In the summer of 1990, Ranulph Fiennes and Michael Stroud set out on their
fourth attempt to be the first to walk to the North Pole unsupported. After
walking 500 miles they were beaten by stretches of open water only 90 miles
from the pole – but they did achieve a world record for the longest
unsupported polar walk. More importantly, this was Fiennes’s first sponsored
expedition, and it raised more than £2 million for the
Multiple Sclerosis Society.
The society is now spending the money on research aimed at both prevention
and cure of the disease, which shows a vision and audacity in keeping with
Fiennes’s polar adventures. It is funding a research unit within the Medical
Research Council’s Cambridge Centre for Brain Research. Scientists there
aim to persuade new cells to grow within the central nervous system of
people with MS, to replace those damaged by the disease. Despite its
relatively high profile and all the research to date, the cause of MS
remains elusive. Yet, the Cambridge scientists are optimistic that they will
be able to restore some nerve function, reversing the creeping paralysis
which is the hallmark of the disease. Team leader Alastair Compston says: ‘I
would be surprised if we hadn’t sought to apply the strategy in man by the
turn of the century.’
Around 80 000 people in Britain are known to have MS. There is little
consistency in the development of the disease – it may progress rapidly, or
at the other extreme be so mild as to remain unnoticed. Symptoms are highly
variable. The course of MS is characterised by recurrent relapses followed
by remissions. For the majority the effects will be small. But for the
unlucky minority, MS is seriously debilitating and even fatal. In many ways
the disease remains a puzzle. Certain areas of the central nervous system,
notably the optic nerve and the cervical spinal cord appear to be most
susceptible. It affects more women than men, in a ratio of three to two,
and is less prevalent at the equator, increasing in incidence towards the
Earth’s poles – the prevalence could be as much as eighty times greater at
the most northerly towns and cities in the northern hemisphere than it is at
the equator. There are no explanations for these anomalies.
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MS is thought to be an autoimmune disease, because the immune system in
people with the disease seems to turn against myelin, one of the body’s own
proteins. Myelin forms a fatty insulating sheath around nerve fibres. These
fibres, or axons, carry nerve impulses, and without an insulating layer the
signals ‘leak out’ and the nerve becomes useless. The result is the classic
symptoms of MS – impaired vision, slurred speech, difficulty in walking and
other problems of coordination depending on which part of the central
nervous system is damaged. Even a few years ago the prospect of repairing
the myelin sheath or of regenerating any part of the nervous system would
have been regarded as fanciful. Following recent research, though, the
improbable is beginning to look possible.
What gives researchers hope is that even after the myelin sheath has been
stripped away, nerve cells remain undamaged for a considerable time. Normal
functioning might be restored if new myelin could be introduced at this
stage. Also, damage is confined to small, localised regions which can
easily be identified using magnetic resonance scans. Until quite recently,
it was thought that the nervous system was unable to regenerate. Now there
is evidence, particularly in the peripheral nervous system, that, given the
right circumstances, it can. Charles ffrench-Constant, a member of the team
at the Center for Brain Research, points out that in the early stages of MS
and in some newly formed lesions there is clear evidence of remyelination.
But for some reason it is inadequate. ‘Perhaps a chemical trigger might be
found to improve the limited capacity for healing that is already there, by
stimulating the mechanisms that once created the central nervous system.’
If remyelination could be encouraged, repair of just 5 per cent of the
damaged nerve fibres would give significant benefits to MS sufferers,
restoring bladder control, for example. This is because there are many
nerves working in parallel in the human body. The main problem with any
attempt at remyelination, though, will be preventing the immune system from
attacking the new myelin.
The starting point for this research is the healthy human brain. There is
still a lot to be learnt about the development of the nervous system and the
roles of the various cell types involved. In MS the cells at the heart of
the problem are the oligodendrocytes. During normal development these very
elongated fatty cells attach to nerves and wind around their axons to form
the insulating myelin sheath. ‘We need to know,’ says Compston, ‘where the
cells that end up as oligodendrocytes come from. And we need to know whether
those same cells are still available in the adult brain. The problem is that
so far as we know the oligodendrocyte is a fully differentiated mature cell
– it can neither proliferate, differentiate or migrate further.’
But do humans have stem cells somewhere in the nervous system? If we do,
then can these cells be persuaded to produce the oligodendrocyte precursors
which may in turn be coaxed to migrate to where they are needed,
differentiate into oligodendrocytes and repair the myelin sheath in the
damaged areas? Until some years ago the consensus would have been no. But
work in rats in the early 1980s suggested that the adult nervous system does
contain a pool of these stem cells that were thought to have been used up.
If humans also turn out to have these cells, then remyelination might be
possible.
STICKY MOLECULES
‘One can foresee a situation in which we find the adult brain does contain
enough stem cells which are capable, at least in principle, of growing and
moving,’ says Compston. In that case, the problem will be encouraging them
to migrate to where they are needed. ‘The solution might well be to
rearrange the chemical environment so recreating the conditions present when
the brain originally developed.’
Cell development is a special area of interest for ffrench-Constant and he
has spent the past year and a half devising ways to analyse the processes
involved. His focus has been on the migration of oligodendrocyte precursors.
He says that in normal development these stem cells are ‘astonishingly
migratory’. They are formed in very limited areas of the brain – the
sub-ventricular zone and the innermost layer of the spinal cord – and
migrate through the entire developing central nervous system. The hope is
that by understanding the mechanisms in normal development, the same level
of mobility might be encouraged in adults.
In his work on these cells taken from rats, ffrench-Constant has focused on
the role of the extracellular matrix – very large, complicated molecules
that lie in the space between cells. He believes these molecules play a
critical role in instructing cells on their behaviour and movement. His team
is looking for the ‘sticky molecules’, or integrins, which bind to the
extracellular matrix molecules. Oligodendrocyte precursors can then attach
to these molecular complexes and extract information from extracellular
matrix molecule. This, it seems, instructs embryonic precursor cells to
migrate to the part of the developing brain where they are required and
informs their behaviour when they get there.
The mechanisms involved in normal development will also be those needed for
repair. Despite the mature brain’s inability to regenerate, there is
evidence that the adult human body does not entirely lose this capacity to
direct cells. Extracellular molecules involved in early skin development are
naturally re-expressed to promote the healing of skin. Neuroscientists are
optimistic that the integrins found in developing embryos could also be
produced in the mature central nervous system, provided the right gene was
stimulated.
Increasingly, neuroscientists are realising the importance of another group
of chemicals known as growth factors which help to orchestrate cell
development. Compston wants to discover which factors are present in the
developing brain and how they influence the differentiation of stem cells
into mature oligodendrocytes.
But even assuming that the stem cells can be found, that they can be
persuaded to migrate and then differentiate to give a new myelin sheath,
there is another obstacle. Scar tissue forms around the demyelinated areas
after someone with MS suffers an attack. These scars encase the demyelinated
area and could prevent the oligodendrocyte precursor cells attaching to the
axon where they are needed.
Breaking down this barrier is the responsibility of James Fawcett. By
growing such material in his laboratory, Fawcett has shown these scars are a
tangled mass of star-shaped cells that looks impenetrable. But further
experiments suggest that these scars need not be a physical barriers to
repair. In frogs, where regeneration of the central nervous system is
possible, research shows that axons can grow back through scar tissue
similar to that found in MS sufferers. This suggests that the scar is not a
physical barrier, but that in humans the tissue may be producing molecules
which prevent the repair process. If these molecules could be identified,
then it might be possible to use antibodies to block or even stop their
production altogether. However, it may transpire that the factors required
to promote migration of precursor cells are sufficient to overcome the
barrier of the scar.
If Compston, ffrench-Constant and Fawcett are successful, an existing but
inadequate repair capability in the central nervous system might be coaxed
to work more effectively. But the pitfalls are numerous – it could prove
impossible to find enough stem cells in the adult central nervous system,
the precursors may not be able to migrate far enough to reach the damaged
areas, or maybe the right chemical environment will be impossible to
replicate. So the team is already pursuing other options.
One alternative being considered is to remove stem cells from the patient,
perhaps in the very early stages of demyelination, and to culture them in
the laboratory. Then after a serious attack the cultured cells, together
with the necessary growth factors, could be reintroduced into the damaged
area. This would pose no danger of rejection, but the snag is that there is
no guarantee that adults can provide the necessary stem cells for culture.
Bill Blakemore, the fourth member of the group, is taking a different tack –
culturing donor stem cells and introducing them into demyelinated nerves.
His results from work with rats has raised considerable optimism.
Remyelination has been achieved in rats, using donor oligodendrocytes
expanded in the test tube with a growth factor and then transplanted into
areas of demyelination in other rats. The advantage is that chances of
rejection are relatively small compared with, say, major organ transplants.
This is because transplanted cells from the central nervous system are not
as recognisably ‘foreign’ to the immune system as other tissues. Suppressing
the immune response sufficiently to prevent attack should prove relatively
easy.
RATS, CATS AND HUMANS
However, Blakemore is cautious about translating his success with rats to
humans. Early results with cats show that scaling up the process is not a
simple matter. It is, he explains, necessary to learn many of the processes
all over again and to develop a new understanding of the relevant cells and
the growth factors involved. Even if donor cells can be transplanted into
humans, he will need to discover the best source of stem cells – those that
exhibit the best response to culturing and which then perform well when
injected into a lesion. It is possible that fetal tissue, the normal source
of human cells, will not prove best for the task. Postnatal tissue might be
needed. This raises the spectre of quite substantial ethical problems. At
least with fetal tissue, there is a precedent – doctors in both Sweden and
America are using cultured fetal tissue in an attempt to treat Parkinson’s
disease.
Ethical and practical problems aside, all this will come to nothing unless
one more obstacle is overcome. There is little point in attempting
remyelination unless demyelination can be stopped. Ideally the Cambridge
team, or some other research group, will discover the cause of MS. But
Compston is not optimistic. Efforts to date have been singularly
unsuccessful. Conventional wisdom has it that MS has a genetic component –
one that confers a predisposition to the condition rather than being a
direct cause. It is thought to be the culmination of many linked factors
which may also vary from one patient to another. Fortunately an
understanding of the cause of MS is not a prerequisite for preventing
demyelination.
Several groups around the world are working on the hypothesis that if the
immune system is responsible for demyelination, then suppressing it should
switch off the damage. In MS there is a characteristic inflammation of
tissues at the lead-ing edges of myelin destruction. ‘What we need to do,’
says Compston, ‘is to understand in detail the nature of the inflammatory
process and to spot the most vulnerable point in it and intervene at that
±ô±ð±¹±ð±ô.’
One such critical point in the development of inflammation is the movement
of a type of immune cell called T lymphocytes from the blood into the brain.
These cells are primed for action and although they do not directly affect
the myelin they are thought to play a key role in the damaging process that
takes place. ‘If one can limit the entry of these activated T cells into the
brain,’ believes Compston, ‘then you should stop the further chain of
±ð±¹±ð²Ô³Ù²õ.’
He aims to do this by removing T lymphocytes from the patient’s circulation
using monoclonal antibodies which are specifically directed against the T
lymphocytes. The danger is that removing these cells will weaken immune
responses generally, and lay a patient open to attacks from other sources.
Surprisingly, tests on patients so far suggest that this may not be a
problem. However, it is still too early to say whether the treatment does
reduce inflammation and subsequent damage. Compston is cautiously
optimistic. Given the great variation in the course of MS, reliable results
will take some time to obtain. He has found that ‘after a slightly stormy
course early on when damage seems to increase, the patients do appear to
stabilise’. A similar trial is now under way at the National Hospital of
Neurology and Neurosurgery in London, where Ian McDonald is targeting
another lymphocyte using a monoclonal antibody against one of its protein
markers.
Prospects for success at Cambridge look fair. And, for the time being, cash
should not be a problem. Last year Fiennes and Stroud successfully crossed
the Antarctic. They are still collecting sponsorship money at the rate of
£2000 a week and expect the expedition to make more than
£2 million. Fiennes, who admits to having become ‘very
involved’ with the MS Society, says, ‘I hope the money we raised this time
will all go to the same research centre.’
Julian Coleman is a broadcaster and science writer.