Tag Archives: Victorian Life Sciences Computation Initiative

Supercomputer study unlocks secrets of brain

In the seven-year study just released, RMIT University researchers – led by Professor Toby Allen and including Dr Bogdan Lev and Dr Brett Cromer – modelled how protein “switches” are activated by binding molecules to generate electrical signals in the brain. 

The findings, which involved hundreds of millions of computer processing hours, pave the way for understanding how brain activity can be controlled by existing and new drugs, including anaesthetics.

General anaesthetics work by blocking “on” switches and enhancing “off” switches in the brain, leading to loss of sensation and the ability to feel pain. 

“Even though anaesthetics have been used for more than 150 years, scientists still don’t know how they work at the molecular level,” says Allen.

“General anaesthetics are a mainstay of modern medicine, but have a small safety margin, requiring skilled anaesthetists for their safe use. They may also have long-term effects on brain function in both newborns and the elderly.

“Our study has uncovered details of the switching mechanism that will help in the design of new anaesthetics that are safer, both immediately and for long-term brain function, as well as more effective and more targeted use of anaesthetics.”

Allen says the computer models, using the Victorian Life Sciences Computation Initiative, provide an unprecedented level of understanding of the nervous system.

“These protein switches, called ligand-gated ion channels, are primary electrical components of our nervous systems. Understanding how they work is one of the most important questions in biology,” he says.

“Our computer models show something that’s never been seen before. We have discovered how ion channels bind molecules, such as neurotransmitters, and are activated to generate electrical signals in neurons.

“We are now using these models to make important predictions for how the binding of drugs and anaesthetics may control electrical signalling.”

The findings also unlock a range of other potential applications including understanding how ion channel mutations cause diseases like epilepsy and startle disease, as well as new treatments for anxiety, alcoholism, chronic pain, stroke and other neural conditions.

And because all living organisms share similar proteins, the findings could also open up possibilities for safer and more effective insecticides and anti-parasitics, while the computer modelling developed in the study reduces the need to test new drugs on animals.

The study was funded by the National Health and Medical Research Council, as well as the Medical Advances Without Animals Trust.

The findings have been published this month in Proceedings of the National Academy of Sciences USA.

This article was first published by RMIT on 22 May 2017. Read the original article here.

Bioinformatician on the move

In 2001, the Human Genome Project, an international research project whose goal was to determine the sequence of genes that make up a human being, successfully mapped the human genome – the set of genetic instructions, like a recipe book, that contains all the information needed to assemble and form a person.

Thousands of individual human genomes have now been mapped, generating a vast amount of information on the structure and function of genes and revealing a highly complex and intricate genetic landscape that has led to new insights in biology, human evolution and the diagnosis of genetic disorders, such as Huntington’s disease and cystic fibrosis.

Bioinformatician on the move

Harriet Dashnow, a PhD student in the Bioinformatics Group at the Murdoch Childrens Research Institute (MCRI) in Melbourne, is one of the intrepid explorers navigating this terrain. Her research is seeking to understand how variations in the location and pattern of specific genes can lead to genetic disorders.

“One of the problems is that we’re very good at understanding simple mutations inside genes,” explains Dashnow, “but it’s clear that there are lots of different kinds of variation we don’t understand, and we have a lot of trouble testing for. So the focus of my PhD is to look at a particular type of variation called a microsatellite or a short tandem repeat.”

Short tandem repeats (STRs) are sequences of deoxyribonucleic acid (DNA) – the molecule that contains most of the genetic instructions for all living organisms – comprising 2–5 base pairs, which repeat throughout a human genome. Base pairs, linked nitrogen-containing biological compounds represented by A-T and C-G, are the building blocks of DNA.

Short tandem repeats can appear at thousands of different locations throughout the human genome, and are noteworthy for their high diversity within the population as well as their high mutation rates.

A repeated sequence, for example ATATATAT, will have a different number of copies of AT from one person to the next: “This is a kind of variation that we’re not good at measuring,” explains Dashnow, “so my work is trying to measure this variation so we can look for it in a clinical setting and figure out when it’s causing a disease.

“Genetic disorders such as ataxia [a dysfunction of the nervous system that affects movement] are often caused by these kinds of repetitive mutations, but it’s actually quite difficult to test for these using genome sequencing.”

Enter the interdisciplinary field of bioinformatics, which employs the power of computer science, statistics and engineering to analyse and interpret biological data in order to tackle some of the most challenging questions facing biology today.

“When I was undertaking the biochemistry and genetics part of my undergraduate degree I was starting to hear how computational methods were being used to solve biological questions,” says Dashnow. “It became increasingly clear to me that was the direction biology was going in. So it was going to be important for people to have these computational skills.”

Dashnow, who clearly thrives on challenges, undertook a double degree in science and arts – with majors in biochemistry, genetics and psychology – at the University of Melbourne. And she believes this has proved to be highly beneficial: “It has given me the ability and confidence to write, which has been incredibly valuable, and it’s something that people who just study science don’t always get an opportunity to explore.”

Although she enjoyed the experience of studying literature and psychology as part of her arts degree, Dashnow is a scientist at heart. “I’ve always wanted to be a scientist ever since I was very little. In primary school I thought I wanted to be a physicist, but when I started to take science classes in high school I became really fascinated by biology and genetics, and how genes make us who we are,” she says, recalling the moment when her path in science became apparent to her.

After graduating, Dashnow took up a position as a bioinformatician at the Victorian Life Sciences Computation Initiative (VLSCI), working on the Melbourne Genomics Health Alliance project, whose aim is to integrate genomics – the study of the structure and function of genes – into everyday healthcare.

“It will become more and more common to sequence people’s genomes when they get sick,” says Dashnow. “So understanding and interpreting information provided by genome sequencing will allow us to diagnose more diseases and come up with appropriate treatments.”

Dashnow did a Master’s degree in Bioinformatics at the University of Melbourne then worked at VLSCI for over a year before starting a PhD. The research she is now undertaking for her PhD follows on from her Master’s work, and has already been recognised through the awarding of a highly competitive MCRI PhD top-up scholarship.

Dashnow is currently visiting the Broad Institute, a world-class genomics and biological research centre that emerged from initiatives at Harvard University and the Massachusetts Institute of Technology, where she will undertake collaborative research on muscle disorders, furthering her knowledge and understanding in the field.

– Carl Williams