Tuesday, March 16, 2010
Wallingford is a scientist doing basic research at The University of Texas at Austin. Using frogs and mice as models, he studies how embryos develop and what can go wrong in development.
The scientist and the surgeon have teamed up to find ways to translate the basic discoveries made in Wallingford’s laboratory for use in George’s examination room.
They want to reduce birth defects, particularly neural tube defects, the second most common class of birth defects behind heart problems. Spina bifida, a condition in which the spine does not close completely, is an NTD.
The work of turning lab discoveries into therapies will take place in the Dell Pediatric Research Institute, where other researchers will work to bridge the distance from Wallingford’s laboratory bench to George’s hospital bedside.
“We are two bookends,” Wallingford says. “If we can fill in the center, we will have the group in place to really do something great.”
“You need to cover the whole spectrum,” George says. “That really makes what you do, all of it, productive.”
It’s a bit unusual for a basic scientist and a physician to develop a close working relationship and perhaps especially so for Wallingford and George. When they met in 2003, Wallingford was in Texas and George was at Duke Medical School in North Carolina.
Their mutual interest drew them to the International Neural Tube Defects Conference. It brings together people from a range of disciplines interested in addressing birth defects. There are basic biologists such as Wallingford and clinicians such as George as well as animal and human geneticists, public health officials and others.
Dell Children’s Hospital brought George to Austin at the head of pediatric neurosurgery in 2006.
“One of the attractions of coming here was the fact that John was here,” George says. “I knew the sort of work he was doing and that was an attraction.”
George received an appointment as an adjunct professor in the Section of Molecular Cell and Developmental Biology at the university.
Wallingford works in the same Patterson Hall office he did as a Ph.D. student. Back then he shared it with four others.
High on the wall above Wallingford’s desk are images of the stages of egg development drawn by a professor back then.
“We’re a basic research unit here,” Wallingford says. “We discover genes and we figure out what genes do.”
Part of the work in Wallingford’s lab is to study how cells decide what they are and where they go.
When cells start the process of forming a neural tube the shape of their mass is round and flat—like a tortilla.
Then the sides begin to move inward toward each other, the way a tortilla wraps around eggs and bacon inside a breakfast taco. It’s wider at the top, where the brain forms and narrower at the bottom, where the spine is.
“The sheet is rolling up,” Wallingford says, describing the process. “But one end is a bowl closing up and you can imagine how that’s going to make a brain whereas this part down here is going to make this long, narrow spinal cord.”
When something goes wrong, the result can be an NTD.
He’s trying to identify the genes that direct this process and how they work together.
Much of Wallingford’s work has been done with frog embryos. He’s moving into a mouse model, which should more closely resemble what happens in the human system.
At some point, Wallingford developed an interest in finding applications for his research.
“As I got older two things happened,” he says. “One, I needed to get grants to fund my lab. But I also had a couple of kids. I don’t know how it’s all mixed up, but sort of my giving serious thought to biomedical application came at around the time that I started my family.”
In 2008, Wallingford was selected to be a Howard Hughes Medical Institute (HHMI) Early Career Scientist. The HHMI will pay for Wallingford’s research for six years, enabling him to pursue his best ideas.
At Dell Children’s Medical Center, children clutch their parents’ hands as they walk into doctors’ offices. Some parents show more apprehension on their faces than their children do. Staff members and volunteers bustle about.
George’s patients are children—ranging from newborns to older kids—with serious problems.
“What I do on a daily basis, at its fundamental essence, is take care of kids with a many diseases that affect the nervous system,” he says. “A large component of those are kids with congenital anomalies.”
He diagnoses problems and prescribes therapeutic solutions. And he operates, going in to reroute bad plumbing in tiny brains.
“We reconfigure the defect to make it more functional, in an attempt to correct the imparment that it causes,” George says.
An example of an NTD with which George deals is myelomeningocele, in which the backbone and spinal canal do not close before birth. The condition is a type of spina bifida.
“A lot of those kids end up with some degree of spinal cord dysfunction leading to paralysis,” he says. “And that can vary from partial to total.”
Furthermore, it can cause hydrocephalus, a swelling of the brain. That requires spinal fluid diversionto relieve the pressure.
“That’s a plumbing issue,” says George, borrowing imagery from his father’s profession to describe what he does. “We repair it by roto-rootering out the blockage of flow, or by putting new pipes in.”
George is happy that he can use his surgical skills to help a child suffering from an NTD, but he’d rather it not come to that.
“I don’t have a problem rerouting the fluids and re-plumbing the plumbing, but that is not treating the main disease,” he says. “It is only controlling it to some degree. We need to find either better ways of preventing it from happening or really or rebuilding it so that it’s fixed, not just managed.”
To mix metaphors, what the bookends needed was a bridge.
“I’ve worked in basic science and John has some translational work,” George says. “We have to figure out a way to marry those two together.”
As Wallingford and George were plotting their birth defect research, the Michael and Susan Dell Foundation was planning to work with The University of Texas at Austin to open a research institute to address children’s health.
“It’s great to be in the right place at the right time,” George says, “because the research institute was being developed and built and that, to me, was a great sign that there was an opportunity for having a physical space right adjacent to the hospital, which was designed to be collaborative to the hospital.”
The thing is, George and Wallingford might not work directly together. Wallingford would, in effect, hand off his research results to the scientists in the institute and they would hand off to George (not including clinical trials, governmental approvals and a long list of other requirements).
Here’s how Wallingford sees the collaboration, at least part of it, working:
“Tim has access to patients, he brings them in, he sees them, we have a human geneticist in the DPRI. Tim sees patients. That gives us additional access to biological samples. The human geneticist identifies the genes that are involved in the different deformities that Tim sees. My lab figures out what those genes do, that gives us insight into how we can change it.”
Besides the diagnostic and therapeutic advances that might result from their collaboration, George and Wallingford see it having a long-term impact on the basic scientist-clinician relationship.
Students working with them can move back and forth between basic and applied research and help develop a common language that hasn’t been spoken before.
“What I really enjoy is the fact that he has a shared vision,” George says of Wallingford. “He has the same passion. We actually get along and that makes it fun. I think there are a lot more relationships that can happen like that. But no one has even been in a place that can get together and talk. That’s where I think the DPRI comes into play.”