Scientists have traditionally relied on rodents when developing treatments for human brain diseases – but that’s starting to change thanks to revolutionary new techniques that enable experts to glean unprecedented information from fragments of living human brain.
That’s according to Ed Lein, who is ushering in a new era of brain research using live bits of brain, with the patient’s permission, that have been cut away in biopsies or to get to the problem area for an operation.
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Many of these samples remain viable for tests for three days, while some tiny slices can continue to function for a month or more if properly handled.
Dr Lein is leading a drive to create the first detailed atlas of the brain to increase understanding of how this mysterious organ works and, in turn, the prospect of treating disorders from Alzheimer’s and autism to epilepsy, schizophrenia and Parkinson’s.
Mice and humans
And while it’s early days, initial findings suggest that differences between the brains of mice – which have informed many treatments for human disorders – are more different from humans than had previously been supposed, potentially helping to explain why effective drugs, based on rodent studies, have largely proved elusive.
Work into the Cerebral cortex – the wrinkly outermost layer of brain responsible for processing different types of sensory information – suggests it is certainly different enough to be treating brain studies on mice with a degree of caution when applying them to humans, Dr Lein said at the American Association for the Advancement of Science meeting in Seattle.
“A lot of the [science] community focuses on rodents. But there’s only so much one can do – without knowing how good a model it is. It’s a preposterous place to be,” said Dr Lein, of the Allen Institute for Brain Science in Seattle. The institute was set up by the late Microsoft co-founder Paul Allen with a $500 million grant – his single biggest philanthropic project.
“We can see really significant differences between the organisation of the human cortex and the mouse. How profound this difference is will remain to be tested. What’s clear is we have to be cautious about using model organisms,” he said.
“With living tissue, we get to ask questions about the dynamic properties of cells. In dead tissue cells no longer have an active membrane. We can’t ask, ‘How does the cell respond when stimulated?’ We want to understand functional properties of cells,” he said.
Don’t mention Frankenstein
Asked if keeping a brain alive in a ‘jar’ makes him he feel a bit like Mr Frankenstein, the fictional Swiss scientist in Mary Shelley’s novel, Dr Lein says: “That piece of brain was participating in that person’s thoughts not long before.
“That makes this work a lot more meaningful. We are studying an intimate piece of personality at some level. On the other hand, that piece of tissue isn’t conscious on its own.”
Scientists have been using live parts of human brains for research on and off for around two decades. However, in the past two years or so these studies have become far more frequent and effective, as people increasingly volunteer to give up brain tissue and new techniques allow for much better analysis of it.
How the process works
- Surgeon snips away tissue from brain in biopsy or other operation and instead of burning it as medical waste the surgeon alerts researchers at the Allen Institute for Brain Science in Seattle.
- The brain sample is delivered in a beaker from the operating theatre to a research assistant waiting outside with a wheeled cart and small cooler.
- The beaker is hooked to an oxygen tank, put in the cooler and taken to the back of a van.
- On arrival at the lab, scientists descend on the chunk and separate it into smaller pieces.
- These are sliced into paper-thin slivers the size of fish scales using an instrument called a vibratome.
- During the process the tissues are kept alive with constant oxygenation and perfusion with a mix of nutrients and chemicals.
- The researchers begin examining the tissue using the latest remote-controlled electrode, 3D imaging and virus engineering techniques.
- The information is fed into the institute’s free online brain ‘observatory’ for other researchers to access and work on.
The new techniques
These include the development of tiny remote-controlled glass electrodes that can focus on a small slice of the human brain. The researchers can zoom in on a single cell and guide the electrode until it just touches the membrane, delivering an electrical jolt and recording the cell’s response.
Other new techniques include improved 3D imaging involving dye highlights and advances in engineering harmless viruses that can spread various stimuli throughout the brain tissue.
The Allen Institute is assembling the world’s first ‘periodic table’ of neuron types and their properties in the human brain – of which there are expected to be at least a thousand.