When the first human genome was decoded, cataloging the sequence of DNA that makes each of us unique cost about $3 billion and took over a decade. Twenty plus years later, it takes less than a day and costs about $100.
“Anybody can get their genome sequenced now,” said biomedical engineer Charles Gersbach. “The problem is that we don’t know what to do with most of that information.”
Gersbach, John W. Strohbehn Distinguished Professor of Biomedical Engineering, runs the Center for Advanced Genomic Technologies at Duke, bringing together biologists, engineers, clinicians, computer scientists and more to tackle one of the most challenging medical frontiers – unlocking the “dark matter” of the human genome.
Astronomers estimate that about three quarters of all the mass in the universe is a mysterious form of matter they call dark matter – because they can’t see it using any telescope or observatory. Similarly, back here on Earth, our genomes are filled with mysterious DNA. Our blueprints of life contain about 20,000 genes, discrete segments of genetic code that are translated into useful proteins, but that makes up only about 2% of our genomes. Almost all of our DNA is actually this dark matter, seemingly taunting researchers with its enigmatic nature.
For years, this genetic matter was considered junk, but researchers like Gersbach are finding a new layer of influence: epigenetics. Epigenetics allows for genes to be turned on and off without changing the underlying DNA, usually by attaching chemical compounds to the DNA to make it unreadable by our cellular machinery. It’s like adding spikes to a fence so birds can’t perch on it.
By developing high-throughput technologies for modulating these chemical features, Gersbach has shown that epigenetic changes in the dark matter regions can control levels of gene activity. He likens it to a dimmer switch, with the dark matter DNA and corresponding chemical changes turning up or down how much a gene is activated and, therefore, how much protein it produces. Working at Duke, Gersbach and colleagues have cataloged about two million of these dimmer switches, starting to illuminate many of these genomic shadows.
Gersbach’s dream is to use this information to tackle difficult diseases that plague us. Certain pathologies, such as sickle cell anemia, can be traced to single mutations, and a gene therapy that pastes in the corrected code can be curative.
But diseases such as Parkinson’s, schizophrenia, heart disease and diabetes have multiple genes involved and often have an environmental component. Understanding how these factors interplay is opening up a new treatment strategy: Targeting the epigenome.
Patients are taking notice. Gersbach hears regularly from parents of children with a rare disease looking for any new approaches. It motivates him and the team to keep working, and to think about the impact they can have, especially since their work is partially funded by foundations made up of families affected by these diseases.
“When we go to these foundation meetings, the audience is filled with family members and people affected by the disease,” Gersbach said. “You think about how to present this work a little differently to people who are personally affected by it.”
Research from Gersbach’s lab has been spun out into a company, Tune Therapeutics, whose epigenetic editing technology entered clinical trials in the past year.
There is still work to do. “We don’t know what one out of three of our 20,000 genes actually do,” Gersbach said. “We know what less than 1% of those 2 million dimmer switches do.”