And what happens when they stop talking?

Dr William Roman is growing human muscles on a chip. He’s using them to understand how the skeletal muscle cell, the largest cell in a human body, connects with neurons and tendons to create working muscles.

William is using his ‘mini-muscles’ as a model to understand the fundamental principles of intercellular communication, and hopes this work will enable researchers to better mimic organs outside the body.

He is also studying what happens when communication between neurons and muscle cells breaks down as we age, and in degenerative diseases such as motor neuron disease (MND).

His team’s research at Monash University’s Australian Regenerative Medicine Institute (ARMI), will lead to stem cell technologies for disease modelling, drug screening, cellular agriculture, and biorobotics.

Next week, William will receive a $60,000 Metcalf Prize from the National Stem Cell Foundation of Australia in 2024.

William says: “Researchers around the world are mimicking organs, growing mini- kidneys, mini-hearts, even mini-brains. However, a key challenge with these organ-on-chip models is that different cell types do not naturally interact to form the mature connections seen in real organs. We first need a deep understanding of how stem cells communicate in space and time during development.”

Why muscle cells?

Growing up in France, where Duchenne muscular dystrophy was discovered, William watched annual Téléthon fundraising events, which helped shape his quest to understand how muscles work, and ultimately to improve the lives of people living with a range of neuromuscular and general muscle disorders.

He also credits the influence of his grandmother, who taught him “communication is the most important thing in life”.

His focus is on skeletal muscle cells, also known as muscle fibres. They are two to three centimetres long, which makes them easier to work with.

Following his PhD he founded and led MyoChip, a multinational project to build a muscle on a chip. Now he plans to go further and persuade the muscle fibres to connect with tendons forming a complex structure, known as a myotendinous junction, that transmits force from our muscles to our tendons.

“We can already put two cells next to each other in a dish, but it doesn’t seem like they’re interacting the way they should,” William says.

“So, what we’re trying to understand is how good relationships naturally form. And then we want to reproduce that in a dish, providing the right factors or ambience, for two cells to want to interact, at the right time and place in their development process, to form stable, long-term relationships.”

To achieve this, his team is first focused on understanding the cross-talk between cells – aka “good communication” – which contributes to stable relationships in the development of a healthy myotendinous junction. 

“This approach will serve as proof of concept to determine if mapping intercellular communication can be used for tissue engineering,” he says.

“And, if we can do that in muscles, it can then be applied to engineer next-generation organ-on-chip systems, using a controlled, bottom-up approach akin to building cars – starting from scratch and piecing together all the different components to recreate organs.”

Then he hopes to teach his ‘muscles’ to connect with neurons to form a neuromuscular junction, in which a neuron forms synaptic connections with a muscle cell. And that would transform research into debilitating muscular and neuromuscular disorders – including MND in which people lose control over skeletal muscles that allow them to move, talk, eat and, ultimately, breathe.

“Modelling a neuromuscular junction will allow us to tackle neuromuscular diseases that are poorly understood and for which there’s no cure,” William says.

“We’re still trying to form a mature neuromuscular junction that better mimics what happens in our bodies. Right now, nobody has been able to do this in a dish.”

MND is a difficult disease to model given 90 per cent of cases are ‘sporadic’, involving random, non-hereditary gene mutations; and 10 per cent ‘familial’, involving inherited, known gene mutations.

Every day in Australia, two people die from MND and another two people are diagnosed with the disease, which has an average life expectancy of two to three years from diagnosis. Yet the disease is still poorly understood, with ongoing debate about the biggest contributor.

“We still don’t really know if it’s just a neuron disease, and the muscle is kind of an unlucky bystander or if the muscle actually plays a role,” William says.

“What we do know is the motor neuron, which controls muscle contraction, detaches from the muscle, causing the neuromuscular junction to become unstable. And, when the neuron no longer touches the muscle, people with MND lose voluntary muscle mobility.

“Little by little, they lose the ability to move and do activities until eating becomes difficult, speaking becomes difficult, and then breathing, which usually leads to death.

“Our hope is to delay or completely prevent the detachment of the neuron from the muscle by improving communication between the cells, enabling people living with MND to keep control over their movements.”

William obtained a Master of Science (Physiology) from Montreal’s McGill University, before completing his PhD in muscle cell biology, split between Paris Descartes University and Berlin’s Freie University, focusing on nuclear positioning during skeletal muscle development. He undertook post-doctoral research on induced pluripotent stem cells (iPSCs), in Kyoto; stem cell biology, in Barcelona; and spatial genomics at California’s Stanford University – all while leading the tissue engineering MyoChip team in Lisbon.

William joined the Australian Regenerative Medicine Institute in June 2023 as an EMBL Australia Group Leader.

Photos for media use