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MGA News

September 1998

Piecing the Genetic Jigsaw Together

David Fishlock

Dr David Beeson and Professor Doug Turnbull speak to David Fishlock about the increasing understanding of the rarer Inherited Myasthenic syndromes and the Mitochondrial Myopathies

Dr David Beeson is a Genetic Engineer who specialises in understanding a rare group of inherited disorders called Congenital Myasthenia Syndromes (CMS).

David, in his mid-30s, has devoted his career to the molecular biology of these conditions, which often appear at birth or within the first two years of life. Disability may be mild or severe but doesn't usually worsen with time, and may even improve. Although there are treatments which can help, there is no cure for CMS, and the best hope lies in understanding the genetics sufficiently well to eventually repair nature's flaws.

The Institute of Molecular Medicine, where David works, at John Radcliffe Hospital, was set up by the Medical Research Council in 1988, to apply the new understanding of genetics to patients. David read natural sciences at Cambridge University where he elected to study the new technology of DNA cloning, and specifically its use in identifying the genes of acetylcholine receptors for his doctorate in 1982.

Acetylcholine receptors lie at the heart of myasthenic disorders. The cause of muscle weakness has been traced to the transfer of information between nerve and muscle fibre, and to two ways in which data transfer can be impaired. One is if antibodies are binding to the muscle receptors and suppressing the incoming nerve signals, explains David. The other is when the receptors themselves have a genetic fault that weakens the signal and hence the muscle's response.

For his Ph.D. research David was 'farmed out', as he puts it, to one of Europe's - if not the world's - leading commercial centres of genetic engineering, the High Wycombe laboratories of G.D. Searle, a family-owned US pharmaceutical group.

Successful isolation

Early in his project, to clone the gene for a chicken receptor, Searle scientists cloned the first receptor gene, from the torpedo ray. This marine species has receptors numerous enough to emit bursts of electricity - powerful enough to shock an adversary. "I was in right at the start".

Armed with Searle's expertise on cloning beta-interferon and other potential drugs, David first isolated his chicken receptor to earn his Ph.D. in 1986. Then he began to isolate, one by one, the five genes of the human acetylcholine receptor, first in professor Newsom-Davis's group at the Royal Free Hospital, then when it transferred to Oxford in 1988. "What attracted me was the clinical application of the research - the human input", he says.

Professor Newsom-Davis, when head of the Department of Clinical Neurology at the Royal Free, had recruited David so that he could apply the new techniques of molecular medicine to his speciality, the diagnosis and care of Myasthenia Gravis. The disorder came within the ambit of the Muscular Dystrophy Group. He is strongly supported by the Myasthenia Gravis Association. It was categorised as an autoimmune disease in which the body targets its own muscle receptors.

David's small group succeeded in cloning the fifth receptor gene in 1992. It had proved the most difficult. This one is present only at the neuromuscular junction, whereas the other four are present all over muscle. "It was extremely difficult to clone - several years of hard work - but has proved to be the most interesting".

It turns out that this gene is the focus of most of the mutations that underlie CMS. He published the achievement in 1993.

For the last five years his group has been screening all five subunits and domains of the acetylcholine gene for the mutations in patients with inherited myasthenic syndromes. They have developed a 'library' of new reagents and ways of making them, now used by researchers worldwide to study the disorder.

"The last two years have proved very fruitful", he says. "In 60-70 per cent of people with Congenital Myasthenia Syndrome we found mutations in genes coding for their receptors". Moreover, 80-90 per cent of those mutations occur in what is known as the epsilon subunit of the gene - the last one to be cloned.

Their screening programme has been organised nationally to pick up mutations. It's now clear that the disorder, though still rare, is more widespread than was previously believed, possibly because more cases are being diagnosed confidently as CMS where previously they were simply recorded as muscle weakness of unknown cause. Where a few years ago his group were receiving samples of four or five confirmed cases a year, today it is about 100.

Subunit substitution

They have identified no single site for mutations that cause CMS, the mutations are spread throughout the epsilon subunit gene. This implies no one original founding effect that has spread through the population.

But there is an idea that another sub-unit might be able to substitute for the flawed one. It's an idea with a parallel in Professor Kay Davies' notion of a genetically engineered form of utrophin, a protein with close resemblance to dystrophin, the protein at fault in muscular dystrophy.

David is quick to stress that this idea is not yet proven. But he's in regular discussion with Kay, who is professor of genetics at Oxford University. If it works, the idea would be to administer a drug that would 'turn on' natural production of the substitute gene in the patient.

He speaks warmly of his love for molecular biology - the precise manipulation of DNA by the latest technologies to truly justify the term 'genetic engineering'. Therein lies the hope - if still long-term -of a cure for this disabling disorder.

MGA NEWS September 1998
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