Subtle Differences In Brain Cells Hint at Why Many Drugs Help Mice But Not People | WGLT

Subtle Differences In Brain Cells Hint at Why Many Drugs Help Mice But Not People

Aug 21, 2019
Originally published on August 22, 2019 6:57 pm

In mice, scientists have used a variety of drugs to treat brain disorders including murine versions of Alzheimer's disease, depression and schizophrenia. But in people, these same treatments usually fail.

And now researchers are beginning to understand why.

A detailed comparison of the cell types in mouse and human brain tissue found subtle but important differences that could affect the response to many drugs, a team reports Wednesday in the journal Nature.

"If you want to develop a drug that targets a specific receptor in a specific disease, then these differences really matter," says Christof Koch, an author of the study and chief scientist and president of the Allen Institute for Brain Science in Seattle.

One key difference involved genes that cause a cell to respond to the chemical messenger serotonin, says Ed Lein, a study author and investigator at the institute.

"They're expressed in both mouse and human, but they're not in the same types of cells," Lein says. As a result, "serotonin would have a very different function when released into the cortex of the two species."

That's potentially a big deal because antidepressants like Prozac act on the brain's serotonin system. So testing these drugs on mice could be misleading, Lein says.

The comparison was possible because of new technology that allows scientists to quickly identify which of the hundreds of types of brain cells are present in a particular bit of brain tissue.

The technology does this by detecting which genes are switched on in each cell. That reveals a genetic signature indicating the type of cell.

"In one fell swoop you can get a more or less comprehensive understanding of all of the different types of cells that make up a brain region," Lein says.

This also makes it much easier to compare brain tissue from different species, he says.

"We now have access to this fine level of resolution in the human brain and the ability to compare across and see how good a model a mouse or a monkey actually is," Lein says.

The list of cell types also should help researchers see what goes wrong in human brain disorders, Koch says.

"A lot of neurological diseases, a lot of psychiatric diseases that we're suffering from are due to specific defects in particular types of cells," Koch says.

For example, Parkinson's disease affects brain cells that make a substance called dopamine. And epilepsy involves special cells that tamp down brain activity.

Now, researchers have a way to make sure the types of cells involved in a particular disease work the same way in people as in an animal model, Koch says.

"The technology finally caught up with what we've been needing to do for probably over 40 years," says Tomasz Nowakowski, an assistant professor of anatomy at the University of California, San Francisco who co-wrote an editorial that accompanied the study.

To compare mouse and human brain cells, researchers first analyzed sixteen thousand human brain cells taken from the middle temporal gyrus, a part of the cortex, the brain's outermost layer. Then they looked at cells taken from the same area of a mouse brain.

"In one sense, they are remarkable similar," Koch says, noting that both mice and people had about 100 different types of cells in this region of the brain.

But a close comparison of 75 of these brain cell types revealed small differences.

Nowakowsky is especially intrigued by the finding that cells called microglia have a slightly different genetic signature in mice and people.

"Those cells are the immune cells of the brain," he says. "And you might imagine that studies or insights into neuroimmune disorders, for example, might be vastly affected by this difference."

Neuroimmune disorders include multiple sclerosis, systemic lupus, and amyotrophic lateral sclerosis. But there's growing evidence that microglia also play an important role in Alzheimer's disease.

And that could be one reason experimental Alzheimer's drugs have helped mice, but not people.

Copyright 2019 NPR. To see more, visit https://www.npr.org.

AUDIE CORNISH, HOST:

Another science story now. In mice, it's possible to treat brain disorders like Alzheimer's disease. In people, the same treatments usually fail. Researchers are beginning to understand why. NPR's Jon Hamilton reports on a study that found small but important differences between the brain cells in mice and the cells in our own heads.

JON HAMILTON, BYLINE: Brain cells are a bit like orchids. There are hundreds of varieties, and they can be hard to tell apart. But in the past few years, scientists have developed technology that can quickly identify every type of cell in a bit of brain tissue. Ed Lein of the Allen Institute for Brain Science in Seattle says the key is reading each cell's genetic signature by detecting which genes are switched on.

ED LEIN: In one fell swoop, you can get a more or less comprehensive understanding of all of the different types of cells that make up a brain region.

HAMILTON: Lein says this also makes it possible to compare brain tissue from different species.

LEIN: We now have access to this fine level of resolution in the human brain and the ability to compare across and see how good a model a mouse or a monkey actually is.

HAMILTON: Lein was part of a team that analyzed 16,000 human brain cells taken from a part of the cortex, the brain's outermost layer. Then they compared those cells with cells taken from the same area of a mouse brain. Christof Koch, the Allen Institute's chief scientist, says at first glance, the cells look the same.

CHRISTOF KOCH: In one sense, they're remarkably similar. The number of cell types in a human brain and a mouse brain in similar regions of the cortex are roughly similar.

HAMILTON: A closer look revealed that there were some differences, but Lein says they were subtle.

LEIN: On the other hand, these differences can be really quite profound.

HAMILTON: For example, Lein says, take the genes that allow a cell to respond to the chemical messenger serotonin.

LEIN: They're expressed in both mouse and human, but they're not in the same types of cells, which means that serotonin would have a very different function when released into the cortex of the two species.

HAMILTON: That's potentially a big deal because depression drugs like Prozac act on the brain's serotonin system, so testing these drugs on mice could be misleading. Koch says other subtle differences could help explain why so many experimental brain drugs have helped mice but not people.

KOCH: A lot of neurological diseases, a lot of psychiatric diseases that we're suffering from are due to specific defects in particular types of cells.

HAMILTON: Koch says now researchers have a way to see whether those types of cells act in the same way in mice as in people. Tom Nowakowski of the University of California, San Francisco says the advance is long overdue.

TOM NOWAKOWSKI: The technology finally caught up with what we've been needing to do for probably over 40 years.

HAMILTON: Nowakowski wrote an editorial that accompanied the study, which appears in the journal Nature. He says he's especially intrigued by the finding that cells called microglia have a slightly different genetic signature in mice and people.

NOWAKOWSKI: Those cells are the immune cells of the brain, and you might imagine that studies or insights into neuroimmune disorders, for example, may be vastly affected by this difference.

HAMILTON: These disorders include multiple sclerosis and systemic lupus, and there's growing evidence that microglia also play an important role in Alzheimer's disease, which might help explain why experimental Alzheimer's drugs have helped mice but not people.

Jon Hamilton, NPR News.

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