Integrative research: the approach at the Harvard Stem Cell Institute.

Perhaps no area of biologic research has so excited the public imagination in the past decade as stem cell science, which both the general public and scientific community believe holds great promise for future therapies for disease and traumatic injury. Even though the science is in its early stages, it is clear from what we already know that the research holds the key to great advances in the understanding and treatment of many diseases, including diabetes, heart disease, some forms of paralysis, multiple nervous system disorders, kidney disease, macular degeneration, many forms of cancer, as well as trauma repair. But why has Harvard University, an institution known for the independence of its constituent parts, and one already committed in so many areas, become so deeply involved in this effort?

Harvard University created the Harvard Stem Cell Institute (HSCI)--and dedicated significant resources to it--because the University's leaders believe that the obligations of the University to society as a leader in education, research, and clinical care required it to bring its multiple resources together to tackle the problem and the opportunity provided by the new technology of stem cells. With entire affiliated institutions devoted to advancing the treatment of single diseases, such as the Joslin Diabetes Center and the Dana-Farber Cancer Institute, on the one hand, and world experts in key technologies such as cell biology and tissue engineering on the other, the Harvard "network" has a skillset and resource base that few other institutions can match, allowing HSCI to make a unique contribution to the field. This collection of skills and resources is needed because to move from "bench to bedside" requires multiple domains of knowledge, whether understanding the pathogenesis of a particular disease, or knowing how the differentiation and growth processes of one cell type differ from those of another.

And these relevant domains of knowledge are not limited to science. The Harvard Stem Cell Institute is in a unique position in its ability to draw upon the expertise of the faculties of the University's schools of law, business, and divinity, in addition to the undergraduate, graduate and medical school faculties. As a result, we can explore in depth the multiple social, political, religious, ethical, and financial issues that surround stem cell research. Aware that Harvard's obligation to society is as much educational as it is scientific, we address these issues in a few ways. For instance, an undergraduate course, "Ethics, Biotechnology and the Future of Human Nature," explores these issues head on, with the professors inviting well-known opponents of embryonic stem cell research to meet with both students and faculty. In a lecture series entitled "Between Two Cultures," HSCI investigators debated leading bioethicists about their work. At the graduate level, HSCI brings the medical school ethics class to the stem cell community through monthly seminars. And externally, we work with legislators, conduct training for high school teachers, and hold conferences that include leaders from varying schools of thought.

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Clearly, we established the Harvard Stem Cell Institute, fully aware of the complexity of this research, including the depth of opposition. The majority of this opposition is based on the perspective that all human life, no matter what its stage, is worthy of equal protection. Those who hold this belief argue that embryonic stem cell research is unjustifiable because it requires the destruction of human embryos, albeit embryos in the blastocyst stage. Some assert that this "inalienable right to life" is an inviolable religious belief, but it is important to note that religions differ on this point. In some religions and cultures, life and "personhood" don't exist until birth; others argue for the moment of conception. In the latter case, it would be true that use of embryonic stem cells, extraction of which destroys the embryo, would be murder. But that requires attributing full "personhood" and moral status as a member of society to the fertilized egg, even before it has reached the blastocyst stage.

And that seems problematic. When life begins and when a fertilized egg turns into a human being tend to become conflated issues. One can say that life technically begins at conception at the same time as saying that the acquisition of moral, human status occurs over time, on a sliding scale as it were, as the egg turns into a sentient being. How else could society sanction the fact that every day embryos at IVF clinics are being stored in freezers or discard them after having deliberately created them in the first place? Furthermore, even the moment of conception is philosophically and biologically problematic. For the first couple of weeks of gestation, a single egg can split into multiple ones and pairs of eggs can combine. How can we attribute personhood and moral status to an entity that could become multiple, different beings? Clearly, this at least has to be admitted to be a gray area.

We believe that those conducting embryonic stem cell research have taken the "pro-life" position--committed to understanding, and eventually developing treatments for chronic diseases that affect many people, have a large impact on national healthcare costs and, currently at least, are untreatable by other means. How, we have asked, when the Centers for Medicaid and Medicare Services (CMS) estimates that by 2010 the United States will spend $600 billion to $1 trillion dollars a year for the direct and indirect costs of treating diabetes, cancer, cardiac disease and selected neurologic disorders, can we not do everything ethically and scientifically possible to search for cures for those diseases? How can we tell one of the 250,000 sufferers of spinal cord injury struggling in a wheelchair that a one week old blastocyst is more important to society than they are? And the list of examples could go on. The matter thus comes down to one of relative value, both social and financial. That is, how do we balance ethical concerns and the status and rights of the individual with the real needs of individual patients and the overall needs of the nation's healthcare system?

Much of the public discourse focuses on embryonic stem cells as the basis for therapy and that may be where the true excitement lies. It is quite clear, however, that that no matter how promising stem cell science may be, cures for these diseases are not right around the corner and in most cases may be decades away. But stem cells can be tools as well as providing direct therapies. That is why HSCI is establishing a center that will use stem cells as screening tools to identify drug candidates. In general, one can use stem cells as screening targets to identify molecules that either stimulate or interfere with signaling pathways that control cell differentiation and proliferation. More specifically, one can use disease-specific stem cells created by somatic cell nuclear transfer (SCNT) to identify compounds that stop or impede the progression of a given disease. In essence, by moving the study of a disease from the patient to the Petri dish, we believe we will be able to accelerate the discovery of new drugs and be able to repurpose existing ones. Admittedly, the Petri dish does not have all the environmental and structural complexity of the human body, but one could argue that it is much more ethical and humane to experiment on human cells in dishes than on human beings--which is essentially our current drug discovery process today. Creating disease-specific cell lines to identify and test drugs will still require validation in accepted animal and human models, but those experiments will be more targeted and safer if this approach is successful.

From a longer term therapeutic perspective, SCNT is important because, if successful, it makes embryonic stem cells with a specific genetic makeup. Again, we do not yet know whether the technique will work in human cells, but believe it is worth doing so that one can study how a genetic disease impacts early tissue formation or how to avoid transplant rejection and the need for immunosuppression. Again, the trade-offs for society are that we currently have a shortfall of suitable donor tissue for transplantation therapy. Most people who would probably benefit from bone marrow, liver, or pancreatic transplantation (to name only a few) will never get one simply because they don't have a suitable tissue donor. We hope to figure out ways that cells grown in a lab can be that donor. Defining how to make regenerative patient-specific tissues using embryonic stem cells is critical to this goal.

Since the major chronic, degenerative diseases are multi-genic, are subject to environmental factors, and are revealed in patients over highly variable time periods, and have not been amenable to cure by standard pharmaceutical treatment, we believe that they are good candidates for stem cell therapy. We also believe that adult, somatic cells, although highly useful in many applications, because of their inherent restrictions will not solve all these problems and therefore embryonic cells will play a critical role. It is true that at this point we do not know which types of cells--embryonic, adult, cord blood--will ultimately prove most valuable, but that is precisely why researchers should have all types of stem cells available to them.

That said, we do need to set limits on the technology so that we avoid certain outcomes, such as reproductive cloning and "fountain of youth" solutions. Before its recent announcement of initiating somatic cell nuclear transfer research, Harvard undertook an intensive two year policy review process to ensure the correct oversight was in place, that potential donors would suffer from no financial or other coercive effect, etc. As stem cell research here and at other institutions moves forward, we will soon have the need to coordinate these policies. As a community we will need to take on questions such as: When do the National Academy of Sciences (NAS) guidelines take on the force of regulation? When, in an interinstitutional collaboration, does one Institutional Review Board (IRB) or Embryonic Stem Cell Research Oversight Committee (ESCRO) yield to another? If one country has developed certain policies and procedures, can, or should, others simply adopt those as the International Society for Stem Cell Research (ISSCR) is now thinking about? The complexity of the science will require the community to collaborate; the importance of the ethical and social issues requires that collaboration to occur in a properly regulated framework; the immediacy and immensity of patient needs requires that we do so effectively and efficiently without reinventing the wheel.

Brock C. Reeve, MBA 

From the Harvard Stem Cell Institute, Boston, MA.

Reprint requests to Brock C. Reeve, MBA, Executive Director, Harvard Stem Cell Institute, 42 Church Street, Cambridge, MA. Email: [e-mail]