This article appears in the May 2001edition of the Catholic Medical Quarterly

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NEW GERM CELLS FROM OLD

Neil Scolding

In the UK, the House of Commons, and now the House of Lords, have voted to legalise research involving stem cells derived from cloned human embryos. Cloning entails the transferring of nuclei from differentiated cells into enucleated human ova (somatic-cell nuclear transfer), and the generation and growing of embryos, which may then be used as a source of stem cells. A surfeit of advice was offered, the bulk in favour of legalisation. Yvette Cooper, the Public Health Minister, articulating Government support, said that "could prove the Holy Grail in finding treatments for cancer, Parkinson�s disease, diabetes, osteoporosis, spinal cord injuries, Alzheimer s disease leukaemia and multiple sclerosis. . . . transform(ing) the lives of hundreds of thousands of people." The widespread view seems to be that research using human embryos is the only available approach to the development of stem-cell therapies, and that objecting to such research is to "deny sufferers of devastating illnesses the chance of a cure".

This view has been based not least on the serious contributions of the Royal Society, the Medical Research Council, the Wellcome Trust, and the British Medical Association, as well as the Chief Medical Officer�s report (Donaldson report). All agree that the human embryo has "special status", but all take the view that this status may be overridden in the interests of therapeutic research.

But is the matter so straightforward? Two important points seem to underlie the Government s stance. The first is that embryo-derived stem cells are poised to unleash imminently their "huge power to end suffering". The second is that there is no realistic alternative.

Most clinical scientists would agree that stem-cell research does have enormous potential1, but they would also agree with that part of the Donaldson Report (on which the proposed legislation is based) that repeatedly emphasises that stem-cell research is "basic research which . . . . would precede by many years any application to treatment."1 Despite the high profile that this rightly enjoys, animal studies exploring the potential benefits of stem-cell transplantation are few, and still in their infancy. Many clinicians and, some scientists too, consequently consider that even the small amount of stem-cell clinical-trial work now underway is premature. Although definite tumour formation has not been reported, sufficient long-term experiments have not been done to allay concerns about this serious hypothetical hazard. The potential adverse effects are well illustrated by a report describing the development and "overgrowth" of ectodermal and mesenchymal tissue (hyaline cartilage, bone, squamous epithelium, and hair shafts) filling and obstructing the cerebral ventricles in a patient with Parkinson�s disease who received intraventricular allographs of (human) fetal tissue. Admittedly, the investigators could not tell whether this finding was due to the inclusion of pluripotent cells or contamination of the original graft by non-neural tissue. Nevertheless, to imply a striking and imminent therapeutic dividend is to replay the past decade�s unfortunate saga of uncritically accepting the potential of gene therapy.

To dismiss potential alternatives is no longer sustainable. The past year or two have seen striking potential therapeutic value of stem cells (and progenitors of various types) derived from adult tissue. It is indeed the near breath-taking pace of this research now four key papers appeared in Dec. 2000, alone - that perhaps explains the lack of enthusiasm for adult-stem cells expressed in the Donaldson and Royal Society reports, both of which were prepared at least 12 months ago.

For several years the adult rodent brain has been known to contain neural stem cells.9 After trans plantation (into brains of laboratory animals), these cells still yield neurons, astrocytes and oligodendrocytes, and the neurons so generated are region-specific and respond to local environmental cues. Stem cells prepared from the adult (rat) central nervous system retain an extensive capacity to effect precisely the type of myelin repair that most interests those clinical scientists seeking to develop regenerative therapies for diseases such as multiple sclerosis.10

The pluripotentiality of adult neural stem cells greatly exceeds early expectations: they can also yield cells of haemopoietic lineage.11 Moreover, the reverse also obtains: cells derived from the bone marrow of adult mice can develop into neurons and glia7-8. These findings advance recentresearch show ing that stromal cells obtained from adult bone marrow yield hepatocytes, chondrocytes, osteoblasts, vascular endothelial cells, adipocytes, and skeletal and cardiac myocytes (as well as, of course, haemopoietic cells). 12 Bone-marrow trans plantation in mouse models of muscular dystrophy partly restored dystrophin expression in dystrophic muscle.

How far can this laboratory work be extrapolated to human beings? It is now clear that the adult human brain contains stem cells capable of generating both glia and neurons.14-15 Likewise adult human bone marrow is known to contain stem cells that can yield not only bone, cartilage, fat, tendon, and muscle (and marrow cells), 16 but also neurons and glia.17 Bone-marrow transplantation is already an established treatment for several malignant diseases and for certain inherited metabolic disorders, and it is being explored as possible treatment for auto-immune disease. Adult human stem cells will have (unknowingly) been transplanted into thousands of patients: there is therefore a far superior bank of knowledge concerning the likely safety of the procedure than is available for embryonic cells. In addition, the therapeutic potential of human stromal cells is already being systematically explored in children with diseases such as osteogenesis imperfecta. 18

Even before the UK vote Britain was said to be "at the far end of the moral spectrum, being one of the few countries in the world to authorise the utilitarian deliberate creation of embryos for research, a practice that runs against the European Convention on Human Rights and Biomedicine". 19 The European Group on Ethics in Science and New Technologies also recently concluded that "the creation of embryos by somatic cell nuclear transfer would be premature". 19 The vote now takes the UK still further away from the moral norm.

The delays for further study that must precede the proper development of any stem-cell therapy, the rapid progress made in research with stem cells from adults, and the clear evidence of the potential therapeutic value of these stem cells make it misleading to suggest that arguing against legalising embryo research is to deny sufferers hope, or to prevent scientific or therapeutic progress. If the "special status" of the human embryo means any thing, surely the emergence of a perfectly viable and ethically robust alternative, which will neither delay nor limit the development of these exciting and much-needed treatments, should have dissuaded the UK Parliament from approving the cloning of human embryos purely as a means of production of stem cells.

REFERENCES

  1. The Chief Medical Officer s Experts Group on Therapeutic Cloning. Stem cell research medical progress with responsibility. The Donaldson Report Norwich: Stationery Office, 2000.

  2. Richards T. Stem cell research, The UK government should sanction carefully regulated research. BMJ 2000; 321:1427-28

  3. Weissman IL. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 2000; 287:1442-46.

  4. Folkerth RD, Durso R. Survival and proliferation of nonneural tissues, with obstruction of cerebral ventricles, in a parkinsonian patient treated with fetal allografts (see comments). Neurology 1996: 46:1219-25.

  5. Ladywell ED, Rakic P. Kukekov VG, Holland EC, Steindler DA. Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc NatlAcad Sci USA 2000; 97:13883-88.

  6. Shibabuddin IS. Homer PJ, Ray J, Gage FH. Adult spinal cord stem cells generate neurons after transplantation in the adult rat dentate gyms. J Neurosci 2000; 20:8727-35.

  7. Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR. Turning blood into brain cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000; 290:1779-82.

  8. Brazelton TR, Rossi FM, Keshet GI, Blau HM. From marrow to brain: expression of neuronal phenotypes in adult mice. Science 2000, 290:1775-79.

  9. Morshead C, Reynolds BA, Craig CG, et al. Neural stem cells in the adult mammalian forebrain: a relatively quiescent sub-population of sub-ependymal cells. Neuron 1994;13:1071-82.

  10. Zhang SC, Ge B, Duncan ID. Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity. Pro NatlAcad. Sci USA 1999; 96:4089-94.

  11. Bjomson Cr, Rietze RJ, Reynolds BA, Magli CM, Vescov AL. Turning brain into blood: a haematopoietic fate adopted by adult neural stem cells in vivo. Science 1999, 283:534-37.

  12. Mezey E, Chandriss KJ. Bone marrow: a possible alternative source of cells in the adult nervous system. Eur J Pharmacol 2000, 405:297-302.

  13. Gussoni E, Soneoka Y, Scrickland CD, et al. Dystrophin expression an the mdx mouse re stored by stem cell transplantation. Nature 1999; 401:390-94.

  14. Johansson CB, Svenson M, Wallsteds L, Janson AM, Frisen J. Neural stem cells in the adult human brain. Exp Cell Res 1999; 253:733-36.

  15. Kudekov CG, Laywell ED, Suslov 0, et al. Multipotent stem/progenitor cells with similar properties arise from two neurogenic regions of adult human brain. Exp Neurol 1999; 156: 333-44.

  16. Pittenger MF, Mackay AM, Beck Sc, et al. Multilineage potential of adult human mesen chymal stem cells. Science 1999; 284: 143-47.

  17. Woodbury D, Schrarz EJ, Prockap DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. JNeurasci Res 2000; 61:364-70.

  18. Horwitz EM, Prockop DJ, Fitzpatrick LA,et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in chil dren with ostengenesis imperfecta. Nat Med 1999; 5:-13.

  19. Anon. Ethics can boost science. Nature 2000; 408:275.

Reprinted from The Lancet, Vol. 357, February 3, 2001, pp 229-30

Dr NJ. Scolding BSc, MRCP is Clinical Research Officer, Dept. of Neurology, University of Wales College of Medicine.

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