‘When I told my dad I was studying disorder he said, “yes, that makes sense”’, Dr Gabi Heller says, grinning.
There’s a persistent stereotype that scientific labs are very serious places. But for Gabi, the word she uses over and over again is ‘fun’. Taking on a challenge that experts swear is impossible is ‘fun’. Making a technical breakthrough is ‘fun’. Discovering and naming a new biological process is ‘really fun’. And looking at her face, full of energy, you can see she means every word of it.
The disorder she studies is at the protein level within our bodies – specifically, biomolecules called ‘intrinsically disordered proteins’.
‘I’m not going to have an Alzheimer’s drug next year. I may not even have a drug in ten years…’
Most biological functions in the body are carried out by biomolecules called proteins, which have a three-dimensional structure. As Gabi is proud to say, Newnham has an extraordinary history in this area of science. Rosalind Franklin was a pioneer in studying the structures of biomolecules, followed by Nobel-prize winner Dorothy Hodgkin.
Both Franklin and Hodgkin used the technique of X-ray crystallography to examine their biomolecules. That technique was a breakthrough in studying proteins with a largely fixed 3D structure, Gabi explains – but it initially led scientists to miss the fact that not all proteins have a fixed shape.
Over the past twenty years, scientists have realised that about a third of proteins are highly dynamic, rapidly changing between different structures. Known as intrinsically disordered proteins, or IDPs, they play a crucial role in the body: their ability to transform means that they can interact with many other biomolecules, bringing different systems together and responding in a highly sensitive manner to their environments.
However, ‘when things go wrong with IDPs, they go really wrong,’ Gabi explains. Malfunctioning IDPs are involved in a whole range of diseases, and understanding them is crucial for treating cancer and neurological diseases. Alzheimer’s, for example, is one of the diseases on Gabi’s hit list.
But the shape-shifting nature of IDPs is precisely why diseases such as Alzheimer’s are so difficult to treat. Gabi explains: ‘Almost all drugs today work by fitting in some way into a protein’s structure – like a key into a lock – and changing ever so slightly how it moves.’ That works because the drugs are interacting with a relatively fixed-shape protein, the ‘lock’.
But the IDPs are more like a floppy piece of spaghetti than a lock – and if you imagine trying to unlock a bowl of spaghetti with a key, you’ll see why the problem has been so intractable.
Cue Gabi’s research. Despite the many experts who thought her project was impossible, she was determined to find a way in which drugs could target IDPs. ‘What I got to do is to have a lot of fun trying to understand the physics of how this would work,’ she says, cheerfully. ‘And what I’ve shown is that actually may be possible. It’s a new kind of binding.’
Gabi’s metaphor for this new form of binding, which would allow drugs to target IDPs as they morph, is a dancer with a long ribbon. The dancer is the drug, the ribbon the protein: the ribbon swirls around the dancer as she moves. Gabi’s disordered proteins swirl and morph around the drug, constantly changing shape.
‘One of my dreams is to get a performer to illustrate this. I think of a ribbon dancer – I think of the drug as the dancer and the protein as the ribbon, spinning and twirling around it.’
This is an entirely new mechanism, which could revolutionise pharmaceuticals. ‘We got to name it which is really fun,’ she says. ‘We’ve named it “entropic expansion”. But we’re really just beginning the earliest stages of being able to design a unique type of drug, for many diseases.’
The next task is to begin the drug design process. Gabi’s proof-of-concept work has been done in a type of worm, C. elegans, which is often used as a model organism for studying Alzheimer’s.
Alzheimer’s is, in part, caused by a disordered protein, called amyloid-β, which aggregates into abnormal structures, called ‘fibril plaques’, in the brain. The right drug will be able to prevent the proteins forming plaques.
‘This was the first real test,’ she says. The IDPs in the ‘Alzheimer’s worms’ produce additional fibrils in the muscles, reducing the worms’ mobility. After treatment with a drug-like molecule, the IDPs were prevented from forming these fibrils. This was a clear indication that the new binding approach is successful.
However, Gabi emphasises that this is a new approach, rather than a new drug: ‘This drug is not going to be in clinics – it’s a model drug that shows how future drugs could function.’
As she says, ‘I’m not going to have an Alzheimer’s drug next year. I may not even have a drug in ten years.’ But, at some point, she hopes that this discovery will become a key part of the pharmaceutical process. If so, people the world over will benefit from the research done here at Newnham College, by a young woman who grins when she is told that her plans are impossible.