Alternative Methods of Producing Stem Cells: No Substitute for Embryonic Stem Cell Research

The Coalition for the Advancement of Medical Research (CAMR) has written
a statement in response to a bill being considered in Congress that would fund studies to determine the feasibility of alternative methods for deriving pluripotent stem cells. The ISSCR reiterates its support of H.R. 810, which proposes to allow federal funds to be used to study hESC derived after August 9, 2001.

H.R. 810 has recently passed in the House of Representatives by a bipartisan majority. Below, the ISSCR reprints the CAMR statement, which provides an excellent explanation and critical evaluation of the proposed alternative methods for the generation of pluripotent stem cells.

1. Deriving Stem Cells from Embryos that Have Stopped Developing

Researchers Donald Landry and Howard Zucker have proposed that stem cells could be derived from embryos that are left over from IVF procedures and have failed to divide after 24 hours in culture. The rationale is that these embryos are, in essence, "biologically dead," and thus harvesting stem cell from them is similar to harvesting organs from cadavers for transplantation. The researchers plan to monitor several hundred excess embryos that have stopped developing and look for chemical and genetic "signatures" that reliably indicate arrested development. Those signatures would be used in ongoing research to deem a particular embryo "dead" and thus available for use to create stem cells.

Limitations:

• Diagnosing such embryo death requires methods for determining irreversible arrest, and objective criteria for determining irreversible arrest do not currently exist. As Michigan State University stem cell researcher Jose Cibelli has said, "We don't have an EEG machine we can plug into the embryo."
• It is unknown whether such embryos could really yield cell lines, and if so, whether the stem cells would be normal and healthy.
• Stem cell scientists prefer to work with the best materials available. As the President's Council on Bioethics observed, why would scientists settle for cells derived from dead embryos, especially since embryos that die early are generally abnormal, either chromosomally or in other ways? As one council member pointed out, it seems illogical to ask scientists to make strenuous efforts to rescue cells, potentially normal but potentially abnormal, only from those thawed embryos that have spontaneously stopped dividing, while forbidding them from using large numbers of unwanted but otherwise normal and viable IVF embryos.
  

2. Deriving Stem Cells from A Single Cell (Blastomere) Separated from a Live Embryo

The procedure involves growing embryonic stem cell lines from single cells ("blastomeres") that have been detached from embryos without damaging them. (This method is already used for pre-implantation genetic diagnosis, to see whether the embryo carries a genetic disease.)

The appeal of this approach is that the original embryo retains the capacity to develop into a human, and a new stem cell line can be created without destroying a potential human life. However the feasibility and reliability of this method has not been proven, and it actually raises more ethical objections than does deriving stem cells from excess IVF embryos.

Limitations:

• The proposed procedure is highly theoretical and should not be regarded as a proven alternative to current methods of deriving stem cells, which are reliable, solidly established, and constantly improving. The technology is not proven and could take years of intensive investigation by leading embryonic stem cell researchers to see whether it would reliably work. The best researchers would be starting over pursuing a course of research that is unexplored and offers no therapeutic advantage over the current method of producing stem cell lines.
• The blastomere method does NOT avoid the ethical dilemma over whether it is acceptable to destroy an embryo to derive stem cells. In order for the blastomere method to work, researchers have to remove a blastomere from an early (four or eight-cell) embryo and then stimulate that blastomere to begin dividing and developing to the blastocyst stage, at which it can be a source of stem cells. The fact that the blastomere developed into a blastocyst means that it has the same potential as the original embryo. So if destroying the original embryo is unethical, then destroying the blastomere-created embryo is just as unacceptable.
• Furthermore, the original embryo from which the cell is taken is being subjected to as-yet-unknown risks from the separation process. The original embryo, in a sense, is being exploited for the benefit of others. Those opposed to the creation of embryonic stem cells because it uses an embryo for utilitarian reasons (rather than the embryo's own benefit) also would oppose this method because the original embryo is exposed to a procedure that could potentially bring harm. As Leon Kass, chairman of the President's Council on Bioethics told reporters on May 12: "Blastomere extraction from living embryos, we found unacceptable ethically in humans because we do not believe that one should impose risks on living embryos destined to become children for the sake of getting stem cells for research. One might try this in animals, but it's not clear to us how the results from animal experimentation could alter this assessment of the ethical impropriety of doing this in humans."
  

3. Deriving Stem Cells from Biological Artifacts ("Altered Nuclear Transfer")

This method, proposed by William Hurlbut of Stanford, involves creating a kind of "disorganized" cloned embryo that would be incapable of completing its first stage of development. Before implanting DNA from a nuclear donor cell into an egg, scientists would turn off a gene that is essential for directing the proper formation of the embryo. This reprogrammed cell would still be capable of producing stem cells, but an actual embryo would never be created. Since correct development was never possible, an embryo is considered to never have existed.

Limitations:

• There is no evidence that this technique will work. Top stem cell scientists, writing in the New England Journal of Medicine, argued that Hurlbut's proposal has no scientific validity:
  
  • There is no basis for concluding that the action of any one gene represents a transition point at which a human embryo acquires moral status;
  • There is no way for determining the moral status of embryos disrupted at different stages by different mutations.
  • Establishing that the technique will work would require experimentation on many hundreds or thousands of human eggs. This raises a serious ethical dilemma, for what would be the source of the eggs?
    
• As this is a variation of somatic cell nuclear transfer, those opposed to therapeutic cloning would have similar objections to this approach. The 'altered nuclear transfer' approach raises ethical questions about purposefully creating and mutating embryos.
  

4. Reprogramming Adult Cells to Revert to Early, Undifferentiated Stage

Because this approach involves neither the creation nor the destruction of embryos, it would not prompt the main ethical objection to embryonic stem cell research. Such stem cells might then serve as a potential source of replacement cells for the donor of the adult cell. These replacement cells would be genetically identical to the donor and thus would probably not be rejected.

Limitations:

• There is no way of knowing whether this method will ever succeed. Research in this area is at a very preliminary stage, and scientists do not know whether it's even possible to dedifferentiate cells, let alone have them go back to the early stage and then forward. Researchers are already struggling with the second half of this process – coaxing cells to develop into an intended cell type – and expect years of very hard work before having success. Given the urgency of stem cell research to produce new therapies, it would be foolhardy to add an even more difficult, if not impossible, step to the process.
• Even if the method is successful, the resulting cells produced by the technique might not be normal. Cells do not naturally revert to their earliest stage and then develop into a different cell type. It is impossible to gauge how reprogramming the cells might affect expression of the genes in the cells, possibly causing them to malfunction at some point.
  

5. Deriving Stem Cells From Unfertilized Eggs Induced to Divide

This method involves "tricking" unfertilized human eggs to divide by injecting them with an enzyme that is normally supplied by sperm. (This dividing egg is called a parthenote.) The British researchers who developed this technique used standard chemical treatments to force the eggs to retain both copies of the egg donors' chromosomes. (The donor carries one set from each of her parents, so the eggs do also.) The embryos appear to undergo the same changes as naturally fertilized eggs.

Limitations:

• No stem cells have been isolated from human parthenotes. It is not clear whether the technique will work or if so, whether stem cells derived from parthenotes will be normal.
• Some would consider the parthenote to be a potential human life. Spurring a human egg to divide does not avoid the ethical dilemma over whether it is acceptable to destroy a potential life to derive stem cells.
• Establishing that the technique will work would require experimentation on many hundreds or thousands of human eggs. This raises the same ethical dilemma mentioned in the "altered nuclear transfer" method – what would be the source of the eggs?
  

For more information, visit www.CAMRAdvocacy.org.

Updated: August 2, 2005