Guidelines for Embryonic Stem Cell Research

Bishops' Conference Comments on NIH Guidelines for Embryonic Stem Cell Research

January 31, 2000

Stem Cell Guidelines
NIH Office of Science Policy
1 Center Drive, Building 1, Room 218
Bethesda, MD 20892

To Whom It May Concern:

On behalf of the United States Catholic Conference ("Conference"), I offer the following comments on guidelines proposed by the National Institutes of Health ("NIH") for research involving human pluripotent stem cells [64 Fed.Reg. 67576 (Dec. 2, 1999)].

Interest of the United States Catholic Conference

The Conference is a non-profit corporation organized under the laws of the District of Columbia. All active Catholic bishops in the United States are members of the Conference. The Catholic Church, the largest religious denomination in the United States, has over 62 million adherents in over 19,000 parishes throughout the country. The Conference advocates and promotes the pastoral teachings of the bishops in such diverse areas as education, family life, health care, social welfare, immigration, civil rights, and the economy. The Conference participates in rulemaking proceedings of importance to the Catholic Church and its people in the United States. Rulemaking that concerns or, as in this case, undercuts, the protection of unborn human life and the ethical integrity of medicine is of paramount concern to the Conference.

Comments

The guidelines, for the first time in our national history, authorize the federal government to approve and regulate destruction of innocent human life for research purposes. They instruct researchers in how to harvest versatile "stem cells" from living week-old human embryos, a procedure which kills the embryos. They also establish standards for harvesting similar cells from dead unborn children after induced abortions -- a practice that has its own increasingly obvious moral problems, but is in accord with a federal law enacted in 1993. Because the new moral and legal frontier broached by these guidelines is the destruction of live embryos specifically for federally funded research, our comments focus on this aspect of the proposal.

The NIH Guidelines Demean Human Life and Undermine Longstanding Federal Policy on Protection of Human Subjects

The proposed guidelines are not designed to implement longstanding federal policy on research involving human subjects, which has been reflected in federal laws and regulations for 25 years. Rather, the guidelines seek to reverse that policy. In doing so they violate fundamental moral norms on human experimentation and fall far beyond the proper authority of the National Institutes of Health.

Since 1975, when the federal government first established federal regulations for protection of human subjects in medical research, human embryos from the time of implantation in the womb (about a week after fertilization) have been included under the federal definition of "fetus" and hence treated as "human subjects" deserving protection from harmful research.1 In 1985 Congress further clarified this standard by amending the National Institutes of Health reauthorization act: In research involving live fetuses in utero, protection from risk must be "the same for fetuses which are intended to be aborted and fetuses which are intended to be carried to term" (42 USC §289g). No matter what fate may be planned for the developing human being by others, the government must still make its own moral decision to respect life -- it cannot single out certain lives as disposable, or as uniquely fit for harmful research, simply because someone else plans to destroy those lives.

Even when authorizing federal funding for the use of fetal tissue after induced abortions in 1993, Congress sought to ensure that researchers receiving federal funds would not be involved in the destruction of fetal life. Fetal tissue -- defined as "tissue or cells obtained from a dead human embryo or fetus after a spontaneous or induced abortion, or after a stillbirth"2 -- may be used for "therapeutic purposes" only if various safeguards are followed to ensure that the researcher avoids participating in the abortion and does not influence the "timing, method, or procedures used to terminate the pregnancy."3

Experimentation involving human embryos outside the womb -- such as embryos produced by in vitro fertilization (IVF) or cloning -- has never received federal support. The federal regulations of 1975 prevented funding of IVF experiments unless such experiments were deemed acceptable by an Ethics Advisory Board -- and after the first such board produced inconclusive results in 1979, public opposition to such research persuaded the Carter Administration to dissolve the Board and to refrain from funding these experiments.4 In 1994, after the regulation demanding prior approval by an Ethics Advisory Board was rescinded by Congress, a Human Embryo Research Panel recommended that the National Institutes of Health fund certain kinds of harmful nontherapeutic experiments on human embryos -- including experiments in the use of embryonic stem cells -- but the Panel's recommendations were rejected in part by President Clinton, then rejected in their entirety by Congress. Since 1996, all Labor/HHS appropriations bills have included a ban on funding research in which human embryos in the laboratory are destroyed, discarded or subjected to risk of harm or death greater than that permitted for fetuses in utero under federal regulations. Since 1997 this law has explicitly banned funding of experiments involving embryos produced by cloning using human body cells.5

Clearly, it is Congress's intent that human embryos outside the womb be treated with the same respect it has already accorded to embryos and fetuses inside the womb.6 Even the NIH's own Human Embryo Research Panel in 1994, and President Clinton's National Bioethics Advisory Commission in 1999, have conceded that such embryos deserve respect as a form of human life.7

In radical discontinuity with this tradition, the policy of the new NIH guidelines is that human embryos outside the womb may be exploited and killed as nothing more than "tissue." The guidelines tell researchers to assure parents that their "early human embryos ... will not survive" the harvesting process, but "will be handled respectfully, as is appropriate for all human tissue used in research" (p. 67578). In short, live human embryos are dismissed as mere "tissue" to be destroyed for useful cells.8

According to the guidelines, such destruction is justified by, among other things, the prospect that use of the resulting cells may reduce the need to use "laboratory animals" for drug testing (p. 67576). Under this policy, far from being treated as a human subject, the human embryo effectively ranks lower in status than a laboratory animal.

The guidelines' effort to justify destructive experiments on donated embryos from fertility clinics, on the grounds that such embryos are deemed by parents or the clinic to be "in excess of clinical need" (p. 67577), runs contrary to Congress's insistence that unborn children intended for abortion be treated with the same respect in federally funded research as children intended for live birth. The guidelines' policy of allowing federally funded researchers themselves to destroy live embryos for their stem cells (so long as private funds are used for the act of destruction) contradicts statutory safeguards on fetal tissue, which forbid researchers to harvest tissue from live embryos or fetuses or to participate in or influence an abortion that may produce tissue for research.9 In every possible way, it seems, 25 years of reflection and action on such issues by Congress and successive Administrations has been set aside.

Longstanding federal policy on fetal and embryonic research is no mere political compromise. It is a reflection of universally accepted ethical principles governing experiments on human subjects -- principles reflected as well in the Nuremberg Code, the World Medical Association's Declaration of Helsinki and other statements. Members of the human species who cannot give informed consent for research should not be the subjects of an experiment unless they personally may benefit from it, or the experiment carries no significant risk of harming them. Only by such ethical principles do we prevent treating people as things -- as mere means to obtaining knowledge or benefits for others. These principles are ignored in the draft guidelines.

The Proposed Guidelines Violate the Appropriations Act

On November 29, 1999, the President signed into law the Fiscal Year 2000 Consolidated Appropriations Act, 2000 ("the Appropriations Act"), continuing the federal ban on use of appropriated moneys for "research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero" under existing regulation and statute. Three days later, NIH issued the pending guidelines to allow precisely such research with appropriated funds, by authorizing federal grants for researchers who destroy human embryos (or commission their destruction) to obtain stem cells for federally funded research.

The contradiction could not be plainer. It is undisputed, and the guidelines acknowledge, that appropriated monies may not be used for the actual destruction of a human embryo. 64 Fed.Reg. at 67577 ("funds may not be used for the derivation of human pluripotent stem cells from early human embryos"). But Congress's limitation on use of appropriated monies goes further. It states:

(a) None of the funds made available in this Act may be used for --

the creation of a human embryo or embryos for research purposes; or research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero under 45 CFR §46.208(a)(2) and Section 498(b) of the Public Health Service Act (42 USC §289g(b)). (emphasis added.)

Subsection 1 prohibits use of appropriated funds for "the creation" of a human embryo. Had Congress intended to prohibit use of appropriated funds for "the destruction" of a human embryo, it would have said so in language paralleling subsection 1. That Congress did not ban use of funds merely for the "the destruction" of a human embryo, but instead prohibited use of appropriated funds any "research in which a human embryo or embryos are destroyed," etc., demonstrates that Congress intended to ban not just the destruction of the embryo, but research that requires or relies upon the deliberate destruction of human embryos.

The proposed guidelines themselves clearly demonstrate the close bond between human embryo destruction and the embryonic stem cell research the NIH wishes to fund. Despite their title, the guidelines say almost nothing about standards for conducting "stem cell research." They deal almost exclusively with the procedures for obtaining and destroying embryos in what the NIH deems an "ethical" manner (p. 67576). No one reading the statutory ban could possibly conclude that Congress intended to authorize the NIH to provide approval and guidance for research that includes the "ethical" destruction of human embryos.

NIH's interpretation, limiting the funding ban only to the act of destruction itself, violates two principles of statutory construction. First a statute must be construed to avoid rendering any of its words superfluous. Walters v. Metropolitan Educational Enterprises, 519 U.S. 202, 209-10 (1997); United States v. Menasche, 348 U.S. 528, 538-39 (1955). NIH's interpretation renders the words "research in which" superfluous. Second, when Congress chooses different language in proximate subsections of the same statute -- one narrow, the other broad -- the statute must be construed to give effect to those differences. Russello v. United States, 464 U.S. 16, 23 (1983), and cases cited therein. The NIH guidelines fail to give effect to the difference between subsection 1 and 2 and the broader scope of the latter.

This new interpretation of the statutory ban also contradicts the NIH's past statements and implementation of the ban. In 1997, an NIH grant was terminated and the researcher dismissed from his NIH post because he had, in the NIH's view, violated the statutory ban. His violation was that he had used NIH funds and equipment to test genetic material that he had obtained (using other funds) from human embryos. At that time the NIH said this was a clear abuse of the law and told Congress it would take steps to ensure that such infractions do not occur again.10 What was seen as a violation of the law two years ago is now being proposed as a way of implementing the same law.

In short, the guidelines permit precisely what Congress and the President forbade with passage and signing of the Appropriations Act: the use of federal taxpayer dollars for research that involves the killing of human embryos.

The Guidelines Ignore Alternative Means for Pluripotent Stem Cell Research

The guidelines purport to set standards for research using "human pluripotent stem cells." They then simply equate "pluripotent stem cells" with "embryonic stem cells" (page 67577). To justify this definitional sleight-of-hand, the guidelines specify that stem cells will be deemed "pluripotent" only if they "have the potential to develop into all of the three major tissue types" (id.)11 This ad hoc definition is not standard scientific usage. Researchers often deem as "pluripotent" any stem cell that can produce a variety of other cell types (whether or not these types derive from all three of the major tissue types).12

Even by this narrow definition, however, it is not at all clear that adult stem cells cannot be made "pluripotent."

A year ago it was claimed that embryonic cells were necessary for stem cell research because they were unique in their ability to self-renew for long periods and to create tissues and cells of widely differing types. But this claim is well on its way to being discredited. For example, stem cells from muscle tissue have now been used to produce a wide array of blood cells;13 bone marrow stem cells have produced liver and other tissue;14 and nerve stem cells have been found capable of producing blood cells.15

A leading researcher in this field has concluded that "there is a stem cell in the adult bone marrow that is capable of becoming anything if you give it the right signal."16 Another comments: "The limits of cell differentiation are not bound by embryologic origin...Every cell contains the whole genome, so maybe [changing a cell's behavior is simply a matter of] putting the cell in the right microenvironment. I no longer have logical reasons to draw a line anywhere."17

This newfound versatility of adult stem cells is supplemented by new advances in "immortalizing" adult cell cultures and by progress in maintaining adult stem cells in a relatively undifferentiated state for months at a time.18 The "self-renewing" quality of embryonic stem cells can no longer be claimed as unique to those cells. Moreover, any approach involving the adaptation and use of a patient's own stem cells would circumvent all problems of tissue rejection, which pose a serious barrier to the transplantation of foreign stem cells into patients.

The existence of such startling new alternatives, which may be much more amenable to clinical use and do not require any destruction of human life, poses a significant new issue for ethics and public policy. Even the NIH Human Embryo Research Panel and the National Bioethics Advisory Commission have said that human embryos should not be exploited except for vitally important research that cannot otherwise be done.19 In light of recent developments in adult stem cells and other advances, embryonic stem cell research cannot be shown to meet that test. The only responsible course is to use federal funds now to explore the promise of adult stem cells and other alternatives, so the alleged need to destroy human embryos for stem cells can be reassessed before American taxpayers are required to participate in doing irreversible harm to fellow human beings.

The Guidelines Set the Stage for Further Abuses

The NIH guidelines seek to limit their authorization for research relying on destruction of human embryos, to prevent expansion of this policy to even more controversial areas of law and ethics. This effort is remarkably unsuccessful.

"Spare" vs. "research" embryos

The guidelines seek to forbid the use of stem cells "derived from human embryos created for research purposes, rather than for infertility treatment" (p. 67579). No basis is provided for this distinction. While President Clinton issued an order in December 1994 disallowing use of federal funds for the creation of human embryos for research purposes, it is NIH's claim (based on the HHS legal opinion) that the research proposed here is not human embryo research -- presumably rendering the President's order and Congress's broader ban in the Appropriations Act equally irrelevant.

The ethical basis for the proposed distinction is problematic. If it is wrong to create human embryos for destructive research, that is largely because such destructive research is itself wrong. Yet these guidelines actively facilitate and encourage such destruction. In any event the distinction is difficult or impossible to enforce in the best of circumstances, as experts in other countries have acknowledged. Fertility clinics can easily create more embryos at the beginning of the process, supposedly "for infertility treatment," to ensure that they will have an adequate supply for research at the end of the process.20 Clinics will have a financial incentive to do just that, as they will receive "payment" for "reasonable costs" associated with providing the stem cells (p. 67578).

The NIH's "reach-back" mechanism, designed to regulate the donation and destruction of human embryos without directly funding such activity, multiplies these difficulties. Regarding the researcher's own activities at the fertility clinic, the NIH will know only what that researcher chooses to reveal; regarding the activities of those who created the embryos, who are required by the guidelines to be distinct from the researcher, the NIH will have no knowledge or jurisdiction. There will be no reliable or independent way to determine how or why the embryos were created.

The National Bioethics Advisory Commission has noted that the NIH's arbitrary distinction between "use" and "derivation" of these stem cells "diminishes the scientific value of the activities receiving federal support."21 It also makes effective enforcement of the NIH's own guidelines impossible.

Limits on funding "research in which" abuses occur

The guidelines forbid support for "research in which" stem cells are used to create a human embryo, are combined with an animal embryo, or are used for "reproductive cloning" of a human (p. 67579). But these limitations are rendered essentially meaningless by the HHS legal opinion on which the NIH bases the legitimacy of its guidelines. For according to that opinion, the congressional ban on "research in which" embryos are destroyed is reduced to a simple ban on direct federal funding of the destructive act. By the logic of this reading, NIH will now support research involving the creation of human embryos, reproductive cloning, etc. -- so long as the specific act of cloning, for example, is privately funded.

These limitations are meaningful only if "research in which" is read more broadly, so that the NIH will not support research that is directed toward such abuses or relies upon them. But if "research in which" is read more broadly, the guidelines on embryonic stem cells violate federal law in their entirety.

Moreover, the limitation on use of stem cells to engage in "reproductive cloning" seems intended to permit use of these cells to create human embryos by cloning for destructive research. The NIH has consistently used the euphemism "reproductive cloning" to refer solely to cloning followed by efforts to bring the resulting child to live birth. Thus this provision places no limit on involvement in cloning, so long as the resulting embryos are subsequently destroyed. It is especially ironic, in guidelines purporting to implement a congressional ban on destroying human embryos, that compliance with the guidelines will in some cases require such destruction.

"Stem cells" vs. "embryos"

The HHS legal opinion and the NIH guidelines claim that this research does not violate the congressional ban on federally funded embryo research, because they involve research on stem cells -- and "such cells are not embryos" (p. 67576). Besides misrepresenting the current congressional ban and violating principles of statutory construction as noted above, this argument is deficient in three ways.

First, even the NIH Director has said that he is not sure this is true. At a congressional hearing on January 26, this organization expressed the concern that stem cells derived from embryos sometimes are said to recongregate and begin the early stages of embryonic development.22 NIH Director Varmus replied that he did not know whether this may sometimes occur, because it would be unethical to try to determine whether the concern is valid -- because such determination would require implanting the stem cells in a woman's uterus to ascertain whether they can produce a live birth. The Director's standard for determining whether an entity is an "embryo" was arbitrary, and contrary to current federal law: The current congressional ban defines as an "embryo" not only a living human organism that will survive to live birth in the future, but an organism that is alive and developing . But regardless of the standard used, the Director conceded that the "stem cell is not an embryo" claim is on precarious ground. In effect, the NIH is saying that it will proceed with this research because it does not know whether it violates the law.

Second, these guidelines refer to the embryo itself as mere "tissue" as noted above. If the NIH cannot determine the difference between an embryo and embryonic tissue, it is ill-equipped to determine reliably the difference between embryos and embryonic stem cells.

Third, the apparent significance of this distinction is that, in the view of the NIH, research on these stem cells would be valid regardless of the moral and legal status of the embryo. The argument here seems to be: Even if the human embryo has the status claimed by NIH's critics and the supporters of the congressional ban, that is irrelevant because the proposed research involves stem cells and not embryos. But in that case, it must be the NIH's position that the same policy could be followed for stem cells and other tissues obtained from those who are clearly human subjects, such as children and adults. On what basis, for example, would the NIH now refuse to fund research using hearts and livers harvested from Dr. Jack Kevorkian's assisted suicide clients, or from condemned prisoners who were executed by the excision of vital organs from their living bodies? Logically the policy would have to be that such research can use federal funds, because "a heart or liver is not a human subject." The NIH's claim that stem cells are not embryos proves nothing because it proves far too much, opening up a broad arena for government-sanctioned abuse of human subjects.

For all the above reasons, we believe the NIH's only morally and legally responsible course is to withdraw the guidelines on stem cells derived from early human embryos.Thank you for considering these comments.

Sincerely,

Rev. Msgr. Dennis N. Schnurr

General Secretary

Notes

1. See 45 CFR §46.201 et seq. (additional protections for fetuses as human subjects), §46.203(c) (definition of "fetus").
2. 42 USC §289g-1(g) (emphasis added).
3. 42 USC §289g-1(b)(2).
4. The Board concluded that support could be "acceptable from an ethical standpoint," but refrained from recommending such support, citing "uncertain risks" to mother and offspring, "the dangers of abuse" such as experimental manipulation of the embryo, and the fact that such research would be "morally objectionable to many." "Report of the Ethics Advisory Board," 44 Fed. Reg. 35033 (June 18, 1979) at 35056-8.
5. The current funding ban is Section 510 of the Fiscal Year 2000 Labor/HHS Appropriations Act (reprinted in 145 Cong. Record, Nov. 17, 1999, p. H12400); enacted by cross-reference, Section 1000(a)(4) of the Fiscal Year 2000 Consolidated Appropriations Act (P.L. 106- 113).
6. The provision defines an embryo as "any organism, not protected as a human subject under 45 CFR 46 as of the date of enactment of this Act, that is derived by fertilization, parthenogenesis, cloning, or any other means...". The provision proceeds to require that this embryo be treated exactly like protected human subjects, by extending to the embryo in the laboratory the protective standard already in effect for all fetuses in utero.
7. The early human embryo "warrants serious moral consideration as a developing form of human life" (National Institutes of Health, Final Report of the Human Embryo Research Panel (1994), p. 2); "wide agreement exists that human embryos deserve respect as a form of human life" (Letter of Dr. Harold Shapiro, Chairman of National Bioethics Advisory Commission, to President William J. Clinton, Sept. 7, 1999).
8. The instruction that parents be told that embryos "will not survive" the process is too evasive and euphemistic for meaningful informed consent. The National Bioethics Advisory Commission has recommended that such information "make clear that the research will involve the destruction of the embryos." National Bioethics Advisory Commission, Ethical Issues in Human Stem Cell Research (Rockville, MD: Sept. 1999), Volume I, p. 72. Of course, using such candid language would have made the guidelines' incompatibility with current federal law inescapably clear.
9. The guidelines' effort to "avoid possible conflicts of interest" requires only that "the attending physician responsible for the fertility treatment and the researcher or investigator deriving and/or proposing to utilize human pluripotent stem cells should not have been one and the same person" (p. 67577, emphasis added). The more serious conflict of interest remains firmly in place: The embryos can be destroyed by the same researcher who then reaps a federal monetary reward (a grant for research "utilizing" the fruits of that destruction).
10. See Continued Management Concerns at the NIH, Hearing before the Subcommittee on Oversight and Investigations of the House Commerce Committee, June 19, 1997 (Serial No. 105-26). At this hearing the NIH presented documentation on its faithful implementation of the statutory ban, including a letter to a grantee stating: "As a federally supported IRTA at NIH you may not engage in embryo related research with funds, equipment or other support from NCHGR. This includes preimplantation genetics involving molecular or cytogenetic analysis from DNA derived from a human embryo or a single cell from a human blastomere from a cleavage stage embryo" (p. 34).
11. Embryonic development produces three layers of tissue: the ectoderm (leading to production of hair and nerve tissue), endoderm (producing lungs, liver and gut endothelium) and mesoderm (producing blood, bone and striated muscle). A conventional scientific dogma holds that once adult development takes place, cells cannot cross from one category of embryonic layer to produce cells belonging to another. Increasingly it seems this dogma must be abandoned.
12. The NIH's own "primer" on stem cells defines "pluripotent" simply as "capable of giving rise to most tissues of an organism." It also says of "pluripotent" cells that "they can give rise to many types of cells but not all types of cells necessary for fetal development" (emphasis added). "Multipotent" stem cells are described as those which give rise to a variety of cells within one narrow category-- for example, "blood stem cells which give rise to red blood cells, white blood cells and platelets" (www.nih.gov/news/stemcell/primer.htm). By this usage, which is common among researchers, adult stem cells from brain or muscle which produce blood, or bone marrow stem cells which produce liver cells, are "pluripotent," not merely "multipotent."
13. K. Jackson et al., "Hematopoietic potential of stem cells isolated from murine skeletal muscle," 96 Proceedings of the National Academy of Sciences 14482-6 (Dec. 7, 1999).
14. B. Petersen et al., "Bone Marrow as a Potential Source of Hepatic Oval Cells," 284 Science 1168-70 (14 May 1999).
15. C. Bjornson et al., "Turning Brain Into Blood: A Hematopoietic Fate Adopted by Adult Neural Stem Cells in Vivo," 283 Science 534-7 (22 January 1999).
16. Bryon Petersen of University of Pittsburgh Medical Center, quoted in P. Recer, "Cell Used to Make New Liver Tissue," Associated Press, May 13, 1999.
17. Neil D. Theise of New York University School of Medicine, quoted in K. Monroe, "Liver Cells Generated from Bone Marrow Cells," UniSci (Daily University Science News), Jan. 3, 2000 [unisci.com/stories/20001/0103003.htm].
18. C. Morales et al., "Absence of cancer-associated changes in human fibroblasts immortalized with telomerase," 21 Nature Genetics 115-8 (1998); M. Yagi et al., "Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin," 96 Proceedings of the National Academy of Sciences 126-31 (July 6, 1999).
19. Human embryos are to be used in research only if "the research goals cannot be otherwise accomplished" by other means (Final Report of the Human Embryo Research Panel, op. cit., p. 3); the derivation of stem cells from embryos is justifiable "only if no less morally problematic alternatives are available for advancing the research" (National Bioethics Advisory Commission, op. cit., p. 53).
20. This was readily acknowledged, for example, in expert testimony on both sides of the embryo research issue in Australia. The parliamentary committee therefore decided not to make a legislative distinction between "spare" and "specially created" embryos, but to forbid destructive research on both. Commonwealth of Australia, Senate Select Committee on the Human Embryo Experimentation Bill 1985 (Canberra: Official Hansard Report 1986), Volume I, pp.391-2; Volume III, p. 1578.
21. National Bioethics Advisory Commission, op. cit., p.71.
22. In Dr. Gearhart's experiment deriving stem cells from fetal tissue, for example, "embryoid bodies" had formed "complex structures" in culture "closely resembling an embryo during early development"; these structures "appear to recapitulate the normal developmental processes of early embryonic stages and promote the cell-cell interaction required for cell differentiation." M. Shamblott et al., "Derivation of pluripotent stem cells from cultured human primordial germ cells," 95 Proceedings of the National Academy of Sciences 13726- 13731 (November 1998) at 13726, 13729.