Thinking about thinking

April is Autism Awareness Month and Professor Robert Burgess, Ph.D., is doing a lot of thinking about cognitive disorders and mental illness, as he does daily every other month as well. 

Burgess has spent the last dozen years at The Jackson Laboratory investigating how brains are wired and how their instructions reach distant parts of the body. In neuroscience, researchers are just beginning to understand how our brains and nerves work when everything goes right.

Basic research is absolutely vital to understanding disease and disease processes. Understanding standard neurological function is very important. Investigating an organ as complicated as the brain—Burgess characterizes it as "bordering on chaos"—lays a foundation for knowing what happens when something goes slightly wrong, as in cognitive disorders and mental illness. Autism spectrum disorders are a good example.

"With autism, we’re trying to describe a disease state when we really don’t understand the healthy state," says Burgess. "To fix it, you have to know how it’s supposed to work. How are we wired? How are all the connections and networks set up correctly in our brains? We have found a gene in my lab that seems to play a role, but we still don’t really know how it works, how it interacts with the other genes involved, and exactly how it contributes to brain development. We need to figure that out before we can see how it applies in autism."

A neurological contrast

Burgess’ interest in brain development and function was triggered when, as a teenager, he saw stark contrasts within his own family. His paternal grandfather developed vascular dementia, while his maternal grandmother lived to age 96 with no loss of mental acuity whatsoever. His advanced-biology class also introduced him to ways that scientists were able to manipulate genes, a concept that was "really cool, hot new stuff at the time."

His biochemistry major at Michigan State University took him away from the biological end of the spectrum for a time, but as a senior he returned to the brain, completing a project on the enzymes that control brain metabolism. Burgess studied drosophila (fruit fly) genetics during graduate school at Stanford University, then faced a choice of animal models for postdoctoral work. His eventual transition to mouse genetics was more by chance than design.

"I looked at a drosophila lab, a C. elegans (worm) lab, a straight biochemistry lab and a mouse lab," says Burgess. "The mouse investigator was doing very exciting work overall. He also had a project that would have scared away mouse geneticists, but as a fly guy it sounded OK to me, and I was able to do it."

Burgess came to JAX from his postdoctoral fellowship to further his work in mice. Attracted by the resources and scientific opportunities available, he has also benefited greatly from the expertise of his colleagues and the Laboratory’s collaborative atmosphere.

"There’s a huge benefit to anybody’s research program to having good colleagues and people to discuss new ideas with," says Burgess. "So, if I’m studying what I think is a neurological mutation and then I find out that the immune system is involved, I don’t have to throw up my hands. I can go down the hall to an immunologist and ask how to study this. I’ve never been turned away by another investigator if I had questions or if we wanted to start a collaborative project."

Associate Professor Greg Cox, Ph.D., who often works closely with Burgess, studies the genetics underlying neuromuscular disease, including amyotrophic lateral sclerosis and muscular dystrophy.

"Having Rob as a colleague and lab neighbor—our two groups share lab space—has significantly extended the kinds of questions that we can address with our research," says Cox. "Many of our projects have benefited from this close collaboration as we can attack a disease from multiple angles. Many of the disease models we work on will pass from lab to lab as we each make our contribution to understanding the causes and potential treatments that can be applied to patients with these same devastating disorders."

Precision wiring

Burgess’ current research focuses on brain development, including how neurons assemble in the elaborate three-dimensional networks that underlie our cognitive function. "Didn’t wire up quite right" is a common theme in research into the genes underlying diseases such as autism, epilepsy and cognitive disorders, but there is much to learn about how exactly it does wire up right.

Burgess also studies the structure and function of peripheral nerves, the ones that deliver instructions to the muscles. Interestingly, one of the first uses of whole-genome sequencing to find a human disease mutation landed right in his peripheral nerve research area.

James Lupski, a geneticist at Baylor University, published findings in 2010 in which he identifies the genetic basis of his own case of Charcot-Marie Tooth (CMT) disease. CMT is a degenerative disease of the peripheral nerves, in which strength and sensation are gradually lost in the extremities (lower legs, feet, forearms and hands), though severity varies significantly from patient to patient. Lupski is from a family in which four of eight siblings have CMT, clearly indicating a familial genetic basis. Sure enough, the whole-genome sequencing identified the culprit: multiple mutations in a gene, SH3TC2, that had previously been associated with CMT but had remained undetected in Lupski's own case.

Burgess’ current research is looking into a mouse strain with a Sh3tc2 mutation that develops a far more severe disease that eventually leads to paralysis. Analysis found a second mutation in another gene, called Nrcam. Knocking out just Nrcam function in mice does very little—in fact, the mice look normal. But the mice with both Sh3tc2 and Nrcam mutations rapidly lose movement, and the effects are more than the sum of the two mutations.

"The exciting thing about this is it will help us understand the process," says Burgess. "Why do the two mutations together create a disease far worse than you’d expect based on the single mutants? It might help explain why human CMT patients are so variable in their disease. Some, like Lupski, are still pretty mobile, but others are confined to wheelchairs. There are studies under way to see if NRCAM plays a role in that variability."

The root cause

While both of Burgess’ areas of study have important human disease implications, his drive to understand the details of normal function underscores a philosophical conflict in research that has profound implications.

Traditionally, scientific discovery has proceeded from basic research—seeking biological understanding without a defined end goal—to translational research —aiming for a specific goal. Ultimately, clinical research brings benefits to patient care. Translational research has been all the rage lately, however. It’s easy to understand why. The success stories provide straightforward narratives for funders and others who support biomedical research.

"Humans are going to be the disease-discovery model at this point," says Burgess. "But determining cause and effect is very hard in human patients. What are you going to do with all the information you get in humans? We must have model organisms to test the mechanisms."

The utility of basic biomedical science is being questioned and funding is shrinking. But it’s essential for providing the understanding needed for effective translational research. And when a scientist is studying the brain, where so much of what happens remains unknown and even unexplored, few translational bridges exist.

"Basic research is absolutely vital to understanding disease and disease processes," says Burgess. "If we don’t understand basic biology, you can never understand how to cure a disease. You can treat the symptoms, you can treat the downstream effects, but you can never get at the root cause."