Smoking Ears and Screaming Teeth - Trevor Norton (2010)

Trials and Tribulations

‘We often make people pay dearly for what we give them’ –

Comtesse Diane

Even with anaesthetics, operations remain a daunting prospect so it is comforting to believe that there is a gentler treatment for our illness. We put great faith in ‘cures’. Patients who depart from the consulting room without a prescription may feel that they have been cheated. Our faith in drugs is so powerful that even if given a pill with no curative powers whatsoever, many people feel better. There has always been the whiff of magic in medicine.

The ancients had an appetite for noxious nostrums for diseases, and love philtres for unrequited desires. Herbalism was the midwife of both botany and medicine. For two hundred years virtually all botanists were also physicians or apothecaries, and herbals were the pharmacopoeias of their day. John Gerard’s Herball, published in 1597, became the most famous botanical book ever printed.

Unfortunately, herbalists were shackled to the ‘doctrine of signatures’, a belief that the nature of its healing powers was stamped on every plant. A resemblance to a part of the human body indicated the organ that it treated, hence lungwort, bladderwort, toothwort, and anything with a suggestive protuberance was of course an aphrodisiac. To the active imagination mandrake root was shaped like a naked manikin and was reputed to scream when uprooted from the ground. It could cause paralysis and madness, so it was used in love potions.

Because plants are treasure houses of drugs, a few of the herbalists’ concoctions actually worked: Jesuit’s Bark (quinine) from the Cinchona tree was indeed a treatment for ague (malaria), digitalis from foxglove leaves is a heart stimulant, senna pods are a useful purge, and centuries later salicylic acid from willow bark would be marketed as Aspirin.

In 1733 Poor Richard’s Almanac contained sage advice: ‘He’s the best physician that knows the worthlessness of the most medicines.’ Although they promised much, the majority of the herbalist’s remedies were useless or even dangerous. A buttercup ensured that he who takes it ‘leaves this life laughing’, but the herbal fails to make clear whether without the help of the buttercup he might not have left at all.

When fewer surgeons were part-time barbers and doctoring became a semi-respectable trade, ‘trained’ surgeons and physicians emerged from universities. In the eighteenth century a medical degree could be bought for twenty pounds even from some of the most prestigious institutions in Scotland without having to attend a single lecture. The standard of the student intake, even as late as 1869, may be judged from a statement by the Dean of Harvard Medical School who revealed that they set no written examinations because the ‘majority of students cannot write well enough’. A graduate who had suffered years of examinations and dissections qualified ‘never having dressed a wound, given an injection, seen a birth or attended at the bedside in a professional capacity’. Even the most experienced practitioners were powerless in the face of almost all the great killer diseases until the dawn of the twentieth century.

Many people did not survive infancy, because of the ravages of incurable chickenpox, diphtheria, dysentery and measles. Legions of adults were cut down by meningitis, tuberculosis and pneumonia; sex came seasoned with syphilis, and giving birth included the horrors of childbed fever brought by surgeons coming to the delivery room straight from the mortuary.

Confronted by such foes, doctors fell back on Voltaire’s advice: ‘The art of medicine consists in amusing the patient while nature effects the cure’ – or until he dies. The helpless physician could only indulge in ‘heroic cupping and vigorous blooding’ and refining his bedside manner. When prescribing drugs he plumped for the old standbys: poisonous antimony for fever, with side effects such as cardiovascular failure and sudden death; generous doses of toxic mercury against venereal disease with the added benefits of loss of teeth and floods of bloody diarrhoea followed by circulatory and kidney failure; opium for pain relief and a lifetime without relief from addiction. A century later Mark Twain could still claim that ‘a natural death is where you die without a doctor’.

The quality of doctoring may be judged by that of the royal physician who treated the madness of King George with leeches to the legs, a stream of emetics and by blistering the monarch’s shaved scalp to ‘extract the poisonous matter from his brain’. No wonder an eighteenth-century cynic wrote: ‘It is often ask’d, what Disease a Man died of … but properly speaking, the Question should be … what Doctor he died of.’ It is likely that the best-selling powders of an Oxford-trained doctor accelerated the demise of numerous patients including Laurence Sterne and Oliver Goldsmith.

Physicians were also inordinately expensive. Even the wealthy baulked at their bills. George III accused one of his physicians of belonging to a profession that ‘I most heartily detest’. The medic protested that Jesus healed the sick. ‘Yes,’ said the King, ‘but not at £700 [a year] for it.’ Later the King’s widow spent so much on doctor’s bills that she had to sell most of the furniture from her home at Frogmore.

Untrained quacks on the other hand were cheap. In eighteenth-century England anyone could patent a medicine and, as the ingredients were not regulated, the content could be adulterated at random. To describe the status of these dispensers a contemporary invented the phrase ‘licensed to kill’. The satirical cartoonist William Hogarth called quacks ‘The Company of Undertakers’.

Daniel Defoe described how: ‘Corners of Streets were plaster’d over with Doctors’ Bills and Papers of ignorant fellows; quacking and tampering in Physick, and inviting the People to come to them for Remedies.’ All the treatments were of course ‘Infallible’. Medicine was big business and some quacks made a fortune. Careless experiments in the bedroom led to a brisk demand for cures for the clap. In 1750 three out of every four doctors relied on venereal infections for their business.

Mountebanks were distinguished from other practitioners by the shameless promotion of their products. If their handbills were to be believed, their miracle potions were more than a match for any disease:

Here take my bills,

I cure all ills,

The Cramp, the Stitch,

The Gout, the Itch,

The Squirt, the Stone, the Pox,

The Mulligrubs,

The Bonny Scrubs,

And all Pandora’s box.

At a penny a pill, how could a wretch with mulligrubs resist? An impoverished population riddled with disease was vulnerable to shysters who ‘pretend to perform matters beyond reason’. Winter’s Elixir Vitae was advertised as having ‘revived great numbers of people supposed to be dead’. It was ever thus: the ‘sick trade’ is lucrative and misfortune is ripe for exploitation.

There were also so-called ‘piss prophets’ who could diagnose any illness with a glance at the patient’s urine. When ‘Doctor’ Myerbach was handed a flask of cow’s pee he instantly identified ‘too great a pleasure in women’.

Ben Jonson condemned the itinerant quack as ‘a turdy-facy, nasty-paty, lousy fartical rogue’ more interested in lucre than the welfare of a patient he would never meet again. Most quacks were showmen as well as salesmen. They would first draw a crowd and then a tooth or two, with loud music to drown the cries, and finally hawk remedies such as Scot’s Pills – ‘excellent for hard drinking’, Rose’s Balsamic Elixir for curing ‘Frenchify’d (i.e. syphilitic) patients’ or Horseballs for coughs.

While quacks charmed the punters with their slick, persuasive patter, educated physicians bamboozled them with impressive jargon. Fielding lampooned them with the doctor in Tom Jones: the patient, he opined ‘had received a violent contusion in his tibia by which the exterior cutis was lacerated, so there was profuse sanguinary discharge … Some febrile symptoms intervening at the same time (for the pulse was exuberant and indicated some phlebotomy), I apprehended an immediate mortification.’

Even reputable physicians learned largely from experience, and some quacks became more adept at tooth-pulling and bone-setting than most qualified doctors. Sir Hans Sloane, the President of the Royal College of Physicians, chose ‘Crazy Sally’ Mapp, the ‘Epsom bone-setter’ to treat his niece’s chronic back problem rather than risk the ministrations of his fellow doctors.

In Georgian England people could pick and mix what treatment they used. They often turned to self-dosing in the belief that taking control of their treatment was safer. Self-dosing became known as ‘quacking yourself’. Horace Walpole said that his father, the statesman Sir Robert Walpole, had ‘quacked his life away’.

To guide the self-experimenter there were do-it-to-yourself books which the poet Southey thought should be entitled Every Man His Own Poisoner. This was a time when even the official pharmacopoeias on which doctors relied endorsed the medicinal virtues of ground woodlice, crab’s eyes, and crushed bedbugs in white wine. They had only just abandoned recommending unicorn’s horn. The self-help guides and herbals were similar collections of improbabilities. The Poor Man’s Medicine Chest advised stocking up on such essentials as extract of toxic lead ‘for rough but safe purges’, and saltpetre (an ingredient of gunpowder), perhaps for even less safe purges. Some purges were said to work fifteen times or more with a single dose.

Medical guidebooks became best-sellers and gave rise to ‘schools’ of self-treatment. Isaiah Coffin’s book stimulated ‘Coffinism’, a term offering little prospect of a happy outcome. Samuel Thomson’s Physick for Families went through numerous editions and became a standard health manual for over 150 years.

The first thing was to denigrate the opposition. Thomson devoted an entire section to ‘How doctors shorten the lives of their patients’. The book is a mix of good sense and nonsense. His axiom was ‘an ounce of prevention is better than a pound of cure’. He rightly rails against doctors treating fever with ‘bleeding, blistering, starving, all their refrigeratives, their opium, mercury, arsenic, antimony, nitre, etc. are so many deadly engines combined with the disease, against the constitution and life of the patient.’

He was especially agitated by the practice then (as now) of keeping feverish patients cool to bring their temperature down. Thomson assures the reader that ‘No person yet died of fever.’ The culprit was ‘cold’, so the answer was to toss more coal on the fire. After all, he reasoned, the dead are cold so cooling kills. Thomson was an American and the bee in his buckskin was the deadly imbalance between body temperature and the outside temperature, resulting in ‘obstructed perspiration’, the ‘cause of all disorders’. In the ‘constant warfare’ between cold and heat, cold phlegm nourished worms and internal cooling manifested itself as dropsy, dysentery, canker, tuberculosis, pleurisy, even birth pangs.

Thomson also provided handy hints on what to do if you were spiked in the eye with a pitchfork or bitten by a mad rat. He describes how he cured a stinking black gangrenous foot with nothing more than a meal poultice.

Such manuals allowed people to self-diagnose, which added to the dangers of self-medicating. It was easy to get hold of virtually any remedy. Provincial papers were kept afloat by the revenue from adverts for proprietary medicines such as Daffy’s Elixir and Storey’s Worm Cakes. One powdered panacea could cure everything from cancer to red hair.

Queen Victoria scoured the papers for the latest remedies. She was a renowned imaginary invalid. Physicians had always cultivated the worried well and did little to dispel unfounded concerns in their wealthier patients. Self-diagnosis nurtured morbid health worries in the bourgeoisie to such a degree that hypochondria became known as the ‘English malady’. Those in denial boasted that hypochondria was the only disease they didn’t have.

Certain ailments became popular until they slipped out of fashion; ‘nostalgia’ had been commonplace until supplanted by ‘the vapours’ which in turn gave way to biliousness, with melancholia waiting its turn in the wings. Many of those who had escaped the clammy grasp of the physician fell into an obsessive craving for cures and the embrace of addictive drugs. Queen Victoria was never without Brown’s Chlorodyne, a heady mixture of chloroform, cannabis and morphine.

Commercial quackery suffered a severe blow at the close of the nineteenth century. With influenza sweeping across Russia and Europe, a company marketed their Carbolic Smoke Ball, an inhaler containing powder impregnated with phenol. They boldly offered a reward of £100 to anyone who caught the flu after using their device. Louise Carlill, who unluckily for them was married to a lawyer, used the smoke ball assiduously, caught the flu and sued the firm. The company’s defence was that the adverts were ‘mere puffery’ and only an idiot would believe such extravagant claims. The judge ruled that a vendor making such promises ‘must not be surprised if occasionally he is held to his promise’.

Today, thanks to the Web, self-diagnosis is again on the rise and many un-examined people are self-dosing with drugs that have never seen a pharmacy and may even be fakes. Quackery still flourishes. Britons spend £4.5 billion on ‘alternative medicine’. In the United States people visit purveyors of untested, unregulated and unlikely remedies more often than they consult conventional physicians. Numerous people still drink urine in the belief that it can cure everything including diabetes and cancer. There may even be an opening for a modern ‘piss prophet’.

For centuries the safety of proprietary drugs was effectively tested on the population at large. Most drugs are dangerous if the patient is overdosed, and no one knew what the safe levels were. Prescribing was a case of suck it and see – the patients sucked it and the physician would see whether they died or got better.

Things began to change when medics stepped into the breach to act as human guinea pigs. In 1803 Friedrich Serturner, a young German pharmacist fired with the scientist’s ‘need to know’, set out on a dangerous career of self-experimentation. In spite of fanciful theories, no one knew why even the most useful drugs worked, so Serturner tried to find their active ingredients. He developed a method for systematically analysing the constituents of drugs.

His first success was to show that the principal actions of opium were dependent on a substance he called morphine (from Morpheus, the Greek god of sleep and dreams). He first tested the effects of pure morphine by salting the food of house mice and feral dogs. It put them to sleep – permanently. Undeterred, he tried morphine on himself and his pals to determine the safe dose. They began by ingesting ten times more than is now considered safe. Soon they became feverish and nauseous with severe stomach cramps. Clearly they had poisoned themselves, perhaps fatally. Drinking pure vinegar induced vomiting and they fell unconscious. Thanks to the vinegar they survived, but the pains lasted for days.

Serturner continued to experiment with morphine and found that when opium failed to dull the pain of toothache a small dose of morphine did the trick. He hoped that ‘qualified physicians might soon concern themselves with this matter, because opium is one of our most effective drugs’.

His analytical methods were refined and used to isolate numerous useful compounds related to morphine including adrenaline (a heart stimulant); caffeine (a stimulant used in tonics and painkillers); cocaine (a local anaesthetic); codeine (a sedative and painkiller); ephedrine (used to treat asthma and hay fever) and many more.

Serturner went on to test other drugs and had many nasty moments. He was not alone. In 1819 a Czech medical student called Jan Purkinje also began to sniff and swallow drugs to test their action. He was aware of the dangers and knew that a self-experimenter should ‘exercise care lest he offer himself as a sacrifice by exposing himself to danger’. Nonetheless, he took risks.

Digitalis was widely used as a heart stimulant, but it also blurred the patient’s vision. So Purkinje overdosed on digitalis to study what was going on – a dose only a tenth as big had killed laboratory animals. Although his heartbeat became worryingly erratic and his eyesight was disrupted for a fortnight, he was able to make fundamental observations on the nature of vision. Purkinje discovered that colour was not perceived at the edge of the retina, and the blood capillaries serving the retina (now called ‘Purkinje’s tree’) could be examined by shining a light through the white of the eye. His techniques paved the way for the ophthalmoscope for examining the interior of the eye.

He carried out dozens of self-experiments to test the safety of drugs, including belladonna (extracted from Atropa, deadly nightshade), which he drank and put in his eyes. As a result the active ingredient, atropine, was later purified and is now used to dilate the pupils for examining the eye. It is also used to treat stomach ulcers and to counteract the nerve agents used in chemical warfare.

Camphor is now best known as the smelly ingredient of moth repellents, but in Purkinje’s day it was mixed with opium and given to children as a cough medicine. Purkinje’s tests of camphor left him unconscious and entirely disorientated for days, while the reported effects on children were even worse. He concluded that children would be better off with the cough (and possibly moths) rather than the cure.

Thanks to Purkinje, physicians were alerted to the importance of fixing a safe dose for every drug and to the dangers of one drug amplifying the ill effects of another. When he wasn’t putting his health on the line he studied lines, in the form of the ridges on fingertips, which eventually led to the forensic use of fingerprints.

In Victorian times arsenic and other potentially deadly poisons were readily available at every chemist’s shop and poisoners were among the best known celebrities of the day. Francis Galton, who is now best remembered for founding the study of eugenics – selective breeding to improve the human race – spent his early days in charge of a pharmacy. To get a working knowledge of his wares he swallowed them. He began to work his way through them in alphabetical order but soon ran into trouble with aconitum and arsenic. He gave up after croton oil, one of the most powerful purgatives known to man.

Industrial workers were also exposed to a rich menu of toxic substances. There was an urgent need for an antidote. In 1813 a chemist called Bertrand swallowed arsenic mixed with charcoal and suffered no adverse symptoms. The charcoal had absorbed and effectively inactivated the poison. This result intrigued Pierre-Fleurus Touéry. Could charcoal neutralise other toxins? Nowadays charcoal is given to dogs embarrassed by aromatic wind, but Touéry spent two decades testing the consequences of giving dogs charcoal with various poisons. The medical establishment was doubtful about the value of his results so in front of a crowded gathering at the Académie des Sciences he swallowed ten times the fatal dose of strychnine – plus charcoal. The atmosphere in the lecture theatre was electric. Everyone in the audience expected him to collapse and writhe around on the floor, dying before their eyes. They knew of no antidote. Fortunately Touéry survived, but he had taken a tremendous risk because the absorptive properties of charcoal varied immensely: a poor batch would have done for him. Thanks to his courage we now routinely use charcoal to absorb noxious gases and to treat poisoning by alkaloids and similar drugs.

Seemingly unlikely compounds were found to be useful drugs. Anyone who has seen Henri-Georges Clouzot’s wonderful thriller Le Salaire de la Peur (The Wages of Fear) will know not to shake a bottle of nitroglycerine, but medics were once convinced that it could soothe nervous disorders. In 1858 Doctor Field, an English physician, tasted nitroglycerine, an unstable high explosive produced from glycerine plus nitric and sulphuric acid. He immediately blanched and collapsed, convinced that his head would explode. His pulse faded to nothing, but his attendants brought him round with great difficulty.

Despite Field’s close call a young physician called William Murrell later repeated the experiment. He was astonishingly casual, licking a cork moistened with nitroglycerine and then starting his normal routine of consultations. Soon, however, his head was throbbing and his heart pounding. It ‘became so severe that each beat of the heart seemed to shake my entire body … the pen I was holding was violently jerked with every beat’. Nonetheless, he went on to dose himself with nitroglycerine perhaps forty times more. The astute doctor noted that some of the effects were similar to those produced by a drug then used to dilate blood vessels narrowed by disease so he trialled it on his patients. Today nitroglycerine is the standard treatment to relieve the oppressive pains of angina.

Virtually all drugs were once taken by mouth. Then Enoch Hale Jr, while working at the Massachusetts General Hospital in Boston, had a seriously ill patient who couldn’t swallow. But how else could a drug be delivered into his body? Hale realised that to inject a drug directly into the bloodstream was ‘highly dangerous, or at best of very doubtful safety’. Many dangerous drugs are at least partially inactivated by the digestive acids in the stomach. Morphine, for example, is vastly more potent when injected than when taken orally. To bypass this ‘safety valve’ was risky but it was worth a try. So he injected castor oil, a mild purgative, into rabbits and when there were no obvious ill effects he injected some of it into his own vein. Soon he felt enfeebled with headaches and ever-worsening stomach cramps. His face muscles became partially paralysed and for hours he couldn’t speak properly or eat. Even a month later he had not fully recovered. But the genie was out of the syringe and injection became an essential means of getting drugs as rapidly as possible to their site of action in the body.

A problem for drug testers is that a similar dose of the same drug may have very different effects on different people. A self-experimenter is only a sample of one. But if he survives and his experiments on animals and cell cultures go well, the drug may be deemed sufficiently promising to be trialled by volunteers. The point of these trials is first to ensure the drug is safe and then to establish that it is effective at combating a disease.

Many pharmaceutical firms once had in-house teams of volunteer testers but now they contract out to firms specialising in arranging drug trials. The drug trial business rakes in $24 billion a year. In Britain alone there are over 1,000 drug trials a year involving 100,000 or so volunteers. It has been estimated that at any given time around 50 million people worldwide are guinea pigs in clinical trials.

Volunteers are reimbursed for their time, often generously. But paying significant sums attracts those in developing countries who need the money. In the United States it is creating a growing band of ‘professional guinea pigs’. It is estimated that there are around 10,000 volunteers for whom participating in clinical trials is their main income. One serial volunteer spent 500 nights in research facilities in five years. This is not good for his health. Flitting from one trial to another to maximise his income may also encourage him not to observe the thirty-day ‘wash-out period’ that ensures all traces of previous medication have gone before his body is challenged again. Flouting this caveat may result in a dangerous combination of drugs in his system. ‘Career guinea pigs’ are also less likely to own up to side effects that might get them dropped from the trial and reduce their fee.

Over a series of trials each new drug may be tested on 10,000 people before being licensed for clinical use. Most drugs never make it to that stage. Many fail the laboratory tests and even those that have showed early promise are often disappointingly ineffective when tested on people. Of the numerous anti-cancer drugs that pass trials on humans, only five per cent are ever approved for general use.

All drugs can have unpleasant side effects. Approval is based on balancing the risk of adverse effects against the benefits that the drug might bring. I have occasionally taken a non-steroidal anti-inflammatory drug. The accompanying leaflet listed no fewer than sixty side effects. Large-scale trials on humans enable the manufacturer to estimate how frequently particular ill effects may occur. For this drug one in ten patients might feel somewhat short-changed to get only a little dizziness, diarrhoea or a skin rash. One in a hundred recipients may be troubled by swollen ankles, stomach bleeding, difficulties in breathing and hepatitis. But Mr One-in-100,000 enjoys numerous ordeals including hearing loss, a swollen tongue, bloody urine, fits and nightmares, hair loss and impotence. All these were worse than the condition for which I was taking the tablets. There was, however, a reassuring footnote: ‘Do not be alarmed by this list.’ Too late: I was already a nervous wreck.

The worst problem occurs when a really serious effect only comes to light after the drug has been in use for some time. In the 1960s thalidomide, a sleeping pill, was found to have produced extreme birth defects if taken by pregnant women. It was such a potent substance that it could disrupt the development of any animal and even the embryos of plants were grossly malformed by it, but pregnant animals had never been tested. For several decades a synthetic oestrogen called diethylstilbesterol was prescribed to prevent miscarriages. In 1971 it was found to cause vaginal cancer in daughters of patients who had taken the drug, but in the United States it continued to be prescribed for some time as a ‘morning after’ pill. Recently a new painkiller caused heart attacks and strokes, many of them fatal. In 2001 the manufacturer paid out $4.85 billion in compensation.

The purpose of initial drug trials on human volunteers is to find unexpected side effects. These so-called ‘phase one’ trials are the most risky and they usually involve only ten to twenty people at a time. In March 2006 a German biotech company hired Parexel, an American drug-testing firm in London, to test their latest product. Eight volunteers were chosen from respondents to an advertisement on the internet. They were contracted to stay at the clinic for two days during the trial and then attend several times later on for check-ups. They would be paid £2,000 each.

The healthy young volunteers were infused with the drug one after another. They had been warned that they might experience slight headache or perhaps some nausea. But as the last man was being injected one of the others began to feel ill. Soon he was screaming with pain. He tore off his shirt, shouting that he was burning; then he convulsed and collapsed. One by one the others followed suit, writhing on the floor and begging the doctors for help. Within minutes the calm of the clinic had given way to the chaos of a Victorian asylum. Two of the volunteers watched in horror, waiting their turn to collapse, but luckily they had been given a placebo and were safe. The other six were far from safe. Within ninety minutes they were having difficulty breathing and their pulse rates had doubled. This was an unprecedented emergency. Now comatose, they were rushed to hospital. The staff at the intensive-care unit had never seen anything like this before. Nine hours after taking the drug the men were unable to breathe unaided and were facing multiple organ failure.

It was twelve hours before relatives were allowed to see them. They couldn’t believe their eyes. The face and neck of twenty-one-year-old Ryan were swollen to twice their normal size; his body had inflated to that of a 190-kilogram (thirty-stone) man and his skin was purple. The partner of twenty-eight-year-old Nino said he looked like the Elephant Man. The doctor confided that Nino and Ryan ‘needed a miracle’.

Ryan, the most badly affected, was in a coma for three weeks, suffering with heart, kidney and liver failure as well as septicaemia and pneumonia. His fingers and toes were black with dry gangrene and as hard as stone. Several were amputated. He was not released from hospital for three and a half months.

So what went wrong? The drug being tested was TGN1412, a monoclonal antibody developed by a company called TeGenero (which translates creepily into ‘I create you’). Monoclonal antibodies are artificial versions of the body’s natural antibodies that fight off disease. The Nobel Prize was awarded to the British scientists who developed them and they are the great hope for twenty-first-century medicine. Dozens of them are now in medical use and many more are being tested. Herceptin, for example, treats breast cancer by attaching to malignant cells and stopping them from multiplying, thus curbing the tumour’s spread.

TGN1412, on the other hand, could also stimulate cells to divide. It targets white blood cells called T-cells, a major player in the body’s defences. The hope was that TGN1412 would boost the body’s immune system into action by creating reinforcements to attack the rapidly proliferating cells of lymphatic leukaemia.

It would seem sensible to test a new drug on fit and healthy volunteers who could cope with any adverse side effects, but in this case it was a disaster. Cancer victims are under siege and have weakened immune systems that are desperately in need of a boost, but healthy people do not. Inside the volunteers’ bodies TGN1412 stimulated a chain reaction, releasing millions of cytokines, the immune system’s messengers, which in turn triggered T-cells to liberate even more cytokines. This caused a ‘cytokine storm’, a deadly overreaction in which the immune system attacks the body, inflaming blood vessels and consuming internal organs. No wonder the victims thought they were on fire.

When humans are first exposed to an untested drug it is usual to dose a single volunteer to begin with, then observe how he gets on before exposing anyone else. The second volunteer might be tested several hours, days or even weeks later. Those testing TGN1412 were dosed within only a few minutes of each other, thus putting all six of them in danger.

TeGenero claimed that there was nothing in the laboratory experiments to suggest there might be a violent reaction to the drug. But what occurs in cell cultures exposed to a drug is not a reliable indicator of what might happen inside the human body. Nor were experiments on animals a good guide in this case. The TGN1412 antibody was made up mostly from human protein and there are biochemical reasons to suppose that the response might therefore be far greater in humans than in rats or rabbits.

The after-effects were not entirely a surprise. Parexel had indicated in the contract signed by all the volunteers that cytokine release was a possible consequence of taking the drug, and TeGenero had notified the Medicines and Healthcare Products Regulation Agency, who authorised the trials, that there was a risk of cytokine release and that a similar drug had induced a bad reaction.

TeGenero went into bankruptcy. A government inquiry into what had gone wrong made many recommendations to prevent another such incident but failed to apportion blame. There had never been such a disastrous trial before, nor has there been one since.

The victims still suffer from the physical and psychological aftermaths of their traumas. One of the participants, David, has memory loss and the early indications of an aggressive cancer. Nino has numerous tender lumps emerging all over his body. His partner, Myfanwy, naturally wishes that he had never involved himself in the trial. At the time she had voiced her qualms, but he had reassured her – it was not just the £2,000 fee, he was testing a cure for leukaemia and helping mankind.

What would we do without such willing volunteers? Myfanwy thought that we should be thankful to these men ‘for having the courage to help bring medicines to us all’. Indeed we should.

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Mandrake root whose anatomy suggested it would work wonders in love potions.