by Dan Ariely
Jake is allergic to many things—mold, peanut butter, dogs, cats—and his asthma is severe. In 2009 he almost died because he couldn’t breathe. “The scary thing was, within seconds, he was in respiratory and cardiac arrest,” his mother recalls. “No warning. No lip swelling or dizziness or mouth burning. He just went down.”
Eczema’s strong link to allergies suggests that the immune system is key to the development of the disease, and researchers have focused on inflammation for decades. So how does the skin microbiome fit into this picture? In 2006, a coalition of researchers from the United States, France, Ireland, and the UK discovered that up to half of people with eczema have mutations in filaggrin, a protein in the skin barrier, the top layers of the skin. Now some researchers suspect that this flaw in the skin barrier allows entry to particles that trigger the immune response and creates an ecological niche for a different set of microbes.
To uncover any link between the skin barrier and microbes, Kong and Segre are sampling Jake and other children with eczema at three points: during a normal, or baseline, period; during a flare; and two weeks after treatment. In a preliminary analysis of data from ten patients, Kong and Segre have confirmed older studies showing that there are huge amounts of Staphylococcus aureus on the skin during a flare. What wasn’t known before, however, is that S. aureus crowds out the other bacterial species during a flare. Kong and Segre are trying to figure out how treating these patients changes their bacterial diversity and leads to better individual results.
Segre doesn’t know whether bacteria associated with eczema are the cause of the disease or simply a consequence of living with it. To find out, she plans to perform a metagenomic analysis of the samples. During a metagenomic analysis, scientists compare thousands of genes present in a particular species’ DNA. By looking at the biological function of the genes—what kinds of proteins they make and what kinds of biological pathways those proteins are involved in—the scientists can make educated guesses about the role of each species and how different species may work with one another and with our own genome.
“We all believe there’s an interdependency among these organisms. They’re highly dependent on their neighbors for their survival,” says Claire Fraser-Liggett, director of the Institute for Genome Sciences at the University of Maryland. Metagenomics, however, is immensely complicated. Researchers know little about how the millions of microbial genes might work together, and it’s difficult to sort out which patterns are signatures of disease versus part of normal variation between people. “There’s no way to overemphasize the analytical challenges,” Fraser-Liggett says. “It’s something that everybody is struggling with.”
Early results from Segre’s study indicate that researchers might not have to decode the entire microbiome to better treat children’s skin diseases. She says she envisions a day in the not-too-distant future when a dermatologist, during an office visit, will drop a skin sample into a machine that spits out a signature of the microbiome.
If she finds certain microbial profiles that predict the onset of an eczema flare, for example, doctors could use that data as a guide for action. They might tell the patient to take a few extra bleach baths that week or to skip football practice. Researchers might even be able to create “probiotic” concoctions to replace the bacterial species that patients lack during a flare, Segre says. Hospitals are already routinely swabbing people’s noses to screen for drug-resistant bacteria. “You get that result in less than an hour,” Segre says. If the screen turns up MRSA (methicillin-resistant S. aureus), for example, doctors can prescribe an antibiotic known to be effective against the species.
These potential applications are many years off, and Segre’s initial studies probably won’t have much effect on Jake’s eczema. Still, the Harveys are happy to be moving the field forward. “It’s probably going to be a while before Jake’s helped,” Debbie says. “But in the future, if someone else can avoid sitting up all night scratching their legs, that would be great.”
JEROME GROOPMAN
The Peanut Puzzle
FROM The New Yorker
JILL MINDLIN PRIDES HERSELF on being a good parent. An attorney who lives on the North Shore of Long Island, she read books about how to raise healthy and happy children and dutifully followed their advice. She bought the car seat with the highest safety rating and covered her son and daughter with sunblock whenever they went outside. With her pediatrician’s approval, she breast-fed her children until they were at least a year old and gave them “no formula whatsoever” and no milk products or peanuts. As the American Academy of Pediatrics recommended in 2000, she introduced solid foods slowly and in small amounts.
In 2002, when her daughter, Maya Konoff, was nine months old, Mindlin took Maya for a checkup, and she got several immunizations. After they came home, Mindlin gave her a little yogurt. Soon, Mindlin told me, “Maya blew up like a tomato, bright red, swelling from head to toe.” She called the office, assuming that her daughter was reacting to the immunizations. The pediatrician told her that it was more likely an allergy of some kind. “Fortunately, there was liquid Benadryl in the house, and I was able to get Maya to take some,” Mindlin said. The reaction slowly subsided.
Several days later, Mindlin took Maya to see a pediatric allergist at a hospital on Long Island, and he told her it was unlikely that her daughter had a dairy allergy, since she had been breast-fed and was on a restricted diet. But Mindlin asked that Maya be examined, and the allergist placed a small amount of milk protein under the baby’s skin. Within minutes, she broke out in hives. As it turned out, Maya was also allergic to eggs, peanuts, tree nuts, and sesame seeds.
Despite her mother’s vigilance, Maya has had other frightening reactions. On a family outing to the Long Island Children’s Museum a few months later, after eating something labeled “vegetarian cheese,” Maya struggled to breathe and then lost consciousness. On vacation in South Carolina in 2003, Maya wanted a hot dog. “We asked the waiter to be sure that there were no dairy products in the food,” Mindlin recalled. “He came back to the table and said that the package said a hundred percent beef.” But a few minutes after eating the hot dog Maya began vomiting and swelling up. Mindlin later learned that the hot dog contained a milk protein. This time the doctor in the ER gave Maya an epinephrine injection. Epinephrine, another term for adrenaline, can rapidly shut off a severe allergic reaction, and Mindlin now makes sure there are syringes of it in each of her handbags and in Maya’s knapsack.
Dr. Hugh Sampson, the director of the Jaffe Food Allergy Institute at Mount Sinai Medical Center in New York and an international expert on food allergy, is Maya’s doctor. He is a tall sixty-year-old with an athletic build and a full head of graying hair. Sampson and Dr. Scott Sicherer, a pediatric allergist who is also at Mount Sinai, have conducted extensive studies throughout the United States that show that the rate of allergy is rising sharply. Sampson estimates that three to five percent of the population is allergic to milk, eggs, peanuts, tree nuts, or seafood. In the past decade, allergies to peanuts have doubled. Other researchers have found the same phenomenon in Great Britain. “This increase in the incidence of food allergy is real,” Sampson said when we spoke recently. He cannot say what is causing the increase, but he now thinks the conventional approach to preventing food allergies is misconceived. For most of his career, he believed, like most allergists, that children are far less likely to become allergic to problematic foods if they are not exposed to them as infants. But now Sampson and other specialists believe that early exposure may actually help prevent food allergies.
Sampson recalls that in 1980, when he started researching the subject as a fellow in immunology at Duke University, “food allergy was not a field that anybody wanted to get into.” Many doctors said that patients who claimed that food allergies were causing stomachaches and rashes were often just manifesting psychosomatic symptoms. “I approached the subject with the assumption that I would prove it didn’t exist,” Sampson said.
Sampson watched as the incidence of food allergies rose alarmingly in the West while cases remained rare in Africa and Asia. He and other researchers began to investigate whether the problem could be prevented if Western mothers continued breast-feeding as long as possible. This would keep their babies away from potentially allergenic foods until their immune systems had developed sufficiently. Laboratory studies reinforced the theory. Sampson’s research group and others found that mice that had never been exposed to a particular food protein couldn’t mount an allergic reaction to it. This suggested that isolating young children from even minor exposure to potentially allergic foods would be beneficial.
In 1989 Dr. Robert Zeiger, a pediatric allergist and immunologist at Kaiser Permanente Medical Center in San Diego, published related results from one of the only controlled research studies on the subject. In the Zeiger study, which appeared in the Journal of Allergy and Clinical Immunology, mothers prone to allergy were randomly assigned a restricted diet. They avoided cow’s milk, eggs, and peanuts during the last trimester of pregnancy and during breast-feeding; their infants were given the supplement Nutramigen, derived from casein, and kept off all solid foods for six months; cow’s milk, corn, soy, citrus, and wheat were prohibited for twelve months, and egg, peanut, and fish for twenty-four months. After one year, the infants on the restricted diet had significantly fewer allergies than those in the control group. “Reduced exposure of infants to allergenic foods appeared to reduce food sensitization and allergy primarily during the first year of life,” Zeiger wrote.
A few experts believed that Zeiger’s research had not yielded results from which one could draw major conclusions. But Sampson was influenced by the article, and most of the other leading thinkers in the field agreed with the findings. “We know that the human immune system is immature for the first year or so. So I was thinking initially that as long as we don’t expose babies to a food, they can’t make an immune response,” Sampson said, “and if we can wait until their immune system matures after a few years, they could do better when later exposed to the food.”
In 1998 the Department of Health in the United Kingdom issued guidelines for doctors and families codifying these recommendations. In 2000, the American Academy of Pediatrics did the same.
The proteins in eggs, milk, peanuts, tree nuts, fish, shellfish, wheat, and soy that trigger allergic reactions don’t readily decompose when exposed to heat in certain types of cooking or to the acid in our stomachs. Within the gastrointestinal tract, the immune system battles pathogens while it ignores harmless food proteins and allows nonthreatening bacteria to reproduce. Proteins that are easily broken down by heat or digestion, such as many of those found in fruits, generally pass by. Proteins that resist breakdown are more likely to stimulate an allergic reaction.
People with the worst food allergies usually have very high levels of an antibody called immunoglobulin E (IgE). When someone like Maya drinks milk, the IgE grabs hold of specific proteins that trigger the body’s release of potent molecules like histamine and cytokines. The immune system overreacts to fight the protein that most people’s bodies ignore. When Maya “blew up like a tomato” and stopped breathing, it was because these molecules created so much swelling and inflammation that her throat closed up. For reasons that are still not completely understood, some people manifest their allergic reactions with nothing more than an outbreak of eczema. While there is a genetic predisposition to food allergies, no one has identified the specific genes, and there is no biological explanation for their existence.
“From an evolutionary biology point of view, food allergy makes no sense at all,” Dr. Scott Sicherer, Sampson’s colleague at Mount Sinai, said. Hunters and gatherers who had potentially fatal reactions to tree nuts, peanuts, seeds, and fish would be at a distinct evolutionary disadvantage and were less likely to pass on their DNA to progeny. “It seems pretty clear that food allergy is a condition that resulted from the environment we created,” Sicherer said.
One explanation for the rise in food allergies is called the “hygiene hypothesis.” The natural environment exposes us to microbes that help teach our immune system to differentiate between dangerous pathogens and nonthreatening nutrients. When we shield children from dirt in the playground and from sick kids in preschool, we may limit their infections while also reducing their exposure to healthy microbes. This could make them susceptible to food allergies. Studies of mice raised in a germ-free environment show that they have abnormal immune systems and are more prone to allergic reactions. It is possible that we are doing the same thing to ourselves.
Researchers have also proposed several theories based on observations of geography and diet. Vitamin D is believed to reduce the development of allergies, and sunshine promotes vitamin-D production. Doctors in cold parts of the United States write three or four times as many prescriptions for epinephrine to treat food allergies as do doctors in warm locales. Dietary changes might also play a role. Eating more animal fat can increase the presence of a chemical, prostaglandin, that contributes to the body’s inflammatory responses. And as people also eat fewer fresh fruits and vegetables, they fail to take in substances, such as beta carotene, that limit inflammation in tissues.
One of the few pediatric allergists who questioned the guidelines written in 1998 and 2000 was Dr. Gideon Lack, at St. Mary’s Hospital in London. Lack studied philosophy and psychology before medicine, and his background is evident in his approach to science. “If eating eggs or eating peanuts in an allergic sufferer causes a reaction, then clearly the way to prevent a reaction from occurring is by not eating egg or peanut,” he said. “That makes sense. But that’s different from saying that clearly the way to not become allergic in the first place is not to eat egg or peanut.”
Lack published letters in The Lancet and the British Medical Journal that pointed out the absence of compelling evidence used to support the expert guidelines. His skepticism was not well received. “It was very hard to get any grant support to study my ideas,” he said.
In 2003, Lack gave a lecture in Israel about the apparent rise of peanut allergies in the United Kingdom. “It was a large lecture hall in Tel Aviv, filled with pediatricians and allergists. And I asked them, ‘How many of you have seen a case of peanut allergy in the past year?’ Something like three hands shot up.” Lack told me that if he had asked that question in the United Kingdom, 90 to 95 percent would have raised their hands.
Working with researchers in Israel, Lack surveyed more than five thousand children in Jewish schools in North London and more than five thousand schoolchildren in an ethnically and economically similar region of Tel Aviv. The team obtained detailed information about the families’ consumption of foods like peanuts, sesame, and tree nuts. They also cataloged other allergic diseases, such as asthma, eczema, and hay fever. The risk for peanut allergy among Jewish children in the London area was nearly eleven times higher than among those in Tel Aviv. Tree-nut allergy was fourteen times higher, and sesame five times higher in the United Kingdom. The relative risk for milk and egg allergy was about two to three times higher.
Lack’s study does not offer any proof about the cause of the variance in allergies between Jewish children in London and in Tel Aviv, but he believes the striking discrepancy may be due to a difference in diet between Israel and England. “The joke in Israel is that the first three words a child says are abba, meaning ‘father,’ ima, meaning ‘mother,’ and Bamba,” Lack said. Bamba is a peanut c
oncoction that looks like a Cheez Doodle, and it is a staple of infants’ diets in Israel.
Lack did part of his training in pediatric allergy at the National Jewish Medical and Research Center in Denver, where he discovered that mice could develop allergies to a particular egg protein that was first rubbed on their skin or inhaled before they had ever eaten it. He wondered whether children in the United States and the United Kingdom might become allergic to peanuts through a similar mechanism. In a study published in the New England Journal of Medicine in 2003, he reported that children with eczema had often been previously exposed to an ointment containing peanut oil and were later found to be allergic to peanuts. He also determined that there was no correlation between women who had eaten peanuts while pregnant and the development of peanut allergies in their children. His study challenged the idea that restricting a mother’s diet would prevent peanut allergy and highlighted how children can inadvertently be exposed to food proteins.
In 2006 Lack received support from the National Institutes of Health as well as from two charitable organizations, the Food Allergy Initiative and the Food Allergy and Anaphylaxis Network. He is now more than halfway through the LEAP study—Learning Early About Peanut Allergy. Six hundred and forty babies have been enrolled in the trial. The children are randomly selected either to eat peanut products or to avoid them entirely. The study will compare the rates of peanut allergy between the two groups. Lack is also conducting a study funded by the Food Standards Agency and the Medical Research Council in the United Kingdom about when to wean children from breast-feeding and how a baby’s consumption of allergenic foods affects her later development of allergies. As part of that work, he is examining thirteen hundred babies in the United Kingdom.