KANSAS CITY, KAN. — A pairing of next-generation and century-old research methods is helping scientists at Kansas University Medical Center learn more about genetic disorders in children.
The new is a roughly $1 million machine that can sequence a person’s DNA in as fast as two days.
The old has been used in labs for a century or more: watching mice run mazes.
Peter Smith, KU Medical Center professor of molecular and integrative physiology, directs the Institute for Neurological Discoveries and co-directs the Intellectual and Developmental Disabilities Research Center.
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Smith’s research includes analyzing genes of children with rare, undiagnosed disorders, as well as children with complex but known disorders, such as autism and Tourette syndrome.
Some of the DNA he researches comes from patients across town at Children’s Mercy Hospital.
The hospital’s Center for Pediatric Genomic Medicine has DNA sequencing capabilities, but not the level of animal testing facilities that can take genomic discoveries a step further, center director Sarah Soden said. That’s where KU Medical Center and its mice help.
“It’s really important to have people like Dr. Smith to work with to develop more evidence to determine if we’re on the right track,” Soden said. “Animal models are really important.”
Previously a common theory was that a mutation of a particular gene created a particular disorder, and mutation of another created another disorder, and so on, said John Colombo, director of KU’s Life Span Institute, home to the Intellectual and Developmental Disabilities Research Center, which he also directs.
The more scientists learn about genomics, however, the more they’re seeing it’s not so simple.
In fact, it appears that not one, but a configuration of genes causes intellectual and developmental disabilities, Colombo said. He said environmental conditions that turn genes on and off may also be at work.
“It’s a very complicated, intertwined story,” he said.
In short, that’s why a fancy machine alone — even if it can identify which of a person’s genes is broken — can’t always explain why a child is sick.
Looking a little like a mini-fridge attached to a computer, KU Medical Center’s genomic sequencing machine sits on a counter in a lab at the Hemenway Life Sciences Innovation Center.
It’s a confocal microscope, high-sensitivity camera, computer and storage device all in one, Smith said. Each specimen — cells from a cheek swab, for example — takes two to 12 days and about four terabytes of memory to run.
Bioinformatics specialists, also at KU, analyze all that data, Smith said. The process reveals which of the person’s genes are mutated.
However, even healthy people have 50 to 100 mutations, Smith said. So proving which gene — or could it be genes? — is causing a disorder can require more research.
After a little more modern science, that’s where the mice in mazes come in.
In another lab at the Hemenway building, scientific director Jay Vivian and his staff in the Transgenic and Gene-Targeting Institutional Facility create mouse embryos with genetic mutations matching the human profiles they are trying to study.
Once the special mice are born and mature, he said, they go to the Rodent Behavioral Facility.
There, facility director Ken McCarson and his staff observe and record their behavior, looking for symptoms that match the ones reported in the sick child.
Some tests are high-tech, such as a box that electronically records weight shifts, such as those that might indicate a lack of balance, he said.
Others are decidedly old-school, such as the Y-maze. A healthy mouse would explore all the arms, while one with cognitive loss would not, McCarson said.
While the DNA sequencing machine takes days, the tedious mouse breeding and developing and watching process might take years.
When a mouse’s behavior matches the person’s, a sign the genes were correctly identified, “that can be very exciting when it happens,” McCarson said.
At the same time, he said, when results aren’t as hoped, it’s extra-disappointing.
One example Smith is working on with Children’s Mercy involves three brothers with Tourette syndrome, he said.
They’ve created mice with genetic mutations matching the boys’ parents, and plan to breed those mice together, in hopes of learning more about what’s affecting the brothers.
The most exciting thing about his work is the possibility of translating diagnoses into therapies, Smith said.
But that’s a long-term goal.
It’s taken decades for genomics to get where it is now, Smith said, and much of his research is still in the early stages.
There are some children whom genetic discoveries are helping immediately, Soden said.
She gave an example of two brothers with life-threatening gastrointestinal disorders, symptoms of which showed up in infancy. The brothers received bone-marrow transplants and, although one died from complications, the other was cured.
Until science advances, however, simply being able to identify disorders by using DNA sequencing is a welcome breakthrough from years ago.
“The vast majority of kinds that I see, we are just able to tell the parents why,” Soden said. “And over and over again, I’ve been told that that’s been life-changing for them, just understanding.”