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In 2007, at her high school graduation in Quesnel, British Columbia, Ivana Topic stood at the top of the auditorium stairs, her long gown skimming the floor, her dark brown hair spilling over her shoulders. She had on ridiculously high heels. As she eased down the stairs, very slowly, she hung on to her date. She was afraid her knees would collapse, as her muscles were too weak for her age.

From the audience, Ivana’s mother Marijana watched her daughter’s every step, silently panicking and breaking into a sweat. She knew Ivana could easily tumble down the stairs and break a limb. The year before, Ivana had been diagnosed with muscular dystrophy, an incurable genetic disease characterized by progressive weakening of the muscles. Antonia, Ivana’s younger sister by five years, was later diagnosed with the same disease.

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Around the time of Ivana’s graduation, the Topics, an unassuming family originally from Croatia, had begun adjusting their lives as best they could, inquiring about ramps everywhere they went, avoiding walking in snow and sleet. For years, Ivana and Antonia had been subjected to endless medical tests. In 2010, they learned they had a rare form of muscular dystrophy, calpainopathy, which affects about 1 in 200,000 people. The diagnosis meant both would likely be bound to wheelchairs while they were still young women.

Today, Ivana is 24. In May, she graduated from college with a bachelor’s degree in finance and general business. She still walks up stairs in her house; her bedroom is upstairs. “I’m definitely a fighter, and will try and walk for as long as I can,” she says. “When I notice I’m falling a lot, when I need help a lot, I will go in a chair.”

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Muscular dystrophy is subject to only palliative medications and therapies. Ivana herself practices yoga. While researchers worldwide are working on lasting cures for muscular dystrophy (funded in part by the famous Jerry Lewis Telethons), rare forms like calpainopathy are “orphans,” with only a fraction of researchers and funds devoted to them. With quiet stoicism, the Topics have accepted that modern medicine may not have a solution for their daughters’ disease. Still, says Marijana Topic, “Without hope, there’s no life.”

“I’m definitely a fighter, and will try and walk for as long as I can. When I notice I’m falling a lot, when I need help a lot, I will go in a chair.”

Following a current grassroots trend in medicine, many individuals with orphan diseases do not wait for the medical industry to care about them. Facing unlikely odds, they are forced to raise money to find a potential cure themselves. But the Topics live by modest means—Marijana runs a daycare center and her husband and the childrens’ father Niko works for a lumber company—and are in no position to mount a quest.

But then there’s Michele Wrubel, 49, a stay-at-home parent from Connecticut who has calpainopathy. For years, Wrubel has been a passionate crusader for a cure. Affluent and well connected, she doesn’t varnish the truth about what it has taken to make the medical industry pay attention to her. “To make a difference in this disease, you need money and meetings,” she says. “Researchers are not going to study a disease unless there’s money behind it to fund the research.” For the Topics, Wrubel may be their best hope. 

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The Global Genes Project, an advocacy group, estimates 350 million people suffer from orphan diseases worldwide. Most rare diseases are genetic and tend to appear early in life. About 30 percent of children who have them die before reaching their fifth birthday. The rest battle their conditions throughout life, as most orphan diseases have no cure. Out of the 7,000 orphan diseases identified to date, with about 250 new ones added annually, less than 400 can be treated therapeutically. 

This year the European Commission gave 144 million euros to develop 200 new therapies and the National Institute of Health allocated $3.5 billion dollars to research. Yet some diseases are so rare that they remain stepchildren even among orphans. As a result, they receive little research attention and funding. Neither do they fit the list of billable insurance procedures. There’s no standard healthcare path to diagnosis, let alone treatment. Similarly to the Topics, many patients go through the disheartening ordeal, which Marijana describes as “a blur,” only to find out that medicine can’t help them.

Orphan disease organizations, such as the National Organization for Rare Disorders and Rare Disease Foundation, encourage patients to take matters into their own hands. “Families have to advocate,” says Isabel Jordan, chair of the Rare Disease Foundation. She encourages patients to form organizations, find new methods of funding, and push for research.

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“Push for research” could be Michele Wrubel’s calling card. She was diagnosed with muscular dystrophy in her mid-20s. But even though calpainopathy was identified nearly 20 years ago—about the same time Wrubel got her initial diagnosis—it took almost the entire second half of her life to determine that she was afflicted with calpainopathy. There were no clinical procedures that would lead to an answer.

“It took a really long time and a very concerted effort,” says Wrubel, who walks with canes, submitting to a wheelchair for long trips or when in crowded places. “If you don’t know what you’re looking for, they don’t know what to tell you or how to help you,” she says.

In 2008, gene sequencing had come of age, which aided physicians in diagnosing muscular dystrophy subtypes. That year, Wrubel’s husband, Lee, who holds a medical degree and a master’s in public health from Tufts, an MBA from Columbia University, and is a venture capitalist in the medical field, tracked down a neurologist who sequenced his wife’s genome. He paid several thousand dollars from his own pocket to learn his wife had calpainopathy.

The Topics had no such luxury. But they did have luck. Cornelius Boerkoel, a clinical geneticist at the University of British Columbia, enrolled the Topics in one of his studies, and so they didn’t have to pay to have each of the family member’s genome sequenced. The results gave Ivana and Antonia the bad news about calpainopathy. Their younger brother, Mario, is free of the disease.

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Scientists classify calpainopathy, or “calpain,” as a limb-girdle muscular dystrophy Type 2a, caused by a mutation in the gene calpain 3, predominantly expressed in skeletal muscle. Those who suffer from Type 2a, such as Wrubel, Ivana, and Antonia, generally exhibit weak hip flexors—muscles that lift up the thigh. The weak flexors give them an awkward gait; they swing their legs forward, landing on their toes, and then sometimes on the sides or soles of their feet. Some walk only on the balls of their feet. The upper body muscle weakness creates abnormally prominent shoulder blades.

Melissa Spencer from the University of California, Los Angeles, who has studied calpainopathy for 14 years, explains that the disease contains many subtypes. The problem with Type 2a, she says, “was a really strange gene mutation that was completely inexplicable.” She says it has been a hard disease to study, partially because the implicated protein is unstable and partially because it was a rarity among the orphans. When it comes to funding, calpainopathy has been overshadowed by other forms of muscular dystrophy. “Muscle studies have been underfunded forever and certainly a rare disease like 2a especially underfunded,” Spencer says.

In 2010, Wrubel formed the nonprofit Coalition to Cure Calpain 3. In the quest for a cure, she says, “It’s a matter of patients taking charge of their diagnosis.” She reached out to other sufferers via Facebook, and some donated money. She partnered up with two other nonprofits, both started by those afflicted with Type 2a, which had raised funds on their own. So far Wrubel’s efforts have gathered close to half a million dollars. With that money, she has funded a project with Louis Kunkel, professor of genetics and pediatrics at Boston Children’s Hospital, one of the nation’s key muscular dystrophy researchers.

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Her coalition also organized a conference to bring calpainopathy researchers together, including Spencer. In 2005, Spencer had made a significant breakthrough. She discovered that calpainopathy, unlike more common forms of muscular dystrophy, was not a weakening of the muscle but a growth problem—muscle forms but fails to grow because of the missing protein. It is different from other muscular dystrophies in which the lack of dystrophin protein complex damages muscles’ membrane. “With calpainopathy, the muscles lack the growth signal,” she says.  “It’s not transmitted properly.” That difference makes a drug cure more possible. “I think this is going to be the easiest muscular dystrophy to cure,” she says.

In the quest for a cure, she says, “It’s a matter of patients taking charge of their diagnosis.”

Encouraged by the promise, the Coalition to Cure Calpain 3 gave Spencer’s lab a $260,000 grant to investigate how to circumvent the signaling problem and come up with a drug to fix it. But because the United States Food and Drug Administration already has a library of approved compounds that stimulate cell growth in muscle, Spencer’s team may arrive at a solution sooner. With the help of the coalition’s money, her lab is now plowing through the thousands of existing compounds, choosing those fit for testing. “I think it will be five years before we start thinking about clinical trials,” Spencer says—and then another five years before the drugs can be commercially available, she estimates.

Wrubel’s coalition intends to get pharmaceutical companies interested, too. “Many pharmaceutical companies see treating orphan diseases as a way to increase profits,” Wrubel says. Her husband, Lee Wrubel, adds, “The whole model for big pharmaceutical companies going forward is different. There is too little in the big pharmaceutical pipeline, and they’re looking to feed that beast as much as possible.” (A 2012 Thomson Reuters study found that drugs companies stand to profit from orphan drugs because, compared to drugs for common afflictions, they often have shorter and less expensive clinical trials, with more success. Spencer says a drug for calpainopathy, for instance, would also be useful for patients with Lou Gehrig’s Disease and bed rest patients, as it would help arrest the loss of bone and muscle mass.) Wrubel hopes to bring Cydan Development, a venture-capital backed orphan drug developer, to their upcoming fall conference in the Netherlands.

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As for the Topics, they were excited to learn about Wrubel from Nautilus. Ivana recently connected with Wrubel through Facebook. “I only talked with her a little bit, but she seems ambitious and driven,” Ivana says. “Definitely not someone who is going to sit around and wait for something to happen. Definitely inspiring. And the possibility that something might help in any way is a good thing to hear, for sure.” Ivana says she now wants to get involved and advocate for her own disease. “I definitely want to do something,” she says, and Wrubel’s coalition “would be a good place to start.”

Jude Isabella is a science writer based in Victoria, British Columbia. Her new book, Salmon, A Scientific Memoir, will be released next year.

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