HERE’S AN OFFER most people can easily refuse: Donate part of your brain to science — while you’re still alive.
But in the Seattle area, about 50 people every year say, “Sure.”
Gary Williams is one of them.
A LIVING BRAIN CELL: Watch an image of a living human brain cell morph into a color-coded map
The former logger and Army veteran suffers from epilepsy so severe he was forced to give up the job he loved as a tattoo artist. The electrical storms in his brain robbed him of a near-photographic memory. He can’t even ride his mountain bike anymore for fear the exertion will bring on an attack.
So on the morning of his 48th birthday, Williams is lying in a bed at Harborview Medical Center, waiting to be wheeled into the operating room. Bearded and heavily inked with designs that range from Sasquatch and Mount Rainier to a pot-smoking gypsy, he also sports a small checkmark on his left temple. It confirms the spot where neurosurgeons will soon open his skull and attempt to cut out the part of his brain responsible for seizures that wrack his body and leave him limp and shattered for days at a time.
In order to reach that faulty patch of brain, Williams’ surgeon will first have to snip out a marble-sized piece of healthy cerebral cortex — the wrinkled, outermost layer of the brain, where our higher cognitive abilities reside. At most hospitals, the bits of normal tissue excised during surgeries for epilepsy or brain tumors are burned as medical waste. But to scientists in Seattle, they’re a treasure trove — an astonishingly rare opportunity to peer into the workings of the living human brain.
By rushing the tissue from the OR to laboratories in South Lake Union, researchers at the Allen Institute for Brain Science can study the cells while they’re still alive and connected to each other, crackling with the electrical impulses that are the currency of thoughts, memories and perception. Many samples remain viable for three days. With special handling and treatment, some of the tiny slices will continue to function for a month or more.
If you’ve watched many horror movies, the notion of scientists zapping human brain tissue in the lab might conjure images of Dr. Frankenstein screaming, “It’s ALIVE!” But these bits of tissue lack anything approaching sentience, and the Seattle work has more noble goals. The loftiest is a better understanding of how billions of neurons collectively give rise to human consciousness. Studying live human brain tissue is the only way to learn how those neurons actually function within the body’s most complicated organ, the researchers say. And because decades of mouse studies have yet to yield cures for Alzheimer’s, autism, epilepsy and a host of other vexing disorders, many experts argue that live human brain tissue might offer a more effective way to figure out what goes awry in diseases and how to fix it.
“This is very cutting-edge stuff,” says neuroscientist Jonathan Ting, a leader of the project. “We don’t even know the limits of what we can do or the questions we can ask with these techniques.”
None of it would be possible without people like Williams, who’s happy to see his surgical leftovers put to good use.
“Why wouldn’t I want to help other people that have the same problems as me?” he asks, shrugging.
FOR A MAN about to have a 3-inch hole cut in his head, Williams is remarkably calm.
“I’m a combat veteran,” he says, as machines beep and monitor his vital signs. “I’ve been through worse.”
During the operation, UW Medicine neurosurgeon Dr. Jeffrey Ojemannwill do his best to avoid critical areas of Williams’ brain. But the procedure carries risks, including memory and speech impairment. Williams is betting on the upside: that he will have fewer seizures and a clearer head.
“I’m being reborn,” he says, with a grin.
Ninety minutes later, Williams is out cold and covered with blue surgical drapes. Only the left side of his cranium is visible. After bone is cut and the tough, protective dura peeled back, Williams’ brain is exposed, glistening and pulsing gently. Ojemann slides a strip of electrodes into the area where he suspects the epilepsy originates. EEG tracings race across a screen, some jumbled and staccato.
“That’s really abnormal,” Ojemann says, pointing to a pattern of frenetic peaks. “It’s like a mini-seizure.”
Ojemann was born to the brain business. His father and brother are neurosurgeons, as was his late uncle; his mother is a neurologist who specializes in epilepsy. When he’s not operating, Ojemann analyzes brainwave recordings to find better treatments for stroke and epilepsy. He was eager to collaborate when the Allen Institute started its human brain tissue initiative five years ago.
“I hope this helps us treat epilepsy and helps us develop new therapies,” he says. “I think the sky’s the limit on what they can learn.”
Once he’s pinpointed the troublesome portion of Williams’ brain, Ojemann is ready to begin cutting. Peering through a surgical microscope, he teases away a disc of tissue from the outermost layer of the temporal lobe, a part of the cerebral cortex involved in memory, speech and comprehension. He places the pinkish blob in a beaker filled with a frozen slurry of artificial cerebrospinal fluid.
It’s just the beginning of Williams’ surgery, which will continue for another two hours. But the race is on to get that morsel of brain into the lab.
TAMARA CASPER, a research associate at the Allen Institute, is waiting in the hall with a wheeled cart and a small blue cooler. She hooks the beaker to an oxygen tank, tucks it in the cooler and rolls the cart into the back of a white van for the 1.8-mile trip through some of Seattle’s worst traffic.
About 15 minutes later, the blob is the center of attention in a narrow lab where half a dozen people swarm purposefully. Some examine the chunk and separate it into smaller bits. A technician uses an instrument called a vibratome to slice the brain pieces into paper-thin slivers the size of fish scales.
“Literally, it’s like slicing through a hot dog,” Ting says.
The brightly lit room has only one thing in common with the dungeons where Hollywood’s mad scientists cackle over brains in jars: lots of bubbling fluid. Keeping the tissue alive requires constant oxygenation and perfusion with a cold broth of nutrients, chemicals and buffers, Ting explains.
It’s an unusually busy day.
Another human specimen arrived earlier, from an emergency brain surgery at Swedish Neuroscience Institute. “It’s always boom or bust,” Ting says. Sometimes the researchers pull all-nighters when tissue arrives in the evening. “There’s a lot of pressure, because you’re feeling like this is the most precious material you can possibly handle.”
Eight Seattle neurosurgeons participate in the program, and roughly 50 patients a year donate tissue. That’s nearly a fourfold increase since Ting joined the institute to help launch the human tissue work after several frustrating years in university labs trying to understand mental illness by studying mice. “It’s hard to convince yourself, let alone anyone else in the academic community, that these things are relevant for human use,” he says. But the new project was so risky, even the institute’s chief scientist wasn’t sure it would pan out.
“He thought it was the craziest idea ever,” Ting recalls.
Most studies of the human brain rely on organs from cadavers, which can reveal a lot about structure and the makeup of neurons. MRI scans and other imaging methods can measure activity in the living brain, but yield only a crude view. Researchers first experimented with human brain tissue from surgeries more than 30 years ago, but the technology didn’t exist until recently to extract much useful information, says Dutch neuroscientist Huib Mansvelder. His lab at the Free University of Amsterdam is one of a handful around the world reviving the approach. But no one does it in a bigger way than the Allen Institute.
“They can achieve things on a scale that is unthinkable for an ordinary academic lab,” Mansvelder says.
Founded in 2003 by the late Paul Allen, Microsoft’s eccentric co-founder and one of the world’s richest people, the institute aims to advance understanding of the brain by generating vast databases on neurons and brain regions and developing experimental tools and techniques — then making them freely available through an online brain “observatory.” Their first project was a detailed atlas of the mouse brain that was consulted more than 220,000 times last year by researchers worldwide. But Allen’s interest in neuroscience was spurred in part by his mother’s Alzheimer’s, and he urged the team to move beyond rodents and tackle the human brain. He also poured $500 million into the institute — his single largest philanthropic endeavor.
As part of the federal BRAIN Initiative launched by the Obama Administration, the institute recently won $100 million in grants to accelerate its work with live human tissue and lead a collaboration to complete an ambitious atlas of mouse and human brain-cell types.
THE INSTITUTE’S industrial-scale approach is on display in the electrophysiology lab, where a controlled frenzy of cell-zapping is underway with the fresh tissue. Researchers sit at eight identical stations, each with a powerful microscope and a tiny, remote-controlled glass electrode focused on a small slice of live human brain, some from Williams, some from the patient at Swedish. The researchers zoom in on a single cell, maneuver the electrode until it just touches the membrane, then deliver an electrical ping and record the cell’s response. At other stations, operators listen in as eight separate neurons “talk” to each other.
“Last year, we recorded from 6,500 cells — both mouse and human,” says Jim Berg, a lab manager. “In graduate school, I think my entire dissertation was maybe 90 cells.”
A neuron’s electrical properties are a kind of fingerprint that holds fundamental information about how the cell functions and how it communicates and interacts with other neurons. Misfiring neurons play a role in many diseases, including epilepsy. Working with similar bits of brain tissue, Mansvelder found people with higher IQs have larger neurons that generate electrical signals more quickly.
The Seattle scientists also inject the living neurons with dye, which spreads to the tips of the threadlike dendrites that receive impulses from other cells. The results are stunning, 3-D images that help relate the cells’ shapes to their functions. Some are wreathed with so many dendrites they look like intricately woven baskets. Others have long, sturdy axons, or nerve fibers, that seem designed to fast-track signals from one place to another.
The final step in the Allen Institute’s futuristic cell assembly-line is perhaps the most extraordinary.
Researcher Lindsay Ng demonstrates, manipulating controls to plunge the electrode deep into a cell, spear its nucleus, then slowly ease the probe out. The shadowy microscope image shows the cell membrane stretching like a soap bubble, then snapping back as the electrode exits. Ng deposits the nucleus — invisible to the naked eye — into a plastic tube tinier than a doll’s cup. Now the researchers have the neuron’s genetic blueprint, which they will analyze to see which genes are switched on and off — information that could be directly relevant to human brain disorders.
Collecting data on individual neurons might seem esoteric, but there’s no other way to understand the building blocks of the brain — many of which are still unknown, says institute investigator Ed Lein.
“Most research doesn’t treat the brain with enough granularity to understand what goes wrong in disease,” he says. “They treat it as a series of regions without understanding which cell types are affected.”
With the detailed cell profiles, the researchers are assembling a first-of-its kind “periodic table” of neuron types in the human brain and their properties, says Lein, who leads that effort. No one knows how many there are, but estimates start at 1,000 and go up. So far, the institute has identified 75 in the temporal lobe alone, most of which have never been described in such detail before. The team recently made the first electrical recordings of spindle-shaped brain cells called von Economo neurons — believed to be pivotal to complex social emotions, like empathy and guilt — in a snippet of tissue taken from deep in a patient’s brain during an unusual surgery at Swedish.
The work also is uncovering telling differences between mouse and human brains that might help explain why mouse studies often fail to translate to human disease. Among them is the fact that human tissue seems sturdier and survives much longer in the lab than mouse brain.
“That was one of the great surprises,” Ting says.
IN ANOTHER LAB upstairs. Ting is preparing slices of Williams’ brain for long-term culture, which can keep them alive for weeks. That extra time allows Ting to treat the tissue with inactivated viruses that deliver fluorescent tags to specific types of neurons. The technique, which causes the labeled cells to glow bright green under a microscope, lets Ting locate needle-in-a-haystack neurons that might play key roles in orchestrating mental and disease processes.
“Some of these cells are so rare that (without the labeling) you might sample for five years and only encounter one of them,” Ting explains.
Someday, he hopes his technique will be adapted to go far beyond labeling cells to one of the ultimate goals of medical science: gene therapy for diseases like Parkinson’s, ALS, schizophrenia and other debilitating brain conditions. If viruses can be engineered to target specific types of cells in the living human brain and deliver fluorescent tags, then they probably also can be engineered to deliver other types of cargo — like missing genes, or replacements for defective genes.
“At the moment, it’s science fiction,” says Mansvelder, who is collaborating with the Allen Institute. “But that’s our business, to make science out of science fiction.”
TWO WEEKS AFTER Williams’ surgery, the tissue he donated to the Allen Institute has been used up — every last bit of information wrung from the cells and added to a database that includes genetic analyses of 2.5 million living human brain cells and electrical measurements from more than 13,000.
Williams is still grappling with the trauma of today’s blunt-force approach to brain disorders like epilepsy. He has a hard time carrying on conversations and will start speech therapy soon. It could take months for his energy to come back and even longer before he sees improvements from the operation.
Ojemann estimates the surgery has a 50 to 70 percent chance of eliminating Williams’ seizures. Williams’ dearest hope is that it will stop the tremors in his right hand so he can get back to the tattoo business. If that happens, he’s promised Ojemann and his staff free ink work — if they’re game.