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Prof Neil Scolding
Frenchay Hospital, University of Bristol
13 September 2004
Professor Scolding has been working in the area of brain diseases for over ten years, and gave an overview of the present state of knowledge of the causes and prospects for multiple sclerosis.
Work by Ramon y Cajal in 1914 of brain disorders led him to the dictum that ‘Everything may die; nothing may be regenerated’ when defining the apparent loss of cells in brain disease and no obvious means in which it might repair itself. But he did not despair and challenged the future to find out more. We now know that multiple sclerosis may in fact be peculiarly susceptible to treatment.
The axons of cells in the brain carry signals between cells, and they are made more efficient by an insulating sheath of myelin made by specialised cells called oligodendrocytes. If these cells die, then the myelin sheaths fail, and the signals are no longer conducted so well, giving rise to a degeneration of function. The cells are still connected, but by noisy communication channels. This is the cause of the symptoms of multiple sclerosis, although it would seem that about 10% of the failures get repaired. The question is whether we can encourage this repair mechanism. In the last couple of years, experiments on animal models have shown that repair is indeed possible by injecting extra cells which then take up the task of providing the sheaths where cells have died away. But where can we find progenitors of these cells in sufficient quantities to boost the repairs?
What we need are cells that have two properties. First, they must be capable of turning into the types of cells we need. And secondly, they must be able to divide enormously to provide the quantities needed. This is an ambitious aim, but stem cells have exactly these properties. But where can we get them, and how do we ensure they are compatible with the patient?
The obvious place to look was in embryos, because that is what an embryo does when it grows. Cells are diversifying and dividing throughout the whole of its growth, as was recognised in 1998-99. There were two sources of this type of stem cell, from abortions and IVF clinics. Then a third source came on the horizon when a sheep was cloned to produce Dolly the Sheep. As a result, the UK legalised cloning for stem cell creation, but there were many who thought this was not ethically acceptable. To find them it would still be necessary to work within the Nuremburg Code of 1947, which proclaimed that experiments on an individual can only be done if it is of benefit to that individual.
A better source would be adult cell tissue, if that could be done. Additionally, there are a number of biological hurdles that must be overcome in any case. Firstly, the new tissue may be rejected by the patient, an eventuality which is reasonably well understood. Secondly, there is a real danger that the new cells may propagate in an uncontrolled manner and create a cancer, especially one called a teratoma tumour. This has to be considered a possibility because we are asking stem cells to do what they have not been evolved to do. Development in an embryo is not the same as development in an adult.
Then there was an unexpected breakthrough. When biopsies of the brain were taken for other purposes, or after certain types of brain surgery, the samples of brain tissue were examined and it was found that not only were there oligodendrocytes present in all the tissues, there were also many cells that were progenitors of these cells. Unfortunately, these were very difficult to grow in culture, and when experimental injection of these cells in rats and mice were done, there was only a weak response and the new sheaths were thin. Something else was clearly needed.
It was also known that there are neural stem cells in the adult brain too, which can make all the types of neurones and astrocytes. Could they be used? Experiments carried out by an Italian team showed good promise. But how could we obtain enough of these?
All organs of the body contain stem cells for that organ, and they form part of the organ repair mechanism when damage occurs. But there is one organ that is special, and that is bone marrow. These stem cells slowly leak into the blood stream where they circulate through all parts of the body. When damage to an organ occurs, it emits two chemical signals; one to stimulate production of more marrow stem cells, and the other to trap them when they arrive at the place of damage. The bone marrow cells can then become part of any organ like the heart, liver, kidneys, skin etc. and most interestingly the brain too. They can be used to mend all types of tissue at all times throughout life.
Bone marrow has been used in transplants for several reasons for many years and is a relatively easy operation. A donor has to be compatible with the recipient, but they do not have to be the same sex. So when post mortem examinations were made of the brains of female patients who had received male marrow transplants, the Y chromosome turned up, showing clearly that the new marrow cells could become brain cells as well as other organs.Animal studies have shown the benefit of harvesting bone marrow and using them for direct injection into a damaged organs. Some cases of human heart attacks have been given marrow cells and it seems to work; but there is still a long way to go before this becomes routine with the brain. Although there have been no recorded cases of teratoma, the brain is not the place to start the experiment.
A number of extra points were brought out. Auto-immune diseases show particularly difficult problems, because if the original cells have been attacked by the immune defences, then why should the replacements not also be attacked? Multiple sclerosis may be an auto-immune disease, in which case it may be necessary to inject new cells at regular intervals. At the moment we have no idea what causes MS. A number of viruses have been suggested, and there may be a weak genetic component too. But all attempts to identify these have so far failed. It is twice as common in women as in men, and this is true at all age levels, so that rules out any effect from pregnancy risks.
It is curious that there is about an 80% redundancy in the brain, meaning that for many of the functions, if the relevant part of the brain is cut back to about 20% it still works perfectly normally. But below that there is a sharp cutoff of the function. This may mean that only a few more cells are needed to restore the function.
Because of the government's stance on stem cells and the legislation passed, 95% of the money is channelled to embryonic stem cell research. But the commercial biotech industry is interested in faster returns, and they are turning their attention more towards adult stem cell work.