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07/12/2005

The Yammer Begins: Senate Appropriations Subcommittee on Labor Health etc. Takes Up the “Alternative Sources of Stem Cells” Nonsense

George Daley testified this morning and hit the ball out of the part. This is longish, but deserves presentation since you wouldn’t see it anywhere else without searching the web like an MIT brat. Daley, who wrote the “Missed opportunities in stem cell research” piece in New England Journal last year, testifies:

Senator Specter, members of the Committee, thank you for inviting me to testify before you. My name is George Daley. I am here today representing the American Society for Cell Biology, a professional society of nearly 12,000 basic biomedical researchers in the United States and 50 nations around the world. I am Associate Professor of Pediatrics and Biological Chemistry at Boston Childrens Hospital and Harvard Medical School, the Associate Director of the Stem Cell Program at Childrens Hospital, a member of the Executive Committee of the Harvard Stem Cell Institute, and Board Member and President-elect of the International Society for Stem Cell Research (term to begin June 2007). My research is focused on using embryonic stem cells and adult stem cells to study blood development, and to develop new treatments for leukemia, and genetic diseases like immune deficiency, sickle cell anemia, thalassemia, and Fanconis anemia. I am also clinically active as a hematologist at Childrens Hospital, where I see first-hand the pain and suffering inflicted by these diseases on children and their families. My career is dedicated to making a difference in their lives through research and patient care.

I am here today to state my strong support for Senate passage of HR 810, which has already passed the House of Representatives by an impressive and bipartisan margin. HR 810 would ensure that scientists can use Federal grant funds to study the wide range of valuable human embryonic stem cell lines that have been created since August 9, 2001, the date that President Bush announced his restrictive stem cell research policy. HR 810 would expand research opportunities and accelerate progress towards newer and better therapies for the many children I currently cannot treat successfully.

I am also here to give scientific perspective on the several additional strategies proposed for deriving human pluripotent stem cells that have been considered recently by the Presidents Council on Bioethics, and which are the subject of this hearing today. I want to state at the outset that I support efforts to derive pluripotent stem cells by methods that would be ethically acceptable to all, but I do not support delaying the pursuit of medical research on existing human embryonic stem cell lines while these more speculative methods are tested. I believe that Senate passage of HR 810 is the surest means of supporting stem cell research at this juncture.

First let me emphasize why research on human embryonic stem cells is so vitally important, and why alternative forms of adult stem cell research cannot substitute for the study of embryonic stem cells.

Critics of embryonic stem cell research are fond of saying that adult stem cells have been used to cure dozens of diseases while embryonic stem cells have helped no one. I would like to examine that claim. In essentially all cases adult stem cell therapy really means transplantation of blood stem cells to treat leukemia, lymphoma, and various genetic diseases of the blood. Although bone marrow transplants have saved many lives, bone marrow transplant is never a certain cure. Even after many decades of clinical experience, bone marrow transplant remains an aggressive and toxic therapy that carries the highest mortality rate of any medical procedure that is routinely performed. For patients whose only bone marrow match is from unrelated donors outside the family, the treatment itself claims the lives of ~30% of patients in the first year. Indeed, I have cared for many patients who have died during treatment. All of us working in hematology today agree that additional research is needed.

My laboratory is studying embryonic stem cells in hopes of making blood stem cell transplants safer and more widely applicable. A critical part of the strategy is using somatic cell nuclear transfer to generate stem cells that are customized to the specific patients I mentioned earlier, kids with leukemia, immune deficiency, and sickle cell anemia. We hope to correct the genetic defects in these patient-specific cells, direct their differentiation into blood, and transplant kids with these genetically matched autologous cells. This strategy is already working in mice, and we are eager to translate this work into humans. The current Federal funding policies have held us back.

Although it is true that no one has to date been treated with cellular therapies based on human embryonic stem cells, I can assure you that mouse embryonic stem cells have had a major impact on medical research. Over the past 25 years, mouse embryonic stem cells have been used to create models for scores of human diseases, including cancer, heart disease, obesity, and Alzheimers. Research discoveries based on these models has led to new drug development and therefore touched countless lives. As for the criticism that no one has been cured with embryonic stem cells, the field of human embryonic stem cell research is a mere 7 years old, so it is premature to expect successful cell therapies to have already been delivered to patients. I believe it is only a matter of time before human embryonic stem cells are used in drug development research and become the basis for important new cell therapies.

As further evidence of how human embryonic stem cells enable unique opportunities to study disease, consider research on Fanconis anemia. Kids with Fanconis anemia suffer bone marrow failure, and often develop leukemia. Scientists have tried to model this disease in mice, but the mice do not develop bone marrow failure, and the adult blood stem cells from Fanconis patients cannot be maintained in culture. Recently, a team from the Reproductive Genetics Institute of Chicago isolated a human embryonic stem cell line that carries a Fanconis gene mutation. This cell line could enable us to study the uniquely human aspects of Fanconis anemia. However, because of the current Presidential policy, we cannot study these cells with our Federal grant dollars. Thus my lab has been left to attempt to generate a Fanconis model in one of our Presidential stem cell lines, which has proven to be far more cumbersome than simply obtaining the cells from Chicago. To date, we have not succeeded. By this direct example, the Presidents policy is hindering our research on this terrible childhood disease. Senate passage of HR 810 would make available Federal funds to perform this important medical research. [I have written about the missed opportunities for human embryonic stem cell research under the current Presidential policies, and wish to introduce this article into the record.

Let me now turn to the several proposed new methods for making pluripotent human stem cells that are designed to avoid the destruction of a human embryo. These so-called alternatives are not TRUE alternatives, as they currently represent only speculative proposals for research that might yield new stem cell lines, and are fraught with their own ethical problems. In most of these cases, the experiments needed to establish feasibility of these proposals would require research on human embryos, and thus would be prohibited under current Federal law by the Dickey amendment. Far preferable to spending limited research dollars on these speculative proposals, in my opinion, is support for research on additional embryonic stem cell lines that are available todaylines that are similar to those already approved under the Bush policy. Senate passage of HR 810 would advance research that we know works, research where the ethical dilemmas have been understood and accepted by most.

Among the speculative methods under discussion, the first involves extracting stem cells from embryos that could be considered dead, because they have stopped dividing and will not develop further. If individual cells remain alive (and hopefully normal), they might be used to initiate lines of stem cells. The Presidents Council found this strategy ethically sound and scientifically feasible and so endorsed it. However, I anticipate that attempts to generate pluripotent cells from these defective embryos will be far less efficient than from excess IVF embryos. Even if cell lines can be generated, I imagine scientists will remain suspicious that they are abnormal and might lead to erroneous conclusions in research.

The second speculative method derives from pre-implantation genetic diagnosis, or PGD, in which one or two cells are removed from an early embryo and analyzed to diagnose serious inherited diseases like Sickle Cell Anemia. PGD insures that only embryos found free of gene defects are transferred to the woman so that she may have a healthy child. The suggestion has been made that biopsied cells might be used to produce pluripotent stem cell lines, and this would be ethically acceptable if the embryo remained unharmed. Dr. Lanza is here to represent his as yet unpublished success in using this strategy to produce pluripotent stem cell lines from mouse embryos. However, the biopsy procedure raises all sorts of ethical concerns and indeed has been dismissed as unacceptable during the initial inquiries of the Presidents Council. [Those who equate the zygote to a human being would reject the use of embryo biopsy because it removes cells at a stage when they might be considered developmentally equivalent to the zygotethat is, totipotent. Removing a totipotent blastomere is then the moral equivalent of producing a twin, which, in the view of opponents of embryonic stem cell research could not then be sacrificed for research. Embryo biopsy for stem cell research entails risks to embryos that are wanted for making a baby, rather than destined to be discarded as medical waste. If my wife and I carried a genetic disease we would accept the risk of the embryo biopsy procedure to insure we could have the healthiest child possible, but if we were simply infertile and using IVF to assist us in reproduction, we would not consent to having our healthy embryos biopsied; we would chose instead to donate our excess embryos to stem cell research. Dr. Lanza may suggest that lines be derived only from embryos already being biopsied for PGD, but the more cells one biopsies to accommodate both PGD and stem cell derivations, the greater the risk for embryo loss. As a practical and scientific matter, embryo biopsy for derivation of pluripotent cell lines is an unacceptable option.]

The third speculative method involves deriving pluripotent stem cells from something the Presidents Council has termed biological artifacts. The best described of this procedure is called Altered Nuclear Transfer, which entails introducing a genetic defect into a somatic donor cell prior to nuclear transfer, so that a disordered embryo results that can be a source of pluripotent stem cells but cannot develop into a human. According to Dr. Hurlbut, the methods chief proponent, what is produced would lack the essential attributes and capacities of a human embryo, a biological artifact whose destruction to produce pluripotent stem cells would be ethically justified. Such a strategy is technically feasible but in a piece written for the New England Journal of Medicine, my colleagues and I have rejected this concept as flawed2. In reasoning echoed by the Presidents Council, we questioned whether the planned creation of what amounts to a defective embryo would silence ethical objections.

A more recent proposal put forth by Markus Grompe is a variation on Altered Nuclear Transfer called Oocyte Assisted Reprogramming, (OAR). Grompe also suggests altering the input somatic cell so as to preclude formation of a viable human embryo. He proposes using a gene like nanog, which might promote reprogramming of the donor somatic cell directly to something that resembles an embryonic stem cell, which is pluripotent, and avoids generating a cell like a zygote, which is totipotentthat is, able to divide on its own and form a viable human blastocyst. Scientifically, this idea is a reasonable hypothesis that must be tested and might or might not work. But even if this strategy works in mice, there is no guarantee it will work in humans, and verification would then require the creation and destruction of many manipulated human embryos, which might or might not have the altered characteristics that would make this method ethically acceptable. If it works, I am concerned that in order to use Federal dollars for research US Scientists will be relegated to less-efficient processes like Altered Nuclear Transfer, while Korean scientists employ superior techniques.

The fourth speculative approach is to derive pluripotent cells via direct de-differentiation of somatic cells to an embryonic stem cell-like state using chemical treatments or cell culture manipulation alone. The Presidents Council found merit in this fourth proposal, but also raised the technically thorny issue of how to rule out whether a totipotent and therefore morally significant cell might be created by this procedure. In my view, these last two proposals raise a curious and challenging question: can we distinguish the moral value of a human cell based on its particular gene expression pattern? Can humanity really be diagnosed at the level of a single cell?

From my view, this last approach has scientific merit. We know cellular de-differentiation is possible; indeed, that is precisely what we do when we perform somatic cell nuclear transfer and reprogram a somatic cell back to a zygote. The Federal Government is already funding research into such cellular reprogramming. Indeed, last year I was one of nine recipients of the inaugural Pioneer Award from the Director of the National Institutes of Health to support highly innovative (that is, speculative) research of exactly this type. Although this strategy is worth pursuing, it is extremely high-risk, and may take years to perfect, and may never work as well as nuclear transfer, which we know we can practice today.

Research on each of these proposed strategies is at present untested in human cells, but if judged to be meritorious by the peer review process, should be funded. However, the already proven routes to obtaining embryonic stem cells from excess IVF embryos or through the use of somatic cell nuclear transfer should not be put on hold pending the outcomes of the more speculative methods.

Finally, let me emphasize that research on embryonic stem cells and embryo research in general is not solely about making tissues for transplantation to treat disease. Although the promise of new therapies is perhaps the most compelling reason to support expanded access to embryonic stem cells for research, I stress that it is equally important to pursue research that addresses fundamental questions about the earliest stages of human development. We know that a variety of birth defects can be traced to abnormal cell divisions during the first few days of life, and that infertility and miscarriage can also be traced to defects in the early embryo. We cannot learn everything there is to learn about these human disease conditions from studying animals. We must study the unique aspects of human embryo biology directly, and the Federal government should support this vitally important basic research.

Science certainly cannot define when in the gradual course of human development we deserve individual and autonomous rights. I do not agree with the premise that the single celled zygote should be given the same considerations as living persons and I do not view the embryo as a human being, particularly when it is frozen in a freezer. As a physician and as a scientist and as a father I live in a practical world of choices, and a world in which disease is a grim reality. Unless we want to turn back the clock, and outlaw in vitro fertilization, then we as a society have already accepted that many more embryos are created than will ever become children. I feel it is morally justified to derive benefit from these embryos through medical research instead of relegating them to medical waste. And unless we are willing to argue the biological absurdity that our humanity can be defined by a particular signature of gene expression that exists in the totipotent cells of the early human embryo, then we must support the vitally important applications of embryonic stem cells to medical research.

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