Your Beautiful Brain

BY BILL RETHERFORD BILL BY YOUR BRAIN

BEAUTIFUL

GETTY IMAGES 11/14/16 10:12 AM 4.16_Neuroscience_FINAL.indd 12 YOUR BEAUTIFUL BRAIN

DISPATCHES

FROM THE

FRONTIERS OF

NEUROSCIENCE

GETTY IMAGES BY BILL RETHERFORD

COLUMBIA WINTER 2016 13

4.16_Neuroscience_FINAL.indd 13 11/14/16 10:13 AM eer into the human Each neuron typically links to thousands more, ’28LAW, ’83HON, was an attorney, real-estate skull, probe the brain’s perhaps up to fifteen thousand more, drawing on developer, and billionaire; he graduated from tofu-like texture, and the measliest of electrical currents (0.07 volts — an Columbia Law School just before the Great there, in that microscopic AA battery carries twenty times as much). Those Depression began. Over the next seventy-one terrain, the neurons exist, currents, moving neuron to neuron, sprint through years, he would give hundreds of millions of nearly infinitesimal. Fifty of them would fit a phalanx of connectors, called synapses, at speeds dollars to charitable causes. He died in 1999, on the period at the end of this sentence. up to almost three hundred miles per hour. Signals age ninety-three, one of New York City’s most Most form before birth and stay with us until from the brain’s motor cortex, for example, rush powerful figures. Even after death he endures: death, although some, due to disease or disuse, through the central nervous system to the neuronal the name on the building is the Jerome L. eventually shrink, slow down, or succumb. The networks in the legs. Those electrical pokes Greene Science Center. brains of frogs hold sixteen million neuronal regulate balance, direction, stride, and speed, along The building’s approximately eight hundred cells; fox terriers, one hundred sixty million. with dozens of other things; such is the abridged tenants will include scientists, principal PYet the human brain, with its eighty-six billion neurological backstory to taking a single step. investigators, lab managers, postdocs, graduate neurons, still doesn’t house the most. The By the end of adolescence, the neurons will have students, and sta— from Columbia’s Mortimer B. African elephant has three times as many, and engineered five hundred trillion connections. Take Zuckerman Mind Brain Behavior Institute, itself blue whales likely have billions more, though no those connections — from just one brain, mind you relatively new. The institute was established in one is certain. — string them along Interstate 95 somehow, and December 2012 with a $200 million gift from Individual neurons are not self-aware. They do they would stretch from Columbia University to Zuckerman ’14HON, owner of the New York not know what they are, where they are, or who Columbia, South Carolina. Daily News and chairman of U.S. News & World you are. They do not think. Rather, they permit us Neurons are colloquially called the brain’s Report. Says Thomas M. Jessell, one of the to think. Like the frenzy within a pinball machine, “basic building blocks.” And we do know the Zuckerman Institute’s three codirectors and a basics about how individual neurons work. But Columbia professor of biochemistry, molecular fathoming how trillions of them talk across biophysics, and neuroscience: “Our simple task seventy-eight compartments of brain topography now is to create the best institute for neural is a conundrum. And repairing flawed networks science in the US, and, arguably, in the world.” to conclusively cure brain disorders, like autism The move into the Greene Science Center or Alzheimer’s, remains an enigma — looming, kickstarts that assignment. “Really great daunting, slow to undrape itself. “I don’t want science is going to come from it,” says Shadlen, to make it sound like we know nothing,” says a Zuckerman Institute principal investigator. A Michael Shadlen, a professor of neuroscience at the place for “the collision of ideas,” as Jessell likes Columbia University Herbert and Florence Irving to say. Right now, the institute’s scientists are Medical Center (CUMC). “But there are basic, largely disconnected, geographically speaking; basic phenomena that we know nothing about. they’re spread across six buildings throughout Everything we discover provokes deeper questions.” the Morningside Heights and medical center Wrapping one’s head around the human mind campuses. “We’ve really been constrained, is very hard. Figuring yourself out always is. “The hindered, slowed down by all these labs that have greatest scientific challenge we are now facing,” similar interests, scattered all over,” says Randy says Charles Zuker, professor of biochemistry, Bruno, another Zuckerman Institute investigator. molecular biophysics, and neuroscience at CUMC, Just as neurons need to commingle, apparently “is to understand the workings of the brain.” so do scientists. The stereotype of a lone researcher experiencing a eureka moment in a The glass building awaits in West Harlem, at secluded little lab survives only as a science-fiction the intersection of Broadway and 129th Street, trope. In real life, discovery hardly ever happens thirteen blocks north of the Morningside Heights that way. “These are complex problems, and we campus gates. Overshadowing a space previously have not broken them,” says Richard Axel ’67CC, Thomas M. Jessell the neurons fling directives back and forth, occupied by long-abandoned warehouses, it was a Zuckerman Institute codirector and Columbia likes to call the ceaselessly communicating and connecting with the first structure erected on the school’s new professor of biochemistry, molecular biophysics, Jerome L. Greene Science Center other nerve cells. These neuronal networks control seventeen-acre Manhattanville campus. A $250 pathology, and neuroscience. “The ability to a place for “the every thought, feeling, sensation, and movement. million gift helped make it happen — from the understand will require looking at a problem collision of ideas.” They are the conduits that lead to consciousness; Renzo Piano ’14HON design to the construction of through a multiplicity of eyes.” The relocation to they make sense of our senses. Only because of the building’s more than fifty laboratories. the Greene Science Center collects researchers

them do our brains and bodies work. Minus the Dawn M. Greene ’08HON, the philanthropist, JILL L E from more than twenty disciplines throughout

networks, our minds would be slush, gibberish. bestowed the gift in 2006. Her husband of VINE Columbia: neuroscientists, data scientists, Phantasms would replace perceptions. nineteen years, Jerome L. Greene ’26CC, molecular biologists, stem-cell biologists, electrical

14 COLUMBIA WINTER 2016

4.16_Neuroscience_FINAL.indd 14 11/14/16 10:13 AM Each neuron typically links to thousands more, ’28LAW, ’83HON, was an attorney, real-estate engineers, biomedical engineers, psychologists, perhaps up to fifteen thousand more, drawing on developer, and billionaire; he graduated from mathematicians, physicists, theorists, and the measliest of electrical currents (0.07 volts — an Columbia Law School just before the Great model builders. “If you only talk to people who AA battery carries twenty times as much). Those Depression began. Over the next seventy-one work on the exact same thing you work on, you currents, moving neuron to neuron, sprint through years, he would give hundreds of millions of probably don’t generate as many new ideas a phalanx of connectors, called synapses, at speeds dollars to charitable causes. He died in 1999, as you could,” says Bruno. “Getting together up to almost three hundred miles per hour. Signals age ninety-three, one of New York City’s most from the brain’s motor cortex, for example, rush powerful figures. Even after death he endures: through the central nervous system to the neuronal the name on the building is the Jerome L. The stereotype of a lone researcher networks in the legs. Those electrical pokes Greene Science Center. experiencing a eureka moment in a regulate balance, direction, stride, and speed, along The building’s approximately eight hundred secluded little lab survives only as a with dozens of other things; such is the abridged tenants will include scientists, principal neurological backstory to taking a single step. investigators, lab managers, postdocs, graduate science-fiction trope. By the end of adolescence, the neurons will have students, and staŽ from Columbia’s Mortimer B. engineered five hundred trillion connections. Take Zuckerman Mind Brain Behavior Institute, itself those connections — from just one brain, mind you relatively new. The institute was established in — string them along Interstate 95 somehow, and December 2012 with a $200 million gift from people with diŽerent expertise, very diŽerent they would stretch from Columbia University to Zuckerman ’14HON, owner of the New York research programs, but a common purpose of Columbia, South Carolina. Daily News and chairman of U.S. News & World understanding the mind — yeah, that’s fabulous.” Neurons are colloquially called the brain’s Report. Says Thomas M. Jessell, one of the Scientists don’t necessarily put a premium “basic building blocks.” And we do know the Zuckerman Institute’s three codirectors and a on luck, but they do subscribe to serendipity basics about how individual neurons work. But Columbia professor of biochemistry, molecular — of which proximity is a catalyst. “Science is a fathoming how trillions of them talk across biophysics, and neuroscience: “Our simple task completely social interaction,” says Eric Kandel, seventy-eight compartments of brain topography now is to create the best institute for neural the third Zuckerman Institute codirector, is a conundrum. And repairing flawed networks science in the US, and, arguably, in the world.” and a professor of neuroscience, psychiatry, to conclusively cure brain disorders, like autism The move into the Greene Science Center biochemistry, and biophysics at CUMC. “I met or Alzheimer’s, remains an enigma — looming, kickstarts that assignment. “Really great Richard Axel in the late seventies. He became daunting, slow to undrape itself. “I don’t want science is going to come from it,” says Shadlen, interested in the brain and nervous system. to make it sound like we know nothing,” says a Zuckerman Institute principal investigator. A I wanted to learn molecular biology. Axel Michael Shadlen, a professor of neuroscience at the place for “the collision of ideas,” as Jessell likes knew nothing about the brain. I knew nothing Columbia University Herbert and Florence Irving to say. Right now, the institute’s scientists are about molecular biology. And so we started to Medical Center (CUMC). “But there are basic, largely disconnected, geographically speaking; collaborate. He moved full-time into the brain, basic phenomena that we know nothing about. they’re spread across six buildings throughout and I became comfortable with molecular Everything we discover provokes deeper questions.” the Morningside Heights and medical center biology.” Since that collaboration began, both men Wrapping one’s head around the human mind campuses. “We’ve really been constrained, have become Nobel laureates. is very hard. Figuring yourself out always is. “The hindered, slowed down by all these labs that have At the Greene Science Center, a neuroscientist greatest scientific challenge we are now facing,” similar interests, scattered all over,” says Randy could, and almost certainly will, run into an says Charles Zuker, professor of biochemistry, Bruno, another Zuckerman Institute investigator. electrical engineer or stem-cell biologist in a molecular biophysics, and neuroscience at CUMC, Just as neurons need to commingle, apparently hallway, engage in conversation, and — eureka, “is to understand the workings of the brain.” so do scientists. The stereotype of a lone ideas collide — that brief exchange may kindle researcher experiencing a eureka moment in a new research, which may lead to collaboration, The glass building awaits in West Harlem, at secluded little lab survives only as a science-fiction and after years or decades, maybe a cure. Like the intersection of Broadway and 129th Street, trope. In real life, discovery hardly ever happens neural connections, discovery happens for one thirteen blocks north of the Morningside Heights that way. “These are complex problems, and we reason. Someone gets excited. campus gates. Overshadowing a space previously have not broken them,” says Richard Axel ’67CC, occupied by long-abandoned warehouses, it was a Zuckerman Institute codirector and Columbia Kandel, eighty-seven, has been at Columbia the first structure erected on the school’s new professor of biochemistry, molecular biophysics, forty-three years. On his o£ce desk sits Principles seventeen-acre Manhattanville campus. A $250 pathology, and neuroscience. “The ability to of Neural Science, a textbook he coauthored in million gift helped make it happen — from the understand will require looking at a problem 1981, and now in its fifth edition. This particular Renzo Piano ’14HON design to the construction of through a multiplicity of eyes.” The relocation to copy, hardly conspicuous, lays beneath his the building’s more than fifty laboratories. the Greene Science Center collects researchers computer monitor and serves as a screen booster.

Dawn M. Greene ’08HON, the philanthropist, JILL L E from more than twenty disciplines throughout “Look, I’ve been in the field for sixty years,” says Kandel. “We’ve made a lot of progress. But we’re at bestowed the gift in 2006. Her husband of VINE Columbia: neuroscientists, data scientists, nineteen years, Jerome L. Greene ’26CC, molecular biologists, stem-cell biologists, electrical the beginning.”

COLUMBIA WINTER 2016 15

4.16_Neuroscience_FINAL.indd 15 11/14/16 10:13 AM Back in 1952, when Kandel was an NYU even when the experiment is a simple one. Put ultimately follow. And that, really, is the crux of medical student, science really, really didn’t know a lab mouse on a treadmill, scan the neurons the institute’s mission. “Understand first how the much about the brain: “We didn’t know how smell twinkling in its hippocampus for a half-hour — normal brain works, and then you have a much worked. How taste worked. We knew nothing and a terabyte of information emerges, enough to better chance of assessing how abnormalities about learning and memory and emotion.” During keep Zuckerman Institute mathematicians and arise,” says Jessell. the fifties, says Kandel, the only major brain lab statisticians decoding for weeks. That is where the slog work comes in. in New York City was Columbia’s. Even the word Two-photon microscopy is state-of-the-art, but Cultivating stem cells in a petri dish, then “neuroscience” wasn’t coined until 1962. He perhaps only for the moment. Fortified with a tweaking them so they’ll morph into certain kinds recollects the first annual meeting of the Society $1.8 million grant from the National Institutes of of neurons, is a comparatively modest enterprise, Health, Zuckerman Institute principal investigator but often takes months. Learning how to record and biomedical engineer Elizabeth Hillman is the neural activity in a mouse brain could require “There are so many psychiatric and developing SCAPE, a microscope that widens the years. And a grad student within any of the neurological diseases that we view from small neuronal groups to whole brains. neuroscience disciplines could spend more than a “With SCAPE, we can see the entire brain of an half decade exhaustively scrutinizing what appear just don’t understand and don’t adult fruit fly in real time as it walks, crawls, even to be minutiae. “There’s a lot of labor pain in treat successfully.” as it makes decisions,” says Hillman; SCAPE’s science,” says Behnia. three-dimensional images generate ten to one Frequently, the basic research goes nowhere. hundred times faster than the two-photon. “This Science, seldom a linear excursion, typically advance,” says Jessell, could “unlock the secrets sputters ahead in spasms and is routinely cratered for Neuroscience in 1971; 1,400 scientists showed of brain activity in ways barely imaginable a few with crash landings and wipeouts. “You put a lot up. Today, more than thirty thousand from eighty years ago.” of time and e¦ort into something, and you have countries attend. “And now you can’t walk down And it could lead to cures. Already, researchers to be OK with it not giving you anything,” says Broadway without running into a half dozen brain routinely manipulate individual neurons with Behnia. “It happens to everyone. You have to let it researchers,” Kandel says, half joking. He joined electronic nudges, and can even turn o¦ the go and start all over. It’s hard. You learn through Columbia in 1973, but even then: “So little was genes inside a fruit fly’s motor neurons (a nifty your failures. But nothing really fails, because you known. Almost everything you learned trick, given that a fruit fly’s entire brain is barely learn what doesn’t work.” The converse is also true. was something new.” bigger than the tip of a toothpick). Now, after As Jessell says to every last one of his graduate That is still true today. “There are shutting o¦ the relevant genes, scientists may use students: “You’ll probably discover something no so many psychiatric and neurological SCAPE to look for the fly’s motor impairments, one else in the history of mankind ever realized. It diseases that we just don’t understand identify its faltering genes — then (one day) map may not be a big thing. But if you enjoy the clarity and don’t treat successfully,” says the results onto the counterpart human genes. that arises from small discoveries, then you’re Kandel. “This is a phenomenal Somewhere therein could be clues to curing ALS, attuned to being a scientist.” problem facing humanity.” Among a grim and currently irreversible motor-neuron Those “small discoveries” may someday lead to the more common brain disorders: disease. “Science goes schlepping along,” says cures, and perhaps sooner than you might think. Parkinson’s, Huntington’s, Tourette’s, Zuker. “Then breakthroughs come that let you “These may be the early days,” says Bruno. “But epilepsy, narcolepsy, depression, panic jump the steps. You go boom, you jump — boom, some of the most fundamental discoveries will be attacks, anxiety, ADHD, OCD, and you jump — and a mega-barrier is lifted. How made in the early days.” PTSD (there are hundreds more). soon can discoveries be brought to patients? I “You have to be an optimist in this cannot tell you. But we are far closer than we Sarah Woolley, a Columbia professor of psychology field,” says Jessell. “It’s big and it’s were before.” and a Zuckerman Institute principal investigator, complicated. It’ll take time to achieve Even with extraordinary tech advances, has been studying songbirds for more than twenty satisfying answers to some of the basic research — the day-to-day slog work — is years. Take the zebra finch, for example, one of five bigger questions.” indispensable. Without it, scientists will never thousand species of songbird and one of the few But an imposing technological unleash the miracle treatments awaited by that sing only one song. “They breed in the lab,” apparatus, which may help fast-track millions. “You can’t fix a car if you don’t know she says. “They sing, they court, they mate for life, potential treatments, is arriving. what’s under the hood,” says Rudy Behnia, a they make a nest, they raise babies, all in the lab.” One example: in the basement of the CUMC assistant professor of neuroscience and a What attracts Woolley is the singing part — Eric Kandel Greene Science Center will be an array of eighteen principal investigator at the Zuckerman Institute. and the similarities between how songbirds and says that when he two-photon microscopes. With them, scientists “To cure problems of the brain, we first need people learn to vocalize. That’s something almost came to Columbia, in 1973, “almost will see neuronal communities talk to each other to understand it.” By gradually mapping those no other animal does: just humans, parrots, everything you in real time; researchers will record those glinting trillions of neuronal circuits — by looking under hummingbirds, dolphins (probably), bats (maybe), learned was images and replay them endlessly for study. Five the hood — Columbia scientists will eventually and songbirds. “An ape does not learn to vocalize,” something new.”

years ago, none of this was possible. The amount grasp how the engine runs; e¦ective treatments CUMC says Woolley. Dogs don’t learn to bark, and cats

of data generated by the two-photon is immense, for neurological and psychiatric diseases will JOHN ABBOTT don’t learn to purr either. Those sounds surely

16 COLUMBIA WINTER 2016

4.16_Neuroscience_FINAL.indd 16 11/14/16 10:14 AM even when the experiment is a simple one. Put ultimately follow. And that, really, is the crux of a lab mouse on a treadmill, scan the neurons the institute’s mission. “Understand first how the twinkling in its hippocampus for a half-hour — normal brain works, and then you have a much and a terabyte of information emerges, enough to better chance of assessing how abnormalities keep Zuckerman Institute mathematicians and arise,” says Jessell. statisticians decoding for weeks. That is where the slog work comes in. Two-photon microscopy is state-of-the-art, but Cultivating stem cells in a petri dish, then perhaps only for the moment. Fortified with a tweaking them so they’ll morph into certain kinds $1.8 million grant from the National Institutes of of neurons, is a comparatively modest enterprise, Health, Zuckerman Institute principal investigator but often takes months. Learning how to record and biomedical engineer Elizabeth Hillman is the neural activity in a mouse brain could require developing SCAPE, a microscope that widens the years. And a grad student within any of the view from small neuronal groups to whole brains. neuroscience disciplines could spend more than a “With SCAPE, we can see the entire brain of an half decade exhaustively scrutinizing what appear adult fruit fly in real time as it walks, crawls, even to be minutiae. “There’s a lot of labor pain in as it makes decisions,” says Hillman; SCAPE’s science,” says Behnia. three-dimensional images generate ten to one Frequently, the basic research goes nowhere. convey a message — a monkey shrieks to let its Sarah Woolley’s hundred times faster than the two-photon. “This Science, seldom a linear excursion, typically troop know a snake is coming. “But that’s not studies of songbirds may shed light on advance,” says Jessell, could “unlock the secrets sputters ahead in spasms and is routinely cratered learned,” says Woolley. “Those are calls built into why autistic children of brain activity in ways barely imaginable a few with crash landings and wipeouts. “You put a lot the brain.” find it difficult to years ago.” of time and eŽort into something, and you have A baby zebra finch, however, learns to sing by communicate. And it could lead to cures. Already, researchers to be OK with it not giving you anything,” says listening to its father. That’s pretty much the way routinely manipulate individual neurons with Behnia. “It happens to everyone. You have to let it people learn to speak; infants access language by electronic nudges, and can even turn oŽ the go and start all over. It’s hard. You learn through listening to and socializing with their parents — or genes inside a fruit fly’s motor neurons (a nifty your failures. But nothing really fails, because you whoever’s around them the most. Sure enough, trick, given that a fruit fly’s entire brain is barely learn what doesn’t work.” The converse is also true. when Woolley slips a baby zebra finch into the nest bigger than the tip of a toothpick). Now, after As Jessell says to every last one of his graduate of another species (the Bengalese finch), the baby shutting oŽ the relevant genes, scientists may use students: “You’ll probably discover something no learns the foster dad’s song. “That shows the power SCAPE to look for the fly’s motor impairments, one else in the history of mankind ever realized. It of live social interactions for baby birds to learn identify its faltering genes — then (one day) map may not be a big thing. But if you enjoy the clarity how to communicate,” she says. In both humans the results onto the counterpart human genes. that arises from small discoveries, then you’re and songbirds, Woolley theorizes, a set of neurons Somewhere therein could be clues to curing ALS, attuned to being a scientist.” in the brain rouse a distinct kind of learning, one a grim and currently irreversible motor-neuron Those “small discoveries” may someday lead to stimulated by social relationships. Those neurons, disease. “Science goes schlepping along,” says cures, and perhaps sooner than you might think. she suggests, “may send signals that say, ‘OK, learn Zuker. “Then breakthroughs come that let you “These may be the early days,” says Bruno. “But this, this is important, this matters.’” jump the steps. You go boom, you jump — boom, some of the most fundamental discoveries will be Now the kicker. Woolley suspects those you jump — and a mega-barrier is lifted. How made in the early days.” corresponding neurons in humans somehow soon can discoveries be brought to patients? I malfunction in autistic children. For them, cannot tell you. But we are far closer than we Sarah Woolley, a Columbia professor of psychology acquiring language is often an enormous obstacle. were before.” and a Zuckerman Institute principal investigator, “Maybe the signals that say ‘learn’ do not go to Even with extraordinary tech advances, has been studying songbirds for more than twenty the auditory system or the brain circuits that basic research — the day-to-day slog work — is years. Take the zebra finch, for example, one of five form memory,” she says. What is known: sensory indispensable. Without it, scientists will never thousand species of songbird and one of the few processing is glitchy in autistic kids. A touch on unleash the miracle treatments awaited by that sing only one song. “They breed in the lab,” the shoulder may repel them, a direct look might millions. “You can’t fix a car if you don’t know she says. “They sing, they court, they mate for life, make them shudder, and a loud sound is often what’s under the hood,” says Rudy Behnia, a they make a nest, they raise babies, all in the lab.” excruciating. No wonder so many of them avoid CUMC assistant professor of neuroscience and a What attracts Woolley is the singing part — social interactions. Bonding may induce learning, principal investigator at the Zuckerman Institute. and the similarities between how songbirds and but if bonding is painful, then so is learning — and “To cure problems of the brain, we first need people learn to vocalize. That’s something almost it doesn’t happen. “But if we can figure out in our to understand it.” By gradually mapping those no other animal does: just humans, parrots, birds what makes their brains able to learn based trillions of neuronal circuits — by looking under hummingbirds, dolphins (probably), bats (maybe), on social interactions,” says Woolley, “then we might the hood — Columbia scientists will eventually and songbirds. “An ape does not learn to vocalize,” be able to find ways to help the autistic brain.”

grasp how the engine runs; eŽective treatments CUMC says Woolley. Dogs don’t learn to bark, and cats In some ways, human brains and bird brains

for neurological and psychiatric diseases will JOHN ABBOTT don’t learn to purr either. Those sounds surely are unnervingly alike. “As we study the auditory

COLUMBIA WINTER 2016 17

4.16_Neuroscience_FINAL.indd 17 11/14/16 10:14 AM cortex of the zebra finch, we find similarity after could lead to clues in controlling our cravings. In reveals something much more tantalizing: similarity after similarity after similarity,” Woolley research with mice, Zuker’s team shined a fiber- “What we’re working on now is top brain and says. If she can identify those neurons in the optic light over their thirst neurons. The mice bottom brain.” baby zebra finch, then Woolley can predict the instantly sprinted to the water spout. “Even if For more than twenty years, Bruno has been approximate location of the comparable human the mouse is not thirsty, the mouse will think it’s investigating the cerebral cortex, an outer neurons. “I can map my bird’s neurons onto a thirsty, and look for water to drink,” he says. “Isn’t sliver of brain barely thicker than a credit card mammal’s neurons,” she says, “and thus onto a that remarkable?” and critical for higher-order functions like human’s neurons.” Someday, Woolley’s displaced The same seems to apply to taste. The perception and attention. In mammals, the baby songbirds might help millions of autistic messages from the mouse tongue travel directly cortex envelops nearly the entire organ, and children reconnect. to its taste neurons. Just as in humans, those divides into “upper” and “deeper” layers. Our nerve cells are dedicated strictly to the five basic deeper layers, evolutionarily older, faintly evoke For decades, scientists readily swallowed the taste qualities. Activate the bitter neurons while the reptilian brain. Indeed, today’s alligators, notion that a “taste map” partitions your tongue a mouse drinks regular water, and it’s repelled. turtles, and snakes have only the lower layers. — sweet at the front, salty at the sides. “It’s all (The mouse squints, shudders, and jiggles its “There’s a really good reason for why mammals incorrect,” says Charles Zuker, the Columbia head, just like someone who bit into a lemon.) developed the upper layers,” says Bruno. “But I neuroscientist, who has spent the last fifteen But silence the bitter neurons, and the mouse don’t know what the answer is.” years studying how we will slurp bitter liquid. Neuroscientists long assumed the upper cortex perceive taste. “There’s The inferences are dumbfounding. Could transmitted its sensory data — that’s everything no taste map.” Instead, physicians someday manipulate neurons to you see, hear, smell, taste, and feel — directly he says, thousands regulate diet, consumption, and sugar cravings to the deeper cortex. Without that, researchers of taste buds are — perhaps with a pill? “There are amazing believed, the lower region in mammals would scattered around your implications,” says Zuker. “I think the field is poised never detect an outside world. But in 2013, tongue, with sweet, to do something very special.” Then, reining it Bruno and his team shut oƒ the upper cortex salty, sour, bitter, and in: “There are challenges — making sure [a pill] in a mouse. What happened (or what didn’t umami receptor cells acts on the right group of cells, that it targets the happen) startled everyone, not just in Bruno’s throughout. right circuit.” And a reminder: “We are still doing lab, but in the scientific community worldwide. Nor do our taste basic neuroscience. We are still at the stage of “Nothing changed,” he says. Turns out the buds actually decide uncovering fundamental logic and principles.” Yet deep layers weren’t relying on the upper cortex how the food tastes. from his lab’s ever-accumulating data, one can at all; they still received the incoming sensory They do the detection extrapolate the prospective human applications — information. The two cortex regions, Bruno work, definitely, but controlling anorexia, obesity, and diabetes. discovered, can operate independently of each they serve primarily More than one-third of adult Americans today other. Independent yet intertwined: “They do as relays, dispatching are obese, and at increased risk for heart disease, work together,” he says. “But they also look like signals directly to the stroke, and cancer. Thirty million Americans they have diƒerent jobs. What’s the job of this half brain. “Sweet taste cells have diabetes, and three hundred thousand die of the cortex versus the other half? I don’t know.” in the tongue talk to from it annually. Overeating and excessive sugar But he already has a hypothesis. Perhaps, sweet neurons,” says consumption are the causes of both obesity and Bruno says, the upper layers mediate “context- Zuker. “Salty to salty. diabetes. Finding a way to govern them with dependent” behaviors, and make sense of Bitter to bitter.” Within pharmaceuticals would be a miracle. “And now intermingling and often conflicting situations. those micro-groups of we can begin to ask,” says Zuker, “if we can control (A rabbit is hungry. It sees wildflowers nearby. neuronal constellations, feeding and sugar craving to make a meaningful But a hawk hovers overhead. Does the rabbit the taste is given a diƒerence. I believe the answer will be yes.” chance it and go for the wildflowers? Or take oƒ definition. That’s how and go hungry?) The computations performed you know the diƒerence The decades-old “left brain–right brain” in the upper layers, suggests Bruno, are good between strudel and paradigm, although not completely discarded at evaluating conflicting data in context. They sauerkraut. by researchers, now survives considerably decide what to do. Charles Zuker and When humans are hungry, or thirsty, those diminished, a moldy scientific chestnut (left- If that’s so, then another theory, even more his research lab neurons will ping us to eat something, or to get brainers, supposedly, are analytical and good provocative, surfaces. Psychiatric patients often plan to map the taste and thirst a glass of water. “Evolution is smart. Clean, clear, at math; right-brainers, emotional and hyper- have problems making decisions that involve neurons in the and simple,” says Zuker. “This is what innate imaginative). “There is some truth to it,” says context. “Schizophrenics are an example,” says human brain. hardwired circuits are all about.” Now Zuker Randy Bruno, a CUMC associate professor Bruno. “Interpreting sensory signals in context and his lab of twenty-two researchers want to of neuroscience. “But not all functions are JOHN ABBOTT is di¢cult for them. They really struggle with map precisely where the taste and thirst neurons completely one side or another. Some things are it. They can’t deal with it.” Which raises the

are located in the human brain. Finding them not lateralized at all.” Instead, Bruno’s research JOHN ABBOTT question: could the malfunctioning neuronal

18 COLUMBIA WINTER 2016

4.16_Neuroscience_FINAL.indd 18 11/14/16 10:14 AM could lead to clues in controlling our cravings. In reveals something much more tantalizing: research with mice, Zuker’s team shined a fiber- “What we’re working on now is top brain and optic light over their thirst neurons. The mice bottom brain.” instantly sprinted to the water spout. “Even if For more than twenty years, Bruno has been the mouse is not thirsty, the mouse will think it’s investigating the cerebral cortex, an outer thirsty, and look for water to drink,” he says. “Isn’t sliver of brain barely thicker than a credit card that remarkable?” and critical for higher-order functions like The same seems to apply to taste. The perception and attention. In mammals, the messages from the mouse tongue travel directly cortex envelops nearly the entire organ, and to its taste neurons. Just as in humans, those divides into “upper” and “deeper” layers. Our nerve cells are dedicated strictly to the five basic deeper layers, evolutionarily older, faintly evoke taste qualities. Activate the bitter neurons while the reptilian brain. Indeed, today’s alligators, a mouse drinks regular water, and it’s repelled. turtles, and snakes have only the lower layers. (The mouse squints, shudders, and jiggles its “There’s a really good reason for why mammals head, just like someone who bit into a lemon.) developed the upper layers,” says Bruno. “But I networks that cause schizophrenia and other Randy Bruno is But silence the bitter neurons, and the mouse don’t know what the answer is.” psychiatric disorders reside somewhere in the investigating why mammals have will slurp bitter liquid. Neuroscientists long assumed the upper cortex upper layers? “upper” brain layers The inferences are dumbfounding. Could transmitted its sensory data — that’s everything Determining that — the approximate vicinity that reptiles lack. physicians someday manipulate neurons to you see, hear, smell, taste, and feel — directly of the faulty networks — is huge. “We would regulate diet, consumption, and sugar cravings to the deeper cortex. Without that, researchers know where to start looking,” says Bruno. “We — perhaps with a pill? “There are amazing believed, the lower region in mammals would could narrow down the places where the actual implications,” says Zuker. “I think the field is poised never detect an outside world. But in 2013, biological defect is occurring.” If researchers could to do something very special.” Then, reining it Bruno and his team shut o“ the upper cortex then pinpoint those dysfunctional neurons and in: “There are challenges — making sure [a pill] in a mouse. What happened (or what didn’t target them with drugs, e“ective treatments for acts on the right group of cells, that it targets the happen) startled everyone, not just in Bruno’s psychological disease could eventually result. right circuit.” And a reminder: “We are still doing lab, but in the scientific community worldwide. Lots of ifs. “Until we finish the science, that part basic neuroscience. We are still at the stage of “Nothing changed,” he says. Turns out the is still science fiction,” Bruno says. “But that’s the uncovering fundamental logic and principles.” Yet deep layers weren’t relying on the upper cortex hope, right?” from his lab’s ever-accumulating data, one can at all; they still received the incoming sensory extrapolate the prospective human applications — information. The two cortex regions, Bruno Nearly no one knows this about the nose, but controlling anorexia, obesity, and diabetes. discovered, can operate independently of each “most odors,” says Richard Axel, “do not elicit More than one-third of adult Americans today other. Independent yet intertwined: “They do any behavioral responses without learning or are obese, and at increased risk for heart disease, work together,” he says. “But they also look like experience.” That means your reaction to smell stroke, and cancer. Thirty million Americans they have di“erent jobs. What’s the job of this half is tightly twined to memory. Whether garlic have diabetes, and three hundred thousand die of the cortex versus the other half? I don’t know.” from it annually. Overeating and excessive sugar But he already has a hypothesis. Perhaps, “ Evolution is smart. Clean, clear, and consumption are the causes of both obesity and Bruno says, the upper layers mediate “context- diabetes. Finding a way to govern them with dependent” behaviors, and make sense of simple. This is what innate hardwired pharmaceuticals would be a miracle. “And now intermingling and often conflicting situations. circuits are all about.” we can begin to ask,” says Zuker, “if we can control (A rabbit is hungry. It sees wildflowers nearby. feeding and sugar craving to make a meaningful But a hawk hovers overhead. Does the rabbit di“erence. I believe the answer will be yes.” chance it and go for the wildflowers? Or take o“ and go hungry?) The computations performed or gasoline, cologne or co“ee, just-cut grass or The decades-old “left brain–right brain” in the upper layers, suggests Bruno, are good just-smoked grass, your brain, not your nose, paradigm, although not completely discarded at evaluating conflicting data in context. They determines if you like or loathe the smell. Aromas by researchers, now survives considerably decide what to do. transport you to memories that your brain has diminished, a moldy scientific chestnut (left- If that’s so, then another theory, even more catalogued as pleasant or unpleasant; you respond brainers, supposedly, are analytical and good provocative, surfaces. Psychiatric patients often accordingly. This is the core of Axel’s current at math; right-brainers, emotional and hyper- have problems making decisions that involve research. “We are interested in how meaning is imaginative). “There is some truth to it,” says context. “Schizophrenics are an example,” says imposed on odor,” he says. Randy Bruno, a CUMC associate professor Bruno. “Interpreting sensory signals in context Already, at literally a neuronal level of detail, of neuroscience. “But not all functions are JOHN ABBOTT is di¢cult for them. They really struggle with Axel has essentially explained why we can smell; completely one side or another. Some things are it. They can’t deal with it.” Which raises the he has identified more than one thousand receptor

not lateralized at all.” Instead, Bruno’s research JOHN ABBOTT question: could the malfunctioning neuronal cells in the nose that talk to the olfactory bulb, the

COLUMBIA WINTER 2016 19

4.16_Neuroscience_FINAL.indd 19 11/14/16 10:14 AM brain’s first relay station for smell. There, the odors experiment designed to understand one aspect of memory as they get older. And MRI images are fine-tuned, processed, and propelled to other science can open up something more profound,” of patients with age-related memory loss, as parts of the brain (“to at least five higher olfactory he says. “You go in, not knowing what is going to demonstrated by CUMC neurology professor centers,” he says). For his seminal mapping of the come out.” Scott Small ’92PS, have revealed defects in a brain smell system’s molecular bedrock, Axel won the region di erent from those of the early-stage 2004 Nobel Prize in Physiology or Medicine. In 1962, Eric Kandel commenced research on Alzheimer’s patients. “A given odor will call forth di erent Aplysia — the sea hare — a blobby mollusk with Kandel also knew mice didn’t get Alzheimer’s. experiences and produce di erent emotional protruding feelers that resemble rabbit ears. He wondered if they got age-related memory responses for di erent individuals,” he says. Studying sea hares, friends and colleagues warned, loss. If they did, that would be another sign Those flexible behavioral responses — fashioned was a calamitous blunder; fifty-four years later, the disorders were di erent. His lab soon between the olfactory bulb and the hippocampus, Kandel remembers their disapproval. “Everyone demonstrated that mice, which typically have where we collect memories — are more robust thought I was throwing my career away,” he says. a two-year lifespan, do exhibit a significant with smell than with any of the other four senses. But Aplysia, with only twenty thousand neurons decrease in memory at twelve months. With Even the fragrance of in its central nervous system, became Kandel’s that revelation, Kandel and others deduced jasmine, supposedly odd little portal into the human brain: “It has the Alzheimer’s and age-related memory loss are the most sensual of largest nerve cells in the animal kingdom. You distinct, unconnected diseases. scents, is contingent can see them with the naked eye. They’re gigantic. Then Kandel’s lab (again, with assistance from on context, says Axel. They’re beautiful.” Four decades later, Kandel won Small) discovered that RbAp48 — a protein Breathe it in while the 2000 Nobel Prize for Physiology or Medicine. abundant in mice and men — was a central spending an evening He had discovered how those neurons in Aplysia’s chemical cog in regulating memory loss. A deficit with someone you brain constructed and catalogued memories. of RbAp48 apparently accelerates the decline. love. “Then jasmine Today, as neuroscientists worldwide pursue Knocking out RbAp48, even in a young mouse would elicit a very remedies for Alzheimer’s and age-related brain, produces age-related memory loss. But pleasant response,” he memory loss, Kandel’s half century of findings restoring RbAp48 to an old mouse brain reverses it. says. But that could are considered indispensable. Substantive Now what may be the eureka moment — this change, based on new therapies for Alzheimer’s in particular are from Gerard Karsenty, chairman of CUMC’s experience: “Suppose “poised for success,” says Jessell, a colleague of department of genetics and development: bones that same person Kandel’s for thirty-five years. “We’re on the cusp release a hormone called osteocalcin. And turned around and of making a di erence.” But accompanying that Kandel later found that osteocalcin, upon release, hurt you seriously. claim is a caveat; the fledgling remedies are not increases the level of RbAp48. Then jasmine no panaceas. “We’re not necessarily talking about “So give osteocalcin to an old mouse, and boom! longer will have the curing the disease,” he says. “But we are talking Age-related memory loss goes away.” same e ect on you.” about slowing the symptomatic progression of The same may prove true in humans. A pill or In simpler brains, the disease so significantly that lifestyles are injectable could work, says Kandel: “Osteocalcin many aromas provoke improved in a dramatic way. If in ten years we in a form people can take is something very doable an instinctive and have not made significant progress, if we are not and not very far away.” In less than a decade, age- unalterable response. slowing the progression of Alzheimer’s, then we related memory loss might be treatable. “This,” he When mice get a whi have to look very seriously at ourselves and ask, says, “is the hope.” Richard Axel of fox urine, their hardwired neural pathway sends ‘What went wrong?’” has identified them running. “That’s because mice, for a long Breakthroughs could happen sooner, however. As the ambitions of neuroscientists accelerate, the more than one thousand receptor time, have been prey to foxes,” says Axel. Only a Some of the Alzheimer’s medications available field has moved its goalposts to a faraway place. cells in the nose few scents, however, are hardwired in humans. now “probably work,” says Kandel, except for one “We’re trying to understand behavior,” says Bruno. that convey data Smoke, probably, is one. Anything rotting is obstacle: “By the time patients see a physician, “Behavior is not straightforward. It’s an incredibly to the brain. another (the stench of sulfur, akin to rotten eggs, they’ve had the disease for ten years. They’ve lost ill-defined problem.” is revolting to most everybody). But that’s about it. so many nerve cells, there’s nothing you can do for Behavior encompasses everything. Perception, Says Axel: “It’s very hard to conjure up odors that them.” Possibly, with earlier detection, “those same emotion, memory, cognition, invention, obsession, elicit innate responses in people.” drugs might be e ective.” That’s not a certainty, infatuation, creativity, happiness, despair. To After four decades of foundational work, insists Kandel, only a “hunch.” completely understand how the brain governs Axel recognizes the connection between his Years ago, Kandel had another hunch — that behavior, to neurologically plumb the wisps of fundamental research and the furthermost cures. age-related memory loss was not just early-stage human thought, one must unshroud innumerable

Discovering what’s under the hood could help Alzheimer’s, as many neuroscientists believed, COLUMBIA NEWS obscurities at the subcellular level. “How do clarify the latest curiosity about Alzheimer’s: but an altogether separate disease. After all, you define happiness or beauty? Somehow it’s for many patients, an early symptom is losing not everyone gets Alzheimer’s, but “practically based on connections in the brain,” says Jessell. their sense of smell. “What can emerge from an everyone,” says Kandel, loses some aspects of Always, it gets back to the ever-pinging networks:

20 COLUMBIA WINTER 2016

4.16_Neuroscience_FINAL.indd 20 11/14/16 10:15 AM experiment designed to understand one aspect of memory as they get older. And MRI images “Without knowing the links between these eighty- science can open up something more profound,” of patients with age-related memory loss, as six billion neurons that exist within the human he says. “You go in, not knowing what is going to demonstrated by CUMC neurology professor brain, we don’t have a hope of understanding any come out.” Scott Small ’92PS, have revealed defects in a brain aspect of human behavior.” region di‘erent from those of the early-stage Decipher those links, and we will have figured In 1962, Eric Kandel commenced research on Alzheimer’s patients. out how we figure things out. How brain Aplysia — the sea hare — a blobby mollusk with Kandel also knew mice didn’t get Alzheimer’s. connections, for instance, ignite love connections. protruding feelers that resemble rabbit ears. He wondered if they got age-related memory We could, conceivably, fathom ourselves Studying sea hares, friends and colleagues warned, loss. If they did, that would be another sign practically down to the last neuron. Says Axel: was a calamitous blunder; fifty-four years later, the disorders were di‘erent. His lab soon “Do we understand perception, emotion, Kandel remembers their disapproval. “Everyone demonstrated that mice, which typically have memory, cognition? No. But we’re developing thought I was throwing my career away,” he says. a two-year lifespan, do exhibit a significant technology which might allow us entry into these But Aplysia, with only twenty thousand neurons decrease in memory at twelve months. With arenas for the first time. Perhaps we will get in its central nervous system, became Kandel’s that revelation, Kandel and others deduced there. Perhaps.” odd little portal into the human brain: “It has the Alzheimer’s and age-related memory loss are “We are tackling infinity,” says Bruno. “Behavior largest nerve cells in the animal kingdom. You distinct, unconnected diseases. is this infinite space of ideas. Oh, probably not can see them with the naked eye. They’re gigantic. Then Kandel’s lab (again, with assistance from truly infinite. We’re finite beings. Only so many They’re beautiful.” Four decades later, Kandel won Small) discovered that RbAp48 — a protein neurons are in our heads. But think about all you the 2000 Nobel Prize for Physiology or Medicine. abundant in mice and men — was a central can do, and the vast realm of possibilities you He had discovered how those neurons in Aplysia’s chemical cog in regulating memory loss. A deficit can react to. Think about how large a set that is. brain constructed and catalogued memories. of RbAp48 apparently accelerates the decline. I mean, you can’t count all of those things. The Today, as neuroscientists worldwide pursue Knocking out RbAp48, even in a young mouse range of human possibility is staggering.” remedies for Alzheimer’s and age-related brain, produces age-related memory loss. But Acknowledge this, and one could easily argue memory loss, Kandel’s half century of findings restoring RbAp48 to an old mouse brain reverses it. we’ve barely begun to know the brain. “We really are considered indispensable. Substantive Now what may be the eureka moment — this are at the very beginning,” says Bruno. “How far therapies for Alzheimer’s in particular are from Gerard Karsenty, chairman of CUMC’s along? I’d say 5 percent. We’re trying to tackle a “poised for success,” says Jessell, a colleague of department of genetics and development: bones collection of problems and questions that put us Kandel’s for thirty-five years. “We’re on the cusp release a hormone called osteocalcin. And on the 5 percent end.” of making a di‘erence.” But accompanying that Kandel later found that osteocalcin, upon release, claim is a caveat; the fledgling remedies are not increases the level of RbAp48. “ I think we have at least fifty years panaceas. “We’re not necessarily talking about “So give osteocalcin to an old mouse, and boom! curing the disease,” he says. “But we are talking Age-related memory loss goes away.” before we can explain every aspect about slowing the symptomatic progression of The same may prove true in humans. A pill or of human behavior.” the disease so significantly that lifestyles are injectable could work, says Kandel: “Osteocalcin improved in a dramatic way. If in ten years we in a form people can take is something very doable have not made significant progress, if we are not and not very far away.” In less than a decade, age- slowing the progression of Alzheimer’s, then we related memory loss might be treatable. “This,” he Learn the rest — the remaining 95 percent — have to look very seriously at ourselves and ask, says, “is the hope.” and we will quite literally understand ourselves. ‘What went wrong?’” But this will take time. “We have a very fragile Breakthroughs could happen sooner, however. As the ambitions of neuroscientists accelerate, the understanding of the principles by which these Some of the Alzheimer’s medications available field has moved its goalposts to a faraway place. things work,” says Jessell. “I think we have at now “probably work,” says Kandel, except for one “We’re trying to understand behavior,” says Bruno. least fifty years before we can explain every obstacle: “By the time patients see a physician, “Behavior is not straightforward. It’s an incredibly aspect of human behavior.” Or possibly longer. they’ve had the disease for ten years. They’ve lost ill-defined problem.” Says Kandel: “On this — to have a satisfying so many nerve cells, there’s nothing you can do for Behavior encompasses everything. Perception, understanding of the brain — I think we’re a them.” Possibly, with earlier detection, “those same emotion, memory, cognition, invention, obsession, century away.” drugs might be e‘ective.” That’s not a certainty, infatuation, creativity, happiness, despair. To So little is known. Almost everything we learn insists Kandel, only a “hunch.” completely understand how the brain governs is something new. What now? Tackling infinity, Years ago, Kandel had another hunch — that behavior, to neurologically plumb the wisps of of course. “What could be more important,” says age-related memory loss was not just early-stage human thought, one must unshroud innumerable Axel, “than to understand the most elusive, the

Alzheimer’s, as many neuroscientists believed, COLUMBIA NEWS obscurities at the subcellular level. “How do most complex, the most mysterious structure but an altogether separate disease. After all, you define happiness or beauty? Somehow it’s that we know of in our universe? That’s pretty not everyone gets Alzheimer’s, but “practically based on connections in the brain,” says Jessell. damn important.” The answers, always within, everyone,” says Kandel, loses some aspects of Always, it gets back to the ever-pinging networks: now lie ahead.

COLUMBIA WINTER 2016 21

4.16_Neuroscience_FINAL.indd 21 11/14/16 10:15 AM