This story first appeared on Mosaic and is republished here under a Creative Commons license.
by Carl Zimmer
For me, it was hornets.
One summer afternoon when I was 12, I ran into an overgrown field near a friend’s house and kicked a hornet nest the size of a football. An angry squadron of insects clamped onto my leg; their stings felt like scorching needles. I swatted the hornets away and ran for help, but within minutes I realised something else was happening. A constellation of pink stars had appeared around the stings. The hives swelled, and new ones began appearing farther up my legs. I was having an allergic reaction.
My friend’s mother gave me antihistamines and loaded me into her van. We set out for the county hospital, my dread growing as we drove. I was vaguely aware of the horrible things that can happen when allergies run amok. I imagined the hives reaching my throat and sealing it shut.
I lived to tell the tale: my hives subsided at the hospital, leaving behind a lingering fear of hornets. But an allergy test confirmed that I was sensitive to the insects. Not to honey bees or wasps or yellow jackets. Just the particular type of hornet that had stung me. The emergency room doctor said I might not be so fortunate the next time I encountered a nest of them. She handed me an EpiPen and told me to ram the syringe into my thigh if I was stung again. The epinephrine would lower my blood pressure, open my airway – and perhaps save my life. I’ve been lucky: that afternoon was 35 years ago, and I haven’t encountered a hornet’s nest since. I lost track of that EpiPen years ago.
Anyone with an allergy has their origin story, a tale of how they discovered that their immune system goes haywire when some arbitrarily particular molecule gets into their body. There are hundreds of millions of these stories. In the USA alone, an estimated 18 million people suffer from hay fever, and food allergies affect millions of American children. The prevalence of allergies in many other countries is rising. The list of allergens includes – but is not limited to – latex, gold, pollen (ragweed, cockleweed and pigweed are especially bad), penicillin, insect venom, peanuts, papayas, jellyfish stings, perfume, eggs, the faeces of house mites, pecans, salmon, beef and nickel.
Once these substances trigger an allergy, the symptoms can run the gamut from annoying to deadly. Hives appear, lips swell. Hay fever brings sniffles and stinging eyes; allergies to food can cause vomiting and diarrhoea. For an unlucky minority, allergies can trigger a potentially fatal whole-body reaction known as anaphylactic shock.
The collective burden of these woes is tremendous, yet the treatment options are limited. EpiPens save lives, but the available long-term treatments offer mixed results to those exhausted by an allergy to mould or the annual release of pollen. Antihistamines can often reduce sufferers’ symptoms, but these drugs also cause drowsiness, as do some other treatments.
We might have more effective treatments if scientists understood allergies, but a maddening web of causes underlies allergic reactions. Cells are aroused, chemicals released, signals relayed. Scientists have only partially mapped the process. And there’s an even bigger mystery underlying this biochemical web: why do we even get allergies at all?
“That is exactly the problem I love,” Ruslan Medzhitov told me recently. “It’s very big, it’s very fundamental, and completely unknown.”
Photo: Flickr
Medzhitov and I were wandering through his laboratory, which is located on the top floor of the Anlyan Center for Medical Research and Education at the Yale School of Medicine. His team of postdocs and graduate students were wedged tight among man-sized tanks of oxygen and incubators full of immune cells. “It’s a mess, but a productive mess,” he said with a shrug. Medzhitov has a boxer’s face – massive, circular, with a broad, flat nose – but he spoke with a soft elegance.
Medzhitov’s mess has been exceptionally productive. Over the past 20 years, he has made fundamental discoveries about the immune system, for which he has been awarded a string of major prizes. Last year he was the first recipient of the €4 million Else Kröner Fresenius Award. And though Medzhitov hasn’t won a Nobel, many of his peers think he should have: in 2011, 26 leading immunologists wrote to Nature protesting that Medzhitov’s research had been overlooked for the prize.
Now Medzhitov is turning his attention to a question that could change immunology yet again: why do we get allergies? No one has a firm answer, but what is arguably the leading theory suggests that allergies are a misfiring of a defence against parasitic worms. In the industrialised world, where such infections are rare, this system reacts in an exaggerated fashion to harmless targets, making us miserable in the process.
Medzhitov thinks that’s wrong. Allergies are not simply a biological blunder. Instead, they’re an essential defence against noxious chemicals – a defence that has served our ancestors for tens of millions of years and continues to do so today. It’s a controversial theory, Medzhitov acknowledges. But he’s also confident that history will prove him right. “I think the field will go around in that stage where there’s a lot of resistance to the idea,” he told me. “Until everybody says, ‘Oh yeah, it’s obvious. Of course it works that way.’”
The physicians of the ancient world knew about allergies. Three thousand years ago, Chinese doctors described a “plant fever” that caused runny noses in autumn. There is evidence that the Egyptian pharaoh Menes died from the sting of a wasp in 2641 BCE. Two and a half millennia later, the Roman philosopher Lucretius wrote, “What is food to one is to others bitter poison.”
But it was a little more than a century ago when scientists realised that these diverse symptoms are different heads on the same hydra. By then researchers had discovered that many diseases are caused by bacteria and other pathogens, and that we fight these invaders with an immune system – an army of cells that can unleash deadly chemicals and precisely targeted antibodies. They soon realised that the immune system can also cause harm. In the early 1900s, the French scientists Charles Richet and Paul Portier were studying how toxins affect the body. They injected small doses of poison from sea anemones into dogs, then waited a week or so before delivering an even smaller dose. Within minutes, the dogs went into shock and died. Instead of protecting the animals from harm, the immune system appeared to make them more susceptible.
Other researchers observed that some medical drugs caused hives and other symptoms. And this sensitivity increased with exposure – the opposite of the protection that antibodies provided against infectious diseases. The Austrian doctor Clemens von Pirquet wondered how it was that substances entering the body could change the way the body reacted. To describe this response, he coined the word ‘allergy’, from the Greek words allos (‘other’) and ergon (‘work’).
In the decades that followed, scientists discovered that the molecular stages of these reactions were remarkably similar. The process begins when an allergen lands on one of the body’s surfaces – skin, eye, nasal passage, mouth, airway or gut. These surfaces are loaded with immune cells that act as border sentries. When a sentry encounters an allergen, it first engulfs and demolishes the invader, then decorates its outer surface with fragments of the substance. Next the cell locates some lymph tissue. There it passes on the fragments to other immune cells, which produce a distinctive fork-shaped antibody, known as immunoglobulin E, or IgE.
These antibodies will trigger a response if they encounter the allergen again. The reaction begins when an antibody activates a component of the immune system known as a mast cell, which then blasts out a barrage of chemicals. Some of these chemicals latch onto nerves, triggering itchiness and coughing. Sometimes mucus is produced. Airway muscles can contract, making it hard to breathe.
This picture, built up in labs over the past century, answered the ‘how?’ part of the allergies mystery. Left unanswered, however, was ‘why?’ And that’s surprising, because the question had a pretty clear answer for most parts of the immune system. Our ancestors faced a constant assault of pathogens. Natural selection favoured mutations that helped them fend off these attacks, and those mutations accumulated to produce the sophisticated defences we have today.
It was harder to see how natural selection could have produced allergies. Reacting to harmless things with a huge immune response probably wouldn’t have aided the survival of our ancestors. Allergies are also strangely selective. Only some people have allergies, and only some substances are allergens. Sometimes people develop allergies relatively late in life; sometimes childhood allergies disappear. And for decades, nobody could even figure out what IgE was for. It showed no ability to stop any virus or bacteria. It was as if we evolved one special kind of antibody just to make us miserable.
One early clue came in 1964. A parasitologist named Bridget Ogilvie was investigating how the immune system repelled parasitic worms, and she noticed that rats infected with worms produced large amounts of what would later be called IgE. Subsequent studies revealed that the antibodies signalled the immune system to unleash a damaging assault on the worms.
Parasitic worms represent a serious threat – not just to rats, but to humans too. Hookworms can drain off blood from the gut. Liver flukes can damage liver tissue and cause cancer. Tapeworms can cause cysts in the brain. More than 20 per cent of all people on Earth carry such an infection, most of them in low-income countries. Before modern public health and food safety systems, our ancestors faced a lifelong struggle against these worms, as well as ticks and other parasitic animals.
During the 1980s, several scientists argued forcefully for a link between these parasites and allergies. Perhaps our ancestors evolved an ability to recognise the proteins on the surface of worms and to respond with IgE antibodies. The antibodies primed immune system cells in the skin and gut to quickly repel any parasite trying to push its way in. “You’ve got about an hour to react very dramatically in order to reduce the chance of these parasites surviving,” said David Dunne, a parasitologist at the University of Cambridge.
According to the worm theory, the proteins of parasitic worms are similar in shape to other molecules we regularly encounter in our lives. If we encounter those molecules, we mount a pointless defence. “Allergy is just an unfortunate side-effect of defence against parasitic worms,” says Dunne.
When he was an immunologist in training, Medzhitov was taught the worm theory of allergies. But ten years ago he started to develop doubts. “I was seeing that it doesn’t make sense,” he said. So Medzhitov began thinking about a theory of his own.
Thinking is a big part of Medzhitov’s science. It’s a legacy of his training in the Soviet Union in the 1980s and 1990s, when universities had little equipment and even less interest in producing good scientists. For his undergraduate degree, Medzhitov went to Tashkent State University in Uzbekistan. Every autumn the professors sent the students out into the cotton fields to help take in the harvest. They worked daily from dawn to dusk. “It was terrible,” said Medzhitov. “If you don’t do that, you get expelled from college.” He recalls sneaking biochemistry textbooks into the fields – and being reprimanded by a department chair for doing so.
Graduate school wasn’t much better. Medzhitov arrived at Moscow State University just as the Soviet regime collapsed. The university was broke, and Medzhitov didn’t have the equipment he needed to run experiments. “I was basically spending all of my time reading and thinking,” Medzhitov told me.
Mostly, he thought about how our bodies perceive the outside world. We can recognise patterns of photons with our eyes and patterns of air vibrations with our ears. To Medzhitov, the immune system was another pattern recognition system – one that detected molecular signatures instead of light or sound.
As Medzhitov searched for papers on this subject, he came across references to a 1989 essay written by Charles Janeway, an immunologist at Yale, titled ‘Approaching the Asymptote? Evolution and revolution in immunology’. Medzhitov was intrigued and used several months’ of his stipend to buy a reprint of the paper. It was worth the wait, because the paper exposed him to Janeway’s theories, and those theories would change his life.
At the time, Janeway was arguing that antibodies have a big drawback: it takes days for the immune system to develop an effective antibody against a new invader. He speculated that the immune system might have another line of defence that could offer faster protection. Perhaps the immune system could use a pattern-recognition system to detect bacteria and viruses quickly, allowing it to immediately launch a response.
Medzhitov had been thinking about the same thing, and he immediately emailed Janeway. Janeway responded, and they began an exchange that would ultimately bring Medzhitov to New Haven, Connecticut, in 1994, to become a postdoctoral researcher in Janeway’s lab. (Janeway died in 2003.)
“He turned out to speak very little English, and had almost no experience in a wet laboratory,” says Derek Sant’Angelo, who worked in the lab at the time. Sant’Angelo, now at the Robert Wood Johnson Medical School in New Jersey, recalls coming across Medzhitov at the bench one night. In one hand, Medzhitov held a mechanical pipette. In the other hand, he held a tube of bacteria. Medzhitov needed to use the pipette to remove a few drops of bacteria from the tube and place them on a plate on the lab bench in front of him. “He was slowly looking back and forth from the pipette down to the plate to the bacteria,” says Sant’Angelo. “He knew in theory that the pipette was used to put the bacteria on the plate. But he simply had absolutely no idea how to do it.”
How to correctly use a pipette. Photo: Flickr
Medzhitov still marvels that Janeway agreed to work with him. “I think that the only reason that he took me in his lab is that nobody else wanted to touch this idea,” he recalled.
With help from Sant’Angelo and other members of the lab, Medzhitov learned very quickly. Soon he and Janeway discovered a new class of sensor on the surface of a certain kind of immune cell. Confronted with an invader, the sensors would clasp onto the intruder and trigger a chemical alarm that promoted other immune cells to search the area for pathogens to kill. It was a fast, accurate way to sense and remove bacterial invaders.
Medzhitov and Janeway’s discovery of the sensors, now known as toll-like receptors, revealed a new dimension to our immune defences, and has been hailed as a fundamental principle of immunology. It also helped solve a medical mystery.
Infections sometimes produce a catastrophic body-wide inflammation known as sepsis. It is thought to strike around a million people a year in the USA alone, up to half of whom die. For years, scientists thought that a bacterial toxin might cause the immune system to malfunction in this way – but sepsis is actually just an exaggeration of one of the usual immune defences against bacteria and other invaders. Instead of acting locally, the immune system accidentally responds throughout the body. “What happens in septic shock is that these mechanisms become activated much more strongly than necessary,” said Medzhitov. “And that’s what kills.”
Medzhitov isn’t driven to do science to cure people; he’s more interested in basic questions about the immune system. But he argues that cures won’t be found if researchers have the wrong answers for basic questions. Only now that scientists have a clear understanding of the biology underlying sepsis can they develop treatments that target the real cause of the condition – the over-reaction of the toll-like receptors. (Tests are ongoing, and the results so far are promising). “Thirty years ago, it was, ‘Whatever causes septic shock is bad.’ Well, now we know it’s not,” said Medzhitov.
Medzhitov kept thinking after he and Janeway discovered toll-like receptors. If the immune system has special sensors for bacteria and other invaders, perhaps it had undiscovered sensors for other enemies. That’s when he started thinking about parasitic worms, IgE and allergies. And when he thought about them, things didn’t add up.
It’s true that the immune system makes IgE when it detects parasitic worms. But some studies suggest that IgE isn’t actually essential to fight these invaders. Scientists have engineered mice that can’t make IgE, for instance, and have found that the animals can still mount a defence against parasitic worms. And Medzhitov was sceptical of the idea that allergens mimic parasite proteins. A lot of allergens, such as nickel or penicillin, have no possible counterpart in the molecular biology of a parasite.
The more Medzhitov thought about allergens, the less important their structure seemed. Maybe what ties allergens together was not their shape, but what they do.
We know that allergens often cause physical damage. They rip open cells, irritate membranes, slice proteins into tatters. Maybe, Medzhitov thought, allergens do so much damage that we need a defence against them. “If you think of all the major symptoms of allergic reactions – runny noses, tears, sneezing, coughing, itching, vomiting and diarrhoea – all of these things have one thing in common,” said Medzhitov. “They all have to do with expulsion.” Suddenly the misery of allergies took on a new look. Allergies weren’t the body going haywire; they were the body’s strategy for getting rid of the allergens.
As Medzhitov explored this possibility, he found that the idea had surfaced from time to time over the years, only to be buried again. In 1991, for example, the evolutionary biologist Margie Profet argued that allergies fought toxins. Immunologists dismissed the idea, perhaps because Profet was an outsider. Medzhitov found it hugely helpful. “It was liberating,” he said.
Together with two of his students, Noah Palm and Rachel Rosenstein, Medzhitov published his theory in Nature in 2012. Then he began testing it. First he checked for a link between damage and allergies. He and colleagues injected mice with PLA2, an allergen that’s found in honey-bee venom and tears apart cell membranes. As Medzhitov had predicted, the animals’ immune systems didn’t respond to PLA2 itself. Only when PLA2 ripped open cells did the immune system produce IgE antibodies.
Another prediction of Medzhitov’s theory was that these antibodies would protect the mice, rather than just make them ill. To test this, Medzhitov and his colleagues followed their initial injection of PLA2 with a second, much bigger dose. If the animals had not previously been exposed to PLA2, the dose sent their body temperature plunging, sometimes fatally. But the mice that had been exposed marshalled an allergic reaction that, for reasons that aren’t yet clear, lessened the impact of the PLA2.
Medzhitov didn’t know it, but on the other side of the country another scientist was running an experiment that would provide even stronger support for his theory. Stephen Galli, chair of the Pathology Department at Stanford University School of Medicine, had spent years studying mast cells, the enigmatic immune cells that can kill people during allergic reactions. He suspected mast cells may actually help the body. In 2006, for example, Galli and colleagues found that mast cells destroy a toxin found in viper venom. That discovery led Galli to wonder, like Medzhitov, whether allergies might be protective.
To find out, Galli and colleagues injected one to two stings’ worth of honey-bee venom into mice, prompting an allergic reaction. Then they injected the same animals with a potentially lethal dose, to see if the reaction improved the animal’s chance of survival. It did. What’s more, when Galli’s team injected the IgE antibodies into mice that had never been exposed to the venom, those animals were also protected against a potentially lethal dose.
Medzhitov was delighted to discover Galli’s paper in the same issue of Immunity that carried his own. “It was very good to see that somebody got the same results using a very different model. That’s always very reassuring,” Medzhitov told me.
Still, the experiments left a lot unanswered. How precisely did the damage caused by the bee venom lead to an IgE response? And how did IgE protect the mice? These are the kinds of questions that Medzhitov’s team is now investigating. He showed me some of the experiments when I visited again last month. We sidled past a hulking new freezer blocking a corridor to slip into a room where Jaime Cullen, a researcher associate in the lab, spends much of her time. She put a flask of pink syrup under a microscope and invited me to look. I could see a flotilla of melon-shaped objects.
“These are the cells that cause all the problems,” said Medzhitov. I was looking at mast cells, the key agents of allergic reactions. Cullen is studying how IgE antibodies latch onto mast cells and prime them to become sensitive – or, in some cases, oversensitive – to allergens.
Medzhitov predicts that these experiments will show that allergen detection is like a home-alarm system. “You can detect a burglar, not by recognising his face, but by a broken window,” he said. The damage caused by an allergen rouses the immune system, which gathers up molecules in the vicinity and makes antibodies to them. Now the criminal has been identified and can be more easily apprehended next time he tries to break in.
Allergies make a lot more sense in terms of evolution when seen as a home-alarm system, argues Medzhitov. Toxic chemicals, whether from venomous animals or plants, have long threatened human health. Allergies would have protected our ancestors by flushing out these chemicals. And the discomfort our ancestors felt when exposed to these allergens might have led them to move to safer parts of their environment.
Like many adaptations, allergies weren’t perfect. They lowered the odds of dying from toxins but didn’t eliminate the risk. And the immune system might sometimes round up a harmless molecular bystander when it responded to an allergy alarm. But overall, Medzhitov argues, the benefits of allergies outstripped their drawbacks.
That balance shifted with the rise of modern Western life, he adds. As we created more synthetic chemicals, we exposed ourselves to a wider range of compounds, each of which could potentially cause damage and trigger an allergic reaction. Our ancestors could avoid allergens by moving to the other side of the forest, but we can’t escape so easily. “In this particular case, the environment we’d have to avoid is living indoors,” said Medzhitov.
Scientists are taking this theory very seriously. “Ruslan is one of the most distinguished immunologists in the world,” said Galli. “If he thinks there’s validity to this idea, I think it gets a lot of traction.”
Dunne, on the other hand, is sceptical about the idea that Medzhitov’s theory explains all allergies. Medzhitov is underestimating the huge diversity of proteins that Dunne and others are finding on the surface of worms – proteins that could be mimicked by a huge range of allergens in the modern world. “My money’s more on the worm one,” he said.
Over the next few years, Medzhitov hopes to persuade sceptics with another experiment. It’s unlikely to end the debate, but positive results would bring many more people over to his way of thinking. And that might eventually lead to a revolution in the way we treat allergies.
Sitting on Cullen’s lab bench is a plastic box that houses a pair of mice. There are dozens more of these boxes in the basement of their building. Some of the mice are ordinary, but others are not: using genetic engineering techniques, Medzhitov’s team has removed the animals’ ability to make IgE. They can’t get allergies.
Medzhitov and Cullen will be observing these allergy-free mice for the next couple of years. The animals may be spared the misery of hay fever caused by the ragweed pollen that will inevitably drift into their box on currents of air. But Medzhitov predicts that they will be worse for it. Unable to fight the pollen and other allergens, they will let these toxic molecules pass into their bodies, where they will damage organs and tissues.
“It’s never been done before, so we don’t know what the consequences will be,” says Medzhitov. But if his theory is right, the experiment will reveal the invisible shield that allergies provide us.
Even if the experiment works out just as he predicts, Medzhitov doesn’t think his ideas about allergies will win out as quickly as his ideas about toll-like receptors. The idea that allergic reactions are bad is ingrained in the minds of physicians. “There’s going to be more inertia,” he said.
But understanding the purpose of allergies could lead to dramatic changes in how they’re treated. “One implication of our view is that any attempt to completely block allergic defences would be a bad idea,” he said. Instead, allergists should be learning why a minority of people turn a protective response into a hypersensitive one. “It’s the same as with pain,” said Medzhitov. “No pain at all is deadly; normal pain is good; too much pain is bad.”
For now, however, Medzhitov would just be happy to get people to stop seeing allergies as a disease, despite the misery they cause. “You’re sneezing to protect yourself. The fact that you don’t like the sneezing, that’s tough luck,” he said, with a slight shrug. “Evolution doesn’t care how you feel.”
This story first appeared on Mosaic and is republished here under a Creative Commons licence.
