A big brainstorm is on the horizon in neuroscience

The Globe and Mail

A brand new look: This image of neural pathways as captured by researchers bankrolled by the U.S. National Institutes of Health is part of an attempt to compile and comprehend an unparalleled amount of data about the human brain. (Human Connectome Project)

For much of its relatively short history, the science of the human brain has been a piecemeal affair: Neuroanatomists have charted the organ’s creases and folds down to the microscopic level. Behaviourists have devised a carnival of ingenious puzzles, mazes and perceptual challenges to test their bemused subjects. In another domain, therapists and clinicians have listened, observed and recommended treatments for patients labouring in the shadows of brain injury or mental illness.

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But these avenues into what makes us tick have always fallen short of answering deeper questions about the field’s mysterious core: How does the brain work? How does it develop in response to the world around it? How does it break down?

Experts say that getting at such questions requires an understanding well beyond treating the brain as the sum of its parts, its responses or its pathologies. Instead, they say, the brain must be considered it in its entirety: a vast and interconnected whole, the most complex system in the known universe.

Now, a remarkable confluence of tools and techniques is bringing the brain into focus as never before. Propelled by novel imaging technologies, massive computing power and the genetic revolution, several large-scale projects around the world promise to accelerate an already fast-changing field. At last, researchers are seeing their dream of comprehending the brain at its most fundamental level turn into a realizable goal.

“Almost everything we know about the brain we know from the last 10 or 15 years,” says David Kaplan, Canada Research Chair in cancer and neuroscience at the University of Toronto and the Hospital for Sick Children. “This is a time of exponential learning.”

But Dr. Kaplan, who also co-chairs a scientific advisory council for Montreal-based Brain Canada, which solicits and shepherds research funds, cautions that the unfolding revolution comes with a price tag. “Technology has really helped us,” he says. “Unfortunately, technology is expensive.”

To help Canadian researchers stay in the brain game in an era of budget austerity, Brain Canada wants to maximize a major opportunity announced by the federal government last May. If the organization can raise up to $100-million over the next six years, Ottawa will match the amount, dollar for dollar, to support innovative Canadian research.

In just eight months, private donors have put more than $22-million on the table, says Brain Canada president Inez Jabalpurwala. The first call for proposals drew 165 submissions, at least five of which will be selected this month by an international panel. In making the case for increased investment, she points to a sobering reality. “The collective impact of brain disease is greater than cancer and cardiovascular disease combined. It’s the single biggest health burden for this century.”

The scale of the effort, significant for Canada, is paralleled by a growing international trend toward bigger, more collaborative projects that approach the brain at a deeper, systemic level. The change reflects not only the new tools that make such an approach possible but a transition by many brain researchers into the domain of “big science.” Instead of an army of small teams working away in their selected specialties, the field is spawning big-picture projects reminiscent of the Human Genome Project or the space program.

A U.S. effort that invites this comparison is One Mind for Research, an organization founded by former congressman Patrick Kennedy, son of the late senator Edward Kennedy, and philanthropists Garen and Shari Staglin. Launched in May, 2011, on the 50th anniversary of president John F. Kennedy’s famous speech committing the U.S. to putting a man on the moon, it aims to channel billions in private and government funding toward research into brain disease and dysfunction over the next decade, fuelling a “moon shot to the mind.”

The basic science of the brain is also scaling up. In 2011, the U.S. National Institutes of Health committed $38.5-million over five years to the Human Connectome Project, which unites teams at several universities in seeking to map the entire spaghetti-like tangle of major neural connections that make up the healthy human brain. Instead of the older, coarser model of the brain as a pastiche of regions that light up when certain tasks are performed, the new panoramic view is closer to the brain’s true nature: a stunningly intricate set of interconnected neural networks.

A process known as diffusion scanning is what makes the mapping possible, says Arthur Toga, a neurologist at the University of California, Los Angeles, and one of the project’s leaders. “It allows us to mathematically derive bundles of fibres and how they course through the brain. That’s an important bit of information that can help us to understand how the brain is organized.”

Significantly, the project will produce maps not for one brain but for those of 1,200 healthy participants, some of them siblings, including twins. The strategy is designed to tease out how genes and life experience can act to make each human brain – and therefore each human being – unique.

“There is a fair amount of variability,” Dr. Toga says, in the way different brains are wired. “We have to understand the origins of that variability.” That, in turn, will help researchers make sense of what is going on in brains that are not working properly, and look for ways to effect repairs.

The fine-scale mapping of the Human Connectome Project will complement other emerging techniques that can reveal both the activation of brain cells under various circumstances and the underlying connections between them. The result gives researchers a better sense not only of how the brain looks as a giant circuit, but can expose which neural pathways are used and for what purpose – the property known as functional connectivity.

“Just because there’s a wire between two areas doesn’t mean it’s used,” says Tim Murphy at the Brain Research Centre, based in Vancouver. “By looking at functional connectivity, we’re reflecting the strength of connections.”

Researchers in Dr. Murphy’s lab are exploiting a powerful new way of mapping functional connectivity called “optogenetics.” It involves using the methods of genetic research to coax different classes of brain cells to make proteins that are sensitive to light. Then, they can be triggered simply by being exposed to a light source, giving scientists a direct way to see what role the cells play in different brain functions, from motor control to sleep.

Previously, “we were more or less spectators, with respect to brain activity,” Dr. Murphy says.

Researchers have also manipulated the DNA of brain cells to create fluorescing proteins that can glow, depending on the cells’ changing conditions, allowing researchers to observe the cells with high-powered microscopes. In the past, says Yves De Koninck, who specializes in the method at Laval University, neuroscientists were reduced to guesswork – cutting away bits of research animal brains to see what happens.

Now they can watch cells in action, which has “revolutionized our ability to probe the brain and understand how it works.”

The genetic revolution is pushing brain science forward in many avenues, exemplified by work at the Allen Brain Institute in Seattle, supported to the tune of $500-million by Microsoft co-founder Paul Allen. The institute has shouldered what Dr. Murphy calls the “grunt work” of developing a massive atlas of the mouse brain that can be linked to specific genetic mutations and serve as a crucial reference for work on neurological disorders in humans.

Of equal importance to researchers is the revolution in bioinformatics, which brings the power of 21st-century computing to the massive amounts of data needed to comprehend the inner workings of the brain. Looking still further, some neuroscientists continue to pursue the elusive goal of simulating the brain in its entirely as a computer program. The task is daunting, says Chris Eliasmith, director of the Centre for Theoretical Neuroscience at the University of Waterloo, in part because with 100 billion neurons capable of forming thousands of connections, the complexity of the brain dwarfs its would-be digital mimics. “The single biggest challenge is trying to reproduce the amount of communication that there is in the brain,” he says.

That has not held back Henry Markram at the Swiss Federal Institute of Technology in Lausanne from proposing the Human Brain Project, a massive effort to incorporate everything known about the brain in a massive computer simulation. Some experts question what it will show, but the project is shortlisted for as much as a billion euros from the European Commission over the next decade.

Even if Dr. Markram doesn’t succeed, the number and scale of brain-related projects now emerging suggests a turning point for the field, a sort of “Galileo moment” that could open the workings of the human mind as never before.

Funding here remains modest, but opportunities for Canadian researchers abound, Dr. Kaplan says, in part because what the field needs most is not just big money, but fresh thinking.

“What we’re best at in Canada is coming up with new ideas.”

With Brain Canada and others providing a push, he hopes that enough of those ideas will come to fruition to turn the brain’s inner space into a universe of discovery.

Follow on Twitter: @ivansemeniuk

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