Adapted from an article that originally appeared in Mosaic.
It is early morning in early summer, and I am tracing my way through the woods of central North Carolina, steering cautiously around S-curves and braking hard when what looks like a small rise turns into a narrow bridge. I am on my way to meet Tami McGraw, who lives with her husband and the youngest of their kids in a sprawling development of old trees and wide lawns just south of Chapel Hill. Before I reach her, McGraw emails. She wants to feed me when I get there: "Would you like to try emu?" she asks. "Or perhaps some duck?"
These are not normal breakfast offerings. But for years, nothing about McGraw's life has been normal. She cannot eat beef or pork, or drink milk or eat cheese, or snack on a gelatin containing dessert without feeling her throat close and her blood pressure drop. Wearing a wool sweater raises hives on her skin; inhaling the fumes of bacon sizzling on a stove will knock her to the ground. Everywhere she goes, she carries an array of tablets that can beat back an allergy attack, and an auto-injecting EpiPen that can jolt her system out of anaphylactic shock.
McGraw is allergic to the meat of mammals and everything else that comes from them: dairy products, wool and fiber, gelatin from their hooves, char from their bones. This syndrome affects some thousands of people in the United States and an uncertain but likely larger number worldwide, and after a decade of research, scientists have begun to understand what causes it. It's brought on by the bite of a tick — picked up on a hike, or brushed against in a garden, or hitchhiking on the fur of a pet that was roaming outside.
The illness, which generally goes by the name "alpha-gal allergy" after the component of meat that triggers it, is a trial that McGraw and her family are still learning to cope with. In much the same way, medicine is grappling with it, too. Allergies occur when our immune systems perceive something that ought to be familiar as foreign. For scientists, alpha-gal is forcing a remapping of basic tenets of immunology: how allergies occur, how they are triggered, whom they put in danger and when.
For those affected, alpha-gal is transforming the landscapes they live in, turning the reliable comforts of home — the plants in their gardens, the food on their plates — into an uncertain terrain of risk. In her memory, McGraw's symptoms began after 2010. That was the year she and her husband, Tom, a retired surgeon, spied a housing bargain in North Carolina in a development next to a nature reserve. The leafy spread of streams and woodland pockets was everything she wanted in a home. She didn't realize that it offered everything that deer and birds and rodents, the main hosts of ticks, want as well.
She remembers one tick that attached to her scalp, raising such a welt the spot was red for months afterward, and a swarm of baby ticks that climbed her legs and had to be scrubbed off in a hot bath laced with bleach. Unpredictably, at odd intervals, she began to get dizzy and sick.
"I'd have unexplained allergic reactions, and I'd break out in hives and my blood pressure would go crazy," she told me. The necklines of all her T-shirts were stretched, because she tugged at them to relieve the feeling she couldn't take a deep breath. She trekked to an array of doctors who diagnosed her with asthma or early menopause or a tumor on her pituitary gland. They prescribed antibiotics and inhalers and steroids.
They sent her for MRI scans, pulmonary function tests, echocardiograms of her heart. Nothing yielded a result. Looking back, she realizes she missed clues as to the source of her problem. She would feel short of breath and need to visit an urgent care clinic on Saturdays — which always started, in her household, with a big breakfast of eggs and sausages.
Then a close friend had a scary episode, going for a run, arriving home and passing out on the hot concrete of her driveway. Once she had recovered, McGraw quizzed her. Her friend said: "They thought I got stung by a bee while I was running. But now they think maybe I have a red-meat allergy." McGraw remembers her first reaction was: That's crazy. Her second was: Maybe I have that, too.
She Googled, and then she asked her doctor to order a little-known blood test that would show if her immune system was reacting to a component of mammal meat. The result was so strongly positive that her doctor called her at home to tell her to step away from the stove.
The surprising story of how doctors in the U.S. discovered alpha-gal allergy 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 who 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.
But 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 hospitalization. At about the same time, a patient who got cetuximab in a cancer clinic in Bentonville, Arkansas`, collapsed and died after the first dose.
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.
A team of allergy specialists led by Dr. Thomas Platts-Mills at the University of Virginia scrutinized 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.
Then Dr. Christine Chung, a Nashville researcher recruited to the team, stumbled onto an intriguing clue. Almost one in five of the patients enrolled at a cancer clinic at her hospital had high levels of IgE antibodies linked to alpha-gal allergy. But when she checked those patients' neighbors, the same almost one in five had those antibodies, too. The alpha-gal reaction, it turned out "had nothing to do with cancer," says Platts-Mills. "It had everything to do with rural Tennessee."
The question then became: What in rural Tennessee could trigger a reaction like this? A clue emerged: Rocky Mountain spotted fever is transmitted by the bite of a tick, Amblyomma americanum, one of the most common ticks in the southeastern U.S. 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 tick-caused 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' 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'd 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, a postgraduate fellow in Platts-Mills' group, took it upon himself to phone every new patient to ask whether they'd ever suffered a tick bite. "I think 94.6 percent of them answered affirmatively," he says. "And the other few percent 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.'"
There has been so little research into alpha-gal allergy that scientists can't agree on exactly what stage of the bite starts victims' sensitization. It is possible that a fragment of a previous blood meal, from a mouse, bird, or deer, lingers in a tick's guts and works its way up through its mouth and into its human victim. It's also possible that some still- unidentified compound in tick saliva is chemically close enough to alpha-gal to produce the same effect.
One aspect of its epidemiology is becoming clear, though. The allergy isn't caused only by the lone star ticknor did it begin in the U.S. In 1987, Dr. Sheryl van Nunen was confronted with a puzzle. The head of the allergy department at a regional hospital outside Sydney, Van Nunen saw a patient who kept waking up, in the middle of the night, in the grip of some profound reaction. The only potential allergen that returned a positive result was meat. Then a few more such patients came her way. By 2003, she had seen at least 70, all apparently affected by meat they had eaten a few hours before. "And invariably, these people would say to me, ‘I haven't been bitten by a bee or a wasp, but I've had lots of tick bites," Van Nunen recalls.
Van Nunen wrote up a description of 25 meat-allergic patients whose reactions she had confirmed with a skin-prick test. All but two had had severe skin reactions to a tick bite; more than half had suffered severe anaphylaxis. That abstract formed the basis of a talk she gave later that year to an Australian medical association.
It took until 2009 for the Virginia group to catch up to Van Nunen's work, after they had already published their first alert. The crucial detail in Van Nunen's research that Platts-Mills' team didn't know about wasn't just that her cases were earlier than the first round of American ones. It was that they were caused by bites from a different tick: Ixodes holocyclus, called the paralysis tick.
Alpha-gal allergy was not just an odd occurrence in one part of the U.S. It had occurred in the opposite hemisphere, making it possible that it was a global problem. And so it has proved. Alpha-gal reactions linked to tick bites have now been found in the U.K., France, Spain, Germany, Italy, Switzerland, Japan, South Korea, Sweden, Norway, Panama, Brazil, Côte d'Ivoire, and South Africa. These cases trace back to at least six additional tick species.
Wherever ticks bite people — everywhere other than the Arctic and Antarctic — alpha-gal allergy has been recorded. In Belgium, patients reacted badly to a drug produced in rabbit cells. In the Italian Alps, men who went hunting in the forests were more at risk than women who stayed in their village. In Germany, the most reactive food was a traditional delicacy, pork kidneys. In Sweden, it was moose.
Van Nunen herself has now seen more than 1,200 patients. "The next busiest clinic, about 350," she says. Those cases have all occurred in two decades. As in America, the surge leaves Van Nunen mystified as to what the cause might be. She reasons that the rise cannot be due to something in her patients; neither genetic nor epigenetic change could occur so quickly. "It has to be environmental," she says. Last August, Commins gave a talk on alpha-gal allergy at the International Conference on Emerging Infectious Diseases, a conference held every two or so years and sponsored by the Centers for Disease Control and Prevention that often surfaces the earliest signals of illnesses that are destined to become big problems.
The CDC's director of foodborne illness was in the audience; so was its director of vector-borne diseases, the department that deals with ticks. Afterward, they both zoomed up to ask him questions. "I kind of had the impression this was just a weird, small thing," Dr. Lyle Petersen, the vector- borne director, told him. "But this seems like kind of a big deal."With the NIH and the CDC paying attention, research into alpha-gal might be reaching a threshold at which isolated investigations coalesce into answers. For the patients, those answers can't come soon enough.