The work of DU researchers may improve the quality of life for those with Down syndrome, including Janet Kay Zaborek, age 9. Photo: Michael Richmond
In May 2001, a sea of beaming parents watched their children accept diplomas from Monarch High School in Louisville, Colo. None were more joyful than Susie and Jack Doherty, MBA ’68, as they watched their daughter Meghan graduate.
Meghan, 23, has Down syndrome and has spent her entire life confounding those who would saddle her with low expectations.
She is one of more than 350,000 Americans with Down syndrome — the most common genetic disorder. For a team of University of Denver researchers, people like Meghan are the most compelling reason to explore Down syndrome.
“Our goal,” says DU biology Prof. David Patterson, “is to improve their quality of life.”
Brighter outlook
Down syndrome begins in the womb with a genetic defect known as Trisomy 21, which causes a fetus to develop with three copies of chromosome 21 instead of two. This small irregularity appears in every cell in the baby’s body, with profound results. Eighty percent of fetuses with Trisomy 21 do not even survive to full term.
The syndrome’s most noticeable physical characteristic is the distinctive skull and facial structure that gives those with Down syndrome a “family” resemblance. Other obvious traits include short stature, clumsiness, and speech and language difficulties.
But the greatest impact is cognitive. The average IQ of those with Down is 50 points, compared to a 100-point average for the general population.
People with Trisomy 21 also face lifelong medical issues, including heart defects, leukemia and Alzheimer’s disease, which afflicts many people with Down syndrome. Other common ailments include diabetes, poor eyesight, thyroid disorders, sleep apnea, ear infections, seizures, weak neck muscles and depression. Gastrointestinal ailments are frequent, including a dietary sensitivity to wheat or gluten. Accelerated aging also is a problem, and women with Down syndrome experience premature menopause.
McKenna Wohlers, 5, has Down syndrome accompanied by hypothyroidism, which can exacerbate cognitive delays and cause weight and lethargy issues if not caught early. McKenna — daughter of Rick, BSBA ’88, and Darii Wohlers — started speech therapy, physical therapy and occupational therapy early.
“I don’t want it to sound like it’s no problem, because it is challenging,” says Darii, BA ’89. “But, the challenges are not so much that the child has Down syndrome as the way society deals with your child.”
Even so, life has never been better for people like McKenna Wohlers and Meghan Doherty, thanks to medical advances and changing attitudes. The ability to treat pneumonia, infections and heart conditions means people with Down syndrome routinely survive infancy. And, their life expectancy has doubled in the last 20 years to nearly 60.
Still, University of Denver scientists believe that outlook could be better.
“We’d like to improve intellectual ability and delay or prevent the onset of Alzheimer’s disease,” says Patterson, a faculty member at DU’s Eleanor Roosevelt Institute (ERI) — a world leader in Down syndrome research. “Hopefully, research on related disorders like autism could lessen the chance that someone with Down syndrome could get autism.”
Patterson and his colleagues currently are investigating a region of chromosome 21 that holds promise for breast cancer treatments and might also be associated with autism, which affects about 7 percent of people with Down syndrome.
Initially, Patterson set out to fight cancer by understanding the genetic pathways affecting purine synthesis. Purines — energy-storage molecules within cells — are necessary for cell division and are mimicked by some of the most widely used anti-cancer drugs. Patterson developed a hybrid cell with a gene that affects purine synthesis. It was located on chromosome 21.
“I realized that if we can make a hybrid cell to study the purine pathway, we can make a hybrid cell to study Down syndrome,” he says.
Using a genetically engineered mouse with Down syndrome, Patterson’s team works to determine which metabolic pathways might be perturbed in Down syndrome in ways leading to cognitive abnormalities. He’s particularly interested in the CBS (cystathionine _ synthase) and RFC (reduced folate carrier) genes.
Mutations in CBS often cause significant intellectual impairments, Patterson explains. And, he adds, the CBS gene also seems to influence susceptibility to some anti-leukemia drugs. “That’s interesting,” he says, “because children with Down syndrome have an increased risk of leukemia and are unusually sensitive to some of these drugs.”
The RFC gene regulates how cells absorb folic acid and methotrexate — a leukemia drug that causes sensitivity in kids with Down syndrome — from the bloodstream. The protein encoded by RFC may also affect oxidative stress caused by free radicals, which have been implicated in aging.
Patterson’s team has engineered mice with an extra CBS or RFC gene and are exploring whether or not the extra genes cause the mice to create more CBS or RFC protein in the brain.
“We know the extra genes are active, but we don’t know how active or where they are active,” Patterson explains. “We need to know if that activity is causing a problem.
“These experiments are attempts to manipulate metabolic systems in which chromosome 21 genes play a part and which might be involved in cognitive disability,” he adds. “If we could also help with leukemia, that would be great.”
Unraveling the mystery
Patterson’s project is just one of several ERI Down syndrome studies funded by the National Institutes of Health and other organizations to the tune of nearly $1 million annually. In fact, DU’s is one of the nation’s largest Trisomy 21 research programs.
ERI Research Prof. Katheleen Gardiner also is working to unravel the mysteries of Down syndrome. Following her work with an international Human Genome Project team studying chromosome 21, Gardiner launched the Chromosome 21/Down Syndrome-Relevant Pathway Database to identify, organize and disseminate all the scientific information about chromosome 21.
The Human Genome Project, an effort to identify and sequence all of the 25,000 human genes comprising human DNA, concluded in 2003. Once chromosome 21 was sequenced by colleagues in Germany and Japan, Gardiner worked to identify its genes and verify their structures.
Now, Gardiner pores over scientific papers seeking relevant connections, which she refers to the computer experts who maintain the chromosome 21 database. Meanwhile, she is working with DU’s computer science department to develop a curriculum in bioinformatics, an emerging field that uses computers to organize the oceans of data generated by modern genetics.
She’s not a data miner, because miners know what they’re looking for, she explains. Rather, she says, “We’re more data surveyors. We collect all these data and put them all in one place. The hope is that people interested in Down syndrome, chromosome 21 or some other area will come to this database and be enlightened.”
“When you get all that information in one place, you come across serendipitous discoveries,” notes Muriel Davisson, genetic resources director and senior staff scientist at the Jackson Laboratory in Bar Harbor, Maine, and the developer of a genetically engineered mouse-Ts65Dn- with Down syndrome. “While some of us are trying to make mouse models, Katheleen was one of the first to say you need to look at the pathway to determine which genes are the most important.”
DU psychology Prof. Bruce Pennington spent nearly 10 years looking for Down syndrome pathways, but rather than biology, his work focused on the relationship between brain function and behavior in those with Down.
Pennington studied executive functions — planning, working memory and impulse control — governed by the brain’s frontal lobe, and long-term memory, which is affected by the hippocampus. Both the hippocampus and the frontal lobe are disproportionately small in people with Down syndrome, whose brains are smaller than normal.
He set out to understand why those with Down syndrome exhibit mental retardation. “Is it because the entire brain functions less well, or is it because some brain structures work particularly badly?” he says. “Maybe the retardation is simply because they have poor memory, but it might be that they can’t plan ahead, solve problems and inhibit inappropriate impulses. If we could understand what it is about their brains that gives them a lower IQ, it could lead to a therapy.”
Pennington and his colleagues tested adolescents with Down syndrome and a “mental-age equivalent” control group of younger children without the disorder. Long-term memory tests required participants to learn and recall an object’s location, a design or a word list. Executive function tests required subjects to solve a planning or spatial memory problem.
“The Down group was worse than the mental-age control group on hippocampal measures, but they weren’t worse on executive-function measures, which is consistent with results seen in mice,” Pennington explains. Subjects with Down syndrome still struggled with executive tasks but were no worse than the control group. But, follow-up studies with different age groups showed some executive functions were indeed impaired amongst those with Down syndrome.
Today, DU psychology doctoral candidate Nancy Raitano is continuing Pennington’s work, studying verbal short-term memory in Down syndrome. Verbal short-term memory — epitomized by the ability to repeat a string of digits — is particularly poor in people with Down. “This is important for understanding why they struggle with language comprehension,” Pennington says. Such studies also can shed light on normal language development, which relies on short-term verbal memory.
Although she’s an adult, Meghan Doherty reads at a third-grade level. Still, she manages to surprise her parents, who had to sue the school district in Granby, Conn., to get her mainstreamed.
“She came home from middle school once and had signed herself up for a theatre group she learned about by reading a poster,” Susie Doherty proudly recalls. “It sounded like something she wanted to do, so she signed up.”
Consequences, not cures
Like Jack Doherty, ERI Assoc. Research Prof. Alberto Costa is no stranger to the difficulties, and delights, of raising a child with Down syndrome.
Costa’s 10-year-old daughter, Tyche, has the disorder — a development that led him to redirect his career to understanding Trisomy 21.
Today, Costa studies Ts65Dn mice in the laboratory then performs parallel studies on humans with Down syndrome. One such study investigated how irregularities in eye movement affect balance in people with the syndrome. Another investigated how an electrochemical mechanism in neurons correlates with memory formation and how the gait of trisomic mice differs from that of normal mice.
“The overall thread of my research is excitation in the brain — the ability of a neuron to respond to stimuli and how it differs in folks with Down syndrome,” he explains.
“We’re looking at proteins that regulate neurotransmitters and receptors. We also look at metabolic processes downstream from neurotransmission, but we tend to focus more on that part that stays in the synapses because that’s where we’ve been most successful in developing psychiatric and neurological therapies.”
“Most researchers get the stereotypical version of what you think a person with Down syndrome should be,” Costa reflects. “When you get to see a person with Down syndrome every day and follow her development because she’s your daughter, you have less of a pre-formed idea.”
“Alberto never takes his research results for granted,” Davisson adds.
Tyche, whose name means “fortune” in Greek, demonstrates that each child with Down has unique strengths and weaknesses. Although her gross motor skills are comparable to a toddler, she has excellent handwriting and is the No. 2 speller in her class, her father boasts. “You get an idea of the potential these folks have,” Costa says.
Most parents of children with Down syndrome likely would agree. Meghan Doherty works part-time as a grocery clerk, and her parents beam when they announce that she recently moved into her own assisted-living apartment.
“In many regards, she is a typical little girl,” says Darii Wohlers of her daughter McKenna. “She loves to play with dolls and friends. She takes dance class and gymnastics, and loves her little brother — most of the time.”
McKenna recently mastered somersaults, a skill other kids learn by age 3. “She has the capacity to do most anything any other kid her age could do or would do, but it just takes her a lot more repetitions,” her mother says.
Although DU’s Down syndrome experts are hopeful, none expect an outright cure.
“For the most part, we don’t cure things in medicine, except for bacterial infections and appendicitis,” Costa says. “We develop therapies; we control things; we improve function. We control hypertension, cardiac function, depression and epilepsy, but we don’t cure those things.”
But, he adds, “It’s one of my dreams that we might be able to do something that has some beneficial consequence for my child, even if it takes years.”