Team members scrutinised the patients and their families for anything that could explain the problem. The reactions appeared regional – patients in Arkansas and North Carolina and Tennessee experienced the hypersensitivity, but ones in Boston and northern California did not. They investigated parasites, moulds and diseases that occur only in pockets of the USA.

Alpha-gal is familiar to many scientists because it is responsible for an enduring disappointment: its ability to trigger intense immune reactions is the reason that organs taken from animals have never successfully been transplanted into people. The puzzle was why the drug recipients were reacting to it. To have an allergic reaction, someone needs to have been primed with a prior exposure to a substance – but the trial recipients who reacted badly were all on their first dose of cetuximab.

Platts-Mills pulled together a team, looping in Hatley and several current research fellows as well. Fairly quickly, they discovered the source of the problem. People were reacting to the drug because they had a pre-existing sensitivity, indicated by a high level of antibodies (called immunoglobulin E, or IgE for short) to a sugar that is present in the muscles of most mammals, though not in humans or other primates. The name of the sugar was galactose-alpha-1,3-galactose, known for short as alpha-gal.

The bad responses to the drug looked like allergic reactions, and they were common enough – and far enough from the manufacturer’s expectations – to be an intriguing research opportunity.

Then the first coincidence occurred: a nurse whose husband worked at the Bentonville clinic mentioned the death to Dr Tina Hatley, an immunologist in private practice in Bentonville. Hatley had recently finished postgraduate training at the University of Virginia’s allergy centre, and she mentioned the death to her former supervisor, Dr Thomas Platts-Mills.

The manufacturers, ImClone and Bristol-Myers Squibb, checked every obvious thing about the trial: the drug’s ingredients, the cleanliness of the manufacturing plants, even the practices at the medical centres where cetuximab had been administered. Nothing stood out. The most that researchers could guess at the time was that the unlucky recipients might have some kind of mouse allergy.

That 1–2 per cent stayed consistent as cetuximab was given to larger and larger groups. And then there was an aberration. In clinics in North Carolina and Tennessee, 25 of 88 recipients were hypersensitive to the drug, with some so sick they needed emergency shots of epinephrine and hospitalisation. At about the same time, a patient who was receiving a first dose of cetuximab in a cancer clinic in Bentonville, Arkansas, collapsed and died.

The story begins with a cancer drug called cetuximab, which came onto the market in 2004. Cetuximab is a protein grown in cells taken from mice. For any new drug, there are likely to be a few people that react badly to it, and that was true for cetuximab. In its earliest trials , one or two of every 100 cancer patients who got it infused into their veins had a hypersensitivity reaction: their blood pressure dropped and they had difficulty breathing.

That is the story of the discovery of CFS/ME and Lyme disease, among others. But it is not the story of alpha-gal allergy. An odd set of coincidences brought the bizarre illness to the attention of researchers almost as soon as it occurred.

The discovery of new diseases often follows a pattern. Scattered patients realise they are experiencing strange symptoms. They find each other, face to face in a neighbourhood or across the world on the internet. They bring their experience to medicine, and medicine is sceptical. And then, after some period of pain and recalcitrance, medicine admits that, in fact, the patients were right.

The researchers wondered – if the mystery reactions shared a footprint with a disease, and ticks caused the disease, could ticks be linked to the reactions too?

Then Dr Christine Chung, a Nashville researcher recruited to the team, stumbled on an intriguing clue. Almost one in five of the patients enrolled at a cancer clinic at her hospital had high levels of IgE to alpha-gal. But when she checked those patients’ near neighbours, treating them as a control group – that is, people who lived their lives in the same way, but did not have cancer and had no reason to have received the drug – almost one in five had antibodies to alpha-gal as well.

Almost a decade later, that correlation still makes Platts-Mills chuckle. The alpha-gal reaction “had nothing to do with cancer,” he says. “It had everything to do with rural Tennessee.”

The question then became: what in rural Tennessee could trigger a reaction like this? The answer arose from a second coincidence. Dr Jacob Hosen, a researcher in Platts-Mills’s lab, stumbled across a map drawn by the Centers for Disease Control and Prevention (CDC) showing the prevalence of an infection called Rocky Mountain spotted fever. It exactly overlapped the hot spots where the cetuximab reactions had occurred.

Rocky Mountain spotted fever is transmitted by the bite of ticks, including Amblyomma americanum, one of the most common ticks in south-eastern USA. It’s known as the lone star tick for a blotch of white on the back of the female’s body.

The researchers wondered – if the mystery reactions shared a footprint with a disease, and ticks caused the disease, could ticks be linked to the reactions too?

It was an intriguing hypothesis, and was reinforced by a new set of patients who came trickling into Platts-Mills’s clinic at about the same time. They were all adults, and that was odd to start with, because allergies tend to show up in childhood. They had never had an allergic reaction before, but now they were experiencing allergy symptoms: swelling, hives and in the worst cases anaphylactic shock. They too had high levels of IgE antibodies to alpha-gal.

None of them, though, were cancer patients. They told the physicians that they had no proof of what was causing their reactions – but more than a few of them sensed it had something to do with eating meat.

Dr Scott Commins, another postgraduate fellow in Platts-Mills’s group, took it upon himself to phone every new patient to ask whether they’d ever suffered a tick bite. “I think 94.6 per cent of them answered affirmatively,” he says. “And the other few per cent would say, ‘You know, I’m outdoors all the time. I can’t remember an actual tick that was attached, but I know I’d get bites.’”

Meat from mammals inevitably contains alpha-gal – so in already sensitised individuals, eating meat might constitute a second exposure, in the same way infusing cetuximab had been.

If tick bites had sensitised them, then the alpha-gal reaction might be a food allergy as well as a drug reaction. But the connection was speculative, and cementing cause and effect would take one final, extraordinary coincidence.

As it happens, Platts-Mills likes to hike. One weekend he took off across the central Virginia hills, tramping through grassy underbrush. He came home five hours later, peeled off his boots and socks, and discovered his legs and feet were speckled with tiny dots. They looked like ground pepper, but they were dug into his skin – he had to use a dull knife to scrape them off – and they itched something fierce. He saved a few, and sent them to an entomologist. They were the larval form of lone star ticks.

This, he realised, was an opportunity. As soon as the work week started, he had his lab team draw his blood and check his IgE levels. They were low to start with, and then week by week began to climb. Platts-Mills is English – his father was a Member of Parliament – and in the midst of having his IgE tracked, he went to an event at the Royal Society of Medicine in London. “And at that point,” he says cheerfully, “I ate two lamb chops and drank two glasses of wine.”

In the middle of the night, he woke up covered in hives.