This profile was originally published as part of the MRC Annual Review 06/07: People behind discovery. The review tells the stories of just a handful of MRC scientists, the work they do and the career paths they have chosen.
Programme leader and professor of neuroscience at the MRC Toxicology Unit, Leicester.
Professor Giovanna Mallucci is an MRC scientist investigating the fundamental mechanisms of neurodegenerative diseases.
It’s often said that in science the ‘negative’ results — where things don’t turn out as a researcher might expect — are just as important, or sometimes more important, than those that continue to lead researchers down their envisaged path.
Professor Giovanna Mallucci might agree with this. For her PhD in the Prion Disease Group at St Mary’s Hospital in London, she set out to investigate how neurons die in prion diseases — a group of neurodegenerative diseases caused by infectious, malformed versions of prion protein, PrP. We now know that the malformed versions encourage normal protein to misfold too, aggregating in the brain in clumps.
At the time, people weren’t sure what caused brain cells to die in prion disease: was it because the malformed prions were toxic, or because the misfolded PrP could no longer do a vital job? Giovanna created a transgenic mouse that stopped making normal PrP proteins once it was an adult, to see if it was losing the protein that killed neurons.
“It wasn’t,” she says. “But I loved the fact that molecular biology tools really do work — you can follow a formula to create a mouse that produces, or cuts out, the protein you want, when you want. You might not get the results you expected, but that can lead to real progress.”
Giovanna knew while reading medicine at Oxford that she wanted to go into research, but was advised to finish her medical training before branching out into science. After qualifying, she did a conventional hospital rotation in general medicine and then specialist neurology training, which included her PhD research.
It was then that she started to develop her independent research career. She stayed on after her PhD to lead a small group in what became the MRC Prion Unit. They used the same mouse model — which stops making normal PrP protein as an adult — but this time infected it with prions when it was young. They found that when the mice stopped making normal protein, the disease was reversed: with no normal protein present to misfold, the disease couldn’t progress, and the mice recovered memories and began behaving normally.
Giovanna spent half her time in clinical work finishing specialist training during this phase, and half in the lab. After accrediting as a consultant neurologist she became more research focused, but continued to do a weekly dementia clinic at the National Hospital for Neurology and Neurosurgery.
“The two aspects of my job are so different — research is highly creative, but it’s a real waiting game and you have to have a long-term vision. But clinical work has an immediacy to it, and keeps me in touch with the patients we, as researchers, are trying to help,” she says.
On the move
In 2008, Giovanna was offered the chance to join the MRC Toxicology Unit in Leicester to build a new lab and set up a new — much bigger — group. She has used the opportunity to broaden the focus of her research from a disease-oriented approach to one that looks for factors common to many types of neurodegenerative disease, a group that includes Alzheimer’s and Parkinson’s diseases, and all of which are associated with misfolded proteins in the brain.
“My vision is to model, and ultimately treat, neurodegeneration by looking at the central processes that go wrong. We’ve been doing some pretty creative thinking; high-risk, high-gain research,” she says.
Her most recent research, published in Nature in May 2012, has continued to work with the mouse model of prion disease, “because it is the only mouse model of neurodegenerative disease that sufficiently mirrors the human disease”.
Giovanna and her team found that when misfolded proteins build up in the brains of mice with prion disease, the brain tries to protect itself by switching on a cellular pathway which blocks protein synthesis. But because the misfolded proteins keep building up, the block on protein synthesis persists and key proteins aren’t made. These include the proteins needed for the brain’s synapses — the communication gaps between neurons. The loss of synaptic proteins prevents the synapses from working and kills the neurons.
The team was able to reverse this block, ‘rescuing’ neurons that hadn’t yet died and increasing mouse survival. The activation of this cellular pathway is common to many types of neurodegenerative disease, says Giovanna, and the research suggests that targeting this common pathway could rescue neurons in other neurodegenerative diseases.
She credits being in the MRC Toxicology Unit with making this kind of discovery.
“Being just down the corridor from experts in other fields really makes a difference: you can ask the right questions of the right people and learn how it answer them. It is a very exciting place to be in at the moment.”
Highs and lows
Giovanna seems never happier than when getting results. “Even if they’re not what we’re expecting and I have to take a step back and think about what’s happening, it’s incredibly liberating.”
“Of course there are low points too. You have to be tenacious to cope with the long periods where things don’t seem to be working or going anywhere — to take a long-term view and see the big picture. And you have to carry others through these troughs.”
Updated May 2012