This story was originally published on the BU Research website.

For decades, some of the most exciting research at Boston University has been unfolding in a row of buildings hidden on Cummington Mall, designed originally for making carriages instead of studying the life sciences.

Now University President Robert A. Brown is giving science a more prominent address on the University’s main thoroughfare. In late May or early summer 2015, at what is now a parking lot at 610 Commonwealth Avenue, BU will break ground for its new Center for Integrated Life Sciences & Engineering (CILSE), a $140 million, state-of-the-art, nine-story research facility that will bring together life scientists, engineers, and physicians from the Medical and Charles River Campuses. The building will be dedicated to systems neuroscience, cognitive neuroimaging, and biological design. With shared, flexible lab spaces, meeting rooms, and other common areas, it is being designed to encourage the kind of collaborative, interdisciplinary research that will be the hallmark of 21st-century science.

“Today, many of the outstanding challenges in science lie at the boundaries between traditional disciplines or the unchartered spaces between them,” says Brown. These unchartered spaces will be explored at CILSE, a place he says will foster “major interdisciplinary research efforts led by faculty from many departments and schools, but with common interests.”

CILSE will be built adjacent to historic Morse Auditorium and is expected to be finished in late 2016 or early 2017. It will contain lab space for approximately 160 researchers, postdoctoral students, and staff, 270 graduate students, and additional space for future faculty. The architects are from Payette, a Boston firm that has built prizewinning science buildings for major research universities and other institutions around the world.

The 170,000-square-foot building will house the Center for Systems Neuroscience, the Biological Design Center, the Center for Sensory Communication and Neuroengineering Technology, and the Cognitive Neuroimaging Center, with a 3 Tesla fMRI—a fundamental tool for studying the brain’s trillions of neural connections and how they relate to human behavior. The imaging technology will serve faculty from schools and departments across BU’s sprawling neuroscience community—and from other universities around Boston—who study brain topics from how we learn, think, and remember to traumatic brain injury and Alzheimer’s disease.

Barbara Shinn-Cunningham, a College of Engineering professor of biomedical engineering. Photo by Vernon Doucette

“In the life sciences and engineering, we have world-class faculty. We need facilities to match,” says Gloria Waters, vice president and associate provost for research. “We decided to invest in better lab space that would bring faculty together in a very unique and interdisciplinary environment.”

The new Center for Sensory Communication and Neuroengineering Technology will be directed by Barbara Shinn-Cunningham, a College of Engineering professor of biomedical engineering, and will bring together neuroscientists and sensory physiologists who study hearing, speech, and language, as well as mathematicians who investigate neural coding. The center will connect scientists in these areas to enhance technological innovation and develop technologies such as neural prosthetics and brain-computer interfaces.

Chantal Stern, a College of Arts & Sciences professor of psychological and brain sciences and the director of the Brain, Behavior and Cognition program, will direct the Cognitive Neuroimaging Center. She says the building—and especially the new imaging technology—signals the administration’s commitment to first-class research at BU.

The University boasts one of the nation’s largest clusters of researchers in the emerging fields of systems neuroscience, which examines brain function at the cellular, molecular, and cognitive levels, and biological design, which seeks to build new biological systems with the tools and techniques of engineering. These interdisciplinary fields tackle some of the thorniest problems in science and medicine, like the detection and treatment of infectious diseases, treatments for Parkinson’s and Alzheimer’s diseases, how memory works, and the root causes of autism. These problems draw researchers from diverse fields who are currently spread across both campuses.

“One of the great things about BU is that we have spectacular faculty from many different disciplines,” says Waters. “This building will allow us to bring them together in ways that wouldn’t happen if they occupied space in their individual school or college. By placing new groups in proximity to one another, we are hoping to develop collaborations that would not happen otherwise, and ultimately some unique areas of excellence.”

It will contain lab space for approximately 160 researchers, postdoctoral students, and staff, 270 graduate students, and additional space for future faculty.

Like many scientists working across disciplines, Douglas Densmore, an ENG assistant professor of electrical and computer engineering and of biomedical engineering and a primary investigator in the young field of biological design, has multiple offices and students scattered in buildings across campus. CILSE will allow him to gather his various research projects, and his students, under one roof. “I want students to be able to see each other,” says Densmore. “It will be great to be in a welcoming environment that facilitates collaboration.”

Ask other researchers what tops their wish list for the new building and many of them echo Densmore. Their number-one priority is simple: finally having a place to bring their colleagues together.

Douglas Densmore, an ENG assistant professor of electrical and computer engineering and of biomedical engineering. Photo by Jessica Scranton

“You find neuroscientists and people who define themselves as neuroscientists on both campuses—in psychological and brain sciences, biomedical engineering, biology, at Sargent College, in mathematics, physics, radiology, psychiatry, anatomy, neurobiology, pharmacology—and they’re all in different buildings,” Stern says. She is looking forward to the collaborative projects these researchers might be inspired to undertake once they’re under the same roof.

So how do you encourage biologists to talk to engineers? One way to do that, says principal architect Charles Klee, is by creating lab spaces large enough—the plan for CILSE is 17,000 to 20,000 square feet per research floor—to put two or three principal investigators on each floor. “With people in the same space, you can say, ‘I’m having a problem with my protein sequencer; have you ever seen this?’ Another person can answer, ‘Sure—someone over here can help you with that,’” says Klee.

Scientists from different disciplines may also share lab space on the same floor in some instances. In addition to the abundance of other common spaces, there will be kitchenettes on each research floor and—one of Klee’s favorite ideas for promoting serendipitous, cross-disciplinary encounters—an inviting, open stairway connecting the kitchenettes.

“We understand you’ll talk to someone when you have to,” says Klee. “What we’re looking for is the chance discussion that happens just because you bump into someone. It jars something loose in your mind, causes you to think about something in a new way—that’s very much what this kind of a building is trying to do.”

As science has evolved, so has the design of science buildings. “When I was beginning my career, most buildings were designed to function within single disciplines,” says Brown. “I have seen this change dramatically over the last two decades. Now, almost all universities are focused on allocating quality space to strategically important interdisciplinary research.”

For modern research, quality space also means specific building capabilities, such as flexible lab space and testing centers, so scientists can configure different experiments.

“Whenever they ask if we want a wall or not, we say no wall,” says Densmore. “You need this flexibility or you’re going to paint yourself into a corner.” Densmore imagines a futuristic lab space for his work in biological design, with multiple microfluidic devices, 3-D printers creating custom equipment, and RFID-enabled name tags to track students’ experiments. “When people walk in, they’ll say, ‘Something different is going on here,’” he says.

Other scientists have different ambitions for the building, especially for the Cognitive Neuroimaging Center. “We want to have room to put in an exercise bike, in case we want to study exercise and the brain,” says Tyler Perrachione, a Sargent College assistant professor of speech, language, and hearing sciences and a Peter Paul Career Development Professor. “Or beds, so we can study sleep and the brain. We’ll have the ability to study the biology of the brain in action.”

Perrachione, who plans to use the Cognitive Neuroimaging Center primarily for pediatric imaging, has been working with the architect to make sure it will be welcoming for children. “It turns out when you set up a center that’s friendly for kids,” he says, “it’s friendly for adults, too.”

Perrachione notes that the neuroimaging facility will also include a “mock scanner” (“kind of like a scanner play set,” he says) that will allow special populations—children, people with autism or anxiety, the elderly—to become familiar with the MRI before entering the actual scanner.

Michael Hasselmo, director of the Center for Systems Neuroscience and a CAS professor of psychological and brain sciences. Photo by Kalman Zabarsky

Another critically important feature for neuroscientists at CILSE will be the sophisticated testing rooms that will minimize vibrations and shield experiments from electrical noise and electromagnetic interference. These factors can hinder research, whether it involves interviewing human subjects or the painstaking work of recording signals from individual neurons. Some of the lab space will have special floors that minimize everyday vibrations—from, say, footsteps—that could get in the way of research.

“It’s very different than setting up an office building—it’s not just a computer and desk,” says Michael Hasselmo, director of the Center for Systems Neuroscience and a CAS professor of psychological and brain sciences. “A person walking past your lab can ruin your whole experiment.”

When it comes to the exterior, says Klee, the new science building will be “airy, transparent, beautiful.” He says his team is mindful that CILSE should not overshadow iconic Morse Auditorium, which is eligible for historic landmark status. “This will be a quiet building,” he says. “It won’t shout.”

And that, the architect says, seems to suit the researchers. They just want to get inside and do their work. “Research is much more than a job; it’s not a 9-to-5 activity,” he says. “There’s this kind of passion. They want a facility that will let them do what they want to do. Come hell or high water, it has to function.”

Brown has emphasized that the research inside the building be reflected in its exterior, says Klee. Just as EPIC (the new Engineering Product Innovation Center on Commonwealth Avenue) allows the public to see the hands-on nature of engineering, CILSE’s glass-walled exterior will provide a window onto basic science research at BU.

“This is not a building that wants to be ashamed that it’s a research building,” Klee says. “You’ll be able to see the exhaust fans on the roof, for example. It’s transparent. You can see life in it. A lot of buildings are opaque—you have no idea whether it’s a dorm, an office building, or a bank. We’re giving science a front door on Commonwealth Avenue.”

Sara Rimer can be reached at srimer@bu.edu. Barbara Moran can be reached at bmoran@bu.edu.

Starting a scientific revolution in 2014 requires some powerful weaponry.

So Thomas Insel, who at the moment is trying to persuade a roomful of mental health advocates that our treatments for diseased minds lack a foundation in, of all things, science, hauls out his biggest gun.

Insel screens slides depicting the plunging mortality rate from childhood leukemia (fatal in 95 percent of cases 30 years ago, today it’s cured that often), heart disease (deaths have fallen 63 percent), AIDS (“essentially a death sentence” 15 years ago, today it’s “considered a chronic disease”), and strokes (20,000 fewer deaths annually than a few decades ago). “You know things are changing when Hallmark comes out with a centenary card,” Insel says.

Then he shows them the suicide count.

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The anaesthetized zebra finch slumbers peacefully on a lab table, a tiny feathered bundle save for the top of its head, which sports a fleshy oval from which feathers, skin, and bone have been peeled back. Alert: no birds were harmed in the making of this experiment. In fact, for the next year or two after this surgery, Tim Gardner and his lab assistants will monitor the finch as it fulfills a primal urge: to sing.

The operation will implant in the finch’s brain Lilliputian carbon fiber electrodes invented by Gardner, a College of Arts & Sciences assistant professor of biology. What will happen next can be seen in a cage against the back wall. There, another finch with electrodes already implanted hops to and fro with a wire trailing out of its head and into a nearby console. A screen displays the spiking of the brain neurons that control the finch’s song.

This is not a birdwatcher’s hobby: the readings tell Gardner how specific neuron types are activated as the finch runs through its repertoire. The technology enabling this glimpse inside another species’ mind is also contributing to the development of treatments for debilitating conditions in humans, possibly including amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, Parkinson’s disease, rheumatoid arthritis, and even asthma and infertility.

Finches “are just driven to sing, even if they’re alone,” says Gardner, who also holds an appointment at the College of Engineering and recently won a three-year Innovation Career Development Professorship, given by BU to assistant professors doing promising work towards future licensed technology. “We’re eavesdropping on the brain as they sing, but they’re doing all the hard work. They put in hundreds or thousands of hours practicing to produce this song stably.”

Until now, monitoring the brains of these feathered maestros has been impeded by the existing clunky electrodes that break blood vessels, damaging tissue and inducing the birds’ immune system to reject the implants. Gardner has been using his miniaturized invention—he’s seeking a patent—to research finches’ brains for three years. No more than a centimeter long, the carbon fibers are four microns in diameter; 16 bundled together resemble a bit of beard stubble.

Electrodes this small can be implanted without the birds’ bodies rejecting them; Gardner’s lab has been recording some individual finches’ brain waves for a year or two. Therein lies the potential for helping humans: the electrodes are small enough to also go into visceral nerves the size of a human hair (Gardner’s lab has implanted 16 electrodes into such nerves). Pharmaceutical companies are researching such so-called electroceuticals to stimulate nerves and restore bodily function in patients with diseases that can respond to nerve stimulation. Some companies are trying to develop therapies based on Gardner’s technology.

Zebra finches are workaholics, spending countless hours practicing their singing. Photo by Flickr contributor Jordan Brock

Microelectrodes have been around for decades, but “to be effective in all of these domains, electrodes really need to be miniaturized,” Gardner says. The challenge has been that such tiny fibers are not stiff enough to implant, and no one had succeeded in implanting arrays of multiple fibers. “We’ve spent many hundreds of hours manipulating these small fibers,” Gardner says, before discovering that dipping the fibers into water and removing them caused them to cling together, similar to a wet paintbrush’s bristles. Once dry, the clustered carbon strands are stiff enough to implant, yet they splay open when inserted in the brain and don’t break through blood vessels.

What they reveal is no less than the working of a zebra finch’s mind. “As they sing, they’re always trying to improve their songs,” Gardner says. “That’s a process that we want to understand in detail—how birds maintain their songs through trial-and-error learning.” Typically, the lab monitors a bird for a week or so, then takes new readings a year or two later, plugging the bird into the brain-scanning machinery via a connector that’s left on its skull. With such checkups over time, the researchers study the cellular basis of memory stability and motor skill maintenance.

Gardner says that the electrodes’ ability to continue working over a long period could mean, among other things, that ALS patients “could receive brain implants to control cursors and gain access to the world,” communicating via computers as the renowned physicist Stephen Hawking, who suffers from ALS, does. “A real tragedy of existing technologies is that they often stop functioning after a period of a month or two,” Gardner says, “and this is clearly related to the large, stiff structure of existing electrodes.” His work, funded by the National Institutes of Health and its BRAIN Initiative, gave Gardner’s lab funds to develop stimulating electrodes based on these small fibers.

Gardner originally studied physics, segueing into biology out of personal as well as scientific interest. A decade ago, “as I was deciding whether or not to do postdoc work in bird song–related neuroscience, my mother-in-law was diagnosed with ALS. And I remember really thinking that I had the skills to make an impact on that kind of field, but I was intellectually very drawn towards this other field of basic neurobiology and sensory vocal learning” in birds. “I remember it being a very difficult decision. I felt like, if I followed my passion, I wasn’t going to end up building devices for treating ALS.” As it turned out, both interests merged in his current research. (His mother-in-law has a slow version of the disease and “is doing well in many respects,” Gardner says.)

The potential crossover of Gardner’s work into alleviating human suffering is one reason that the Office of the Provost chose him for the Innovation Career Development Professorship.

“As a global research university, it is inspiring each day to see the embrace of innovation and the development of exciting ideas into impactful, commercially viable solutions,” says Jean Morrison, University provost. “The translational research Professor Gardner is performing in capturing the neural recordings of animals represents a major technological advance in systems neuroscience and shows what is possible through ingenuity and incredibly hard work.”

Emily Browne is laughing, and nobody really knows why. The 14-year-old with a broad face and a mop of curly brown hair has autism. She drifts through her backyard in Boston’s Dorchester neighborhood, either staring into the distance or eyeballing a visitor chatting with her dad, Brendan, and her 15-year-old sister, Jennifer, on the nearby patio. That’s where the laughter started—a conversational chuckle from somebody on the patio that Emily answered with a rollicking, high-pitched guffaw. Then another, and another, and another.

Emily can’t join the conversation. She is among the 30 percent of children with autism who never learn to speak more than a few words—those considered “nonverbal” or “minimally verbal.” Emily was diagnosed with autism at two, but Brendan and his wife, Jeannie, knew something was wrong well before then. “There was no babbling. She didn’t play with anything. You could be standing beside her and call her name, and she wouldn’t look at you,” says her dad. “Emily was in her own little world.”

But why? What is it about the brains of “minimally verbal” kids like Emily that short-circuits the connections between them and everyone else? And can it be overcome? That’s the research mission of Boston University’s new Center for Autism Research Excellence, where Emily is a study subject.

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As the 100 million viewers tuning in to this Sunday’s Super Bowl can attest, Americans adore football. And for many, the love affair begins in childhood: Pop Warner Tiny-Mites start as young as age five, and many adults retain warm memories and friendships from their youth football days.

But a new study from BU School of Medicine researchers points to a possible increased risk of cognitive impairment from playing youth football. The National Institutes of Health–funded study, published online in the January 28, 2015, edition of the journal Neurology, finds that former National Football League players who participated in tackle football before the age of 12 are more likely to have memory and thinking problems as adults.

The study contradicts conventional wisdom that children’s more plastic brains might recover from injury better than those of adults, and suggests that they may actually be more vulnerable to repeated head impacts, especially if injuries occur during a critical period of growth and development.

“Sports offer huge benefits to kids, as far as work ethic, leadership, and fitness, and we think kids should participate,” says study lead author Julie Stamm (MED’15), a PhD candidate in anatomy and neurobiology. “But there’s increasing evidence that children respond differently to head trauma than adults. Kids who are hitting their heads over and over during this important time of brain development may have consequences later in life.”

“This is one study, with limitations,” adds study senior author Robert Stern, a MED professor of neurology, neurosurgery, and anatomy and neurobiology and director of the Alzheimer’s Disease Center’s Clinical Core. “But the findings support the idea that it may not make sense to allow children—at a time when their brain is rapidly developing—to be exposed to repetitive hits to the head. If larger studies confirm this one, we may need to consider safety changes in youth sports.”

MED Professor Robert Stern, senior author on the Neurology study. Photo courtesy of Robert Stern

In the study, researchers reexamined data from BU’s ongoing DETECT (Diagnosing and Evaluating Traumatic Encephalopathy Using Clinical Tests) study, which aims to develop methods of diagnosing chronic traumatic encephalopathy (CTE) during life. CTE is a neurodegenerative disease often found in professional football players, boxers, and other athletes who have a history of repetitive brain trauma. It can currently be diagnosed only by autopsy.

For this latest study, scientists examined test scores of 42 former NFL players, with an average age of 52, all of whom had experienced memory and thinking problems for at least six months. Half the players had played tackle football before age 12, and half had not. Significantly, the total number of concussions was similar between the two groups. Researchers found that the players exposed to tackle football before age 12 had greater impairment in mental flexibility, memory, and intelligence—a 20 percent difference in some cases. These findings held up even after statistically removing the effects of the total number of years the participants played football. Both groups scored below average on many of the tests.

“We were surprised by how striking the results were,” says Stamm. “Every single test was significantly different, by a lot.”

Stamm says that the researchers were especially surprised by the scores on a reading test called the WRAT-4, which has participants read words of increasing difficulty. A person’s score depends on the ability to pronounce the words correctly, indicating the person’s familiarity with complex vocabulary. The low scores may be significant, she says, because they suggest that repeated head trauma at a young age might limit peak intelligence. She emphasizes, however, that there may be other reasons for a low score, and that more research is needed.

The authors chose age 12 as the cutoff because significant peaks in brain development occur in boys around that age. (This happens for girls a bit earlier, on average.) Around age 12, says Stern, blood flow to the brain increases, and brain structures such as the hippocampus, which is critical for memory, reach their highest volume. Boys’ brains also reach a peak in their rate of myelination—the process in which the long tendrils of brain cells are coated with a fatty sheath, allowing neurons to communicate quickly and efficiently. Because of these developmental changes, Stern says, this age may possibly represent a “window of vulnerability,” when the brain may be especially sensitive to repeated trauma.

“If you take just the hippocampus, that’s a really important part of your brain,” he says. “It may be that if you hit your head a lot during this important period, you might have significant memory problems later on.”

Stern adds that a study by another group of researchers of the number and severity of hits in football players aged 9 to 12, using accelerometers in helmets, found that players received an average of 240 high-magnitude hits per season, sometimes with a force similar to that experienced by high school and college players.

With approximately 4.8 million athletes playing youth football in the United States, the long-term consequences of brain injury represent a growing public health concern. This study comes at a time of increasing awareness of the dangers of concussions—and subconcussive hits—in youth sports like football, hockey, and soccer. In 2012, Pop Warner football, the oldest and largest youth football organization in the country, changed its rules to limit contact during practices and banned intentional head-to-head contact. When reached by phone at the organization’s headquarters in Langhorne, Pa., a Pop Warner spokesman declined to comment on the study until they had more time to examine the results in detail.

Julie Stamm (MED’15), a PhD candidate in anatomy and neurobiology and lead author on the study. Photo courtesy of Julie Stamm

“Football has the highest injury rate among team sports,” writes Christopher M. Filley, a fellow with the American Academy of Neurology, in an editorial accompanying the Neurology article. “Given that 70 percent of all football players in the United States are under the age of 14, and every child aged 9 to 12 can be exposed to 240 head impacts during a single football season, a better understanding of how these impacts may affect children’s brains is urgently needed.”

Filley’s editorial cautions that the study has limitations: because the researchers could not precisely determine the players’ lifetime number of head impacts, it may be the total number of hits—rather than the age of a player—that is the more critical measurement. In addition, because the study focuses on professional athletes, the results may not apply to recreational players who participated in youth football, but did not play beyond high school.

Stamm says that the next stage of research is to work with colleagues at Brigham and Women’s Hospital to conduct detailed neuroimaging of the same types of players involved in the current study, looking for underlying changes in brain anatomy that might correlate to the cognitive impairment.

She adds that this paper is a small, first-of-its-kind study, and needs to be expanded and replicated before scientists can make further recommendations about children playing contact sports. But she hopes the study will shed more light on the possible consequences of repeated head trauma in children. She notes that some youth football organizations have taken great steps in reducing the numbers of hits to the head. However, more research is needed to see if these measures are sufficient, or if additional precautions, like substituting flag football for tackle football in those under 12, may be necessary.

“Sports are important, and we want kids to participate in football,” says Stamm. “But no eight-year-old should play a sport with his friends and end up with long-term problems. We just want kids to play sports more safely.”

A version of this story was originally published on BU Research.

Barbara Moran can be reached at bmoran@bu.edu.

For Ann McKee, every brain tells a story. And sometimes it’s a tragic one. McKee, a School of Medicine professor of neurology and pathology, is the director of neuropathology for the Veterans Affairs New England Health Care System and also directs BU’s Chronic Traumatic Encephalopathy Center. Chronic traumatic encephalopathy (CTE) is a degenerative brain disease found in athletes with a history of repetitive brain trauma. McKee first identified its telltale mark—tiny tangles of a protein called tau, clustered around blood vessels—in the dissected brain of a boxer who had been diagnosed with Alzheimer’s disease.

Although most people associate CTE with professional football players, McKee has found it in the brains of soccer, hockey, rugby, and baseball players as well. Her research has alerted the public to the long-term dangers of repetitive hits in sports and raised tough questions about safety. McKee was invited to speak about this growing public health concern at the annual meeting of the American Association for the Advancement of Science, the world’s largest general scientific society, held February 2015 in San Jose, Calif. She told BU Today the story behind her discovery of CTE, and what it might mean for the future of sports.

BU Today: You’re a world expert on tau protein, which has been implicated in Alzheimer’s, CTE, and other brain diseases. Have you studied tau your whole career?

McKee: Yes. I love tau.

Why?

It’s beautiful, the way it collects throughout the nervous system and just sort of fills up the nerve cell. It’s always been quite lovely to look at, visually captivating. I mean, how crazy is that? But it’s true.

When you started studying tau, you were studying Alzheimer’s disease?

I was interested in Alzheimer’s, but I also worked on PSP (progressive supernuclear palsy), and something called corticobasal degeneration.

Those are not so famous.

No, they’re not so famous. But I got very involved in defining what these individual diseases looked like. It’s like being at the Smithsonian and being really interested in one collection of pottery or something. And once you start understanding it, you start seeing all these differences, and it’s like, Whoa!

Brains with CTE show a distinct pattern of tau protein, seen here in brown. The two slides on the bottom come from the brain of a 66-year-old ex-NFL player. The slides on top are from a 65-year-old man without CTE. Photo courtesy of Ann McKee

Do you remember the first time you saw a brain with CTE?

Yes. It was phenomenally interesting. The first case was Paul Pender, a professional boxer here in the Boston area. He had twice been world champion. That was my first time seeing it under the microscope. I looked at the slide and it was like, Oh, my God. This is so amazing. I’ve never seen anything like this. It just blew my mind. That was 2003.

How did it look different than, say, a brain with Alzheimer’s?

Alzheimer’s disease has these beta amyloid plaques that look like small puffs of smoke throughout the brain. You have to have these plaques in fairly high numbers to make the diagnosis of Alzheimer’s disease. In most cases, and certainly below the age of 50, CTE doesn’t have any plaques. The other difference is the tau pattern. Tau clusters in little tangles, and in CTE they’re always around blood vessels. So the blood vessels are a clue to the origins of CTE—we think it might be damage to the vessels and leakiness of the vessels that’s causing it.

How did you end up with this boxer’s brain?

He was a veteran and died at the Bedford VA with a diagnosis of Alzheimer’s disease. And there was no amyloid, so it was like, well, it’s not Alzheimer’s disease. And the tau pattern was so unusual that I asked my technician to do this very old technique that people used to use in neuroanatomy before everything was automated. It’s difficult—you cut the brain very slowly in these big sections that contain the whole hemisphere, then you have to stain it while it’s floating in water, and then you have to very painstakingly lay it all out on the slide. It was amazing, because it allowed you to see the landscape of the brain. So it’s phenomenally informative. It allows you to see nuances that you can’t really appreciate with tinier, thinner specimens. The technique contributed to our recognition that this was really something quite extraordinary. This was something really different.

That was 2003. Was CTE a known disease?

Not really. It was primarily called dementia pugilistica and most people thought it affected only boxers. Then, in 2008, I had the opportunity to look at a football player who had had some cognitive issues, and it was like, Oh, my God, another one. And what I couldn’t believe was that the football player was 45. If you’re used to studying neurodegenerative diseases, 45 is incredibly young. So after that case, we started the center and started collecting more brains. The next brain we got was from a football player who died at the age of 45, too. And it was the same disease. It was like, What? Holy Christmas.

And you now have 240 brains in the CTE bank. Are most of them football players?

Yes. We have more football players in the bank than any other sport. But we have boxers, we have hockey players, we have a few soccer players, a couple of rugby players. We have military.

When CTE started coming into the public perception, it was just about the NFL. Now it’s getting bigger and bigger.

That’s exactly right. We’ve seen it in all these professional players, but we’re finding it in nonprofessional players, college players. And I think, from the public health perspective, that’s what’s really important.

Are there implications for kids’ sports?

There’s a lot of interest now in heading in soccer, because that would be something easy to take out. It wouldn’t destroy the game, especially at the lower levels. But also in football, which is such a hugely popular sport, we need to understand the risks for young athletes and reevaluate whether or not young kids should even be playing this game. Their bodies are immature, their necks aren’t very well developed, they’re not very coordinated. Plus, they’re literally walking bobbleheads with big heads, thin necks, and small bodies. Your brain is adult-size by age four, and it’s relatively heavy for those little bodies. The only good thing is, they’re low to the ground.

What surprises you most about CTE?

The thing that is shocking to me, and continues to be shocking, are the 25-year-olds who have died with this disease. Not because of it—it’s usually a suicide or an accidental death. I can’t say that CTE caused their suicide. But for me, it’s shocking to see neurodegenerative disease in a 25-year-old. It’s horrible. And it’s undeniable. We’ve seen it in enough 20-somethings now that you can’t escape this. It’s a shock to think, that guy looks so young, and he’s dead. And he’s dead with this.

A version of this story appears on the BU Research website.

Barbara Moran can be reached at bmoran@bu.edu.

Ant and human, eyeball to eyeball. We are linked with ants in ways both surprising and profound. Humans, as you may have guessed, are the other dominant social organism on the planet. Both ants and humans divide labor and form complex social networks. Both work in groups to accomplish tasks—leaf nests, Maya temples—that no individual could complete alone. Both raise their young in families. Both use the same class of neurotransmitters—biogenic amines like dopamine and serotonin—to govern behavior. Both go to war.

There are differences, of course, and here’s a big one: with brains that are large relative to their body size, humans build skyscrapers and societies. Ants weave nests, navigate dark forests, and even farm food with brains that are downright diminutive. This may not seem surprising at first, but consider this: only a measly 2 percent of insects—ants, bees, some wasps and termites—live in societies. Most insects are like fruit flies, buzzing around, doing their own thing, every fly for himself. So the ultrasocial ants, operating with brains up to 600 million times smaller than humans, made even Charles Darwin step back in awe. “The brain of an ant is one of the most marvelous atoms of matter in the world,” he wrote in 1871, “perhaps more so than the brain of man.”

How can ants do so much, with such tiny brains? That leads to the central question of College of Arts & Sciences Professor James Traniello’s research: how does collective intelligence influence brain evolution? And how does brain size and shape and neurochemistry relate to social behavior?

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Binge-eating disorder affects nearly 10 million American adults, by some estimates. It’s a vicious condition in which people repeatedly eat huge amounts of food—often high-calorie sweets and/or fatty snacks—in a couple of hours or less. Perhaps the worst part of the disorder is that each binge leads to feelings of embarrassment, self-disgust, and depression.

Now, new research from School of Medicine scientists, published online in Neuropsychopharmacology, demonstrates that an Alzheimer’s drug called memantine may reduce the impulse to binge eat by acting on an area of brain associated with addictive behavior. The research, funded by the National Institute on Drug Abuse and the National Institute of Mental Health, may eventually lead to new treatments for the disorder.

“The disorder resembles addiction more than any other eating disorder. Binge eaters understand the consequences of their behavior, but they can’t stop. It’s a compulsion,” says senior author Pietro Cottone, a MED associate professor of pharmacology and psychiatry and codirector of the Laboratory of Addictive Disorders.

Cottone, who has been studying addiction for over a decade, says that binge eating triggers patterns of chemical responses in the brain that are similar to those in drug and alcohol addiction. In all these disorders, he says, a region called the nucleus accumbens, which provides a communication link between the emotional and reasoning centers of the brain, is particularly important because of its role in eliciting and modulating behavior.

“When you eat, have sex, do drugs—all that stuff—this area gets activated,” says Cottone. During binge-eating episodes, the nucleus accumbens does not function properly. That’s where the Alzheimer’s drug memantine comes in.

Memantine blocks receptors in the brain that bond with glutamate, a neurotransmitter known to stimulate neurons. In Alzheimer’s disease, dying brain cells release excess glutamate, which overstimulates healthy cells and can kill them. So by blocking glutamate receptors, memantine protects healthy cells in the Alzheimer’s brain. Cottone suspected that the drug, by blocking glutamate receptors, could also curb binge eating. With glutamate locked out, he believed the nucleus accumbens wouldn’t reinforce the stimuli associated with junk food so much, and the urge to binge eat should fade.

Cottone tested the hypothesis with two groups of rats. One group was fed a diet of regular rat food. The others also got regular food, but for one hour a day they were also offered junk food, which contained an extra dose of sugar. It was the rat equivalent of jelly beans and gumdrops, and “they loved it,” says Cottone.

Within days, the junk food rats started bingeing. “We made them into binge eaters just by giving them access for one hour,” he says. “It was insane.” And even worse: the more the rats binged on junk food, the less they ate the regular food. “Exactly what happens in people, we did with rats,” he says.

Cottone wondered if the binge-eating rats would take more risks to reach their junk food. He put the rats into a box that was half dark and half brightly lit. Rats are nocturnal and will usually do anything to avoid bright light: when he  put a bowl of junk food in the middle of the bright box, the regular-chow rats wouldn’t touch it. “They don’t even think about eating the food,” he says. “They were like, no way!” But the binge eaters couldn’t stop themselves—they ran into the light, stuck their snouts into the junky kibble, and gobbled it up. “This is a lapse of judgment,” says Cottone, noting that such behavior is a hallmark of addiction. “They know the environment is potentially dangerous, but they go there anyway.”

All this changed when memantine entered the mix. The scientists injected the drug into both groups of rats. In the regular-chow rats, it had no effect. But for the binge eaters, the changes were profound. Not only did their binge eating decrease dramatically, but they were no longer willing to take risks to get their junk food. The scientists found the same effect when they injected memantine directly into the shell of the nucleus accumbens.

Cottone and his team hope that memantine may prove a useful treatment for binge-eating disorder, for which there are currently no Food and Drug Administration–approved drugs. “Individuals with binge-eating disorder have a very poor quality of life. Our study gives a better understanding of the underpinning neurobiological mechanisms of the disorder,” says article coauthor Valentina Sabino, a MED assistant professor of pharmacology and psychiatry and codirector of the Laboratory of Addictive Disorders.

Although one small 2008 study in the International Journal of Eating Disorders found that memantine may be useful for treating binge eating in humans, there has been little additional research in this area. “We hope that this paper will help revitalize this line of research,” says Cottone, who anticipates seeing larger, more robust human trials in the future. “We need more pharmacological approaches.”

A version of this article appears on the BU Research website.

Barbara Moran can be reached at bmoran@bu.edu.

Bobby Kasthuri needs a map. Not your everyday, get-me-to-Kenmore-Square kind of map. He’s got something else in mind. What Kasthuri needs is a map of all the connections in the human brain—kind of a wiring diagram for neurons. Kasthuri, a School of Medicine assistant professor of anatomy and neurobiology, thinks that this map—the so-called connectome—could help explain how our brains develop from childhood and give deep insights into memory and consciousness.

But there’s a problem: the data. The map of one mouse brain would consume about two exabytes—that’s two billion gigabytes—of storage. (For comparison, the iPhone 6 comes with a mere 128GB.) With some creative help from a handful of high school students, Kasthuri has analyzed a sliver of mouse brain and created stunning images of neurons. The exquisitely detailed images hint at the power of big data, the complexity of the connectome, and some of the secrets that may lie waiting for us in the brain.

BU Today talked to Kasthuri of mice and men, small worms and bold ideas, and how Big Oil may save neuroscience.

Mapping the Connectome

The connectome could hold the secrets to how the brain works, but how will we map it? Kasthuri shows how electron microscopes and diamond edges help him to view detailed images of the brain. Video by Joe Chan

BU Today: So, what is a connectome, exactly?

Kasthuri: It’s this idea that, for a brain, you know how every neuron connects to every other neuron.

Why would you want to know that?

If you look at a neuron of a human and a neuron of a mouse, they look essentially the same. We share 98 percent of our genome. So the strong hypothesis is that we have the same LEGO® blocks, but we build a huge palace with our LEGO blocks, and mice build more of a hut. And if that’s true, it would imply that connections are deeply correlative and causative to things like our memories, our personalities, and our fears. The connectome would be the map of that.

So far, scientists have mapped the connectome of one organism—a worm called C. elegans?

Yes, it’s a roundworm about a millimeter long, with exactly 302 neurons. And they have very simple behavior. I think they squirt forward, they squirt backwards. Squirt forward, squirt backwards. It took scientists about a decade to do a wiring diagram of C. elegans, completely by hand.

So the worm has 302 neurons. How many neurons do people have?

People claim 100 trillion.

That seems extremely difficult. Where do you start?

We start with a big volume of an adult mouse brain, let’s say a millimeter cubed.

That’s it? I was thinking you’d do half the brain.

I wish.

Information Overload

Imaging all the components of even a tiny sliver of brain, as in this video, takes enormous computing power. Kasthuri estimates that completely mapping one mm cubed of brain tissue will require about two million gigabytes of data, more than exists in the entire Library of Congress. Video courtesy of Bobby Kasthuri

So you take this little teeny-weeny part of the mouse brain, and what do you do with it?

You have to cut it in slices, take a picture of each slice, and then put the images back together on the computer. But here’s the problem: a millimeter cubed, at the resolution we would like, is about two million gigabytes of data.

Can you compare that to something that people would understand?

So the whole human genome is about three to five gigabytes.

Oh. You’re dead.

You’re right But listen, when they sequenced the genome in the ’90s, people were like, “three to five gigabytes? That’s impossible.” But they did it. Now I’m talking about 200,000 times more, but the world is being pushed toward this, independent of what we do.

Exactly. Everybody needs somewhere to put their data. Maybe the Google guys will figure it out.

I think Google might figure it out. I’ve heard that the people who work with the biggest data sets in the world are oil companies, because they make these tremendous models of where the oil is. And for them, finding the oil is worth the investment of supercomputers and huge data sets.

How Exxon Saved Neuroscience?

Right, exactly.

So once you’ve sliced up this little bit of mouse brain, can you do anything with it?

It’s a great question. I still haven’t gotten to the hard part: analyzing the data. I like to use this Kennedy quote: “We choose to go to the moon in this decade and do the other things, not because they are easy, but because they are hard.” We went to the moon. Right? We went to the moon. Is analyzing this data that much harder than sending human beings to the moon and coming back?

Coloring the Connectome

Thin slices of mouse brain are scanned with an electron microscope and stacked in order. Students recruited by Kasthuri trace the paths of individual neurons in different colors. The resulting images are used to create 3D models of neurons. Video courtesy of Bobby Kasthuri

I don’t know; maybe?

OK, that’s fair. So now I have two million gigabytes of information. And now we get to the hard part, the really, truly hard part: humans are very good at following the same neuron from section to section to section, but computers are much worse than us. So we have to figure out a way to analyze two million gigabytes of data with some combination of computers and humans.

So here’s my current version of that: I teach neuroscience at one local high school, Masconomet Regional High School. I teach them what a neuron looks like, I teach them how to trace something, and they work on my data. So they’re free, which is an advantage for me, and it’s educational. And so far, they love it.

So you have the students trace neurons on sequential photographs, and with them helping, how much mouse brain have you been able to analyze?

Barely a fraction of the mouse brain. It’s so small, it’s embarrassing. We’re going to get faster, I hope, if I have any chance of making a career out of this. But this is the new reality. And the question is, do we want to face reality or not?

And?

I have to. I can’t turn back now.

I bet there are a lot of other things you could do.

No, no. I just couldn’t do science, or at least neuroscience. I can’t go back.

What if it turns out that the connectome doesn’t matter? Maybe everything that makes us human just lies in the genes and how they are turned on and off.

Yes, it could be. My view is not that we have the right answer, but my view is we’ve got to try. Let’s just do it, man. I guarantee we’ll find a surprise that’s going to change how we think about brains.

Barbara Moran can be reached at bmoran@bu.edu.

A version of this story was originally published on BU Research.

Steve Ramirez and Eran Hodis are making an impact in very different areas of science, working in labs only a short walk apart in Cambridge’s Kendall Square. And both Boston University graduates are among six alums who made the Forbes “30 Under 30” list of young “game changers, movers, and makers” in fields such as business, sports, and science.

Ramirez (CAS’10), 27, a neuroscience researcher and PhD candidate at MIT, earned a spot on the list for his work altering the memories of mice, which could have profound implications for humans in areas such as post-traumatic stress disorder (PTSD). Hodis (CAS’07), 29, a cancer researcher and MD/PhD student at Harvard, was named for his work identifying significant genetic mutations in cancer cells, which could lead to better treatments for the disease and eventually unravel its causes.

Hodis works at the Broad Institute of MIT and Harvard, and Ramirez works around the corner at MIT’s Picower Institute for Learning and Memory.

“It’s inspiring to see how these two talented alums have used the excellent undergraduate education they received at BU as springboards for careers that address fundamentally important questions about human life,” says Elizabeth Loizeaux, BU associate provost for undergraduate affairs.

The mouse memory breakthrough by Ramirez and his colleague Xu Liu began with their placing a mouse in a box long enough to form a benign memory of the box and then identifying the brain cells associated with that memory. The following day they put the mouse in a different box and gave it a mild electrical shock—while simultaneously using a laser on those same brain cells to trigger its memory of the first box. On the third day, the mouse was returned to the first box and immediately froze in fear, as if expecting to be shocked. The researchers had implanted in the mouse’s brain a memory of being shocked in a box where there had been no shock.

They began their experiments using a fear response, because it offers the clearest results, but Ramirez says they’ve now moved in a different direction. “We take animals that show certain symptoms that look like depression,” he says, “and we try to reverse those symptoms or alleviate them by artificially reactivating positive memories in their brain.”

And while their work has been likened to science fiction—usually the movie Inception—Ramirez says it has tremendous potential in treating PTSD and other memory-related conditions. Their successes have already brought the team national media recognition, a TED Talk, and now the Forbes “30 Under 30” list.

“The joke I always make is: this is the only way scientists successfully reproduce themselves,” says Ramirez with a grin. “Having things like Forbes as a forum where you can begin to disseminate these ideas that we believe in—because we’re dedicating our lives to them—I think is fantastic. And then hopefully the random high schooler, the random college student who sees this and reads it is like, ‘Oh my god! I didn’t know. The stuff of science fiction is becoming science fact in labs just around the corner in Boston every day.’”

Ramirez says he fully appreciates the value of such inspiration: his parents came here to escape the 1980s civil war in El Salvador.

Paul Lipton (GRS’01), a College of Arts & Sciences professor of neuroscience and director of the undergraduate neuroscience program, points out that Ramirez was in the first cohort of students when the program began in 2008. “Now he is the embodiment of a number of the goals we have for the program,” says Lipton, who is also the Undergraduate Research Opportunities Program (UROP) director. “They are scientific literacy, being a responsible consumer of science, and being able to speak on behalf of science.”

The work that brought Hodis to Forbes’ attention stemmed from the analysis of reams of data that helped identify worrisome mutations in melanoma cells. With colleague Franklin W. Huang, Hodis identified two mutations that could contribute to cells’ runaway growth, and that happen to be among the most common mutations in all of cancer.

“In melanoma, you have one of the highest mutation rates of any cancer,” says Hodis. “You’re looking at hundreds to thousands of mutations in protein-coding genes per sample. The real question is, which of those mutations are crucial to forming the cancer?”

Hodis has since worked on projects identifying mutations in the RNF43 gene that may drive 20 percent of endometrial and colorectal cancers. His work at the Broad Institute explores an existing list of mutations, and he hopes to “understand how they, together in combinations, cooperate to make a melanoma.”

Both scientists credit UROP, which provides financial support for student research under the guidance of a BU faculty mentor, for helping them get started.

Eran Hodis works at the Broad Institute, identifying mutations that contribute to cells’ runaway growth. Photo by Moti Hodis

“I spent nine-to-five in labs my whole summer,” Ramirez says. “UROP was awesome, because I got to throw myself off the deep end and see whether I enjoy it.”

“That was really my first exposure to research,” says Hodis. “I am really grateful to Professor Joyce Wong for taking me into her lab and starting to introduce me to scientific investigation.”

Hodis was born in Israel and returned there for graduate school at the Weizmann Institute of Science in Eran Segal’s lab, where he learned computational biology and focused on transcriptional regulation in yeast. He returned to the United States in 2010 and changed his research focus after his mother was diagnosed with cancer.

“When his mother died of cancer, that really caused him to shift things,” says Wong, a College of Engineering professor of biomedical engineering. “I could see that changed him a lot and made him focus in terms of wanting to really do something to make a difference.”

Other BU alums named on the Forbes “30 Under 30” list: in the sports category, Michael Kasparian (ENG’12,’14), cofounder of Atlas Wearables, which makes fitness trackers providing 3-D body tracking and advanced data analytics, and Arian Radmand (CAS’08), cofounder of CoachUp, an app connecting athletes to private coaches in their sports; in marketing and advertising, James “Nooka” Jones (COM’10), marketing manager for Google Creative Lab; and in games, Dave Bisceglia (SMG’09), cofounder of Tap Lab, which makes location-aware mobile games such as Bigfoot Hunter.

Among famous under-30 names in various categories are actress Blake Lively, NBA all-star James Harden, and the band Florida Georgia Line, aka Tyler Hubbard and Brian Kelley. Each list was judged by a trio of prominent people in the field. The science judges were MIT mathematician Max Tegmark, Bahija Jallal, executive vice president of MedImmune, and UC Berkeley cell biologist Jennifer Doudna.

Joel Brown can be reached at jbnbpt@bu.edu.

At three pounds, your brain is only about 2 percent of your body weight. Yet it makes you you, rather than a chimp or a silkworm. With neuroscience learning more about why and how this organ works, student members of BU’s Mind and Brain Society will run interactive events and videos this Sunday showcasing what one organizer calls “the wonders and mysteries” of the brain.

Bringing Recognition And Interest to Neuroscience (or B.R.A.I.N., as your advanced human brain will tell you) Day is free and open to the University community and area grade school kids, parents, and teachers, but registration is required. The event is sponsored by the Mind and Brain Society, which hosts neuroscience presentations for BU undergraduates, and the University’s Undergraduate Program in Neuroscience (UPN).

This is the University’s second B.R.A.I.N. Day and the first open to the BU community, says UPN program manager Ashley Hoesing. Involving BU students made sense, as other brain-focused events that have been open to University students “are always a hit,” says UPN director Paul Lipton, a College of Arts & Sciences professor of neuroscience, who is also director of the Undergraduate Research Opportunities Program. “These events are an opportunity for our students to be the experts, to share with their peers their disciplinary interests, and to provide exposure to topics and questions to which folks might otherwise never be introduced.”

The event is BU’s way of observing Brain Awareness Week, a worldwide campaign to promote brain research, held this year from March 16 to 22, sponsored by the New York–based Dana Foundation, a private philanthropic organization that supports brain research through grants, publications, and educational programs.

The brain’s operation “happens seamlessly and effortlessly,” Hoesing says, “and we often take for granted the fruits of our brain’s labor.” While we know a lot about how this operation works, she says, “we don’t know what happens in the brain to produce our unique subjective experience of the internal and external world.”

Last year’s event drew about 100 grade school students. This year’s participants will be able to record neuron activity, perform tests of such brain functions as attention, memory, and language ability, and operate robots—without using hands—among many other activities.

“The goal is to teach folks a little about how the brain processes information and leave them with an impression of the brain’s complexity,” Hoesing says. “The activities are designed to demonstrate some of the different ways we engage with the external world—that is, our senses. Our brains rely on our sense organs to translate signals from the external world into a language our brains can understand.”

“We are exited to teach kids more about neuroscience,” B.R.A.I.N. Day volunteer Annalyse Kohley (CAS’17) says, “and I hope the volunteers find this rewarding, as well as learn more about neuroscience through the preparation.”

B.R.A.I.N. Day runs from 11 a.m. to 2 p.m. this Sunday, March 22, in the George Sherman Union Ziskind Lounge, second floor, 775 Commonwealth Ave. It is free and open to the University community and area grade school students, parents, and teachers; register here.

Are you one of the scores of people who moan about how much time we all spend staring at our smartphones and tablets? You won’t hear Wendy Damon among the complainers.

For Damon, with her spiky dark hair, wrist-full of silver bangles, and the word “Aphasia” tattooed on her right upper arm, her iPad has been an unqualified positive—and not just because she can use it to check email.

After a stroke at age 54, in June 2012, Damon emerged physically fine, but suffering from cognitive issues and aphasia, a brain disorder that seriously inhibits language.

Now, an iPad is helping her recover what she lost: the ability to speak in full, quick sentences, to follow directions, to remember things, to do basic math. Using a specialized app, Damon practices rebuilding these skills on her iPad for about an hour a day, and she swears it’s helping her.

“If a couple days go by and I don’t do it, I feel like I’ve backslid a bit,” she says in measured, deliberate tones as she concentrates on assembling the sentence. Each year, an estimated 200,000 people acquire aphasia, which is usually the result of a stroke. After her stroke, Damon could repeat only single words, like “Door, door, door,” when she wanted to say, “Close the door.”

A combination of in-person therapy sessions and near-daily practice on the iPad has built her language skills back up. She’s not where she used to be—not by a long shot, she says, not yet—but it’s miles better than where she was.

And now a research study coauthored by Swathi Kiran, a Sargent College professor of speech, language, and hearing sciences, recently published in Frontiers in Human Neuroscience, shows that people like Damon really are improving, even years after the brain damage occurred. The research further supports the idea that the brain is far more plastic and moldable than previously imagined, and it presents a simple, relatively inexpensive way for people to improve their long-term health.

Carrie Des Roches, a research assistant in the Aphasia Research Laboratory and one of the study’s authors (right), with Damon.

With funding from the Wallace H. Coulter Foundation, Sargent College gave 51 aphasia sufferers an iPad. The goal of the study was to determine how effective iPads could be in delivering personalized therapy to people with aphasia, and to determine whether a structured iPad-based software therapy program that includes homework leads to significant gains in overall communication.

Participants were split into two groups: a control group and an experimental group. All participants had a weekly one-hour session with a clinician using the iPad therapy. But the people in the experimental group were also asked to practice a set of personalized tasks at home using the iPad software. They showed significant improvements, ranging from 2 to 11 points on a range of standard tests for language, memory, executive function, and attention. The control group did not experience any significant changes on those tests.

The most encouraging sign? The people who were more severely affected showed more improvements after therapy than those who were less impaired, according to Kiran, director of BU’s Aphasia Research Laboratory. That’s significant, she says, because people who are worse off after brain damage are the most likely to be written off, and this study shows that they should not be. The study further found that even those participating in the control group, who used the iPad therapy only during their weekly meetings with a clinician, experienced some improvement.

All types of aphasia sufferers need better long-term care, Kiran says. When someone has a stroke or other aphasia-causing injury, insurance typically covers only a patient’s acute care and maybe a couple of months of rehabilitation. Unless you have fantastic insurance, she says, you’re on your own after that. The upshot is that there is a huge problem in providing the continued communication rehabilitation that those with aphasia require.

That’s exactly the situation Damon found herself in by November 2012, when she was discharged from outpatient therapy several months after her stroke. “According to them, I was better,” she says, a note of frustration creeping into her voice. Her insurance coverage ran out, and the rehabilitation center had taken her as far as she could go.

But as neuroscientists are realizing, the brain can be worked and improved even after years of decline or decreased ability. However, Kiran notes, it takes a bit of strategy and a whole lot of work to make progress. “In the context of what we know about neuroplasticity, the main thing is you have to have repeated practice, repeated exposure, and you need to do it in a very structured way,” she says.

Mobile devices loaded with specialized apps could make that crucial practice possible. That’s where Newton-based start-up Constant Therapy comes in. Constant Therapy, cofounded by Kiran and CEO Veera Anantha, provides personalized iPad-based therapy for people with traumatic brain injuries, stroke, aphasia, and learning disabilities. So while Kiran’s team designed the rehabilitation tasks, Constant Therapy, one of whose investors is BU, made them available for download.

Use of the iPad-based software platform Constant Therapy was effective in helping patients with poststroke aphasia, according to the study by BU researchers.

The Constant Therapy system is flexible. Users can pick and choose the tasks they want to work on, they can rely on the app to provide tasks for them based on their scores, or a clinician can select tasks personalized to an individual’s needs.

Kiran and her colleagues focused on the latter approach for the study. The experimental group had one hour of therapy a week with a BU clinician, who assigned tasks based on the patient’s specific performance. Then the patient was free to go home and do the homework—or choose not to.

But overwhelmingly, Kiran says, those patients wanted to work. The average time they spent on the iPad was four hours and eight minutes a week, but a few did much more. Some aphasia sufferers worked a whopping 17 hours a week on the tasks.

With technology that allows them to work on their abilities anytime and anywhere, they’ll often take full advantage, Kiran says. “They’re superdetermined to get better.”

The study showed preliminary evidence that structured, tablet-based individualized therapy can be provided to aphasia patients. Kiran and Constant Therapy are now collaborating with other researchers in the area to apply the apps’ tasks to other types of patients, such as people with dementia, mild cognitive impairment, and epilepsy and children with language deficiencies. Many of the same tasks that helped the aphasia sufferers can be applied to other types of disorders. And as Kiran notes, patients of all types are eager to improve their skills—they just need the opportunity.

“When you empower patients to take control of their rehabilitation, they actually do it,” she says.

Nancy Kopell, a William Fairfield Warren Distinguished Professor and a College of Arts & Sciences professor of applied mathematics and dynamical systems, has been awarded the $100,000 Mathematical Neuroscience Prize by the nonprofit Israel Brain Technologies.

Kopell, codirector of BU’s Center for Computational Neuroscience & Neural Technology (CompNet), is one of two 2015 winners of the prize, which honors researchers who have significantly advanced our understanding of the neural mechanisms of perception, behavior, and thought through the application of mathematical analysis and theoretical modeling. The other recipient is G. Bard Ermentrout, Distinguished University Professor at the University of Pittsburgh.

“I’m highly honored by this award,” says Kopell, “and in this time of federal budget cutbacks, the flexible funds that come with the award will be very useful in keeping my work on brain dynamics going. I’m very grateful to Israel Brain Technologies for sponsoring this prize.”

Kopell is the director of the Cognitive Rhythms Collaborative, a group of scientists in the Boston area who work together to advance the understanding of the brain dynamics underlying cognitive function in areas such as sensory processing, attention, learning, memory, and motor planning.

“We are delighted that Nancy has received the $100,000 Mathematical Neuroscience Prize from Israel Brain Technologies,” says Tasso Kaper, chair of the mathematics and statistics department. “She is one of the founders and international trendsetters of the field of mathematical neuroscience. Indeed, soon after she completed her PhD in pure mathematics at UC Berkeley, she began working on mathematical models in biology, including those of electrical activity in nerve cells. Over more than three decades, she has made critical discoveries about brain rhythms and the roles these rhythms play in cognition, motor control, sleep, attention, memory, Parkinson’s disease, schizophrenia, and alternate states of consciousness such as those induced by anesthesia. Through her mathematical research laboratory and famous weekly NaK [Neural Dynamics Group] meetings, she has also trained many scientists who work in the field of mathematical neuroscience.”

Kopell is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. She is an honorary member of the London Mathematical Society, a distinction given to only one or two mathematicians each year. She is a recipient of a MacArthur genius award and Sloan and Guggenheim fellowships.

Sara Rimer can be reached at srimer@bu.edu.

A version of this article originally appeared on the BU Research website.

Mark Kramer has won a $253,000 National Science Foundation (NSF) CAREER award for his work in better understanding the brain mechanisms that drive seizures in people with epilepsy. He is the third member of the College of Arts & Sciences mathematics and statistics department to win a CAREER award in the past five years.

“I’m excited to use the award to continue our interdisciplinary research efforts to understand human epilepsy,” says Kramer, a associate professor of mathematical neuroscience. “We’ll use the award to build and analyze mathematical models of the human brain’s activity during a seizure. It’s a highly collaborative effort, which would not be possible without the support of my fantastic colleagues in the department and amazing collaborators at Harvard and Massachusetts General Hospital.”

Epilepsy, the condition of recurrent, unprovoked seizures, is a brain disorder that affects nearly three million people in the United States, according to the Centers for Disease Control and Prevention. The brain processes that cause seizures are poorly understood, and in one-third of patients with epilepsy seizures are not adequately controlled. Kramer says he hopes his research will lead to novel approaches in management of epilepsy. Each year, the NSF gives out about 20 CAREER awards in the mathematical sciences nationally to tenure-track assistant professors (Kramer was promoted to associate professor after he applied for the award). The other two CAREER winners are both now associate professors, Sam Isaacson, who won one of the awards in 2013, and Uri Eden, who received one in 2011.

“Mark is an outstanding young colleague who is recognized internationally for his pioneering research in mathematics and neuroscience,” says Tasso Kaper, a CAS professor and department chair. “He addresses fundamental questions about brain rhythms, the onset of epileptic seizures in humans, the dynamics of networks of neurons in the cortex, as well as precursors to Alzheimer’s disease. His modeling work for these pressing biological and medical problems has led to important advances in the mathematical sciences, including for dynamical systems, differential equations, and statistics.” Kramer takes a multidisciplinary approach, Kaper adds, “working on joint research grants with medical researchers and biomedical engineers.”

Kramer’s description of his project for the NSF notes that while animal studies provide “powerful methods to uncover the potential mechanisms for epilepsy, how the results from these studies relate to human epilepsy remains unclear.” And while some mechanisms of epilepsy may be consistent in animal models and humans, he says, there are also differences that are critical to understanding and treating the disorder.

To improve understanding of the mechanisms behind human seizures, he will analyze brain voltage recordings made directly from human patients and use that data to develop mathematical models of the activity of individual brain neurons and interacting neurons. Further from his NSF project description: “The mathematical models will then be used to study the biological mechanisms that support the different brain voltage rhythms that appear during seizure and how these rhythms move across the surface of the brain.”

Kramer is exceptionally gifted at explaining his field, Kaper says, and he will incorporate his research on the mechanisms of seizures into an undergraduate course in computational neuroscience, a textbook and online course in neuronal data analysis, and undergraduate and graduate research training in computational neuroscience.

A version of this article originally appeared on BU Research.

Sara Rimer can be reached at srimer@bu.edu.

The cerebral cortex is what most people imagine when they think of the word “brain.” It’s the convoluted mass of gray matter that’s responsible for memory, thought, language, consciousness—things that make us unique. “It’s the seat of all our higher functions,” says Tarik Haydar, a School of Medicine associate professor of anatomy and neurobiology. “Understanding how it comes together is part of the challenge and the excitement of our work.”

Haydar and his colleague Jennifer Luebke (GRS’90), a MED associate professor of anatomy and neurobiology, are trying to understand how and when the complexity of the cerebral cortex is first established. Their discoveries, published in the Journal of Neuroscience in April 2015, show that this process begins when stem cells generate neurons even before we are born. Their work offers the first direct evidence that distinct lines of neurons are generated from different types of neural stem and progenitor cells, and that these diverse neurons populate regions of the brain once thought to be homogenous. The work, funded by the National Institutes of Health and the Rafael del Pino Foundation, has widespread implications for our basic understanding of the brain, especially against the backdrop of the European Union’s Human Brain Project and the US BRAIN Initiative, whose goal is to map our neural circuits in fine detail.

“If we have a better understanding of how the brain works under normal conditions, at the most basic level, then we can have a better understanding of how it works when things go wrong,” says Luebke. “Why are some neurons more vulnerable to Alzheimer’s and Parkinson’s diseases? We need an understanding of how neural diversity is generated to answer these questions.”

The human brain contains billions of neurons, all slightly different from one another. Why they are different and how they got that way are some of the current puzzles of neuroscience. Brain growth starts early in fetal development. At this stage, neural stem cells—think of them as the grandparents of your brain cells—differentiate into a handful of intermediate “progenitor” cells, akin to parents. The various progenitors then give rise to the end products: neurons. And the neurons, like human children, are somehow all different. But when do these differences first arise? And how? “Our molecular understanding of the neural progenitors has changed dramatically in the past 10 years or so. Using this new knowledge, we were able to ask focused questions about how they work,” says Haydar. “We now know there isn’t just one type of progenitor cell in the brain, and particularly in the cerebral cortex, but there are half a dozen, maybe even more. We wondered why there are so many types of progenitors. What’s their purpose and function?”

For many years, scientists theorized that we had so many different progenitors because more progenitor cells meant more neurons, leading to our big human brains. “That sort of made sense,” says Haydar, “but it turns out that all the progenitor types in the really complicated human brain are also found in the simpler mouse brain. So it seemed that something else might be going on.”

Haydar’s group wondered if the many types of progenitor cells led not to more neurons, but to different kinds of neurons. To test the idea, they needed a way to build a genealogy of the brain, tracing which progenitor cells led to which neurons. Then they could test the descendants for differences. Bill Tyler, a postdoctoral fellow in Haydar’s lab, created the tools to do it.

Stem cells were tagged with red or green fluorescent protein, colors that lit up in their descendant cells. Scientists found striking differences in the electrical and physical characteristics of the different neurons. Photo courtesy of Tarik Haydar

Tyler focused on one type of cell called the basal intermediate progenitor, which was thought for many years to give rise to most of the neurons in the upper layers of the cortex. These particular cells express a gene called T-box brain protein 2 (TBR2) while other progenitors in the fetal brain don’t. Tyler used this to his advantage, designing a genetic tagging technique that labeled basal intermediate progenitors in fetal mice with a fluorescent protein called mCherry. That way, the progenitors and all of their descendant cells would glow red. At the same time, Tyler’s method marked all the other progenitor cells green with a fluorescent protein called ZsGreen. Then he waited until the mice were born, and looked at their brains with a laser microscope, which gave him the high resolution needed to see tiny details of the neurons.

The picture he saw revealed that the astounding complexity of the cortex was now slightly ordered by the two fluorescent proteins: red and green brain cells popped brightly against a black background, their colored tendrils snaking off in all directions. But besides the obvious color difference, were the red and green neurons different in any other way? If so, how? “So what we did then was go into the brain and measure the precise shapes and activities of the red and green neurons,” says Haydar.

That’s where Luebke entered the picture. Her lab specializes in neuron electrophysiology—measuring the electrical output of single brain cells. It’s a challenging process. “It’s not that easy to get the readings. A lot of things have to go right,” says Luebke. “Each recording takes about an hour. Sometimes you think you’re on a cell, and then you’re not. In any given animal, we’d only be able to record from three or four cells that could be subsequently reconstructed.”

The painstaking teamwork paid off with some remarkable results—they discovered that the red and green neurons were strikingly different. “The red cells were much more excitable,” says Luebke. Although the red neurons were physically simpler than their green cousins, they fired off many more electrical impulses when stimulated. The cells also differed in their “input resistance,” which strongly influences their response to an incoming electrical signal. “The red neurons and the green neurons were very different from one another, even though they were all born at the same time and were going to the same place,” says Haydar. “I think what this shows is that there are fundamental components of a neuron’s identity that are formed at very early stages of development.”

The scientists think that this ability of stem cells to generate early differences between neurons plays a large role in the how the healthy brain functions. One of their next steps is to see whether changes in progenitors may cause cognitive problems in specific human disorders. Tyler and Haydar recently showed that one type of progenitor cell is reduced in the fetal brain of a mouse model of Down syndrome. These changes could mean that neuron diversity may be altered at very early stages of life, and that this disorder may take root in the brain before neurons are even made. A deeper understanding of this basic science may one day lead to better treatments for developmental disabilities.

“The brain is a vast number of interconnected circuits, and we’re just at the very beginning of understanding how the circuits work, let alone how they come to be,” says Haydar. “But this work opens up a new understanding and a brand-new arena of research.”

Barbara Moran can be reached at bmoran@bu.edu.

A version of this article originally appeared on BU Research.

The silver screen is rarely kind to the humble ant. Usually portrayed as creepy-crawly and mindless, movie ants threaten humans as freakish giants (Them! 1954) or deadly swarms (Empire of the Ants 1977), rather than living alongside us in harmony.

But wait long enough, and every ant will have his (actually her) day. In the summer blockbuster Ant-Man, currently #1 at the box office, actor Paul Rudd plays an ex-con with an engineering degree who turns superhero with a suit that gives him the ability to change size and control ants. He shrinks to ant size and learns how to harness the ants’ collective intelligence. For once, insects are the heroes.

“It’s a turning point for ants in cinema,” says James Traniello, a College of Arts & Sciences professor of biology, who joined BU Today for a matinee viewing of the film. Traniello has spent his career studying the social behavior of ants, and is also—perhaps not surprisingly—a connoisseur of insect films. He gives Ant-Man an enthusiastic thumbs-up, though he had a few quibbles with the science.

BU Today: What did you like about the film?

Traniello: For once ants were portrayed as cooperative and in line with human interests, as opposed to being a force that’s out to destroy humans. The other movies about ants show science trespassing on nature, like tests of atomic bombs in the desert that generate radioactive fallout and create mutants—the result of humans playing with technologies that they shouldn’t be playing with. And invertebrates got involved in this in the fifties, with giant spider, scorpion, octopus, and locust films, and Them! in 1954.

Ant-Man was different. I guess the new view of science trespassing on humanity involves the theme of weaponization, which is really very modern. That is, you weaponize microbes, like anthrax, and you weaponize altruism through religion, and now you weaponize body size.

Ants in the Movies!

Them! (1954)
Ants get nuked by atomic tests, mutate into monsters that threaten civilization.

The Naked Jungle (1954)
Charlton Heston on a Brazilian plantation trying to hold off an army ant attack.

Phase IV (1974)
Desert ants form a collective intelligence and wage war.

Empire of the Ants (1977)
Joan Collins is a scam artist in Florida, selling land overtaken by giant ants.

Antz (1998)
Ant tries to break from totalitarian society, win affection of the princess he loves.

Ant-Man (2015)
Ex-con uses super-suit to win back his daughter and save the world.

The New York Times review had an interesting quote: “Ants are not known for individualism, which makes them, in some ways, a less promising platform for superheroism than spiders or bats.”

Well, Ant-Man is not really an ant. And one thing that they totally gloss over—which is as amazing as being able to shift your size—is that he could translate human thought into brain waves, and then translate that into a chemical language to communicate with ants. That’s better, to me, than getting big and small.

Ants don’t really communicate through electromagnetic waves, right?

No, it’s mainly chemicals and substrate vibration.

There was only one point in the movie where I heard you snicker. That was when the scientist played by Michael Douglas—he looked great, by the way, don’t you think?

Yes, he did. If you looked deep enough into his eyes you could see Spartacus.

I thought he made science seem very cool and sexy. Anyway, at one point he says something like: “Ants can do incredible things, but they need a leader.” And then you groaned.

Yes, that’s not true.

What about the queen? Doesn’t she kind of direct the colony?

The queen isn’t a leader. She’s basically a giant ovary—she just lays eggs. Ant colonies don’t have leaders. Their abilities to build elaborate nests and do other amazing tasks as groups come from the emergent properties of individuals acting on local information. Normally they do things like that when they’re foraging. So they’ll turn foraging on and off, depending upon the colony’s needs for nutrition.

I think the movie got at that when the ants wrote numbers on the floor and made a raft and built bridges.

Yes, they should have had weaver ants building living chains and bridges, since they do it naturally. I was hoping to see them in the movie, but that’s OK.

Any other scientific quibbles?

The ants were always guys, which is not how it really works. They’re all female, except for males, which are only flying sperm dispensers that die after mating. The ant that Paul Rudd was riding—a carpenter ant virgin queen—was a female but he called her “Antony.” And when the actor climbed onto the ant the scientist said, “Put your foot on the—I think they said “node.” I think they wanted to say “petiole.”

They got thorax right.

More like mesosoma or alitrunk. It was also interesting how Ant-Man had a personal relationship with Antony. He was sad when the ant was killed. The closest thing to that I’ve seen is in the movie Phase IV. The ant colony is portrayed as having an incredible collective intelligence, which is interesting and true, or at least partially true. And they end up communicating with people through computers. The upshot is that the ants want humans to be brought into their world, instead of there being opposition between nature and humanity. So whether that was something like a latent Rachel Carson reference—I don’t know.

Two thumbs up! Biologist James Traniello, an expert in ant behavior, went to the theater with the author to see Ant-Man. Photo by Cydney Scott

What do you think of having a yellowjacket as the bad guy?

Actually there’s a giant hornet in Japan that attacks honey bee colonies. There is a naturally antagonistic relationship between wasps and army ants, but ants are the predators of wasps.

Then why did they pick a yellowjacket?

Maybe because he could wear a cool yellow and black suit?

Overall, do you think the movie is good for ants or bad for ants?

I think it’s good. I was hoping there would have been more emphasis on the theme of cooperation in nature, and the important ecological role played by ants. You can’t pull ants out of an ecosystem without it collapsing. They modify and aerate soil, transfer nutrients, form mutualisms, and are important in food webs. So maybe they could have got a little of that science into it somewhere. But it’s an entertaining movie, not a documentary.

At the end, the little girl did adopt a giant ant as a pet.

Yes, feeding the ant under the table like a dog—that was a nice touch. I usually feed ants when they’re on top of the table.

Barbara Moran can be reached at bmoran@bu.edu.

Last January, HBO’s Real Sports host Bryant Gumbel interviewed former NFL coach and player Mike Ditka. One of the things Gumbel asked Ditka was, if he had an eight-year-old son now, would he allow him to play football. “Nope,” Ditka said. “That’s sad. I wouldn’t, and my whole life was football. I think the risk is worse than the reward.”

Ditka was referring to recent studies showing that former professional football players who suffered repetitive head trauma during their careers were developing chronic traumatic encephalopathy (CTE), a neurodegenerative disease that can cause dementia, memory loss, aggression, and depression.

Now a new study by a team of researchers from the BU School of Medicine and Brigham and Women’s Hospital confirms Ditka’s reservations. The study, published online in the Journal of Neurotrauma in July, found that former NFL players who started playing tackle football before the age of 12 had a higher risk of altered brain development compared to those who started the sport when they were older.

The study, funded by the National Institutes of Health (NIH), is the first to show a link between early exposure to repetitive head impacts and structural brain changes later in life, the researchers said.

The corresponding author on the study, Robert Stern, a MED professor of neurology, neurosurgery, and anatomy and neurobiology and director of the Clinical Core of the BU Alzheimer’s Disease Center, cautions that the findings “are not necessarily indicative of chronic traumatic encephalopathy,” a disease that can currently be diagnosed only by autopsy.

“While this study adds to the growing concern that exposing children to repetitive hits to the head in tackle football may have long-lasting consequences,” Stern says, “there are likely other contributing factors that contribute to overall risk for CTE.”

The study is part of BU’s Diagnosing and Evaluating Traumatic Encephalopathy Using Clinical Tests (DETECT) project, which works to develop methods of diagnosing CTE during a patient’s lifetime.

The researchers tested 40 former NFL players (none of whom were identified) between the ages of 40 and 65 who had spent more than 12 years playing organized football, with at least 2 years playing in the NFL. Half of the players started playing tackle football before the age of 12, and the other half after they turned 12. The number of concussions was similar between the two groups, and all of the players had experienced memory and thinking problems for at least six months.

The study used an advanced type of MRI (magnetic resonance imaging) on the former players that specifically looked at the movement of water molecules along the brain’s white matter tracts. These tracts are the superhighways within the brain that relay commands and information. The researchers found that the players who started to play tackle football before age 12 were more likely to have changes of the white matter tracts of the corpus callosum, which connects the two halves, or hemispheres, of the brain.

The research team points to growing evidence of a “critical window” of brain development for children between the ages of 10 and 12, when the brain may be especially susceptible to injury.

“This development process may be disrupted by repeated head impacts in childhood possibly leading to lasting changes in brain structure,” explains lead author Julie Stamm (MED’15), a postdoctoral fellow at the University of Wisconsin School of Medicine and Public Health, who conducted the study as part of her MED doctoral dissertation.

The authors stress that the study, with just 40 athletes, was a small one, and they say that the results cannot be generalized to include those who began to play tackle football before the age of 12, but did not go on to play professional football. Rather than proving a cause-and-effect relationship, the study demonstrates the “association between younger age of first exposure to tackle football and abnormal brain imaging patterns later in life,” says study senior author Martha Shenton, director of Harvard Medical School’s Psychiatry Neuroimaging Laboratory.

Previous research by the research team published in January found that former NFL players who started playing tackle football before age 12 were at a higher risk of developing mood, behavioral, or cognitive impairment later in life than those who took up the game after age 12.

In both studies, the authors say more investigation is needed into later-life consequences of childhood exposure to repetitive head impacts. Their ultimate goal, they stress, is to increase safety in youth sports and to help young athletes compete without putting their health at risk. Professional athletes in other sports, such as hockey, wrestling, boxing, and baseball, have also been found to have CTE.

Parents appear to be taking note. The number of kids ages 6 to 12 playing football fell 29 percent, to 1.3 million, from 2008 to 2013, according to the Sports & Fitness Industry Association.

Around the turn of the 20th century, a Spanish neuroscientist named Santiago Ramón y Cajal created intricate images of intertwined neurons that changed brain science forever. His exquisite illustrations helped scientists understand some fundamental facts about the brain, namely that long-armed neurons—communicating over gaps called synapses—are the basic unit of our nervous system.

Now, a team of Boston scientists, working with funding from the National Institutes of Health, the National Science Foundation, and the Howard Hughes Medical Institute, among others, has created a new system for imaging and analyzing neurons on a much finer scale, one they hope will produce insights into issues from developing brains to devastating mental disorders. Details of the system, as well as their analysis of a sliver of mouse cortex, were published in the July 30, 2015, edition of the journal Cell.

“The complexity of the brain is much more than what we had ever imagined,” says study first author Narayanan “Bobby” Kasthuri, a School of Medicine assistant professor of anatomy and neurobiology, who coauthored the Cell paper with Jeff Lichtman of Harvard University. “We had this clean idea of how there’s a really nice order to how neurons connect with each other, but if you actually look at the material it’s not like that.”

The work overturns a long-standing assumption, known as “Peter’s Rule,” that if two neurons are close to each other, they are likely to form synapses that allow them to communicate. It seems logical, but, Kasthuri learned, it turns out to be false, at least in this particular part of the mouse brain, a piece of cortex that receives sensory information from whiskers.

“Just because two neurons spend a lot of time together doesn’t mean they make a connection,” he says. “Now, that’s the rule for this part of the brain in an adult mammal. It could be that in different parts of the brain, or in a baby’s brain, every neuron is connecting to its neighbors. That’s why we want to do this imaging in other brains and in a baby’s brain—that’s how we’ll figure this out.”

A high-resolution image of two adjacent neurons, one colored in green and one in blue. The numbered areas, in yellow, are synapses—gaps where the neurons communicate via chemicals called neurotransmitters. “Every neuron has thousands of places to synapse with another,” says Kasthuri. “Why does it keep choosing the same ones?” Photo courtesy of Kasthuri, et al./Cell 2015

The imaging system contains both hardware, which slices and photographs brain samples, and software, which analyzes the data. The patented hardware, developed by Kasthuri and scientists at Harvard, is called ATUM, for automated tape collecting ultra-microtome. It uses a diamond knife to cut stained, plasticized samples of brain tissue into 30-nanometer slices, then collects and photographs the samples with an electron microscope and stores the data. The scientists used a program called VAST, developed by coauthor Daniel Berger of Harvard and the Massachusetts Institute of Technology, to analyze the data, creating vivid color images of neurons at the level of individual synapses.

The cost and data storage demands for this research are still high, but the researchers expect expenses to drop over time, just as it has for genome sequencing. To facilitate data sharing, the scientists are partnering with Argonne National Laboratory and hoping to create a national brain laboratory that neuroscientists worldwide can access within the next few years. Kasthuri likens the idea to the Human Genome Project, an undertaking that spawned new insights and technology, but also criticism.

“Some scientists have a fundamental problem with this type of work because it’s not hypothesis-driven,” says Kasthuri. “We want to collect a huge data set and then look for patterns. And we think it will pay off.”

“As long as data is showing you things that are unexpected, then you’re definitely doing the right thing,” says senior study author Lichtman. “And we are certainly far from being out of the surprise element. There’s never a time when we look at this data that we don’t see something that we’ve never seen before.”

Barbara Moran can be reached at bmoran@bu.edu.

A version of this article originally appeared on BU Research.

The patient seemed to be pulling through.

After the accident, he was rushed into surgery and, from there, into the intensive care unit, where he was recovering. But, days later, the dominoes started falling. One by one, his organs failed. The patient didn’t survive. Later, trying to understand what went wrong, doctors ordered an autopsy. But the result was a puzzle: the organs weren’t damaged. So why did they shut down?

This is a typical story of multiple organ dysfunction syndrome, better known as multiple organ failure. Although it’s the leading cause of death in patients who make it through the first few hours after a trauma, its origins remain a mystery.

Plamen Christov Ivanov (GRS’99), a research professor of physics in Boston University’s College of Arts & Sciences, and his colleagues at BU’s Laboratory for Network Physiology think the answer may lie not in the individual organs but in the biological communications network that keeps them working in sync. Now, with the support of a $1 million, four-year grant from the W. M. Keck Foundation, they are laying the groundwork for an emerging field—network physiology—to study these connections and generate a new human “atlas” that will reveal how organ systems interact in both sick and healthy patients.

Ivanov introduced the field to the scientific community with a 2012 paper in Nature Communications, and he delivered the opening lecture at a Harvard symposium on network medicine later that year. A special issue of the New Journal of Physics followed in 2013. “We were really opening a blank page,” Ivanov says. With most federal funding reserved for advancing established fields, not launching new ones, the project could have stalled. But the Keck Foundation, established in 1954 by the founder of Superior Oil, the late W. M. Keck, provides funding specifically for pioneering work in science, engineering, and medical research that has the potential to lead to new paradigms, technologies, and discoveries that will save lives. They saw potential in the high-risk, high-reward work. “It allows us to really do something new as a field: develop the first analytic methods and theoretical framework to address the unique problems we encounter in network physiology,” says Ivanov.

Biologists and doctors have typically studied organs in isolation. If you’re having heart trouble, you go to the cardiologist; if your eyes are bothering you, you see an eye doctor. This “reductionist” approach “has been very useful scientifically in every field for the last two to three hundred years, but it has its limitations,” especially in biomedicine, where it is impossible to isolate the systems that make up the whole, says Joseph Loscalzo, who studies the related field of network medicine, which aims to understand the relation between diseases and genetic mutations using graphs and networks. He is Hersey Professor of the Theory and Practice of Medicine at Harvard Medical School, chair of Harvard’s Department of Medicine, and Physician-in-Chief at Brigham and Women’s Hospital. Loscalzo and Ivanov discovered that they were both interested in developing novel network approaches to medicine and the human body when Ivanov joined Harvard Medical School’s Sleep Medicine division. 

Treating organs in isolation also can’t explain medical crises that seem to happen in the space between individual organs, like multiple organ dysfunction, or altered states like coma.

Yet examining the linkages between the organs is a major challenge. For one thing, there’s the problem of time: each organ seems to hear the ticking of a different clock. The eyes and brain exchange lightning-quick signals in a matter of milliseconds; the kidneys plod along through a 24-hour cycle; the heart beats every second or so. Communication between the organs takes multiple forms, too. Electrical signals combine with chemical messengers like hormones to form a sort of internal full-body internet. And, of course, we still don’t have a complete understanding of how individual organs work.

But to figure out how the network functions, Ivanov and his colleagues have to start with even more basic questions, says Ronny Bartsch, formerly a BU research assistant professor of physics and now part of the faculty at Bar-Ilan University in Israel, who has worked with Ivanov since 2008. “What do we measure?” he asks. “Do we have the technology to measure it? And can we make sense of the measurements?” It isn’t as simple as just collecting heart rate or EKG readings, points out Ivanov: the real challenge is getting useful information from these signals.

To address this challenge, Ivanov has assembled an interdisciplinary team of scientists at BU, including researchers with backgrounds in statistical and computational physics, neuroscience, physiology, applied mathematics, and biomedical engineering. The team also works with collaborators throughout Boston, including intensive care clinicians at Massachusetts General Hospital, sleep researchers at Brigham and Women’s Hospital, and biomedical engineers at MD PnP, a maker of innovative biomedical devices. Ivanov is also an associate physiologist at Brigham and Women’s Hospital and a lecturer on medicine in Harvard Medical School’s Division of Sleep Medicine.

The ultimate result of their work, they hope, will be a new way of looking at the human body—what Ivanov calls a dynamic “atlas” animated with the living, changing connections between organs. Ivanov describes the atlas as a collection of “blueprint reference maps” that will ultimately show how the body’s systems interact under all sorts of human conditions: healthy and sick, young and old, awake and asleep, stressed and relaxed. This atlas will be to the traditional, encyclopedia-style atlas of human anatomy what a live traffic report is to a paper road map, revealing not just the “infrastructure” of the body but the traffic that animates it.

“We want to understand how systems talk to each other,” but to do that, the systems have to be under certain controlled conditions, says Kang Liu, a research scientist in the physics department who earned his PhD from BU in 2013. So Ivanov and his colleagues asked themselves: When is the body most isolated from all the noises, sights, smells, and activity of the world? Answer: During sleep. Sleep also presented a compelling scientific mystery: How do the body and brain manage to seamlessly transition from one sleep stage to another, over and over again, each night?

Ivanov had previously studied how variations in heart rate change during each stage of sleep. The next step would be to see not just how individual systems operate during sleep, but to map how the connections between brain and body change as a person passes into light sleep, deep sleep, and REM sleep. For full eight-hour sleep periods, Ivanov and his colleagues tracked subjects’ brain activity, eye movement, breathing, heart rate, and leg and chin movement. Then they looked for correlations between activity in each part of the body.

During deep sleep, they found, most of the body’s systems seemed to be disconnected. But new linkups suddenly switched on when each subject shifted into REM sleep. Even more connections flipped on for light sleep until, when subjects woke up, all the connections were suddenly illuminated. His team was astonished to find how quickly the communication network could be rearranged, Ivanov recalls. Though researchers had expected that the body’s “network topology”—that is, the shape of a map that represents its connectivity—would change over hours or days, no one had anticipated that it might change in a matter of seconds. The results were published in Nature Communications in 2012.

Sleep, though, is just the first test case in a much broader research program. In 2015, with the support of the Keck grant, Ivanov’s team will bring their work into a real-world laboratory where the stakes are, literally, life-and-death: the Medical Intensive Care Unit (MICU) at Massachusetts General Hospital (MGH), which takes a multidisciplinary approach to caring for severely ill patients. The goal: a new model of ICU monitoring in which the connections between a patient’s body systems are being constantly mapped in real time, so that dangerous breakdowns, like the ones that might cause multiple organ dysfunction, can be anticipated and even prevented.

Today’s monitoring devices aren’t capable of taking in and integrating all this data from multiple systems, says Ivanov. That’s where the device makers at MD PnP come in. Working with MGH’s MICU physicians and members of the Network Physiology Lab, they will be designing new all-in-one monitors that record heart rate, respiration, and more.

Making sense of all that data, and discovering which dropped connections should raise alarms, will fall to data scientists like Aijing Lin, who is visiting the Network Physiology Lab from Beijing Jiaotong University in China, and Xiaolin Huang, a biomedical signals expert visiting from Nanjing University. With the right biomedical data in hand, they hope, it may even be possible to flip the “reactive” model of critical care on its head and prevent the events, like heart failure, that send patients to the ICU in the first place.

“It’s very difficult to predict sudden cardiovascular events,” says Huang. Doctors track patients’ blood pressure and heart rate, but by the time blood pressure starts dropping, says Huang, it is too late to stop a heart attack. “Maybe we can see something in the coupling between systems that we cannot see in the individual systems,” says Ivanov. That could help doctors predict imminent cardiac events before heart rate and blood pressure change.

Such developments are still years or even decades away, emphasizes Ivanov. “This Keck-funded pioneering research program is in a similar stage to what the Human Genome project was 25 years ago, when they started to develop first genomic maps,” he says. Just as it has been a long road from the first human genome to meaningful medical applications, it will take time for network physiology to mature into new diagnostics and treatments. When it does, though, Ivanov hopes that it will reveal a fresh picture not just of illness, but of health, too. “Most biologists have a healthy skepticism about whether this approach will yield new insight. But the evidence that it will is growing,” says Loscalzo.

“The human body is like an orchestra,” says Ivanov. “Each instrument has its own sound and frequency. Each works on a different timescale, with different dynamics. If the musicians are all playing different tunes, it doesn’t matter how skillfully they are performing—the result will be a cacophony. But when they all come together as an orchestra, the result is something beautiful.”

A version of this article originally appeared on BU Research.

The statistics are grim. Veterans of the conflicts in Iraq and Afghanistan have a 41 to 61 percent higher risk of suicide than the general US population, according to a 2014 study in the Annals of Epidemiology. This risk is far higher than seen in veterans from earlier wars, so high that the US Senate and the House of Representatives unanimously passed a bill in early 2015 to improve suicide prevention programs at the US Department of Veterans Affairs (VA).

The suicide risk is “alarmingly high,” says Naomi Sadeh, a School of Medicine assistant professor of psychiatry and a psychologist at the National Center for PTSD. And the numbers raise important questions for researchers: which veterans will turn to suicide, and why? While risk rises for many reasons, PTSD (post-traumatic stress disorder) has emerged as one of the strongest predictors. But “not every veteran develops PTSD or becomes suicidal,” says Sadeh. “Our biggest challenge right now is predicting who is going to attempt suicide—we’re not really very good at that yet.”

Sadeh is lead author on a September 2015 study in Molecular Psychiatry pointing to a biomarker that might bring researchers a little closer to the goal of better predicting—and perhaps treating—PTSD and suicide risk: a gene called SKA2. Biomarkers, short for “biological markers,” are measurable indicators of health or disease, things like blood cholesterol or antibody levels. Many biomarkers don’t provide a definitive diagnosis of disease, but in conjunction with other health information, can indicate risk, and also possible avenues of treatment. Scientists across disciplines are actively searching for biomarkers that may indicate early signs of diseases like Alzheimer’s, Parkinson’s, lung cancer, and in this case, risk of suicide. “In the past, we’ve relied on self-reporting to estimate suicide risk: veterans telling us when they have depression or symptoms of PTSD,” says Sadeh. “The field is looking for more objective measurements, and that’s where biomarkers come in.”

MED researchers Mark Miller and Naomi Sadeh study whether genetic changes may lead to a heightened risk of suicide in veterans. Photo by Cydney Scott

“At first I was skeptical about trying to find a genetic association for anything as complicated as suicide risk, because there are so many factors that go into it,” says Mark Miller, a MED associate professor of psychiatry and senior author on the study, whose work is supported by the National Institute of Mental Health and the VA. “But within the last few years researchers have made many advances in identifying molecular markers that may be linked to suicide.”

SKA2 emerged as a possible biomarker for suicide risk in 2014, when researchers from Johns Hopkins compared the brains of people who had died from suicide to those who died from other causes. When screening the genomes of people who had died from suicide, the researchers looked for genes that were methylated—tagged with a tiny molecule of one carbon and three hydrogen atoms known as a methyl group—differently than in other genome samples. Methylation is one of the primary ways that the body (or the environment) switches genes on and off. The Johns Hopkins group found that in the brains of people who had died from suicide, the SKA2 gene was methylated in a certain location and thereby switched off. That study, published in the American Journal of Psychiatry in 2014, also found the same changes in SKA2 in the blood of live patients experiencing suicidal thoughts.

Although researchers still aren’t sure exactly what role SKA2 plays in the body, or why turning it off might increase risk for suicide, studies have shown that it helps regulate the HPA (hypothalamic-pituitary-adrenal) axis, a hormonal system that plays a role in our fight-or-flight response and other reactions to stress. Early research indicates that the SKA2 protein protects brain cells from damage, and that when the gene is turned off, stress hormones in the brain can cause cell damage and death.

The Hopkins study turned a spotlight on SKA2 and caught the eye of Miller and Sadeh. “It was a great study,” says Sadeh, “but one limitation was that it didn’t look at the brains of living individuals. So we wondered if we could bridge the gap between postmortem brains and living people.”

To cross this divide, Sadeh examined data from the VA’s Translational Research Center for TBI and Stress Disorders database, which contains health information—including brain scans, blood tests, and the results of comprehensive psychological exams—from about 200 veterans who have faced trauma. By analyzing the data, she found that methylated SKA2 was associated with more severe symptoms of PTSD and a loss of tissue in several regions of the brain. The team did not find any correlation between methylated SKA2 and depression.

“If you think about how PTSD relates to suicide, emerging evidence suggests that anxiety and stress, and the biochemical correlates of that stress, take a toll on the brain, especially in areas of the prefrontal cortex that regulate emotion and would normally inhibit self-destructive impulses,” says Miller. “Identifying the genes involved may give us new insights into the biological mechanisms linking PTSD to suicide.”

Even if other studies continue to correlate SKA2 with PTSD and brain cell death, this biomarker is unlikely to become a stand-alone indicator of suicide risk, Sadeh says. Whether or not a person is at risk for suicide depends not just on genetics, but on family history, social supports, mental illness, access to firearms, and myriad other factors. But she thinks this biomarker could provide a useful tool in conjunction with other tests.

“It might help us improve risk prediction,” she says. “And if you have limited resources, it would help us direct them to those people who are at the highest risk.”

The possibility of genetic tests for PTSD or suicide risk raises questions, as well: could the tests someday prevent soldiers from entering combat, or screen people out of the military altogether? Miller says a genetic screen is unlikely in the foreseeable future, given the complex nature of PTSD and suicide risk. But he hopes that understanding genes like SKA2 will lead to better treatments. “The psychiatric medications we have for PTSD are still in early stages of development and only modestly effective,” he says. “If SKA2 expression turns out to be really important for brain health, we could try to develop drugs that enhance its activity or act on methylation at a particular brain site or use genetic profiles to match treatments to patients—that’s the exciting potential.”

Miller also hopes that the research may eventually apply to other groups known to suffer from PTSD and higher risk of suicide, such as victims of child abuse and sexual assault. “We’re still a ways from knowing whether studies in veterans apply to other at-risk populations,” he says, “but PTSD is not unique to veterans, nor is suicide.”

A version of this article was originally published in BU Research.