Genetic Cartography
Creating a Roadmap for Treatment
Dr. D. Woodrow Benson is director of Cardiovascular Genetics at Cincinnati Children’s and a professor in the Department of Pediatrics at the University of Cincinnati College of Medicine.
Learn more about Dr. Benson’s NIH-funded work.
Just listening to D. Woodrow Benson, MD, PhD, describe what he does at Cincinnati Children’s is enough to wear a person out. A clinician and researcher in the Division of Cardiology, he is the principal investigator for two NIH-sponsored programs: a Specialized Center for Clinically Oriented Research and the Pediatric Heart Network. He is also director of Cardiovascular Genetics and, in his words, “a born-again geneticist.”
“I didn’t set out to be a geneticist,” he says. “But I discovered around 15 years ago that the genetic approach offered an effective way to get a handle on why pediatric patients have certain heart problems.” This discovery led him to focus on a search for the genetic building blocks of two pediatric heart conditions thought to be genetically related: bicuspid aortic valve (BAV) and hypoplastic left heart syndrome (HLHS).
Bedside to Bench and Back
“One of our big research resources here at Cincinnati Children’s is the patients that we treat, and one of the challenges is how to use what we know about their disease to understand more about why they have these problems,” says Dr. Benson.
In a process he calls “bedside to bench and back,” he describes how his research cycle begins. “We start with the patients and take the information they provide us back to the laboratory,” he explains. “We go from the bedside to the bench with the idea that with our discoveries, we can go back to the patient with new ideas about diagnosis or options for treatment.”
At the Bedside
Dr. Benson’s genetic research into BAV and HLHS illustrates how it works. “We use a family-based approach,” he says. “First we identify a pediatric patient with one of these conditions, do echocardiograms on all the first-degree family members and take a detailed family history. If we find other affected people, we extend this to other generations.” Dr. Benson works closely with Robert Hinton, MD, of the Division of Cardiology, to enlist children and families for these studies.
At the Bench
After collecting all the data, the bench phase begins. It involves sifting through a seemingly endless array of genetic information and finding commonalities that may contribute to these heart conditions.
Explains Dr. Benson, “We have some 1,500 people now in our study and we know a great deal about their hearts. We’ve done kind of a genetic scan of the whole human genome, looking for those parts that are related to the problems that we’re interested in.”
This process, known as linkage analysis, is “like making a genetic roadmap for each individual person,” he explains. “We look at all the genetic information to see how it’s related to what we know about the hearts, and try to find out if there are parts of the chromosome that go with the heart problems.”
As a result, they have identified small areas of a particular chromosome, known as loci, that could be where the culprits responsible for BAV and HLHS are located.
“There are about 10 of these loci and each might contain 100 or 150 genes,” he says. “Our genetic studies tell us that one of the genes in here is the gene we’re looking for. That’s where we are now. We have these 10 loci, each with 100-150 genes, and now we have to sort through them to get to the one we’re looking for.”
And Back - the Clinical Implications
It will still take some time to get to the “and back” phase of Dr. Benson’s approach, but he believes his search holds enormous promise for improving the diagnosis and treatment of pediatric heart disease. Now that his team has reduced the number of genetic possibilities, a combination of two strategies seems to be the best approach.
One strategy would begin mapping each locus in more detail. “Now we can focus and do additional genetic mapping to make our locus a little smaller,” says Dr. Benson. “So we could reduce from 150 to 10 genes. If we’re down to 10 genes, we can look at each one individually.”
The second approach is similar, but establishes priorities. “If we’re looking at a locus with more than 100 genes, because of the sequencing of the human genome project, we know what all those genes are,” Dr. Benson explains. He has collaborated closely with Katherine Yutzey, PhD, of the Division of Molecular and Cardiovascular Biology, to more fully understand the genetic basis of heart valve development. “Because we’ve become familiar with valve development, we could cross check and say, ‘OK, here are the genes that are in our locus, here are the genes involved in valve development, are there any matches?’ These get priority. Let’s look at them first.”
Sifting through the reams of genetic information to find those genes involved in valve development is an enormous undertaking, but, says Dr. Benson, the potential clinical benefits of this effort are significant.
“Understanding the genetic basis of BAV and HLHS promises to lead to better insight into these abnormalities and, ultimately, to improved diagnostic capabilities and alternative therapies.”
