In high school biology, students are taught the central concept of genetics in a very simple way: DNA makes RNA, RNA makes protein, and protein makes life.
In this way, RNA is central to everything in biology — and, you could argue, central to life itself.
Biologically, DNA is the code, RNA is the messenger, and proteins are the molecular machines that do the work inside our cells.
For this reason, proteins have been the main biological component used to create medicines and improve human health for centuries.
Their use in the field of medicine changed the world as we know it, beginning with the smallpox vaccine first discovered in 1796.
British doctor Edward Jenner took fluid from a cowpox blister — containing proteins from the cowpox virus — and scratched it into the skin of an eight-year-old boy.
The proteins triggered an immune response and created a “memory” in the boy’s immune system. He subsequently became immune to smallpox, a similar but much more virulent disease.
Since the late 18th century, vaccine production using proteins has been massively improved.
But with the battle against COVID-19, scientists turned to a new type of vaccine to increase manufacturing speeds and reduce the cost of production.
This time they used messenger RNA, instead of protein. And its arrival signals the beginning of a much bigger therapeutic and diagnostic revolution.
There’s more inside the RNA universe
Vaccines that contain messenger RNA, or mRNA, have been studied for decades, but the release of them during the COVID-19 pandemic was the first of its kind.
Both Pfizer and Moderna developed mRNA vaccines that work by delivering a blueprint to the body in the form of genetic material — which the body then uses to build proteins and mount an immune defence.
But mRNA is only one type of RNA.
Beyond mRNA, there exists an unexplored universe of other types of RNA in human biology that play a role in everything from child development, to memory formation, to the development of disease.
Unlike mRNA, other types of RNA do not code for proteins, and were initially considered a kind of biological “junk”.
But since the turn of the century, scientists have discovered that some types of RNA actually block and regulate mRNA, and act to inhibit biological reactions involved in infections and disease.
This process is known as “RNA interference”, and is mediated in large part by a group of RNA called microRNA.
In a way, microRNA act as controllers, determining which mRNA are read and which proteins are made.
Several microRNA drugs have made it to clinical trials for the treatment of cancers, as some cancers have been linked to the dysregulation of microRNAs.
Understanding how these processes work could potentially open the floodgates to new possibilities for improving human health.
The power of microRNA
The real power of microRNA lies in its ability to control multiple molecules at once.
This makes it particularly attractive for use as a therapeutic for complex diseases such as cancer and neurological diseases.
Essentially, microRNA controls entire biological pathways rather than single molecules.
To explain, imagine the streets in your neighbourhood represent a complex web of biological pathways, and the houses on the streets represent individual molecules.
One street has a problem that is affecting every house (or molecules).
A “traditional” drug would try to fix just one of the houses in the hope that this would help the overall integrity of the street.
But a drug that uses microRNA — either by increasing or inhibiting its function — could fix the majority of houses on the street at the same time.
This approach is what Viridian Therapeutics (formerly known as miRagen Therapeutics) tried to address when developing a drug to block a specific microRNA known as microRNA-155.
MicroRNA-155 has been heavily implicated in tumours and the progression of lymphoma and leukemia, as well as amyotrophic lateral sclerosis (ALS).
Their drug, which made it to stage 2 clinical trials but didn’t progress due to commercial reasons, actively stopped the activity of this microRNA, leading to alleviation of symptoms with these cancers.
This is just one example of the many microRNA based therapeutics currently in phase one and two clinical trials for a wide range of complex diseases.
Developing new therapies
RNA research, therapeutics and diagnostics have long been in the shadows of DNA, thanks to the alluring promise of gene therapies, and Big Pharma’s major focus on protein-based drugs.
RNA drugs can be produced at scale and in a cost-effective manner.
They are relatively simple to produce and can target previously untargetable pathways.
The infrastructure that has been put in place to rapidly develop RNA vaccines could be utilised to develop the next generation of RNA therapeutics.
This will change the standard of care for many diseases, and allow for personalised medicine.
Associate Professor Riccardo Natoli is the head of the Clear Vision Research Laboratory and a member of the Shine Dalgarno Centre for RNA Innovation at the Australian National University.
Dr Joshua Chu-Tan is a research fellow and business development manager at ANU. He was also one of the ABC’s Top 5 scientists for 2021.