Associate Professor James Hudson: mapping the heart using organoids

Thursday, 23 Jul 2020

Can you sum up this research program in 10 words?
Understanding the heart in unprecedented depth to improve cardiac health.

What have you discovered so far in this area?
Human heart tissue does not grow and turnover of cardiomyocytes in the human heart is very low (< 0.5% per year), so we need to create it rather than taking cellular biopsies. Over the past 10 years we have optimised protocols to make cardiac cells from human pluripotent stem cells. Unlike stem cells people derive from patients, these are a specialised stem cell capable of generating any cell type in the body, and also expanding into billions of cells for experiments. As these cells are only similar to ‘embryonic’ heart cells we have created human cardiac organoids and used conditions that underpin heart maturation in vivo  to promote the maturation of the organoids. We have used these organoids to discover putative new therapeutics for regeneration and now have multiple programs for inflammation, inotropes and metabolic disease.

Cardiologists know hearts. What info are we missing?
Cardiologists understand the physiology very well. However, we only understand the tip of the iceberg in terms of the biology behind the physiological changes in diseases such as heart failure. Even for a well described biological process such as phosphorylation events in signaling we only understand <5% of the function, and this is mostly in cancer and neurological research. It is well known that patients respond differently to our current therapeutic treatments and it is becoming clearer that diseases such as heart failure with preserved ejection fraction are quite heterogeneous in nature. Together this means that there may be very different biological mechanisms underlying the different responses to drugs and the disease phenotypes, even though physiologically it may result in the same outcome. A clearer understanding of the underlying biology will lead to improved patient stratification, treatment and new therapeutic targets to pursue. Currently the therapeutic pipeline in cardiovascular disease is flat, noting that there are ~7 fold more therapeutics in the cancer therapeutic pipeline where there is a greater understanding of the underlying biology.

How much will you be able to glean from the proposed 80,000 organoids?
We will generate the most comprehensive ‘encyclopedia’ of cardiac biology to date understanding how each one of ~8,500 genes control the overall cellular phenotype and function. This information will be integrated and also mapped to human hearts using machine learning approaches. This will enable us to make potentially the most accurate predictions to date of patient phenotypes, and potential therapeutic targets to date, which we will test these in pre-clinical animal models.

What aspect of this research excites you the most?
This is a new approach to research (for all research fields) that may revolutionise cardiac research. It may be applied more broadly to other organ systems in the future.

What’s a fascinating fact about human organoids?
The cells self-organise into similar structures to those formed in vivo. Ours form elongated and striated cardiomyocytes, epicardial layers, integrated fibroblasts through the muscle bundles and even vessels throughout the organoids, just like those in the heart. It is fascinating how billions of years of evolution have led to some of the most complex and versatile control systems in the cells that facilitate these features.

How long before this work might impact on patient care?
Our intention is to make discoveries with large impact rather than incremental gains. The origins of our biggest medical breakthroughs have been carefully studied and documented and it has been shown that the vast majority originated from basic science leading to patient care with a median time frame of 36 years for older discoveries and 26 years for newer ones. For example, the role of the renin-angiotensin system in regulating blood pressure was discovered over 120 years ago in 1898 by Tigerstedt and Bergman, and is still one of the leading cardiac therapeutic targets. With our new technology we hope this will speed things up considerably, but important problems require time to solve. That being said, we have a few things in the pipeline for our current work that may have an impact in a much shorter timeframe and have already finished preclinical studies which we hope to publish soon.

What has been your biggest research hurdle?
Consistent funding – the importance the new Snow Medical funding scheme cannot be overstated, as it’s the only initiative for long term sustained funding for a basic research program trying to tackle big issues. I also found it difficult to initially break through the ‘barrier’ to get fair reviews of papers and grants.

What’s your Holy Grail – the one thing you’d like to achieve in your research career?
I hope to make discoveries that will improve the cardiovascular health of people worldwide. Knowledge gain and research is also a never ending quest so I also hope to train some of the best future researchers to make sure our future is in good hands.

Who has inspired you most – in work or life?
Many people outside of research may think that we ‘expert’ researchers understand exactly how our cells work and the underlying events causing disease. However, it is quite the opposite and all researchers will agree that we need to understand a lot more. This is why researchers will never give a definite answer. The quest for knowledge and solving one of the most complex systems (the cells and organs) is what excites and drives my work. Sometimes getting too bogged down in details can lead to roadblocks in thinking, so I truly believe that the work-life balance is extremely important. Many times on the drive back from a surf at the Sunshine Coast is when I will have the clarity in thinking to solve a key research issue at work the following week.

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