Andra LimOn a winter evening in 1997, two dozen members of Los Angeles' Persian-Jewish community gathered in a spacious house in Woodland Hills.
The home belonged to Houshang and Shokouh Darvish, Persian Jews who had fled Iran for Southern California in the wake of the revolution. And by that night, everyone knew that the couple's two sons — Daniel, 30, and Bobby, 28 — had a long struggle ahead of them.
Both recent graduates of medical school, the brothers looked just fine. A discerning eye might have seen a slight strain in their steps, no more.
But their lives were slowly beginning to change. Bobby Darvish could no longer line up his fingers to play chords on his guitar. Daniel Darvish found it difficult to run up and down stairs.
And so that night, the Darvishes' friends sat in the living room and listened attentively to a presentation by the brothers. The young physicians explained that their symptoms had led them to self-diagnose a disease they called a “peculiar muscular disorder.” At the time, the disease was nameless — so rare that the Darvishes could find only two medical reports that mentioned it.
But they did know the disorder likely would leave them both in wheelchairs in around 10 years — unable to walk or lift their arms for extended periods of time, their fingers naturally curling inward. They also knew the condition disproportionately affected Persian Jews.
“What's the chance of two physician brothers being affected by the same disorder?” Bobby says. “It's almost like we were being called upon to do something.”
They needed money to start an organization, to fund research, Shokouh Darvish told the room. She pulled out her checkbook and wrote a check for $1,000. Others followed suit, and by the time the five-hour meeting ended around midnight, they had raised $18,000.
The Darvishes donated the money to a small laboratory that was researching the disorder. But that was only the beginning. They continued fundraising, and their nonprofit Advancement of Research for Myopathies was formally incorporated in 2000. Within five years, they would open a lab of their own, which is almost entirely funded by donations channeled through the nonprofit.
Finding a cure for the disease they eventually identified as hereditary inclusion body myopathy, or HIBM, would consume the whole family. Shokouh Darvish quit her job as a preschool teacher to become a spokesperson for their nonprofit organization. The brothers' wives devoted themselves to fundraising. And their father, until he died several months ago, labored to make more money, hoping he could give a sum to his children to help the cause.
But no one has been more committed than Bobby and Daniel Darvish, now ages 43 and 45. Both began using wheelchairs about six years ago. And both are working frantically for a cure while they are still able — even as they know it's probably too late for them.
“The reality is that people in wheelchairs have a shorter lifespan,” Daniel says. “It's entirely possible that 10 years from now, neither of us will be here.”
From the time Bobby Darvish was born in Shiraz, Iran, about two years after Daniel, the brothers always had each other. Their family left Iran during the revolution — their father, Houshang, a successful businessman with a family estate worth around $35 million, was suspected of being sympathetic to the shah. They bounced around Europe with the intention of heading to America.
But their mother couldn't get a U.S. visa and was sent back to Iran. Their father returned for her, and the brothers ended up in New York, living with a family they had never met before.
“We were each other's parents,” Bobby says. “If he had a toothache, I stayed up at night to nurse him.”
In 1981, the family reunited and moved to Southern California with virtually no money. Daniel, and then Bobby, attended Pierce College in Woodland Hills.
Bobby took a class with a physics professor who had taught his brother.
“He recognized my name and said, 'Do you know Daniel? He's the best student I've had in 20 years, and I expect the same thing from you,' ” Bobby says.
When Bobby earned an F on the first test, he could read the disappointment etched on the professor's face. He pulled a 100 on the next test. The class set Bobby on the path to medical school — the same path as his big brother. (Daniel went to George Washington University School of Medicine; Bobby went to Ohio State University College of Medicine.)
These days, Bobby works at the Veterans Administration in West Los Angeles, teaching other doctors and fitting veterans with medical equipment, such as wheelchairs and stair lifts. He likes the VA, even though it pays about a fifth what he could earn in the private sector. Working for the government is less demanding, which gives him more time for HIBM work.
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Talk comes naturally to Bobby, who liberally peppers his speech with humor, frankness and a cuss word or two. When he earnestly compares his youthful self to George Clooney and says he was popular with the ladies, it's not a stretch to believe him. He labels himself the “person at the podium” — the one who convinces the audience to pull out their checkbooks and make a donation.
Or, to use an anatomical analogy, Bobby Darvish calls himself the “heart” of their organization. Daniel, he says, is the “brains.”
Daniel leads research at the lab. In order to funnel donations to the lab's work, Daniel takes no salary. He lives off disability payments and his wife's small salary, which she earns as the lab's administrator.
More reserved than his younger brother, Daniel speaks insistently, trying to clearly explain the work he is determined to see through to the end.
“For me, it has still not reconciled. I'm very dissatisfied [with my condition],” Daniel says. “I think dissatisfaction is a good thing. It's what drives me every day.”
They both first noticed their physical strength was diminishing when Bobby was still in medical school. (Daniel had just finished.) Shokouh Darvish, now 62, recalls noticing that her sons weren't as happy when they called home. She chalked it up to the stress of their work.
Then, when Bobby came home for Christmas, she asked him to wring the water out of a sweater she'd just washed.
“I can't do that,” Bobby was forced to admit.
Daniel's weakness also was becoming visible. He fell often and ripped his pants, typically at the knees, he says.
No doctor could tell the brothers what was wrong, and they ended up diagnosing themselves after about a year of searching for answers. Bobby inspected his own muscle biopsy under a microscope, and they both pored over medical literature. When they found vague references to HIBM in a few reports, they realized the descriptions perfectly aligned with their symptoms.
In the early 2000s, there were only a few, scattered researchers who studied HIBM — and none made it their first priority, Bobby says. Initially, the Darvishes sent these researchers checks from their fundraising efforts and hoped for the best.
At the time, HIBM research centered on finding the mutated gene that caused the disorder. Once that was discovered, scientists could develop a treatment that targeted the abnormalities in the gene.
But progress came slowly. The various labs studying the disorder did not share information with each other. Instead, they tried to beat each other to the punch, Bobby says. After all, scientists who find a new gene can patent it, and then receive royalties from researchers who perform tests with the gene.
“It was fairly discouraging, to the point where finally we just got fed up and said, 'Let's set up our own lab,' ” Bobby says.
Daniel had specialized in internal medicine in school, and for a few years after completing his residency, he worked in nonsurgical cosmetics — hair removal and laser vein treatment — as well as in other areas, earning about $500,000 annually. It took him about four years of training himself and reading the literature on muscles to get fully up to speed.
“Money was not as important as [HIBM research], so I focused on research,” Daniel says. “In retrospect, I don't know if I made the right decision. If you make more money, you can do more. But if I had chosen that other path, I don't know that our research would be where it is today.”
Daniel began his own work on uncovering the gene, and he shared his findings with the other researchers — an unorthodox move. Other scientists responded by speeding up their own efforts, and in 2001, an Israeli lab found the gene.
“Everything was sparked when the gene was found,” says Dr. Marjan Huizing, a scientist at the National Genome Research Institute in Bethesda, Md.
In an ironic twist, the mutated gene that caused HIBM was one that had already been described, meaning it was not patentable or profitable. The researchers who had hoarded their work, it turned out, had been selfish for no reason.
The mutation causes a deficiency of sialic acid — a sugar that helps muscles accept proteins, says Dr. Yadira Valles-Ayoub, director of research and development at the Darvishes' lab. Without enough sialic acid, muscles grow steadily weaker.
“Your DNA of that gene has 2,000 bases. One of them is semi-broken,” Valles-Ayoub says. “There are mutations where a bunch of bases are broken, a bunch of bases are missing. In [the Darvishes'] case, it's one single mutation.”
Daniel remembers the first time he saw his brother in a wheelchair.
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“It was a reminder that I needed to get things done faster,” Daniel says in a low, slow voice. The moment, he says, was “heartbreaking.” “Knowing that I had this disease wasn't as hard as knowing Bobby had this disease.”
Bobby says it's been harder on his brother.
“I accepted [the disease] very early. I went through the stages of loss very fast. I found new ways to enjoy things,” he says.
Not so his brother: “Danny is a fighter. He's never really truly accepted it.”
Before his HIBM progressed, Bobby Darvish had a picture-perfect life. He had finished medical school and had married an “exotic brunette with shiny hair and multicolor eyes.” They threw lots of parties in their Sherman Oaks apartment — she was a fabulous hostess and cook.
When they first married, Bobby was still capable of most physical functions, though his wife had to help him put on his socks. But as the effects of HIBM worsened, it strained their sex life and caused deep fault lines in their relationship. They divorced in 2002. By that time, Bobby was limping and had started using a cane.
Bobby believes his first marriage gave him a glimpse of what his life would have been like without illness.
“If I didn't have HIBM, that probably would have continued — the doctor, the trophy wife, the nice house, the nice car. But there wasn't a real foundation or a soul mate kind of thing. I got to see that,” he says. “But it's hard to do what-ifs.”
Bobby tends to describe life in terms of a storybook — with interesting “twists” and central “themes.” He sees the hand of fate in how his life has unfolded.
“Even though I'm a scientist through and through, there's something,” he says. “And that something's watching over us. That something is rooting for us.”
Around the time he divorced, Bobby went to a conference in Vancouver to talk about the HIBM research lab. One day he took a tour, and ended up falling in love with his guide. When he returned to L.A., he told his friends he'd met the girl he was going to marry and have kids with.
Later, Bobby and Sandra eloped to Kauai, with the wedding ceremony on the beach at sunset. Sandra Darvish was approaching 40 when they started trying to have children via artificial insemination. About four years ago, she gave birth to their son, Niels.
Sandra devotes her days to taking care of her family, in addition to helping the Darvishes with fundraising and outreach efforts — she plans parties, helps out with a newsletter and answers patients' questions about HIBM online.
“I love [Bobby], I want to be with him, and I don't want him to go through it by himself,” Sandra says. “That was just not an option for me.”
Daniel's love story also was shaped by HIBM. He initially hired the woman who was to become his wife, Sheila, as a lab administrator, and she moved to the U.S. from the Philippines for the job. She needed a place to stay and ended up living with Daniel and his mother, acting as a part-time caretaker for him and sleeping on a mattress in the living room.
While waiting for her visa to be processed, Daniel proposed to Sheila several times so that she could visit the Philippines and return to the United States. She turned him down each time, believing that the only reason to marry is for love. But eventually, feelings developed.
“We were really getting close — not kissing, but holding hands,” Sheila says. Both she and Daniel are old-fashioned and committed to their religious beliefs, she says.
Finally, the last time he proposed, about eight months after they first met, she said yes. Their son, E.J., is now 2½ years old. He was an accident — Sheila didn't want kids, thinking that it would be too much given her husband's condition. But once she became pregnant, she changed her mind.
Both wives say that looking after their husbands and sons can be exhausting. Each night, they wake up three or four times to roll their husbands over in bed, as the brothers are unable to turn over themselves.
Start to finish, research and development for a new medicine takes around eight years and typically costs between $4 billion and $11 billion, according to an estimate from the InnoThink Center for Research in Biomedical Innovation. The Darvish lab has subsisted off a mere $4 million over 10 years, sometimes delaying the next step in its research because funds are lacking.
The lab is housed in Reseda, in a strip mall that contains more than a dozen other companies, including a nail salon. There are four rooms — the main one is filled with equipment, most of it hand-me-downs.
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“We count every single penny,” Valles-Ayoub says.
The lab runs almost entirely on funds from its nonprofit fundraising arm, supplemented by small grants from the government and other groups, says Valles-Ayoub. Its only researchers are the Darvish brothers; seven undergraduate interns, who are all aspiring medical students; and Valles-Ayoub. Her salary is $4,000 a month — a pittance for someone with both an M.D. and a Ph.D.
“It's all about the money,” Bobby says. “If I had it, I wouldn't have to deal with other politics, the pharmaceutical industry and so on.”
The problem is that HIBM only affects about one in a million people worldwide. Given the small market size, along with the high costs of bringing a new drug to market, pharmaceutical companies historically have not seen a way to profit from developing treatments for rare diseases — even though cumulatively, rare diseases affect approximately 30 million people in the United States.
Such disorders are difficult even to diagnose. For one-third of patients with a rare disease, it takes five years or more to obtain an accurate diagnosis, says Mary Dunkle, a spokeswoman for the National Organization for Rare Disorders (NORD).
After that, treatment is frequently nonexistent. Of the 7,000 or so known rare diseases, medications are available for fewer than 300.
The small number of people affected by each rare disease can be a major obstacle, says Ian Phillips, who directs the Center for Rare Disease Therapies at the Keck Graduate Institute in Claremont. It may be difficult to gather enough patients to test drugs on, he says.
This issue is particularly acute for HIBM because the Persian-Jewish community looks down on the disorder, discouraging those with the condition from telling others about it. If a family member has HIBM, then those related by blood are carriers of the disease as well — the Darvish brothers' parents were first cousins, and both carriers. People do not want to be linked with carriers of the disorder, for fear of having children with HIBM. The simple fact that the disorder runs in a family can break up engagements or marriages, Bobby says.
For years, the Darvishes' science has informed worldwide efforts to study HIBM. After the gene was isolated, Daniel created a faster and more accurate way to test DNA to see whether a person has HIBM. Hospitals from all over the world send in blood samples for examination, Valles-Ayoub says. Meanwhile, Bobby built an animal model that their lab and other researchers have used to test treatments.
Against all odds, the brothers are close to developing a treatment for HIBM. The Darvishes' lab is almost ready to begin testing gene therapy on a handful of patients, pending approval by the Food and Drug Administration. (The lab recently finished tests of the treatment on animals, mandated by the FDA.) The trial will cost upwards of $100,000 per person, Daniel says.
The idea behind the gene therapy is simple: A patient undergoes therapy once or a few times, the broken gene gets repaired, and the patient never has to be treated again.
The brothers' lab also has played a part in helping others develop drugs that HIBM patients could take on a regular basis, for the rest of their lives. (Though these medications might stop or slow down the disorder for those in the early stages, they will do practically nothing for the Darvishes.)
A government lab is creating one drug, and a startup biotech company, Ultra-genyx, is building the other. The field of companies interested in developing rare-disease drugs has expanded in recent years.
“The stars are just kind of aligning right now,” NORD's Dunkle says.
Pharmaceutical companies are beginning to realize that placing their money on rare-disease medicines is a smart bet, says Emil Kakkis, the CEO of Ultra- genyx. Whereas such companies typically perform all the research behind a new drug, the science is already there for rare-disease drugs: Researchers like the Darvishes have done the homework. In those cases, a nonprofit lab like the Darvishes' or a university lab typically will build the treatment, then hand it off to a drug maker on a silver platter, says Wayne Grody, a professor who directs the Diagnostic Molecular Pathology Laboratory at UCLA's David Geffen School of Medicine.
The companies know that those affected by the disease will purchase their drug; the patients have no other options. And a 1983 law gives seven years of market exclusivity for companies that produce drugs for rare diseases, ruling out any competition. By charging insurance companies high prices for the drugs — sometimes hundreds of thousands of dollars — pharmaceutical and biotech companies can be sure they'll reap a profit.
“It's sort of virgin territory, because it hasn't been explored,” Grody says of developing rare-disease drugs. The science is at a tipping point; in coming years, he says, there will be more and more rare-disease medications on the market.
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This realignment is meaningful for the Darvishes — and also for the Los Angeles area. Locally, there is a hub of activity, with companies, private labs and universities all focusing on rare diseases, says Nicole Boice, founder and CEO of the RARE Project, which is based in Orange County.
Grody attributes all this activity to Los Angeles' diversity. Each ethnic group has rare diseases that particularly affect it — for example, one in 10 Persian Jews is a carrier of the HIBM gene, Grody says, and the muscular disorder is also found in other Middle Eastern and Asian cultural groups. The number of relatively insular ethnic groups in Los Angeles means that patients with a variety of rare diseases can be found here, he says.
Local neuromuscular specialists now know what HIBM is, Bobby says, which is a far cry from when no one could diagnose him or his brother. And for the handful of younger HIBM patients in the area, Bobby is hopeful that the disorder will not be a life-changing problem. By the time their HIBM would have them using a wheelchair, he's certain there will be a treatment or a cure.
But they're not there yet. Because the Darvishes were unable to gather enough funds for a set of drug tests, their timeline has been pushed back by two to three years. Daniel now estimates the therapy will be entirely finished in five to 15 years.
That's too late for the brothers.
“Is Daniel working for his own treatment?” Valles-Ayoub asks. “No. He's in a wheelchair already. He's working for people who can still be cured. … You can repair the gene, but how can you repair the muscle fiber?”
It's Wednesday night, and the Darvish brothers, their families and their mother have gathered at Daniel's condo in Sherman Oaks. Bobby lives in the condo next door.
Shokouh Darvish, who typically makes dinner for the whole family four times each week, has done the cooking tonight.
“You should come on Friday,” Bobby says of the spread on the table, covered with his mother's dishes. “This is nothing.”
Among Shokouh's preparations are gondi — a dish of turkey or chicken with chickpeas — and a stew of chicken and potatoes. She stands next to Bobby, feeding him mouthfuls of food.
Later, sitting on the couch, she speaks just above a whisper, describing a poem she wrote in Persian about her sons, at the time they started the nonprofit. There is a Persian metaphor where candles, a butterfly, a bird and flowers signify completion. In the poem, she compares candles to her sons, burning with fight and determination. She is the butterfly, flitting around them, and HIBM advocates are the birds. The flowers, she says, represent the people who have donated to the nonprofit.
Everything is in place, she says, for a cure.
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