RE:  TRANSFER OF HUMAN NUCLEI INTO ANIMAL OOCYTES

  I am writing to emphasis the important contribution to the treatment of inherited human disease that would be made by development of effective methods for the derivation of stem cell lines from human embryos produced by transfer of human nuclei into animal oocytes. I will use Motor Neurone Disease as a suitable example of a disease that might be studied in this way, but there are many others including other neurodegenerative diseases, causes of sudden heart failure (Cardiomyopathy) some cancers and some psychiatric diseases. There is no fully effective treatment for any of these diseases and in some cases there is none at all.

  The objective of the proposed research is to discover the cause of the disease and to use that knowledge to develop treatments. Specifically, the aim is to identify a change in the cells associated with the disease that could be used as the basis for laboratory tests. It might be found, for example, that proteins within the cell clump together in an abnormal manner that could be detected by inspection on a microscope. Methods are available to automate a test to discover if potential medicines are able to prevent that change. Once compounds are identified they would then be tested in animals before possible use in human patients. This approach would have the ability to assess thousands of compounds each year, many times more than can be assessed in any other way.

  The genetic error (mutation) that caused the disease is known in only 2% of cases. In these cases it is possible in principle to introduce the error into existing human embryo stem cell lines and to compare cells from the original line with those into which the error has been introduced. This is an ideal comparison because the cells differ only the present or absence of the mutation. Unfortunately this approach can only be used to study 2-3% of cases.

  Motor Neurone Disease is really a family of diseases rather than single disease and it would be extremely important to be able to study other causes of the disease. Genetic research has established that there are four other genes that may cause the disease, but they have not yet been identified, despite twenty years intensive research. At the present time production of cells from embryos produced by somatic cell nuclear transfer is the only technique with the potential to provide cells from such patients for study and use in drug screening. This approach will make it possible to study cells from a further 8% of patients, making 10% in total.

  There is every reason to expect that methods can be established to produce human cells in this way. Somatic cell nuclear transfer has been used for the production of mouse embryo stem cell lines in several different laboratories. It is very encouraging to note that the proportion of embryos from which stem cell lines can be obtained is very much greater than the proportion that would have developed to become offspring had they been transferred into surrogate mothers (2% v 16%). Furthermore the cell lines that were tested had an apparently normal ability to form all of the different tissues of an adult.

  Somatic cell nuclear replacement for this research involves two cells: an unfertilized egg at the stage at which it might be fertilized and a cell from a patient. The genetic information in the chromosomes is removed with a very small pipette before the introduction of the genetic information from the patients cells. Usually this is by fusing the two cells together. The new embryo is then stimulated to begin development before it is cultured in the laboratory for six to seven days. By that time it may have developed to the stage from which embryo stem cells are obtained, the blastocyst stage which has approximately 150-200 cells.

  At the present time, the only stem cell lines to be produced from cloned human embryos were produced after transfer of human genetic information into a rabbit unfertilized egg. Several groups have described development of embryos to the blastocyst stage after transfer of human genetic information into human eggs, but no embryo stem cell lines were obtained. There are many possible reasons for this failure, including the possibility that there are differences in an aspect of early development between primates and other mammals that have not yet been identified. Important differences between species were identified during earlier research with laboratory and farm animals and birth of offspring from cloned embryos depended upon adapting the procedures for each new species. It is possible that such a modification is required for production of cells from embryos produced after transfer of a human nucleus into a human egg. In this regard a comparison of events after transfer of nuclei into human and rabbit eggs would be very informative.

  There is now a considerable body of evidence to show that development may be obtained after transfer of nuclei from one species to another. Several groups have observed development to the blastocyst stage after transfer of human nuclei into animal eggs, although the study in rabbits mentioned previously is the only one to obtain embryo stem cell lines. Rabbit and cow are the two species. Comparable development has also been obtained after transfer of nuclei from other primate species into rabbit eggs.

  In short, at the present time it is likely that the greatest progress to the goal of producing embryo stem cell lines from human embryos produced by nuclear transfer would be made by research with a variety of recipient eggs, including rabbit, cow and human. The cell lines would be produced specifically for research and not considered for transplantation into people.

  There are a variety of reasons why we should consider this research to be important. First, the compassionate wish to be able to provide effective treatment for those who suffer from the diseases that might be studied in this way. Secondly, the global market for drugs found to be effective against some of the more common diseases, such as Parkinson's Disease, would be enormous. Third, both of the key techniques were originally developed in the United Kingdom. Embryo stem cells were first derived mouse embryos in Cambridge and the nuclear transfer was established in Roslin Institute, near Edinburgh. It would be sad to miss an opportunity that was created in the UK. I hope that you will be able to support the case for transfer of nuclei into animal oocytes for research purposes.

January 2007