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The Long Road to Discovery
Changsoo Kang, Ph.D., a visiting fellow in NIDCD’s Laboratory of Molecular Genetics, remembers the day vividly. Sitting in an undergraduate Introduction to Biomedical Science class in South Korea, he was asked what role genes play in humans.
Changsoo Kang, Ph.D. (l), and Dennis Drayna, Ph.D.
“I said that genes are involved in functions having to do with thinking and speaking, and was told that I was wrong.”
More than 17 years later, Dr. Kang and an international group of researchers led by Dennis Drayna, Ph.D., have shown that genes do indeed play a role, at least in speaking, with the discovery of genes associated with stuttering. Stuttering is a communication disorder that affects more than 3 million people in America, and another 60 million worldwide. Their discovery is beginning to push back the fog of mystery that surrounds stuttering and opening up new avenues for treatment.
How this discovery was made is a tale of ingenuity, perseverance, and the ability to recognize what you’re looking for in unexpected places.
The story begins in Pakistan with a cluster of families with a high incidence of stuttering. Scientists have always suspected that there is a genetic component to stuttering because it tends to run in families, but finding the right families to study, and enough of them, is challenging. It turns out that Pakistan is a very good place to study genetic diseases.
“There is a high rate of intermarriage within extended families, often cousins marrying cousins, which has been going on for centuries,” says Dr. Drayna, chief of the Section on Systems Biology of Communication Disorders in the Laboratory of Molecular Genetics at NIDCD. Consequently, this narrows the gene pool and makes mutations easier to find using genetic linkage studies, which are the main tools scientists have for tracking down the locations of genes.
Dr. Drayna had already done linkage studies with the Pakistani group and had turned up a promising candidate region on chromosome 12 that was likely to harbor a mutant gene, but further progress proved difficult.
There’s a reason for that, says Dr. Kang, who inherited the linkage studies when he came to NIDCD to work in Dr. Drayna’s lab. “Some people naturally recover from stuttering as they grow older, so it’s difficult to define who’s affected and who’s unaffected by the mutation. Finding a gene for stuttering is hard because there’s no precise genotype-phenotype match.” For a scientist, this means there isn’t a consistent and predictable outcome between the gene mutation and its trait or symptom. It also means that establishing the one-to-one relationship of gene to trait is much more difficult to prove.
This was where Dr. Kang and Dr. Drayna began. They recruited more Pakistani families, plus additional unrelated individuals with stuttering in Great Britain and the United States, and gathered DNA from them and from a group of controls in the same populations. The controls were people who had no history of stuttering in their family. Back at the lab, Dr. Kang began sequencing. It turned out that the region of interest on chromosome 12 contained 87 genes, which meant 87 genes had to be sequenced and analyzed to see if anything interesting turned up.
Forty-five genes and three years later, Dr. Kang felt as if he was working on a project that was going nowhere. “I was tired and frustrated and wanted to give up and go back to Korea,” he said. “So I went to Dennis’s office and told him how I felt.”
From the beginning, Dr. Drayna had known that this was a high-risk, high-reward project and there was a possibility that the dice wouldn’t roll in their favor. He couldn’t blame Dr. Kang for wanting to give up. He had nothing to show for three years of hard work. The advancement of his career was on the line.
“For the next week, I didn’t do any experiments,” says Dr. Kang. “I sat at my desk. And then one day, I picked up my lab notebook and started to look through it because I was going to have to hand it over to the new postdoc who would take my place. And I saw something.”
What he saw was a mutation in a gene that he’d noticed before, but hadn’t thought much of. The gene, GNPTAB, was related to a group of diseases known as the mucolipidoses—metabolic disorders that are so lethal, most babies diagnosed with them die in early childhood. He doubted a gene for a metabolic disorder could have anything to do with a speech disorder such as stuttering. Curious, however, he began to look through the scientific literature to find what he could about the mucolipidoses. That was when he came across something intriguing. Children with milder forms of the disorder, who live past infancy, have delayed speech development or speech abnormalities.
Dr. Kang knew he was on to something but he couldn’t find any papers in the scientific literature that specifically addressed speech problems in the mucolipidoses. So he did what we all do when we need to know something right away—he Googled. “Mucolipodosis + speech” turned up a site that described a type of mucolipidosis in which children don’t speak at all. Not a word. With that, he knew he had to be headed in the right direction.
Further sequencing of the DNA from the Pakistani families showed that the mutation was present in some people who stuttered. Sequencing also revealed that the same mutation was found in members of the original linkage study group. Since the GNPTAB gene was known to work with two other genes—GNPTG and NAGPA—he sequenced them and found mutations that were present in stutterers and their families, but not in the control groups. In fact, no one had ever found a human with any disease associated with mutations in NAGPA, until now. Its only known effect is stuttering.
"This project serves as a ‘poster child’ for the intramural program of the NIH," says Dr. Drayna. "It's taken us more than a decade to get this first major result, and Dr. Kang's Herculean efforts eventually paid off, but it took quite a bit of time. It's a tremendous privilege to serve in an institution that allows long-term, high-risk research."
As Dr. Kang thinks back on his days as an undergraduate, when he was asked about the roles genes play in humans, he can’t help but laugh at the irony. “My instructor said that genes had nothing to do with speech. But it turned out that they did, and I discovered one of them. It’s an amazing thing.”