Investigators at HudsonAlpha are conducting whole-genome sequencing as well as deeper, targeted sequencing, said Dr. Rick Myers, faculty investigator, director and president of HudsonAlpha Institute. He spoke at a recent NHGRI lecture in Lipsett Amphitheater. Lab data already has helped uncover genetic causes of more than 10 inherited diseases, including autism, ALS (amyotrophic lateral sclerosis), diabetes and bipolar disorder. Projects are also under way to delve deeper into the genetic causes of cardiovascular disease and kidney cancer.
The institute’s Genomic Services Laboratory operates more than a dozen high-performance sequencing instruments, Myers said, and recently acquired several Illumina X Ten systems—the latest, fastest and most powerful for whole-genome sequencing. Since its founding in 2009, HudsonAlpha has processed more than 80,000 samples and collaborated on more than 1,800 projects with hundreds of labs worldwide.
Investigators have made promising advances in their study of ALS, a progressive disease characterized by muscle atrophy. Part of a 2-year collaborative project, the study is examining 3,000 ALS cases through custom capture and whole-genome sequencing. So far, they’ve found at least 9 familial forms of ALS and several genes of interest, including a gene involved in loss of function mutations that plays a role in inflammation and autophagy (the breakdown, discarding and recycling of cells). And biotech companies are interested in these genes as targets. Myers said, “The hope is the drugs may even work for multiple diseases.”
Sequencing projects are also under way for cancer patients. From findings of gene fusions in breast cancer, one company is manufacturing antibodies to recognize these fusions and develop a cellular toxin to kill the cancerous cells. Another promising development is a biochemical process called DNA methylation that’s helping investigators search for biomarkers to predict risk and recurrence probability for aggressive forms of cancer. “The remarkable thing is [that] the specificity and sensitivity of any 3 or 4 of these biomarkers is amazing,” said Myers. The hope, he said, is to test DNA in urine and blood to improve routine screening for earlier detection and better treatment.
Each spring, runners traverse the 1-mile path along Genome Way in McMillian Park (Huntsville, AL) for the Double Helix Dash, a community event organized by the HudsonAlpha Institute for Biotechnology.
Photo: Marty Sellers
Another focus of HudsonAlpha research is childhood genetic disorders, often characterized by intellectual disability, developmental delay, heart defects, craniofacial abnormalities and/or seizures. Some 1.5-3 percent of children worldwide are born with one or more of these anomalies.
“These are significant public health problems,” said Myers. “We believe that most of these are genetic and that’s starting to pan out, a function of doing these kinds of projects.”
In one ongoing pediatric project, part of CSER (Clinical Sequencing Exploratory Research) in conjunction with NHGRI, investigators are recruiting and conducting whole-genome sequencing on 450 families. Since we all carry mutations, said Myers, it takes time to discern if there’s a single gene for a disorder. He cited a curious example of atypical Rett syndrome, where they found two unrelated kids who had different mutations yet neither child had seizures, a common symptom of the disease. In analyzing the results, Myers said, it’s an arduous task figuring out whether variants are pathogenic. “As soon as you get 2 or 3 or 4 mutations with a similar phenotype,” he said, “you’ll probably know that you’ve got it.”
A frustration with patients of any age, said Myers, is the needless anguish caused by undiagnosed diseases. Patients might see many doctors and go through years of futile, invasive testing at great personal expense only to get an inaccurate diagnosis or none at all.
That’s why identifying root genetic causes is important. “You can’t do anything if you don’t know the cause,” said Myers. Some conditions may appear similar but we can’t be sure without knowing the phenotype, and there are many genes and potentially many, maybe thousands, of causes. “I learned this from my first foray into human genetics: When people don’t know, they blame themselves, which is horrible,” said Myers. “If you can figure out the cause, [it can make a huge difference] in the relatively few cases where you can actually do something about it.”
While working on many genomic projects, HudsonAlpha also seeks to educate and inspire future generations of scientists. The institute sponsors “cradle-to-grave education,” said Myers; every kid across Alabama gets free lessons. In addition to courses, he said, their publications highlight “exciting happenings in genomics written in everyday language where everybody can understand it. This is something we put enormous effort into and we think it’s as important, if not more important, than our research.”