Jen Grannis sits in her home workshop, drill in one hand, plastic isosahedral die in the other. With practiced precision she nudges the spinning drillbit into place. The bit plunges in, sending a small cloud of plastic dust into the air. The heat from the friction ahelts some of the acrylic and wraps it around the bit. The sulfur smell of acrylic dust hits my nose. At her ankles, a small cat with deformed paws cries for attention. Jen’s eyes smile from behind her cloth mask. “You want my attention, Origami? She’s just jealous that I’m not looking at her,” she says.
Grannis makes jewelry out of dice. Bracelets out of iridescent plastic six-sided dice, earrings out of twenty-sided dice, and cufflinks out of dice of all shapes and sizes. She sells them at gaming conventions like PAX and online. She works from home so she can control her immune system. She has severe respiratory allergies and a paralytic autoimmune disorder called Guillian-Barre syndrome. “I can’t get certain vaccinations because I might be paralyzed,” Grannis had explained earlier over coffee.
When she was 19, she worked at McDonald’s as a manager. One day she started feeling hot, with an itchy throat. She felt bad enough to head home, which was unusual for her. On the way home, her legs went numb, and when she arrived, her hands were numb. Her parents told her to sleep it off, but she convinced her father to drive her to the hospital. Partially paralyzed, she did not come home for nine days.
“It took mono, strep, and Guillian-Barre to take me down,” she said. “Every time I get pins and needles I’m afraid it’s coming back. I still don’t have 100% of my leg strength. I’m like 80% of what I was.”
The co-infection triggered a rare autoimmune response. Her overwhelmed immune system began attacking nerves and the Schwann cells that insulate and protect them. The nerves, damaged by inflammation, weakened. Muscle weakness, tingling sensations and, in Grannis’ case, paralysis and respiratory failure followed.
The underlying cause of Guillain-Barre is a mystery to researchers. It appears sporadically in the population, rarely runs in families, and mimics other neuroinflammatory disorders like vascular neuropathy. One Iranian study linked Guillian-Barre to multiple sclerosis, which is itself linked to allergies and psoriasis. But there isn’t much research available.
Grannis told me that past doctors didn’t believe her diagnosis.
When I told Grannis that her experiences were shockingly common for people with rare diseases, she shrugged. I was once an immunologist, so I asked her if anybody had told her that autoimmune disorders and allergies are often linked. “No,” she said, “That’s news to me.”
Grannis is not alone. Her experience is common for people with rare diseases. Diagnosis, medical expertise, receiving treatment, and being believed are not givens; they are hurdles in the way of receiving care.
Rare diseases are at a junction where the healthcare system, our scientific understanding, and our capacity for compassion are tested until they break. The realm of rare disease is tangled and thorny. It’s ethically challenging, though most involved professionals are in it for the right reasons. This confusing landscape begins with definitions. Rareness is a legal definition, not an epidemiological one, that varies across geographies. In the United States, a rare disease is one that affects fewer than 7.5:10,000; in Japan, fewer than 4:10,000; and in the European Union, fewer than 5:10,000. The EU also limits rare diseases to conditions that are chronic, debilitating, and life-threatening. The U.S., with the Orphan Drug Act, frames rareness as a question of prevalence and access to pharmaceuticals. In other words, the EU frames rareness as a challenge to patients and the healthcare system, while the U.S. frames it as a question of consumer-access.
Meanwhile, patients and advocacy groups define rareness as a lived experience.
Nobody knows how many rare diseases there are, but public health agencies estimate that between 5,000-7,000 rare diseases exist. Rare diseases, in aggregate, affect an estimated 6-10% of the world’s population. Advocacy groups like the National Organization for Rare Disorders and Global Genes estimate that 25 million Americans have rare diseases.
Rare diseases are difficult to diagnose. Clinical presentations vary wildly from disease to disease and from patient to patient. Many rare diseases are genetic in origin and “variably penetrant,” which means that they don’t act the same in every patients. Take neurofibromatosis, a rare disease afflicting 1 in 3,000 people that causes tumor growth in cells that protect the nervous system. Phenotypes range from individual tumors, to facial growths, to systemic tumors that cause degenerative deafness, pain, and mobility issues. Often, neurofibromatosis patients display no outward physical characteristics of having a degenerative disorder.
In other cases, the disease may be so rare that it hasn’t been characterized. The rarest known disease, Ribose-5-phosphate isomerase deficiency, has been diagnosed only once in the 27 years since its discovery. In cases like this, geneticists and other diagnostic specialists are needed but in short supply.
Patients can go for years without answers.
The Manton Center is a tiny core within the sprawling Boston Children’s Hospital where families and patients from all over the world come for diagnosis. Researchers at the center try to find patterns, identify disease genes, and build cohorts of similar cases. The work is tedious. Some diagnoses can take years and involve everything from whole exome sequencing to identifying spelling errors in the entire genome, to building transgenic mice to see if specific mutations create disease phenotypes in lab animals.
“By the time they come to us they have exhausted all other options,” said Dr. Pankaj Agrawal, the Medical Officer of the Manton Center for Orphan Diseases. “We are trying to bridge the gap that exists where, clinically, all other options are exhausted.”
Few diagnostic centers address these diseases the way Manton Center does. The Broad Institute’s Mendelian Genetics Program runs patient samples through a growing database of genes, looking for new disease genes. Patients receive swab kits in the mail and give their consent to be used in the study through video calls. The samples run through a battery of tests. But even the best test, exome sequencing, diagnoses only 30% of patients. All patient data is stored in an anonymized database and shared with research partners. As more data is added and more disease genes are discovered, some undiagnosed patients get diagnoses.
“We’re finding hundreds of disease genes a year,” said Dr. Laura O’Donnell, Associate Director of the Mendelian Genetics program, “A big chunk are something we sequenced but didn’t know caused disease.”
For researchers identifying a disease gene brings new insights. When a mutant gene causes disease it often reveals something about the function of that gene. In the case of rare diseases, it reveals functions in places that haven’t been studied or haven’t been thought to have functionality at all. Some rare diseases provide insights into more common ones too. Rare tumor-forming or rare oncogenic mutations, for example, can open doors for more common cancers. The diseases are rare, but the implications are huge.
“Each child opens a window to an entirely new world,” Said Dr. Argawal. “Each child is a new field of science.”
Patients and their families want diagnosis to get a sense of prognosis and treatment. Parents want to know if they can safely have other children.
My younger sister, Celia, has a rare disease. She’s been in medical journals. When she visits the hospital, we have to fend off curious medical students who have never seen a patient like her. Her medical experience is far outside of standard medical care. It’s experimental. Iterative. Confusing.
Celia is fourteen. She’s bright and empathic. She’s a fish in the water. She’s obsessed with painting landscapes. Taking after her mother, she’s an Original Generation Trekkie. During a recent visit home, I was roped into building a scale model of the Enterprise with her. We boldly went into a land of poorly written instructions and fiddly plastic bits. After several confusing hours The Enterprise came out fine, but the Botany Bay was abandoned due to missing parts.
That same weekend, Celia had a speaking part in a play, a youth production called The Bakerstreet Irregulars. A whodunit in Sherlock Holmes’s London with an all-child cast. She played a whip-wielding animal tamer in an orphan-staffed circus, delivering her lines with a kind of laconic sarcasm that I swear she stole from our brother Anthony.
The play almost didn’t happen because Celia was in an experimental drug trial. It’s essentially a chemotherapy trial. The side effects are debilitating nausea and fatigue. My mother put her foot down. “I told them that if they scheduled an infusion this week that we weren’t coming in.” She told me over speakerphone in the car, “The play is too important. Celia needs to do this.”
I can’t understate the role my sister’s disorder has played in her life. She’s had dozens of surgeries. She understands hospitals in a way no fourteen year old should. She’s hard of hearing, has mobility issues, and chronic pain.
My family has exhausted what doctors call Standard of Care. Nobody is sure what’s left to do after this drug trial comes to an end. On the phone and in person, Mom relays the doctors’ uncertainty.
We just don’t know what’s coming. But I don’t want to overstate her disorder either. Celia is not a walking etiology. She’s a person no matter what happens.
I recently attended the invitation-only MassBio Rare Disease Day in Boston. I wasn’t invited though. When they found out I was writing a story on rare diseases, they were happy to admit me. It took place on February 28. The attendees, a mixture of patients, parents, doctors, researchers and biopharma types, mingled thirty-two stories up, sipping coffee, and nibbling on continental breakfasts.
“Alone we are rare, together we are strong. Come on people, say it with me,” said an organizer leading the room in a chant.
The atmosphere was somewhere between that of a research conference and a networking event with some exceptions. A boy, maybe 7, ran around in an over-large tee shirt with the words: “I’ve stumped 100 doctors. What’s your super power?” in big block letters. His father leaned to me conspiratorially and complained about Big Pharma hoarding genetic databases to make money off them. Paintings and portraits of children with rare diseases smiled at the chattering crowd.
There was tension in the air during the morning Shortening the Diagnostic Odyssey panel. Parents and patients stood at the edges of the seated attendees. The panelists talked about the arduous diagnostic process. Not enough funding. Health insurance companies deny and obstruct genetic testing, which can cost thousands of dollars. Patients are isolated. Parents said that pediatricians, used to ear infections and tummy aches, ignore their concerns.
I think back to my own family’s pediatrician, Dr. Ruppel. He had been my doctor and my brother’s doctor, since we were toddlers. He was the kind of pediatrician who wasn’t afraid to laugh or joke with his patients. When Celia entered the picture and the magnitude of her symptoms became clear, my family’s relationship with Dr. Ruppel changed. During routine checkups I’d see a sad helplessness in his eyes and frustration in my mother’s. Like lots of well-meaning pediatricians he was simply out of his depth. Like a lot of parents, my mother was frustrated and angry. Neither was prepared to do battle with medical uncertainty, the bleeding edge of science, and the insurance industry. Nobody gets trained for that.
“What I’m taking from all of this,” one mother shouted from the back of the crowd, “is that we have to trust ourselves. Trust our instincts. Something is wrong with our kids.”
The tense atmosphere in the room changed when Jen Melenson took the podium. She eloquently and succinctly described her battle with rare disease and the fear she felt when she and her son were diagnosed with the same disorder. She choked up when she talked about her experience with the National Institutes of Health, how a researcher-physician gave her control of her life back. The crowd couldn’t contain themselves. Melenson was cheered with a standing ovation, surrounded by an eager crowd.
Most of the research that’s done on rare diseases is government-funded. But government funding is tenuous. In the past 30 years, the National Institutes of Health, the government body that gives the grants to conduct medical research, has seen a 22% budget loss due to cuts, sequestration, and failure to keep up with inflation. When Trump came into office he threatened 20-30% cuts to the NIH overall but this year walked that back to stagnant, pre-sequestration funding.
Private research grants aren’t much better in terms of money. Even though the NIH has experienced setbacks, its $26.9 billion dollar budget dwarfs both philanthropic and individual giving. The Science Philanthropy Alliance estimates that 4 billion was given to scientific research. Most of that goes to diseases like cancer or heart disease. Rare diseases are a hard sell.
“Diseases like cancer opens all doors. But with rare diseases you need something, a celebrity or viral video to break through to the public conscious. Until then research funding is largely dependent on networks of friends and family, NGOs and lobbying.”
“You shouldn’t have to be a member of the sexy disease club,” said retired rare disease advocate John Hieropolis. He described what he called “The celebrity problem.” Diseases like cancer open all doors. But with rare diseases you need something, a celebrity or viral video to break through to the public conscious. Until then research funding is largely dependent on networks of friends and family, NGOs, and lobbying.
Hieropolis has a working-class Boston accent and was a Greek Orthodox priest for 20 years before leaving the church. “My job was to prick the conscious of a cold and fractured world,” he explained. When he left the church he ended up working as a patient advocate in the Children’s Tumor Foundation. The Foundation was set up primarily as a research organization, granting startup money to early-career researchers for treatments and cures.
That’s the model of many rare disease advocacy organizations. Small staffs, cure-focused research initiatives funded by cure-focused donors. With minimal funding it’s hard to expand much beyond that.
“We have a staff of three.” explained June Kinoshita of the Facioscapulohumeral Muscular Dystrophy (FSHD) Society. “We just don’t have the bandwidth to take on every project.”
People with FSHD experience degenerative loss of skeletal muscle strength. Some patients essentially become quadriplegic. Others are milder, experiencing weakness and mobility issues. All are at risk of respiratory failure due to muscle weakness. Kinoshita told me that the foundation was very sensitive to the concerns of its constituents, not all of whom were interested in a cure. The most serious patients were interested in quality of life. Because FSHD is genetic, “They hear the word cure and they think ‘you’re trying to get rid of people like me,’” Kinoshita explained.
“The holy grail of the milder cases is cure.” She said, “I think we can serve both.” Kinoshita stressed that to advocate for her constituents meant expanding beyond cures. The mission is ultimately to advocate for healthier lives for everyone. That can mean everything from taking a pill to symptom management to social support. “Many people suffer because they’re isolated. Patients have a huge amount of knowledge about how to hack their way around disability.”
Hacking disability was a big part of Melenson’s experience. Melenson’s story is complex and spans more than a decade, but I’ll summarize it here. After surgery for an inflamed thyroid, Melenson lost function in her parathyroid glands, which were near the surgical site. The parathyroids manage levels of calcium, which is essential for nerve function. Melenson’s calcium levels were crashing and her nerves spasming. She was a nurse’s aide at a local ER, so she reached out to coworkers for advice. Slowly, she learned to read her tremors, spasms, and fatigue and to control them with calcium supplements. Melenson also developed an aggressive rheumatoid arthritis. All while concealing her illness from her children and working 60 hours a week to keep her health insurance.
“It almost killed me. I was in heart failure. I was constantly trying to find the right balance of meds.”
Later her teenage son developed strange lumps along his lymph nodes and what appeared to be an extreme form of colitis. After almost a year of testing he was diagnosed with a rare genetic disorder, CTLA4 haploinsufficiency. The disorder was only discovered in 2014. Melenson also had the disease. It probably caused the initial thyroid problems. She suspects her father, who died of lymphoma, had it too.
“I never understood noncompliant patients until now,” she said. Melenson used to get annoyed when she saw patients come in who were ignoring doctor’s orders. “Now I’m more sympathetic. Sometimes you just get tired of it and don’t want to deal with it anymore.”
My own family has certainly experienced their share of disease fatigue, but we’ve also experienced something I call “cure fatigue.” There’s an expectation that we can fix these diseases. That all these problems can go away. But when a rare disease is degenerative or causes disability, “cure” seems hollow. Cure-focused advocacy ignores that many people with rare diseases are people with disabilities and needs.
“The fact of the matter is that even if you develop a treatment that recovers function, it’s not going to be 100%. It might be 10%.” said Dr. Mahadeo Sukhai, former Head of Research and Chief Accessibility Officer of the Canadian National Institute for the Blind. “But we don’t accept that. We don’t accept loss of function.”
My interview with Dr. Sukhai, coincidentally, took place the day that Dr. Steven Hawking passed away at age 78, far past the life expectancy of someone with Hawking’s rare muscular dystrophy. To Dr. Sukhai, Hawking represents the best possible scenario for someone with a rare disorder. Hawking had excellent medical care. He was supported and kept within the community. All of those things are incredibly rare for people with rare diseases.
“Our medical system, even Canada’s public healthcare, is governed by a triage model,” Dr. Sukhai said. While effective at treating acute illnesses or injuries with rapid interventions, the triage model poorly serves chronic illnesses. Chronic or rare diseases are never as important to that kind of medical system because acute emergencies push those conditions to the end of the line. Chronic conditions don’t respond well to short-term interventions; they need managed, “wellness” focused care.
Care like this is expensive and often experimental. It’s iterative and academic. Often it blurs the line between researcher and physician. When your doctor is also a researcher it can be hard to distinguish between which procedures keep you healthy and which investigate the disease. It’s a balancing act that is extraordinarily difficult and requires teams of clinicians, support workers, and the support of a research institution. It’s another reason why rare disease patients find themselves attached to urban biomedical research hubs. Like Boston.
Outside of places like Boston support is much harder to come by. Rare disease patients and people with disabilities often find themselves warehoused in nursing homes where they have no autonomy. Some disability rights groups, like ADAPT, are pushing back.
ADAPT captured the national spotlight during the 2017 Medicaid cut protests when they took over Senator Mitch McConnell’s office. Their members were taken out of their wheelchairs and carried away in handcuffs. Now they’re pushing for The Disability Integration Act. The Act would unify existing services for disabled people, and force insurance companies to cover long-term care outside of nursing homes. Rhoda Gibson, a spokesperson for the Massachusetts ADAPT chapter said, “This act will cover you from birth to death, no matter what disability you have, rare disease or no.”
Waltham was cold that day. Rain threatened to break. I was talking to June Kinoshita in a local haunt, The Cafe on the Commons. A round, faux-granite Formica table wobbled unsteadily between us, but not so unsteadily as to spill our coffee. The space echoed, like it was designed with noise-dampening racks of clothes or store shelves in mind. Kinoshita was pensive, her dark eyes looked down. Her fingers played with each other. We’d been talking for about an hour. My coffee had cooled. She looked up suddenly. A man was wandering unsteadily through the café. A barista on a cordless landline followed, peppering him with questions, trying to keep his attention.
He was having a heart attack.
I offered my chair for him to sit. Kinoshita retrieved a bag the man could not seem to find in his disorientation, placing it gently in his hands. He babbled. I heard the barista ask, “You’re sending an ambulance?” as if she’s searching for an excuse to feel some relief. June and I got out of the way.
The ambulance came. The man was taken off in a stretcher. We continued our interview.
Chance is capricious. Health is vulnerable. We are all, forever, at risk of something going wrong. Unlike a heart attack, rare disease can’t be fixed by a rapid intervention, can’t be identified by a panicked stranger on the phone with a dispatcher. Rare disease is having a heart attack spread out over months and years where you often don’t know what’s going on. While you and your doctor try to figure it out, you run the risk of disability or death. It’s a slow emergency but an emergency nonetheless.