Are you tall, short, or somewhere in between? Are you brainy? Athletic? Emotional? What’s your shoe size? We are distinguished from one another by the spiraling ladders of chemical compounds that make up our DNA. An alteration to just one rung of the ladder can mean the difference between brown eyes and blue—or the onset of developmental problems, like the language, communication, and social impairments common to autism spectrum disorder. The fastest-escalating developmental disability in the United States, autism affects more than 3.5 million Americans (1 in every 68 births).
Those infinitesimal changes to our DNA that cause autism and other neurodevelopmental disorders are the focus of biologist Angela Ho’s research. The challenge for researchers, Ho says, is that “the biology is incredibly diverse behind this type of disorder,” which makes tracing its myriad sources a daunting task. Previous studies have suggested that certain prescription drugs taken during pregnancy, conceiving children at an advanced age, and genetic or chromosomal conditions may increase the risk of autism, but no exact origin has been pinpointed. Ho and her team have dug to the root of one possible cause: a genetic mutation that throws a wrench in the communication between neurons during brain development.
Ho, a CAS assistant professor of biology, says she has always been fascinated by the question, “How does the brain develop its beautiful architecture?” In this intricate process, which begins in the embryonic period, the brain forms approximately 100 billion neurons, cells whose job is to transmit information as electrical signals from one neuron to the next at speeds of up to 200 miles per hour. Even a miniscule hitch can disrupt the flow of information through the brain’s delicate circuitry.
The organ’s complexity provides almost limitless potential for exploration, Ho says. The thirst for discovery has driven her work, from early research on a rare syndrome in which cancer antibodies target brain cells, to studies on how Parkinson’s disease stops the brain from repairing itself.
As a postdoc at the University of Texas Southwestern Medical Center at Dallas, Ho studied how neurons communicate at the synapse and the processes that cause Alzheimer’s disease in relation to a protein—Munc-18-Interacting Protein (MINT)—that’s found only in the brain. In the degenerative disease Alzheimer’s, MINT changes another protein in the brain so it forms the plaques that kill neurons.
It was MINT that led Ho to autism—and to her husband. Uwe Beffert, a fellow postdoc who is now a research assistant professor of biology at BU, was studying neurodevelopmental disorders at another UT Southwestern lab. They discovered many of the same proteins mutate in both disorders. In 2009, the researchers joined forces to study MINT’s role in autism. Now married, they colead a lab in her name at CAS.
While an accurate diagnosis can often be made by the time a child is two, earlier identification would mean earlier intervention, which has been proven to improve a child’s ability to develop crucial skills like social interaction, walking, and talking.
To take a closer look at how MINT works—and what happens when it doesn’t—Ho, Beffert, and their team of undergraduate and graduate researchers isolate mouse neurons in a culture dish and remove the gene that produces the MINT protein to see how its absence changes the development and function of neurons.
The research is funded, in part, by the Harold and Margaret Southerland Alzheimer’s Research Fund.
In a typically functioning brain, MINT plays a crucial role in helping a neuron release chemicals that carry signals to the next neuron; it also supports other proteins in their jobs, such as regulating the neurotransmission. In a brain with autism, MINT malfunctions due to a single defective rung in the strand of DNA that contains instructions for making the protein. And when MINT isn’t working properly, neurons can’t connect with each other, interrupting communication between the parts of the brain responsible for language, vision, and behavior and leading to the symptoms we associate with autism.
“It’s very powerful to get to the understanding that a single change in our DNA can lead to a single change in a protein” and exert a dramatic impact on an individual’s development and behavior, says Beffert.
When working under a microscope, it’s easy to get lost in the circuitry of the brain and become removed from the human side of research, Ho says. “In the lab, we’re trying to understand one basic question, but autism is complex.” She hopes her team’s findings, which will be published in 2016, will illuminate just one of autism’s many facets.
“It is maybe not solving the whole picture,” says Amy Ying Lin (GRS’17), one of Ho’s graduate research assistants, “but contributing to a small piece of the puzzle to see how one protein—and the dysfunction of that protein—can lead to the pathogenesis of autism.” Lin hopes that identifying the genetic causes for autism will help other researchers develop more effective tools for diagnoses and intervention. There is no medical test—like a blood or genetics analysis—for autism; the disorder is diagnosed by the child’s behavior and social and physical development. While an accurate diagnosis can often be made by the time a child is two, earlier identification would mean earlier intervention, which has been proven to improve a child’s ability to develop crucial skills like social interaction, walking, and talking.
“Our goal is to understand the basic biological function and bring it back to the patients to help them,” Ho says. “If we can give one insight into that long road to understanding this complex disease, we did our part.”