When Patricia White Flatley’s fifth child, Daniel, was born, she looked at his hand. A crease traced straight across his palm. “I said, ‘I believe the baby has Down syndrome.’”
Flatley, a doctor of internal medicine, says two questions immediately hit her: "What does this mean? What are the medical implications?”
From there, she says, “I ran through the list in my head: Okay, a lot of heart defects, but they’re correctible by surgery; an increased incidence of leukemia, but childhood leukemia is very responsive to new therapy now; maybe some thyroid issues, those are easily treated. But the biggest issue was: What about the learning difficulties? And my mind went blank.”
So Flatley quizzed the geneticist. “I asked, ‘Has there been any progress?’ Her response was ‘Don’t even go there. There’s nothing that can be done; it’s a whole chromosome disorder.’ Those words really stuck with me because it was such a closing of the door. . . . This was a newborn baby — he was hours old — with his whole life ahead of him.”
Caused by an extra, third copy of chromosome 21 in every cell, Down syndrome results in intellectual disability and a host of medical complications, including heart defects and a higher incidence of leukemia in childhood and dementia in adulthood. People with Down syndrome often share distinctive features, among them a flattened facial structure and upward-slanting eyes, and small hands with the single transverse crease.
Down syndrome is among the most complex genetic disorders compatible with survival, and it is the most common chromosome disorder. In the United States, an estimated 400,000 people have it and, of every 800 or so babies born, one has Down syndrome.
“I remember feeling very protective,” Patricia says. “I also remember thinking that Daniel was the most beautiful baby I’d ever seen, and he was. He had the most beautifully colored blonde hair that just reminded me of wheat.”Daniel is 9 now, a small, cuddly boy with that tousle of wheat blonde hair. When we meet at the Flatleys’ home in New Vernon, New Jersey, he grabs both my hands and wants to dance with and twirl me, a tricky proposition given our differences in height. When he first started walking on his own, the week of his 4th birthday, abandoning his baby walker, he led his brothers and sisters in circles around the basement, clapping his hands to the steady tune of their walking song, “Walk, walk, walk, walk, walk, walk, walk, walk . . .”
Dan Flatley ’75 and Patricia likewise have focused on forward motion. Patricia, who retired from an assistant professorship at New York Medical College in 2001 after having her fifth child, and Dan — a partner in a venture capital firm, Masthead Venture Partners, and an asset management firm, Chancellor Capital — have contributed significant sums of time and money to support Down syndrome research. In 2009 they launched a nonprofit foundation, Research Down Syndrome, which funds research into improving cognitive function in individuals with Down syndrome.
Per its official statement, “Our mission is to educate and inspire a caring society to fund and support biomedical research — resulting in safe and effective drug therapies designed to enhance and expand life opportunities, helping people of all ages with Down syndrome lead more independent lives.”
“We’re just trying to expand the awareness, expand the fundraising as quickly as we can because we all believe — and the scientists, they all believe — that we’re really on the cusp of really significant things happening here, and the sooner they happen the better,” says Dan.
Scientists have made significant strides in basic research in the last five years and report being on the verge of clinical trials to test drugs that could improve learning, memory and attention in individuals with Down syndrome. It’s still in early stages, but the research could one day change conceptions of intellectual disability from a fixed, immutable state to a medical condition that is treatable, at least to some degree.
“What really is the sea change is that, for the 20 years before this, pretty much every scientist thought that Down syndrome was a hopeless case,” says Roger H. Reeves, a professor in the department of physiology at the Johns Hopkins University School of Medicine. “You have as many as 500 genes that are subtly but consistently over-expressed, in every cell in the body, affecting every process in development and life.
“Really, we didn’t think there was a lot we could do about Down syndrome. And that simply turns out not to be the case.”
A clear goal
No scientist is speaking of a “cure” for Down syndrome. But working with a mouse model of Down syndrome, scientists are identifying the causes of cognitive impairment at the level of neurons and neurotransmitters, synapses and cells — and they are experimenting with potential drug interventions. Their shared goal is to improve cognition so that more people with Down syndrome, whose retardation generally ranges from mild to moderate, can live independently.
“Imagine,” says Reeves, “you could raise the IQ of everybody who has Down syndrome by 10 points. Well, now there are thousands upon thousands of people who needed to live with really quite a lot of care who suddenly are capable of living, maybe, in a group house, having a job. Instead of spending $100,000 a year in care, now they’re making $25,000 a year, doing something, being productive.
“The idea is by raising abilities not very much above what the median intellectual ability would be in Down syndrome, you could vastly expand the potential of these people to live fuller, more independent lives,” he adds. “That said, we have no idea how much impact might be possible. In mouse models, we restore these [cognitive] functions essentially as far as we can go.”
“We’re not talking about one silver bullet, one drug that will fix everything,” says Craig Garner, co-director of Stanford University’s Center for Research and Treatment of Down Syndrome, and a professor in the department of psychiatry and behavioral sciences. “There are many systems that are not working, and we’ll probably have to address this like we do in all of medicine, in that we’re going to have very specific drugs that improve part A or part B or part C.”
At different labs across the country, scientists have tackled different parts of the problem. For example, Garner’s lab at Stanford has focused on the problem of excessive inhibition, which is linked to impaired function of the hippocampus, a part of the brain important in learning and memory and disproportionately impacted in Down syndrome. Three types of circuits code information in the brain: excitatory circuits, inhibitory circuits, which act as a check against excessive excitation, and modulatory circuits, which modulate the other two systems.
When there’s an imbalance between these three systems, problems can result. An excess of excitation, for instance, can cause epileptic seizures, while excessive inhibition would, on the extreme end, cause a coma. In Down syndrome model mice, excessive inhibition is linked to impaired performance on tests of memory function — unlike normal mice, the Down syndrome model mice do not recognize objects that they’ve seen before, for instance.
Because the major inhibitory circuits in the brain use a neurotransmitter called GABA, Garner’s lab has experimented with several different drugs that reduce GABA function. After a three-week course of drugs, the Down syndrome model mice perform equally well on the memory tasks as do the normal mice. “We could not distinguish between them any longer,” says Garner.
While reducing levels of GABA represents one line of inquiry, another involves increasing levels of a different neurotransmitter, norepinephrine. Again using the Down syndrome model mice, scientists at Stanford and the University of California, San Diego have linked problems in contextual learning and memory — the mice perform poorly on tasks like nest-building, for instance, compared with normal mice — with degeneration of neurons in a part of the brain called the locus coeruleus (LC). The neurons in the LC use norepinephrine to communicate with the hippocampus, but as they degenerate the LC neurons lose their ability to release norepinephrine effectively. By restoring norepinephrine levels, researchers were able to restore performance in contextual learning tasks, like nest-building.
Another line of research involves the heartbreaking intersection of Down syndrome and Alzheimer’s disease. As people with Down syndrome live longer — life expectancy has doubled from 25 years in 1983 to more than 50 today — they face a greatly increased risk of Alzheimer’s. By age 60, between 50 and 70 percent of people with Down syndrome develop dementia. They carry an extra, third copy of a risk factor, the amyloid precursor protein (APP) gene; in Alzheimer’s, APP accumulates to form plaques that damage the brain. Reducing levels of APP, or otherwise interfering with APP processing, is a major focus of Alzheimer’s research.
While people with Down syndrome uniformly develop these microscopic plaques at an early age, not all will develop dementia. In people without Down syndrome, however, these plaques almost always occur with dementia. This difference in pathology could provide insights into reducing the severity of Alzheimer’s in all people.
Meanwhile, the Reeves lab at Johns Hopkins has focused not on cognitive decline but on brain development, specifically, the role of the sonic hedgehog homolog (named by a fruit fly researcher with a sense of humor) in inducing cell division. The sonic hedgehog protein is crucial in cell-to-cell signaling during development. In the cerebellum, for instance, which is disproportionately small in people with Down syndrome, sonic hedgehog is the main signal triggering the division of granule cell precursors, which become granule cell neurons, which represent half the neurons in a person’s brain.
In Down syndrome mouse models, the granule cell precursors show an attenuated response to sonic hedgehog and so divide at lower levels — therefore leading to lower brain volume. By increasing levels of sonic hedgehog in these mice on just the day of birth, researchers were able to restore the cerebellum to normal size, and these effects persisted throughout life. This could have implications for learning and memory in people with Down syndrome. While the cerebellum is commonly associated with motor control and movement, which are not greatly affected in Down syndrome, recent research suggests that the cerebellum also plays an important role in the function of the hippocampus.
All of these and other advances are at the basic science level, in mice, although scientists are hopeful they could translate into clinical trials in humans in the short term.
“While this problem is very complex, I’m surprised by the progress that has been made in the last few years, and I think that parents of children with Down syndrome can have a reasonable hope that there will be trials of well-justified drug candidates in the next five to 10 years,” says William Mobley, who chairs the neuroscience department at the University of California, San Diego, and was among the authors of the study on norepinephrine. In other words, “There’s reason for hope but not reason for celebration.”
None of this comes cheaply. Stanford’s Garner, who would like to begin a clinical trial within the year, estimated just a Phase 1 trial would cost between $5 million and $6 million, and that development of a single drug over five or six years could cost $100 million. “This is really expensive, and part of what determines how long this takes is really about raising money. And there’s very little money,” Garner says.
“This whole process of trying to understand a) what’s wrong and b) to identify initial targets and then to develop drugs for those targets and then to move those drugs into the clinic and have them tested and get approved by the FDA [Food and Drug Administration] — this is a long, long process.
“We’ve made tremendous progress in finding the first targets that we can begin to focus on for drug development," he adds. "But the phases forward are significant. We’re going to need a lot more basic research on each of these.”
The dollar question
The Flatleys say they hope their new Research Down Syndrome foundation will supplement the good work of the Down Syndrome Research and Treatment Foundation (DSRTF) that, since its founding in 2004, has provided about $5.6 million to support cognitive research, including research by professors Garner, Mobley and Reeves. Patricia formerly was chair of the DSRTF board and remains a board member.
“We thought we could augment what they’re doing by trying to expand the awareness,” says Dan.
When it first launched, Research Down Syndrome provided small, $1,000 grants to support research at the universities of Johns Hopkins; Stanford; California, San Diego; Colorado; and Arizona (where the psychologist Lynn Nadel is leading an effort to create a battery of cognitive tests specific for people with Down syndrome).
It was a modest beginning but ambitions for the new foundation are high. Robert C. Schoen ’75, the president of Research Down Syndrome (and Dan’s college roommate), says he’s starting with a fundraising goal in the hundreds of thousands but hopes the foundation will soon grow into one that can raise $1 million to $2 million or more a year. Because Patricia and Dan are currently covering the foundation’s administrative costs, they pledge that every dollar donated will go toward research. Schoen, in fact, is the foundation’s sole staffer, although significant help comes from ND-related supporters, such as Schoen’s sister Mary Beth (SMC ’72) as well as Patty Watson (SMC ’88) of Dallas.
“A great deal of the funding that has been raised for cognitive research for Down syndrome is from parents and close friends of people with Down syndrome,” says Schoen. “It’s our goal to reach out beyond.“Unlike cancer and diabetes, I don’t have to worry about contracting Down syndrome. People don’t contract it, so unless they have a connection they wouldn’t be all that concerned about it. But we need to be concerned about everybody.
“We’ve come up with drugs to help people fight cancer. We’ve come up with therapies to help people breathe more freely. Why don’t we, as a caring society, from a fairness and social justice standpoint, why don’t we support a cause that helps a good size of the population of this country think better, learn more readily and so forth?”
The debate
The use of pharmacology to improve cognition can be controversial. After the publication of the study on norepinephrine last November, The New York Times published a blog post, “Should Down Syndrome Be Cured?” It raised a provocative set of questions: “Who decided that smarter is better? Who decided that independence takes precedence over community? Who decided that both the individual and the society are better off without Down syndrome?”
From Patricia’s perspective, “It’s a matter of having the option [for treatment] available. And it’s a matter of social justice.
“People with Down syndrome add a lot to our lives; we feel good about them. But how do we show respect for them? Do we show respect for them by saying, ‘You’re very nice people, and I’ll be kind to you?’ Or do we really address them as fellow humans and say, ‘What is it you would like?’ And what they would like is just what we would like. They would like to be working, they would like to have the option of independent living, they’d like to participate fully in the educational system, they’d like to have friends — and their learning abilities do impede their abilities to do these things.”
While Patricia frames the issue in terms of social justice, she also mentions respect for life. Using prenatal tests like amniocentesis, doctors can diagnose Down syndrome in utero. About 90 percent of pregnant women who receive a diagnosis of Down syndrome choose to abort.
Patricia did not undergo amniocentesis. When Daniel was born, the Flatleys recall that the hospital staff was abuzz: “How can a doctor have a child with Down syndrome?”
“People are going to come down on all different sides of these issues, but at the very least I think that everyone, no matter how they feel about the life issue and the debate, has to acknowledge that this new information should be part of the discussion, that the discussion cannot fairly exclude the information that scientists believe they can do something,” she says.
There again, says Dan, "Let’s get after the science and get it done so that it’s not just theoretically ‘this is what could happen’ but ‘this is actually what is happening,’ so people can factor that into their thinking.
“We’re in this to help Daniel and to help the Down syndrome community as they exist today, but we’re in it, also, I guess, for the people yet to come.”
Part of the family
When Daniel was born, a doctor suggested the possibility that he be directed toward some form of foster care. Before 1960 a majority of children with Down syndrome were institutionalized, and in general people with the condition were hidden away. But in the past half century the paradigm has shifted from one of isolation to one of inclusion and family.
“I would say the biggest single event that enhanced the well-being of people with Down syndrome was when people kept them home, prevented them from going to institutions. If we ever as medical researchers make as big of a difference as that, we can be proud,” says Mobley, the neuroscience chair at the University of California, San Diego.
Each of Daniel’s siblings shares a special routine with him. A member of Notre Dame’s class of 2013, Catherine, 19, who interned for the National Down Syndrome Society for two summers while in high school, Skypes with him from campus. Andrew, 17, is concerned, almost as a parent would be, with Daniel’s speech and behavior, and coaches him on the proper enunciation of words, among other lessons. Thomas, 16, wrestles with him. Elizabeth, 13, reads next to Daniel at night so he can fall asleep, knowing someone else is in the room.
Raising Daniel, her fifth child, “didn’t really seem different except it was slowed down,” says Patricia. “He goes through every phase. He gets to the next level; it just takes longer. With the other babies each stage would fly by in the blink of an eye. For Daniel, it’s more slow motion.
“And it doesn’t happen always in the same sequence,” she adds. “He might make some observation that is typical of a 9-year-old and then two minutes later do something for the first time that a 4-year-old will do, but it will be the first time he’s done it.”
She relates one typical example. “Today he had blood work done, and he doesn’t cry, even though it hurts him and he cringes. He’s just so grown-up about it. He even comforts the technician after he gets the blood drawn; he pats the technician on the arm, so it’s very adult. But on the way home we passed an auto shop, and he said, ‘sick cars.’"
Daniel apparently recognized that the auto shop was a place for broken cars, Patricia says, but most 9-year-olds would be able to call the business by its name. “Yet I can tell you that 9-year-olds typically when they get blood drawn are not comforting the technician. It’s interesting.”
Potential
Daniel’s speech is impaired, and he can be difficult to understand. But I can tell he is making fun of me.
I put my hands on my hips; he puts his hands on his hips. I laugh nervously; he laughs mischievously. “Are you making fun of me?” I finally ask, cocking my head. He cocks his head, too, and his father calls him a joker. He’s a great mimic but not a good communicator. “It’s harder for us to understand what he’s saying than for him to understand,” his father explains.
“You look at him relative to the other kids,” says Dan. “We always talk about this: We say there’s more that’s locked in. You know it’s there, but you can’t get to it. That’s frustrating for him, I think, frustrating for me, frustrating for both of us.
“There are a lot of people who have children with Down syndrome or relatives with Down syndrome who think that they’re great, they are who they are and that’s fantastic — and that is fantastic. But from our perspective, if there is a way to unlock the potential that’s in there, our choice would be to do it — safely, obviously, not to damage his health — but to gain access to that potential, that’s really where our focus is.”
Daniel was born with low muscle tone but otherwise has been a healthy child. He attended a special school for children with Down syndrome, Stepping Stones, in his early years, but he now attends public school, splitting his school day between a special education and typical classroom. He will remain in a school setting until age 21. “After that,” says Patricia, “it’s uncertain.
“I don’t know whether he will be someone who will go into vocational training or a postsecondary school. Eventually we hope the research we’re talking about will impact that.
“That really is the goal of the research, to increase options.”
As Patricia, Dan and I talk, Daniel, dressed sharply in a blue, checkered shirt and brown corduroys, crawls onto a chair and listens.
Elizabeth Redden is an MFA student in nonfiction writing at Columbia University and a freelance journalist. A former staff reporter for Inside Higher Ed, where she wrote extensively about Catholic colleges, her writing has appeared in such publications as Orion Magazine, The Washington Post, Tricycle: The Buddhist Review and The Swarthmore College Bulletin.