Human embryonic stem cells: a justification for their use in medical therapeutics.

It seems widely accepted that the United Kingdom (UK) has led the way in introducing legislation to regulate clinical practice in assisted reproduction. The UK Human Fertilization and Embryology Act was passed in 1990 and has been mimicked by similar legislation in many other countries. The Act, and the Human Fertilization and Embryology Authority (HFEA) that it created, has been updated and amended to reflect changes in public opinion concerning in vitro fertilization (IVF) and related technologies, and we are now, in 2006, up to the Sixth Revision of the HFEA Guidelines. There is no shortage of legislative influence over Assisted Reproductive Technologies (ART) in the UK.

The original HFEA Act allowed research on human embryos generated by in vitro fertilization (IVF) in strictly limited circumstances (Table). However, these rules were drawn up before the work from Thompson's group in Wisconsin demonstrated that human embryonic stem cells (hESC) could be derived from blastocysts and effectively immortalized in culture.

Publication of these "proof of principle" studies led to widespread interest among scientists around the world. The clinical potential of hESC derivatives was obvious, and many research groups with experience in molecular and cell biology turned their attention to this area. However, use of human embryonic tissue for ESC derivation brought equally obvious ethical questions that were debated and explored alongside the basic and clinical research.

Opinions on the ethics of hESC research varied widely around the world. Public and media attention led to the involvement of governmental bodies, to Parliamentary debates, and to legislative changes. Possibly, this process of translation from questions of basic science to issues of ethics was easier in the UK than elsewhere because of the prior work done by the Warnock Committee and Human Fertilization and Embryology Authority. Parliament and the public had already accepted the concept of use of human embryos for research in certain circumstances, and UK IVF centers and embryological scientists were used to working in an atmosphere of regulation and inspection. After an erudite and wide-ranging free debate in the UK Parliament, the House of Lords approved the Human Fertilization and Embryology (Research Purposes) Regulations in January 2001. This permitted research using human embryo derivatives for three further purposes: to increase the knowledge of the development of embryos, to increase the knowledge about serious disease and to enable such knowledge to be used for treatment.

Following this ruling, research into the derivation and immortalization of hESCs has flourished in the UK. Our own center has recently opened a Medical Research Council-funded, GMP (good manufacturing practice) stem cell laboratory, which will in time generate cell lines that are of sufficient quality for use in clinical trials. Although many obstacles blocking progress remain, it seems possible that clinical trials in areas as diverse as juvenile diabetes, Parkinson disease, retinal degeneration and myocardial repair may start within the decade. Therein lies the attraction of this research: it has clear application in areas of medicine that are currently therapeutic dead ends. Modem medicine can slow progression and ameliorate symptoms but does not "cure" these many disorders. Clinicians are all too aware of their shortcomings when counseling patients, and we all await clinical developments with eager anticipation. Patient groups representing those suffering from degenerative disorders actively campaign for funding and governmental support, and there appears to be widespread public acceptance that this technology should be researched and developed.

Despite public and governmental enthusiasm, others continue to have misgivings about the "rightness" of this policy. Alternative sources of stem cells are available, but none appear to be as pluripotent and malleable as those derived from the inner cell mass of the blastocyst. While it is clearly appropriate to explore other routes, hESC derivatives still seem to be the most likely to lead to early therapeutic developments. The proponents of hESC research see the dissection of the microscopic ball of cells that is the blastocyst as nothing more than the early stages of production of an immortalized cell line to be studied, nurtured and developed into pancreatic islets or substantia nigra. The opponents of the research see the destruction of a potential human life as an act of murder that should not be permitted in a civilized society.

While it is probably impossible to achieve any form of consensus between these opinions, many of us who work at the clinical end of this research feel that the UK government has "got it right." We would not be permitted to work on trivial uses for hESCs--products for cosmetics, for example. We are restricted by Parliament to the treatment of serious disorders. We are accustomed to living and working in a tightly regulated and inspected environment. We separate clinical practice and clinical embryology from the research team, and we do not offer any coercion or inducements to couples who might wish to donate their embryos for research.

IVF will continue to produce embryos that are "surplus to requirements"--the couple has achieved the family they desired and can therefore choose to destroy the remaining embryos, donate them for the treatment of another couple or donate them to research. Within the HF & E Act, these couples have ten years from initial IVF within which to make this decision; many are generous enough to consent to donation to research. Many will have seen the tragedy of Parkinson, Alzheimer or other degenerative diseases in their families and wish to make this altruistic donation to help others avoid these disorders. The widely held view in the UK is that this is a laudable and proper decision, driven not by commercial motives but by a genuine desire to contribute to medical progress. Thankfully, our Parliament has endorsed this practice, and we continue to research within a restrictive but permissive environment. The view of the majority prevails, as it should in a democracy, and human embryonic stem cell research will continue to progress in the UK for the foreseeable future.

Education is the ability to listen to almost anything without losing
your temper or your self-confidence.
--Robert Frost

William L. Ledger, MA, DPhil

From the Academic Unit of Reproductive and Developmental Medicine, University of Sheffield, Sheffield, United Kingdom.

Reprint requests to William L. Ledger, Professor of Obstetrics and Gynecology, Academic Unit of Reproductive and Developmental Medicine, University of Sheffield, Room 5, Level 4 Jessop Wing, Tree Root Walk, Sheffield, S10 2SF, United Kingdom. Email: [e-mail]

Table. Areas of research on human embryos permitted under the 1990 HFEA
Act

* Advance treatment of infertility
* Increase the knowledge of congenital disease
* Increase the knowledge of causes of miscarriage
* Develop more effective contraception
* Develop methods for detection of gene/chromosome abnormalities