Our research is primarily aimed at understanding the causes of the symptoms of MS, and developing novel therapies 1) to avoid getting symptoms, 2) to treat the symptoms once they arise, and 3) to protect the brain from the damage that causes symptoms.
The symptoms of MS arise from a number of mechanisms. Inflammation, demyelination (loss of the insulating layer of myelin from around nerve fibres) and degeneration (death of nerve cells and nerve fibres) are all important. Symptoms due to inflammation and demyelination can improve after a short period (e.g. a few weeks) but symptoms that have been present for years are likely to be due to degeneration and that is more difficult for the brain to overcome. It is not usually possible to be certain which type of damage is causing a particular symptom.
Understanding the symptoms of MS
The symptoms of MS are particularly varied, and can affect movement, and any of the senses such as vision, touch and taste. It is not possible to assign a particular symptom to a particular type of brain pathology, because almost any symptom can result from any of the main types of pathology, namely demyelination, degeneration and inflammation. Each of these changes can block, or impair, the passage of nerve impulses, and thus the ability of the brain to function properly.
Demyelination (i.e. loss of the insulating layer of myelin from nerve fibres) causes symptoms (such as visual problems, weakness and numbness) by disrupting impulse conduction along nerve fibres, and we are searching for ways to improve conduction so that symptoms are alleviated. Acting in different ways, demyelination can also contribute to the tingling sensations experienced by many MS patients because it can make nerve fibres generate impulses inappropriately - the fibres become hyperexcitable and just make lots of meaningless impulses that are felt as tingling.
If nerve cells or nerve fibres die they undergo degeneration and this causes persistent loss of function. We have identified a mechanism that we believe is responsible for at least some of the degeneration in MS. We have also developed a therapy to protect from degeneration (based on the partial blockade of sodium channels), and this therapy is inexpensive, and safe for long term administration. The therapy has been tested in clinical trials, first in secondary progressive MS (SPMS), and then in optic neuritis. The trial in SPMS appeared to show that the drug was not effective, because the primary outcome measure was not met, but looking at the data with current knowledge the drug probably did achieve its aim of protecting the brain against degeneration. The second trial showed unambiguously that the therapy was beneficial.
Another project explores the ability of tissue affected by inflammation to work normally. We are particularly interested in whether the inflamed tissue has enough energy to work properly. In fact, we suspect that it does not, and that this shortage directly causes symptoms because the nerve cells do not have enough energy to make impulses properly. Worse, we suspect that the cells have so little energy that they can die, causing some of the demyelination and degeneration. In this way, an energy shortage may cause multiple problems in MS.
An energy deficit and oxygen shortage
What causes the energy deficit? There are several reasons, but we have found that there can be a shortage of oxygen in the brain, especially in the inflamed regions, and this may be one of the most important reasons. In fact, there is so little oxygen that the brain tissue stops working properly, and this can cause symptoms such as weakness, and problems with eyesight. Oxygen is of course vital for life, and it is used by tiny particles in cells, called mitochondria, which turn oxygen and glucose into energy so that cells can function and survive. Without sufficient oxygen, the mitochondria suffer and get damaged: we have several projects exploring brain oxygenation and the properties of mitochondria.
We are also very interested in the blood supply to the brain, because this transports both the oxygen and the glucose. We have found that the blood supply to inflamed brain tissue is reduced, and it becomes inadequate to supply the oxygen required.
If inflamed brain tissue can be short of oxygen, improving the oxygen supply could be beneficial and, in fact, we have found that increasing the breathed oxygen concentration can reduce the severity of some symptoms. The beneficial effect was demonstrated at the onset of new inflammatory damage in a laboratory model of MS, and we are now examining the potential benefit of oxygen later in the disease. Oxygen is unlikely to improve symptoms resulting from degeneration, but not all symptoms are due to degeneration. We note that our research, like all research, needs to be replicated in other laboratories before it is accepted. Oxygen is not a cure, and it does not fully restore function.
The fact that oxygen is essential for our lives encourages the widespread belief that oxygen is safe. Oxygen is, after all, commonly given in hospitals for a range of ailments. However, we caution that oxygen can be dangerous. In fact, oxygen should be regarded in the same way as a medicinal drug, and drugs have side effects, and it is possible to overdose - it may be surprising, but breathing pure oxygen for a week is lethal. Thus although we have shown that breathing oxygen at normal pressure can have prompt beneficial effects in the laboratory, this does not mean that there are no bad effects - we simply don’t yet know. Also, if a little oxygen might be beneficial, it does not automatically follow that more oxygen would be better still. There is likely to be a peak at which any beneficial effects of oxygen are achieved, but beyond which any deleterious effects become more apparent: we do not yet know what this peak is. We know that some people with MS take hyperbaric oxygen as a therapy, but our research does not allow us to know whether oxygen at hyperbaric pressure is likely to be beneficial, or not - we have not explored the effects of oxygen at hyperbaric pressure. We clearly need further research to understand the beneficial effects of oxygen therapy in more detail, and also the potential risks.