The switch

Her head peeks out from behind a large screen displaying endless rows of numbers, just like the other screens in the room. The blinds are half-closed. At first glance, it could be the set of a dystopian film, but then biostatistician Luisa Foco smiles, the lights come on, and the atmosphere changes completely. Foco has spent hours and hours behind that screen, analyzing every detail of a handful of genes associated with arrhythmogenic cardiomyopathy. Far from dystopia, the computers glow with purpose and potential.

It all starts with people, in anonymized form

“Some colleagues at our institute have been studying arrhythmogenic cardiomyopathy for years, a rare but very serious disease, often manifesting itself with sudden death in very young people,” Foco begins. “They pointed out some genes involved in the disease, and we decided to study them together in detail in a healthy population to try to better understand the pathology.” So, Foco turned to the data from CHRIS, the population study that Eurac Research has been conducting for many years in collaboration with the regional Health Authority. With patience, she cross-referenced the anonymized electrocardiogram data with the genetic data of over 13,000 participants choosing the biostatistical analysis models best suited to the needs of her research.  Luisa meticulously imagined, examined, and interpreted the numbers. And that’s how she found something special...

The finding: a variant that changes the QRS curve by a few milliseconds. The QRS curve is the time it takes for the ventricle to activate. “It doesn’t have any pathological consequences, but it made us flag that genetic region for closer observation,” Foco explains. “And that’s where we made another discovery – the most interesting one.”

Credit: Eurac Research | Andrea De Giovanni

A matter of serendipity

It is said that in 1928, scientist Alexander Fleming noticed that a mold of the genus Penicillium had accidentally contaminated a container where he was growing Staphylococcus bacteria and that the bacteria were no longer growing around the mold. Fleming realized that this mold must produce a substance capable of killing bacteria, and thus the first antibiotic, penicillin, was discovered, which has saved countless lives since then. This episode is considered the most striking example of serendipity, the term used to describe the discovery of something unexpected while looking for something else.
The research team at the Eurac Research Institute of Biomedicine is also convinced that serendipity led to its breakthrough.
“While trying to understand the effects of the variant we had identified, we discovered something else. We found DSP-AS1, a molecule belonging to a family of special RNAs called long non-coding RNAs, which are able to regulate specific genes by giving them instructions on how to function,“ recalls Foco. ”In particular, DSP-AS1 ultimately decreases the production of the desmoplakin protein, which helps keep heart cells together and makes the heart beat regularly.”
The research team was looking for variants that could explain the variability in heartbeat in healthy people and instead discovered a molecule that acts as a biological switch.
So far, these are the results on paper. Or rather, on screen.

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Arrhythmia and more

The group at Eurac Research that studies heart disease, particularly arrhythmias, has so far focused on the accumulation of fat that gradually suffocates the heart cells of people with arrhythmogenic cardiomyopathy, with encouraging results.
“For some time now, the scientific community has observed that in patients who lack desmoplakin, the disease has particular characteristics and is often more severe from an arrhythmic point of view. In addition to fat accumulation, there is much more fibrosis,” explains Marzia De Bortoli, the biologist who heads the team, as she slips on a white coat and walks down the laboratory corridors. She stops in front of a door, enters confidently, and sits down at a workstation. In front of her is a microscope and some cell culture containers. “When Luisa and Cristian Pattaro, head of the CHRIS study and biostatistics group, told me about DSP-AS1, we immediately got to work. We wanted to test its function in the laboratory and, above all, we wanted to see if inhibiting it would increase the production of desmoplakin by the cells.”
So, De Bortoli and her team created heart cells from induced pluripotent stem cells and designed molecules, called “antisense oligonucleotides” in technical jargon, that could interact with DSP-AS1, inhibiting it; that is, regulate the switch.
The tests on two-dimensional cell models worked.
The researchers identified a specific antisense oligonucleotide capable of acting on DSP-AS1. By partially inhibiting DSP-AS1, heart cells produce more desmoplakin.

This is good news for people with arrhythmogenic cardiomyopathy, who have a desmoplakin deficiency, but not only for them. Since desmoplakin works together with other proteins as a binder between cells, its absence affects not only the heartbeat, which becomes less regular without it, but it also has an impact on other organs. One example is that a lack of desmoplakin in the lungs is associated with fibrosis.

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Everything comes back to people, in a personalized way

“We are now testing this molecule on cellular models of real patients, not only two-dimensional ones  but also three-dimensional, ‘engineered heart tissues’,” continues De Bortoli. “If the results are confirmed, this same molecule could form the basis of a drug capable of intervening in people with arrhythmogenic cardiomyopathy who produce low levels of desmoplakin in a targeted manner.”
This is the principle of precision health, an approach to health that personalizes the prevention, diagnosis, and treatment of diseases, taking into account individual factors such as genetics, environment, and lifestyle. Unlike traditional healthcare, which uses a one-size-fits-all approach, precision health aims to provide more accurate and tailored care for each person, improving the effectiveness of treatments and reducing side effects.

There is still a long way to go from engineered heart tissue from patients to actual patients. More tests, more checks, and more years are needed. It is not even certain that it will work: many promising molecules in the laboratory prove to be unusable in people. But for now, in Eurac Research’s heart cell plates, that switch works. And it’s a great start.