At the University of Denver’s Eleanor Roosevelt Institute (ERI), founded in 1961 to conduct pioneering biomedical and genetic research, undergraduate and graduate students partner with world-renowned scholars in a quest to unravel the mysteries of disease.
For Nathan Duval, a PhD candidate in biological sciences, that quest has personal significance.
“My mother has lupus,” he explains, so he is well acquainted with the toll that disease takes on overall health and day-to-day life. “And I’m interested in disease processes — the idea that certain genetic mechanisms can cause disruptions in your physiology and lead to disease.”
While casting about for a graduate program that would address two priorities — furthering his understanding of how diseases behave and enhancing his career prospects in biomedical research — Duval learned about the groundbreaking work under way in the lab of Professor David Patterson. That, as well as the chance to work with interdisciplinary research teams at the ERI, convinced him to apply to DU.
His decision has paid off in hands-on opportunity. He and Patterson are collaborating on a handful of projects that could improve what Duval calls “the health-span” in people contending with an array of genetic diseases and disorders. What’s more, he has already secured publication credits as the first author on an article, published with Patterson, in “Molecular Genetics and Metabolism.”
Patterson, who holds DU’s Theodore Puck Endowed Chair, is known internationally for his decades of research on Down syndrome. In fact, his part in the mapping of chromosome 21, which contains the blueprint for Down syndrome, has added significantly to the scientific community’s understanding of the genetic condition.
To advance that understanding even further, Patterson and Duval are working with the Ts65Dn mouse model of Down syndrome. The Ts65Dn is a genetically altered model for Down syndrome.
“The mouse has a lot of features that are very similar to Down syndrome,” Patterson says. “It has learning and memory deficits and it has skeletal differences. It also has a precursor of leukemia. A lot of those things happen in people with Down syndrome. It also ages differently, and that’s been our hypothesis for people with Down syndrome for a long time.”
Using the Ts65Dn mouse model, Duval and Patterson are studying the metabolome and physiological changes that accompany aging in Down syndrome. “We are trying to understand the metabolomics, or changes in small molecules and metabolites, that may be part of, or due to, the genetic and physiological alterations that accompany Down syndrome and aging,” Duval explains.
This quest has ramifications for scientists and, in time, the medical community. After all, the better scientists understand the pathways involved in aging, the better able they’ll be to address health-span issues, such as deteriorating cognition or muscular function.
As they age, Patterson notes, “People with Down syndrome are at remarkably increased risk of developing Alzheimer’s disease. So could we slow that down or prevent it? That wouldn’t cure Down syndrome, but it would sure make life better for people with Down syndrome. And if we learn something about Alzheimer’s disease in people with Down syndrome, one hopes that it would be applicable to everyone with Alzheimer’s disease.”
Closer to home, perhaps the work will even be applicable to the complex but much-misunderstood autoimmune disease that troubles Duval’s mother. “Lupus happens to be an aging-related disease, though not in the sense that as you get older you are more susceptible,” Duval says. “Rather, lupus accelerates the rate of aging. A person afflicted with Lupus may appear normal, but physiologically they are much older.”
Patterson and Duval are also seeking to determine whether rapamycin, a drug that has been shown to extend life span — and health systems — in typical mice (as well as other evolutionarily divergent species) will do the same in the Ts65Dn mice.
“Mice will eventually die of the things mice die of, but it will be 20 percent later,” Patterson says of rapamycin. “The idea is to see whether this particular drug also could be beneficial to people with Down syndrome.”
Like so much scientific research, this work will unfold over years. “A lot of it involves waiting while the mice get old,” Patterson says.
As he monitors and tends to the aging mice, Duval is immersed in another Patterson project, investigating a cell culture model associated with a little-known metabolic disorder known as ADSL deficiency.
“People with ADSL deficiency have a highly variable constellation of features,” Patterson says. These include everything from mild developmental delays to muscle wasting and epilepsy. It has also been associated with prenatal death.
“It’s a confusing situation because … from person to person the physiological features [of the disorder] are remarkably different,” Patterson explains.
So little is known about ADSL deficiency that many people afflicted with it often go undiagnosed. Patterson and Duval hope that their foundational work can aid in both diagnosis and treatment of the condition.
In many of their projects, Patterson and Duval work with interdisciplinary teams that include biophysicists, physicists and chemists. For example, biophysicists and chemists can help biologists understand how a certain protein’s actions may change due to different mutations and how these changes affect physiology.
“I think that now we’re starting to understand, in science as a whole, that the interactions between all these different levels — the genome, the proteome and the metabolome — all play a role in the disease,” Duval says. “Understanding disease is not just a biological problem. Diseases need to be approached from as many different angles as possible to further our understanding.”