John Michael Walshe – Born 24 April 1920, Died 14 October 2022

John Walshe's discovery of penicillamine as a treatment for Wilson's disease owed little to chance and a great deal to his deep immersion in metabolic medicine and the techniques of molecular and analytical chemistry. In the months before his death, at the age of 102, he was still in contact by phone and letter with one of the first patients he had treated successfully in the late 1950's.

Walshe was born in Kensington, London, the younger son of Sir Frances Walshe, one of England's greatest neurologists. He was educated at Beaumont College, a boarding school run by the Society of Jesus in Windsor, and in 1939 he went up to Trinity College, Cambridge to read natural sciences. During the war he served as a Captain of the Royal Medical Corps in the Middle East before returning to complete his undergraduate studies at University College Hospital in London.

By the early 1950's it was recognized that damage to the liver, brain and other vital organs in Wilson's disease could be limited by removing copper from the body. Walshe had just started working on inborn errors of amino acid metabolism with Charles Dent at University College Hospital and in the course of his research on disorders of amino acid excretion he identified d‐penicillamine in the urine of a patient with liver disease, who was coincidentally taking penicillin. A colleague was then roped in to inject him with a hefty intravenous dose of penicillin, allowing him to replicate his earlier serendipitous chromatographic finding on himself. This confirmed for the first time that d‐penicillamine, an amino acid related to cysteine was an important catabolite of penicillin. His doctoral thesis that included these novel findings was rejected by the University of Cambridge. Shortly afterwards he obtained a Fulbright scholarship to work under Charles Davidson in the Thorndike Memorial Laboratory at Boston City Hospital. At the time Derek Denny‐Brown, the head of neurology at the hospital was treating a man with Wilson's disease with injections of British Anti‐Lewisite and asked Davidson advice on how to manage the patient's liver failure. On the walk back from the ward, after seeing the patient, Walshe suggested to Davidson that penicillamine had a chemical formula that might give it copper chelating properties. Davidson was enthusiastic about the suggestion and managed to obtain 2g of the sulfurous smelling crystalline powder. Walshe took 1g himself with no ill effect and then gave Denny‐Brown's patient the rest demonstrating a very satisfactory increase in urinary copper excretion. His scholarship year over, Walshe returned to University College Hospital in 1956 and eventually managed to obtain sufficient quantities of penicillamine to pursue his clinical research. His father, who had trained under Kinnier Wilson, and was on the staff at University College Hospital and Queen Square, was able to locate three Wilson's disease volunteers. All three had a marked cupriuresis to a test dose of penicillamine but the two that were under the care of physicians at the National Hospital were advised by John Cummings, then the Professor of Clinical Pathology to take British Anti‐Lewisite. The third patient, a 16‐year‐old girl under the care of Dr Ashby at the Whittington Hospital agreed to continue with penicillamine. Before treatment she was bedbound, unable to walk, feed or dress herself and shook uncontrollably. After a year of sustained treatment it was evident to everyone that the signs of Parkinsonism had improved.

Walshe then took up a clinical academic post in the Department of Investigative Medicine at the University of Cambridge and an honorary consultant post at Addenbrooke's Hospital. His claims for penicillamine were still regarded with skepticism by leaders in the Wilson's disease field although both Denny‐Brown and Cummings accepted that better treatments were needed. It was not until 1960 after he had published further data in the Lancet and similar positive results had been reported by Scheinberg and Sternlieb that the treatment gained favor. When asked many years later about where his penicillamine brainwave had come from, Walshe would look to the heavens or say the idea had floated out of the ether. Even if this were true it is certain the idea would not have come to him without his knowledge of molecular chemistry. Penicillamine was soon accepted as a life saver but by this time Walshe was already aware of its potentially serious side effects and shortcomings. Over the next 30 years his perseverance and innovation combined with his knowledge of molecular chemistry led to the discovery of two more efficacious Wilson's disease treatments, triethylenetetramine (trientine) in the 1960's and ammonium tetrathiomolybdate 20 years later.

Almost all his most impactful papers were single author publications and like others of his generation he was a great believer in self‐experimentation in situations where he felt it was justifiable. Although he was a lone wolf by nature he had strong collaborative links and friendships with several metabolic physicians, neurologists and hepatologists.

In 1987 at the age of 67 he was forced to relinquish his post in Cambridge and after his brief retirement he jumped at an invitation to continue his clinical research at the Middlesex Hospital, Mortimer Street, by that stage amalgamated with his alma mater, University College Hospital. There he continued to treat many of his former patients and the occasional newly diagnosed case (he had a database of 320 Wilson's disease patients).

In jest he would quip that had he had only ever made two diagnoses in his life, ‘This is Wilson's disease or this is not Wilson's disease’. There at his monthly clinic he introduced me to the value of the legendary Walshe elephant used to assess motor coordination and insisted I carry a hand lens in my doctor's bag to help confirm the presence of Kayser‐Fleischer rings. At the end of the clinic he usually left carrying samples for the clinical pathology laboratory where he would discuss issues of quality control of assays, calculate free copper values on his patients and discuss the perennial difficulties in getting reliable 24‐hour urinary copper samples. If any of his patients were on the ward for investigation he would always go and see them before heading back to Cambridgeshire on the train. One day shortly after his 80th birthday, he arrived at the clinic crestfallen to say that his wife had told him that he should now cease clinical practice both for his own good and for that of his patients. Although heeding her counsel, ever resourceful, he decamped to his garage‐cum‐laboratory at his home in the village of Hemingford Gray where he kept in contact with some of his devoted patients by phone. He also remained in great demand as a lecturer at postgraduate medical meetings and as a second opinion up until his late nineties.

Walshe was a man of immense integrity whose conscience and experience guided his decision making. Although he was interested in Gothic architecture and stained‐glass, metabolic medicine remained his overriding interest. He championed the Wilson's Disease Support Group‐UK attending many of their meetings and shortly after his 100th birthday he campaigned against the egregious and unjustified rise in the price of trientene (an overnight increase from £400 pounds to £3400 for 100 capsules occurred in the United Kingdom). He pointed out to those who were prepared to listen that drug companies had never developed a treatment for Wilson's disease but they had been keen to market and make profits acceptable to their shareholders from molecules tested by academics working in universities. It is worth recording that he refused to receive any money for any of his medical discoveries.

Walshe did not suffer fools gladly and was also not afraid to publicly expose the hypocrisy of medical academia. At times he could also be cantankerous and prickly and in his younger years he gained a reputation in some academic circles as being difficult and awkward. He was proposed three times for fellowship to the Royal Society but was blackballed on each occasion, attempts to get him a knighthood were thwarted by the refusal of former colleagues at Cambridge to provide commendations and in spite of discovering three effective treatments for a previously fatal genetic disease his research was overlooked by the Nobel Committee.

Walshe either liked you or he didn't and in the narrow research realm of Wilson's disease you were either with him or against him. But he was an exemplary physician who through his perseverance and dedication showed us all that medical science and compassionate doctoring can be compatible bedfellows.

I am grateful to Claire Armstrong, John Walshe's daughter, for approving the obituary and providing important detail. Further reading is recommended in the References. ¹ , ² , ³ , ⁴