3125. An Epidemic of Allergy to Meat?

By Maryn McKenna, Mosaic, December 11, 2018

Tick bites are fueling the rise of allergies to the meat of mammals and everything else that comes from them.

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 gelatine-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 USA and an uncertain but likely larger number worldwide, and after a decade of research, scientists have begun to understand what causes it. It is created 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.

Tami McGraw cannot eat any products from mammals without feeling her throat close and her blood pressure drop.

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.

The allergy puzzle

In 1987, Dr Sheryl van Nunen was confronted with a puzzle. She was the head of the allergy department at a regional hospital in the suburbs of Sydney, Australia, and had a reputation among her colleagues for sorting out mysterious episodes of anaphylaxis. This time, a man had been sent to see her who kept waking up, in the middle of the night, in the grip of some profound reaction.

Van Nunen checked the man for the obvious irritants and, when those tests came up negative, took a thorough look at his medical history and did a skin test for everything he had eaten and touched in the hours before bedtime. The only potential allergen that returned a positive result was meat.

Then a few more such patients came her way. There were six additional ones across the 1990s; by 2003, she had seen at least 70, all with the same problem, all apparently affected by meat they had eaten a few hours before. Groping for an explanation, she lengthened the list of questions she asked, quizzing the patients about whether they or their families had ever reacted to anything else: detergents, fabrics, plants in their gardens, insects on the plants.A tick at the University of Massachusetts' TickReport laboratory.

When a new disease is discovered, there is usually a long, painful period of time, before it becomes the focus of scientific research. In this case, an odd set of coincidences brought alpha-gal allergy to the attention of researchers almost as soon as it occurred in patients.

The story begins with a cancer drug called cetuximab, which came onto the market in 2004. 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 was receiving a first dose of cetuximab in a cancer clinic in Bentonville, Arkansas, collapsed and died.

News of this death soon reached Dr Thomas Platts-Mills, an allergy researcher at the University of Virginia, who saw these reactions as an intriguing research opportunity.

Platts-Mills pulled together a team, and 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.

Team members scrutinized the patients and their famlilies 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.

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 neighbors, 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 lone star tick

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 a tick: 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.

A vial of live lone star ticks. The ticks -- a species native to Texas and Oklahoma -- were placed within a containment vessel at a lyme disease research site in Cape Elizabeth.

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?

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 sensitized individuals, eating meat might constitute a second exposure, in the same way infusing cetuximab had been.

If tick bites had sensitized 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.

Wisconsin reports first death from Rocky Mountain spotted fever

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 realized, 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.

A global problem

The lone star tick doesn't receive much attention in the USA, but its range appears to be expanding. "The northern edge of where these ticks are abundant is moving," says Dr Rick Ostfeld, a disease ecologist at the Cary Institute of Ecosystem Studies, north of New York City. "It is now well-established further north, into Michigan, Pennsylvania, New York and well up into New England.

"Climate change is likely playing a role in the northward expansion," Ostfeld adds, but acknowledges that we don't know what else could also be contributing.

Alpha-gal reactions linked to tick bites have now been found in the UK, 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. (An online map on which patients list themselves includes over a dozen more countries.)

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, less than the span of a single human generation. 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.

What does the future hold?

Platts-Mills points out that the prevalence of high levels of alpha-gal IgE in his earliest studies was up to 20 per cent in some communities, "but that was absolutely not the prevalence of allergic reactions to meat," he says. "So there are clearly plenty of people out there who've got the antibody but don't have this syndrome."

What this all means is that there are almost certainly people for whom a meat-containing meal or medical intervention could trigger an alpha-gal reaction of unknown severity.

There may be further peril awaiting them. In June, Platts-Mills and other researchers revealed that more than a quarter of patients who came to the University of Virginia's medical center for cardiac catheterization, to clear out life-threatening blood-vessel blockages, were sensitized to alpha-gal without knowing it.

The patients with the undetected allergy had more arterial plaque than the ones without, and, most worrisome to the researchers, their plaques were of a type that is more likely to break away from the arterial wall and cause heart attacks and strokes.

Though the research is early -- done in one group of 118 patients, in a known hotspot for alpha-gal -- Platts-Mills worries it presages a risk for heart disease that is larger than anyone expects.

In 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 CDC 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. Afterwards, 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 an increasing number of academics and institutions paying attention, research into alpha-gal might be reaching a threshold, a moment at which isolated investigations might coalesce into answers. For the patients, who feel isolated too, that can't come soon enough.

3040. Clean Meat Anyone?

By Nathaniel Popper, The New York Times, September 30, 2018 

Clean meat is laboratory grown meat from stem cells of animals

BERKELEY, Calif. — Rabbi Gavriel Price has thousands of years of Jewish religious law to draw on when he is on the job, determining whether a new food item can get a kosher certification from his organization, the Orthodox Union.

But all the rules about meat and milk, and the prohibitions on eating pork and sciatic nerves, are of limited use for Rabbi Price’s latest assignment.

The rabbi is in charge of figuring out how the Orthodox Union, the largest kosher certifying organization in the world, should deal with what is known as clean meat — meat that is grown in laboratories from animal cells. This brings him in touch with a possibility for Jewish cuisine that had previously seemed impossible: kosher bacon.

Clean meat is still not available in stores, but start-ups working on it say it could be by next year. When it is, they want a kosher stamp on their product, which indicates it adheres to quality and preparation standards and follows a set of biblical laws. That brought Rabbi Price, a tall, lanky father of eight, to Berkeley recently, to meet with companies in the business.

Clean meat, also known by names like cell-based agriculture, begins with cells taken from an animal, often stem cells that are primed to grow. Once these cells are isolated, they are put into a solution that mimics blood and encourages the cells to replicate.

This process is very new. The first hamburger produced in a lab was served with great fanfare in 2013 and cost $325,000. But the number of companies competing to create the first commercially available product is growing rapidly.

Rabbi Price’s investigation touches on questions that anyone might have when confronted with clean meat. What exactly is it? And should we want to eat it someday?

His first stop was a lab operated by Mission Barns, a start-up with six employees and millions of dollars in funding. It is growing duck, chicken and pig meat in clear flasks, lined up inside temperature-controlled incubators.

He looked through a microscope at a dish of long, pointy duck cells and peppered the scientists with basic questions about where the cells had come from, and what was in the red liquid that was helping the cells to replicate and grow.

“I’d like to spend more time, because I think it’s an important process to understand in a deep way, and there’s no precedent for it really,” Rabbi Price said after the tour.

The issue he is addressing is much more complicated than the kosher designation of plant-based meat substitutes already available in grocery stores.

Perhaps the best-known company of its kind, Impossible Foods, has created a burger that is made from all-vegetarian ingredients but tastes more like meat thanks to a chemical process involving yeast and soy. Like most vegetarian foods, these burgers have received a kosher stamp.

Mission Barns, the start-up in Berkeley, is focused on creating animal fat, where much of the distinctive flavor of meat resides. It recently mixed the fat with other ingredients to create duck sausages that it served to investors and employees. Creating more structured meat products, like a duck breast or a steak, is expected to take much longer.

Environmentalists and animal activists are proponents of the technology because it could produce the flavor of hamburgers and sausages without the greenhouse gases and animal suffering of the factory farming system.

Saam Shahrokhi, left and Mr. Maciag in the Mission Barns lab in Berkeley, Calif. Mission Barns is focused on creating animal fat, where much of the distinctive flavor of meat resides.

“I’m extremely excited about it,” said Rabbi Menachem Genack, who leads the kosher certifying division of the Orthodox Union. “The impact for us will be very profound, in terms of the economics of kosher meat.”

There are polls that show that many Americans are turned off by the prospect of lab-grown meat. And the technology has already generated questions far beyond the Jewish community.

The United States Cattlemen’s Association requested this year that American authorities allow the meat label only on products that come from slaughtered animals. While large meat companies have pushed back against the cattle ranchers, in part because they are developing their own clean meat products, it is unclear if regulators will handle lab-grown meat with the same rules they use for traditional meat.

Jewish authorities have been studying this because several synthetic meat start-ups are based in Israel.

A number of Israeli rabbis told one start-up, SuperMeat, that previous rulings in religious law might allow clean meat to be categorized as pareve, a religious label that is applied to things that are kosher but not derived from animals.

A pareve label would mean that observant Jews could eat it with dairy products, like cheese, which cannot be eaten with traditional meat. In other words, a kosher cheeseburger might be possible.

Rabbi Genack, Rabbi Price’s boss at the Orthodox Union, initially thought clean meat could be pareve, based on his belief that clean meat was created from an animal’s genetic code. But because the process involves an animal cell, replicating itself millions of times, he now believes the product should be thought of as meat.

When Rabbi Price visited the Mission Barns labs, he asked questions specific to kosher certification. He wanted to be sure, for instance, that the pork cells growing in one incubator never come into contact with the duck cells in the incubator next to it, and that the centrifuge where the meat cells are processed is cleaned thoroughly between processing.

He also wanted to know if the cells in the flasks changed as they replicated, to be sure that they do not morph into something that no longer resembles the original animal cells.

“The identity of a given cell, and ensuring that its identity is preserved and verifiable, would be crucial to our being able to certify a product,” the rabbi said.

The day after his visit to Mission Barns, Rabbi Price attended a conference held by the Good Food Institute, an organization that is encouraging the move away from animal meat.

He dived into long conversations with people working for the food start-ups. They discussed topics as diverse as the kosher status of gelatin, the religious rulings of venerated medieval rabbis and the ingredients of the solution that encourages lab-grown meat to grow.

“Does that cell need to consume all kosher ingredients for it to be kosher?” the rabbi was asked by Aryé Elfenbein, the founder of Wild Type, a start-up in San Francisco that is focused on lab-grown salmon.

The rabbi explained that just as kosher cows can eat non-kosher insects, he is working from the assumption that the growth solution will not have to be certified as kosher as long as it is cleaned from the surface of the final cells.

Flasks of cell culture media at the Mission Barns lab. When Rabbi Price visited the lab, he wanted to know if the cells in the flasks changed as they replicated, to be sure that they don’t morph into something that no longer resembles the original animal cells.

Many of the questions came back to the original cells that go into the solution. The rabbi said those cells would have to be kosher, from an animal that was properly slaughtered and not scraped off a live animal. (There is a Jewish law against eating live animals.)

This was not well received by some of the clean meat companies, which want to produce something that does not involve killing any animals.

The liveliest conversation grew out of research that is looking into whether clean meat might be derived from cells in animal saliva or hair.

The rabbi said those substances are not meat, so they might be used to produce clean meat that would not be categorized as meat by Jewish law.

Eitan Fischer, the chief executive of Mission Barns, said he was hopeful that through some creative chemistry, his company could grow pork that would get a kosher designation.