The unknown is unusually appealing to neuroscientist Cathryn Ugalde. Undertaking research at La Trobe’s Hill Laboratory, she had no idea whether she’d reach the goals she’d set. But for Cathryn, the challenge of working at the sharp edge of science, where much is undiscovered, is what she loves most about the field.
“The central nervous system is very complex. You start your project and you don’t know if it’s going to work. I like trying to piece it together, to explore what we think is happening. It’s important to see if something that’s known is still the same in a different context.”
In Cathryn’s case, that different context is ground-breaking.
Brain slices that behave as if they were still alive
Cathryn is using organotypic brain slices to model how nerve cells die during prion diseases, a group of rare and fatal neurodegenerative conditions. Prion diseases are caused by mis-folded proteins (‘prions’) that damage the brain structure and exponentially kill-off healthy nerve cells. They include mad cow disease in cattle and Creutzfeldt-Jakob disease in humans.
Organotypic brain slice cultures are a revolutionary way to model prion diseases, because the brain slices behave as if they are still part of a living organ.
“I expose these brain slices to prions. And I can watch how these brain slices develop disease,” Cathryn says.
Cathryn’s approach has advantages over other ways to study prion diseases, such as using cultured cells. Because cultured cells are grown outside of their living environment, they behave less like they would in a living organ. Crucially, they don’t develop neuronal loss. This means it’s not possible to use them to understand how prions cause brain cells to die.
“A cultured cell system can help us look at the mis-folding of the proteins and its ability to be infectious, but it’s not very good at telling us how the brain cells die. This is very important for therapeutic interventions because the main agent to target is the neurotoxic compound. We need to know what that is.”
Brain slices have other benefits, too. They allow scientists to hand-pick a neuron-rich region of the brain, which increases the odds of seeing any kind of significant difference. The slivers of ‘brain in a dish’ Cathryn uses are sections of a mouse’s cerebellum, an area that holds over 60 per cent of brain neurons in mice. Plus, being able to use the same tissue from the same animal provides an internal control, which in turn improves research validity.
Protecting brain cells: a step towards treating prion disease
There’s currently no effective treatment or cure for prion disease. But by using organotypic brain cultures, Cathryn was able to experiment with the way diseased nerve cells die. She introduced a potentially therapeutic compound and found that it protected brain slices from neurotoxicity.
“I found that I can change the way the protein mis-folds in my brain slices, to protect them from developing neuronal toxicity. It’s a compound that people think is therapeutic, but there’s not a lot of work out there on it. So now I’m trying to pull apart the mechanisms of its action,” she says.
Understanding how this mis-folding protein causes nerve cells to die is key to delaying the development of prion disease.
“It might not necessarily cure the disease, but it might slow down the progression – and that’s very important. If you can even just slow it, you can have some pretty substantial impacts,” Cathryn says.
“It’s exciting to be involved in something that’s really relevant and can make a difference.”
Cathryn’s research has moved neuroscience closer to slowing down the progression of prion disease in humans. It’s also given her a bigger picture view of the skills scientists need to succeed.
“In my field, a lot of the decisions came along the way. Science isn’t a linear thing. You have to be adaptable and respond quickly to what your results are telling you and what the literature is telling you,” she says.
“Working on the central nervous system, you need to be open to any kind of interpretation of the data. There’s so much we don’t know about it and you have to respect that. You need to see where your science takes you.”
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