The Laser is not built for leisurely sailing. With a sleek hull just under 14 feet long, a tall mast, simple sail, and minimal controls, this craft has one purpose: to race. The singular helmsman—almost always a “he” because of the physical demands—must scramble, in a race on high seas, from one side of the craft to the other, suspend himself outboard straight-legged against a stiff wind, and torque his body in response to every wave. Since all Lasers are structurally identical, winning or losing lies entirely in his hands.
Mark Bear—a champion helmsman and neuroscientist at the Massachusetts Institute of Technology—says he applies the same principles to racing and research.
“You begin with probabilities. You don’t know a priori whether heading off to the left side of the racecourse or the right is the way to go. So you collect information, make observations, test hypotheses. You do a few pilot experiments, sailing upwind a little in either direction, to see what looks promising. You make a plan, and take measurements of whether or not the plan is working. If you made a wrong guess, you make on-course corrections.
“But what really separates great sailors from less great sailors,” adds the HHMI investigator, “is that they see things that other people don’t.”
|Year-round sailor: Hear Bear talk about his passion for sailing. Watch more video of Mark Bear on sailgroove.org|
He should know. On the water, in a boat inaptly named “Fat Bastard,” Bear has won the U.S. Masters National Championship and the New England Championship. In the lab, he’s challenged reigning dogmas in neuroscience.
Over a quarter century, Bear has tacked toward elusive problems in his field. His main obsession has been brain plasticity: the process by which neurons change in response to experience. Early on, he explored neural connections in the hippocampus, which plays a key role in long-term memory and spatial navigation. Controversially, he used these findings as a model for a very different part of the brain, the visual cortex.
More recently, Bear has applied his discoveries in brain plasticity to understanding fragile X syndrome, an inherited form of mental impairment. He has described surprising mechanisms underlying fragile X and has shepherded a promising treatment through phase 2 clinical trials testing for efficacy in patients. The course he has charted may yield the first neurobehavioral targeted pharmaceutical treatment that grew from the bottom up: from gene discovery to an understanding of pathophysiology to a targeted drug.
On November 22, 1963, the day President John F. Kennedy was assassinated, six-year-old Mark Bear was glued to the television. What transfixed him, even then, were the early conjectures from newscasters about what Kennedy’s life would be like if he survived the gunshots to his head and neck. “I remember being astounded: so much resides in the brain,” Bear says. The next Christmas, he asked his parents for a human brain modeling kit.
Now 53, Bear has the look of an ageless East Coast postdoc: neat but decidedly casual—khakis, crew neck sweater, hiking boots. He is tall and fine-featured, with a slightly receding hairline and an early morning hint of a five-o’clock shadow. His eyes often have an abstracted and amused expression, as if he’s formulating a joke.
Across the street from where he works on the MIT campus, dominating the view through his lab’s plate glass windows, is Frank Gehry’s Stata Center: big and boxy, with defiantly jangled angles. It’s an odd panorama. In his unassuming office, Bear—sometimes slouched, sometimes leaning forward to explain a fine point of science—is soft-spoken but plainly passionate about the mysteries of the brain.
In the decades since JFK’s death, neuroscience came of age, and Bear caught the wave. Researchers learned that the brain’s adaptive plasticity extends into adulthood. And this plasticity is centered in the synapse—the junction across which a nerve impulse passes from one neuron to another. At the synapses, axons—the long, slender projections of nerve cells that conduct electrical impulses to target cells—connect to dendrites, the short-branched extensions of nerve cells that ferry impulses toward the cell body. The terminus of the sending cell contains neurotransmitters, chemicals that diffuse across the gap and activate sites on the target cell, called receptors. Synaptic plasticity is the ability of the connection between two neurons to change in strength.
Figuring out the basis of this plasticity has been Bear’s mission from the start. To convey how he has gone about that quest, he switches metaphors from the sea to the casino. “Imagine nature as a deck of cards,” he says. “The first experiment you do should not be one where you peel off a card from the top. It should be the deck-splitting experiment. The most incisive experiment. The experiment that most narrows the range of possibilities and will define your subsequent course.”
Bear launched his career as a doctoral student at Brown University, followed by a postdoctoral fellowship with Wolf Singer at the Max Planck Institute for Brain Research, in Frankfurt, and a return to Brown with his own lab. His research spun off from a well-studied phenomenon known as long-term potentiation, or LTP. When a rapid train of strong nerve impulses hurtles down an axon, the synapses that connect the axon to the dendrites of other neurons are strengthened, or “potentiated.” LTP is one of the cellular processes underlying learning and memory.
What piqued Bear’s interest was the opposite process: synaptic weakening, a phenomenon known as long-term depression, or LTD. He was inspired by classic experiments performed in the early 1960s by Harvard University’s David Hubel and Torsten Wiesel that won them the 1981 Nobel Prize in Physiology or Medicine. They temporarily sealed one eye in infant kittens. When the eye was reopened weeks later, neurons in each animal’s visual cortex no longer responded to stimulation, while brain cells compensated by responding more strongly to inputs from the open eye. In effect, the kittens’ brains had rewired themselves under visual deprivation—enough to cause permanent blindness.
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The kitten experiment “was the most exciting demonstration of experience-dependent brain plasticity ever,” says Bear. “I wanted to understand the mechanisms at the synaptic level and ultimately at the molecular level.” He focused on a group of receptors known as metabotropic glutamate receptors, or mGluRs, which are especially active during periods of high plasticity.
But he took an unconventional route to the answer. He employed a formula in computational biology known as the BCM theory—for Bienenstock, Cooper, and Munro—a model of how synapses change and respond selectively to stimulation. This theory suggested that LTD is a consequence of synaptic activity that fails to strongly activate the target neuron. Using stimulating and recording electrodes, Bear and his graduate student Serena Dudek looked for LTD in the hippocampus, an easy site to study synaptic physiology. They eventually were able to reliably trigger LTD in hippocampal slices freshly prepared from mice and rats, with both electrical stimulation of synapses and with chemicals that stimulate glutamate receptors. Further experiments showed that LTD was widespread in slices from different brain regions—including the visual cortex.
Next, he temporarily deprived young kittens of sight in one eye in two different ways, either by anesthetizing the retina or by closing the eyelid, which allowed the retinal cells to continue firing nerve impulses randomly. A few days later, after the anesthesia wore off and the closed eyes were reopened, the scientists displayed visual patterns to each eye and measured brain activity.
What really separates great sailors from less great sailors is that they see things that other people don’t.
In animals whose eye had been closed temporarily, synapses had predictably weakened. But in animals whose retinas had been anesthetized—and therefore sent no signals to the brain—the cortex responded about equally to stimuli from both eyes. This suggested it wasn’t the absence of visual stimulation that caused blindness—“use it or lose it”—but a mismatch of activity between the signals the brain was getting from the open and closed eyes. Synaptic strength declined through the active process of LTD. Bear had illuminated the mechanisms of the famous Hubel and Wiesel experiments decades earlier.
“He was willing to stick his neck out,” says Richard Huganir, an HHMI investigator and neuroscientist at Johns Hopkins University, coauthor on several of Bear’s papers and a longtime friend. Bear had used discoveries about how LTD takes place in the hippocampus—where it wasn’t even clear what effects that plasticity had—and applied it to the visual cortex, where the end results were obvious: blindness. The conceptual leap drew flak from fellow scientists. As Bear drily recalls, “I can still remember someone saying, ‘The visual cortex is not a hippocampal slice with eyes.’”
Yet his findings were later replicated. Indeed, Bear’s lab is still working on the problem, publishing important papers in 2009 and 2010 that explore molecular mechanisms for perceptual learning and the mechanisms of visual cortex plasticity. “We half-joke about ‘the curing blindness experiment,’” he says. “We haven’t quite succeeded yet, but we’re going to, I hope.”
“He’s one of the few neuroscientists who pays any attention to theoretical arguments,” notes Leon Cooper, director of Brown University’s Institute for Brain and Neural Systems and Bear’s mentor at Brown. (Cooper—the “C” in the BCM theory—shared the 1972 Nobel Prize in Physics for studies on the theory of superconductivity.) “Mark developed a rather deep understanding of theories of synaptic modification and realized that they depended on assumptions about cell behavior that hadn’t been checked. He set out to check them—and in the process, discovered some remarkable new phenomena, including LTD.”
Cooper says this approach to discovery sets Bear apart from many scientists. “They say seeing is believing, but Mark had to believe in order to see.”
Fragile X syndrome is the most common inherited form of intellectual impairment and the most common known genetic cause of autism. Though its symptoms vary among individuals, they are profound and devastating: low IQ, seizures, autistic behavior, anxiety, attention deficit, and sometimes an abnormal physical appearance. It strikes 1 in 4,000 boys and 1 in 8,000 girls. There is no cure—only treatments for problems such as anxiety and impulsive behavior.
Fragile X is caused by a mutation in the FMR1 gene, discovered in 1991, which leads to loss of a protein, the fragile X mental retardation protein, or FMRP. Under a microscope, the defective X chromosome looks broken—fragile—where the FMR1 gene is disrupted and mutated. In 1994, researchers created an Fmr1 knockout mouse.
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At an HHMI science meeting in 2000, Bear unexpectedly crossed paths with fragile X. In a prepared lecture, he explained the link between protein synthesis and memory. When he returned to his seat, the stranger next to him leaned over, complimented him on the talk, and offered to send him some fragile X knockout mice, which lack the Fmr1 gene. The stranger was then-HHMI investigator Stephen Warren, the geneticist at Emory University who had discovered the mutation for fragile X.
Bear enthusiastically accepted. The conventional wisdom was that LTD’s synaptic weakening was a result of protein synthesis and that one of those LTD proteins was FMRP. That meant that Warren’s Fmr1 knockout mice would presumably show fewer signs of LTD. In Bear’s lab, postdoc Kimberly Huber, a gifted physiologist, performed experiments comparing hippocampal LTD in the knockouts with that in wild–type mice. The experiments were blinded—that is, she didn’t know at the outset which animals were the knockouts and which were wild type.
When the experiment was completed and the scientists finally genotyped the animals, Bear and Huber were dumbfounded. Contrary to expectations, it was the knockout mice that showed high levels of LTD, not the wild type. “I swear to God, I thought somebody had mixed up the code,” says Bear. They repeated the experiment: same incongruous result.
Being born with a developmental brain disorder may not be an irrevocable sentence.
“If you’re doing an experiment, and you’ve worked very hard at it, and you get a bizarre result, chances are 99 out of 100 that the bizarre result is just some kind of fluke,” explains Cooper. “But 1 time in 100 it’s not a fluke. That’s up to the taste, the discretion, the daring of the experimentalist. And Mark is a daring experimentalist.”
After pondering the results for several months, Bear came up with an explanation that turned the conventional wisdom on its head. Simply put, it states that mGluR5 drives protein synthesis to keep up with the demands of the cell. FMRP acts as a brake on protein translation. Without FMRP, mGluR5-triggered protein synthesis goes unchecked, eventually disrupting synaptic function.
In 2002, Bear presented the idea at a conference on fragile X at Cold Spring Harbor Laboratory. “I was the last speaker of the meeting. I laid out this idea. And there was a sort of stunned silence. I felt relieved that I hadn’t been laughed at.”
In 2004, based on this single experiment and an exhaustive literature search on the downstream effects of mGluR5, he published a paper in Trends in Neurosciences boldly titled “The mGluR theory of fragile X mental retardation.” It suggested that a vast array of fragile X symptoms—epilepsy, cognitive impairments, developmental delays, loss of motor coordination, anxiety, autistic behavior, habit formation, sensitivity to touch, even changes in gastrointestinal motility—could be accounted for by runaway effects of mGluR5. Fragile X, Bear wrote, was a disease of excess: excessive sensitivity to environmental change, excessive neural connectivity, excessive protein synthesis, excessive excitability, excessive body growth. Was it possible to undo this cellular chain of events?
Bear and his colleagues at MIT later performed a genetic rescue experiment in mice—“rescuing” normal behavior through DNA manipulation. They crossed mice that were heterozygous for the gene that encodes mGluR5 with Fmr1 knockout mice, which lacked the gene for FMRP that restrains protein synthesis. The offspring had only half of the normal mGluR5 receptors and so produced only half the normal amount of mGluR5 protein. Reducing mGluR5 compensated for the lack of FMRP and eliminated many of the symptoms of fragile X. It was as if the genetic manipulation had compensated for lack of a protein synthesis brake by taking the foot off the gas pedal.
In the genetically engineered mice, seven of eight fragile X phenotypes similar to those in humans were corrected or prevented. (The only phenotype not corrected was abnormally large testes.) The animals didn’t have exaggerated LTD, they didn’t suffer seizures when exposed to a loud noise, they didn’t gain abnormal weight, and their neurons didn’t show the abnormal dendrites seen in the Fmr1 knockout mice.
While the results are encouraging—suggesting global effects of a single medication—“the behavioral manifestations of fragile X are different in a mouse than in a human,” Bear says. “It is hard to know a priori which aspects will be helped and which will not.”
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The experiment did demonstrate that mGluR5 was a valid target for drug therapy. Other investigators have found that the interaction between FMRP and mGluRs is highly conserved in evolution, showing up in fruit flies and zebrafish in addition to mammals. This evolutionary conservation boosts confidence that pharmacologic approaches successful in animals may fare well in humans.
In 2005, Bear cofounded Seaside Therapeutics, Inc., a Cambridge, Massachusetts-based company dedicated to creating treatments to correct or improve the course of fragile X syndrome, autism, and other disorders of brain development. In July 2010, Seaside announced positive data from a randomized, placebo-controlled phase 2 study of pediatric patients with fragile X syndrome. Seaside used an experimental drug dubbed STX209, or arbaclofen, which inhibits glutamate signaling.
The trial showed that the drug reduced outbursts and tantrums and boosted sociability and communication. In September 2010, the company announced promising results from an “open label” phase 2 study of the drug in young patients with autism spectrum disorders, where the participants knew what drug they were receiving. These patients likewise were less irritable and less socially withdrawn.
The company has received federal regulatory approval to undertake larger trials of children with fragile X and autism. Meanwhile, another Seaside drug—STX107, which selectively blocks mGluR5—is in the pipeline. Other companies, including Novartis and Roche, are also working on glutamate inhibitors for fragile X.
Mark Bear makes an impact on his students.
How would a treatment that could ease the symptoms of fragile X change people’s lives? “It’s like asking: What would it be like to have the best dream you could ever have come true?” says Katie Clapp, parent of a 21-year-old son with the disease. Clapp cofounded the FRAXA Research Foundation, which is dedicated to finding treatments and a cure for fragile X syndrome and has funded some of Bear’s work.
But Bear cautions that there may be limits to the mGluR theory. Most neurodevelopmental disorders are not diagnosed until well after symptoms begin, suggesting that doctors may not be able to give drug treatments early enough to stave off the worst effects of the disease, such as severe cognitive impairments. As Bear conceded in a 2008 paper in Neuropsychopharmacology, “derailment in brain development might be difficult to reverse retrospectively.” Some drugs may also carry intolerable side effects. In early clinical trials of glutamate inhibitors, a small proportion of patients suffered adverse events such as upper respiratory infections, sedation, and headache.
Despite these cautions, the recent clinical trials represent a dramatic shift in thinking. Scientists had long assumed that genetically based developmental disorders of the brain were permanent. But Bear has shown that treating the functional deficits with small molecule therapies may alter one’s fate in life, even if the gene remains unchanged. “Being born with a developmental brain disorder,” he says, “may not be an irrevocable sentence.”
And fragile X may just be the start. “The big splitting-the-deck question now,” he says, “is whether other rare, single-gene causes of autism—such as Rett syndrome and tuberous sclerosis complex—share similar characteristics with fragile X syndrome.” Even autism without a known cause may respond to the treatment. If so, mGluR5 blockers (or, with some disorders, enhancers) could have wide applications. Returning to a familiar metaphor, Bear calls this new line of thinking—and of hope—“a sea change.”