Mini-brains used at MRC Laboratory of Molecular Biology to study development and disease
Can we really study the human brain in a dish?
Pioneering work using cerebral organoids - or ‘mini-brains’ - at the MRC Laboratory of Molecular Biology in Cambridge is enabling researchers to do just that.
And they have already discovered why human brains grow larger than those of other primates, shown how the Covid-19 virus is able to infect brain cells and are exploring the development of neurological diseases.
The initial creation of cerebral organoids – which feature 3D tissues grown from human stem cells - was serendipitous, but also a classic example of a scientific curiosity by Madeline Lancaster, who is now group leader in the LMB’s Cell Biology Division.
“I’d set out to grow neural stem cells on the surface of a Petri dish but within a day, I’d realised something had gone wrong,” she recalled. “The protein preparation I was using to coat the bottom of the dish was quite old, which meant that the cells were not sticking as they were meant to. Instead they formed these floating balls.
“A lot of people would probably have just thrown these balls of cells away, but I let them continue growing. Quite soon, I could see structures inside them that, as a neurobiologist, I recognised as certain features you would see in the brain.
“It was serendipitous in the sense that these beings just sort of appeared in the dish when I wasn’t expecting them. The timing was also very nice as the discovery happened early on in my post-doctoral fellowship, which meant that I was free to explore and let whatever observations I might make guide me.”
Madeline, who studied for her undergraduate degree and PhD in California, was working on her post-doctoral fellowship in Dr Juergen Knoblich’s lab at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna, Austria.
“Over the next several months to a year, I would repeat these experiments, adding different combinations of ‘food’ supplements to the cells, diligently recording the outcome in my lab book. Eventually I discovered that a particular protein gel called Matrigel provided enough support to allow the cells to self-organise into three-dimensional tissues,” she explained.
Organoids offer insight into the workings of an organ in a way that two-dimensional cell culture cannot. Across the Cambridge region, scientists are similarly using mini-lungs, mini-livers and mini-guts, grown from stem cells, to gain greater insight into their respective organs.
“Human stem-cell-derived neurons grown in 2D have provided valuable insights about the cells themselves, but neurons don’t exist in isolation and so there’s a limit to how much we can understand about the way the brain works from these studies. Brain organoids give us something that looks and behaves a lot more like the real thing,” said Madeline.
“They have allowed us to ask questions about why we are uniquely susceptible to neurological and mental health conditions like schizophrenia that don’t appear to affect animals. And a particular focus of my lab is what makes the human brain so special.”
Why, for example, are human brains so much larger than those of apes?
“Great apes’ brains are around three times smaller than ours – in fact my recent calculations showed they are closer in size to a mouse’s brain!” noted Madeline, who joined the LMB in 2015 and recently became a fellow of Clare Hall at the University of Cambridge.
“We grew organoids from the cells of humans and our closest living relatives: chimpanzees and gorillas. We found that there were differences very early on in development. The human stem cells were slower than our ape relatives to transition into a state that would allow neurons to grow. This very subtle variation at this key stage when cells are expanding exponentially has dramatic effects on the end-product.
“We also found that human organoids are double the size, compared with the chimpanzee and the gorilla. This matches very nicely with what you see in terms of brain size. Specifically, in the cerebral cortex, the number of neurons in the human brain is double that of the brains of great apes.”
Madeline also uses cerebral organoids to explore the development of neurological diseases unique to humans, such as microcephaly, a condition in which the brain is too small.
Deriving organoids from patient cells enables her group to examine mechanisms of pathogenesis.
And the group has investigated how the Covid-19 virus, SARS-CoV-2, is able to infect cells in our brain and produce new virus within choroid plexus (ChP) epithelial cells. This may cause long-term neurological impacts, such as chronic fatigue.
“I’m excited to see how organoids can help answer other research questions,” said Madeline. “For instance, we’re seeing more and more interest in using the tool to study the blood-brain barrier, epilepsy and neurodegeneration.”
The groundbreaking work recently earned Madeline a prestigious Vallee Scholarship.
She is one of six scientists awarded a grant this year by The Vallee Foundation, which aims to enhance international collaboration and communication among scientists.
‘I am truly honoured to be among this year’s awardees of this prestigious prize,” said Madeline. “It is fantastic for myself and my lab to be recognised in this way, and the award will make a big impact for our future research.”
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