Interview with Dr. Tim Audas

Department of Molecular Biology & Biochemistry

(RNA Biology, Amyloidogenesis, Neurological Diseases)

Joined SFU in September 2016

Dr. Audas is interested in how cells respond to changes in their environment. Recently, he showed that a class of biological molecules – noncoding RNA – is essential to many of the stress response pathways used by cells to adapt to changing conditions.  In particular, he discovered a noncoding RNA-mediated pathway that causes cellular proteins to clump (i.e., form amyloids) under stress conditions; he suspects that this pathway can go awry and lead to neurological disorders, like Alzheimer’s or Parkinson’s. Could these diseases be activated by cellular stress events? The increasing incidence of neurological diseases motivates Dr. Audas to unravel how this pathway works and identify compounds that may cause or disassemble amyloids.

What life experiences led you to pursue a career in research?
Growing up I wanted to be a veterinarian. I worked part-time at an animal clinic and I had summer jobs at a local zoo. Eventually, I found it to be very repetitive and I realized I wasn’t excited about the career anymore. Around that time, I signed up for a fourth-year undergraduate Honours project at the University of Guelph and I discovered how science offers something new every day. I realized how interesting it is to investigate something that no one else has ever worked on.

What part of your research gives you the most satisfaction?
The best part is not knowing where your research will take you. Some of our recent work is a prime example. I worked on noncoding RNA but all of a sudden, I had to learn about amyloid aggregation, neurological disease, and cancer. Sometimes you get the results and they lead you into a completely different area of science. I find that you always need to keep an open mind, because you never know when you’re about to stumble upon something really incredible.

Why don’t we hear very much about noncoding RNA as a functional molecule? The focus seems to be on proteins.
I think RNA research has been hampered by a fundamental misunderstanding of the central dogma of molecular biology. If you read Francis Crick’s original article you’ll see that he never suggested that RNA’s only role was to encode proteins. In fact, he fully endorsed the idea that RNA could have many noncoding and functional properties. Unfortunately, over time this part of the theory was set aside in favour of the more memorable quote, “DNA makes RNA makes protein.” It’s possible that this simplified view has delayed our acceptance of RNA as a functional molecule.

Was there a turning point, or has RNA biology research expanded gradually?
The field picked up when powerful molecular biology tools were developed in the early 2000s. All of a sudden, researchers were finding thousands more RNA transcripts than anyone thought could exist. This led many to believe that RNA could actually be an important biological molecule, with a functional diversity that might rival that of proteins. Around that time the conversations started to change from “can RNA be a functional molecule” to “what else can it do” – that’s where my work comes in. It’s a really exciting time to be an RNA biologist, because we’ve just scratched the surface of what some of these molecules can do.

How did your work on noncoding RNA lead you to Alzheimer's research?
One of the biggest problems with neurodegenerative disease research is that there are no basic biological pathways attributed to the amyloid aggregation events found in the Alzheimer's or Parkinson’s patients. This sets it apart from a lot of other disorders, because unless you know how something works, how can you know how to fix it?

Recently, we found that certain noncoding RNAs trigger a reversible form of natural amyloid aggregation that is very similar to the disease state. Now we want to explore whether misregulation of these noncoding RNAs or other regulators of this pathway occurs in people with Alzheimer's disease. It’s very possible that dysregulation of this normal pathway may lead to Alzheimer's symptoms.

How will your research program contribute to drug discovery for treating neurological diseases like Alzheimer's and Parkinson's?
Our system is unique because we can rapidly produce a large amount of natural amyloid material for use in tests. In the near future, we’re hoping to screen thousands of drugs to see which ones break down the amyloids, leading to potential treatment options. We’re also very interested in looking for chemicals that cause amyloids to form. Right now, there is no known cause of Alzheimer’s disease. It’s possible that something we eat or breathe could trigger the symptoms. If we could identify these potential triggers, then we could help reduce the prevalence of these diseases.

SFU's new Centre for High-Throughput Chemical Biology will allow us to conduct such screenings using living cells and microscopy to detect the presence or absence of amyloids. We can use this process to identify lead compounds that can potentially be developed into drugs.

What is known about the RNA molecules that trigger amyloid formation?
I'm excited to investigate how these RNAs are different from other cellular RNAs that do not cause amyloid aggregation. So far, we have found five or six noncoding RNAs that cause amyloid formation.

We don't know much about these amyloid-causing RNAs yet, but there must be something very unique about them. It could be some interesting structure or multiplex formation, because from a sequence standpoint, nothing stands out.

We’re also interested in determining their three-dimensional shape, which may give us some hints into how they change protein conformations so dramatically that amyloid formation occurs – that's a really interesting basic science question.

What educational background and personal strengths do you look for in prospective graduate students?
There are so many ups and downs that come with doing research, so I look for evidence that a prospective student is willing to take on challenges and adversity, whether it be in their education or extracurricular activities. In addition to Molecular Biology and Biochemistry experience, students with backgrounds in Neuroscience, Cell Biology, or Toxicology could bring different ideas and ways of thinking to my research program.

What is the biggest challenge faced by RNA researchers today?
While we’ve made a lot of progress in the last decade, I feel like functional RNA research is still struggling to gain widespread acceptance in the scientific community.

Overall, we’ve yet to discover the breadth of functionality that these molecules exhibit. My program aims to help change this.

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Read more: Dr. Audas’ Department of Molecular Biology & Biochemistry website, his lab website and the New Science Faculty page

Interview by Jacqueline Watson with Theresa Kitos