An interview with Dr Ashwin Unnikrishnan about his myelodysplastic syndrome research

An interview with Dr Ashwin Unnikrishnan about his myelodysplastic syndrome research

Dr Ashwin Unnikrishnan is one of the recipients of the “Leukemia & Lymphoma Society-Snowdome Foundation-Leukaemia Foundation (LLS-SF-LF) Translational Research Project” Grants. His project is in the area of myelodysplastic syndrome (MDS). He kindly took time out of his busy schedule to answer some questions.

Q.You have a special interest in MDS – how did this come about?

My interest in MDS was spurred by events on two fronts – one personal and another professional. On the personal side, as a young adult, I watched a favourite granduncle succumb to the disease and experienced at first hand the suffering and toll the disease can exact (on both patients and their families).

On the professional front, I was drawn to study MDS as a result of my long-standing interest in epigenetics. Epigenetics, which translates to “on top of” genetics, is an emerging field of biology that focuses on how modifications of DNA (or of proteins associated with DNA) can affect the activity of genes without any changes to the DNA sequence itself. We are beginning to realise that aberrations in epigenetics underlie a number of different diseases, including MDS. I became fascinated with epigenetics after being introduced to it as an undergraduate (at Washington University in St. Louis, USA), to the extent that I decided to pursue a PhD in the field (at The Fred Hutchinson Cancer Research Centre, in Seattle, USA).

Towards the end of my PhD, I realised that I could apply my expertise in epigenetics to better understand MDS. What is particularly interesting about MDS (and a closely related disease, Chronic Myelomonocytic Leukaemia/CMML) is that some patients respond exceptionally well to treatment with a drug (5-Azacytidine/AZA; commercially known as Vidaza™) that alters the epigenetics of a cell. However, important details pertaining to the biology of how, or why, AZA therapy actually works remain poorly understood. This is an important unknown to resolve because of the unfortunate reality that AZA only works in about half of the patients who are treated. Additionally, AZA is not a cure and in the long-term, many of the patients who initially respond to treatment will relapse. The prognosis is poor in patients for whom AZA therapy fails, highlighting a need to discover more effective therapies in MDS.

We think that by better understanding how AZA therapy works in some people, why it doesn’t work in others and why it stops working eventually in yet others, we can lay the foundation for developing more effective treatments for patients.

Q. If you had to summarise what your LLS-SD-LF research project is about in 1 sentence what would it be?
It is to lay the groundwork for developing more effective therapies in MDS.

Q. What has been your most exciting discovery?
Our discovery that a particular molecular aberration (“cell cycle quiescence”) exists within the bone marrow cells of MDS and CMML patients who fail to respond to AZA treatment. In healthy individuals as well as in patients who respond favourably to AZA, specific types of bone marrow cells divide and replicate as part of normal blood production. However, we identified that these cells were not dividing as much or as frequently (i.e. they were “quiescent”) in patients who did not respond to AZA. We reported this discovery in a paper in 2017 (https://doi.org/10.1016/j.celrep.2017.06.067).

This is an important discovery for a couple of reasons. Firstly, it hints at the biological reason why AZA therapy fails in some patients. For AZA to work, cells need to copy their DNA, which occurs when cells divide. If cells are quiescent, they are not copying their DNA as frequently and AZA therapy consequently is less effective. Importantly, our discovery also shines a light on the path forward. If we could coax quiescent cells back into cell division, we might be able to make these cells more receptive to AZA therapy. This is an active line of research we are currently pursuing in the lab.

Secondly, the discovery of cell cycle quiescence also provides a means (a “biomarker”) to potentially identify, early on, patients who will not respond to AZA treatment. Currently, there aren’t such means and it often requires up to 6 months of potentially futile treatment before a patient can be adjudged to be a non-responder. Developing a reliable means to identify non-responders early would offer physicians the possibility of attempting alternative treatment options for such patients. We are currently developing technologies that could enable this, and some of these are being tested in an ongoing investigator-initiated clinical trial (https://clinicaltrials.gov/ct2/show/NCT03493646) that involves a number of hospitals across NSW and is based out of the UNSW. However, there is still a lot of testing and validation that requires to be done before these technologies could ever be used in the clinic.

Q. What has been your most frustrating project?
There have been far too many to name! The very essence of the scientific method involves doing experiments to test the validity of hypotheses, and results more often than not in either the rejection or refinement of the original hypothesis based on the experimental data. Thus, frustrations and “failures” are an everyday reality in the life of a researcher.

However, it is equally important to learn from each of these setbacks. Experience has taught me that there is a lot of wisdom in, and succour to be gleaned from, a quote by Thomas Edison, “I have not failed. I’ve just found 10,000 ways that won’t work”. My ongoing challenge remains in convincing the less experienced members of my research staff of the truth in this aphorism.

Q. How important are independent grants funded by Philanthropic donations compared to NHMRC or Pharmaceutical grants?
They are vital! Research is the lifeblood of therapies of the future. Discoveries made today can translate into practical benefits of tomorrow, sometimes in wholly unanticipated ways. It is therefore essential for society to support scientific research.

However, research work requires funds to support it; from enabling experiments to be performed to paying salaries of the researchers who carry out the science. Around the world, the vast majority of research is supported by grants from governmental agencies (just as it is in Australia, with the NHMRC). However, there remains the persistent challenge of best allocating a limited pot of money across the most worthwhile causes.

Philanthropic donations not only supplement funds provided by the NHMRC and private organisations, but they can also spur research in areas that aren’t always adequately funded. For example, by highlighting areas of high interest relevant to the treatment of blood cancers, the Snowdome Foundation, Leukemia Foundation and similar charitable foundations can facilitate research into specific areas that may be overlooked by other agencies, who have to support a diverse range of projects across multiple fields.

Q. How will your research impact MDS patients?
I think that our work, encapsulated around the themes of: 1.) better understanding the basis for how AZA therapy works in some patients; 2.) why it doesn’t work in others, and; 3.) why it eventually stops working in yet others, will uncover the pathways tor developing more effective and durable treatments for patients.

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