The golf ball–sized chunk of brain is not cooperating. It’s thicker than usual, and bloodier. One side has a swath of tissue that looks, to my untrained eye, like gristle.
Nick Dee, the neuroscientist charged with quickly cutting the chunk into neat pieces, confers with his colleagues. “We can trim off that ugliness on the side,” he says. The “ugliness” is the brain’s connective tissue called white matter.
To produce useful slices for experiments, the brain tissue must be trimmed, superglued to a lipstick-sized base and then fed into a lab version of a deli slicer. But this difficult chunk isn’t cutting nicely. Dee and colleagues pull it off the base, trim it again and reglue.
Half an hour earlier, this piece of neural tissue was tucked inside a 41-year-old woman’s head, on her left side, just above the ear. Surgeons removed the tissue to reach a deeper part of her brain thought to be causing severe seizures. Privacy rules prevent me from knowing much about her; I don’t know her name, much less her first memory, favorite meal or sense of humor. But within this piece of tissue, which the patient generously donated, are clues to how her brain — all of our brains, really — create the mind.
Dee’s team is working fast because this piece of brain is alive. Some of the cells can still behave as if they are a part of a person’s brain, which means they hold enormous potential for scientists who want to understand how we remember, plan, behave and feel. After Dee and his team do their part, pieces of the woman’s brain will be whisked into the hands of eager scientists, where the cells will be photographed, zapped with electricity, relieved of their genetic material and even infected with viruses that make them glow green and red.
It’s all part of a project at the Seattle-based Allen Institute for Brain Science, funded largely by private money plus some U.S. government grants. Now in its sixth year, the project relies on a network of scientists, neurosurgeons and patients who are willing to donate brain tissue removed during surgery. The ultimate aim is to answer one of the biggest questions in neuroscience: What makes us human?
The answer won’t be simple. But already, the project has turned up hints about what makes the human brain so powerful. Live-tissue experiments have revealed cellular quirks that may be specific to primates and have turned up new details about a mysterious type of nerve cell, or neuron. Other tantalizing discoveries show that humans and mice have very similar numbers of neuron types. This kind of detailed cellular reckoning is a necessary early step on the path to understanding human thoughts, behaviors and abilities.
“We want a complete description of all the types of neurons,” says Christof Koch, chief scientist and president of the Allen Institute for Brain Science. Steady progress over the last six years shows that answers are within reach. Once order is given to the tangle of neurons that populate our brains, scientists can turn their sights to the bigger mysteries, like how those cells create our memories, emotions and even consciousness itself.
On the morning of May 14, I waited outside of a basement operating room at the University of Washington’s Harborview Medical Center. Inside, a neurosurgeon was cutting deep into the woman’s brain. At 10:15, the wide swinging doors opened, and a doctor carried out a clear plastic jar with an orange cap.
Settled at the bottom of the liquid inside was a bit of brain, gently sloshing around with the motion. Tissue-procurement team member Tamara Casper was ready with a cart that carried a blue cooler (the same kind I have in my garage) on the top and two gas canisters below. The piece of brain had tinged the clear solution pink.
It was a colorful reminder that this tissue had, minutes earlier, been inside a skull, where it was helping to create a woman’s mind.
Scientists have other methods to mimic human brains: Brain organoids, small balls of neural tissue that are grown from stem cells (SN: 3/3/18, p. 22), and animals raised in labs have been immensely helpful to neuroscientists. “There’s real value there,” says Allen Institute neurobiologist Ed Lein. “But what they’re not good for is studying the specifics of the final product in the mature brain.”
This particular sample submerged in the pink liquid had spent 41 years piloting a woman’s life. “It’s hard to emphasize how different this is,” Lein says of the project. Other laboratories have studied live tissue removed from human brains, but none have scaled up and systematized the process as much as this group in Seattle.
“To me, it’s almost mind-blowing that we can study the human brain outside of the human brain,” says Ryder Gwinn, a neurosurgeon at Swedish Medical Center in Seattle who collaborates with Allen Institute scientists.
Gwinn treats people with epilepsy. Medication doesn’t always stop his patients’ seizures. In severe cases, surgery can be a patient’s best bet. In some of these operations, a surgeon cuts away healthy brain tissue to reach the spot deeper in the brain where seizures first spark. Surgeons peel away the skin and remove a cookie-shaped piece of skull, exposing the temporal lobe of the brain, a stretch of the outermost layer called the cortex. Often, a large piece of the temporal lobe comes out, Gwinn says. Some of that neural tissue goes to pathologists. The rest is typically tossed as medical waste — unless Allen Institute scientists can get their hands on it.
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“The tissue is terribly scarce,” Koch says. Early on, colleagues, including many Allen Institute researchers, were skeptical that enough samples could be found and brought to the lab in good shape. But after about 140 surgeries, more than 30 this year alone, it’s clear that these brain samples survive the journey beautifully.
As soon as the sample came out of the OR, Casper hooked up the oxygen and carbon dioxide gas to keep the tissue alive in the liquid, an artificial cerebrospinal fluid. Then she was off, pushing the cart through the hospital with one hand and texting the Allen Institute team with the other. The cart was loaded into a white van modified to safely hold combustible gas canisters. And with that, the bubbling brain bit was on its way. The van threaded through heavy, rain-soaked Seattle traffic back to the lab, where Dee was ready, scalpel in hand.
After that frustrating start with the uncooperative piece of brain, Dee finally gets enough slices for multiple experiments. A one-hour rest helps the cells recover from the trauma of being separated from the brain. The slices go up to a second-floor lab, where some slices are placed under a powerful microscope and prodded with electricity to study how these live human cells behave. The researchers hope the behavior mimics what the cells did while they were inside their former owner’s skull.
Six scientists sit at “rigs,” each one a microscope mounted inside a black three-sided box. At each rig, a researcher hunts through the woman’s brain tissue for healthy cells — nice and plump, with just the right amount of visibility against the background tissue.
Once they find a good one, the researchers try to latch on with an impossibly thin tube of glass. Called patch-clamp, the technique forces a cellular conversation, which is carried out with electrical signals that move between cells. To get the conversation going requires injecting an electric current into a cell, and then measuring how the cell responds to the artificial message.
Most of these rigs measure the reactions of one neuron at a time. But in the back part of the lab, researcher Lisa Kim pilots a futuristic setup of glistening metal, tangles of blue and black wires and eight needle mounts, all pointing at a different part of a brain slice. While I’m there, this mega-rig is eavesdropping on a kind of party line between seven live neurons. Kim is zipping electricity into each one in turn to see how the signal transmits to its neural neighbors.
The electrical zings of these neurons offer clues about their identities and their relationships; one of the seven cells responds when a neighboring cell gets an electrical zap, a hint that those cells communicated while inside the woman’s head. Other clues come from information about the neurons’ elaborate, gangly shapes created by the signal-sending axons and receiving dendrites. Each neuron reminds me of an impossibly complex map of river tributaries.
An even stronger sense of a cell’s function comes at the end of the patch-clamp experiments. Working the thin glass tube again, a researcher can suck out the nucleus of each live cell. The theft kills the cell but obtains a record of which genes were active when the cell was alive. After Kim finished the game of electrical telephone, she carefully slurped out the nucleus from each of the seven neurons.
All the information gathered from these rigs can help researchers identify neurons that might play a special role in making the human mind. Such scrutiny, for instance, revealed what researchers think is a rare cell called a von Economo neuron, named for the Austrian neurologist who first described the cell type in the 1920s.
The extra-long, extra-spindly neuron was found in live brain tissue donated by a 68-year-old woman who had surgery to remove a tumor. The neuron displayed an unusual electrical response to the current applied to it, Allen Institute scientists and colleagues reported online May 7 at bioRxiv.org. The result was tantalizing, because problems with von Economo neurons are suspected of playing a role in psychiatric conditions and Alzheimer’s disease.
Studies on live human cells also turned up an important difference between humans and mice: A certain kind of human neuron is covered with a protein called an h-channel; in mice, those channels are rare. H-channels help cells respond to electrical signals and can be affected by drugs, including one for epilepsy.
This basic difference, described in 2018 in Neuron, might explain why certain kinds of drugs work differently in the brains of mice and people. More broadly, these newly discovered properties of human neurons might be the things that enable some of the most sophisticated features of our brains.
Taking stock of live human neurons “is essential,” and not just to satisfy humans’ navel-gazing curiosity, says Nenad Sestan, a Yale School of Medicine neuroscientist. Discovering the quirks of human brains “might lead to us understanding one day why we suffer from certain disorders,” Sestan says. Imprecise animal models have stymied research on schizophrenia, autism and Alzheimer’s disease, he says. That’s why studying live, human tissue is so crucial.
From brain to lab
Allen Institute scientists fly into action when a brain sample arrives from a nearby hospital, wringing as much information as they can out of the precious tissue. What the researchers learn about the cells’ behavior, shape and genetic activity is shared publicly in the Allen Brain Atlas. (Bold text shows each step’s duration).
1 to 3 minutes
Surgery: Brain tissue is removed at a Seattle hospital — usually within minutes of a surgeon opening the patient’s skull — and placed into a jar with chilled artificial cerebrospinal fluid bubbling with oxygen and carbon dioxide.
15 to 30 minutes
Transport: A specially equipped van speeds the tissue from the hospital to the Allen Institute.
30 to 60 minutes
Slice: The sample is placed on a dish in a bucket of ice, trimmed and sliced into anywhere from six to more than 30 flakes that are each 0.35 millimeters thick.
Distribute: From each sample, one slice goes into the freezer for future analyses. Every fifth slice is fixed in preservative. The rest are kept alive for more same-day experiments.
Rest: Live cells recover from the trauma of surgery.
Observe behavior: Rested cells move to the electrophysiology lab, where “rig” operators study cell behavior with 30 minutes of electrical prodding.
Map cell shape: Filling some neurons with dye, researchers can see the elaborate projections.
Study the genes: Thin glass pipettes pull out the nucleus of some neurons so researchers can see which genes were active just before the cells died.
Weeks to months
Manipulation: Other tests attempt to insert genetic material into cells that stay alive longer than expected. The cells glow for better visibility.
A blow to the ego
But human brains aren’t always so unique. A new result might disappoint people who think that our brains are teeming with specialized neurons that let us talk and think in ways other animals can’t. The overall number of cell types in the human cortex and in the mouse cortex is roughly the same, says a study led by Allen Institute researchers that is in press at Nature. Koch calls the finding “the biggest result, to my mind.”
“People, including scientists, have this strong need [for] human exceptionalism,” Koch says. But the fact that the overall resident population of the human brain and mouse brain is remarkably similar — based on brain tissue from surgeries as well as postmortem tissue — adds to the list of blows to the human ego.
First, Darwin downgraded humans to just another animal on the tree of life. Then, the Human Genome Project shocked us with the news that we have a similar number of genes as mice (and fewer than water fleas). Now, add brain cell types to the list of things that make people more like other mammals.
The paper coming out in Nature is “historic,” says coauthor Rafael Yuste, a neuroscientist at Columbia University. In terms of understanding how humans compare with other animals, “it’s going to be a before-this and after-this.”
These similarities don’t surprise Suzana Herculano-Houzel, a neurobiologist at Vanderbilt University in Nashville. “We are not special,” she says. Finding that humans and mice have similar types of cells in their brains makes a lot of sense, as does the idea that some cell types and some genes will be species-specific. The question is, she says: “Which of those differences are actually meaningful?”
The explanation for why we’re so smart, then, is not that our brains are teeming with specialized, human-specific neurons. The answer must be found elsewhere. Perhaps it really is in small numbers of rare neurons such as von Economo neurons, or in neurons that haven’t yet been discovered. Still other scientists think that our brainpower might come, in part, from cells in the brain that aren’t neurons, such as the glial cells that perform a range of basic brain jobs that scientists are just beginning to understand (SN: 8/22/15, p. 18).
Or maybe, as Yuste suspects, the answer is the sheer size of our brains compared with our relatively small bodies. Or perhaps our “smarts” are a result of our long life span and the fact that we are immersed in cultures rich with language, literature and customs, as Herculano-Houzel points out.
As Dee did his slicing, neurobiologist Jonathan Ting waited eagerly for his bit of brain. Ting runs experiments that deliver genes to live cells — and he’s kept his cells alive a surprisingly long time.
In his fourth-floor lab, Ting is not happy with the piece he got, calling it “kind of a bloody mess.” But he cuts it up some more and returns the resulting slices to the bubbling solution. Then he pulls what looks like a baking tray out of a nearby incubator, makes a Martha Stewart joke and shows me live brain samples that are weeks old. Some have survived for several months, a hardiness that shocked the researchers when they first began these experiments.
This kind of durability comes in handy as Ting tinkers with how best to infect the cells with viruses. His goal is to use the viruses to deliver genes that make certain groups of live human cells glow. The glow makes it easier to study the cells and, ultimately, to figure out how to change their behavior. To Ting’s delight, he discovered that the virus and its luminescent cargo can be delivered simply by dropping virus-laden liquid on the live brain slices.
As Ting and I look at glowing red and green cells on his microscope’s monitor, he describes the potential of this work with viruses. Not only will the researchers be able to find rare cells in human brains, but they might be able to ultimately control the cells, too. Imagine if a von Economo cell, for instance, could be turned on and off at will with methods that are already under development in animal models.
If the cells are actually involved in a disorder, say, schizophrenia, then this sort of precise control could lead to a targeted treatment that toggles the cells’ activity up or down as needed. It could also ultimately reveal how information flows through these cells, in a way that makes up the mind.
All this tinkering has already turned up big findings. But there is vastly more uncharted territory to explore, Koch says. “The brain is by far, by far the most complex, highly organized piece of active matter anywhere in the universe.”
About this story
Where did the idea come from?
I heard about this project about five years ago at the meeting of the Society for Neuroscience. It wasn’t clear then if the effort would pay off. But with over 100 surgeries and a handful of research papers published, it felt like the story was ripe.
How are we reporting this story?
I had hoped to talk patients and watch surgeries. But that meant getting permission from doctors, hospital administrators, and most importantly, the patient. After several failed attempts, I decided to tell the story with the brain sample itself taking center stage.
I live about four hours south of Seattle. When I got the call that surgery was happening the next morning, I hopped in the car and arrived late that night. I was at Harborview Medical Center just after 9 am to follow a sample of live brain tissue from an operating room to labs across town at the Allen Institute for Brain Science.
I had expected to see frantic speed as scientists raced to study still-living tissue. But I was struck by how much of the process was calm. It was clear that these researchers knew exactly what they needed to do.
— Laura Sanders