Researchers at UNC School of Medicine have discovered a potential environmental cause of autism in a type of chemotherapy drug, and they are beginning to investigate the effects of other non-chemo drugs that work by a similar mechanism.
Professors Mark Zylka and Benjamin Philpot made the discovery while studying a drug that’s effective against cancer, but also shows potential as a treatment for a genetic disease called Angelman syndrome. In the process, they made some new observations that seem to point to a cause of autism. “That’s science,” says Zylka. “You’re trying to do something and you find something else.”
The duo, along with colleagues at UNC Chapel Hill and the University of Connecticut, published their results in the journal Nature on Aug. 28.
On Sept. 30, the National Institutes of Health awarded Zylka a Pioneer Award to continue the autism work. Only about a dozen researchers receive the annual award, which provides up to $2.5 million over five years. According to the NIH website, the award supports researchers of “exceptional creativity, who propose pioneering and possibly transforming approaches to major challenges in biomedical and behavioral research.”
Zylka and Philpot are both associate professors in the department of cell biology and physiology at UNC’s School of Medicine, but they might never have worked together if it weren’t for the proximity of their labs. Zylka studies the neurology of pain; Philpot studies Angelman syndrome, a genetic disorder that is sometimes misdiagnosed as autism or cerebral palsy. The two often discussed their work when they saw each other in the halls or at lunch.
They started collaborating on projects related to the perception of pain in people with Angelman syndrome. Recently, they broadened their collaboration by pooling funds to purchase a genome sequencing machine, which they used to investigate how the cancer drug topotecan affects specific genes. This project grew out of work Philpot did a couple of years ago that showed topotecan might be useful in treating Angelman syndrome.
As a cancer drug, topotecan works by gumming up cell division to halt tumor growth. It does this by inhibiting enzymes called topoisomerases, which keep DNA from becoming knotted up.
In our cells, DNA is typically tightly wound in packages for efficient storage. But DNA must be unwound during two crucial processes: cell division and gene expression. Topoisomerases make this unwinding possible. Zylka calls the enzymes “scissors and glue,” saying, “They cut the DNA, uncoil it, and stick it back together very, very fast.”
In the case of Angelman syndrome, Philpot was interested not in cell division but in gene expression – the process by which genes do their biological jobs, whether specifying eye color or telling a cell to become a neuron.
The ‘eureka’ moment
Philpot, Zylka and their colleagues treated human cells with topotecan and ran the samples through the Next Generation machine, a high-throughput gene sequencer. “It’s incredibly powerful,” Zylka says of the machine, which he and Philpot acquired in March. “You can put a chemical on a cell and see how it affects every single gene in your genome. And it’s fast – the machine takes 24 hours to run.”
The data from the experiment came out on an enormous spreadsheet. The genes were listed in order, with those at the bottom being the least expressed – that is, they were less capable than usual of doing their biological jobs.
Zylka remembers his eureka moment: “I was sitting a computer one evening and I was looking at the genes at the bottom of list and I saw this gene called dystrophin that’s associated with Duchenne muscular dystrophy.” The gene was familiar to him because it was discovered by one of his professors at Harvard. “I remember him telling us this is one of the biggest genes in the human genome, and it was sitting at the bottom of list. I looked at a few other genes and had a sense they might be big.”
A bit more work proved his insight to be correct: Genes at the bottom of the list were all long genes, meaning that topotecan had the most negative impact on long genes.
The ‘long gene’ factor
Zylka noticed something else about the genes at the bottom of the spreadsheet. Other researchers have identified around 300 genes that are associated with autism, and Zylka realized that a fair number of those genes were at the bottom of the list.
“These two unexpected observations centered on gene length: Topoisomerases regulate really long genes, and autism genes are really long,” he said. This led to the insight that inhibiting topoisomerases, as topotecan does, might increase the risk of autism.
Most of the affected genes are related to brain development and do their most important work during times of rapid brain development before birth and in early childhood. That means timing is crucial: Exposure to topotecan during those sensitive times could lead to lifelong effects even after the exposure ended.
Presumably, not many women take topotecan while they are pregnant, but there are other drugs currently on the market that also inhibit topoisomerase enzymes, including some antibiotics and antifungals.
“We want to try to find as many additional chemicals as we can that inhibit long genes, so that we can start to inform the public,” Zylka said. “We aren’t going to be able to prove that any of these things cause autism; ultimately you need epidemiological studies to nail that. But we hope it’s the beginning of a broader base of knowledge that will help people down the road.”
Andy Shih, the senior vice president of scientific affairs at Autism Speaks, calls the results of Zylka and Philpot’s work exciting, and said, “What’s important about this study is that it reveals another potential mechanism by which autism risk could be affected.”
Shih also said the study could inspire ideas for autism treatments: “If we know that topoisomerase is not functioning optimally, you can imagine that a compound or drug that compensates for that change or restores the function of the topoisomerase could have a positive impact on those individuals whose autism is tied to that.”
Back in the lab, Zylka is investigating the impact of other topoisomerase-inhibiting drugs on gene expression. He works with a sense of urgency, fueled on a personal level by questions about how everyday chemicals could be affecting his two young children, and on a societal level by the knowledge that autism rates are continuing to rise in the United States. The Centers for Disease Control estimated in March that 1 in 50 children has an autism spectrum disorder.
“It’s an area of neuroscience where you have the potential to impact a large number of people in a positive way,” Zylka said. “I always try to keep that in mind. It’s easy to get focused on research and not realize the broader context. The public funds us and I try to do the best we can to move fast and make big discoveries that are going to help people.”
Zylka and Philpot’s study was funded by the National Institute of Mental Health, an arm of the NIH.
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