellulaires embryonnaires d'autres pays pour pouvoir poursuivre la recherche sur I'utilisation des cellules embryonnaires; des pressions seront faites sur les chercheurs canadiens pour supprimer I'interdiction de creer des embryons humains pour la recherche.

J Obstet

Gynecol Can 2002;24(2): I 59-63,

INTRODUCTION

The promise of human stem cell research is considerable, including the development of stem cell transplants to treat failing organs and to replace diseased or damaged tissues. In the media there are constant references to future stem cell treatments for Alzheimer's disease, Parkinson's disease, heart disease, chronic liver failure, diabetes, and so on, Some researchers argue that to secure these therapeutic benefits it is necessary to do research involving human embryos, while others insist that the relevant research can be done using stem cells derived from less morally controversial sources. I In time we will know which of these arguments is accurate. Human embryonic stem cell research, though controversial, is being actively pursued in a number of jurisdictions. 2 Human embryonic stem (ES) cell lines can be derived from human embryos created by in vitro fertilization (IVF) or created by somatic cell nuclear transfer (SCNT) involving the enucleation of a woman's oocyte. Indeed, research involving both IVF and SCNT embryos is expressly permitted in some jurisdictions, including, most notably, the United Kingdom. 3,4 In contrast, in Canada the prevailing view is that research to derive human ES cell lines should be limited to the use of cryopreserved IVF embryos remaining after infertility treatment. This is the view expressed in the TN-Council Policy Statement: Ethical Conduct for Research Involving Humans (August 1998),5 the Canadian Institutes of Health Research (CIHR) Discussion Paper Human Stem Cell Research: Opportunities for Health and Ethical Perspectives (March 2001),6 the Government of Canada's FEBRUARY 2002

draft legislation on Assisted Human Reproduction (May 2001),7 and the Report of the House of Commons Standing Committee on Health (December 2001).8 Common to these documents is a prohibition on the purposeful creation of human embryos for research use. Only embryos created by IVF for reproductive purposes but no longer required for these purposes are deemed legitimate research material. The limited number of such embryos raises important questions that must be addressed in a timely and coordinated fashion to ensure that the few human embryos potentially available for stem cell research are not used in less important research endeavours, or used when other biological materials are appropriate, such as polyspermic human embryos from IVF fertilizations.

In Canada, at the present time, there are no regulations or federallegislation governing research involving human embryos, but only research guidelines, as outlined in the Tri-Council Policy Statement. As concerns embryonic stem cell research these guidelines are very thin, and for this reason CIHR is developing additional guidelines. Because guidelines are oflimited force, and because research involving human embryos is morally controversial, the federal government is considering introducing legislation. Such legislation would be the ultimate authority with respect to what embryo research would be permissible in Canada. Hints of what might be legislated can be found in the draft legislation prepared by Health Canada and recently reviewed by the Standing Committee on Health. Below, summary details are provided regarding the policy context in which human embryonic stem cell research may proceed in Canada. TRI-COUNCIL POLICY STATEMENT

The Tri-Council Policy Statement applies

to all research involv-

ing humans, which includes human tissues, biological fluids, embryos, and fetuses. These guidelines govern research directly funded by the federal granting councils (including CIHR) and research in institutions that receive funding from the granting councils. These guidelines stipulate that:

of the embryos; there is no transfer to the uterus of any embryos manipulated in ways not directly relevant to their ongoing normal development; and the research does not exceed 14 days. Further, these guidelines expressly prohibit the cloning of human beings by any means, including SCNT. CIHR AD HOC WORKING GROUP ON STEM CELL RESEARCH

The CIHR Ad Hoc Working Group on Stem Cell Research, in its initial Discussion Paper, proposed that research on existing human ES cell lines should be permitted, as should research to derive and study human ES cell lines using IVF embryos no longer required for reproductive purposes. The cloning of humans for either reproductive or therapeutic purposes should be prohibited. More details regarding the scope of research eligible for CIHR funding and the requirements for a morally valid consent to ES cell research are expected in the final document to be released in early 2002. DRAFT FEDERAL LEGISLATION ON ASSISTED HUMAN REPRODUCTION

The Government of Canada's draft legislation on Assisted Human Reproduction states: "No person shall knowingly create an in vitro embryo solely for research purposes."7 Further, the draft legislation proposes that all research involving human embryos be a controlled activity, only permissible under licence issued in accordance with regulations: No person shall, except under the authority of a licence issued under subsection 12(1), make use of any in vitro embryo or part of one for the purpose of research or the prevention, diagnosis or treatment of a disease, injury or disability. The draft legislation also stipulates that: "No person shall knowingly create or participate in the creation of a human clone ... " A human clone is defined as "an embryo that as a result of the manipulation of human reproductive material contains the same nuclear deoxyribonucleic acid sequence as is found in the cell of a living or deceased human being, foetus or embryo. "7 PARLIAMENTARY STANDING

It is not ethically acceptable to create human embryos specifically for research purposes. However, in those cases where human embryos are created for reproductive purposes and subsequently are no longer required for such purposes, research involving human embryos may be considered to be ethically acceptable ... 5 Such research is ethically acceptable provided free and informed consent of the gamete donors has been given; there are no commercial transactions involved, including exchange for service; the research does not involve any genetic alteration JOGe

COMMITTEE ON HEALTH

The Parliamentary Standing Committee on Health has endorsed the elements of the draft legislation that pertain to research involving human embryos. As regards the use of embryos for stem cell research, the Standing Committee further recommends that no licence be issued "unless the applicant clearly demonstrates that no other category of biological material could be used for the purposes of the proposed research."8 This proposed restriction, were it to be included in the revised Assisted Human Reproduction legislation, would narrow the range of permissible human embryo research in Canada. FEBRUARY 2002

IVF HUMAN EMBRYOS DONATED FOR RESEARCH USE

The consensus in Canada is that human ES cell research should be limited to IVF human embryos originally created fo~ reproductive purposes but now in excess of clinical need. The most probable sources of such embryos are existing IVF human embryos in cryopreservation storage that have been (or will be) donated for research use, and future IVF human embryos that will be created for reproductive purposes and frozen for possible later use. In Canada, the total number of human embryos in storage is unknown, as there is no common repository for this information. The total is believed to be quite limited. Current statistics from the Fertility Centre at the Ottawa HospitalCivic Site will serve to make the point about scarcity. Currently the Ottawa clinic does approximately 10% of the IVF cycles in Canada and the clinic's experience with embryo freezing dates back to 1991. Since 1991, 3,252 human embryos have been frozen and currently there are 815 embryos in storage. From 1991 through 2001, 159 frozen embryos have been donated for research purposes. Of these embryos, 109 have been used for research and there are now 50 embryos in storage that are available for research use. 9 If we extrapolate from this data, we can perhaps estimate that in Canada there are currently 500 frozen "excess" IVF human embryos available for research. This total could be a serious overestimation, however, as not all IVF clinics have a ten-year history of freezing human embryos. A program with a shorter history of embryo freezing would likely have a smaller number of embryos in storage for research or other use. Further, some consent forms will not have described (and requested consent for) the possible future research use of frozen IVF human embryos. Other consent forms will have identified research as an option for the disposal of unwanted frozen embryos, but will have done so in a way that would preclude the use of these embryos for stem cell research. This would be true, for example, with any forms modelled on Schedule 2 of the Human Fertilisation and Embryology Act of the UK, where human embryo research was originally limited to diagnostic methods and fertility treatments. 3 Conversely, the estimated total of 500 frozen IVF human embryos available for research use could be a serious underestimation. One reason for this possibility is that not all IVF clinics have the same consent renewal process. In some clinics, the current wishes of some of those who have embryos in storage is unknown; a subset of these individuals might want to donate their frozen embryos for research use. Another factor that seriously compromises the ability to make any kind of accurate estimate of the total number of frozen IVF human embryos available for research in Canada is the difference in policies and practices among the IVF clinics regarding the research use of frozen embryos. While many clinics in which JOGC

cryopreserved human embryos are available for research will use some of these embryos to test culture conditions, train embryologists, and improve IVF and adjunct technologies such as pre-implantation genetic diagnosis, other clinics will sometimes use polyspermic embryos in these situations and thus may have larger numbers of cryopreserved human embryos still available for research. The scope of research undertaken in the clinic clearly affects the number of embryos in storage and potentially available for research use. In future, might the number of frozen embryos increase? To be sure, increased awareness on the part of clinicians and researchers as to the potential benefits of embryonic stem cell research could result in important changes to current institutional policies, practices, and consent forms, in an effort to increase the number ofIVF embryos available for research generally, and stem cell research particularly. As well, increased media attention on the potential benefits of stem cell transplantation (i.e., regenerative medicine), may encourage persons accessing infertility treatment to donate unwanted embryos for research use. These are reasonable assumptions. It is equally reasonable to suppose, however, that these sorts of changes will not result in a major change in the number of frozen embryos available on a cyclical basis for research use for at least the following reasons. First, IVF clinics are already creating the maximum number of human embryos necessary for reproductive success. To change this practice in order to increase the number of embryos created (and possibly made available for research) would be tantamount to the purposeful creation of human embryos for research purposes, which is prohibited, and would expose women to unnecessary high doses of drugs and other additional treatment risks, which is unethical. Second, there is a growing trend for IVF clinics to culture developing human embryos to the blastocyst stage. Many of these embryos die in vitro, and so a reduction in the overall number of embryos being frozen is to be expected. Third, if Assisted Human Reproduction legislation is introduced, it is reasonable to anticipate that some of the smaller IVF clinics may not be able to meet the practice standards established and may close. Some of the larger clinics may be able to increase the number of cycles they do per year, but owing to certain capacity restrictions, it is equally likely that there will be a reduction in the annual number of IVF cycles in Canada and a concomitant decrease in the number of embryos created and frozen for possible subsequent research use. Finally, if ova storage techniques are perfected, there will be less need for, and use of, embryo freezing. For these reasons, an increase in the number of frozen IVF human embryos available for research use is unlikely. In fact, the opposite is more likely once ova storage techniques are perfected.

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A SCARCE RESOURCE

With this background information about the likely sources of "excess" IYF human embryos for research use, consider the following additional facts: 1. At anyone point in time there will be a limited number of frozen IYF human embryos available for research use and the vast majority of these will be frozen embryos. 2. Of the frozen embryos available for research use, not all will be available for stem cell research. 3. Of those that are destined for stem cell research, approximately 50% will not survive the freeze-thaw process to go on to divide. 4. Of those that do go on to divide, and from which the inner cell mass can be removed for stem cell research, perhaps as few as 7.5% will generate cell lines (this percentage is from research involving fresh embryos created for stem cell research using donor gametes and is likely to be an overestimation of the success rate using previously frozen embryos).10 5. Finally, not all of these cell lines will meet Thomson and colleagues' essential characteristics of human ES cell lines, which include prolonged undifferentiated proliferation and stable developmental potential to form derivatives of all three embryonic germ layers even after prolonged culture. 11 For illustrative purposes, we can apply this reasoning to the estimated 500 frozen IVF embryos currently available for research in Canada. For the sake of argument, let us assume that 250 (50%) of these embryos will be used for stem cell research. Only 125 (50%) of these embryos would be expected to survive the freeze-thaw process and go on to divide. Of these 125 embryos, approximately 9 (7.5%) would be expected to generate cell lines. Some, but not all, of these cell lines would satisfY the criteria for human ES cell lines and be available for select stem cell research projects. The small number of ES cell lines likely to be created from the estimated total of 500 frozen embryos available for research (which may be an overestimation if there are fewer than 500 frozen embryos available for research and ifless than 50% of this total is available for stem cell research) brings into sharp focus the need to attend very carefully to the scientific merit of any proposed embryonic stem cell research project. SCIENTIFIC MERIT AND THE PROBLEM OF WASTAGE Iii'

I

7

The requirement of scientific merit can be parsed into the requirements of scientific validity and scientific value: A study is scientifically valid provided it is designed to yield reliable information according to accepted principles of research practice ... A second and distinct understanding of the requirement of scientific merit focuses upon "value" rather than (mere) "validity". A study may be well designed JOGC

relative to its hypothesis, and therefore be scientifically valid, but nonetheless be of no value, generally because the hypothesis itself is trivial or otherwise uninteresting. 12 In exploring this distinction Freedman concludes that whereas scientific validity is a precondition for ethical research, scientific value "needs to be judged within the context of all other elements of the ethics of research, and so should not be put forth as a prior condition for separate consideration." 12 As such, scientific value is not an absolute prior threshold condition for research involving embryos, whereas scientific validity is. In the context of human embryo research, scientific validity, at minimum, requires good research design based on prior laboratory and animal research, competent investigators, and adequate research facilities. Embryological research that is poorly designed and poorly executed wastes embryos - a scarce and valuable research resource. To avoid such wastage, it is particularly important that any proposed research be sufficiently well designed to achieve its purposes and that it occur within a context where there is confidence that the proposed design will be implemented. Secondly, the requirement of competent investigators and adequate facilities highlights the need to avoid other, perhaps inadvertent, types of embryo wastage. If the investigators lack the requisite training and experience in the techniques being used, if the laboratory conditions do not include good culture facilities, facilities for microscopic examination, appropriate incubators, and training in "non touch" techniques, or if the security, record-keeping, and labelling practices are inadequate, it is again reasonable to anticipate wastage of research material. In addition to the requirement of scientific validity there is the requirement of scientific value. This requirement underlines the need to avoid embryo wastage in experiments where the hypothesis is unimportant and uninteresting, where the research would generate non-generalizable results, or where there is substantial overlap with proven research results. 13 As well, in recent years the requirement of social value has been added to the requirement of scientific value to underline the importance of pursuing research of potential benefit to individuals and the community-at-large. In sum, ethical embryo research must be valuable, where "value" encompasses both scientific interests as well as social consequences. Taken together, these requirements - scientific validity and scientific and social value - argue for a coordinated approach to the research use ofIYF human embryos, to effectively ensure that these embryos are used for the very best project(s), by the very best team(s), with the very best facilities. From this viewpoint, human embryos should not, as a matter of course, be available to the highest bidder, the most senior investigator by reputation, or the most proximate research team. One conclusion that follows from this is that all human embryo research, whether privately or publicly funded, should FEBRUARY 2002

be subject to national rigorous scientific peer review and research ethics review. This review should be of the highest quality and a model of openness and transparency. By itself, however, national review may not address the problem of scarcity, since there may be many more valid and valuable research projects than could successfully be undertaken with the few IVF human embryos available for research. To address this problem, the traditional review system would need to be substantially modified to allow for a comparative evaluation of projects on the basis of "value." Comparing the relative value of different research proposals is what commonly happens with peer review of grant applications where there are limited research resources (i.e., grant funds) to be distributed. The same needs to happen with the review of embryo research where there are limited research resources (i.e., biological material) to be distributed. This suggests a second conclusion: that IVF human embryos should be considered a common resource and that a national electronic registry of human embryos available for research use should be established. To say the least, proceeding in this way and explicitly choosing to consider frozen IVF human embryos as a common resource (for which sound public policies and scientific research procedures must be developed to ensure their careful and proper use), would be a novel way of doing science. It would require of people with unwanted IVF human embryos that they donate these to a common pool (as happens in a therapeutic context with the donation of other tissues such as blood). fu well, this approach would require both willingness and ability on the part of members of the scientific community to harness the efforts of researchers and to orient these to a common national goal. Arguably, Canadians expect no less from the best of their citizens and scientists, whom they presume to be committed to the pursuit of scientifically and ethically sound research. Anything less risks both foreclosing research on the derivation of human embryonic stem cells, and limiting research on the use of human embryonic stem cells to research on imported cell lines. In turn, such consequences could be expected to lead researchers to challenge the current prohibition on creating human embryos for research purposes: a prohibition that is a core aspect of Canadian policy on human embryo research. Upholding this prohibition requires proactive measures of the type described above to minimize the risk of wasting the few IVF human embryos available for research use.

REFERENCES I.

2. 3. 4.

5.

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National Institutes of Health, Stem Cells: Scientific Progress and Future Research Directions,June 200 I. Baylis F. Human embryonic stem cell research. Canadian Chemical News Jan 2002:30-31. Human Fertilisation and Embryology Act, c. 37, 1990. Human Fertilisation and Embryology (Research Purposes) Regulations 200 I, Statutory Instrument 200 I No. 188. The Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans. 1998. Canadian Institutes of Health Research. Human stem cell research: opportunities for health and ethical perspectives: a discussion paper. Health Canada. Draft legislation on assisted human reproduction. . For a brief summary see, Baylis F. Canadian regulation of assisted reproductive technologies? Hastings Center Report 200 I;31 (4):8. For a commentary see, Baylis F. Brickbats and bouquets for the draft legislation on assisted human reproduction. Health Law Review 200 I; IO( I):3-7. Standing Committee on Health. House of Commons Standing Committee of Health Report on Proposal for Legislation on Assisted Human Reproduction. Personal communication Dr. Marie-Claude Leveille, Fertility Centre, Ottawa Hospital - Civic site. Lanzendorf SE, Boyd CA,Wright DL, Muasher S, Oehninger S, Hodgen GD. Use of human gametes obtained from anonymous donors for the production of human embryonic stem cell lines. Fertil Steril 200 I ;76( I): 132-7. Thomson JA, Itskovitz-Eldor J, Shapiro, et al. Embryonic stem cell lines derived from human blastocysts.Science 1998;282:1145-7. Freedman B. Scientific value and validity as ethical requirements for research: a proposed explication.IRB 1987;9(6):7-10. Emanuel E, Wendler D, Grady C. What makes clinical esearch ethical? JAm Med Assoc 2000; 283(20):270 I-I I.

ACKNCNYLEDGEMENTS '§I

Research support provided by fusociated Medical Services Inc. and The Stem Cell Network.

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