Professor Andrew Trafford and colleagues – with help from a Nobel Prize-winning insect – are identifying genes that contribute to heart failure, which could one day help to reverse the condition.

As many as 920,000 people live with heart failure in the UK, often caused by heart attacks, high blood pressure, or diseases of the heart muscle. Heart failure can prevent people from doing normal daily activities and puts them at risk of developing other life-threatening conditions such as stroke.

A key feature of heart failure is the loss of structures called t-tubules. These tiny tunnels stretch deep among the heart muscle fibres and help coordinate the release of calcium, the main driver of muscle contractions. Losing these t-tubules reduces the ability of the heart to contract and pump blood, leading to abnormal heart rhythms, heart failure, and ultimately death.

T-tubules and the proteins that affect them

Professor Andrew Trafford has been studying heart disease for more than 23 years at The University of Manchester, in particular, the way t-tubules and other microscopic structures of the heart contribute to human diseases. He recently found that the loss of t-tubules can be reversed with existing drugs, but the newly reformed t-tubules are disorganised, so normal contraction of the heart is not fully restored.

“We know that if you restore the cellular architecture in cardiac muscle, you will restore the function. But that is not something that the currently used therapeutic approaches are able to achieve,” Professor Trafford says, "so, treatments for heart failure may slow the disease progression down, but they don’t reverse it.”

Professor Trafford’s next task is to identify the proteins which control the organisation of t-tubules. His hope is that by targeting these proteins with drugs, the new t-tubules will be properly organised, meaning that the heart can operate correctly again. However, the list of proteins that could potentially be involved in the t-tubule organisation is significant. A recent study identified 96 proteins in t-tubules, most of which had never been investigated in this context before.

Traditionally, heart scientists might use mice to identify the proteins involved by creating a series of genetically modified mice which each have one gene ‘knocked-out’, meaning the relevant protein is no longer produced. In this case, studying nearly 100 genes this way would require thousands of mice and could take a significant amount of time.

Fruit flies help screen genes

However, a new option was uncovered thanks to a chance encounter with Professor Andreas Prokop, who leads the ‘fly lab’ at The University of Manchester. A conversation between Professor Trafford and Professor Prokop inspired the former with the idea of using fruit flies to help sift through the proteins that may be involved in heart failure. “I can say that within that first half an hour of having a chat with Andreas and one of his colleagues, I could see that two different fields could actually work very cleverly together to really advance our understanding,” Professor Trafford recalls.

Professor Trafford and Professor Prokop and their colleagues Dr Katharine Dibb and Dr James Eales now plan to use fruit flies to identify the genes involved in the t‑tubule organisation, in a PhD studentship project funded by NC3Rs and the British Heart Foundation.  

The fruit fly Drosophila melanogaster has been used as a model organism in research for more than a century and has contributed to six Nobel Prize wins. One reason is the number of similarities between the genes of humans and fruit flies – as many as 75% of human disease genes have a counterpart in the fruit fly. Almost every fly gene already has an ‘off-the-shelf’ fly with the necessary gene removed, which will save the team a significant amount of time.

In a fruit fly, the muscles most like a human heart are not the fly’s equivalent ‘heart’, which is actually little more than a slightly enlarged blood vessel; instead, it’s the somatic muscles of the fly, those controlling the flapping of the adult wings and the wriggling of maggots. As a result, in the Manchester team’s experiments, genes that disrupt t-tubules will cause problems in the movement or flight of the flies, which can then be easily observed. It will take just ten days to understand whether a gene knock-out has affected the muscles, whereas similar experiments in mice could take months.

Reducing animal experiments and understanding heart failure

By using the fruit flies, Professor Trafford and his colleagues could whittle down 80 or more genes to a shortlist of less than ten. The role of these genes in the t-tubule organisation can then be confirmed in other experiments – firstly, in mammalian heart cells grown in the lab, and finally, in mice, after they have identified a few promising candidates. Conducting the gene screening in the fruit flies first will save a considerable amount of time and avoid the use of at least 1,000 mice in their experiments, Professor Trafford estimates.

The methods the team are developing could also be used by other research groups studying heart disease. In some experiments, flies could replace mice entirely. “I think that's part of the exciting thing for me,” Professor Trafford says, “not only are we addressing the questions that have always been interesting, but we’re potentially developing a pipeline that other people can apply.”

The team's work will help identify the key players in the organisation of t‑tubules. One day, this knowledge could help develop treatments which could reverse heart failure and improve the lives of thousands of people. For Professor Trafford, this goal is akin to “the cure for cancer”, and though he knows it will likely be decades before it can be achieved, “we have to start somewhere”.

“If we can reverse that adverse remodelling you see in heart failure, then we’ll have a novel and much more effective therapeutic tool in the toolbox.”