ANALYSIS OF 2009 NIH HUMAN STEM CELL RESEARCH POLICY
Wise Young PhD MD, W. M. Keck Center for Collaborative Neuroscience
Rutgers, State University of New Jersey, Piscataway, NJ 08543-8082
Created July 9, 2009; Revised July 10, 2009
On July 9, 2009, the National Institutes of Health (NIH) issued the 2009 NIH Human Stem Cell Research Policy. NIH issued this policy in response to an Executive Order 13505 on March 9 by President Barack Obama, rescinding the stem cell policy of President George W. Bush and asking NIH to propose a new policy for legally and ethically responsible human stem cell research. On April 23, NIH published Draft Guidelines (74 Fed. Reg. 18578). NIH received over 49,000 comments on the Draft Guidelines from advocacy groups, scientific societies, academic institutions, religious organizations, and private citizens.
I had earlier posted a critique of the Draft Guidelines on the CareCure web site, pointing out that the Guidelines misdefined human embryonic stem cells (hESC) by saying that the cells come from human embryos, had to be cell lines (i.e. grow for prolonged periods in culture without differentiation), and had to make cells of all three primary germ layers. Embryo refers to all stages of human development from implantation through fetus. Strictly speaking, hESC come from the inner cell mass of blastocysts. The cells do not have to grow for prolonged periods in culture to be hESC. Many hESC cell lines have not been shown to produce cells of all three primary germ layers. These requirements would allow many hESC-derived cells to escape regulation.
The Draft Guidelines further restricted hESC research in several ways. First, it proposed strict new consent rules that would make many existing hESC lines ineligible and would ironically even exclude many hESC lines approved under the previous presidential policy. Second, it explicitly forbids NIH funding of hESC lines derived from blastocysts created by somatic cell nuclear transfer (SCNT) and parthenogenesis, as well as blastocysts created by fertilization for research. Third, the draft guidelines restrict transplantation of hESC cells into subhuman primates and other animals where the hESC may interact with germ cells and the animals can reproduce.
The NIH response and the final 2009 Guidelines for Human Stem Cell Research are of great interest because they determine the federal policy towards human stem cells. In the following sections, I will first summarize the NIH response to the commentary and the changes that they made in the final Guidelines in response. Then, I will discuss the consequences of each of the major decisions and the likely impact on human stem cell research in the United States.
NIH Response to Commentary
Public comments on the Draft Guidelines fell into several categories, summarized below.
- Terminology. Patient advocacy and scientific groups criticized the Draft Guidelines for inaccurately defining human embryonic stem cells (hESC). NIH modified the definition of hESC to “cells that are derived from the inner cell mass of blastocyst stage human embryos, are capable of dividing without differentiating for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers.”
- Financial Gain. Some respondents were concerned that derivers of hESC will profit but not the donors. Others noted that the Guidelines favored certain existing patents and this will restrict competition, which may inhibit research and increase cost of eventual clinical therapies. NIH responded that the research would be subject to existing NIH policies and guidance regarding intellectual property and distribution.
- Institutional Review. Many respondents pointed out that existing institutional review board (IRB) procedures under the Common Rule can assess whether the research matches core ethical principles and provide oversight of hESC research. Others urged that NIH establish a NIH registry of eligible hESC lines to avoid burdensome and repetitive assurances of the same cell lines by many NIH applicants. NIH agreed that IRBs provide a comprehensive framework for review but pointed that a uniform standard is needed. They will establish an NIH Registry of hESC subject to this standard.
- Ineligible Sources. The Draft Guidelines disallowed sources of hESC derived from embryos created expressly for research purposes, including parthenogenesis or somatic cell nuclear transfer (SCNT). Only stem cells from embryos created for reproductive purposes will be eligible. Some respondents asked about embryos being discarded after pre-implantation genetic diagnosis (PGD). In the Guidelines, NIH continued to forbid funding of research on hESC derived from parthenogenesis and SCNT but allowed PGD.
- Informed Consent. Many respondents argued that the draft Guidelines were “too procedurally proscriptive” and retrospective application would disallow many existing hESC lines. They urged NIH to “grandfather” existing hESC lines without review. In response, NIH will now grandfather lines already in the NIH Stem Cell Registry and established a review process for other lines and overseas lines.
- Conflict of Interest. Some respondents wanted explicit separation of the IVF physician and hESC researcher to avoid the situation where the IVF doctor may create extra embryos for research. NIH agreed that the IVF physician and researcher should be separate but declined to make this a requirement because there may be certain situations where the IVF doctor and researcher can and should be the same person. •
- HESC versus embryos. Several respondents requested clarification of a statement in the Guidelines: “although human embryonic stem cells are derived from embryos, such stem cells are not themselves human embryos”. The Dickey amendment prohibits research that may harm embryos. NIH has consistently distinguished between hESC and embryos. Congress has accepted this distinction since 2001.
- Revocation of consent. The draft Guidelines stipulated that embryo donors could revoke consent at any time. Respondents pointed out that this might not be possible after hESC are derived and have been “de-identified” from the original donor. NIH modified the guidelines to stipulate that donors can revoke consent until the cells have been derived or information linking the embryo to the donor is no longer retained.
Definition of Human Embryonic Stem Cells
The Draft Guidelines misdefined hESC, describing them as cells derived from human embryos and required that they can grow for prolonged periods in culture without differentiation and that they can produce cells from all three primary germ layers. Since the term embryo encompasses all stages of development from fertilized egg until birth, this definition would have included all pluripotent stem cell lines from all stages of prenatal development whereas the term hESC is usually reserved only for cells derived from the inner cell mass of blastocysts, a well-defined early pre-implantation stage of development.
The NIH modified the definition so that hESC now refers explicitly to cells derived from the inner cell mass of blastocysts. However, the definition continues to specify that the cells must grow for prolonged periods in culture without differentiation, essentially requiring the cells to behave like a cell line. Furthermore, the definition requires that cells to produce cells of all three primary germ layers: epidermal, mesodermal, and endodermal. While hESC lines ideally should be able to grow in culture for long periods without differentiation and should be able to produce cells of all three primary germ layers, not all hESC can do these two tasks.
The fallacy of this definition becomes clear when one considers which hESC today would fulfill this definition. As specified in the current definition, a majority of hESC would not fulfill the definitions as set out by the Guidelines. Many researchers study hESC without making them into cell lines. After all, a transient existence is the natural history of hESC. Many hESC lines have been shown to produce cells of only two and not all three primary germ layers. If a cell does not been made into a cell line, does this mean that it is not and should not be regulated as a hESC?
The Guidelines also do not consider the progeny of hESC. Consider neural stem cells that are derived from hESC. These cells would not fulfill the definition of hESC because they produce cells of only one primary germ layer and many are not and cannot be grown for prolonged periods without differentiation, unless one immortalized the cells with v-myc or other genetic manipulations. Neural stem cells can be derived from stem cells collected from the inner mass of blastocysts. Since they do not come from cells that would fulfill the definition of hESC, such neural stem cells would not be subject to the policy.
NIH should simply refer to hESC cells as pluripotent stem cells derived from the inner cell mass of blastocysts and expand Guidelines to refer to hESC and their progeny. It is the source of the cells and not its characteristics that is crucial for regulation. As it stands now, the NIH has established a review process for cell lines that can be put into the NIH Stem Cell Registry. Hopefully, the reviewers will understand more about what hESC than the writers of the Guidelines and make appropriate decisions concerning what can be included and what should be excluded.
Definition of Embryo
In its response to comments on the Draft Guideline, NIH acknowledges the Dickey Amendment, which prohibits NIH funding of research that may harm human embryos. The Guidelines stated, “Although human embryonic stem cells are derived from embryos, such stem cells are not themselves human embryos”. The Dickey Amendment defines the human embryo as “any organism not protected as a human subject under 45 C.F.R. Part 46 that is derived by fertilization, parthenogenesis, cloning or any other means from one or more human gametes or human diploid cells.”
NIH distinguishes between research on hESC derived from embryos versus research that derive hESC from embryos. If a hESC were an embryo, then hESC research that harms the cells would be against the law. NIH points out that the Department of Health and Human Services (HHS) has consistently recognized the distinction between embryonic stem cell and embryo. Congress has known and accepted this distinction since 2001 when it allowed the research plan proposed by President George W. Bush.
NIH is indirectly acknowledging that a blastocyst is an embryo. If so, NIH cannot fund procedures that harvest, create, or grow blastocysts that be damaged if stem cells are removed from the blastocysts. According to the Dickey Amendment, the term embryo includes those created by “fertilization, parthenogenesis, cloning, or any other means from one or more human gametes or human diploid cells”. But, this prohibition does not prevent NIH funded studies of stem cells from such blastocysts.
Most Americans are not aware that a blastocyst is pre-implantation, i.e. before the egg implants into the uterus. The egg is usually fertilized in the Fallopian tubes and develops into a blastocyst as it progresses towards the uterus. At the time when the inner mass of blastocysts is removed for hESC, the blastocyst has not yet developed the primitive streak, a mark indicating the eventual midline of the embryo. At this point, the blastocyst does not have any recognizable body parts, limbs, organs, or brain. It is just a ball of cells with potential to grow into a fetus.
Most scientists do not consider a blastocyst to be an embryo, in the same way that they would not consider a fertilized egg, a morula or a gastrula to be an embryo. These are pre-embryo stages of development. The definition of embryo usually commences upon implantation and development of a midline. A fetus usually refers to stages when limbs and organs are present. The NIH Guidelines should have taken the opportunity to present the stage of development to the public, to explain the difference instead of obscuring the definition further.
The Draft Guidelines imposed strict consent requirements that would have ruled out most existing HESC lines from NIH research. Many respondents commented that the new consent approach was too “procedurally proscriptive, overly relies on specific details and formats of informed consent documents, and fails to consider the complexity of informed consent processes”. These restrictions would have ruled out many cell lines, even those that were eligible under the previous President’s policy.
In response to the criticism, NIH modified the Guidelines to grandfather all cells currently listed on the NIH Stem Cell Registry but will require all other cell lines to be submitted with supporting information for administrative review by the NIH. These will be reviewed by a Working Group of the Advisory Committee to the Director (ACD), to ascertain whether “core ethical principles and procedures were observed in the process for obtaining informed consent.”
The Guidelines also made an exception for hESC lines derived overseas, recognizing that other countries may not change their donation requirements to comply precisely with the NIH Guidelines and that hESC lines from outside of the United States represent an important scientific asset for the U.S. The NIH ACD will review conditions and procedures. The committee will advise the NIH Director whether the policies in other countries are at least equivalent to those in the Guidelines.
The Guidelines, however, continued to require that consent be obtained at the time of embryo donation and that a blanket authorization at the beginning of IVF procedures would not be sufficient. Although this was criticized, NIH maintained this requirement in the final Guidelines, stating “a general authorization for research donation when consenting for reproductive treatment would comply with the Guidelines only when specific consent for the donation is obtained at the time of donation.”
The Guidelines relented on its requirement that donors may withdraw consent at any time. If this requirement had been maintained, it would have allowed donors to revoke consent just before clinical trial or commercial application in exchange for payment. NIH modified the Guidelines to allow donors to withdraw consent only until the embryos are actually used to derive embryonic stem cells or when information that could link the donor identity with the embryo was no longer retained.
In summary, NIH relaxed some consent-related requirements and set up administrative procedures for reviewing eligibility of stem cells for inclusion into the NIH Stem Cell Registry. For cells that have already been derived, a committee will review them to ensure that they meet core ethical principles. While NIH continued to require consent at the time of donation, they imposed a time limit on consent revocation. While the procedure are still clumsy, the procedures are now workable.
Parthenogenesis, Cloning, or Expressly Created Blastocysts
The 2009 Guidelines explicitly forbids NIH funding of hESC derived from embryos expressly created for research by fertilization, parthenogenesis, or somatic cell nuclear transfer (SCNT). NIH explained that the “Guidelines allow for funding of research using hESC derived from embryos created using in vitro fertilization (IVF) for reproductive purposes and no longer needed for these purposes, assuming the research has scientific merit and the embryos were donated after proper informed consent was obtained from the donor(s). The Guidelines reflect the broad public support for federal funding of research using hESC created from such embryos based on wide and diverse debate on the topic in Congress and elsewhere. The use of additional sources of human pluripotent stem cells proposed by the respondents involve complex ethical and scientific issues on which a similar consensus has not emerged.”
This explanation is disconcerting because it implies that the decision to prohibit the research is political and is not based on ethical, scientific, or legal reason. The Dickey Amendment forbids NIH to fund any research that may harm blastocysts created by fertilization, parthenogenesis, or somatic cell nuclear transfer. NIH asserted that hESC are not embryos and therefore they can fund research on hESC regardless of source. At the same time, they are asserting that using cells from in vitro fertilization clinics is acceptable because of “broad public support” for such use. However, they prohibit other sources because “a similar consensus” has not emerged. In other words, they are saying that the decision to exclude other sources of stem cells is politically based.
This decision to forbid hESC cells from other sources has serious consequences. One of the most important benefits of hESC research is that it would provide pluripotent human cell lines that contain genetic diseases. If a scientist or organization used fertilization, parthenogenesis, or SCNT to create hESC cell lines from individuals who have genetic diseases, these cell lines would not be eligible for NIH funded research. Fortunately, NIH did allow one source of hESC with genetic disease. In vitro fertilization clinics do pre-implantation genetic diagnosis (PGD) by taking several cells and genetically analyzing them for genetic disease. Blastocysts that contain undesirable genetics are discarded. NIH can fund studies of hESC derived from such blastocysts donated by the parents.
In summary, the Guidelines prohibit NIH funding of studies of hESC from blastocysts other than those that were created for reproductive purposes. The rationale for this prohibition was clearly political and not based on clear scientific or ethical principles. One of the most important and accepted benefits of hESC research is that it would allow the creation of human pluripotent cell lines that contain genetic disease. The prohibition of NIH funding of hESC expressly derived from blastocysts created for the purpose to producing such cells would have stopped this potential benefit of hESC research. However, NIH did allow the study of hESC derived from blastocysts that are discarded after PGD.
Restrictions of Human/Animal Chimera Research
The 2009 Guidelines restricts research involving hESC transplantation into non-human primates and into animals where the transplanted cells may contact with germ cells and the animals may have an opportunity to procreate. Creation of such human/animal chimera are controversial, presumably reflecting the unsubstantiated fear that such animals may develop human qualities. However, instead of leaving this matter for Institutional Review Boards (IRB), Animal Use and Care Committee (IACUC), and Embryonic Stem Cell Research Oversight (ESCRO) Committee to assess, NIH decided to use the Guidelines to ban this important arena of research.
The restriction of human/animal chimera experiments has important and potentially devastating consequences on hESC research.
- Tests of pluripotency. The accepted test of pluripotency of human hESC is to transplant the hESC into developing animals and seeing whether the cells incorporate into multiple tissues. The hESC cells may interact with germ cells in the developing animal. Another test is to transplant hESC into adult animals to determine whether the cells develop into a teratoma, a tumor that contains many types of cells. The restrictions imposed by the Guidelines would make such experiments difficult.
- Human-animal chimera models. These models have been used for many years to do in vivo research on human cells without having to use human subjects. For example, chimeric mouse models containing human bone marrow stem cells have been used for many years to assess human immune response to vaccines. Many other disease models involve implanting human cells into animals. There is no convincing evidence that hESC cells pose significantly greater risk than other types of human cells.
- Studies of hESC in transgenic animals. Transplantation of human ESC cells into transgenic mice and other animals is one of the most important methods to study hESC function in different tissue environments. The Guidelines do not provide details concerning how one would protect against unknown risks of chimera studies. For example, would mice receiving hESC transplants have to be spayed before the transplants to avoid any possibility of reproduction by the animals?
One of the most worrisome aspects of these proscriptions is that they not only include hESC but also induced pluripotent stem (IPS) cells. IPS cells are derived by genetically modifying differentiated cells. It is not clear why NIH is prohibiting such research. Human/animal chimera research has been carried out for many years. There is no evidence that either transplantation of hESC or IPS cells into animals pose a significant risk or a greater risk than transplantation of other human cells, such as cancer cells. In the absence of data that indicate that the hESC transplantation in subhuman primates or other animals carries a significant risk of causing harm, there is no justification for prohibiting the research, particularly when such prohibitions will substantially slow progress in the field.
IRB, IACUC, and ESCRO
All NIH grants are subject to extensive ethical and scientific review before funding. For example, the IRB (Institutional Review Board) is involved whenever human subjects are involved. Since hESC are human, IRB should be notified even when the research involve hESC. Likewise, if animals are involved, IACUC (Institutional Animal Care and Use Committee) are involved. The NIH provides both scientific and ethical review.
NIH has traditionally allowed IRB, IACUC, and other review committees to evaluate research risks. Respondents to the Draft Guidelines asked why NIH did not make greater use of these existing review structures for execution of their policy. In their response, NIH agreed that Institutional Review Boards (IRB) procedures under the Common Rule do provide a comprehensive framework for evaluating research risk for human subjects. However, they pointed out that many different organizations have published standards for stem cell research and that a uniform standard was required.
While the lack of uniform standards for evaluating stem cell research is true to some extent and the Guidelines address such lack, it is not clear why the NIH did not utilize IRB and IACUC structures more. This was particularly true in two areas: evaluation of the consent procedures and assessment of risk of hESC and IPS transplantation in subhuman primates and other animals where the cells may interact with germ cells. While the final Guidelines provided new administrative pathways for review and appeal within NIH, it barely mentioned IRB and IACUC review.
Perhaps the most puzzling is why NIH chose to ignore the ESCRO (Embryonic Stem Cell Research Oversight) committees. In 2005, the National Academy of Science recommended the formation of ESCRO committees to evaluate research that involve human embryonic stem cells. Many institutions formed ESCRO committees and they have provided both ethical and scientific review of human embryonic stem cell research for the past four years. Strangely, the Guidelines make no mention of ESCRO committees. It would be useful if the Guidelines defined the roles of IRB, IACUC, and ESCRO committees in institutional reviews of hESC research.
The Guidelines left many questions unanswered. For example, why are existing mechanisms inadequate for evaluating the risk of transplanting hESC into non-human primates and into reproductively active animals? What is the rationale for prohibiting these activities? Do these activities pose such critical dangers that that NIH must prohibit important areas of research without review? As pointed out by the International Society for Stem Cell Research, until such risk can be demonstrated, existing ethical standards should be used (Cell Stem Cell August 2007, 1: 159-163). The NIH has long used well-established regulatory mechanisms to assess ethical and scientific risk of NIH funded research. The NIH should take advantage of these mechanisms for stem cells.
Summary and Conclusions
The Final 2009 NIH Guidelines for Human Stem Cell Research was released on 9 July 2009. The NIH received 49,000 comments on Draft Guidelines published in April 2009. NIH modified the final Guideline in response to the comments:
- Definition of Human Embryonic Stem Cells (hESC). The Guidelines modified the definition of hESC so that it now specifies that the cells come from the inner cell mass of human blastocysts. However, the Guidelines continue to require that the cells grow for prolonged periods in culture without differentiation and that they produce cells of three primary germ layers. These requirements will allow many hESC to be unregulated.
- Less Restrictive Consent Requirements. The Draft Guidelines imposed informed consent criteria that would have made most existing hESC ineligible for the NIH registry. The NIH allowed cell lines that are currently in the NIH Stem Cell Registry but required that all other cells be submitted to a committee that will advise the NIH Director whether the cells meet core ethical principles. HESC derived overseas will be reviewed separately.
- Timing and Revocation of Consent. The Draft Guidelines required that consent be given just before embryo donation and allowed consent to be revoked at any time. These requirements would have disallowed some hESC cells. Revoking consent after derivation of the cells would be difficult to enforce and may allow donors to blackmail companies by revoking consent on the even of commercialization. NIH decided to require consent at donation but limited consent revocation to before the cell were derived or de-identified.
- Parthenogenesis, Cloning, or Expressly Created Blastocysts. The Guidelines explicitly forbids funding studies of stem cells derived from blastocysts created for their stem cells. This would forbid NIH to fund studies of pluripotent human stem cells derived from blastocysts created because they contain genetic disease. Fortunately, NIH allowed use of blastocysts discarded from pre-implantation genetic testing.
- Restrictions of hESC Transplants into Animals. The Guidelines restrict hESC and induced pluripotent stem (IPS) cell transplants into non-human primates and animals where the cells might interact with germ cells. There is little evidence that hESC transplants post greater risk than other human cells, e.g. human cancer cells. These restrictions will restrict studies of hESC pluripotency and interactions with other cells.
- Failure to utilize IRB, IACUC, and ESCRO committees. The Guidelines ignored well-established institutional mechanisms that have traditionally assessed ethical and scientific risks, including ESCRO committees that the National Academy of Sciences recommended as an institutional mechanism for reviewing hESC research.
In conclusion, the 2009 NIH Guidelines for Human Stem Research are better than the Draft Guidelines but unnecessarily banned studies of hESC derived from blastocysts not created for reproductive purposes, i.e. for research by parthenogenesis, cloning, or other methods. The Guidelines restrict transplantation of hESC and even IPS cells into non-human primates or animals where the cells may interact with germ cells. The NIH should use well-established institutional mechanisms to review ethical and scientific risk instead of prohibiting broad areas of research based on theoretical risk and politics.