Spring 2013 Magazine

The Brain

The Brain

Demystifying the body’s most complex organ


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Throughout the ages the brain has been a source of mystery—and often confusion—for scholars. Ancient Egyptians thought the heart, not the brain, was the source of wisdom, emotion, and the soul; while other organs were preserved during embalming rituals, the brain was discarded. Later, pre-Incans bored large holes in patients’ skulls, attempting to treat headaches, mental illness, and epilepsy. In the 19th century phrenologists claimed that measurements of the skull could determine character.

It wasn’t until the turn of the 20th century that researchers began to see the brain for what it is: a massive network of electrically excitable neurons connected through a web of treelike axons and dendrites that relay messages from cell to cell. The amount of information in that network is astounding; at 90,000 miles long, the brain’s nerve fibers could circle the perimeter of the continental United States nine times. At the gaps between neurons are synapses, structures that allow brain cells to send and receive the billions of electrical signals and chemical neurotransmitters that create our thoughts, memories, and movements.

For all that scientists have learned about the brain, there is far more they still don’t know. Eager to change that, McCormick researchers are using their problem-solving skills to decode the mysteries of an organ that in many ways far surpasses the most complex of computers. These efforts are timely, with the Obama administration eager to invest millions in a decade-long scientific effort to map the brain.

The rewards from better understanding the brain would be enormous: improving the lives of people with brain disorders, designing materials and electronics that draw upon the brain’s amazing properties, and even answering fundamental questions about who we are.

From fish brains, a better grasp of ours

With an estimated 100 billion neurons and 100 trillion synapses, it’s no wonder the human brain remains a mystery; its complexity is, simply, overwhelming. Many brain researchers therefore opt to study the brains of animals that have fewer neurons and are more experimentally accessible.

Malcolm MacIverMost of these researchers focus on rodents or primates, but Malcolm MacIver argues that a lowly fish—measuring just four millimeters in length and with one one-millionth the number of neurons that a human has—can teach us volumes about our own minds. It’s not such a stretch, says the associate professor of biomedical engineering and mechanical engineering. “We learned nearly 100 years ago that fruit flies can teach us a lot about genetics. There has been a similar realization about fish in brain research,” says MacIver. “Even though our last common ancestor with fish lived 420 million years ago, our current brain is basically a fish brain with some bells and whistles added.”

MacIver’s species of choice is the larval zebrafish, a fish native to the streams of the Himalayas. What the fish lacks in size it makes up for with a wealth of other characteristics. It is a “model organism,” a widely researched animal whose genome has been completely mapped by scientists. Using video games he designed for the four-millimeter-long zebrafish, Malcolm MacIver simulates prey and measures the fish’s brain response.The fish’s simplicity also allows researchers to more easily and quickly breed fish with genetic modifications. One genetically modified zebrafish has neurons that emit light when they are activated, which are easily seen through the fish’s transparent body.

MacIver is most interested in goal-dependent behaviors—complicated activities, like stalking and capturing prey, that require a sequence of behaviors to achieve a result. “These behaviors are under intense evolutionary pressure. If you don’t get [them] right as a species, you die,” MacIver says. “They are among the most refined and carefully coordinated behaviors that an animal like the larval zebrafish can perform.” For the past year MacIver has worked with collaborator David McLean from the Department of Neurobiology at Northwestern’s Weinberg College of Arts and Sciences to quantify exactly how the fish’s body moves as it hunts paramecia, its 200-micron (0.2-millimeter)-long, single-celled prey.

MacIver and his collaborators have shown that larval zebrafish move their eyes to maximize binocular overlap shortly after detecting their prey. Following detection (left), a combination of body and eye movements results in prey being clustered in a small “capture zone” before the fish initiates a final attack movement (right). These observations form the basis for work now under way on how the brain transforms sensory information into goal-directed movement, a fundamental question in neuroscience.The next step is to understand the brain circuitry that supports this complex behavior. The brain commands come from the optic tectum, a part of the fish’s midbrain that takes in sensory data and generates motor output. (The same structure exists in the human brain, where it is called the superior colliculus.) The researchers will record directly from neurons in the optic tectum to analyze the exact sequence of neuronal firings that occur when the fish spots its prey, initiates motion toward it, and eventually engulfs it.

Getting these data isn’t easy; researchers must use tiny glass pipettes precisely inserted into a single neuron approximately 5 microns (.005 millimeters) in diameter. It is impossible to access those neurons when the fish is swimming, so MacIver and McLean have developed a plan to elicit a natural response from an immobilized fish: fish video games.

While temporarily contained in a jellylike substance, the fish will be shown tiny, true-to-life virtual images of paramecia approaching on a one-inch-wide display screen. “These screens have as many pixels as my computer, so we can display the paramecia at their actual size,” MacIver says. “We’re pretty sure, based on a variety of evidence, that we can get these fish to think they are hunting prey.”

MacIver hopes that the experiments, which he plans to start running this spring, will provide a clearer understanding of how the brain takes in sensory data and translates them into behavior. “With this organism, we and other researchers may obtain the first mechanistic understanding of a complex goal-directed behavior for any animal, from sensory input to motor output,” MacIver says.

Building highways in the brain

Samuel StuppIf you’ve ever wondered how mice sniff out crumbs in the dark, consider this: nature has gifted the rodents with a constantly regenerating sense of smell. Inside mice’s brains, not far from their noses, sits a structure filled with neural stem cells, a type of cell that is able to morph into any type of brain cell. Each day, hundreds of these shape-shifters migrate through a mouse’s brain to its olfactory bulb, where they transform into specialized brain cells called olfactory neurons.

Humans have a store of neural stem cells, too. Researchers aren’t exactly sure what they do, but Samuel I. Stupp is sure of their incredible potential.

A noodle-like construct developed by Samuel Stupp contains millions of nanofibers that may be able to guide the growth of healthy cells in the brain.“These neural stem cells can do anything. They could repopulate the site of a brain injury with healthy neurons. They could regenerate damaged cells at the site of a stroke. They could become specialized, dopamine-generating brain cells to help treat Parkinson’s disease. All we need is a method to transport them from their current location in the human brain, where they may not do much, to places where they can be useful,” says Stupp, Board of Trustees Professor of Materials Science, Chemistry, and Medicine and director of Northwestern’s Institute for BioNanotechnology in Medicine and the Simpson and Querrey Center for Regenerative Nanomedicine.

Transporting neural stem cells is not as easy as inserting a needle and physically moving them to another part of the brain. Stem cells rarely take root in new homes without a support system. So Stupp has called on his expertise in self-assembly, a process by which molecules arrange themselves in a useful structure without any outside help, to try to solve the problem.

A liquid crystal made of bundles of the nanofibers and water forms a gel when it is squeezed out of a syringe into salty water or living tissues.Stupp’s research hinges on his discovery a decade ago that certain molecules can self-assemble into nanofibers in water and mimic those found naturally outside of cells in the human body, in the so-called extracellular matrix of all tissues. The tiny nanofibers—less than 10 nanometers in diameter, tens of thousands of times thinner than a human hair—are able to provide a scaffold that can signal cells for many purposes, or simply help them survive and proliferate.

Stupp has found that these nanofibers have amazing properties. In 2008 Stupp and John Kessler, Ken and Ruth Davee Professor of Stem Cell Biology in the Feinberg School of Medicine, discovered that injecting the nanofibers into mice could partly reverse paralysis from spinal cord injury in just six weeks. (How the nanofibers accomplish this feat is not completely understood, but Kessler and Stupp suspect they suppress or remove scarring on nerve fibers at the site of a spinal cord injury, allowing regeneration of nerve fibers and thus movement to return.)

The process may open doors to a variety of treatment options for injuries and neurodegenerative diseases.More recently Stupp discovered how to create a liquid crystal made of bundles of the nanofibers and water that forms a gel when it is squeezed out of a syringe into salty water or living tissues. “The construct looks like a transparent cooked noodle,” Stupp says.

Inside the “noodles” millions of nanofibers self-align, forming a lattice that can guide the direction in which axons grow or the direction in which cells migrate. Stupp partnered with neuroscientist Georg Khun in Gothenburg, Sweden, to use the aligned scaffold to guide neural stem cells.

“We thought that if we could form this noodle in the brain, starting from the place where the neural stem cells are present and ending in the location where we would like them to be, it would be like creating a highway in the brain,” Stupp says. “The neural stem cells could travel on that highway to precisely where they are needed. Then you have lots of possibilities.”

The research results are promising so far. Stupp and graduate student Eric Berns have worked jointly with Khun to create the noodle in the brains of mice, originating at the location of neural stem cells near the olfactory bulb. The experiment demonstrated that the neural stem cells do, in fact, migrate into the noodle structure.

If perfected, the process may open doors to a variety of treatment options for injuries and neurodegenerative diseases. “The dream would be to introduce these procedures in noninvasive ways and use nanomedicines to direct the stem cells and also to promote their differentiation into the right neurons in the correct part of the brain,” Stupp says.

Link between learning and depression leads to a new drug

Joseph MoskalDepression affects an estimated 19 million Americans, and for many of them treatment is a bumpy road. Today’s antidepressants can be addictive, cause unpleasant side effects, or take weeks to be effective—if they work at all; only half of patients with depression respond to any given drug.

For the past two decades Joseph Moskal, research professor of biomedical engineering at McCormick and director of Northwestern’s Falk Center for Molecular Therapeutics, has been working to translate basic research on the mechanisms of learning and memory into therapeutics for the treatment of neuropsychiatric disorders. His work has recently led to the development of a program for the treatment of major depressive disorder. His goal is a drug that can be effective within hours and remain effective for weeks—with no toxic side effects.

Learning and memory—processes largely regulated by the hippocampus—appear to have an important connection to depression, Joseph Moskal has learned.Moskal’s research stems from his interest in synaptic plasticity, the quality of the connection at the synapses between neurons. In the past several decades, researchers have learned that the strength of synapses changes over time through use or disuse, a process that is now believed to be central to learning and memory. Moskal found that these functions also have an impact on mental health. “It turns out that learning and memory are quite strongly linked to depression,” he says.

Moskal began exploring this avenue by developing monoclonal antibodies that modulate learning and memory processes in animal models. He later was able to convert one of these antibodies into GLYX-13, a small molecule that mimics the antibody and could be further developed for therapeutic use. GLYX-13 works by targeting NMDA (N-methyl-Daspartate) receptors on neurons’ surface. These receptors help control synaptic plasticity, the neurochemical foundation of learning and memory—and perhaps depression, too.

In clinical trials at 12 sites across the country, a single intravenous dose of GLYX-13 was found to reduce depressive symptoms in subjects for whom other antidepressants had failed. Its side effects were negligible and its results nearly immediate. After a single dose the drug’s “effect size,” a measure of the magnitude of its antidepressant effcacy, was nearly double that seen with most other antidepressants that typically require two to four weeks to show their effects. GLYX-13’s results lasted an average of seven days.

Joseph MoskalNow that GLYX-13 has been shown to be efficacious, a second round of clinical trials is under way to find the optimum dose and dosing interval. These studies will be finished by year’s end, and Moskal hopes GLYX-13 will be on the market within four years; as the founder and chief scientific officer of Naurex Inc., the Evanston-based biotechnology company that conducted the clinical study, Moskal and his business development team recently secured $38 million in funding. He is also exploring GLYX-13’s effect on schizophrenia, Alzheimer’s disease, stroke, bipolar disorder, and even cognitive failure due to normal aging.

“While the results we are seeing with GLYX-13 are very encouraging, I believe the most important research is yet to come,” Moskal says. “We have only scratched the surface of its therapeutic potential.”

Keeping watch on brain aneurysms

While many of them don’t know it, about five percent of Americans are living with a brain aneurysm, an abnormal bulge that develops when the wall of a brain artery is weakened. The majority of these people will go through their lives without experiencing any ill effects, but about 30,000 will experience a rupture this year, and the results can be catastrophic.

Ruptured brain aneurysms are fatal in about one-half of cases, and two-thirds of the survivors suffer permanent neurological damage. “When a brain aneurysm ruptures, you have a 50–50 chance of being alive in 24 hours,” says Timothy Carroll, associate professor of biomedical engineering at McCormick and of radiology at the Feinberg School of Medicine. “It’s a huge, huge problem.”

Timothy CarrollTreatments do exist, but they are risky. The long-standing approach has been to “clip” the ballooning arterial wall, a process that entails cutting through the skull to locate the site of the bleeding and clamping it. A newer option is “coiling”— threading a thin catheter from the patient’s groin through the neck and into the brain so that wire coils can be inserted inside the aneurysm, causing blood to clot and sealing of the blood supply.

Early detection can make the difference between life and death, but even when detected, which aneurysms are likely to rupture? One of the most disconcerting aspects of an aneurysm diagnosis is uncertainty. “A patient may have a brain scan performed for some other reason and learn he has a ballooning artery in his brain,” Carroll says. “It may never rupture, or it may rupture tomorrow. Our goal is to develop a way to determine which aneurysms are stable and which need to be closely watched.”

Through a process he developed that measures the slow leakage of an MRI-based contrast agent or “dye,” Carroll can determine the thickness of the aneurysm wall and the severity of the problem; the thicker the wall, the less likely the aneurysm is to burst. He injects a contrast agent into the subject’s arm and collects MRI images as the colored substance makes its way out of the brain artery and into the fluid surrounding the brain. “It turns out that the contrast agent can leak out of the wall of the aneurysm. Some leak very quickly, some more slowly,” Carroll says. “We are trying to determine if the ones that leak more quickly tend to indicate more dangerous cases.”

Awareness of the severity of a brain aneurysm will allow many patients to worry less, and others with serious cases can take precautions to prevent a rupture. Instead of surgery, Carroll foresees a future in which physicians may recommend managing high blood pressure and quitting smoking to mitigate the risk with an aneurysm that has proven to be stable. “My goal,” Carroll says, “is to provide information so patients and physicians can determine the best course of action to mitigate the risk of having an aneurysm.”

Filling in the blanks

The field of neuroscience has advanced more in the past two decades than in perhaps any other period in history. Thanks to both improved experimental techniques and computing capabilities, experimental researchers are able to study the brain as never before. The deluge of data they have acquired begs for computational models to help bring it all together.

William KathFor the past 14 years, applied mathematician William Kath has partnered with experimental researchers, using their lab data to create computational models of brain activity. “Experimental researchers can do so much today. They can record the activity of individual neurons and groups of neurons, and they can collect that data much more rapidly,” says Kath, professor of engineering sciences and applied mathematics at McCormick and professor of neurobiology at Weinberg. “The question then becomes, what does all this data tell us about the neural system as a whole?”

Kath is currently working with Nelson Spruston, a former Northwestern faculty member and now a scientific program director at Howard Hughes Medical Institute Janelia Farm Research Campus in Virginia, to understand the hippocampus, an area of the brain responsible for learning and memory. They are modeling how synapses work—the conditions under which they are activated, what resulting voltage changes are produced inside the neuron, and the level of voltage change that triggers a signal to its output targets.

“These neurons are, in essence, making decisions at the local level—processing inputs and deciding whether the inputs are significant enough to pass on the combined signal to all the neurons they connect to downstream,” Kath says. “One of today’s basic tasks of neuroscience is trying to figure out how this large, connected network of neurons processes information.”

William Kath creates computational models to understand how brain cells work together. One model describes the activity of dendrites, tiny structures that protrude from neurons.These models help Kath make educated guesses about what’s happening in selected parts of the brain. (Modeling the entire human brain in its full detail is far beyond the capabilities of today’s computers, given the brain’s vast number of synapses and multiple types of neurons and neurotransmitters.) The models—which integrate information gathered from a range of experimental tests—can also provide an alternative to physical experiments, particularly when the live options are too expensive or time consuming.

Because experimentalists are constantly improving their techniques, Kath frequently updates his models with new data. For instance, research partners at Stanford University have developed an imaging process called array tomography, which provides extremely precise pictures of cellular anatomy, and Kath is now refining his models with new details about the type and placement of synapses.

Researchers are still far from seeing the “big picture” of the brain. “Our experimental techniques are still so limited,” Kath says. “It’s like trying to put a huge rainbow jigsaw puzzle together. At first all you can see are the blue pieces. Then a new experimental technique comes along and you can see green pieces. Eventually we will be able to see the whole puzzle. But that is a long way off.”

By: Sarah Ostman