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From autism to ALS, scientists at the Brain Science Institute are charting new paths that could fundamentally change the way we approach devastating ailments.
Illustration by James Steinberg | Photography by Chris Hartlove
“By effectively parsing patients into subgroups, each with a different reason for their symptoms, we may finally have a way to effectively treat autism.”
- Gul Dolen
The Brain’s Own GPS
The job that mapping software and GPS perform is a technological marvel—remembering every road, every intersection, every one-way sign or toll road, then integrating all of this information to calculate the best possible route from point A to point B.
Perhaps even more miraculous is that a healthy person’s brain does a similar thing countless times each day: guiding us to the bathroom in the morning, to our favorite lunch spot and to our parked cars after work. Now, research led by the Brain Science Institute’s David Foster, an assistant professor in the Solomon H. Snyder Department of Neuroscience, is getting a handle on how this brain GPS works—and how it goes awry in memory-robbing diseases.
Foster’s lab studies the hippocampus, a seahorse-shaped region buried deep in the brain’s medial temporal lobe that’s responsible for memory—specifically, the type of memory that involves mentally traveling back in time to bring various bits of information back to the present.
“It’s what you use when you’re thinking back on what you had for breakfast this morning,” Foster explains.
While it’s been extremely challenging for neuroscientists to study this type of recall in animal models such as rats and mice—for one, they’re unlikely to answer when you ask them about their breakfast choices—Foster and his colleagues have been able to gather new insights on the hippocampus’ workings by asking these animals a different question: Where’s the chocolate milk?
In a study published last fall, Foster and his team gave rats an opportunity to explore an open arena fitted with 36 small wells. One of these wells was filled with chocolate milk, a special treat for the animals. Inserting tiny, lightweight electrodes into the rats’ brains, the researchers recorded electrical activity from 250 individual cells in the animals’ hippocampi as they spent time exploring their environment, visiting the well again and again.
When the animals sat on the sidelines before each visit to the chocolate milk font, the recordings showed a few brief bursts of neurological activity, each around 150 milliseconds long. That wasn’t surprising, says Foster—other researchers had found the same thing in similar experiments, chalking the activity up to passive offline activity or simple daydreaming.
But looking closer, Foster and his colleagues found something much more interesting. By slowing down these bursts and looking at the cells that fired millisecond by millisecond, the researchers saw that the bursts were really directions based on which cells had been active when the animals were just poking around—their own personal GPS based on previous experience.
“These firing sequences aren’t arbitrary,” Foster says. “They predict where the animal chooses to go next.”
More recent work out of the Foster lab expanded this experiment to a mouse model of schizophrenia, a disease that significantly affects working memory in people. His latest findings show that the neurological bursts these animals produce when they’re planning their next moves are too strong, so the information about the movements is drowned out by erroneous noise. By getting a better handle on the hippocampus through its GPS system, Foster says, neuroscientists may finally find their way in treating memory problems.
The Real Social Network
Derived from the Greek “autos,” meaning “self,” autism is a tendency toward one’s self—a type of turning inward that excludes the interplay with other people that most humans find so valuable.
One of the simplest hypotheses for why people with autism have this social deficit is that they don’t find human interactions rewarding in the same way that other people do, says Gul Dolen, a new faculty member in the Department of Neuroscience and the Brain Science Institute who joined Johns Hopkins in February. But even though this idea is straightforward, proving it—or, if it pans out, finding exactly what’s so unrewarding about social interaction for autistic people—is anything but.
Both mice and humans share a brain region called the nucleus accumbens, which seems to be responsible for the pleasure generated by any rewarding activity—food, gambling, drugs of abuse and social interaction. In turn, receptors for two proteins, serotonin and oxytocin, on cells that feed into this region mediate whether or not the nucleus accumbens produces rewarding feelings. Some research in mice and people suggests that problems in these receptors could contribute to autism.
However, these receptors don’t tell the whole story, says Dolen. It’s still unclear whether problems with social interaction are themselves the primary deficit, leading to autism’s other complex web of symptoms, or whether other glitches happen first that lead to unrewarding social interaction. For example, Dolen theorizes that the problem for some patients might instead be issues in the brain’s language center or elsewhere that make social interactions awkward. With fewer rewarding interactions, these individuals might be set on a downward spiral that eventually results in other autistic symptoms.
In her new position at Johns Hopkins, Dolen is working to answer this chicken-or-egg problem. Using high-tech methods to probe cells in the nucleus accumbens and elsewhere, she and her colleagues plan to look at differences in not only how the reward system operates in various mouse models of autism, but also about the differences in areas whose signals feed into the nucleus accumbens, such as those responsible for language and fear.
Dolen suspects that her work will show that autism has many different primary causes that vary case by case—origins that, if she or other researchers can find an effective way to target, could eventually reverse this puzzling and intractable disorder.
“By effectively parsing patients into subgroups, each with a different reason for their symptoms,” says Dolen, “we may finally have a way to effectively treat autism.”
Personalized Medicine: At the Extreme
In the mid-1990s, Johns Hopkins researchers created some of the first transgenic mice—animals whose DNA had been purposely modified to contain genes that it wouldn’t normally have. Fitted with thousands of different human genes both normal and not, transgenic mice have proven to be powerful models for gaining a better understanding of what happens in human diseases.
However, says Jeffrey Rothstein, director of the Brain Science Institute, the problem with these mice is that they’re, well, mice. Though these animals have provided countless insights over the past few decades on what goes wrong in diseases, they haven’t been particularly useful predicting what drugs will work to treat patients—the ultimate end goal for many conditions.
“As much as we can hope that mouse brains and cells are like humans’, they’re not,” says Rothstein.
Enter a new technology called induced pluripotent stem (IPS) cells. Several years ago, researchers developed a way to turn back the clock on adult cells, transforming scrapings from adult skin into blank slates capable of becoming practically any other cell in the body.
Rothstein and his colleagues see these cells as a fresh new direction for studying neurological diseases, particularly amyotrophic lateral sclerosis (ALS)—the disease that’s been Rothstein’s focus for his entire career. ALS’ relentless onslaught of progressive paralysis that eventually leads to death has been particularly challenging to battle effectively.
Five years ago, Rothstein gathered a select group of ALS researchers from across the country and decided to make a library of IPS cells from ALS patients with inherited mutations known to cause this disease—a tool that could potentially provide new insights on the 10 percent of patients with familial ALS. At the time, the researchers thought the library wouldn’t have any use for the other 90 percent of ALS patients whose disease arises in a sporadic manner.
However, not long after this project was completed, Rothstein’s colleague Bryan Traynor, who studies ALS both at Johns Hopkins and the National Institutes of Health, discovered a new mutation that causes ALS. Found within a gene called C9ORF72, this mutation affects about twice as many ALS patients as all the other known inherited mutations combined, accounting for many of the cases that researchers had previously thought were sporadic. Additionally, Traynor’s research showed that the same mutation can alternatively cause a condition called frontotemporal dementia, a memory-robbing disease that causes similar symptoms to Alzheimer’s.
Right away, Rothstein and his colleagues aggressively began making new IPS cell lines from patients with this mutation to figure out what role the gene plays in causing ALS—work that would have been extremely challenging using transgenic mice. Using these cells and cells from autopsy brain tissue from patients who carried the same mutation, Rothstein’s team spotted the problem: The bulge caused by the faulty gene acted like sticky flypaper for proteins that bind the genetic molecule RNA. Consequently, cells became depleted of these proteins, potentially representing the first insult that leads to this form of ALS and to frontotemporal dementia.
But unlike with the autopsy cells, the researchers could use the IPS cells to test treatments that might prevent this cellular gumming up. Sure enough, molecules called antisense oligonucleotides prevented the C9ORF72 bulge from trapping RNA binding proteins, allowing the IPS cells to continue to function normally. Rothstein and his colleagues are now working with a pharmaceutical company to make these antisense oligonucleotides into drugs for a clinical trial. So, in a very short period of time, the cells provided critical answers as to how the disease occurs and simultaneously provided a platform to find new treatments.
Eventually, he adds, he and other doctors might make IPS cells from every patient so therapies can be truly customized to the peculiarities of each person’s disease.
“This is the real extreme of personalized medicine,” says Rothstein. “The skin can be a window to the brain.”
Move Over, Flipper
“We’re interested in movement,” says John Krakauer of his Brain, Learning, Animation, and Movement (BLAM) Lab at Johns Hopkins, noting that movement encompasses everyone and everything we do: from the professional athlete to the paralyzed stroke patient.
His lab is looking at big questions, such as how practice improves our purposeful movements, how patients who lose movements can regain them or even how we unconsciously control our movements in the first place, since even that fundamental query remains largely unanswered.
To help solve these mind-twisting puzzles, Krakauer co-founded the Kata Project, which looks like a combination of Google, Wired magazine and Pixar, mixed in with the usual clinician-researchers—a collaboration of doctors, physicists, computer scientists, gamers, animators, artists, animal behavior experts and others, all working toward common goals.
“Enough of a single doctor in a white coat holding up an X-ray and a petri dish—that model is old and tired. Medical research needs a bit of a mash-up,” says Krakauer. His project co-founders include Omar Ahmad, Promit Roy and Kat McNally.
The Kata team’s latest project is just as eclectic as its makeup: They’re crafting video games with animal avatars so realistic that users don’t just control them—they become the animal. And by learning to make these animals move, players might be able to relearn movements that they’ve lost or teach researchers about how movements are learned in general.
The work got its start in 2011 when Krakauer teamed up with Ahmad, a computer scientist on Johns Hopkins’ Homewood campus who invented a new way to do ultrarealistic biological simulations; Roy, a software engineer whose work with 3-D rendering and graphics earned him the prestigious Microsoft MVP title; and McNally, a graduate of the Maryland Institute College of Art, recommended by a professor for her superb illustration and seemingly boundless creativity.
Together, this team—later augmented by robotics expert Kevin Olds—set out to create games for tablets, phones and computers that pull patients and research subjects into a world so pleasurable and compelling that participating in therapy or contributing to science is a joy rather than a chore.
Their work recently culminated in a virtual dolphin that they’ve lovingly named Bandit. By flicks of their fingers, wrists and arms, players can make Bandit swim, leap, roll and dive, all the while sending streams of data back to the BLAM Lab. By analyzing data from hundreds of users, the scientists can see how movements and control of this avatar change over the hours that users play the game, providing a wealth of information that would be nearly impossible to gather in a lab setting. In a series of clinical trials, stroke patients will play the game to augment their traditional therapy. If they recover faster than a control group that won’t be meeting Bandit, it could eventually shift the model for stroke rehab.
The work could also signal a new era for biomedical science in general, in which discoveries are made by groups whose disciplines have rarely worked together in the past. “It’s an unusually brilliant team of people doing something completely novel,” says Krakauer. “I think it represents the future.”
Reveling in Science’s Serendipity
For more than two decades, Barbara Slusher has been studying a protein called glutamate carboxypeptidase 2 (GCP-2), which facilitates the release of the neurotransmitter glutamate. Research overwhelmingly shows that decreasing excess glutamate can have therapeutic benefit in various neurodegenerative diseases, stroke and chronic pain. Over the years, Slusher and her colleagues have come up with dozens of potential drugs that potently and selectively target the GCP-2 enzyme. The problem, she says, is getting these compounds where they need to go. None can make it past the blood-brain barrier—which stymies their use for treating pain and neurodegeneration.
“I’m an inventor on more than 50 GCP-2 inhibitor patents, but we haven’t yet been able to find a single one that adequately gets to the brain and could provide benefit in patients with central nervous system disorders,” says Slusher, who directs the Brain Science Institute’s NeuroTranslational Drug Discovery Program.
But that didn’t stop her from finding another purpose entirely.
One morning, she noticed an email alert from a journal she follows regularly telling her about a new paper on GCP-2. Rather than focusing on its role in the nervous system, this paper provided compelling evidence that GCP-2 is overexpressed in a different part of the body: the intestines. The new research showed that patients with inflammatory bowel disease (IBD) seemed to have an overwhelming amount of GCP-2, a factor that those researchers suggested could contribute to IBD symptoms.
Though Slusher’s GCP-2 inhibitors weren’t having much luck making it into the brain, the gut was a whole different story, she reasoned.
To validate her idea, Slusher tracked down gastroenterologist Xuhang Li, who has developed several different mouse models of IBD.
Li says that he was surprised to get a message from someone so far outside his own field. But when he pulled up the paper that Slusher forwarded to him and her request to collaborate, he was intrigued.
“I said, ‘Let’s try it,’” Li remembers. “We decided to use no more than 10 mice, and if something happens, good. If nothing happens, we stop.”
In those first 10 mice, Li got results so promising that he decided to keep the experiment going. Disease symptoms, such as weight loss, bloody stool and diarrhea, saw a significant reduction. In another model, in which colon inflammation is so pronounced that the rectum protrudes in some animals, Li and his colleagues saw this condition reverse—something he’d never seen before.
Slusher, Li and their colleagues are now working with a pharmaceutical company to develop this promising compound into a drug that could work for human IBD patients.
“Probably the coolest thing about science is that you think you’ve understood something, and then something like this happens that you never would have thought of,” Slusher says. “The serendipity of science keeps you on your toes.”
“As much as we can hope that mouse brains and cells are like humans’, they’re not.”
- Jeffrey Rothstein
“Enough of a single doctor in a white coat. medical research needs a bit of a mash-up.”
- John Krakauer
“The serendipity of science keeps you on your toes.”
- Barbara Slusher