We are all familiar with the term DNA, yet many of us may not realise that it is our RNA, or Ribonucleic Acid, that creates the protein vital to our health and wellbeing. So what is RNA, and how is a team of scientists from the Menzies Health Institute Queensland using it to develop direct-acting antiviral therapies?
In this Q&A, Professor Kevin Morris unravels RNA for us and provides a fascinating insight into how direct-acting antiviral therapies can target viruses such as COVID-19, now and in the future.
What is RNA and how does it differ from DNA?
RNA is the medium ground between DNA and protein. DNA is our body’s library containing the code of every gene. It is this code that makes up the protein that is required throughout the body—in our muscle, bone, skin and hair. Because DNA is double-stranded it cannot make protein, so single-stranded RNAs are made as the medium ground between the DNA and the cytoplasm, where the RNA is converted into protein. This is the central dogma of molecular biology. DNA is very stable; it is the nucleus and the guidebook for the body. But RNA is less stable, and a lot of viruses just live in the RNA, never moving to the DNA, and become incorporated in proteins produced by the RNA. An example of such a virus is SARS as it only takes over the RNA pathway. The RNA for HIV, on the other hand, becomes a gene in our DNA, and that is why HIV is such a challenge to eliminate.
What is direct-acting antiviral therapy?
At Griffith University we have designed and tested an antiviral therapy drug that targets the viral RNA genome directly and kills it. And it is the only drug in the world with this capability. Whilst other therapies target all the RNA in a cell, both virus and normal cells, our therapy is very specific—only targeting the protein of the virus. It is a very potent method of targeting and killing the viral RNA. Essentially, RNA interference takes advantage of human cell pathways and that is why we are trying to alter the virus RNA at this point. We design the RNA that kills the virus and then package it into nanoparticles which are injected directly into the blood. Through the blood, the RNA is carried to the lung cells where the virus will be destroyed.
‘At Griffith University we have designed and tested an antiviral therapy drug that targets the viral RNA genome directly and kills it. And it is the only drug in the world with this capability.’
SARS and COVID-19 were the initial focus for the development of this direct-acting antiviral therapy. Both viruses come into the RNA, not the DNA, so the RNA can be altered and targeted. Unlike DNA, RNA isn’t unique. In the case of SARS, although variations or mutations in the virus occur, the virus is fundamentally (80 – 90%) the same. Essentially, although viruses evolve, there are certain regions in the virus and the RNA that you can change for impact. For SARS we designed our therapy against those regions where the virus can mutate, and those regions are in all the betacoronaviruses. So, in theory, our therapy would work on all the betacoronavirus family viruses: one drug for multiple viruses. And the drug is super stable—at four degrees for a year and at room temperature for two months—which is a vital consideration, particularly in third-world countries.
Our next step is to move from the experimental stage to a phase one trial in Australia. That is where we are right now.
How did you start researching the COVID-19 virus?
Back in 2013, when I was at the University of New South Wales, Professor Nigel McMillan at Griffith University was the only person in Australia working on lipid nanoparticle formulations—something I have always been interested in. In my lab at City of Hope (a research and treatment centre in California for cancer, diabetes and other life-threatening diseases), we did some work with nanoparticles so when we moved out here again in 2020, I could bring my research over to Griffith. Whilst we could design all these RNAs and nanoparticles in California we had no way to test them on live viruses. Nigel did have the capability and he was able to obtain Medical Research Future Funding (MRFF) to develop a nanoparticle formulation with our RNA.
Around the same time, COVID-19 hit and the only way to keep the lab open in California was to be doing COVID-19 research. Similar to the flu, we realised early on that COVID-19 required the development of therapies. Basically, we started making the formulations in California, shipping them to Australia and testing them in mice. It is an excellent collaboration as Nigel is very good with nanoparticles and I am very good with the RNA component—a winning combination. The next phase is the manufacture of the drug, which will be outsourced. There is one group in Perth and another group in Vancouver and we will put together the parts and send them to another group to conduct dosage toxicology studies. Then another group will do a 50-person phase one trial in Australia.
As this is a golden opportunity for the government to invest and to create the technology here in Australia, Vice Chancellor and President Professor Carolyn Evans is liaising with the Australian Government on our behalf. Also, it is a golden opportunity for the Gold Coast University Hospital; with the Hospital being on campus, clinicians can team up with the scientists and conduct clinical trials. All that is needed is the development of a translational program.
What sparked your passion for RNA research?
Really, it goes back to when I studied molecular biology at high school. Around this time HIV came out and I was astounded that a virus could kill people—lions and tigers and bears kill people, but the notion that something you couldn’t see could kill you was mind boggling! And studying advanced biology in my senior year, I had the worst grades except for when we studied the micro-organisms inside our mouths. Then I got the highest grade. I think that sparked my innate curiosity about the molecular aspects of life.
‘I am super creative and molecular biology reminds me of playing in the sandbox as a kid and creating worlds and realities … Ultimately you get to see whether your idea or hypotheses can translate into a reality.’
What continues to compel me is the creative side of science. I am super creative and molecular biology reminds me of playing in the sandbox as a kid and creating worlds and realities. That place where you get an idea and start to wonder, and then you create, put it all together, and test it in a living cell. Ultimately you get to see whether your idea or hypotheses can translate into a reality. So, more than anything, for me it is a creative outlet.
What advice would you give to upcoming researchers?
Find your bliss and follow it. Finding what excites and motivates you in whatever you are doing is the biggest hurdle, but it is this motivation that drives the creativity. The drive and inspiration are what will get you over the hill and keep you excited.
Oftentimes when I meet with students, they feel so overwhelmed as they have so many aims and struggle to narrow them down. So, I remind them that they are exploring the unknown and I try to excite them about the fact that no one else on the planet is doing what they are doing and that that is the thing with science—you are doing something in the ether on your own. What they are doing is creating entirely new platforms and new technologies and testing new hypotheses. And a lot of times, new researchers are overwhelmed because they don’t know how to do things yet, but as they learn each technique, they start to understand and just get stuck in.