Memantine works, Costa hypothesizes, not by boosting the growth of brain cells but by normalizing how existing cells use the neurotransmitter glutamate. Because people with Down syndrome have three copies of all or most of the genes on Chromosome 21 instead of just two, they have about 50 percent more of any proteins encoded in that chromosome. One result, Costa has shown, is that the NMDA receptors of Ts65Dn mice are “hyperactive” — they overreact to stimuli. By responding to too many things, they learn too little; the signal is lost amid the noise. But giving memantine to quiet the noisy NMDA receptors, Costa has found, makes the brain cells react almost normally.
Other drugs that work on different systems in the brain have also shown benefits in the Ts65Dn mouse. In 2009, Dr. William C. Mobley, chairman of neurosciences at the University of California, San Diego, and one of the most active and visible researchers in the field, co-wrote a study showing that a combination of drugs designed to raise norepinephrine levels in the brain normalized the mice’s learning abilities. Most recently, last year the Nobel laureate Paul Greengard of Rockefeller University showed that memory and learning could be normalized in Ts65Dn mice by lowering levels of beta amyloid, the protein goop that has long been known to clog the brains of people with Alzheimer’s disease.
“There’s been a sea change in our ability to understand and treat Down syndrome,” Mobley says.
“There’s just been an explosion of information. As recently as the year 2000, no drug company would possibly have thought about developing therapies for Down syndrome. I am now in contact with no less than four companies that are pursuing treatments.”
Costa’s current memantine study began by testing memory and spatial learning in 40 young adults with Down syndrome. Daily, for 16 weeks, half received memantine pills, the other half a placebo. This fall, Costa will present preliminary results at a scientific meeting in Illinois on whether taking the drug made those with Down, in a word, smarter.
A half-hour from his office and laboratory at the University of Colorado-Denver School of Medicine, where he is an associate professor of medicine and neuroscience, Costa pulled into a parking space in front of his modest two-bedroom apartment. The figure of a girl in green dashed toward the car — and then vanished.
We both stepped out to look for her. I found her standing in front of another car, a Subaru Forester, waiting to get in. Dressed in a lime-colored shirt and skirt, the bangs of her mahogany hair framed by a hair band, Tyche stood just 4 feet 6 inches tall, with a round face, broad nose and heavy-lidded eyes.
Seeing my puzzled look, Costa explained that they also owned the Subaru — which he usually drove with Tyche. He led her to the Toyota we’d arrived in, where she sat down in the back seat. As Costa drove us to his office, I asked what she thought of her father’s work.
“He’s the greatest scientist,” she said, in a slurred, high-pitched voice. Then she added with a laugh, “And he builds evil machines.”
“That’s from watching too many cartoons,” Costa said. “Her favorite is ‘Phineas and Ferb.’ Of course, there’s an evil scientist in it who builds all kinds of machines.”
Back at Costa’s office, Tyche demonstrated to me what people with Down can be capable of even without medication. (Because she’s not an adult, Tyche is ineligible to participate in her father’s study.)
On the whiteboard at the front of the room, Costa wrote out an algebra problem for her to solve: 8x
2 - 7 = 505.
“She’s one of only two people with Down syndrome who I’ve ever known to be capable of doing algebra,” Costa said. “Normally we give her a problem before she goes to bed.” As she solved the equation, taking six steps to conclude that X equals 8, he said, “It’s basically instead of a bedtime story.”
This past Christmas, he proudly noted, he gave her the Rosetta Stone language program for learning Portuguese, and by March she had finished with Level 1 and begun Level 2.
It turns out that with vigorous education and support, many people with Down do far better than once thought possible. Medical care of heart and other physical ailments associated with the disorder have likewise achieved significant benefits, doubling the average lifespan from 25 to 49, in just the 14 years between 1983 and 1997.
Still, with an I.Q. that is typically around 50 points lower than average — with some far lower and others, like Tyche, reaching higher — something more than education alone would be necessary to enable the majority of people with Down syndrome to live independently. Costa said he hopes that memantine might be that something, raising I.Q. noticeably, even if modestly. For him, the goal is to help people with Down syndrome achieve autonomy. “At some point, you want your children to have their own life,” he said. “It’s about independence.”
Costa was raised in Brazil, the son of a marine officer and a seamstress. When he was 14, his parents divorced. His father sent little support, and he and his two siblings lived with their mother in poverty. Perhaps inevitably for someone who had to struggle to rise above his circumstances, he comes across as intense and consumed by his work; he hasn’t taken a vacation since Tyche was 3. But he is also devoted to his daughter and wife, spending most of every weekend with them.
“She’s a great kid,” he said. “She has a very strong personality. In many ways she has features of a regular teenager. She doesn’t like me to get into her bedroom. She loves pop music and vampires.” Her relatively high functioning, he told me, is important to him. “If Tyche were really severely affected, I don’t know if I would have had the energy to go on with this business.” Then again, he admits to having paternal feelings toward all 40 young adults in his study, whose cognitive abilities vary widely. “At the end of the day,” he said, “their parents know someone really cares for their kid. It’s not an academic experience for me. It’s my life.”
In January, and again in March, a spate of news reports described new studies of the noninvasive blood tests that would allow pregnant women to check for Down syndrome without the risks and discomfort associated with chorionic villus sampling and amniocentesis. Few of the articles, however, took note of the profound unease many medical ethicists, including some who are ardently pro-choice, feel about the tests and how they might lead to a dramatic reduction in the Down syndrome population.
“Even people who are traditionally against abortion are sometimes willing to condone it when the abortion is of a fetus with a disabling trait,” says Erik Parens, a bioethicist at the Hastings Center in Garrison, N.Y. “But it’s important to recognize that there is a huge range of genetic disorders. In their own way, a lot of kids with Down syndrome flourish, and so do their families.”
Advocates of the new tests insist that parents will be given news of an affected pregnancy by a trained geneticist who will present the information fairly and fully. Critics, including Costa and many other parents of children with Down syndrome, say that such dispassionate approaches rarely happen in practice, with many obstetricians and genetic counselors providing unduly negative or misleading information.
But Stephen Quake, a professor of bioengineering and applied physics at Stanford and a developer of one of the new tests, says: “It’s a gross oversimplification to assume that these tests are going to lead to the wholesale elimination of Down-syndrome births. My wife’s cousin has Down syndrome. We just celebrated his 21st birthday. He’s a wonderful person. It’s not an obvious step that you would terminate an affected pregnancy.”
But Costa points to a falloff in the financing of Down-syndrome research since the prenatal tests have been in development. Although it’s difficult to compare the numbers, money from the National Institutes of Health dropped to $16 million in 2007 from $23 million in 2003, before creeping back up to $22 million in 2011. That’s far less than the $68 million slated for cystic fibrosis, which affects an estimated 30,000 people in the United States, at most one-tenth of the 300,000 to 400,000 people who have Down.
“The geneticists expect Down syndrome to disappear,” Costa says, “so why fund treatments?”
Alan Guttmacher, director of the National Institute of Child Health and Human Development, denies that this is the calculus used by his organization. Yet he offered no clear answer when I asked him why about $3,000 in research dollars is spent by N.I.H. for every person with cystic fibrosis, compared with less than $100 for every person with Down.
“The number affected is a fair metric to use,” Guttmacher said. But, he pointed out, most of N.I.H.’s funding decisions are based on the strength of proposals coming from researchers. Advocacy groups for disorders like AIDS, autism and breast cancer have certainly played a role in their gaining increased funding, he said. And perhaps, he speculated, Down suffers from an image problem. “Part of it is that Down syndrome has been around for so long,” he said.
Representative Cathy McMorris-Rodgers, Republican of Washington, who co-founded the Congressional Down Syndrome Caucus soon after her 4-year-old son, Cole, was born with the disorder, has had little success in having money appropriated for Down research.
“I find myself wondering how N.I.H. really sets their priorities,” she told me. “I’m quite concerned that so many of the researchers in the Down-syndrome field have difficulty getting funded.” She continued, “My fear is that for some, they believe that it’s been taken care of through prenatal diagnosis.”
Even Costa has struggled to secure financing. He lives with Tyche and Daisy in a rented apartment, having never felt he had enough job security to buy a home. At his laboratory, some of his most expensive and sophisticated equipment for studying Down syndrome remains in storage, literally gathering dust for want of financing to use it. One source of his research money has been the Anna and John J. Sie Foundation, based nearby in Denver, and run by Michelle Sie Whitten, whose 8-year-old daughter has Down syndrome. Three years ago, the foundation established a research institute at the University of Colorado in Denver, where Costa works.
Plainly, though, he didn’t get into Down-syndrome research for the money. “There’s a reason why I’m doing what I’m doing,” he told me, nodding toward Tyche.
Not all parents of children with Down syndrome embrace Costa’s vision of a medical treatment targeting intelligence. In a recent survey conducted in Canada, parents were asked what they would do if there was a “cure” for their child’s Down syndrome. A surprising 27 percent said they would definitely not use it, and another 32 percent said they were unsure.
Meanwhile, the major not-for-profit advocacy groups devoted to Down syndrome spend little on research, instead preferring to lobby and offer parental support. Fresh energy has come from two relatively new groups determined to turn the situation around — Research Down Syndrome and the Down Syndrome Research and Treatment Foundation — but even they have so far succeeded in each raising only about $1 million a year, a fraction of the annual research budgets of many other disease-advocacy groups.
Behind the ambivalence toward treatments, some parents say, is a fear that increasing their children’s intelligence might change their personalities — their very identities.
“Nobody would be against giving insulin for diabetes,” said Michael Bérubé, director of the Institute for the Arts and Humanities at Pennsylvania State University and author of the 1996 book
“Life as We Know It,” published five years after his second son, Jamie, was born with the disorder. “But Down syndrome isn’t diabetes or smallpox or cholera. It’s milder and more variable and more complicated. I’d be very leery of messing with the attributes Jamie has. He’s pretty fabulous. At the same time, I’m not doctrinaire. If you’re talking about a medication that allows people to function in society and hold jobs, how can you be against that?”
The parents I met whose children participated in Costa’s study expressed little of Bérubé’s ambivalence. Peggy Hinkle told me about changes she saw in her 26-year-old daughter. “When Christina was on the pills, she told me one morning about a dream she had. She gave me five full, complete sentences. Which is a very big deal. Not only that, she left the room and came back later and told me another sentence about the dream. And she started to do Jumble word puzzles in the newspaper. I don’t know if she was on the drug or on placebo, but after five weeks there was a change. Boom. That’s why we participated: to expand her horizons.”
For his part, Costa has no doubts about the work to which he has devoted the last 15 years of his life. “If you have a disorder that’s changing the function of an organ, which in this case is the brain, and you use a medication to bring the function of that organ closer to where it was meant to be from millions of years of evolution, that’s as fair as treating any other disease,” he said. “I don’t see it as any different.” If his current study is successful, Costa’s ultimate goal is to test it in youths, like Tyche, during the crucial early years of development. Costa is quick to point out that he has not offered her memantine outside the study, and he discourages other physicians from doing so until its safety and effectiveness is proved. But from his perspective as both a researcher and a father, he said: “The sooner you start, obviously, the greater would be your hopes. All I know is, the clock is ticking.”
