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HOW TO BUILD A BRAIN

HOW TO BUILD A BRAIN

Studying the brain is challenging. You can’t chop bits off it. You can’t take it out and put it back in again. Luckily, brain scientists turn out to be a fairly ingenious lot.

Words Lucy Jolin
Photographs Lydia Whitmore
Styling Aliki Kirmitsi

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The human brain floats gently in its tub of formalin: pinkish-brown, shiny and elegantly whorled on the surface, like a magnified fingerprint pattern. PhD student Christina Murray tenderly lifts it out. Underneath floats a rubbery material, like a swimming cap, and a long rope ending in a mass of tiny threads. These are the dura, the brain’s protective covering, and the spinal cord. She points out the brain’s geography. “Here’s your temporal lobe and here’s your occipital lobe, the back of the brain, which is associated with vision,” she explains. “And here’s the frontal pole, where your personality lies.”

This brain, one of around 2,000 held at the Queen Square Brain Bank for Neurological Disorders (QSBB), once held not only the control centre of every aspect of being alive – walking, swallowing, learning – but also memories, likes, dislikes, dreams, hopes; in short, a human mind. It has around 86 billion brain cells that make more than several hundred trillion contacts. The mass of squidgy-looking tissue inside our skulls is more complex than any computer, or any network of computers, ever made. So how do you even begin to study it?

Lighting up the brain

It all starts, naturally, with what you want to find out about it. Dr Hugo Spiers studies spatial cognition – how our brains represent and think about space. If he wants to know more about our sense of time and space, and how warped and biased it can be, he can start with a simple tool: questions. “All I’d need to do is to ask my subject how long they think it will take for them to get to the ground floor from the fifth floor of the 25 Wakefield Road building, for example, and look at how much they under- or over-estimate,” he points out. “But, for me, there are more exciting tools.”

These tools – chiefly magnetic resonance imaging (MRI) – represent one of the biggest leaps forward, allowing researchers to track activity in a living person’s brain. Spiers asks subjects to watch virtual reality simulations of a city environment projected on to a screen within an MRI scanner, and work out how they would get to a certain place within that environment. The scanner takes images of the brain every two to four seconds. What you end up with, however, isn’t the ‘x bit of the brain lights up when you do y’ trope beloved of headline writers.

“It doesn’t light up, there’s no sound, but there’s a vast, complicated web of biology going on in there,” says Spiers. “Certain circuits of beautifully arranged cells are communicating with one another via electrical signals that transmit through the synapses, causing change in the circuits between those cells. So when a bit of the brain ‘lights up’, that means the dynamics of those circuits have changed.”

One limitation of MRI scans, however, is their reach. You can’t put 100,000 people in a scanner. But you can get them to play a computer game on their phones and harness the data, which is the thinking behind Sea Hero Quest, a citizen science project funded by Deutsche Telekom. Spiers is the scientific adviser on the project, which aims to find out how navigational ability changes over time by asking users to play a simple game that involves finding their way around an ocean to capture sea monsters. The resulting data will be analysed to try to build up an understanding of the age at which changes to our brain occur that affect navigational ability, and how we respond to those changes.

“The eventual goal is a universal test for Alzheimer’s – something that doesn’t currently exist,” he points out. “A lot of the current tests are designed for one language or culture, which hampers translation across countries and cultures.” The team was hoping for 100,000 downloads over a year and so far has received nearly a million downloads in a fortnight, generating 1,800 years’ worth of data. “It has been phenomenal, a much greater success than we had possibly hoped for,” says Spiers. The research team at UCL will make their first announcement of the results at a neuroscience meeting in San Diego in November this year.

So what about when you need to actually look at a brain? Familiar diagnostic techniques simply aren’t available to those who study the brain. Brains have limited capacity to repair themselves, unlike other tissues such as skin, muscle and liver, explains Professor Tom Warner, director of the Reta Lila Weston Institute and QSBB at the UCL Institute of Neurology. So a biopsy to study a particular brain disease isn’t usually possible.

In addition, cells taken directly from the living brain don’t like growing in culture dishes, making it hard to study them. Ultimately, the only way to be absolutely sure of a diagnosis such as Parkinson’s or Alzheimer’s disease is to study the brain after death using neuropathological techniques. That’s where the QSBB comes in.

When a patient who has agreed to donate their brain dies, the brain is removed as soon as possible. It’s then couriered to the brain bank, where it is cut in half. One half is snap-frozen (normally in liquid nitrogen to bring its temperature down rapidly) and the other preserved in formalin. From this, sections just seven micrometres in thickness (one micrometre is a thousandth of a millimetre are cut and placed on slides. Those slides are then stained and examined by a neuropathologist, and a definite diagnosis of a particular brain disorder can then be made.

Most of the donated brains are from those who had neurological conditions such as dementia (Alzheimer’s, frontotemporal dementia) or Parkinson’s. Many donors will have died of their condition, but others may have died earlier of a different condition, such as a heart attack, allowing scientists to look at the pathological changes at different stages of the diseases. The bank also holds control brains – often from the partners of patients, who want to help find answers to the condition that took their loved ones. These are critical for comparing normal with affected brains.

The slide may be a faint stain of a tissue slice, but the person it came from is still very much present to those who study it. Every brain is backed up by a full clinical history of its donor, which makes the samples even more valuable. “From those patients who generously joined the donor scheme during life, we have very detailed information about their symptoms and tests. We can see the whole history of what happened to them,” says Warner. “That means we can follow the course of their illness, which is absolutely critical in studying the different types of neurodegeneration and dementia.

“We can correlate what we find in the brain with what happened in life, and use this to understand the disease process and develop markers for clinical trials in the future.” With modern technology, study of postmortem brains is no longer limited to just looking down a microscope, either: DNA/RNA proteins and lipids can now be extracted from the samples, allowing researchers to study the key molecules which play a part in disorders such as Alzheimer’s in far more detail.

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Although we can study the brain at postmortem, it’s a bit like turning up at a crime scene when the criminal is gone. You’ve got to put it together from whatever is left

Dementia in a dish

And there is now a way of following how a neurodegenerative disease progresses – “dementia in a dish” as Dr Selina Wray, Senior Research Associate at the Department of Molecular Neuroscience, puts it. “Although we can study the brain at postmortem, it’s a bit like turning up at a crime scene when the criminal is gone,” she says. “You’re left with all the damage that’s been done but you can’t retrace the steps. You’ve got to put it together from whatever is left at the end. That’s not to say postmortem tissue isn’t valuable, but we need a way to understand in what order things go wrong. And we’ve really struggled with that, as we can’t access the brain easily during life.”

Her team uses techniques developed by Nobel Prize winners Shinya Yamanaka and John Gurdon, who discovered that the body’s mature stem cells can be ‘reprogrammed’ and turn into cells that make up any of the body’s tissues – including brain cells.

They take skin biopsies from patients who have genetic changes known to cause Alzheimer’s disease, turn those skin cells back into stem cells, and then turn them into brain cells. “We can then use them as a discovery tool,” says Wray. “What we’ve got in our culture dish are really young brain cells, so we can study them to see the progress of the diseases. We’re trying to follow the disease in real time so, eventually, we can use this model for drug screening.”

It makes sense, when seeking to understand this most brilliantly complex of organs, that there’s no single best way to study the brain – but gradually, it’s being coaxed to give up its secrets. “There is such a wide range of techniques and they all have their advantages and disadvantages,” says Wray. “We need to use all of them and piece that information together like a jigsaw. Thanks to them, the brain is now more accessible than ever before – and that’s very exciting.”

You can help UCL discover more about the human brain by texting UCDR16 £5 to 70070 to donate to UCL Dementia Research. Or play Sea Hero Quest, available globally for iOS and Android devices. Download for free from the App Store and Google Play, or visit: www.seaheroquest.com

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  • InboxInbox
  • Two new grand challengesTwo new grand challenges
  • Free RadicalFree Radical
  • UCL a “global university”UCL a “global university”
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  • The Strong RoomThe Strong Room
  • CloisteredCloistered
  • Follow the CrowdFollow the Crowd
  • A Time to GiveA Time to Give
  • How to Build a BrainHow to Build a Brain
  • Next MachinaNext Machina
  • Social AnimalsSocial Animals
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  • The power of philanthropyThe power of philanthropy
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  • London  vs  WorldLondon vs World
Portico Issue 3. 2016/17
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