On a June day in New York 15 years ago, Cindy and Michael Parseghian learned that three of their four small children were fated to die from the same genetic disease.
Within a decade or so, all three would be gone — Michael Jr., then 7, and his two younger sisters, Marcia, 5, and Christa, 3. This was not medical guesswork. It was a fact written into the children’s cells, as close as modern science can come to infallible prophecy.
Cindy Parseghian remembers sitting that night in the kitchen of her friends’ Chappaqua home and cursing God. Michael Jr. had been diagnosed with a fatal condition called Niemann-Pick Type C (NPC), and it was clear their two girls had the disease as well. A search for meaning and peace would come later, but that night Parseghian felt numb, raw fury.
“I couldn’t understand why God would do this,” she says. “Michael was such a happy-go-lucky kid. We wanted to keep things normal for the kids, but we felt our whole world was falling apart.”
In an emotional abyss, the Parseghians sought ways to fight what seemed like an implacable condition. Scientists knew little about the disease, making the prospect for treatment more distant. But the work had to start somewhere — doctors could not treat an ailment they did not understand. Within weeks, Cindy Parseghian began a mission to support research on the disease, though it would mean starting a foundation from nothing.
“It was kind of like the lions protecting their cubs,” she says. “If we sat back and let the disease progress, we knew what was going to happen. We just had to fight this.”
They fought as their cheery, dark-haired children slid into the grips of the disease. Marcia, the first child in her dance class to master skipping, became sluggish as the condition sapped her motor abilities. Christa, unusually small from birth, grappled with chronic pneumonia. Michael Jr. started karate classes, though no one knew from one month to the next if he would live long enough to reach the next belt ranking.
Fifteen years after that bleak diagnosis in New York, many scientists say they are astonished at what Cindy Parseghian has accomplished as president of the Ara Parseghian Medical Research Foundation, named in honor of Michael’s father, the Notre Dame coaching legend. They have raised $35 million for research on NPC, bringing new attention to an understudied area of cellular biology. In the last few years the research has started to identify potential drug therapies for the condition, and it has helped fuel Notre Dame’s Center for Rare and Neglected Diseases, which opened in 2008.
Numerous researchers describe the Parseghian foundation as a model of how to foster research on rare diseases.
“It’s a tribute to the Parseghians that they’ve done so much to bring scientists along, to the point that scientists in several continents with varied interests are focusing their energy on this disease,” says Matthew Scott, a member of the foundation’s scientific advisory board and a professor of developmental biology, genetics and bioengineering at Stanford University.
The work led to an emotional high point in May 2009, when Cindy Parseghian received an honorary degree from Notre Dame for her work advancing research on NPC. Standing beside the president of the United States and University leaders, Parseghian was unprepared for the raucous ovation from graduating students as Provost Thomas Burish read her name and accomplishments. Tears came to her eyes as he described her as “a loyal daughter of Notre Dame.”
She cried in gratitude and perhaps a little awe over how far she had come. But she also cried for the faces she did not see in the crowd of cheering people. They were the faces she always knew she might not save, despite tireless work and great medical progress. Her family’s struggle with NPC had been one of steady achievement. It was also one of repeated loss.
On that fine afternoon in May, Cindy Parseghian still could not help feeling that the world was not as it should be.
‘The luckiest woman in the world’
Cindy and Michael Parseghian’s first date in 1975 was a pep rally the night before a Notre Dame football game. They had met while studying in the same section of the library and found they shared high professional ambitions, a deep attachment to Notre Dame and a love of intramural sports (they won a co-ed racquetball tournament).
The couple also liked how their personalities complemented each other. Michael tended to ponder problems in all their complexity while Cindy was geared toward action. When Michael proposed toward the end of their senior year, he gave Cindy a temporary engagement ring — his mother’s diamond Notre Dame ring, which had been a gift from Coach Parseghian’s staff.
They married three months after graduating in 1977 and moved to Chicago, where Michael attended the Northwestern School of Medicine and Cindy worked as an accountant while pursuing an MBA degree at Northwestern. When Michael got his medical degree, they settled in Tucson, Arizona, and started a family. Ara was born in 1984, followed by three more children over the next seven years.
“I thought at the time I was the luckiest woman in the world,” Cindy Parseghian says. “I had four beautiful children, an interesting job and a strong marriage. We probably had a year in there that was just a perfect family year.”
Ara was always healthy. But when Michael Jr. entered kindergarten, his parents noticed he had trouble keeping up with other kids on the playground. His speech was slow to develop, and his eyes seemed to wander in an odd way.
“I thought he was just a distracted 5-year-old,” Cindy Parseghian says. “Really it’s one of the first signs of the disease.”
For the next two years a string of doctors puzzled over Michael Jr.’s condition, building a medical file inches thick. Finally the Parseghians took Michael to see specialists at Columbia University in New York, where doctors realized within minutes that the boy had a probable case of Niemann-Pick. The parents could tell from the doctors’ demeanor that the disorder was fatal.
The medical signs included Michael’s distinctive eye movement and his enlarged spleen — a symptom that set off immediate alarms. His sister, Marcia, also had been diagnosed with an enlarged spleen when she was 6 months old, and Christa was born with the condition. Now it appeared that their symptoms all pointed to the same disease.
“Suddenly we went from thinking it was a problem with Michael to thinking it had reached our girls, too,” Cindy Parseghian says.
Genetic tests soon confirmed their fears. Ara was the only child unaffected. The other three all had the same fatal condition.
Because both parents were carriers of NPC, pure genetic odds would have predicted that each of their children had a one-in-four chance of being affected by the disease. Half of the time, only one parent passes on a damaged copy of the gene implicated in NPC, and the child becomes a carrier. In one out of four cases, the child gets two good copies and is fine. In the remaining one-fourth of cases, the child gets two damaged copies and develops NPC. But these are only averages — for each individual child, the odds play out anew. Luck had run against the Parseghians.
Doctors knew those odds because they had observed how the disease was passed on within families. But at the time the Parseghian kids were diagnosed, researchers had not yet isolated the specific genes that caused the condition. That was among the first projects the new foundation helped to fund, along with basic science that started to puzzle out how the disease does its damage.
Hunting for a gene
At its root, NPC is a cholesterol-storage disorder that affects the nervous system. Every person needs cholesterol to survive; the body produces it and relies on it for a range of biochemical processes. For reasons that scientists did not understand when the Parseghian foundation started, the cells in NPC patients have lost the ability to clear cholesterol, leading to a toxic build-up that over time makes normal metabolism impossible. The children’s muscles fail, their ability to speak fades and most die in their teenage years — though some NPC patients have a slower course of disease that is not even detected until adulthood.
The disease requires expertise in many areas of biology to understand, but because it is rare — striking about 1 in 150,000 children — research money can be scarce. The children’s father, Michael Parseghian, an orthopedic surgeon, turned to his friend Michael Parmacek, a cardiologist then at the University of Chicago, to form the foundation’s scientific advisory board. Several researchers said the foundation has become a model of how a small, privately run group can set up productive competition for research grants, with a constant flow of new applications from scientists with fresh ideas.
“The Parseghian foundation is a wonderful organization,” says Joe Goldstein, a researcher at the University of Texas Southwestern Medical School who won the Nobel Prize in 1985 for his work on cholesterol metabolism. “What makes the foundation unique is that the leaders recognize that solving the puzzle of this devastating disease will not come overnight, and they are committed to the long haul.”
The children’s Grandpa Ara helped start the steady flow of donations by calling on his extensive national network of connections. An army of volunteers pitched in, many after learning of the Parseghians’ struggle through stories in People magazine and the television news show 20/20. The family launched a penny drive at the children’s school with the goal of raising a million pennies — $10,000 — but they far exceeded that. Next they started an annual walkathon, which now raises about $30,000 every year.
One of the first breakthroughs the foundation helped to fund was the discovery by National Institutes of Health scientists in 1997 of the gene NPC1. A mutation of the gene can lead to Niemann-Pick Type C disease. Finding the gene was a triumph, but scientists quickly realized that compensating for alterations of the gene would be immensely difficult.
“This is a very old gene that is used even in single-celled organisms,” says Matt Scott of Stanford. “It has ancient functions that have been preserved for all that time because they’re so important to maintaining life. If you damage that gene, you’re going to have a very serious disease that is very hard to fix.”
As the foundation got rolling, the Parseghians settled into a household routine that seldom allowed more than two hours of solid sleep during the night. They worried constantly about their children’s breathing and the risk of seizures, and would often get up to roll a child over so he or she could breathe more easily.
Then with no immediate warning, Michael Jr. died in his sleep from a massive seizure in March 1997. It was the same month that researchers found the NPC1 gene, and a few days short of Michael Jr.’s 10th birthday.
“We were stunned, because he was still ambulatory and still incredibly engaged in life,” Cindy says.
All along, Michael Jr. had stayed active in karate class. His instructor held him up as an example to the other students, to teach them that the discipline is about dedication as well as skill. It felt only natural to bury Michael Jr. in his karate uniform, but the Parseghians also wanted to keep his blue belt as a token of his love for the sport. His older brother, Ara, offered to have Michael Jr. buried with Ara’s red belt, a gesture whose full meaning Cindy realized only later.
“Because Ara gave away his red belt, the rules said he had to lose his rank in the class,” Cindy says. “Until he earned his black belt he always had to line up in back of his classmates.”
Michael Jr.’s death once more tested the Parseghians’ faith. Since that night in New York when Cindy Parseghian cursed God, she had come to believe that what was happening to her children had little to do with any divine plan. Could a loving God purposely inflict NPC on such loving children? And for what possible reason — so the parents could learn patience? Cindy went back to C.S. Lewis’ writings on pain, which suggest that the nature of life places limits on God’s power.
“I don’t think you can say that God is all-merciful and all-powerful. You have to choose one,” she says. “I look at our children’s diagnosis, and I say it was really bad luck. I cannot blame a higher being for this, because I don’t think he plays that kind of game. I’d much rather have an all-merciful God than an all-powerful God who is involved with every detail of our lives.”
‘I’ll be with you for all of it’
Marcia, who was 8 when Michael Jr. died, knew she and her sister had the same disease that killed him. One Christmas Eve, Cindy was reading Marcia a Sesame Street book — When I Grow Up — when Marcia suddenly started crying.
“Mom, I’m not going to grow up,” she sobbed.
It was the sort of moment the Parseghians had dreaded. They didn’t shield the children from the truth of their disease, but they tried to keep everyone’s lives as normal as possible. Now Marcia understood that she and her older brother shared the same fate, and she was afraid. Cindy resisted the urge to tell Marcia that everything would be fine.
“I just held her and said, ‘Marcia, I’ll be with you. I’ll be with you for all of it.’”
Fortunately such wrenching exchanges were rare. The children kept their sweet dispositions even as their cognitive abilities faded. Christa loved the color purple and always reached for the purple lollipop when candy was passed around. Marcia went horseback riding whenever she could. One of her favorite places was a dude ranch in Colorado where she could ride twice a day.
When the children were first diagnosed, the Parseghians had briefly considered taking them out of school and showing them the world. But that was a grown-up’s idea of what someone with a fatal condition would want. The children hungered for normal lives — the routines of school, the countdowns to birthdays, the company of friends.
They also met famous figures who lent their help. Before he died, Michael Jr. got to meet his idol, the country singer Garth Brooks. The foundation work brought the family close to the band Chicago, whose manager, Pete Schivarelli, a 19’71 Notre Dame graduate, played football under Ara Parseghian. The band raised $100,000 at a single fundraiser the year after Michael Jr. was diagnosed and has remained a regular contributor. Cindy struck up a friendship with the singer Amy Grant, who heard of the Parseghians’ fight through news stories and has helped with the foundation’s fundraising. Grant dedicated her song “Beautiful” to the family, with its lyrics of loss and hope — “How do you prepare when you love someone this way, to let them go a little more each day?”
“We prayed for a miracle early on, but God doesn’t answer prayers the way you think he should,” Cindy Parseghian says. “What he did was bring people into our lives to hold us up.”
They needed more support than ever. Christa, who had been small from birth, struggled from chronic pneumonia for years. She finally succumbed to pneumonia in October 2001, at age 10.
Only Marcia, then 13, was left of the three children who had the disease. As her disease progressed, Marcia, who had learned to read before kindergarten, lost the ability to speak and had to be fed through a tube. The Parseghians always feared that other kids would talk about the grim prognosis in front of Marcia or tease her, but mercifully that never happened. Marcia’s friends even brought her to their high school’s winter prom, and they pushed her in a stroller as they did a 5K walk for the foundation.
Glimmers of new hope
Around 2003, the Parseghians heard that Notre Dame’s chemistry department was stepping up efforts to develop new pharmaceuticals. The foundation also was switching gears. For its first decade it had focused on helping basic research because so little was known about NPC. But it seemed time to push for more applied work.
“There was a perfect alignment of constellations for us to do more work on NPC,” says Paul Helquist, associate chair of Notre Dame’s department of chemistry and biochemistry.
With the help of seed funding from Notre Dame’s Office of Research, a group of chemistry researchers began studying the disease and attending the foundation’s annual meeting. Olaf Wiest, ND professor of chemistry and biochemistry, started a project using computer-aided design to search for new molecules to treat the disease. In 2008 the research became one mission of Notre Dame’s new Center for Rare and Neglected Diseases, which strives to fill gaps in medical research by focusing on rare conditions such as NPC, cystic fibrosis, thalassemia, rare forms of cancer and such neglected diseases as malaria and tuberculosis.
“It really fits the picture we all have of Notre Dame,” Wiest says. “If we’re not doing this work, who will? Industry is never going to do it. They can’t. But we don’t have to think about making a profit, we just have to think about how to help people.”
The challenge is figuring out how to remedy the NPC1 mutations that cause most cases of NPC. “We actually have to repair it,” Wiest says. “The reality in biochemistry is that we’re very good at breaking things but not as good at building things.”
The painstaking work of Wiest, Helquist and other researchers has resulted in dozens of molecules that are being tested in cells and animals for therapeutic activity in NPC. Recently some researchers have raised interest in a compound called cyclodextrin, which may have promise as a way of depleting NPC-affected cells of cholesterol. By trying to solve the molecular transport problems at the heart of NPC, researchers believe they can gain insights into other diseases for which transport is important, such as HIV and Alzheimer’s.
“As always in science, you never know where it could lead you,” Wiest says.
‘She taught me how to live’
In late July of 2005, Marcia Parseghian went once more to the ballet class she loved. As always, her friends spun her around in her wheelchair, and she would smile while extending an arm or a leg with a flourish. The next week she suffered an acute bout of pneumonia and began having massive seizures. In Marcia’s last moments, her mother repeated the words which had comforted them both on that tearful Christmas Eve years earlier: “Marcia, I’ll be with you. I’ll be with you for all of it.”
Marcia lived to be 16, longest of the siblings with the disease. “Every day of my life since kindergarten was the best day because of her,” one of her friends, Perri Blazer, told the obituary writer for the Arizona Daily Star. “She taught me how to live.”
Reminders of the children are everywhere in the Parseghians’ Tucson home. Cindy has covered walls and a big corkboard with their pictures. She’s built a collection of hundreds of crosses, starting with one she was handed from Michael’s grave and one that Christa made using two sticks wrapped with a fake flower.
Their oldest child, Ara, now 25, is married and living in Boston. He had studied the biology of NPC in high school but decided to pursue a medical career only after getting his undergraduate degree from Princeton. He enrolled in a special science program at Tufts University and is now a student in the medical school there. “He has a new appreciation for his dad as a doctor,” Cindy Parseghian says.
When Notre Dame President Father John Jenkins, CSC, sent Cindy a letter inviting her to receive an honorary degree, she wrote back saying she would accept it in honor of the researchers and volunteers she had worked with, and in memory of her three children who struggled with the disease but lived their lives with grace. Coming back to campus for the degree brought her a mix of emotions. She was immensely proud to get the honor from an institution that remains close to her heart. And she says having President Obama on the same stage was “the sprinkling on top of the cake.” But the sadness was not far from her mind.
At the same ceremony where she was honored, one of Michael Jr.’s old school friends from Arizona also graduated from the University. Seeing him gave her a twinge of regret. “There was that thought — Michael should be here,” she says.
Despite all the Parseghians’ hard-won accomplishments, nothing can ease such moments. Though their children’s short lives were rich with joy, they are often reminded of the three adult lives that might have been — the careers they would have found, the help they would have needed.
“There’s a sadness knowing I’ll never hold my daughter’s baby, never help her learn how to mother her children,” Cindy says.
And this, of course, is why Cindy Parseghian persists in her fight, so scientists can help others avoid her pain. The loss fuels an urgent mission, but it is still a loss.
“I think what you learn is that there’s a big black hole in your heart, and you learn to walk around it, but you do fall into it,” she says. “And I’ve learned that’s okay.”
Jeremy Manier has covered science and medicine for the Chicago Tribune and is news director at the University of Chicago.
See more information on the Ara Parseghian Medical Research Foundation.