An Indomitable Mind
By Marcia Goodrich
Researcher discovers genes linked to Lou Gehrig's disease
About five years ago, mathematics professor Shuanglin Zhang received news anyone would dread.
He had amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease. It would creep though his body, the doctors said, slowly destroying the nerves in his brain and spinal cord that control voluntary movement. Eventually he would become paralyzed, unable to move or speak.
Faced with such a sentence, Zhang did not try to fill his remaining able-bodied days with skydiving, safaris, or a visit to the pyramids. The one item on his bucket list was his work. He resolved to enlist his intellect in the war against ALS.
Zhang is a statistical geneticist and the Henes Chair Professor in Mathematical Sciences. Along with his wife, Qiuying Sha, an assistant professor of mathematical sciences, and other members of his research team, he uses statistical techniques to track down the genetic underpinnings of complex diseases. The team had already found eleven genetic variants, called SNPs ("snips," for single-nucleotide polymorphisms) in genes linked to type 2 diabetes.
There are two types of ALS: The familial form, which accounts for about 10 percent of the cases, is inherited. The cause of the sporadic form was unknown. Zhang had sporadic ALS and suspected that, like type 2 diabetes, it was fundamentally linked to the interactions of multiple genes.
With complex inherited conditions, a number of genes can cause disease when they act together. In the past, finding these gene-gene combinations has been almost impossible because of the myriad calculations needed to match up suspect genes among the half million or so in the human genome. More importantly, the DNA datasets needed to perform the analysis are often unavailable or nonexistent.
Then, while exploring The ALS Association's website, Zhang discovered the information he needed. The datasets detail the genetic codes of over five hundred people, about half with sporadic ALS and half without. Zhang and his team applied their methodology, called a two-locus interaction analysis. It revealed that people with sporadic ALS had a combination of three genes with atypical SNPs.
The mathematicians were not surprised when they tracked down the genes' street addresses. "Everybody has twenty-three chromosomes, and the three genes on chromosomes 2, 4, and 10 interact," explains Sha. "If you have this combination of the three genes, you are at high risk of developing the disease."
Xiaofeng Zhu, an associate professor of epidemiology at Case Western Reserve University's School of Medicine, called the study "very nice work."
"It's very challenging to map genes for complex diseases, and while many statistical methods have been developed, most don't work well in practice," says Zhu. "Zhang's group has developed a method to detect genes and gene-gene interaction in complex diseases and provided evidence that it works.
"Their findings will need to be confirmed by other researchers, but I think this will be very useful for the investigators who are trying to find genes underlying complex diseases such as ALS," says Zhu.
While their discovery does not mean an end to ALS, it could provide medical researchers with valuable clues as they search for a cure. If they find one, it will probably be too late to help Zhang. Since he began the effort to uncover the genetic causes of ALS, the disease has taken its toll. He is now almost completely paralyzed and breathes with support from a ventilator. He continues to work at home with the aid of research assistants, his wife, and an ingenious low-tech tool they developed that lets him spell out words, sentences, and research papers.
The letters of the alphabet are written in five rows on a card, with several letters to a row. A helper points at each row in sequence, and Zhang blinks if the letter he wants is in that row. The helper then reads or points across the row, and Zhang blinks again at the correct letter.
It seems like it would take forever. It doesn't. Using this simple grid and a similar chart of mathematical symbols, Zhang recently completed a paper and submitted it for publication. Not everyone who gets ALS is willing to live within these constraints. Some decline the use of mechanical ventilators and perish from respiratory failure. Zhang decided early on that he would fight the disease as long as he could.
"He wants to keep doing his research," explains his wife, Qiuying Sha. "For him, that is the most important thing." Once someone asked him what he would want if he could have one wish granted. "You would think he would say ‘to be cured of ALS,' but he said ‘a breakthrough in my research,'" she recalls.
People with ALS have huge hurdles to overcome, says Sharon Matland, vice president of patient services for The ALS Association. "Despite not being able to speak, not being able to move, they work so hard to stay engaged in life, whether it's doing work, or going to a child's athletic event, or being with their families. They continue to do amazing things."
Many patients participate in research, she says, though rarely as scientists. They volunteer for clinical trials knowing that it may be too late for them to benefit from any discoveries. "They want to do something, and if their participation in a research project will help others, they do it. As in Dr. Zhang's case as an ALS researcher, it is also altruistic.
"It is a devastating disease, and it takes everything away," Matland says. "The fact that Dr. Zhang is able to continue his research is to be applauded. What he has done is outstanding."
Zhang continues to conduct his research four hours a day in collaboration with PhD student Shurong (Rebecca) Fang. He reclines in his chair with a laptop computer mounted above while they work on their most recent paper, "Two-Locus Analysis for Genome-Wide Association Studies."
In the beginning, as ALS burdened him with one constraint after another, Zhang found the disease nearly impossible to bear. Now, as he blinks out elaborate formulae that may one day save lives, he is more resigned.
"Nothing else I can do, and I like to do research," he says, spelling out the message one letter at a time.
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