Diverse thinking allows headway in neuroscience

Translating neuroscience findings from the laboratory into clinical practice is a difficult challenge. To find new treatments for neurodegenerative conditions such as Alzheimer’s disease, academic researchers must work closely with clinicians to learn how molecular pathways observed in the lab generate the symptoms seen in patients.

As neurologist Federica Agosta puts it: “It is fundamental that researchers do not sit in an ivory tower, with no clear awareness of the actual aim of medical research, which is, of course, to provide benefit to patients.”

Agosta works at a translational neuroscience research institute in Italy that highlights the advantages of close links.

IRCCS Ospedale San Raffaele in Milan runs about 100 laboratories and more than 60 specialized clinical units that together see more than 1.5 million patients each year. This allows the hospital to conduct research that is based on clinical observations, including through a dedicated clinical trial centre, and generate findings that feed back into patient care.

Clinical-laboratory dialogue

The hospital is part of a network of institutes with the acronym IRCCS, given special status by the Italian Ministry of Health because they offer high-quality patient care coupled with world leading research and innovation. Agosta heads one of the main neuroimaging research units of San Raffaele, which focuses on neurodegenerative diseases, in particular Alzheimer’s disease, frontotemporal dementia, amyotrophic lateral sclerosis (ALS) and Parkinson’s disease.

In 2012, four years after completing her residency in neurology, Agosta finished her PhD in experimental neurology at Vita-Salute San Raffaele University. Now, also thanks to a European Research Council (ERC) starting grant, she is Associate Professor and group leader in the Division of Neuroscience at Ospedale San Raffaele.

Her unit uses advanced magnetic resonance imaging (MRI) techniques as a window into the ageing brain, a possibility that has long captivated Agosta. “I have always been fascinated by how neuroimaging can photograph an otherwise inaccessible region like the brain,” she says.

Her team is working to identify measurable differences in the brains of people undergoing healthy ageing compared with those in the early stages of neurodegeneration. They hope this could offer a way to diagnose earlier these debilitating and increasingly common conditions.

This is a key motivation for Agosta, whose work as a clinician informs and influences her research.

“I work both as a clinical neurologist and a researcher in order to keep track of the challenges that patients and their caregivers face every day,” she says.

As well as the ability to unite her clinical and research work in one centre, Agosta appreciates the passion of those at San Raffaele, together with the diversity of approaches. Her team includes neurologists, neuroscientists, neuropsychologists, and biomedical engineers.

Challenging the dogma

This type of mix is not unusual at San Raffaele, a centre that prioritizes multidisciplinary teams. Diverse teams encourage unorthodox thinking, says Jean-Michel Cioni, also an ERC grant holder and group leader at San Raffaele.

“One of the key things I learned as a postdoc is not to always stick to the dogma,” he says. Before coming to San Raffaele in 2019, Cioni worked in the lab of Christine Holt, professor of neurodevelopment at the University of Cambridge, in the United Kingdom.

While studying axon guidance there, he developed an interest in the much smaller processes of RNA biology and protein synthesis. “By not being an RNA person, you're not under the dogmas of that world. You are kind of a blank page, and I think that’s a strength,” he explains.

Cioni’s freshness to the field helped him think about RNA differently. A central idea of molecular biology is that DNA is transcribed to mRNA, which moves within the cell from the nucleus to the cytoplasm where it is translated into protein. This protein can then be transported where it is needed.

Cioni is one of a small group of researchers challenging this view, by working on the discovery that mRNA can travel further through the cell, before it is translated into protein, a less error-prone and more efficient process. “After nuclear export, mRNA is not necessarily immediately translated, but can be transported to where it needs to be, where the protein will need to be synthesized at a specific time,” he explains.

Cioni is studying this process in his preferred cell type, the neuron, where the local synthesis of proteins regulates function and survival. “We want to understand how the regulation of RNA transport and translation can control the development of neurons, specific synaptic connections, how neural circuits are made, and how they are maintained over time,” he explains. These questions, though fundamental in nature, are also clinically important – the maintenance of neural circuits is lost in neurodegenerative disease.

Such work highlights the interconnected nature of neuroscience research, something recognised and supported by San Raffaele. The Division of Neuroscience hosts researchers working at the molecular level right up to those who apply a whole-brain perspective. “For us, this is key, because it means we can think about applying our research to absolutely everything,” Cioni says.

One idea is all it takes

To accelerate the translational nature of its work, the hospital also nurtures the relationship between its research and clinical colleagues, offering frequent seminars for both to attend.

These offer fertile ground for basic researchers like Cioni, who stresses that a single idea could lead to a clinical step forward, such as a new biomarker for a disorder or even a new treatment strategy. “Even if it happens only once, it would justify everything,” he explains.

The link between basic and clinical research is neatly demonstrated by some of Cioni’s recent work. His lab is currently working on a signalling pathway that controls the transport of mRNA in neurons. Another of his projects focuses on RNA binding proteins – proteins that attach to and control the fate of mRNAs. Several of these proteins have been directly linked to neurodegenerative conditions, including ALS and Alzheimer’s disease.

“What I've noticed in my projects is that they start with a very basic question, but almost always finish by having some potential clinical relevance,” says Cioni.

It can be a challenge to successfully combine the research and the clinical aspects of the work, Agosta acknowledges. “But I was lucky in finding a good environment to develop both elements of my career.”