[Wise Young]

Originally Posted by Random

Thanks Wise. Unless you tell me not to, I will hold off submitting my comments and asking friends and family to do so until I have those specifics.

Here is my "draft" response to them... I am still adjusting it.

COMMENT ON DRAFT NIH GUIDELINES FOR HUMAN STEM CELL RESEARCH
by Wise Young, PhD MD,
Rutgers University, 604 Allison Road
Piscataway NJ 08854-8082
email: wisey@pipeline.com
10 May 2009

The National Institutes of Health (NIH) is requesting public comment on draft guidelines, entitled “National Institutes of Health Guidelines for Human Stem Cell Research” [1]. These draft guidelines were created in response to Executive Order 13505 by President Barack Obama [2], requesting that NIH establish policy and procedures under which NIH will fund research in the area in accordance to applicable law. Below, I will refer to these as Draft Guidelines.

The deadline for public comments is May 26, 2009 and can be entered at http://nihoerextra.nih.gov/stem_cells/add.htm or mailed to
NIH Stem Cell Guidelines, MSC 7997
9000 Rockville Pike
Bethesda, Maryland, 20892-7997

The applicable law include the “Dickey-Wicker Amendment” [3] which prohibits NIH funding of research that harms human embryos. In addition, there is a long-standing Department of Health and Human Services regulation for Protection of Human subjects, 45 C.F.R. 46 , which establishes safeguards for individuals who are the sources of human tissues used in research. The following are my comments.

Misdefinition of Human Embryonic Stem Cells

The Draft Guidelines misdefines human embryonic stem cells (HESC) as “cells that are derived from human embryos, are capable of dividing without differentiation for a prolonged period in culture, and are known to develop into cells and tissues of the three primary germ layers.” This definition covers some cells that are not human embryonic stem cells and fails to cover some cells that are.

The more accepted scientific definition of HESC is the inner mass cells located in a developing blastocyst or pluripotent cells derived from such cells. The length of time that they can divide in culture without differentiation is irrelevant to the definition. Likewise, the stipulation of “dividing without differentiation” depends on culture conditions and should not be part of the definition.

The definition excludes some cells that would be considered HESC. For example, some cells derived from the inner mass of blastocysts cannot develop into cells and tissues of all three primary germ layers but are still considered HESC because they can make many kinds of cells, including themselves. If HESC is defined only as those stem cells that produce all three primary germ layers, the guidelines would not pertain many HESC lines or their progeny.

The definition includes many cells that would not be considered HESC but are nevertheless derived from human embryos and are pluripotent. For example, several widely used cancer and human teratoma cell lines would fall under the definition. Teratoma cell lines are likely to have originally derived from an embryo, are usually pluripotent, but would be considered cancer cells and not HESC.

Finally, the term “embryo” includes all stage of fetal development. HESC are derived from blastocysts, which are pre-embryonic. An blastocyst does not become an embryo until a midline develops. As written, the definition of HESC stipulating derivation from embryo would include all derived or induced pluripotent cells from any stage of embryonic development. This definition is not only wrong and misleading but introduces unintended and unnecessary regulatory problems.

Mischaracterization of Human Embryonic Stem Cell Research

The Draft Guidelines state that “studies of human stem cells may yield information about the complex events that occur during human development”. Likewise the Guidelines state that HESC “may also be used to test new drugs”. This use of “may” is unnecessarily conservative and misleading in this situation. HESC are already yielding important information on human development and are being used by the pharmaceutical industry to test drugs. The use of the word “may” in this context suggests political motivation to downplay the importance of HESC research.

The Guidelines fail to mention one very important application of HESC. HESC derived from individuals with genetic diseases or genetically modified HESC would allow study of these disease in vitro or in vivo, i.e. HESC cells transplanted into human or animals. Having cells lines that contain human genetic disease, particularly complex genetic diseases tha involve multiple genes, provide powerful tools for studying human disease.

Finally, the statement that “Perhaps the most important potential use of human embryonic stem cells is the generation of cells and tissues that could be used for cell-based therapies” is simply wrong. Clinical application of HESC is the least likely of the many potential uses of HESC. This because HESC (unless they are derived from SCNT) are not immune compatible. The role of HESC for transplantation is being supplanted by induced pluripotent stem cells (IPSC).

It is gravely disappointing that NIH should write Draft Guidelines that provide misleading information to the public concerning the science and potential of embryonic stem cells. It should be written by somebody who is more aware of the latest research in the field.

Unnecessary Restrictions of Human Embryonic Stem Cell Research.

The Draft Guidelines “would allow funding for research using only those human embryonic stem cells that were derived from embryos created by in vitro fertilization (IVF) for reproductive purposes and are no longer needed for that purpose”. This restriction was not stipulated in Executive Order 13505, the Dickey-Wickers amendment, nor the basic HHS Policy for Protection of Human Research Subjects.

The restriction came originally from the Clinton Administration who had proposed that IVF Clinics provide a source of HESC that may be politically acceptable to the public. The Clinton Administration side-stepped the Dickey-Wickers amendment by having outside groups isolate the cells from blastocysts that would be discarded but are donated by the parents for research. This subterfuge relieves NIH of the onus of directly funding handling of blastocysts.

A decade has passed since the original recommendation from the Clinton Administration to use blastocysts from IVF clinics. Much science has developed including many methods for deriving and creating pluripotent stem cells. Given this situation, why has the NIH chosen to restrict the study of HESC to IVF sources? Why have they decided to prohibit cells derived from “somatic cell nuclear transfer, parthenogenesis, and/or IVF embryos created for research purposes”?

The Guidelines said “Funding will continue to be allowed for human stem cell research using adult stem cells and induced pluripotent stem cells”. Unfortunately, it did not define induced pluripotent stem (IPS) cells. For example, would IPS cells from fetal cells be allowed? As IPS cel research has progressed, it has become clear that pluripotency is a condition that is induced by relatively few genes from an enormous variety of cells.

The Guidelines provide no rational, moral, or legal framework for what it prohibits. For example, it is not clear at all why it is all right to study HESC derived IVF blastocysts that are “no longer needed” by the parents but it is not all right to study cells derived from parthenogenesis, a process where an unfertilized egg is fooled into dividing and producing some stem cells, even though it cannot develop further. No human parthenote has ever been produced nor considered possible.

By failing to provide rational, moral, or legal basis for its restrictions, the Guidelines risks being hypocritical and will not be able to withstand the criticism of those who seek to abolish HESC research altogether. For example, the guidelines assume that there is an important moral distinction between embryos that are created for procreation and are no longer needed versus parthenotes, i.e. an never-fertilized egg that is fooled into dividing to produce HESC but cannot develop into a fetus. What is that distinction? Why is one okay and the other not?

Retroactive Informed Consent Requirements

The Draft Guidelines will limit the sources of HESC even more than the Bush Administration. For example, the Guidelines will impose additional requirements on the source of HESC cells. For example, it requires that “all options pertaining to the use of embryos no longer needed for reproductive purposes” be explained to potential donors. Depending on how this is interpreted, this seemingly innocuous requirement can rule out all the HESC stem cells created to date because informed consents from donors are unlikely to include “all options”.

The Guidelines further requires that “no inducements were offered for the donations”, that “a policy is in place at the health care facility where the embryos were donated that neither consenting nor reusing to donate embryos for research would affect the quality of care provided to the potential donor(s)”, that “there was a clear separation between the prospective donor(s)’s decision to create human embryos for reproductive purposes and the... decision to donate human embryos for research purposes”, and a long list of other specific requirements.

It is unclear that any or all these requirements have been met, even in the so-called Presidential lines derived before August 2001. The wording of the Guidelines suggest intent to impose that requirements on existing cell lines. If so, this would essentially rule out NIH funding of any HESC line derived before the Guidelines. The Guidelines specify that these informed consent requirement apply to future cell lines that are derived and not to previously derived cell lines.

Unnecessary Restrictions on HESC and IPSC Transplants into Animals

The Guidelines prohibit two types of research that are not prohibited by current law or regulation. The first is “research in which human embryonic stem cells (even if derived according to these Guidelines) or human induced pluripotent stem cells are introduced into non-human primate blastocysts. The second is “research involving the breeding of animals where the introduction of human embryonic stem cells or human induced pluripotent stem cells may have contributed to the germ line.

At the present, all NIH-funded human stem cell research that is conducted with animals must be reviewed by the Institutional Review Board (IRB) of the research institution, the HESC board of the institution, the Institutional Animal Care and Use Committee, and by several NIH peer-review and ethics boards. Instead of allowing existing mechanisms to review the grant application, the Guidelines are imposing poorly worded sweeping regulations that restrict most human-animal chimera research. Let me explain why.

One of the most important demonstrations of pluripotency at the present is to transplant a putative stem cell line into an immune-suppressed animal and showing that the cells will contribute to many types of tissues or form a teratoma that have many types of cells. The former is usually done by introducing a cell into developing animal blastocyst (the easiest stage to introduce cells). The latter is more difficult and injected into an adult immune-suppressed animal.

Likewise, one of the most important tools for biomedical research is the creation of animal strains that contain human cells that allow prediction of human responses to treatment. The clearest example of this, for example, a mouse strain that was created by Irv Weissman, that has a human immune system. This mouse is a mainstay of human immunological research, allowing the study of human cells in a mouse. Under the proposed rules, the creation of such an animal strain using NIH funds would no longer be allowed.

Even though the Executive Order requested guidelines for use of HESC only, these Draft Guidelines extended HESC prohibitions human IPS cells (IPSC). IPS cells have nothing to do with HESC or embryos. These restrictions will make it significantly more difficult for scientists to develop ways to validate pluripotent cell lines. The Guidelines should require more stringent ethical review of such research but should not issue unnecessary and short-sighted prohibitions in this fashion.

Conclusions

These Guidelines have the unfortunate potential to impose unnecessary regulations on HESC and IPSC research by NIH than the prohibitions under the Bush administration. The Guidelines impose a scientifically incorrect definition of HESC that covers cells that are not HESC and does not cover some cells that are HESC. It misrepresents the promise of HESC research and appears to have been written by non-scientists. Worse, it imposes additional regulations on HESC and IPSC research that are not mandated by existing law or regulations at NIH. As written, these Guidelines will cause more harm to HESC research than it helps. The Guidelines are poorly written, scientifically inaccurate, and impose new restrictions on both HESC and IPSC with little rational, legal, or ethical basis.

Recommendations

I recommend that these Guidelines be changed in the following ways:

1. The definition of HESC should be rewritten to refer specifically to inner mass cells obtained from blastocysts or progeny of these cells.

2. The section on the promise of HESC research should be written by a scientist based on the latest information about HESC.

3. Informed consent requirements should not be imposed retrospectively on HESC lines derived in the past.

4. The Guideline should focus only on HESC and should not refer to IPSC research, which have nothing to do with embryos.

5. The Guidelines should not restrict research not prohibited by current law or regulations, including use of HESC and IPSC in animals.

6. Separate guidelines should be developed for parthenogenesis- and somatic cell nuclear transfer (SCNT) derived HESC.


References

1. Stem Cell Information [World Wide Web site]. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2009 [cited Saturday, May 09, 2009] Available at http://stemcells.nih.gov/policy/2009draft

2. Executive Order 13505: Removing Barriers to Responsible Scientific Research Involving Human Stem Cells (108KB PDF http://edocket.access.gpo.gov/2009/pdf/E9-5441.pdf)

3. Consolidated Appropriations Act, 2009, Pub. L. 110-161, 3/11/09

4. “Basic HHS Policy for Protection of Human Research Subjects, Title 45 Public Welfare Department of Health and Human Services, Part 46 Protection of Human Subjects, revised June 23, 2005. http://www.hhs.gov/ohrp/documents/OHRPRegulations.pdf