The molecular detective

The molecular detective

As an undergraduate, Clare spent her summers at a biological lab in Southampton. The environment triggered something, sending her curiosity into overdrive. 

“It was like somebody switched a lightbulb on,” says Clare. “It changed my life. I was no longer satisfied with simpler explanations: I was like a detective. I needed to know why something was happening on a molecular level. What are the genes and responses going on that trigger a disease process?”

Clare’s curiosity response has been raging ever since. She is now Professor of Innate Immunity at Cambridge, based in both the medical and veterinary schools. 

Her work bridges both the animal and human worlds, like the zoonotic pathogens she holds under the microscope. She investigates organisms that are tolerated in animals but cause humans all kinds of trouble. 

Clare compares how innate immunity works in many species. She tracks potential pandemics as pathogens make their way through animal populations: think SARS-CoV-2 migrating into humans (and after us, mink); or birds managing the threat of avian flu. 

“I’m more interested in how the host sees the pathogen, rather than how the pathogen behaves in the host.”

Some like it hot

Inflammation is a physiological process whose purpose is to fight invaders. It manifests in our bodies in familiar ways: redness (increased blood flow), swelling (fluid gathering around tissue damage), high temperature (turning up the heat kills pathogens, which don’t like it hot), and pain (that stops you using damaged parts of your body). 

Taken as a whole, this suite of bodily behaviours is designed to trigger wound healing. Healthy amounts of inflammation are essential for the healing process, and to protect us against infection. 

In the immune system’s military operation, cells known as macrophages are the infantry. They seek out and destroy pathogens, and produce inflammation. 

In her lab, Clare puts bacteria onto macrophages to see how they’ll respond. She uses CRISPR-Cas9, a genome editing tool, to take genes out of human, bird, chicken and dog cells, and watches how they respond to a given infection.

In recent years, scientists like Clare discovered a curious fact. The same immune receptors that detect invaders also respond to misfolded proteins – like amyloid beta or alpha synuclein – which underlie Alzheimer’s and Parkinson’s. 

“These faulty proteins can trigger inflammation in the same places as a pathogen would.”

So what does this mean for our understanding of inflammation? If it’s not exclusively triggered by outside threats, does that mean it underlies other conditions and diseases? What happens when our reactions are more troublesome than the trigger?

Finding the balance

Encouragingly, lifestyle adjustments could ease the burden of inflammaging. 

“Meditation can reduce overall stress levels. Exercising also helps in regulating your metabolism.”

“But just taking anti-inflammatory drugs like aspirin all the time can be dangerous,” Clare warns. “Side effects come along with prolonged use, such as stomach ulcers.”

In better news, the discovery of new inflammation pathways and proteins has opened up potential drug targets. Clare is part of a drug discovery project, which aims to broaden our arsenal of anti-inflammatories. The project is targeting pathways we didn’t know existed 20 years ago.  

The trick is to switch off chronic inflammation, without making people vulnerable to infection. 

To try and thread this needle, Clare is working with world-leading mathematicians, physicists and chemists from across Cambridge.

Clare needs to watch closely the proteins known to trigger inflammation. Thanks to Chemistry’s David Klenerman, we can now watch individual molecules in any cell in any species, and see where they end up. Scientists like Clare can begin to fit together the biomechanical jigsaw pieces that make up our bodies. 

“We can put a fluorescent label onto an individual protein in a cell. This means we can follow proteins and how they behave in regular circumstances.”

“Much to our surprise, we found that the number of these proteins in the cell are present at vanishingly low levels. These proteins work by clustering together when triggered. Most of the time, you don’t want them to switch on: only when a bug comes along does the switch need to be flipped.”

With Julia Gog from Mathematics, Clare works on experimental design, figuring out which questions she should try and answer. Over coffee with Julia and Physics’ Pietro Cicuta, they ask tough questions and hatch plans. In the past, Pietro has developed entirely new microscope techniques to help satisfy Clare’s relentless curiosity. 

In another Cambridge-spanning project, Clare is leading a project in one of the University’s new GSK collaboration programmes. She’ll head up a respiratory team, alongside Pietro – figuring out the molecular mechanisms of chronic obstructive pulmonary disease (COPD). The team will use ‘lung on a chip’ models to replicate the machinery of our respiratory tract. 

Outside the University, Clare’s Cambridge Enterprise-supported spin-out Polypharmakos is looking for natural products that will reduce inflammation in a sustainable way. Enlisting the expertise of Kew Gardens’ Monique Simmonds, the company is looking for plant cocktails that down-regulate inflammation.

These branching paths may lead to manifold remedies. At the start of each sits Clare and her Cambridge lab, persistently probing the inner workings of our immune system. Clare’s curiosity has led her into the minutiae of our cells, and onto the broadening frontier of medical science.

Since this conversation, Clare has also been made Co-Director of the Engineered Pandemics Risk Management Programme at the Centre for Research in the Arts, Social Sciences and Humanities.

Clare will also be speaking at the Cambridge Festival, on Thursday 27 March, at the Vaccines: Into the future event.