Ariella Cohen had already made nearly a dozen visits in as many months to a Philadelphia emergency room when, in the winter of 2014, she once again grabbed her pre-packed overnight bag and rushed to the hospital with crippling intestinal pain. She didn’t have high expectations: At just 26, she and her family had seen close to 100 doctors and amassed hundreds of thousands of dollars in medical bills attempting to identify and treat the source of her pain, and she arrived with a long-ago memorized script of the many diagnoses she had received since her childhood.

As she sat on a gurney, Cohen recalls calmly explaining her situation to the attending physician. Like so many times before, her body was in mutiny: The assembly line of muscles along her gut had frozen, and she had been constipated for months, with the resulting pain sometimes scorching her insides. That day it had become so horrendous that she collapsed, prompting two of her regular doctors, fearing that the stoppage might tear a hole in her lower intestine, to advise she go to the ER immediately.

According to Cohen, the ER physician that day simply dismissed her symptoms without an examination. If anything was wrong, he implied, it was mental, not physical, and he refused to admit her. Later that winter, during a raging snowstorm, her agony came again, but despite calling ahead to the ER and being told she could see another physician, the same doctor came around again as she was being examined and told her to go home.

Undeterred and frightened of the internal damage her untreated symptoms might cause, she made her way by taxi to another hospital 40 minutes away. The staff there was unable to offer any more insight into her problem, though they were able to complete tests to show that she was not in any imminent danger.

As in the past, the attack eventually eased on its own, but it would take six months before she found steady relief from the worst of her episodes, aided by switching to a higher-fat diet.

“It was terrifying,” Cohen told me in January, as I sat with her, her family, and her boyfriend David in the modest apartment she rents with him in Washington, D.C. “This guy just looked at me and decided that because I looked the way I did, I was fine. And if the doctors who sent me were right, it could have been a really dangerous situation.”

“Like death,” interrupted Cohen’s mother, Ellen.

“Right. That,” Cohen said.

Emergency room visits have become a grim fact of life for Cohen. But her encounters with the Philadelphia doctor were hardly unique, she said, and similar skepticism has followed her and her fraternal twin sister Sarah since childhood, when both of them first began suffering from a mysterious array of ailments.

Medical tests proved fruitless. So the sisters were routinely told that their symptoms — ranging from endless fatigue and dizziness to joints that popped in and out of place, along with countless serious allergic reactions — were the psychosomatic manifestation of stress triggered by watching their father slowly die from cancer during their teens, as well as general emotional stress and turmoil.

“The whole culture of medicine is set up very badly to treat people who are unusual,” said Sarah, who just graduated from medical school and whose symptoms have proven to be a bit more manageable than those of her sister. “There’s no time to do better, and we’re not trained to do better.”

The Cohens are among the millions of Americans languishing on the margins of the health care system with elusive or poorly understood diseases. Some of these maladies have names, but each is essentially a collection of unexplained symptoms lumped together by doctors into a sort of diagnostic checklist, often known as a “syndrome.” And while these conditions — which can include chronic fatigue syndrome, fibromyalgia, and irritable bowel syndrome, among others — can vary in severity and treatability, one thing they share is intangibility. They’re “none of the above” illnesses, and they’re surprisingly common.

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By some estimates, up to 3 percent of the population suffers from chronic fatigue syndrome, which can range from mild to debilitating. Two to 4 percent, according to the American College of Rheumatology, suffer from the chronic pain and soreness that characterizes fibromyalgia; and upward of 10 percent, including Ariella Cohen, deal with irritable bowel syndrome.

“We need to appreciate just how muddled the concept of medically unexplained symptoms is,” said James Coyne, a professor of health psychology at University Medical Center, Groningen, in the Netherlands. It’s meant to serve as a placeholder for patients who complain of vague health issues that can’t be verified through routine testing or whose cause remains uncertain. But often, Coyne said, there’s a degree of mistrust involved, as many health care professionals prefer psychosomatic explanations for these nebulous ailments.

“In one version of the universe, these things are all objective, concrete disease states,” David Jones, a historian of science at Harvard University, told me. “But there’s another version of the universe, where these things are not diseases as traditionally understood, but rather some kind of psychiatric phenomenon.”

The reality is somewhere in between, recent research suggests, and it’s worth remembering that we’re still a long way from unlocking all the secrets of the brain and body. Only a few decades ago, chronic ulcers were chalked up to stress and diet rather than an infection by Helicobacter pylori, because scientists thought it unimaginable that such microorganisms could endure stomach acid.

As Jones put it, “Even though we have extensive knowledge in human physiology and pathology, there is much that continues to be unknown.”

Coyne is quick to caution that there won’t ever be a single discovery that can explain away every case of medically unexplained symptoms as something physical, complex as they are. But for Cohen and many others who have spent years being sick without knowing why, a new hope may lie in the incremental advances in research that are now being pioneered by geneticists and immunologists.

Visual: Federico Morando/Getty

This research, Coyne explained, is working to identify the genetic quirks and abnormalities in the immune systems shared by some of these people with otherwise unexplainable illnesses. Among the researchers leading the way is Dr. Joshua Milner, a pediatric allergist and immunologist, and his team at the Genetics and Pathogenesis of Allergy laboratory at the National Institutes of Health.

“My lab’s modus operandi is to look for genetic diseases of allergy, so we get referred people all the time who have allergic issues, but then something else that makes it look like it could be a syndrome,” he explained.

In 2015, Cohen was referred to Milner’s team by her dermatologist. Patients like Cohen, suffering from strange allergies and chronic symptoms, began showing up at his lab around five years ago, he said. Aside from their conditions, they shared no common lab finding — except for one oddity. Compared to the average person, their blood was filled with high levels of a protein called tryptase.

Discovered in the 1960s, tryptase is itself something of a mystery. Primarily released by the immune system’s mast cells, it comes in two flavors: alpha and beta, with three subtypes under the latter umbrella. The three types of beta-tryptase largely work as enzymes that keep the immune system’s motor running. They catalyze other chemicals secreted by our cells, called substrates, to induce the inflammation that wards off foreign invaders and — in people with hypersensitivity — causes allergic reactions when triggers appear.

But due to mutations in the gene that expresses it, alpha tryptase has not been shown to interact with any known substrates. Nearly one-fourth of us don’t even produce it, and it has no known function in the human body, at least as an enzyme.

As Milner’s team dug deeper into the genetic makeup of nearly 100 patients from 35 families with elevated tryptase levels, they found all had an abnormally high ratio of alpha to beta tryptase. And they also found evidence that at least one copy of the gene that codes for alpha tryptase was duplicated, even tripled occasionally, in the group.

As the team collected more cases, they saw the same pattern: People with elevated tryptase levels also shared abnormally high alpha to beta tryptase ratios. And the more copies of the alpha tryptase gene they had, the more tryptase they had in their blood, and the worse their symptoms.

Sifting through data from other studies, Milner’s team found the same link between gene copies and high tryptase levels. And when they contacted some of the healthy volunteers who participated in one study, they found that one third of those with high amounts of tryptase and the copied gene had been living silently with many of the same complaints as Cohen, though to a lesser degree.

Eventually, Milner was confident enough to start telling his patients what they had found. “A good number of them cry, because they’ve been told it’s nothing for such a long time,” he said. “They’ve assumed there was something wrong with them personally, not their body.”

Others realized, for the first time, that their symptoms weren’t normal. “I literally had a patient who once told me, ‘Well, of course, when you use a hand mixer, that makes your hand and arm itch,’’’ Milner recalled. “And I was like, ‘No, not for most people.’’’

Last November, the team published its findings in Nature Genetics, dubbing the proposed condition hereditary α-tryptasemia syndrome. While their work hasn’t yet yielded any specific treatments, it at least identified a probable — if barely understood — culprit to help explain the suffering of patients like Cohen.

A few years before participating in Milner’s research, Cohen came across a loose-knit coalition of doctors and patients concerned with disorders of the immune system and the underestimated role they play in unexplainable illnesses. It was her experience with this community that eventually led her to Milner’s study.

Doctors have long known that some people can be sickened by producing too many mast cells in their skin, a rare condition called mastocytosis. These people acquire (or are rarely born with) a mutation that causes their mast cells to clump together and then degranulate, releasing a payload of mediator chemicals that kick the immune system into high gear whenever the skin is irritated by allergic triggers, causing hives and lesions.

Beginning in the early 1990s, a small group of researchers theorized that mast cells could misbehave in another way. Some people, they posited, carry a normal amount of mast cells that are wildly sensitive and degranulate at the faintest whisper of a foreign substance. And because mast cells are scattered throughout the body — not just in the skin — this condition, eventually called mast cell activation syndrome, can cause a wide array of symptoms, perhaps even the kind of mental daze and anxiety doctors might otherwise attribute to stress.

“The immune system talks to the vascular system, it talks to the surrounding connective tissue, it talks to the nerve fibers,” explained Dr. Anne Maitland, an allergist and mast cell specialist with a private practice just outside New York City.

Until recently, people like Ariella Cohen with a hodgepodge of nondescript symptoms were unaware that they might have mast cell issues. (Cohen was diagnosed with MCAS in 2013.) Few doctors were aware of mastocytosis, and fewer still had heard of the emerging field of mast cell disease.

But the Mastocytosis Society, a nonprofit group founded in 1995, has helped to spread awareness by lobbying on behalf of patients and funding research into mast cell disease, according to Valerie Slee, a former pediatric nurse and long-time mast cell disease sufferer who is the current chairwoman of the board of directors.

The group ultimately hopes to persuade the medical establishment that mastocytosis isn’t the only — or even the most common — kind of mast cell dysfunction. In fact, their membership rolls and others’ research suggests that many more people, numbering in the millions, are afflicted with MCAS than mastocytosis.

The group’s efforts have been paying off, Slee said. Even though researchers have known since the 1950s that mastocytosis can turn up anywhere in the body, MCAS was only named in 2007. From there, treatments were developed that reduced symptoms by disrupting the release of mediators like histamine. In 2010, the first diagnostic criteria for MCAS was published, followed by attempts to group all kinds of mast cell disease under one banner.

Thanks in part to organizations like the Mastocytosis Society, as well as networks of doctors including Maitland and Dr. Matthew Hamilton of the Brigham and Women’s Hospital in Massachusetts, MCAS was formally included in the International Classification of Diseases, a codebook established by the World Health Organization, last September. And with that, patients could finally worry less about getting insurance coverage for their expensive treatments.

Broadly speaking, MCAS sufferers seem to share the same fundamental problem as Milner’s patients: a haywire immune system that makes them sick in strange, multiple ways. But any link beyond that remains unclear.

Milner’s patients display many of the same symptoms as those with mast cell disease, yet the overwhelming majority do not have acquired MCAS mutations in their mast cells, nor do most of his patients show the other lab results typical of mast cell activation or mastocytosis. Their issues also run in families, strongly suggesting they’re dealing with an inherited problem, not mutations that pop up later in life.

Most MCAS cases, meanwhile, still aren’t linked to any known acquired mutations. Some in the field suspect we simply haven’t discovered the ones that can explain most cases, while others suspect that infections or other environmental factors could be the initial spark. And though many of Milner’s patients like Cohen were tentatively diagnosed with mast cell issues before they entered his lab, there’s also the possibility that his research is uncovering a completely different sort of systemic dysfunction that merely resembles mast cell disease.

The cold reality is that we still don’t know how alpha tryptase does what it seems to be doing in people like Cohen, or even exactly what it’s doing. “There is scant information about what alpha and beta can and can’t do,” Milner said.

Visual: Cat Lane/Getty

About 5 percent of the U.S. population has high tryptase in their blood, and presumably the duplicated gene. But only some, and especially those whose alpha tryptase levels are tripled, appear to be chronically sick. That makes it likely alpha tryptase isn’t the sole perpetrator.

And alpha tryptase can’t explain everything that’s wrong with the families Milner has studied either. For example, Sarah Cohen has some shared symptoms and conditions with Ariella, like Ehlers-Danlos syndrome, which affects a person’s connective tissue and leaves them with painful joints prone to dislocation, along with fragile skin. But she doesn’t have the gene duplication her sister does.

Most kinds of EDS are tied to a precise inherited cause, but rarely theirs, known as type III, or hypermobile EDS. So it’s possible the alpha tryptase gene explains why some like Ariella have EDS (all of Milner’s patients with EDS have type III), while something else entirely explains Sarah’s condition. “There are certainly families where not everything makes sense,” Milner acknowledged.

Milner is careful to caution that his team’s research into tryptasemia is at an early stage. They are still developing a better test to detect the gene duplication and alpha tryptase, narrowing down which symptoms are associated with high tryptase, and creating a model that will allow them to better study it in mice. And it will be a long time before the first hints of a treatment, like something that can block the production of alpha tryptase, will definitively prove his team’s theory.

But even if alpha tryptase does prove to be a crucial lynchpin, Milner knows it won’t cure all that ails his patients. “I am 100 percent sure that some of the symptoms we see have nothing to do with the gene,’’ he said. “I’m just sure that it’s going to end up that way.’’

Nonetheless, his research offers important relief for patients: for example, the same drug treatments that tamp down immune mediators in the body, like histamine, help both groups of patients. And ultimately, if alpha tryptase is the main instigator for sufferers like Cohen, then a future treatment that blocks its production could be a much simpler remedy.

For all the caveats and conundrums, there is a common thread running through all the research — an awareness that illness is enormously complex and the result of many interconnected environmental, biological, and psychological factors. Stress impairs our ability to heal wounds, and everything from lead metal to parasites can tweak our brain chemistry, leading to personality changes and mental illness.

Even social mores play a part in our perception and treatment of disease: Black people are undertreated for pain in the emergency room, studies suggest, supposedly because white doctors presume they have thicker skin or that their blood coagulates faster; women’s heart issues go unrecognized and untreated to a much higher degree than men’s.

Cohen believes one reason she got such a negative reception from doctors was because of her gender. Many are the women whose complaints of chronic fatigue or other mysterious diseases are still tossed aside as the modern-day equivalent of hysteria, Jones notes.

For their part, the Cohen sisters don’t see mental health as irrelevant to their issues, nor discount the value of psychological care. The problem, Sarah explains, is that it has been routinely offered to them as a way to discount their complaints completely, rather than to help them deal with their stress.

In fact, both sisters have used behavioral interventions like biofeedback, while Ariella regularly turns to holistic and integrative treatments like dry needling to help manage her gut and pain problems. She also credits her ability to eat more foods lately to working with a naturopath. Milner has no problem with his patients trying these strategies out if they think it will help, and at least some of his patients have been able to wean themselves off antihistamines as a result.

Having been entangled in the medical world so deeply for so long, perhaps it’s not surprising that both sisters have chosen to devote their lives toward improving it.

Sarah is weighing a career in pediatric pain management, which would allow her to take on cases of fibromyalgia and other controversial illnesses. “You’ve got to listen to the people who have the experiences,” she said. “Because if you’re going in just from the perspective of a doctor, with blinders on, you end up with the problem we had initially, where doctors just brush it off and didn’t believe us.”

Ariella currently works for the Pew Charitable Trusts in the field of health care products. Unlike her sister, who always wanted to be a doctor, it was specifically Ariella’s life experiences — as a patient, but more so in seeing her father succumb to cancer — that motivated her to pursue a career in health law.

“I not only had to watch my dad pass away, but also my mom fight with the insurance companies on a daily basis to get them to cover his treatments,” she said. “That gave me insight into the incredible problems with our insurance and health care system.”

One problem in particular is the difficulty MCAS patients have in affording their drugs. Even with the new ICD-10 codes, some medications aren’t approved by the Food and Drug Administration to treat mast cell diseases. As a result, doctors are often forced to write appeals for patients to insurance companies to get coverage. Other drugs need to be custom-made at specialized pharmacies to avoid allergic ingredients, and these drugs — including many of the 40 to 50 that Ariella takes every day — are often not covered by providers.

“There are a lot of hurdles in place regarding the lack of recognition by health care providers, a lack of education of patients… lack of commercial testing,” said Maitland, the allergist and mast cell specialist. “Patients are grabbing onto us like driftwood in the middle of the ocean.”

Though she is encouraged by the advances in the field, she notes there are only three major medical centers, including one at the NIH, where mast cell issues are easily diagnosable. For private doctors like her, the waiting list for patients can stretch on for six to eight months, and due to New York’s licensing laws, she added, she can’t even use one of the only six commercial tests developed for MCAS. “It’s a lack of awareness that is slowly changing,” she said.

As for Milner, he hopes his tryptase research will provide his patients with validation and direction, and in the process eventually shrink the number of patients tossed into the miscellaneous pile.

“The genomic era helps us say, actually there is something there that may or may not change the way you would deal with the person, but at the very least, there’s a gene there,’’ he said.

Aside from her intestinal flare-ups, Cohen continues to deal with a startling number of allergic triggers she has to avoid: soy, garlic, the metal found in IVs, alcohol, chlorine, nightshade plants like potatoes, most perfumes, raw produce, anything found in a Chinese restaurant, cobalt, and gluten, to name a few. She estimates there are just 35 foods she can safely consume. And that tally includes different varieties of squash, sweet potatoes, and spices.

“I go through phases where I can’t eat anything, or I lose the ability to eat my staple food, and I have to figure out what else in the world is safe,” she said. The week before our interview in January, she made an emergency room visit following a severe reaction brought on by garlic her boyfriend had eaten. In the months after, she had six such attacks within a two-week span.

Despite her struggles, the years since Cohen’s MCAS diagnosis in 2013 and her subsequent participation in Milner’s study have at least given her some assurance that she isn’t alone.

With the help of a dedicated team of physicians and practitioners who regularly communicate with her and with one another, she has gradually learned to identify and manage her symptoms. And with her boyfriend David around, she even goes on regular hiking trips, something she never would have considered in the past. “It’s easier to do something fun now, because I feel safe that if something were to go wrong, I have him,” she said.

That added security, combined with a hard-earned resilience hidden underneath her short, wiry frame, makes Cohen willing to become a spokesperson for others like her.

“I think it’s important for people in my situation to tell the world what this life is like, because maybe a doctor will see this and change their ways,” she said. “Maybe a patient will see this, and think, ‘Oh my god, that’s exactly my life.’ And maybe that’ll help them find some answers.”

At the same time, she doesn’t want pity, nor to be defined by her illness alone.

“Every stage of my life, it’s always like, ‘How the hell am I going to get to this next stage? How will I actually be able to do the things I want to do in life?’” she continued. “But I always get there. It’s just harder for me than it is for everyone else.”

Ed Cara is a Brooklyn-based journalist who has written about psychology, sociology, and public health for a variety of publications, including The Atlantic, Pacific Standard, Vocativ, and Medical Daily.