Professor Christiane Berger-Schaffitzel, professor of biochemistry at the University of Bristol, shares the science behind her groundbreaking Covid-19 discovery, and recalls her surreal lab commute through the deserted city during the peak of the first wave
In autumn 2020, a ‘druggable pocket’ in the SARS-CoV-2 spike protein, which could be used to stop the virus from infecting human cells, was discovered by an international team of scientists led by the University of Bristol. Their findings were deemed potentially game-changing in defeating the pandemic, as it was believed that small molecule anti-viral drugs could be developed to target the pocket they discovered, and eliminate Covid-19. The Berger-Schaffitzel lab’s Professor Christiane tells us what it was like.
TBM: How has it been to work in this field on something so very urgent at a time that will go down in history?
Professor Christiane Berger-Schaffitzel:
The lockdown in March lead us to pivot our activities to Covid-19 research. We assembled a team of very experienced postgraduates who volunteered to use our tools to dissect the SARS-CoV-2 virus. All of us were key workers and part of UNCOVER, University of Bristol’s Covid-19 emergency research group led by Adam Finn from Bristol Medical School. My husband’s team initially produced spike protein for vaccine development and to establish serology testing. Spike is the protein on the surface of the SARS-CoV-2 virus that mediates human cell infection. My team used cryo-electron microscopy to quality control the sample they produced, by determining its 3D structure. It was a unique experience. It felt surreal to walk to work through a deserted Clifton, meet the same few people in otherwise empty laboratories and return again at night through a ghost town. The work was extremely focused and intense. Some team members even spent the night in the laboratory occasionally.
How did the breakthrough come to pass?
When we analysed the atomic structure of the SARS-CoV-2 spike glycoprotein, we discovered a previously unknown pocket – a sort of molecular cave – within in the protein. To our surprise, inside of the pocket, we found a small molecule. It turned out that this small molecule was linoleic acid. With the help of Andrew Davidson, a renowned Bristol coronavirus expert, and his team, we could show that binding of linoleic acid to the spike protein blocks virus replication. Thus, unexpectedly, we discovered not only a druggable pocket in the SARS-CoV-2 spike protein, but also a potential drug, linoleic acid, in the pocket, which could be used as antiviral to protect us for infection by the virus.
The editor of Science asked us upon submission to also alert the World Health Organisation and immediately make our discovery publicly available
Tell us more about druggable pockets…
Similar pockets are found frequently in other proteins which are implicated in diseases. Blocking such a pocket with a drug, typically a small molecule, can inhibit the function of such proteins and provide a cure. In our study, the small molecule is linoleic acid – it binds to the pocket and distorts the spike protein, dialling down the infectivity of the virus. Our data suggests that linoleic acid could be already a drug that could be used as a potent antiviral to protect us from infection. In the future, based on our discovery, new drugs could be developed that bind even better to the pocket to suppress viral infectivity entirely and eliminate Covid-19.
What happens when a team discovers something valuable?
Covid-19 has revolutionised how we publish research findings. We submitted our manuscript describing this work to Science, one of the leading and most respected journals for cutting-edge research. Usually, it takes several months until a manuscript is evaluated and, if deemed important enough, published and thus made available to the public. Now, in contrast, the editor of Science asked us upon submission to also alert the World Health Organisation and immediately make our discovery publicly available by uploading on a preprint server, accessible by everybody prior to peer-review. Today’s speed of research and information sharing is unprecedented.
What is special about linoleic acid?
Linoleic acid is a very special molecule. It is a fatty acid and part of vitamin F. Our body cannot synthesise linoleic acid, we need to take it up with our diet. Under normal circumstances we have enough of it in our bodies, but it was shown that patients who become sick with Covid-19 do not have enough linoleic acid left. Our body requires linoleic acid to protect us against inflammation and to regulate our immune reactions. It is also essential to keep the cell membranes in our lungs soft to allow oxygen to pass through efficiently. When linoleic acid is lacking, all these functions are failing, and this is exactly what we see in severe Covid-19 patients. Providing linoleic acid could therefore serve two vital purposes – suppressing viral infectivity, and, in the unlucky case that we do become sick, helping fight the disease by restoring key body functions.
Have you got further since, in terms of turning your new knowledge against the virus?
The response to our discovery has been overwhelming. I never experienced something like this before. We are still dealing with requests for interviews and writing features or reviews and answering many emails we receive from citizens from all walks of life who encourage us and wish to know more. Importantly, we have been contacted by leading experts from academia and pharma with concrete suggestions how to translate our finding into a treatment against Covid-19. With these experts we have now put together a realistic and fully costed clinical trial plan to translate our discovery to the bedside as soon as possible. Right at this moment, we are working very hard to secure the funding required to realise our vision.
What impact have the vaccines had on what you’re doing?
We all have great hopes that vaccines can help to overcome the pandemic. The current first-generation vaccines are reported to be 90-94% efficient. Many people can or will not take the jabs, and they may not be equally efficient in those who do. In addition to vaccines, we therefore need urgently antiviral drugs for treating Covid-19, and linoleic acid – which is affordable and immediately available – could be a particularly potent one.
Which women in STEM are doing exceptional things at the moment?
There are many women in Bristol who excel in different capacities, take on professional responsibilities and at the same time constantly strive to reconcile the expectations that they and others place in them. In the context of STEM and Covid-19, I would like to mention my colleagues Prof Caroline Relton, Prof Lucy Yardley, Dr Ellen Brooks Pollock, Dr Lucy Selman, Dr Laura Rivino, Prof Linda Wooldridge and their teams who are all making incredibly important contributions to our understanding of the pandemic, what risks factors are, how the virus spreads and how our bodies react. And there are many more women in Bristol and elsewhere who deserve so much credit for their hard work and exciting discoveries.
Is the department working on ways of improving diversity?
We are very international and diverse: members of our laboratory come from the United States, India, Iran, China, South Africa, Germany, France, Italy, Spain, Hungary, Greece, Wales and England. We very much enjoy this cultural diversity. It’s particularly nice when people bring traditional food to share with the team. Half of our team is female. We lack Black minority team members. The University of Bristol has recently announced a scholarship programme scheme to support the study of Black heritage students which hopefully helps drive a cultural change.
It felt surreal to walk to work through a deserted Clifton, meet the same few people in otherwise empty laboratories and return again at night through a ghost town
How did you get into your line of work, and why Bristol?
I started my scientific career in Zürich, Switzerland; there I met my husband who is also a scientist. We both moved as group leaders to the European Molecular Biology Laboratory in Grenoble, France. When we started planning our next joint career move, we received an offer in the UK and contacted our long-time collaborator and friend – a professor at University of Bristol – seeking advice about the ins and outs of job negotiations at UK universities. He made us aware of two open professorship positions in Bristol and encouraged us to apply, and here we are. It turned out to be a fantastic opportunity for us; we work closely together and share all resources.
What do you think you would have gone into if not this?
Research is what I always wanted to do – the intellectual freedom, curiosity and excitement that comes with it is just so attractive. At the same time, I was aware that academic research is a crowded field, and while in Switzerland, I briefly considered teaching chemistry in secondary school. I attended courses in didactics and pedagogics and started giving chemistry lessons to pupils but I realised that I would miss life in the laboratory too much.
How do you like to relax?
I read a wide variety of books, mostly Ian Rankin thrillers and Jeffrey Archer. I recently enjoyed Michael Sandel The Tyranny of Merit: What’s Become of the Common Good? and I plan to read Elena Ferrante’s Neapolitan novels.
What do you love most about the part of the city?
I love that living in Bristol offers all upsides and commodities of a ‘big city’ without really feeling like one. We live in Clifton and I can conveniently walk to the university, to the city centre or to the harbour. I love all the nature and green areas in Bristol. We have foxes in our neighbourhood, and some time ago I even saw a badger racing over the Downs.
To discover more about the research of Professor Christiane Berger-Schaffitzel and the team at Berger Labs visit the Bristol University website : bristol.ac.uk; or follow the team on twitter: @berger_labs
