Select Committee on Science and Technology Written Evidence

Memorandum 64

Supplementary submission from the Centre for Regenerative Medicine, the Queen's Medical Research Institute, University of Edinburgh


  I am writing to address specific questions that you raised in regard to this area of research.

1.   Do you envisage a requirement to take studies using human-animal chimera or hybrid embryos past the 14th day of development as per current HFEA regulations which prohibit the keeping or use of a human embryo which is more than 14 days old?

  I do not envisage a benefit in keeping the embryos beyond day 14. Indeed in the great majority of studies the period of culture would be for six or seven days which is sufficient time for the embryo to reach the stage from which stem cells may be derived.

2.  Assuming that it is possible to produce cells eg embryonic stem cells created through somatic cell nuclear transfer of human genetic material into enucleated animal ova, do you envisage the need to establish totipotency or pluripotency of these cell lines? For what reasons might such studies be required?

  Strictly, a cell is said to be totipotent only if it is able to form an offspring. That would mean transferring the entire reconstructed embryo to a surrogate mother to give it the chance to develop into a child. There is no interest in this information and such a study has already been made illegal.

  By contrast, it is important to understand and define the extent to which a cell population is able to form different tissues, its "developmental potential". This is a very basic step if the cells are to be used. Are they able to form all of the different types of cell of an adult (pluripotency) or is their potential limited (perhaps to multipotentiality). It is absolutely essential that groups working in different parts of the world co-operate to establish and then use standard methods of assessment so that work done in the different laboratories can be compared directly. The Medical Research Council is one organisation that is already supporting such an international initiative with human embryo stem cell lines derived from fertilised embryos (as distinct from those produced by somatic cell nuclear replacement).

3.   What mechanisms would be used to establish totipotency or pluripotency of stem cell lines eg those produced through somatic cell nuclear transfer of human genetic material into enucleated animal ova? Is there a need for implantation of such cells into animals eg animal blastocysts?

  As noted already a test of totipotency is not envisaged.

  In total three tests have been used to assess developmental potential and the methods used in the past to make this assessment have varied with the species from which the cells were obtained. I will return to tests with cells that have developed from stem cells in answer to question 4 later in the letter.

  The most stringent test involves mixing the cells with an embryo. This may be at any early stage of development, but has usually been at the 8-cell stage by aggregation or the blastocyst stage by injecting a small number of cells into the fluid filled cavity of the embryo. The embryo may then be cultured briefly before being transferred to a surrogate female. This method of assessment has only been used with laboratory and farm animals, but not with non-human primate or human embryo stem cell lines. In conversation with international colleagues who work with non-human primate embryo stem cells two reasons are given for the decision not to use this method of assessment. They judge that methods that only use culture provide adequate information. Furthermore, experiments involving chimera production after injecting cells into blastocysts obtained from other primates would be very expensive. In addition to these concerns, in the case of human embryo stem cell lines there are very serious ethical issues. I do not know of any laboratory that envisages inserting human embryo stem cells into an animal blastocyst.

  The second test involves placing the cells in specific sites of immune-deficient mice which are not able to reject the cells. Typically, the cells develop into tumours in which it is possible to see cells of many different kinds, providing evidence that the cell population has the potential to form those cell types, probably all types. This test has been used in all species from which embryo stem cells have been obtained, specifically including human. As it raises different ethical issues and is of considerable cost, this method is used frequently, but is not the initial means of assessment.

  In the least stringent test cells are cultured in systems that promote the formation of many different tissues. Typically, cells are lifted from their attachment to the culture dish and allowed to aggregate in medium that promotes growth and differentiation. Over a short period and in a rather haphazard manner different types of cell are formed. This is the day to day method for assessment of the ability of embryo stem cells to form different types of tissue and would be used routinely in any research to derive cells from human embryos by somatic cell nuclear transfer.

  In summary then, the most frequently used method of assessment is to culture the cells. Greater confidence can be gained by assessing tissue formation within tumours formed in immune-deficient mice.

  In the future it is likely that molecular tests will become more effective means of characterising a cell population than at present. This might involve monitoring the expression of many genes. Alternatively, the quantity of specific proteins on the cell surface might be measured as the cells are passed through scanning equipment able to assess several proteins at the same time, the process is known as FACs scanning or sorting. However, studies in animals will always be required from time to time.

4.  Do you envisage additional requirement for implantation of stem cell lines produced via somatic cell nuclear transfer of human genetic material into enucleated animal ova other than for establishment of pluripotency? For what reasons might such studies need to be conducted?

  Human cells are introduced into experimental animals for different reasons. The most common reason is to discover if healthy cells are able to treat a disease that closely resembles a human disease, such as Parkinson's disease or spinal cord injury. Such a study is an essential preliminary to trials with human patients. At some time in the future this might be necessary if cells from cloned human embryos were being assessed for their therapeutic potential. This approach was that envisaged by Professor Hwang in Korea with his proposed "Patient specific cells".

  The initial research proposals, by contrast, envisage producing cells with the inherited characteristics of a disease so that the disease may be better studied in the laboratory. Placing cells that have been derived from embryo stem cell lines for this purpose into animals may provide important information about the characteristics of the cells. In this case transplantation would be carried out at later stages of development than the blastocyst, perhaps in a fetus or even after birth.

  This situation can be exemplified by a hypothetical experiment to study inherited forms of Parkinson's or Motor Neuron Disease. Cells with the potential to form the nerve cells of the human brain might be introduced into the brains of a mouse fetus. By transplanting into different mice either healthy cells or cells known to be vulnerable to the human disease a comparison could be made of healthy cells with those known to be vulnerable to the disease. These "chimeras" would be made up almost entirely of mouse cells, but with a proportion of human cells in the brain. Once it had been confirmed that the cells showed symptoms of the disease these chimeric animals might then provide a means of assessing the efficacy of new drugs. Such a series of experiments has been initiated in Stanford University and initial findings suggest that the cells are able to integrate in the animal, but that the behaviour of the animal is not changed.

  It should be emphasised that no studies of this kind are envisaged at present, but it would be helpful if the law allowed the regulatory authority the opportunity to approve such studies, should research in the meantime provide evidence that they would be technically feasible and likely to provide important information. Particularly strict requirements for the supervision of the animals could be required.

  I hope that this provides the information that you require, but I would be glad to respond to further questions if you wish. I apologise for the delay in writing.

February 2007

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