Dr. Yorgos Nikas/Photo Researchers, Inc.

The ability to derive embryonic stem cells from cloned human embryos and to control their differentiation into different cell types provides revolutionary new opportunities in biology and medicine. These methods make it possible to study human genetic diseases in entirely new ways and, in the longer term, such cells may be used in the treatment of human disease. Certainly this approach will provide opportunities that are not otherwise available.

Last year, Professor Woo-Suk Hwang in Korea made a significant step forward when he derived stem cells from a cloned human embryo,1 demonstrating for the first time both that it was possible to clone human cells, and that it was possible to obtain embryonic stem cells from the resulting clone.

A few months ago I, along with Christopher Shaw at the Institute of Psychiatry, King's College London, applied to the British government for a...


<p>Ian Wilmut</p>

Motor neuron disease is a relentlessly progressive muscle-wasting disease that causes severe disability from the outset, and death usually within three to five years. Every year, 1,200 people in the United Kingdom die of MND and at present there is no drug treatment that significantly improves survival. Degeneration of motor neurons is the common cause of this fatal condition, but the etiology of the disease is not fully understood.2 It seems likely that several genetic and environmental factors contribute to the disease's pathogenesis.

The great majority of MND cases are sporadic, but between 5% and 10% are inherited. Among these familial cases, mutations in the gene that encodes superoxide dismutase (SOD1) account for approximately 20% of cases, but genetic analyses suggest that at least four other genes remain to be identified.3

Researchers initially assumed MND was caused by reduced SOD1 activity, but this seems not to be the case. Mice in which the endogenous SOD1 gene has been deleted do not develop MND, whereas those that express mutant forms of the human gene develop paralysis.4 As the transgenic mice carrying the human gene also had their own two copies of the gene, this observation suggests that the effect of the mutation is through a cytotoxic effect of the abnormal protein, rather than a loss of function.

To progress in our studies, however, we'll have to move from mouse to man. There are several new potential sources of human cells liable to MND that may reveal the means by which abnormal SOD1 causes neurodegeneration. If preimplantation genetic screening is practiced for those cases in which the mutation has been identified, then embryonic stem cells could be derived from those embryos identified as carrying the mutation. This is not known to be happening at present, but is certainly technically feasible. Alternatively, known mutations could be introduced into embryonic stem cells derived from embryos not known to be liable to MND, and subsequently the MND cells contrasted with the original line.

My group at Roslin Institute and Dr. Shaw's group at the Institute of Psychiatry are using this latter approach in the first part of our collaborative project. This will provide us with the first opportunity to look for the effects of the abnormal protein on the structure and function of nerve cells equivalent to those of a young baby. At present there is no possibility of carrying out that research, so we have no idea what changes occur at this stage in a patient's life, when there are no clinical symptoms.

In those MND cases that are familial, yet in which the mutation has not been identified (8% of all cases), nuclear transfer will also offer new opportunities by enabling us to produce cloned embryos and cells that are genetically identical to those of the patient. Those cells will be vulnerable to the disease, even though we do not know the gene or genes responsible for causing it.

Once embryonic stem cell lines that are vulnerable to MND have been derived – whatever gene causes the disease – they will be differentiated into neural populations by groups working with Professor Shaw in London, and Jim McWhir of the Roslin Institute. These groups will then analyze the cells to determine the mechanisms that underlie motor neuron degeneration and develop a drug-screening program. Using high-throughput screening systems it will be possible to assess several hundred drugs comparatively cheaply.

The same approach could be used to study any human genetic disease, as long as the affected cell types can be produced from embryonic stem cells in the laboratory. The advantage is greatest if the mutation that causes the disease is not known. Candidate conditions for study include cardiomyopathy and some forms of cancer. It is also likely that genetic differences contribute to the "sporadic" cases of diseases such as ALS, in which direct inheritance is not apparent, perhaps by increasing vulnerability to environmental effects. If this is the case, then nuclear transfer may also be used to obtain cells from such families.


In the longer term, embryonic stem cells offer the hope of new treatments for some very unpleasant degenerative diseases. These diseases include cardiovascular disease, spinal cord injury, Parkinson disease, and type 1 diabetes. Methods for the derivation of specific cells types from stem cells lines are being established in our laboratories at Roslin Institute, though it remains to be confirmed that they function normally after being transferred into a patient. In addition, a great deal remains to be learned about the most effective means of introducing the cells into patients.

In any treatment regimen it will be essential to avoid immunological rejection of the transplanted cells, but the immune response is likely to vary from one disease to another. Cells from cloned embryos would be most valuable in conditions such as cardiovascular disease, in which immune rejection could be avoided by transfer of histocompatible cells. By contrast, in the treatment of diseases within the central nervous system cells there is some uncertainty as to whether or not they would be subject to rejection.56 Finally, several of the conditions that are mentioned as candidates for cell therapy are autoimmune diseases, including diabetes type 1. In such cases, transfer of immunologically identical cells to a patient is expected to induce the same rejection.


At present, cloning methods are repeatable and used by many laboratories around the world. Yet they are inefficient. This low overall efficiency reflects a failure of current procedures to reprogram the gene expression patterns from those appropriate for an adult cell to that required for normal embryonic development.7 We do not yet know whether similar abnormalities in gene expression would occur in stem cells derived from cloned embryos. Thus, the first use of cells from cloned embryos should be for research, and not to develop therapies.

Ultimately, such therapies will come, albeit not for many years – but not unless we can develop a clear, coherent, international regulatory framework. At present there are considerable differences between countries in the regulation of nuclear transfer to produce human embryos. In the United Kingdom, projects to derive cells from cloned embryos may be approved by the regulatory authority for the study of serious diseases. Human reproductive cloning, however, is illegal. A similar legal framework exists in some other countries, such as Sweden. In the United States, federal funds cannot be used for research with cloned embryos, but a referendum in California committed taxpayers in that state to massive expenditure over the next 10 years. Research with stem cells from donated embryos is very active in several Asian countries such as Singapore, Japan, and China. Recent action by the United Nations recommended that human cloning of any kind should be banned, but this is only advisory and the British government has made it clear it will not prohibit research of the kind that we are just beginning.

Regardless of what you believe about therapeutic applications, however, these cells will be an extremely important research resource. Cloned embryonic stem cells could allow researchers a glimpse into intractable genetic diseases that cannot be obtained in any other way, especially those for which no defined mutations have been discovered. Biomedicine should forge ahead to find out what it can learn from these unique research tools.

Ian Wilmut, who leads the team that produced Dolly, the first animal to develop after nuclear transfer from an adult cell, is in the Department of Gene Function and Development at the Roslin Institute in Scotland. Wilmut's group focuses on the molecular mechanisms that are important for normal development of cloned embryos and the use of that knowledge in medicine, biology, and agriculture.

He can be contacted at ian.wilmut@bbsrc.ac.uk.

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