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From tiny worms to big discoveries

Dr Della David reflects on her first 12 months at the ̨��swag, reveals the roots of her own scientific curiosity, and explains how a tiny, transparent, short-lived worm is enabling her to discover new ways of promoting healthy ageing. Since arriving at the ̨��swag in spring 2022, Dr Della David has been busy setting up her new group in the Signalling programme. Her work – on protein aggregation and healthy ageing – sits squarely within the ̨��swag’s core mission of healthy ageing research. Attracted by its outstanding research facilities, her research complements and expands cutting-edge work at the ̨��swag.

“Getting to know everyone – all these new personalities – has been really nice, and I’ve been discovering how differently things work here compared with Germany – the communication styles, the hierarchies, the organisation,” she says. “But mainly I’ve really appreciated how welcoming and friendly people are. There are several groups in the ̨��swag’s Signalling programme working on protein quality control and ageing and it’s so stimulating to be able to discuss subjects we’re all really interested in.”

Her interest in ageing began when, as a young undergraduate, she read a pair of papers by two women scientists – Maria Grazia Spillantini, Professor of Molecular Neurology at the University of Cambridge and Cynthia Kenyon, Professor of Biochemistry at the University of California, San Francisco (UCSF).

“The first was on protein aggregation, and that was so cool. The second challenged the prevailing view that ageing was an intractable process of decline, and I thought that was really fascinating,” she recalls. “So I decided to do a PhD on protein aggregation and then a postdoc on ageing in Cynthia’s lab.”

It was during Della’s postdoc at UCSF that she first worked with Caenorhabditis elegans, a tiny nematode, which Sydney Brenner pioneered as a model organism at the Medical ̨��swag Council Laboratory of Molecular Biology in Cambridge during the 1960s. Commonly found on compost heaps eating bacteria and fungi, C. elegans attracted Brenner because it was a comparatively simple organism, had a nervous system, and was easy to grow in bulk and to study with a light microscope.

Sixty years on, it’s helping scientists untangle the role of protein aggregation in ageing. “C. elegans is an amazing model for doing ageing research,” says David. “It’s short-lived, with a life span of two to three weeks, and experiences a number of the declines we see in humans – from wrinkled skin and digestive problems to muscle weakness and memory troubles. It’s a hermaphrodite, so you can produce approximately 300 babies per parent, and it’s transparent. That’s really important because we can tag proteins with fluorescent markers, follow them during the worms’ lives, and watch the proteins clump together into these intractable aggregates.”

Using the worm, David has already achieved groundbreaking results. To date, much research has focused on protein quality control inside cells, where researchers have discovered some 2,000 components that help keep proteins healthy and functional. Much less was known, however, about what happens outside cells, and before arriving at the ̨��swag, David and her team discovered dozens of elements that control protein quality in the so-called extracellular space.

“We and others found that protein aggregation happens both inside and outside cells during normal ageing, as well as part of disease, and that it actively promotes ageing – triggering and accelerating the functional decline of tissues. We also discovered completely new ways of preventing proteins from aggregating to build tissue resilience,” she explains.

At the ̨��swag, her new group’s aims are to understand at the molecular level what’s going on during ageing. Continuing their focus on protein aggregation, the team are investigating the mechanisms that protect against excessive extracellular protein accumulation in worms and then mouse models, and exploring new ways of maintaining the quality of proteins outside the cell. And because ageing is not a linear process, with certain parts of our bodies ageing more rapidly than others, Della is also keen to know what drives this heterogeneity in tissue-specific ageing.

“The ultimate goal of our lab is to discover mechanisms to promote healthy ageing and alleviate age-related diseases,” she says. It’s knowledge David hopes will open up new therapies to delay age-related disabilities in humans: “If you can keep your proteins functional for longer, and avoid them accumulating in these toxic aggregates, your cells and tissues are going to be better off. It’s possible, for example, that we might be able to use gene therapies to express protective proteins in specific areas of the body to promote healthy ageing.”

And to answer these questions, she believes the ̨��swag is the best place to be. “I feel very privileged to be doing science here,” she concludes. “There’s such great expertise here at the ̨��swag and Cambridge area on the mechanisms of protein quality control. Being part of this community and sharing ideas and expertise helps all our research flourish and move forward as fast as possible.”