MS research - theories and areas for progress
Professor Alasdair Compston
Open Door - February 2007 pages 8-9
Professor Alastair Compston
Alastair Compston is head of the Department of Clinical Neurosciences at the University of Cambridge. His research focuses on the clinical science of human demyelinating disease.
This is a summary of his talk given at the Royal Society meeting 'Stem Cells and the Future of MS Research' hosted by the MS Trust in September 2006.
What is MS?
Essentially, MS is a condition in which parts of the brain become inflamed. The inflammation leads to a cascade of events, with the myelin sheath and axons being damaged, followed by partial repair (remyelination) but this is not always successful so that many areas of inflammation end up permanently damaged. These events underlie the pattern of the illness that is typically one of episodes which get better at first, then episodes which may not get completely better, and finally slow (secondary) progression.
One disease or several?
We speak of MS as one disease, but the first challenge to our understanding of the condition is whether MS could actually be several distinct diseases.
Looking at tissue from people who have MS shows three or four quite distinct patterns, each of which is characterised by certain combinations of immune cells. Is this telling us there are three or more different forms of MS? Despite these different patterns, all share a common feature: as time goes by there is a switch from inflammation to underlying nerve cell damage (also known as axon degeneration phase) and as this sets in there is progression of symptoms. Secondary progressive MS is characterised by the loss of nerve fibres (axons) themselves. This loss of axons represents a change from a condition where there is a lot of inflammation and little nerve degeneration to one where there is little inflammation and a lot of nerve degeneration. Recognising this has been an important step forward in our understanding of MS.
The best case for an absolutely different type of MS is Devic's disease (neuromyelitis optica, NMO) which affects the optic nerves and spinal cord, involves a particular combination of immune cells and responds well to plasma exchange. This is the predominant form of MS in certain parts of the world eg Africa, India and the Far East. However, in Japan, over a relatively short period of time, there has been a change from the NMO pattern to one more like the MS seen in Northern Europe. This leads us to believe that we are probably dealing with one disease, but that it is complicated and can appear in different forms.
Causation
We believe that causation depends on an interplay between genetic susceptibility, environmental triggers (probably an infection of some kind) and cultural factors which might, for example, include when people at-risk are exposed to certain triggers.
Genetic risks
About 20% of people with MS will have somebody else in their family also affected. The highest risk is for identical twins while the lowest risk is for people who are a member of an adopted family. So there is clearly a genetic risk, but there are also life events which expose that risk.
Many genes have been found to contribute to susceptibility to MS; one gene which is very much concerned with the body's immune response has been found to be crucially important. Early this year, the biggest study yet looking at genetic risk in MS will be completed. A better understanding of the genetics of MS will ultimately lead us to identify novel ways of interfering with the disease.
Environmental triggers
Progress in this area has been rather slow. The most likely culprit, but by no means proven, is the Epstein Barr virus which causes glandular fever or infectious mononucleosis. Exposure to glandular fever in late teens and early adulthood carries a greater risk.
Treatment
By and large, the standard drug treatments now in clinical practice work on the early inflammatory stages of MS (relapsing/ remitting) and are rather poor at dealing with the later stages (secondary progressive) when axon degeneration predominates.
Ideally, we should treat early and really nail the inflammatory process. If this is not possible we need a different tactic - to repair myelin and protect the axons. Remyelination does happen but it is not perfect and does not appear to last. Neil Scolding and others in the 1980s and 90s established which cells are capable of restoring the myelin. We know that these cells stand their best chance of remyelination at the same time as inflammation is on-going.
How can we enhance remyelination? Are stem cells the answer?
Astonishingly, it is possible to take stem cells from a slice of skin from the thumb, manipulate the cells in the laboratory and turn them into brain cells (maybe that doesn't say much for our brains!).
What are the issues for stem cells and MS?
Control: by manipulating the chemicals used to stimulate stem cells we can turn them into cells that produce myelin
Scale: we can make many millions of cells from just a few
Delivery: how do we make sure that stem cells get to the appropriate places to carry out repair? This aspect of stem cell treatment has worried researchers for some time, but it now seems that stem cells are able to use homing tactics to locate areas where they are needed, so a proportion find their way from the blood stream into the nervous system.
Safety: we need to be sure that transplanted stem cells do not harm the recipient
These four aspects of stem cell treatment have been demonstrated for experimental forms of MS; the challenge now is to turn the research into treatment.
Early aggressive treatment
For newly diagnosed people, there is a lot to be gained from early treatment with a highly effective drug that prevents much of the damage from occuring. This is the rationale behind treatment with Campath-1H, a monoclonal antibody, which has been evaluated in Cambridge. A short course of treatment (one week) early on leads to 95% reduction in relapses and progression of disability is stopped at least over the first few years following treatment. But if treatment is carried out later, once axonal degeneration has taken over from the inflammatory phase, then Campath-1H treatment is not effective and MS continues to progress.
Time scales
When will all this happen?
Causation
We expect the human genome screens to be completed this year
Heterogeneity
One disease or several - evidence would appear to be in favour of one disease; we expect to resolve this over next two years.
Treatment
Results expected in this area within next two years, especially around experience of early aggressive treatment for the recently diagnosed.
- Read more about the Stem Cells and the Future of MS Research event
- This page includes a recording of Professor Compston's talk and also a talk by Professor Neil Scolding
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