Mentored by a Madman Read online

  One unanswered question that intrigued me was why half the rats had consistently circled clockwise and the other half anticlockwise. On my first visit to the United States, I visited the laboratory of Stanley Glick, a scientist working at Mount Sinai Hospital in New York, who told me that he had got the answer. Rats, like humans, have an innate laterality bias with subtle differences in the appearance of the cerebral hemispheres and different levels of grey matter dopamine on the two sides of their brains.

  Parkinson’s disease typically presented with symptoms down one side of the body and there was usually a delay of at least two or three years before disabilities became apparent on the other side. The malady also remained asymmetrical through its whole course and was associated with a spinal curvature to one or other side. My time in the laboratory was almost over, and the circling amphetamine rat gradually lost favour as a test bed for investigating brain dopamine function. I felt an opportunity might have been missed to explain clinical phenomena that continued to defy adequate explanation.

  There was a huge gulf between scientific research and medical practice. Science was all about induction not deduction; discovery and proof were separate activities. My colleagues in the laboratory had been kind and helpful but saw me as a well-paid dilettante, ticking a box on an alien career path. Although I was impressed by the boundless optimism and enthusiasm for exploration of some of the scientists, others came over as menial public servants restricted by government dictates and reluctant to stick their heads above the parapet. One or two seemed to gain greater pleasure from tidying up the laboratory than conducting experiments. I think they were all dismayed at my sloppiness of thinking and subjective, discursive viewpoint. On the other hand, I was astonished by their lack of understanding of the handicaps caused by neurodegenerative disease and surprised that they did not see the importance of talking to patients.

  To be productive most scientists need the company of fellow researchers whose expertise complements their own, a functional laboratory, productive competition and a quiet, conventional life. Discussions over coffee had convinced me that almost all scientific research led nowhere and on the rare occasions when it did, it often kicked off in a completely different direction from where it started. Common sense was as useful in research as it was in clinical practice, and in my view there was no such thing as unprejudiced observation. The scientists I worked with swore, made mistakes and quarrelled but the good ones had honesty and integrity. Good fortune and intuition cropped up everywhere and cherry picking seemed part of the game. The Eureka moments had often come during dreams or states of intoxication. Scientists, like doctors, were of strikingly different temperaments and worked in divergent ways. Explorers, gumshoes, artists and even mystics stood tall in their ranks. Green fingers seemed as important as scrupulous scientific method in sifting a grain of fact from a mountain of fool’s gold.

  I was glad to have gathered an understanding of the difficulties inherent in laboratory work and the discipline needed to create order from mayhem. I had also picked up the rudiments of statistics and learned how many failures lay behind each successful experiment. I now understood that it was the criticism of gathered facts that gave science its true individuality and universalism. If in the future I was to go on to convince myself and others of something I only guessed to be true, I would need to forge lasting collaborations with open-minded and sympathetic neurobiologists who understood that patients must always be centre stage in medical research. Their rigour and ingenuity would guard me against credulity and the illusion of knowledge, and assist me to bridge the chasm between laboratory bench and hospital ward. They would prevent me from becoming a note-taking field worker who contented himself with the mere reporting of detailed but uninterpretable examples. I could help them embed their discoveries in stories. Medical science was richly various and very messy but its spirit was divine. To be successful it required openness, freedom to disagree without censure, and a healthy disrespect for authority.

  7

  – Contraband –

  In 1977, a polythene bag full of white powder was smuggled through Heathrow airport by Professor Merton Sandler in his deep-pocketed ‘flasher’s mac’. It was a cargo of scientific contraband that was to give me a critical edge on New York competitors and launch me on a journey of sacrificial investigation. L-deprenil (E-250), an inhibitor of monoamine oxidase, was a gift from Josef Knoll, Head of Pharmacology at the Semmelweis University in Budapest. He was convinced that his molecule had enormous clinical potential as a psychic energiser and nerve tonic.

  The monoamine oxidases are a family of enzymes responsible for the physiological breakdown of a number of chemical messengers including serotonin, noradrenaline and dopamine, believed to be important in the regulation of mood. They had first become a target for psychopharmacological investigation in the 1950s after a group of patients dying from tuberculosis had been given a new drug called iproniazid (Marsilid). A newspaper reported how some of these consumptives had started to ‘dance for joy’ in the corridors of Sea View Sanatorium on Staten Island. This surprising occurrence led on to a few curious psychiatrists conducting trials with iproniazid on small groups of patients with psychotic depression. Some of the desperate volunteers, who had been resistant to all other therapeutic approaches, reported an increased sense of wellbeing and vitality.

  Iproniazid was soon being trumpeted in the press as the first specific ‘antidepressant’ and between April 1957 and February 1958 an estimated 380,000 psychiatric patients were treated with the drug in the United States. Not long after its introduction, a neurologist reported that every time his wife took iproniazid and then ate cheese, she developed severe headaches and her blood pressure went up to dangerously high levels. This complication of treatment became known as ‘the cheese effect’ and after a few patients had tragically died from haemorrhages into their brain, the regulatory authorities imposed a dietary embargo of tyramine (found in strong cheeses and some other foodstuffs) as a prerequisite for the continuing use of the drug.

  After the discovery of severe dopamine loss in Parkinson’s disease in 1960 the combination of iproniazid with L-DOPA seemed a logical pharmacological strategy for relief of the shaking palsy. By delaying its enzymatic breakdown and reducing the rapid turnover of the remaining ‘natural’ dopamine in the brain, monoamine oxidase inhibitors might be expected to enhance chemical transmission. Unfortunately, severe elevations of blood pressure occurred similar to those seen with tyramine-containing foods and precluded the routine use of what otherwise might have been a useful therapeutic marriage.

  The existence of two distinct forms of monoamine oxidase known as Type A and Type B was suspected by the time Joseph Knoll’s ‘present’ arrived in London and I hoped that L-deprenil (‘depression nil’) and its anagram ‘end peril’ might prove to be an omen.

  Merton Sandler had assured me that deprenil was ‘safe as houses’ and I willingly agreed to become part of my own experiment. I took 10 milligrams a day for a week at the end of which time I was ‘admitted’ to a side cubicle on Ward 5.2 where a colleague plied me with escalating doses of tyramine. Tyramine is a substance that is found in minute quantities in the brain, and in large amounts can displace stored monoamines leading to elevations in blood pressure. The purpose of my self-experimentation was to determine whether deprenil, in contrast to the first wave of non-selective monoamine oxidase inhibitors, could be taken safely with tyramine-rich foodstuffs like Gorgonzola cheese, pickled herrings, chocolate, Chianti wine, pulses and Marmite.

  This ‘single subject research’ conducted in the garret of the Cruciform Building on Gower Street allowed me to experience what it must be like for a patient to volunteer for a trial with an untested drug. L-deprenil made me more alert, created pleasant waking dreams and induced a disarming fatuous euphoria. I was full of beans and my wife felt I ought to continue on the drug permanently. Measurement of my monoamine oxidase levels in blood platelets confirmed that deprenil had long lasting and
powerful selective inhibitory effects on the Type B species of monoamine oxidase. I had also been able to tolerate ‘industrial’ doses of tyramine without any increase in my blood pressure or headaches.

  It was also important to determine if L-deprenil could be used safely with L-DOPA before clinical trials could be contemplated. To my relief, administration of 10mg of deprenil to six L-DOPA treated volunteers with Parkinson’s disease did not cause hypertension. The endgame was in view.

  Understandably, the United Kingdom Medicines Commission felt unable to formally sanction a trial with an illegally acquired substance but common sense prevailed and tacit approval to proceed was granted on the proviso that we obtained ethical approval from the hospital and informed consent from the patients. My main scientific partner on the project, John Elsworth, then got one of his pharmacist friends to produce a few thousand capsules, each containing 5 mg deprenil from Sandler’s bag of white powder without charge. There was no shortage of volunteers desperate to try deprenil even though we had virtually no safety data other than our own experience with the drug. Despite the miracle of L-DOPA, Parkinson’s disease was still a crippling handicap and a great deal was at stake.

  The trial went smoothly and I was able to confirm that deprenil could be used safely in combination with L-DOPA and without the need for tyramine dietary restriction. I also showed with the help of diaries filled in by the patients that the drug could increase the duration of benefit obtained from each dose of L-DOPA. A small number of the volunteers were in the very earliest stages of the disease and had not yet been given L-DOPA. On 10mg a day some felt much more vigilant, optimistic and energetic and described improvement in their speed of movement.

  I concluded that l-deprenil was easy to use and could help to iron out the end of dose deterioration (‘wearing offs’) seen in some patients on chronic L-DOPA treatment, but it was much less potent than bromocriptine and certainly not the wondrous cure that I had hoped for.

  Following the publication of our results in The Lancet, the most prestigious general medicine journal in Britain, I was encouraged to present the data at International Symposia on Parkinson’s disease and it was at one of these – a meeting in Vienna – that I was first introduced to Doctor Josef Knoll. He was a tanned, extremely fit-looking, fifty-five-year-old who spoke English fluently with a thick Hungarian accent. When he spoke his voice was charged with emotion and long passages of words were uttered without break, with the v sound sometimes replacing the letter w. He told me that he had been taking deprenil for several years and that the drug had greatly improved both his mental sharpness and sexual vitality. He was in no doubt that deprenil could lengthen lifespan. What impressed me most on that first meeting was his dynamism and certainty. He came over as God-like and infallible.

  I later learned from Gerald Stern that Knoll had survived Auschwitz where he had seen his parents die, Buchenwald, and finally ridden out the notorious Dachau death train before being liberated by the Americans, weighing just 39 kg. After World War II, he had tried to make sense of his experience in the Nazi concentration camps by studying innate and acquired drives in laboratory animals. As part of this work he had trained rats to search for and jump to the rim of a 30 cm high glass cylinder and then crawl inside. This acquired drive had become so powerful that it could override the rats’ instinctive appetites. In several related experiments he used amphetamines as a way to ignite the brain’s engine. ‘Speed’ excited the midbrain to release noradrenaline and dopamine, two chemical messengers that he believed were critical for the process of transforming novel experiences into acquired drives and ingrained habits.

  Within eighteen months of our Lancet paper being published, investigators in New York and Finland reported similar clinical results. Whether an experiment is carried out on one blinkered scientist or a thousand volunteers, it still requires validation from an external source and it was a great relief to receive confirmation of my results.

  Deprenil soon became a popular adjuvant treatment for Parkinson’s disease. The recommended dose was 5–10 mg a day although it had seemed from the clinical pharmacological studies I had undertaken that 10 mg once a month might be more than adequate to prevent the metabolic degradation of dopamine in the brain. Despite its popularity with doctors and patients, no large pharmaceutical company showed any interest in buying and marketing it.

  The arrival of bromocriptine and deprenil into clinical practice in the late seventies provided an embarrassment of riches in comparison to therapeutic options for other common neurological diseases like Alzheimer’s and multiple sclerosis, but led to increasing uncertainty among neurologists about the best way to initiate treatment in Parkinson’s disease. In an attempt to try to answer this dilemma, the Parkinson’s Disease Research Group of the United Kingdom was set up as a registered charity in 1982. Its remit was to enlist a group of neurologists and some specialists in the care of the elderly to participate in a trial in which hundreds of untreated patients would be recruited and randomised to one of three initial treatments – L-DOPA, deprenil combined with L-DOPA, or bromocriptine. The patients would be followed at three-monthly intervals throughout the entire course of their illness.

  Academic curiosity and a hankering to resolve uncertainties in clinical practice were the motivations for the eighty hospital specialists who recruited patients from their National Health Service practices. Investigators paid their own travel expenses to attend the meetings and gave up considerable amounts of their own time to take part. Most clinical trials sponsored by the pharmaceutical industry focused only on short-term efficacy and excluded patients over the age of seventy-five and also those with co-existing medical conditions like cancer and stroke. In sharp contrast, the primary interest of this trial centred on whether one of the treatments was superior in extending life expectancy. Although a placebo arm was not included in its design, we felt that the long follow-up and liberal inclusion criteria would ultimately prove to be great strengths of the study.

  Not long after the UK Parkinson’s Research Group had started to recruit patients, six heroin addicts presented to emergency rooms around the Bay Area of San Francisco with signs of acute parkinsonism. Neurological detective work revealed that all of them had recently injected the same batch of a designer opioid called MPPP. It was determined that the ‘kitchen chemist’ had taken a shortcut in the drug’s synthesis and the sloppy batch he had sold to his clients was contaminated with a non-narcotic called MPTP.

  MPTP had first been synthesised in 1947 as a potential analgesic by the Hofmann La Roche Company in Switzerland. Immobility and tremor had occurred during testing in laboratory monkeys and two of six human volunteers who were given MPTP mysteriously died. Two scientists working with other companies also came down with ‘MPTP sickness’ and research into the compound was abandoned.

  The tragedy of the Santa Clara frozen addicts led to a frenzy of interest in MPTP but this time as a toxin rather than as a potential painkiller. Scientists showed that an active metabolite of MPTP, a slightly altered compound called MPP+, could destroy the melanin containing nerve cells in the midbrain and induce a behavioural syndrome in monkeys that closely resembled Parkinson’s disease. At the very least it was hoped that the MPTP paradigm would serve as an improved animal model for testing possible new treatments.

  Then an experiment was carried out that would rock the Parkinson’s disease community. Jan Chiba, a graduate student working in San Francisco, was curious to find out how the protoxin MPTP was converted in the brain to MPP+. He hypothesised that MPTP entered the brain where it was mistaken by monoamine oxidase for dopamine and metabolised by the enzyme to MPP+.

  In a series of test tube experiments, Chiba was able to confirm his notion and show that two monoamine oxidase inhibitors, pargyline and deprenil, completely prevented the conversion of MPTP to the toxic species MPP+. William Langston, who had been one of the doctors to first examine the frozen addicts, then initiated further experiments in which monkeys were pretreated
with deprenil and showed that it completely protected their dopamine pathways from the toxin MPP+. It was proposed that deprenil might prevent the accumulation of toxic free radicals like hydrogen peroxide in dopamine nerve cells, and exposure to pesticides with chemical structures similar to MPTP became a serious contender for the cause of Parkinson’s disease.

  Largely as a result of these compelling findings, the National Institutes of Health in Bethesda, USA, agreed to fund the largest trial ever carried out in Parkinson’s disease on eight hundred previously untreated patients with the primary aims of determining if either deprenil or Vitamin E could retard disease deterioration (The Parkinson Study Group DATATOP trial).

  The results of this trial were published in 1989 in the New England Journal of Medicine accompanied by a glowing editorial indicating that deprenil in a dose of 10 milligrams per day could delay the onset of disability associated with early untreated Parkinson’s disease and might prove to be the first ever scientifically proven neuroprotective agent. The news release heralded:

  Miami Beach, May 2nd, 1990 – A new drug therapy used in the early stages of Parkinson’s disease delays the need for L-DOPA therapy and should enable patients to enjoy longer periods of productive employment, family life and well being.

  Doctor Langston, one of the trial investigators, told the press, ‘For the first time, there is hope for patients with Parkinson’s disease.’