Researcher Sunandini Ramnarayanan, shares how the National Genomic Research Library is supporting her to understand the role of 'DNA dark matter' in cancer.
The road to bioinformatics
I didn’t initially intend to work in bioinformatics, it's something I became interested in throughout my studies.
After receiving a scholarship to study at the Indian Institute of Science Education and Research in Mohali, I went on to complete a Bachelor's and a Master's degree majoring in Biology. I tried several different areas before focusing on applying bioinformatics to disease.
I then began a PhD at University College Dublin, which I am still in the process of completing.
I decided to work on a project about something I had never heard of before, called ‘long non-coding RNAs’, studying how they relate to cancer.
What are long non-coding RNAs?
RNA is a complex molecule that acts as a messenger during protein production. It forms the intermediary step between DNA (the genetic blueprint for our bodies), and the final resulting protein.
Long non-coding RNAs are a type of RNA molecule. They play an important role in regulating the expression of our genes, acting as an ‘on’ or ‘off’ switch for whether genes get expressed in the body.
Whilst long non-coding RNAs play a role in protein production, they do not directly give rise to proteins themselves. They belong to what we call the ‘non-protein coding genome’, also known as the DNA dark matter.
Most cancer research focuses on DNA in the protein-coding genome. As a result, long non-coding RNAs are often sidelined.
As part of my work, I look at data from cancer patients, to see whether long non-coding RNA molecules are driving the formation and progression of their tumours.
My goal is to find new targets for cancer treatment
A lot of research has gone into understanding the role of protein-coding genes in cancer. For many patients, we can tell which specific genes have caused their cancer to develop.
However, for those with cancer caused by non-coding genes, the answer is often unclear.
The ultimate goal of my research is to identify the role of long non-coding RNAs in cancer progression. This way, they could be used as potential targets for cancer treatment.
In previous research, my team uncovered evidence that faulty long non-coding RNAs are capable of driving cancer. We also know that they are expressed very specifically in each tumour, making them promising targets for treatment.
Now is an excellent time to expand our focus in cancer research beyond just the protein-coding genome, and to regions such as long non-coding RNAs.
Therapies with fewer side effects
Many patients with cancer have exhausted the list of treatments available to them.
Long non-coding RNAs as therapy targets could offer a new potential option when standard treatments have not worked.
RNA therapies are on the rise in the field of cancer research. Targeting RNA as opposed to protein-coding genes offers a wide new pool of targets to choose from.
By identifying cancer-causing long non-coding RNAs, we could target them using short molecules called antisense oligonucleotides (ASO). These short molecules bind to the long non-coding RNAs, and cause them to break down.
ASO therapies would likely cause far fewer negative side effects than more standard cancer therapies. This is because by targeting long non-coding RNA specifically, we only attack cancerous cells and avoid all of the healthy ones.
Negative side effects from standard cancer treatments can take a long and considerable toll on patients. The potential of ASO therapies to reduce or avoid these effects is very promising.
There is still so much to learn about long non-coding RNAs, however, we are at an excellent point so far. ASO treatments have already shown favourable pre-clinical results in cancers such as skin melanoma.
My work is just a small part of a much bigger picture, and I am excited to be working towards such an important goal.
The value of the National Genomic Research Library
The National Genomic Research Library (NGRL) has been amazing in allowing us to detect long non-coding RNAs in cancer.
When building the software to do our research, we used a dataset called PCWAG, the Pan-cancer Analysis of Whole Genomes. This dataset has about 2,500 tumour whole genomes, and was fantastic for the initial stages of our research.
However, as we continue trying to look for long non-coding RNAs, a bigger dataset is needed to let us detect even more.
The non-coding genome is so vast in comparison to the protein-coding genome. This makes it very difficult to discover signals, and we need huge amounts of data to do it.
In the National Genomic Research Library, there are about 16,000 tumour whole genome samples. It is so rare to find datasets that are this large and yet still consistent in how samples have been produced and processed.
The scale and uniformity of the library have allowed us to discover new, relevant long non-coding RNAs, which we can test in the lab as potential therapy targets.
Our work would have been impossible without the NGRL.
What’s next for me?
I am currently in my 3rd year of a PhD at University College Dublin. Following this, I plan to work in research and development in the biopharmaceutical industry.
I like applying bioinformatics schemes to data to improve our understanding of biology, especially when it could lead to developing therapies for complex diseases.
Though I may not work specifically on long non-coding RNAs, I would love to stay in the RNA field, simply because it is booming. From RNA vaccines for COVID-19, to emerging RNA therapeutics, it’s such a great time to be studying it.
My message to researchers
I absolutely recommend using data from the National Genomic Research Library if it aligns with the goals of your research.
The library is completely unique in the sense that it has so many tumour whole genomes, all under one roof. Large-scale uniform datasets are very hard to come by, but are often so important for bioinformatics research.
The National Genomic Research Library forms the basis for most of my PhD project and thesis, and I am very grateful to have had access to it.
I would like to thank my supervisor, Professor Rory Johnson of University College Dublin, and Science Foundation Ireland, who have financially supported my research as part of the EU’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant.
It is thanks to them that my research is possible.
I would also like to thank Genomics England, and all who have donated their data to the incredible National Genomic Research Library. They continue to allow so much important progress in cancer research.