Copper: Quest for a Cure

The story began in 1912, but my involvement only began in 1951. In 1912 Dr Kinnier Wilson, working at the National Hospital for Nervous Diseases in London described a new illness affecting youngsters, the principal symptoms being loss of control of movement and contractures of the limbs. This was always associated with scarring of the liver. All these patients died with in a few months of diagnosis.

Dr Wilson's life long ambition was to find a cure for this disease which became known as Wilson's disease, technically hepatolenticular degeneration.. In 1948 Professor John Cumings, working at the same hospital, showed that patients dying of Wilson's disease all had large abnormal amounts of copper deposited in the brain and in the liver. He suggested that the new metal binding drug, British Antilewisite (BAL) might be used to arrest the course of the disease.

In 1951, working in the Metabolic Unit at University College Hospital in London I discovered that patients treated with the antibiotic penicillin excreted in their urine, a breakdown product of the drug, penicillamine. Later, when studying as a Fulbright Fellow in the Liver Unit at the Boston City Hospital, I saw a patient with Wilson's disease being treated, with little, benefit, with BAL. I suggested that penicillamine had the right structural formula to bind copper and promote its excretion and this would be a more effective treatment than BAL and, could be given my mouth and not by painful injection, it would be easier to give over a lifetime.

On returning to University College Hospital in London I needed to find patients with this rare disease and supplies of penicillamine to assess its ability to mobilise copper from their abnormal body stores. Three patients were found by my father, Sir Francis Walshe, a distinguished neurologist, and with the small amount of penicillamine available to me I was able to show that in each case penicillamine promoted the excretion of more copper than did BAL. Two patients were returned to their referring physicians but the third stayed with me for over 50 years and made an excellent recovery eventually having three children of her own.

Supplies of penicillamine were secured when I was able to convince the medical director of the Distillers Company, the principal makers of penicillin at the time, to make penicillamine for me.

By the early 1960s reports from my own work and from other centres appeared showing that patients treated with penicillin showed a remarkable improvement in all symptoms.

However Propfessor Denny Brown and Dr Uzman in Boston still believed that Wilson's disease was not due to copper deposition but due to abnormal protein metabolism with abnormal peptides being excreted in the urine. Working with Professor Milne and Dr Asatoor at the Hammersmith Hospital, it was possible to disprove this theory using newer techniques to analyse urine.

In 1957, after failing to get appointed to two different appointments in Oxford I was accepted to a post in the Department of Experimental Medicine in Cambridge.

Having been appointed Assistant Director of Research to Professor McCance in Cambridge I needed to find somewhere to live and to decide upon a line of research in keeping with the facilities available.. Shortly after taking up this new post I was invited, by the British Council, to undertake a lecture tour in South America. On returning from this I succeeded in establishing the methods I needed to estimate abnormalities of copper metabolism and to recruit patients for my studies. I also continued my work with Sydney Osborn, a medical physicist, and we improved our methods of determining the movement of copper in the body using a short half life radioactive isotope of copper.

Whilst the results of treatment with penicillamine were very encouraging I encountered the problem of a patient developing a severe toxic reaction to the drug. A University biochemist, Dr Hal Dixon, suggested I use triethylenetetramine, a known copper binding compound and this proved safe and effective. For several years we produced this in my laboratory to treat a small number of penicillamine intolerant patients. We also found that an impurity in this compound could induced a disastrous fall in blood pressure. During the course of these studies we moved premises twice, first temporary war time huts in Canhams yard and then the old Low Temperature Research building in the Downing Street site. During this time I also had trouble with the Ministry of Health over the question of prescription charges for my patients.

The story resumes with yet another move, the third in all, to new laboratories in the University wing at the New Addenbrooke's Hospital. This had the advantage of being near my ward, the service departments, biochemistry, haematology, radiology and audiovisual aids. It had the disadvantage of removing me from the basic science departments of the University with whom I had had such successful cooperation. In addition my new quarters were much smaller than before and there was no convenient place to see patients. The major problem was the roof. Every time it rained heavily the roof leaked and I had to take unusual action to get this remedied.

However the main problem was the realisation that the impurity in our trientine preparation was not only potentially toxic but, perhaps actually so. This lead to a search for and, eventually thanks again to Hal Dixon, the finding of a solution to the problem. Other activities were a search for a common ancestor to a cluster of Wilson patients centred around the Wash; the search through church records was fascinating but, unfortunately, non productive; the cluster must have been coincidental There was also some work for an ice cream firm who allowed a batch of iced lollies with excess copper onto the market. Finally there was continued work on basic brain chemistry with Sir Rudolph Peters in the University Department of Biochemistry in which we showed how copper might damage the transport of ions through the neuronal membrane........

Although the hospital pharmacy had taken over the production of trientine this drug needed to be put on an official basis with production by a pharmaceutical company. None, however, were interested. A letter to the British Medical Journal aroused some interest but no positive result. In 1976 I convened a conference in Cambridge to which all interested groups were invited to discuss this problem. An unexpected result was that the Department of Health agreed to take out a product license and that the Government Chemist would test the final product for purity if a manufacturer could be found. A small chemical firm Cambrian Chemicals undertook the manufacturer and Rupert Purchase, their principal chemist worked out a large scale method for production. However It took several more years of correspondence with the Department of Health to overcome the bureaucratic baffles and to obtain the necessary product license. This was achieved successfully in 1985, shortly before a similar license was issued in the United States.

Basic work had continued during this time. This included studies with radiolabelled penicillamine to determine its rate of absorption from the gut, distribution in the body and rate of excretion in the urine. Later similar studies were conducted with radiolabellesd trientine. One problem remained, and still remains unsolved. Why does a small percentage of patients fail to respond to any of the currently available lines of treatment. Can it be due to a particularly unfavourable gene mutation?

Inevitably the news of the success of penicillamine treatment for patients with Wilson's disease spread and calls came from abroad for help. My first overseas call for help came from Rheims, then Vienna and the last one was from Rome. Unfortunately I was not able to help any of these patients as they were already on penicillamine and had failed to respond and no other therapies were available at the time of those visits although the patient from Vienna was eventually transferred to Cambridge. However the television programme on the BBC Overseas Service did result in the opening of a flood gate of patients from Europe and then the Middle East. The first of these patients came from Hungary and this was closely followed by patients from Italy, including Sardinia, Spain, Yugoslavia (as was), Greece, Turkey, Iran, Iraq, The Yemen and Egypt. There was also one each from the USA and South Africa.

A new problem arose with a home patient who developed intolerance to penicillamine, trientne BAL and zinc treatment. A new drug had to be found for her. Earlier workers had investigated the use of molybdate on good theoretical basis but had used the wrong salt. This problem was solved by using a sulphur molybdate compound which was known to induce copper deficiency in sheep. As nothing was known of its safety in many I successfully assayed this first on myself.

The average delay in making the correct diagnosis for all patients was 2 years; some were diagnosed relatively quickly others waited many years. This resulted in some unnecessary deaths and some patients being left with severe disabilities and wanting compensation. I was involved in six such cases. In four cases, with the help of my evidence substantial damages were obtained but in two cases, which I think resulted in miscarriages of justice, the patient failed to obtain damages. My first case was in 1974 when a father complained of the late diagnosis of his son's illness which resulted in the boy's death He wanted publicity more than damages in the hope that such an error would not recur. The case was settled out of court with no publicity. Success was also achieved for twins from Belfast and for a civil engineer from England whose diagnosis had been made in the USA having been missed by his consultant in this country. The case of one unfortunate patient who suffered from a very rare abnormality of copper metabolism actually was settled the High Court in the Strand with the award of over one million pounds damages. In two cases my evidence failed to obtain damages, one of these was of a very bad case of case of medical incompetence by a psychiatrist but the plaintiff made her claim too late and the case never came to court. I recommended, in vain, an ex gratia payment should be made.

September in the year 1987 heralded my retirement both as a reader in the University and also that of my honorary appointment as a consultant physician to Addenbrooke's Hospital. At that time I had been unable to make any satisfactory arrangements for the continued specialist care of my patients. A solution was offered in the following summer when Dr Gerald Stern invited me to set up a Wilson's disease clinic at University College Hospital (UCH) in London. One problem had to be solved as to who would do the specialist studies of copper metabolism The UCH laboratory was not able to undertake the preferred method of caeruloplasmin estimation but Scheinberg agreed to do this for me if I mailed him suitable samples to New York. My clinic ran in conjunction with Dr Stern's out patient clinic until we transferred to the Middlesex Hospital and Dr Lees took over from Dr Stern on his retirement. My expenses for the travel to London were met by Aldrich Chemicals, who had taken over the production of Trientine. There were problems over the account of an overseas patient and also a major problem when two Cambridge doctors published results culled from my case notes.. Eventually I tendered my resignation on reaching the age of 80 years and handed over the clinic to Dr. Godfrey Gillett who had joined me some years before. There is also an account of my somewhat unhappy relationship with the University of Cambridge.

Looking back covers the highlights of my career. When I qualified as a doctor in 1945 medicine, by present day standards, was rather primitive with few effective therapies a good bedside manner was important. But there was little bureaucracy. Today it has changed out of all recognition as has the growth of bureaucratic control and meaningless Government targets The 1950s saw the start of this revolution in both new and highly effective drugs and high tech investigative techniques.. Two years in the army taught me little medicine but surely matured my outlook on life. On return to civilian medicine I learned about metabolic medicine and thanks to a year as a Fulbright fellow in the USA I was introduced to the problems of Wilson's disease which set the course for the rest of my life's work. This was continued with the development of effective therapies, in the environment of the University of Cambridge and at Addenbrooke's Hospital. On reaching retiring age I was able to continue work at University College Hospital and then the Middlesex Hospital in London until I took a well earned retirement at the age of 80 years.