Embryonic stem cell research and therapeutic cloning
A Scientists for Labour meeting addressing the science and ethics on cloning and stem cells seemed a good opportunity for me, a chemist, to get to a feel for research my biologist friends are keen to promote, but which many others are keen to prevent. This was held on 21 Nov in the Palace of Westminster for the benefit of MPs and I was not disappointed. I came away much clearer about the issues and well convinced that the benefits to Parkinson's disease sufferers alone justify substantial research efforts to develop our limited understanding into a clinical treatment.
The background: David Lee (Medical Engineering Division, Queen Mary London) introduced us to the topic by outlining the Donaldson Report and its key proposals to extend the areas of research permitted by the 1990 Human Fertilisation and Embryology Act, in particular to develop methods for replacing damaged human cells. The remarkable ability of stem cells formed during the first 5 days after in-vitro fertilisation to divide frequently and develop into a range of specialised cell types cannot yet be utilised for human medical research. Although many different types of stem cell are present in the adult, they are often quite rare and divide infrequently.
The idea behind stem cell therapy, is to isolate these cells, multiply them in vitro and then use them to replace damaged tissue. The analogous technique of cell nuclear replacement (also known as therapeutic cloning) is also not allowed in the UK, so healthy cells cannot yet be taken from a patient and used to create exactly matched copies for transplants to replace damaged or diseased tissues. Many degenerative diseases, ranging from Parkinson's where prospects are promising, to leukaemia, sickle-cell anaemia, muscular dystrophy and diabetes, even to Alzheimer's where evidence is less convincing, could become treatable. However, although prospects are good, it is important not to raise hopes too high or too early.
The science underpinning the debate: Robin Lovell-Badge (National Institute for Medical Research) explained the biological details from his longstanding research experience with embryonic mouse stem cells. Conception produces a single cell (a zygote) which after 3 cell divisions has grown to eight cells, each of which are capable of developing into a complete human if split, say into two as with identical twins. Further division increases the cell number and after 5 days a hollow ball of cells (a blastocyst or preimplantation embryo) forms. The outer cells, together with many of the inner ones, will form part of the placenta and the rest of the embryo support system, the remaining inner cells produce the embryo, although much later, after implantation in the uterus.
Embryonic stem cells can form a wide range of cell types in vitro, e.g. nerve cells, muscle cells, cells that form blood vessels. These can then be grafted back into a mouse, where they have been shown to partially correct a range of diseases, including mouse models of Parkinson's, multiple sclerosis and diabetes. From this it seems likely (except for the big problem of immune rejection) that human embryonic cells could be used to treat a wide range of diseases, by cell-based therapies. The ideal option is to isolate embryonic stem cells from the adult patient. The solution comes from the nuclear transfer (cloning) techniques which gave rise to Dolly the sheep. This showed that it is possible to re-programme the nucleus of an adult cell by removing the original nucleus from an unfertilised egg and replacing it with that of an adult donor cell.
The aim is patient-specific stem cell therapy, whereby a biopsy is taken from a patient and by nuclear transfer, an adult cell is re-programmed and cultured in vitro to the blastocyst stage. By isolating the inner cells, stem cells could be prepared with the same genetic make-up as the patient. Techniques learned from studying mouse stem cells could be applied to direct these stem cells to form the relevant cell type to cure the patient, be it Parkinson's, heart disease or spinal cord injury. Clearly, once embryonic stem cells have been made for an individual, they would be available for treating any other problem present in that person. Alternatively, recent research suggests that it may be possible to obtain a range of stem cells for therapy by redirecting one type of adult stem cell into another. One type of stem cell would be isolated and re-programmed into the type appropriate for curing the disease. However, there are many more practical and theoretical problems to be overcome with this approach than with the Embryonic Stem cell route. Most notably, conditions for growing sufficient numbers of most types of adult stem cells and for changing their fate in culture, both of which are prerequisites for any potential therapeutic use, have not been established. Whereas we already know how to do this for Embryonic Stem cells. Moreover, the ability of Embryonic Stem cells to form a wide range of tissues reflects the normal process of embryonic development, whereas for an adult stem cell to do so is abnormal.
We know it is possible to derive embryonic stem cells from human blastocysts cultured in vitro from spare embryos obtained in IVF programmes. However, we do not yet know if it is possible to use nuclear transfer technology to re-programme adult cells and to obtain suitable blastocyst stage embryos. We also need to do research on the best ways to treat any stem cells such that we could obtain the right cell type to use for therapy. We need to have methods of quality control to know that any cells used will be safe and reliable. All the evidence obtained with mouse ES cells suggests that they probably will be, but it is important to show this for human ES cells.
Potential therapy for Parkinson's sufferers: Robert Meadowcroft (for Parkinson's Disease Society) explained how stem cell therapy provides new hope for the 120,000 people with Parkinson's Disease in this country. He reminded us just how debilitating a disease it is and how it affects all aspects of daily living for the individual and their family. In addition to the well known symptoms of tremor, stiffness and slowness of movement, sufferers experience pain as a constant problem, loss of facial expression and tone of voice, fatigue, difficulties in sleeping, plus depression. It is not surprising that MPs post bags are not dominated by letters from people with Parkinson's - both difficulties with handwriting and the impact on their daily life understandably occupy them with greater priorities.
Parkinson's Disease, first identified in 1817, is a disorder of movement caused by the loss of dopamine (a chemical transmitter) producing cells in the brain. As well as being a brilliant doctor James Parkinson was prominent both in the Church and in politics where he pressed for universal suffrage and only narrowly escaped being charged with treason regarding a plot to assassinate the King.
Parkinson's is a long term degenerative condition whose incidence increases with age. As the loss of dopamine producing cells in the brain continues the symptoms increase in severity and the person with Parkinson's becomes increasingly disabled. Although for many sufferers drug treatments can be effective in the short term, there are longer term severe and frightening complications from drug therapies. Surgical interventions can offer some relief from symptoms in a relatively small number of cases but there are risks involved with surgery, of course, and the disease continues to progress after the surgical intervention. There is no cure at present.
It is stem cell research which offers real hope of "Dopamine Loss Reversal" and which may enable the lost dopamine producing cells to be replaced by new healthy cells. Consequently The Society strongly supports the Donaldson recommendations to extend the areas of research permitted under the 1990 Human Fertilisation and Embryology Act.
The ethical issues: John Harris (Professor of Bioethics, University of Manchester) discussed the thought-provoking ethics of embryonic stem cell research by making us consider the ethics of natural sexual reproduction. This must clearly present a problem for those who feel "natural" processes are innately sacrosanct and can have no unethical basis, but I for one found this comparison most convincing.
The precautionary principle has been invoked to prevent germ-line gene therapy on the basis that changes would adversely affect future generations and may be irreversible. This is effectively countered when you consider that unaltered defective genes are also procreated indefinitely causing unknown future harm. However abandoning hundreds of thousands of people to their fate from a range of diseases simply by dismissing the route to a potential cure is an unacceptable ethical position.
Treatment of pre-implantation embryos receives much attention, what receives less is how nature itself discards 5 out of 6 of them to ensure the objective of producing a healthy baby - naturally no blame is attached to this. Similarly no guilt is attached to natural cloning, i.e. the tens of thousand of identical twins born naturally in the UK. The in vitro production of spare embryos present similar ethical issues.
In Vitro Fertilisation and related techniques leads to the storage of spare embryos for up to 10 years. That is to say to their destruction after 10 years. It is difficult to see how a society that could allow so many spare embryos to be destroyed for no good purpose could object to others being used as source material for therapeutic purposes. It must logically be better to do something good that to do nothing good.
John Harris concluded that "those who would ... object to the harvesting and use of embryonic tissue must show how the death and use of those particular embryos is different in morally relevant ways from those which die in pursuit of normal sexual reproduction. They must also show that ... it is too high a price to pay for the prospect of saving millions of future lives and alleviating untold human misery."
The political dimension: Lord Sainsbury (Minister for Science) reviewed the legislative background and political challenge posed by therapeutic cloning of human embryonic stem cells.
The Human Fertilisation and Embryology Authority (HFEA) set up in 1990 to license and monitor clinics that carry out in vitro fertilisation, donor insemination and human embryo research is able to issue research licenses only for the following purposes:
Public consultation following the cloning of Dolly the Sheep indicated that current measures were ineffective in dealing with new developments relating to human cloning and that safeguards were needed to forbid human reproductive cloning. Legislation to explicitly ban human reproductive cloning regardless of the technique used was recommended, together with an extension to the purposes for research licences are issued to include:-
The potential medical benefits and alternatives have been scrutinised by an expert group under Donaldson who concluded that the proposals did not raise new ethical issues. "A significant body of opinion holds that, as a moral principle, the use of any embryo for research purposes is unethical and unacceptable on the grounds that an embryo should be accorded full human status from the moment of its creation. At the other end of the spectrum, some argue that the embryo requires and deserves no particular moral attention whatsoever. Others accept the special status of an embryo as a potential human being, yet argue that the respect due to the embryo increases as it develops, and that this respect, in the early stages in particular, may properly be weighed against the powerful benefits arising from the proposed research." Current controls on embryo research reflect this latter view.
On the basis of the Donaldson report the Government agreed to the two proposals, drafted changes to the regulations and decided to put them to a free vote in both Houses of Parliament. Lord Sainsbury himself will be voting for the change.
Summary: Professor Lord Robert Winston (Dept of Reproductive Sciences and Medicine, Imperial College School of Medicine) summed up many of the issues raised by others. Some of the points were memorable and quite thought provoking:-
It is worth remembering too that human reproductive cloning is forbidden and will remain a criminal act. It is the responsibility of the HFEA and the police to ensure that fears of human cloning becoming reality do not happen. Perhaps if draconian penalties were extended to include failure to put in place a fail-safe monitoring system by the responsible authorities as well as for the offence itself (with punitive damages as in US law come to mind), this risk would be minimal.
Finally I echo the view of Robin Lovell-Badge. "We are dealing with a question of potential risk versus likely benefits. My personal view is that the benefits are definitely worth pursuing. Moreover, it is better that this type of work is permitted in the context of a well regulated and controlled system (such as that already in place in the UK), where the science can proceed in step with ethical issues (rather than in many countries around the world that have little or no regulation)."
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