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LITTLE GREY CELLS

It might be a weird pinky-grey and look uncannily like a walnut, but the human brain can do amazing things. So just how does it do it?

Words Victoria James Images Michael Kirkham

Neuroscience is a subject in thrall to the fundamental gap in its knowledge. “I do this, because understanding how the brain works is a formidable challenge,” says Professor Tom Mrsic-Flogel. “How an animal sees myriad pieces of information at any one time and how it selects that information to make a decision – is one of the most fascinating questions of our time.”

Professor Michael Hausser says that the operation of the brain’s intricate circuitry is “one of the mysteries of the universe”. And Professor Matteo Carandini sounds positively excited about the sheer unknowability of the brain. “There is not a single behaviour – apart from the knee-jerk reflex – that we truly understand in terms of neuronal activity,” he points out. “We should be able to say, ‘When you do this task, first these neurons fire in this way, then these other neurons fire in this other way, then this happens, then that happens’, and so on. We are not there yet.”

They are far from the first to be captivated. The riddle of how the brain works has gripped scientists and scholars for millennia. Philosopher John Locke – who was also a physician – proposed in his 1690 Essay Concerning Human Understanding that “sense, perception, and knowledge must be a property eternally inseparable from matter and every particle of it”. And yet a quarter of a century later, at the dawn of the Enlightenment, philosopher Gottfried Leibniz countered that “perception, and that which depends on it, are inexplicable by mechanical causes”.

These questions have generated some of the knottiest conundrums of human existence: the ‘mind-body problem’ – working out whether mind and matter are separate or unified – and the infamous ‘hard problem’ of how and why we experience phenomena and sensation. Or, to put it more starkly, just how does a physical mass of blood and tissue generate rocket science, algebra, imagination, a sense of self and a sense of purpose?

In grappling with these questions, however, today’s neuroscientists have at their disposal tools unimaginable to those who came before. (Although that was not for want of trying: Leibniz, for one, fancifully conjured a brain machine, so large that ‘one might go into it as into a mill’ and examine ‘parts which work one upon another’.)

Alongside those new tools, research teams at UCL are also members of the International Brain Laboratory. Funded by the Wellcome Trust and the Simons Foundation, it’s the neuroscience equivalent of CERN, the particle physics collaboration that has accelerated our understanding of the universe. And it’s making a difference. “There’s been incredible progress in the past few decades,” says Hausser, whose research focuses on the cerebellum and neocortex. “We know a great deal about the molecules in the brain cells and how they work. We have a pretty good idea of how the synapses that connect up work.

“On the other end of the scale we now know a lot about human behaviour, psychology, and how large areas of the brain are activated when performing certain tasks. The International Brain Lab research is targeting the giant gap in our knowledge, to link the cellular level and the behavioural by understanding neural circuits.”

What does that gap look like in human terms? Take the moment you decide to do something, like make a cup of coffee. Where does that ‘decision’ start, at a cellular level? What is the instant in which a decision takes place? Neuroscientists are attempting to eavesdrop on this moment with the help of brain probes and staggering computational power.

“We want to understand behaviour at the level just below the level of behaviour – algorithms embedded in neural activity,” says Mrsic-Flogel, who studies neural circuit organisation by evaluating how the brain processes visual information. “We map the detailed connectivity of neural networks to understand how this enables computations relevant for perception and behaviour.”

If you’re thinking that sounds straightforward – think again. Neuroscience has recently discovered that brains work rather differently from the way we previously supposed.

“Textbooks describe the brain as divided into systems: some regions do vision, others do movement, others process rewards, and so on,” says Carandini, who, with colleague Professor Kenneth Harris, explores how the brain processes sensory signals, and integrates them with internal signals to guide decision and action. “We recorded from tens of thousands of neurons in the brains of mice that performed a simple task based on vision and we discovered that some aspects of that textbook view are incorrect. For instance, signals related to body movement are not just in some regions, they seem to be spread all over the brain.”

In other words, looking at one area of the brain – as neuroscientists historically have done – will yield a decidedly incomplete picture. Clearly, big questions need big, joined-up efforts to find answers. And for researchers at UCL, that has meant taking a completely new approach: a large-scale international collaboration. But while it sounds simple, in fact it is something that has never before been attempted in the life sciences, partly for logistical reasons, and partly because of a research culture that privileges individual breakthroughs rather than collective working.

“A small group of us became frustrated with the slow progress in systems neuroscience, even though it’s pretty much at the limits of what’s possible,” explains Hausser. “We wanted to move things more quickly, more efficiently.” And so the International Brain Laboratory (IBL) was born. Launched a year ago, it unites 21 research groups worldwide, all following an agreed research protocol that should ensure findings are both sharable and reproducible.

So, while mice around the globe are looking at screens and deciding about the stimulus that they see, probes are recording their neural activity from multiple brain areas, and that data is being streamed directly to each individual lab’s computers, and from there uploaded to a shared database.

“Individual labs don’t have the resources to record from large brain areas at the same time,” says Hausser. “The only way we can do it is by pooling resources, sharing data, sharing equipment. And the only way that can work is for us to use the same experimental strategy, design and equipment, and share the results. Working independently is a huge missed opportunity. It’s much more efficient, and also more fun, to solve problems together.”

The International Brain Lab’s collaborators enjoy weekly ‘fireside chats’ via video conferencing. “Scientists are very independent and don’t like being being told what to do,” says Mrsic-Flogel, wryly. “But [the IBL research] is done by agreement and consent, not by hierarchy. If even one person disagrees, that is taken seriously. It’s an interesting socio-organisational experiment to be part of.”

And it’s certainly proving productive. Each lab is generating terabytes of data every day. “To be honest, it’s an overwhelming flood of data,” says Hausser. “And we need new theories to make sense of it.”

Which is where another IBL strength comes into play, for the participants are split between applied and theoretical scientists. The integrated collaboration of theorists and experimentalists is a hallmark of the physics research conducted at CERN, but it’s hitherto been elusive in neuroscience.

Could the IBL’s innovative approach be enough finally to unravel the mysteries of the brain? And might its insights yield new approaches to some of our time’s most urgent medical concerns, including Alzheimer’s disease and autism? The UCL collaborators are cautious, but hopeful.

Without the complete ‘brain map’ that the collaboration is working towards, “we have little hope of understanding complex brain function, let alone complex diseases such as schizophrenia,” says Carandini. But that map, once completed, might just be a game-changer.

“Once we’ve achieved this, we can use it to understand what’s going on in diseases of the brain,” agrees Hausser. “Degenerative diseases, like Alzheimer’s and Parkinson’s disease, involve disturbances in networks of neurons in the brain that have serious consequences for processing and decision-making. Once we understand the fundamental principles of how decisions are made, we can use that to tackle the even bigger problem of disease.”

And why stop at human brains? Insights from figuring out how our minds work could be used to help computers think better, too. “There’s lots of conversation between artificial intelligence and machine-learning specialists, and neuroscientists,” says Mrsic-Flogel. “AI researchers could use some of the insights that we come up with to construct better [computer] networks.”

With international collaboration scaling up the cutting-edge research of UCL’s neuroscience labs, those age-old questions of how the brain works may – finally – be about to be answered. And solutions to a very modern set of challenges could follow.

Find out more about the International Brain Laboratory’s collaborative efforts to ‘understand brainwide circuits for complex behaviour’ via their website here.

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Portico Issue 5. 2018/19
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