Blood cancers

Dr Jamie Kuzich: Molecular barcoding the non-genetic heterogeneity in AML

Wednesday, 4 Nov 2020

Can you describe your research project in 10 words?
Molecular barcoding + single-cell technologies = how does AML persist?

What aspect of this research excites you the most?
Coming to scientific research as a clinician, I very much have my eye on the potential clinical translation of discovery science. I’m very excited about the potential for this research to ultimately lead to the development of therapies that prevent relapse in patients with AML. Whilst changes in the DNA sequences of patients with AML provide us some prognostic and therapeutic guidance, it is currently impossible to definitively identify which patients are destined to relapse after initial treatment. This project has the potential to shine further light on this conundrum by characterising the role non-genetic mechanisms play in allowing some AML clones to develop resistance to therapy. Understanding these adaptive mechanisms, and the cellular states that precede and permit them, may then allow us to identify and develop therapies that target the resistant AML clones which inevitably lead to relapse.

What is molecular barcoding?
Molecular barcoding is a technique which allows for longitudinal lineage tracing and serial clonal tracking of cell fate. Thousands of unique nucleotide sequences – “barcodes” – are transduced using viral vectors into the genome of leukaemia cells, which then allows the fate of these cells to be tracked over time (e.g. following challenge with various therapies). Importantly, when we combine this method with single cell sequencing platforms, we are then able to concurrently determine the genetic, epigenetic and transcriptional adaptations that drive cell fate decisions.

What extra information should this technique provide re: AML?
We know a great deal already about the intratumour heterogeneity of AML at a genetic level, however non-genetic heterogeneity (such as the transcriptomic and epigenetic landscape) likely contributes significantly to therapy resistance.
This technique will hopefully not only provide us with an understanding of these non-genetic adaptive mechanisms of AML at single cell resolution, but will also demonstrate how therapeutic pressure shapes this non-genetic resistance over time. The serial clonal tracking of cells will hopefully allow us to determine the origins of the cells which survive therapy – are the genetic, transcriptomic and epigenetic signatures of these surviving cells pre-existent, or is the development of such programs a dynamic, adaptive process? Answering these questions will then hopefully allow us to tailor therapies that target the persistence of these resistant clones.

How long before this work might impact patient care?
This is a difficult question to answer – it depends what we find! There are many new therapies, epigenetic and otherwise, in various phases of development. Some of these may have utility, however we will first need to characterise the mechanisms that govern these non-genetic forms of resistance before we can determine how best to target them.

What’s your Holy Grail – the one thing you’d like to achieve in your research career?
The term “precision medicine” has been around for some time but, outside of a few specific diseases, we are a long way off realising the promise of its vision. I’d love in my professional lifetime to see AML biology characterised comprehensively enough to allow each patient to have a treatment tailored to their disease biology, and for this approach to result in significant improvements in survival and quality of life.

What is your biggest research hurdle?
As a clinician soon to enter the realm of scientific research, I have a very steep learning curve ahead of me. The theoretical, technical and analytical skill set required to undertake this kind of research is very different to the clinical and diagnostic skills that have been the focus of my training so far. I will no doubt require a lot of patience, perseverance and humility and I am very lucky to be supported in this endeavour by my supervisor Professor Mark Dawson and his incredible lab.

Who has inspired you in work or life? 
The courage with which patients with leukaemia face their disease and treatment is one of the first things that inspired me to train in clinical haematology. We ask a great deal of our patients, not just in terms of the toxicity they endure with current treatments, but also the uncertainty they must grapple with at the time of diagnosis and all of the way throughout their treatment and follow-up. Witnessing this in my clinical work continues to motivate me to strive to deepen our understanding of the biology of blood cancers which will hopefully lead to more effective and less toxic treatment options for our patients.

There’s an app for that. What’s new on your phone?
App time limits! Whilst this may go against the spirit of this question, I have found app time limits (with a password held only by my partner) to be a godsend of late. The temptation to scroll through Twitter or the Guardian news app is always a threat to my attention, so I rely on these hard limits to keep me on task!

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