Angela Dulhunty: Into the Basic Questions

Emeritus Professor Angela Dulhunty. Image: Calo Huang

“All my life, I’ve been interested in how things work.”

Over half a century later, Emeritus Professor Angela Dulhunty still feels the drive of the same curiosity that first led her into the fascinating yet puzzling world of science.

“And if you can believe it, I’m still working on the same problem,” said Dulhunty with a smile on her face.

Earlier this month, Professor Dulhunty made the Queen’s Birthday Honours list for 2022. She was appointed a Member of the Order of Australia for her significant service to medical research and to professional organisations.

To her, the appointment came as a “complete surprise”.

“None of us does anything with that in mind,” said Professor Dulhunty, “But it’s very nice to get recognition. Like all academics, we work pretty hard.”

At the age of 76, Professor Dulhunty remains busy—“probably too busy,” as she put it—working on unpublished data from some of her past projects.

“Being a scientist means you’re very reluctant to retire completely,” she laughed.

Muscle detective

Daughter of a geologist at The University of Sydney, Professor Dulhunty was obsessed with science at a very young age.

When she finished high school, Dulhunty knew she wanted to do medical research, although unsure exactly how or where she would do it.

After talking to a biochemist at her father’s university, young Dulhunty decided to get a science degree, majoring in biochemistry.

It was in her undergraduate times that she encountered the fundamental question she would spend her whole life trying to answer.

Whenever you bend your arm or clench a fist, the resulting movements are made possible by a staggeringly rapid transformation of an electrical signal into a mechanical muscle contraction.

The process, known as excitation-contraction coupling, is crucial for almost all movements in the body. The question, however, is what exactly happens in this process.

How, at the molecular level, does muscle work?

“In those days, we didn’t know what proteins were involved,” recalled Professor Dulhunty.

All they knew was that something connecting the muscle surface membrane with the calcium ions-storing structure within muscle cells, turned an explosion of electrical activity (known as an action potential) into the almost instantaneous release of calcium ions that initiate muscle contraction.

There was where Dulhunty started her long journey in muscle research.

“It’s like being a detective,” she remarked, “Delving into the problems, bringing together evidence to find out how things work, how they can go wrong in diseases, and what we might do to correct things that go wrong.”

Life-long career

Completing her PhD in 1973, Dulhunty was awarded a Muscular Dystrophy Association Fellowship and went overseas to the University of Rochester, USA, to work with electron microscopist Clara Franzini-Armstrong.

Together, the duo revealed how indentations on the surface of the muscle fibre affect the mechanical and electrical properties of the muscle cell membranes.

Like most muscle researchers, in the beginning, Dulhunty focused on amphibians as muscle fibres from toads and frogs are relatively easier to prepare and examine.

But within a few years, Dulhunty steered her research into the almost uncharted area of mammalian muscles.

In 1977, Dulhunty published her single-authored Nature paper, which revealed important similarities and differences between mammalian and amphibian skeletal muscle fibres.

Angela Dulhunty in the lab at JCSMR in the 1990s.

In 1984, Dulhunty joined the Department of Physiology at JCSMR. The same year, her Muscle Research Group explored the first step in excitation-contraction coupling by completing one of the world’s first measurements of minute electrical currents known as asymmetrical charge movements in mammalian muscles.

 “The currents are so tiny that you have to get the noise down to very low levels and get rid of background currents completely,” said Professor Dulhunty, “It took us a good year and a half, but that was so exciting.”

While being among the world’s first in accomplishing something feels “pretty cool”, she said, it was not purely a feeling of excitement.

“It’s similar to the reaction I had when I got a grant,” she explained, “it was more relief and achievement that you succeeded in doing something.”

In the late 1980s, scientists identified in muscle cells an elusive calcium release channel essential for excitation-contraction coupling. Due to its high affinity with the compound ryanodine, this protein receptor is known as the ryanodine receptor.

Researchers in Dulhunty’s group soon put efforts into developing techniques for recording activity from ryanodine receptors, making themselves amongst the pioneers in characterising channel activities of the receptor.

“Muscle contraction depends entirely on that release of calcium ions,” noted Dulhunty in The First Fifty Years 1948-1998, a book that discussed the research history of JCSMR. Naturally, research into ryanodine receptors became one of the pillars at Dulhunty’s lab.

Since the mid-1990s, the group has made several remarkable findings around the regulation of the ryanodine receptor, including the regulatory roles of FK506 binding proteins, glutathione transferases, and chloride intracellular channel proteins.

But, not at all surprisingly, as small pieces of discoveries gradually come together, new questions always emerge.

“Over the years, we now know what the proteins are, know the high-resolution structure of the proteins, but we still do not know how they communicate with each other.”

Now, with her lab completely shut down, Professor Dulhunty is working on new data relevant to the FK506-binding protein, hoping to shed more light on the further studies around the ryanodine receptor.

“It’s one of those things that the more you know, the more you know you don’t know. So you never really answer the questions completely.”

Strength via collaboration

In this journey of endless exploration, compared to the career highlights, moments when the dots appear to connect seem to delight Professor Dulhunty more as a scientist.

“I love it when suddenly, the little things you have been curious about for years make sense.”

Throughout the years, the evolving mystery of muscles has led Professor Dulhunty from electrophysiology to molecular biology. During this gradual shift, collaborations between groups and disciplinaries have become increasingly important.

“As we started to do more and more molecular biology and protein chemistry, it needed more people with different expertise,” said Professor Dulhunty.

For years at JCSMR, she has collaborated broadly with Emeritus Professor Philip Board, a prominent molecular biologist, and Associate Professor Marco Casarotto, an expert in structural biology, as well as other groups.

“I’ve done nothing entirely on my own,” she stressed, “It’s always been in collaboration with students, with collaborators with people, postdocs, and those working on the same problem that I was working on.”

Angela Dulhunty (R-1) with Marco Casarotto (L-1), Phil Board (R-2), and their families in 2005.

The importance of collaboration was also emphasised during her mentoring. As a result, her students tended to work with mastery supervisors with different expertise.

“What that meant was the students had a much broader education because they were doing biochemistry, electrophysiology, and even some industrial applications,” she observed, “It broadened the students’ experience, which has been a very good thing.”

In Dulhunty’s opinion, competitiveness is good because it provides an added incentive for discovery.

“But if competitors can collaborate, it’s fantastic,” she said, “I guess that’s what happened with COVID. It was everybody getting together with the cause being more important than the identity of the person who did it.”

The basics matter

When asked about things that fascinate her as a researcher, “basic mechanisms” tops Professor Dulhunty’s list.

“Most of the applications we now see have arisen out of basic observations that people didn’t particularly know at the time how they were going to be used,” she said, “They just had the same kind of mechanistic curiosity that I had.”

As a contributing part of the evolution of muscle research over the past few decades, Professor Dulhunty has witnessed the focus shift from macroscopic properties to molecular mechanisms.

Upon a better understanding of the new basics—molecular structures, functions, and pathways underlying the processes in skeletal and cardiac muscle contraction—novel drugs could be developed to fight heart disease and neuromuscular disorders such as muscular dystrophy.

More importantly, as Professor Dulhunty pointed out, basic research can help advance applications in multiple approaches.

In the past few years, Professor Dulhunty has been looking at a controversy-laden drug used clinically with heart attack victims.

“With the work that we’ve done, we now know a lot more about how this particular drug works on the ryanodine receptor and why, under certain circumstances, it can worsen heart conditions rather than improve them.”

“It’s a new level of ‘application’,” she said, “It’s not going straight into commercialisation and development, but what we’ve learned, I think, is going to reform the clinical application.”

Basic or applied, Professor Dulhunty would like to see students go into medical research with the awareness that they have to be very passionate about their field and that it’s getting harder to have a guaranteed career in research.

“Passion is the biggest driver,” she advised, “It’s not just ‘I’ll do that because nothing else came along’.”

While the path is by no means easy, it eventually grants you the incredibly gratifying freedom as a scientist.

“One of the most amazing things about being a scientist is being able to follow your own thoughts to design what you do with something that really interests you. There aren’t many jobs where you have that freedom. We’re privileged to have that.”