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New imaging method shows how genes activate in the living brain

This could help us develop better treatments for Alzheimer’s

H.Y. Wey, et al., Science Translational Medicine (2016)

For the first time, scientists have figured out how to view changes to gene activity in living brains. The brain scan technique may aid discoveries in how Alzheimer’s treatments, schizophrenia, and other neurological disorders work. And not just that: this approach may also help scientists evaluate whether drugs work the way they’re supposed to.

The researchers focused on molecules that regulate how tightly DNA wraps around the proteins that serve as structural units for our genetic material. Think of the DNA as string and these proteins as a spool; how tightly or loosely the string is wound around the spool has effects on how DNA expresses itself. These molecules, called histone deacetylases, are part of what determines how tightly the DNA is wound. For instance, in Alzheimer’s disease, high levels of these histone deacetylases (HDACs for short) have been found in the parts of the brain that regulates memory.

Today’s results are a big step forward for epigenetics

To get a better sense of how these HDACs work, scientists led by Hsiao-Ying Wey and Tonya Gilbert at the Martinos Center for Biomedical Imaging at Harvard Medical School spent seven years developing the chemical compound described today in the journal Science Translational Medicine. The compound they eventually hit on, called [11c]Martinostat, binds to the HDACs, showing researchers where the enzymes are in the brain, and how much of them there is. In today’s study, scientists injected eight healthy patients with the compound and then tracked it with PET brain scans. This has provided us with "the first glimpse into living human brains" of how these enzymes work, says Jacob Hooker, director of radiochemistry at Martinos and co-author of the study.

Today’s results are a big step forward for a burgeoning field called epigenetics, where scientists are answering the eternal "nature or nurture" question with "both." Nature gives us our DNA code, but nurture can make it work in different ways. Going back to the DNA-as-string metaphor, epigeneticists want to figure out how things like diet and exercise cause chemical changes that make the DNA wind more or less tightly around the spool, and how those changes affect us. It’s been a lesser-known area until recently, but people are excited by new studies that show how the environment and genetics combine to influence a lot of conditions. One notable paper, for example, suggested that schizophrenia develops when the brain gets rid of too many connections between neurons. Not only does today’s study — the first time we’ve seen epigenetic activity in the living human brain — finally move us beyond mice studies, the technique could potentially be used to diagnose disorders. Researchers also learned that the pattern of HDAC enzymes is more consistent than we would have predicted, which suggests further ways to research brain disease.

"It’s extremely important to know directly how the enzymes are distributed."

We’ve long known that these enzymes play a part in disorders like depression and addiction, says Mira Jakovcevski, an epigenetics researcher at Germany’s Max Planck Institute for Psychiatry, who was not part of the study. In the past, scientists studying the brain tissue of psychiatric patients after death found abnormal levels of HDACs, usually too much.

But studies on dead brain tissue or in mice don’t tell us much about how enzymes work in the living human brain. The level of enzymes change rapidly after death and dead brain tissue is usually at least 12 hours old. In addition, scientists studying slices of dead tissue usually only look at one region at a time, while a scan of the living brain lets them look at any region that they want at the same time. "It’s extremely important to know directly how the enzymes are distributed" in the living brain, says Jakovcevski, "and this is a very elegant way of doing it."

Now we know what normal HDAC levels look like and there are a couple surprises. First, it turns out that healthy people at rest basically have the enzyme in all the same places. This is a little unexpected because the core claim of the field is that gene expression can vary widely. In many cases, it can be changed by everything from three months of biking using only one leg to how much fat is in a diet. So we’d expect that to be true here too, with the enzyme showing up at different levels in many different places in the brain. Instead, the eight subjects all had the same pattern: lots of HDACs in the cerebellum, an area important for motor control, and much less in white matter (which is mostly connective tissue), the amygdala (which regulates emotions), and hippocampus (which helps with navigation). The consistency of these results suggest that it is important to study the connection between HDACs and these specific regions’ gene expression to better understand neurological diseases.

The next step is learning to recognize what diseased brains look like

Interestingly, the team thinks brain regions with the most HDAC may also be those with genes that are most "locked in," or resistant to change. We’ve seen that too much HDAC can cause learning problems, so it would make sense that having a lot of these enzymes would prevent learning even in a normal brain.

This isn’t necessarily a bad thing, because too much flexibility in the brain can lead to other problems. Hooker and his colleagues are now developing experiments with in-brain animal scans and HDAC blockers to test this hypothesis.

The new technique isn’t perfect — it’s a first step. We don’t know yet how HDAC levels might change naturally in a healthy brain — for example, as people age over time. The compound [11c]Martinostat binds to three of the 11 types of HDAC known to exist. That means some activity is still a mystery. And the results may not be the same as a drug that binds to only one type, or to all 11. In addition, we still need more methods to track the other HDAC enzymes and build a more complete picture of how they work, notes Jakovcevski.

Before, if researchers tried to track a drug that claims to treat Alzheimer’s in this way, "the image would basically be black."

And it’s always foolish to think that visualizing something means we understand it fully. "Just because we can see where HDACs are working doesn’t automatically mean we understand how to interpret the signals," says Hooker. "The biggest gap is that when we see something different in patients, we’re still not going to know exactly what to do."

For Hooker and his team, the next step is learning to recognize when "something is different" in patients and what that looks like for different conditions. They’ve received funding to study people who have schizophrenia, Alzheimer’s, and Huntington’s disease. Huntington’s, an inherited disease that causes both movement problems and dementia, is an especially interesting case because doctors can predict when certain symptoms will appear long before they actually do. This means the researchers can scan people at diagnosis and know just when to scan in the future to see how enzyme levels change as certain symptoms develop.

Some research suggests that blocking HDAC could help patients with Alzheimer’s. So far, nothing that works on HDAC to treat neurological diseases has been approved by the US Food and Drug Administration, partly because it’s hard to prove a drug works when you can’t really see what it’s doing. Before, if researchers tried to track a drug that claims to treat Alzheimer’s in this way, "the image would basically be black," says Hooker. Behavioral trials can show whether a drug improves someone’s condition, but without seeing how it works directly, it’s hard to prove that it’s worth running these expensive trials. With [11c]Martinoset, scientists know directly if their drug acts on the right enzymes and so he hopes it will be "helpful for us to understand more and companies developing clinical trials and then, of course, to people."