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Brain samples
Slices of human brain tissue, extracted from patients during neurosurgery, are kept alive in a special bath of chilled, oxygenated fluid. (Allen Institute for Brain Science)

Zapping brain cells from living human tissue? It sounds like a creepy Halloween tale, but for the Allen Institute for Brain Science, it’s a clever way to understand more fully how the brain works — and potentially bring healing to future patients.

“It doesn’t creep me out at all,” Jonathan Ting, an assistant investigator at the Seattle institute who’s been deeply involved in the project, told GeekWire. “I feel like it’s our obligation as scientists.”

Ting and the project’s other researchers have no qualms largely because these bits of brain tissue are actually castoffs from surgical procedures at Seattle hospitals.

When neurosurgeons operate on patients to treat conditions such as epilepsy, or to remove brain tumors, they occasionally have to remove small pieces of cortical tissue to get to their target.

That tissue is typically discarded.

An animated GIF morphs back and forth between a photomicrograph of a pyramidal neuron and a digital 3-D reconstruction of the brain cell. (Allen Institute for Brain Science)

“If we were not doing this, this human brain tissue that was part of a living, functioning human being is going into the garbage can,” Ting said. “It’s being incinerated as medical waste. That’s happening all over the country, probably all over the world in operating rooms. I just feel like that’s really a lost opportunity.”

Four years ago, the Allen Institute started working with surgeons and their patients to put that tissue to good use.

The patients, of course, give their consent in advance.

“They actually really want to help researchers try to understand what’s going on in the brain,” Ting said, “with the hope either that we understand the disease process better, or that we have a better foundation of the basic function of the brain to give insights about disease.”

Now the institute is unveiling the payoff from the first four years of experimentation. The first batch of data from human nerve cells has become part of the Allen Cell Types Database, an open-access tool for researchers. Much more data will be added in the years to come.

“Our goal is to truly understand how the human brain works, not just the brains of mice or other animals that most brain scientists study,” Christof Koch, chief scientist and president of the Allen Institute for Brain Science, said today in a news release. “There is no better way to do that than to directly examine live cells of the human cortex.”

‘Almost like science fiction’

The initial data set provides readings of electrical responses for about 300 living neurons taken from 36 patients. For 100 brain cells, the Allen Institute team linked together digital 3-D cell reconstructions with computer simulations of their electrical behavior.

Researchers also sequenced the genetic code from 18,000 individual cells, taken from three human adult brains, to figure out which genes are turned on or off at a given time — a method known as whole transcriptome single-cell analysis.

“It just blows my mind,” Ting said. “I find this remarkable, and almost like science fiction. I never would have imagined you could do that at such a small scale.”

The lengths to which researchers go to harvest and study the cells are mind-blowing as well. The institute started out working with four surgeons at Harborview Medical Center and Swedish Neuroscience Institute in Seattle. Surgeons from the University of Washington Medical Center joined the effort just a few weeks ago.

When a bit of brain tissue — say, the size of a sugar cube — is removed from a patient’s cerebral cortex, it’s immediately immersed in an ice-cold solution that’s oxygenated to keep the brain cells alive. A team from the Allen Institute is on hand to take custody of the sample.

“We essentially have our own van to drive across town, sort of like a mini-ambulance,” Ting said.

The institute’s team has to get the sample back to its lab within a half-hour, and the tissue is prepared for experimentation no more than a half-hour after that. Researchers can then shave off a slice of brain matter as thick as a business card, and subject the neurons within in that slice to electrical testing.

After an initial round of genetic and electrical sampling, the spent cells undergo still more analysis to get a detailed picture of their structure.

A scientific surprise

Ting and his colleagues were surprised to find out how long the brain tissue remained viable. “We can keep taking slices, one after the other, for targeting new cells … for up to several days,” he said. Under similar conditions, mouse brain samples die off six hours after they’re prepared, Ting said.

Why the difference? It’s not clear, but Ting said part of the explanation might be that mice and humans have evolved to have two very different lifespans — two years for mice vs. the potential of more than 100 years for humans. Our resilience may also relate to our higher level of cognition.

“Perhaps these human brain cells that have evolved for species with long lifespans have better ways to cope with insults and challenges like oxidative stress,” he said. “But we don’t have the home-run experimental data to support this just yet.”

Jonathan Ting
Brain researcher Jonathan Ting points to a feature on a computer screen. (Allen Institute Photo)

That’s just one of the mysteries facing neuroscientists in light of the newly released data. Human brain cells are larger and more complex, and they also show differences in electrical signatures at particular spots in the cortex.

“The underlying basis for that is differential expression or function of ion channels in those cell populations,” Ting said. “That could be extremely important, because ion channels and receptors are common targets of drugs for treatment of human brain disorders — for example, like anti-epileptic drugs.”

Researchers are seeing big differences in gene expression as well. Teasing out the factors behind the differences are likely to lead to the development of better drugs that designed from the beginning with humans rather than mice in mind, Ting said.

Almost $100 million in grants

And all this is just the beginning: This week, the Allen Institute announced that it will receive $99.4 million in grants from the National Institutes of Health over the next five years. The funding will help the institute expand upon its work under the aegis of the federally funded BRAIN Initiative.

About $19.4 million of that money will go toward an atlas of human brain cell types, created in cooperation with international partners. Another $14.5 million will help the institute establish the BRAIN Cell Data Center. The remaining $65.5 million will go toward the creation of a comprehensive atlas of cell types in the whole mouse brain.

The grants represent another big boost for an institute that Microsoft co-founder Paul Allen created in 2003, and has supported since then to the tune of $500 million.

Because of the privacy rules surrounding the cell-harvesting operation, Ting and his colleagues don’t know whose neurons they’re getting when the van pulls up with a fresh batch of tissue. But Ting said he often thinks about the people who contributed those cells.

“It actually gives me pleasure to think that after these surgeries, these people recover from the surgery, they’re up and about, moving around, living their life, hopefully with some improvement to the symptoms they’ve had and the suffering they’ve been going through,” he said.

“We’ve processed that tissue, and we’ve explore the features and the functions of the cells in their brain tissue,” Ting said. “And maybe someday, they’ll be reading something in a textbook about the work that we’ve done here, and this will directly lead to new understanding about human brain cell types.”

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