on’t let the pretty tangerine and lemon-yellow glow in the brain pictures fool you. If its inventors are right, an elegant new neuroimaging tool provides more than fetching pictures: It shows for the first time where genes are being turned on or off in living brains, scientists reported on Wednesday.
Until now, gene activation in human brains could be detected only in dead ones. By revealing DNA’s on-off choreography in brains that are still thinking, feeling, and remembering, the new technique promises to reveal genetic underpinnings of mental health and, perhaps one day, detect the earliest hints of a brain being gripped by Alzheimer’s, schizophrenia, or other diseases.
“This is really exciting, pioneering work,” said John Satterlee of the National Institute on Drug Abuse, who coordinated the NIH’s program to study patterns of gene silencing and gene activation, and who was not involved in this study. “They took us to a place we didn’t know anything about” — patterns of gene expression in living human brains — “and showed us the lay of the land.”
Brain epigenetics — which genes are turned on or off in different structures — has become a hot topic, as neuroscientists realized that the sequences of inherited DNA explain very little about psychiatric illnesses. In contrast, which genes are turned on and off might be important in a wide range of brain disorders, including addiction, Alzheimer’s disease, Rett syndrome, depression, and schizophrenia, as well as age-related changes. And because life events can alter genes’ on-off state, epigenetic changes might be how tragedy, trauma, and other experiences cause long-term changes in the brain.
Gene activity “is so responsive to the environment, we simply can’t study it outside of its natural context,” said chemist Jacob Hooker of Massachusetts General Hospital, who led the research, published in Science Translational Medicine. “[Dead] brains and living brains will look very different.”
The new technique is a cousin of PET. Traditional PET detects the emission of subatomic particles called positrons from radioactively tagged glucose, the brain’s energy source, and thus reveals which brain regions are active. This version of PET detects positrons coming from radioactively-tagged “Martinostat,” a small molecule Hooker and his colleagues created in 2012. (They patented and licensed Martinostat.) Given intravenously, the molecule slips through the blood-brain barrier (thanks to a clutch of atoms that “acts like a greaseball,” Hooker said). Once in the brain, it binds to enzymes called HDACs that turn off genes — including genes important in forming synapses and therefore learning and memory. PET detects the positrons, and presto: a brain map showing where genes are being turned off.
That could be a first step at discovering where, in the brain, the genetic lights go out, triggering illness.
Hooker’s team administered Martinostat (named for the Martinos Center for Biomedical Imaging at MGH) to eight healthy volunteers. The scientists were trying to show that the technique could work in living brains, but beyond that proof of principle, they also made some tentative discoveries.
The molecules that silence genes were most abundant in the cerebellum, in the back of the brain, which regulates movements, and the putamen, which does that plus coordinate some forms of learning. The gene-silencing molecules were least abundant in the hippocampus (forming memories) and amygdala (processing and producing emotions such as anger). It’s not clear what might explain that pattern, but one possibility is that regions with the fewest of these molecules have the greatest potential for “neuroplasticity,” or altering their neuronal connections in response to the life the brain’s owner leads.
More striking than the differences among brain regions was the unexpected similarity between people. Regions with lots of gene silencing in one person’s brain were also regions with lots of silencing in others’ brains, while regions without much gene silencing were also mostly the same.
The uniformity suggests there might be a baseline pattern of gene activation in healthy, living brains. If so, then deviations from that pattern might be used to diagnose illnesses before symptoms appear. In the brains of deceased Alzheimer’s patients, for instance, the hippocampus is shot through with gene-silencing molecules.
“I’m hoping these colorful maps let us compare healthy brains with the brains of people with schizophrenia, Alzheimer’s, and other diseases,” pinpointing regions with aberrant patterns of gene expression, Hooker said.
The new PET technique cannot identify which specific genes are being turned off. But that can be done in dead brains, said Hooker, “and we’re trying to map out which genes are involved” in which conditions.
His team has already used the new technique to image the gene-expression patterns in the brains of nine people with schizophrenia and a few with Huntington’s disease. They have funding to start doing so with Alzheimer’s patients. The results might show how gene-silencing gone wrong explains the conditions and, one day, point the way to treatments. “This is really the first step in being able to look” at how genetic on-off signals might cause, or at least be harbingers of, such brain diseases, said the NIH’s Satterlee.
That possibility has already caught the attention of the biotech industry. Cambridge, Mass.-based start-up Rodin Therapeutics is working on developing drugs that, by inhibiting gene-silencing enzymes, might treat Alzheimer’s, Parkinson’s, and PTSD. The approach has enough promise that biotech giant Biogen is willing to pay $500 million for it.