Brain Trust at George Washington

Scientists plan to open a world-class collection of brain tissue and data to preserve and share a dwindling resource that offers unparalleled views into evolution and the mind.

Chet Sherwood
Anthropology Professor Chet Sherwood oversees George Washington University's collection of mammalian brains, which are used to study human evolution and neurobiology. (Logan Werlinger/GW Today)
June 24, 2016

By Sarah Zielinski

In a lab on the sixth floor of George Washington Univeristy’s Science and Engineering Hall, Cheryl Stimpson is working with what looks like a small deli slicer covered in white ice crystals. On a tray sits part of a baboon’s brain, frozen inside a preservative and kept cold with two small troughs of ethanol bubbling with dry ice.

A research associate in the lab of evolutionary neuroscientist Chet Sherwood, Ms. Stimpson methodically draws a sharp blade across the brain, creating a slice only 40 micrometers thick—“thinner than cheese,” she quips—which she lifts off with a small brush and places in a tube. She’s been at this since 8 a.m. and will keep slicing throughout the day.

“This is a bit art,” she says. She has to keep the brain cold, but not too cold. And she must pull the blade fast, but not so fast she tears the slice or cuts herself. It helps to have the right music playing, Ms. Stimpson notes, as the voice of Kermit the Frog comes through a nearby speaker.

When she is done, she’ll place the neatly labeled tubes in one of the lab’s freezers, where they’ll rejoin the more than 650 mammal brains in Dr. Sherwood’s collection. All have come from animals that died of natural causes in zoos or research centers. (There are no live animals here.) Some are from mammals far from the human branch of the evolutionary tree, such as tigers, elephants and kangaroos. But the prizes of the collection are the dozens of primate species, such as the baboon Ms. Stimpson is cutting, and, especially, chimpanzees, humanity’s closest living relatives.

Through comparing species in the collection, Dr. Sherwood and his team have made insights into brain evolution, and they are starting to tease out the qualities that make the human brain unique. Having access to so many brains is what makes this type of research possible—and it’s why Dr. Sherwood’s lab is one of the few places where these studies are done.

Traditionally, scientists have hoarded exclusive resources like these. But there is growing recognition that sharing may be in the broader interest, especially when materials have been developed with taxpayer dollars.

So Dr. Sherwood recently teamed up with two collaborators—William Hopkins of Georgia State University’s Neuroscience Institute and Todd Preuss of the Yerkes National Primate Research Center at Emory University—to create the National Chimpanzee Brain Resource with the aid last year of nearly $1 million from the National Institutes of Health.

The NCBR will be more than a collection of brains, though. Researchers worldwide also will have access to decades’ worth of related data—brain MRIs, and observational and veterinary data—from the chimpanzees.

“We’re limited,” Dr. Sherwood says. “We can investigate questions that we find interesting, but there are a vast number of other fascinating questions and innovative approaches that other labs and investigators might want to address using these resources.”

Building this resource is “just best for science and for our progress in understanding chimpanzee neurobiology for its own sake as well as how humans compare with chimpanzees,” he says.

When Dr. Sherwood talks about his undergraduate years at Columbia University, he says he was “not on a path to becoming any kind of scientist. I didn’t think I had any aptitude for it.” He was a philosophy major who played in a punk band and worked at a radio station.

But a friend recommended he take a class in biological anthropology, which he thought sounded like one of his favorite sci-fi movies, Planet of the Apes (a poster from which now hangs in his office). He ended up captivated by a course that explored how human cognition has evolved through changes in brain structure.

He added classes and earned a PhD in anthropology, studying under the professor who taught that first course, Ralph Holloway, and Patrick Hof, of the Icahn School of Medicine at Mount Sinai, whose collection of mammalian brains became the backbone of Dr. Sherwood’s catalog and of the NCBR.

Now director of the GW Mind-Brain Institute and a member of the Center for Advanced Study of Human Paleobiology, Dr. Sherwood has found a niche for himself straddling the realms of anthropology and neuroscience.

While anthropologists typically have studied the bones of our long-dead ancestors—informing, for instance, how brain size changed in relation to body size over time—neuroscientists have concentrated on how living brains develop and work, and the diseases that can occur when these things go wrong.

Dr. Sherwood is bridging the gap between them by using neuroscience techniques, like MRI scans and examining whole-genome transcription, to compare human brains to those of chimpanzees and other primates. He’s aiming to elucidate the characteristics that make the human brain so capable of exceptional things as well as prone to neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s, that are not found in our close animal relatives.

He has shown that it’s not simply brain size or structure that are important, but that other aspects of biology, such as the human lifespan, may also play roles in the development of brain diseases.

“Human longevity is extraordinary,” Dr. Sherwood says.

Unlike most animals, humans live long after their reproductive years end. But as a person ages, brain structures like the hippocampus and frontal lobe, which are responsible for emotion and memory, decrease in volume. That doesn’t happen in chimpanzees, Dr. Sherwood and his colleagues reported in the Proceedings of the National Academy of Sciences in 2011. Even chimps near the end of their lives experience no declines in brain volume, they found.

“This is a unique part of brain aging in our species,” he says. And it may be the price we pay for having such big brains and long lives.

Comparing human and chimpanzee brains can do more than just offer clues as to why one species gets sick and the other does not, Dr. Sherwood says. Such work might also scratch at the question of why a person can do something like read this article but even our closest-living relatives cannot.

Aida Gómez-Robles, a post-doctoral scientist in Dr. Sherwood’s lab, holds two brightly colored 3-D printed models of brains in her hands. One is a human brain, which always seems somewhat smaller than our egos would like to think, but, at three pounds, is actually quite big for an animal our size. The other belongs to a chimpanzee, and it’s about one-third the size.

There are more differences than just size, though, Dr. Gómez-Robles points out. The human brain has far more folds, for instance, and some areas, such as those responsible for language and problem solving, are even bigger than what would be expected from simply magnifying a chimp brain to the size of a human’s. Humans also have more of the white matter that connects nerve cells. Such differences, she says, help explain the complex cognitive functions that a human brain can perform.

But for all their differences, humans and chimpanzees share a lot of similarities, including some 98 percent of their DNA. That’s because we shared a common evolution up to about 6-8 million years ago.

For decades, this close relationship made chimpanzees relevant research animals, especially in the biomedical field, where they have been important to research on deadly diseases such as hepatitis and Ebola. But over time, people have become less comfortable with using animals that have so many humanlike qualities—and have become so rare in the wild that they are now endangered—when other options may be available.

In 1995, the National Institutes of Health stopped breeding chimpanzees for research, and, in 2013, the agency announced that it would retire most of the chimps it owned or supported, keeping only 50 animals in reserve.

Then last year, the U.S. Fish and Wildlife Service listed captive chimpanzees as endangered under the Endangered Species Act. The listing meant that any research with the animals would be limited, and to get a permit to keep captive chimps, organizations would need to show that their work benefits chimpanzees in the wild or is critical to understanding human disease. Several months later, NIH announced that it would retire all of its remaining research chimps and no longer support invasive research on the primates.

The NIH decision, which has been controversial among researchers, means that chimp brains will become a rare resource after these soon-to-be-former research chimpanzees reach the end of their natural lives. Zoos may still donate brains, but the chimps that have been extensively studied in research facilities are especially significant to scientists, Dr. Sherwood says. The ancestry, behavior and biology of research chimps are often well-documented. The animals may have had MRI scans of their brains while they were alive. The depth that all this extra information adds to the brain itself is “really powerful,” he says.

When an animal dies at a zoo or research facility, a veterinary pathologist performs a necropsy—the animal version of an autopsy. Organs are removed for testing. The brain might be cut into pieces for analysis. The institution completes its study and, often, the process ends there. Although Dr. Sherwood and his NCBR partners are the Association of Zoos and Aquariums-endorsed recipients of brains, there’s no requirement or guarantee a brain will end up with them.

And yet, each year dozens of brains do reach Dr. Sherwood’s lab, and he anticipates the NCBR could receive 10 or so chimpanzee brains per year. So the group is working with veterinary pathologists to create a recommended standard for how zoos, the National Primate Research Centers and the federally supported Chimp Haven sanctuary in Louisiana could best handle a chimpanzee’s brain after death.

Brains typically arrive in one of two forms—preserved in formalin or flash-frozen at -80 degrees Celsius—joining the 230 or so chimp brains already in the collection.

Frozen material preserves proteins and RNA, so these brains are better for studies that examine which genes are active within cells, called gene expression, as well as protein expression. Many biologists are now interested in these types of studies, Dr. Sherwood says.

But the brains fixed in formalin are useful, too. They are perfect for slicing for further study, such as the baboon brain that Ms. Stimpson was cutting up into hundreds of pieces. That material was being prepared for an ongoing cross-species study, but the slices will also be saved for later use.

As the brains are sliced, every 10th piece is stained to illuminate a feature, like neurons or synapses, and put onto a slide. The group of slides creates something of a brain atlas that can be used to direct researchers to the tubes with specific slices they need for a study. The slides also will be scanned and made available online in a zoomable format.

“It’s a method that we’re using to maximize the usage of the brains,” Dr. Sherwood says, “because we expect them to be an incredibly limited resource.”

Each brain also will be photographed when it enters the collection, with the photos to be combined into a 3-D image. At Emory University, brains will undergo high-resolution MRI scans as well as diffusion tensor imaging, a technique for measuring connections between parts of the brain. From both imaging efforts, the team will build online databases of grey and white matter volumes and of brain connectivity.

These types of images have already proven their worth. For example, a team led by Dr. Gómez-Robles used similar images in a study published last year in the Proceedings of the National Academy of Sciences to show that the shape of a human brain depends more on environmental factors than genetics, while for a chimp brain it’s the opposite.

Also included in the NCBR will be behavioral data and a brain template, based on the MRI data.

While this type of information has been around for years, gaining access often required going to multiple research centers that each had different requirements and different protocols. With the NCBR, Dr. Sherwood says, “we’re trying to lower the barrier so more people are able to ask the questions they want to ask.”

Mary Ann Raghanti, a comparative neuroanatomist and biological anthropologist at Kent State University, says the “repository is invaluable.” If researchers like her weren’t able to study chimpanzee brains and make comparisons with those of humans, she says, “then our understanding of humans, not only in terms of evolution, but also in terms of potential susceptibility to neurodegenerative processes—all of that disappears.”

Dr. Sherwood opens the door to one of his lab’s freezers, revealing hundreds of plastic containers in stacks on green wire shelves. Each contains a mammalian brain, some whole, some in pieces. Primates may dominate the collection, but he points to some oddities, like the giant anteater and rock hyrax. The sheer range of materials in the collection have allowed him and his team to make unique insights into brain evolution and the basic biology of the mammalian brain. They’ve shown, for instance, that the structure of neurons, once assumed to be similar in all mammals, instead could vary from species to species.

But the brains of great apes, in particular, fill a gap in neuroscience research, says Katerina Semendeferi, a comparative neuroscientist at the University of California, San Diego.

In that realm, scientists mostly have focused on invasive research in animal models, such as rodents, or used imaging techniques on humans. The NCBR, she says, serves an important role “in terms of translating the model findings … to the human-imaging studies.”

The endeavor is perhaps equally about legacy. The scientists, of course, feel pride in amassing and creating this vast public resource (“We accumulated a lot more materials than we ever thought we would,” says Dr. Hopkins, the NCBR co-founder at Georgia State). And standing with Dr. Sherwood in the cold, surrounded by brain tissue, the group’s reverence for the lives and service of the chimpanzees is palpable. The jars and boxes are labeled not by number, but name—the names by which the chimps were known in life to a generation or two of zoogoers, veterinarians, scientists and graduate students.

In death, Dr. Sherwood says, “we’re trying to just add as much value [as we can] to the lives that they lived.”

For more on the National Chimpanzee Brain Resource, visit chimpanzeebrain.org

 

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