Tales from... Dr Callum Dark

Nature vs Nurture, eat your heart out!

Dr Callum Dark

I can still remember in Year 11 Biology when I first made the decision to become a geneticist. The way that genes influence all living things fascinated me, and I knew that I wanted to pick apart those DNA strands to see what secrets were held within. It’s ironic that my decision to pursue genetics felt so instinctual to me, hardwired like the genes I loved so much, as ultimately I would end up bending my career path purely due to the environment around me. Nature vs Nurture, eat your heart out!

The first of these environmental influences were the psychology classes I attended at university, which directed my love of genetics towards the context of psychiatric disorders. I would eventually investigate genetic variants associated with Attention Deficit Hyperactivity Disorder (ADHD) as the topic of my PhD. Studying ADHD in a zebrafish lab primarily looking into muscle disease was definitely a challenge, but one that helped foster an interest in human genetic disease.

The second major impact on my career trajectory came as a result of my father passing away from cancer towards the end of my PhD. I can honestly say that I had never considered investigating the genetics of cancer until that moment, which is a testament to how the key moments in our lives define us. I remember watching Louise Cheng, who is now my supervisor, deliver a keynote speech at a conference and learning for the first time how cancer cachexia, the systemic breakdown of fat and muscle seen in cancer patients, can contribute to the disease as a whole. With such vivid imagery in my own mind of how cachexia affected someone close to me, I knew it was something I could dedicate myself to.

Cachexia is a metabolic disease that affects around 80% of cancer patients. It involves the tumour actively telling the muscle and fat tissues to break down. The use of secreted signals originating from the tumour is thought to play a major part in this process. As the tumour grows, it releases molecules that interact with other tissues, such as muscle and fat, resulting in a signalling cascade that bring about that tissue’s degradation. The tumour can utilise the building blocks of these tissues to fuel its own growth, but the process of taking them apart is still a mystery.

In the Cheng lab, we use the genetic model organism, Drosophila melanogaster, or more commonly known as the vinegar fly. While it might seem absurd at first, the fly is a fantastic animal to examine the effects of tumours on the body, and in particular, the tissue wasting we see in human cachexia. Flies have an open circulatory system, so they lack arteries and veins, but instead have all their organs and tissues immersed in the fly blood that moves around the body. Therefore, we can induce tumour growth in the fly, and monitor the effects of these tumour secreted molecules on the different tissues.

Of particular interest to me, is how these signals are breaking down the muscle. The muscle is a rich pool of nutrients, so it makes sense that the tumour would want that for itself. Interestingly, flies are not that different from us when it comes to muscle. The smallest building blocks of muscle, called sarcomeres, look and function in almost the same way as humans. We can examine how the muscle responds to changes in the fly’s internal environment and deduce how that may be similar in humans. In our models, we see disturbances to the shape of the muscle, with the muscle getting longer and thinner, as though being stretched. In addition, the levels of important structural proteins decrease, suggesting they are unable to replenish and rebuild. Overall, we get a picture of muscle that is weaker, and that the tumour is profiting from this. If we can block the processes by which the tumour is breaking down these tissues, patients will be better equipped physically when fighting the disease. I hope that one day my work can help to not only improve the quality of life of cancer patients, but give them all of the resources their body needs to overcome their illness.

Figure legend:  Fly larvae without (A), and with (B), a tumour and cachexia symptoms. Muscle is shown in green and fat is shown in red. In B, the tumour is denoted by the arrow, and we can see muscle disruption and fat loss when compared with A.

Dr Callum Dark is a Postdoctoral Researcher in the Cheng laboratory, which is part of the Organogenesis and Cancer Program within the Peter Mac Research Faculty. His expertise includes developmental genetics, human genetic disease, Drosophila research, zebrafish research, disease modelling, imaging, and behavioural analysis.

Dr Callum Dark can be contacted by:

Email: [email protected]

Twitter: https://twitter.com/CallumDark2

Google scholar: https://scholar.google.com.au/citations?user=8rvTDPMAAAAJ&hl=en

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