The big interview: Prof Anne O'Garra

Words: Viel Richardson
Portraits: Orlando Gili

“Discovery without boundaries. This is the core principle underlying the creation of The Francis Crick Institute,” says Professor Anne O’Garra, FMedSci, leading immunologist and associate research director at the revolutionary biomedical research institute, which opened in King’s Cross in August 2016. “The aim of the Crick is to create medical research programmes that produce high quality, paradigm-changing discoveries through highly collaborative working. We are also aiming to develop future science leaders who can advance UK science and innovation.” These are bold aims. In short, the Crick is setting out to become a biomedical research institute and training facility that redefines our approach to fighting disease.

At the heart of its mission is the fostering of a new, multidisciplinary approach to biomedical research. Modern scientific research is so complex and expensive that the days of the lone genius making breakthroughs in a small private laboratory are vanishing fast, and even large institutions that fund their teams to undertake individual research projects are increasingly finding limitations in this approach.

“Traditionally, research teams would be wholly responsible for a project, sometimes in conditions of great secrecy,” Prof O’Garra explains. “The aim was to produce ‘hot’ papers which generated positive interest from the wider scientific community. This interest made it easier to generate funding for further research. Sometimes collaborations were encouraged, but not always. But we have now reached a stage where technologies are so complicated that one laboratory cannot do certain types of research on its own. We believe that fostering collaboration between different disciplines leads to better science and increases the chances of ground-breaking discoveries.”

The impetus for the development of The Francis Crick Institute was provided by the Cooksey Report, an independent review of health research funding in the UK carried out by Sir David Cooksey. Published in 2006, the report assessed the state of the British medical research environment and set out a vision for enhancing its effectiveness.

Innovative therapies
In it, Sir David highlighted the strength of the UK’s research capability and gave great credit to the NHS research and development directorate for its efforts to engage with researchers and healthcare industries in the development of innovative therapies. However, it also concluded that pharmaceutical, diagnostics and biotech companies often found it easier to develop products outside the UK because of high costs and lack of access to patients for clinical trials. The final report recommended that an overall biomedical research environment be developed within the UK to address these concerns.

The Francis Crick Institute was conceived to play a central role in this new landscape. “In order to achieve this aim, the institute has been created in a unique way,” Prof O’Garra explains. “Its foundations are a set of symbiotic relationships between six of the world’s leading biomedical research organisations: the Medical Research Council, Cancer Research UK, the Wellcome Trust, University College London (UCL), Imperial College London and King’s College London.”

This spirit of collaboration has been built into the very fabric of the institute’s tailor-made central London headquarters, designed by HOK with PLP Architecture. The architects wanted to create a space that physically encouraged interaction between the scientists. Laboratories are arranged over four floors, each consisting of four interconnected blocks, and at the centre of each floor is a reception and seating area where researchers can interact.

“The idea is that these interactions will allow for chance meetings as well as planned cross-fertilisation of ideas,” the professor tells me. “The laboratories are also designed to be adaptable, so as new scientific opportunities emerge, the Crick can remain at the forefront of biomedical research.”

Future science leaders
As one of five associate research directors at the institute, Prof O’Garra is responsible for overseeing a programme designed to develop future science leaders. “Group leaders come to us having led excellent post-doctoral projects,” Prof O’Garra explains. “We aim for absolute excellence, so to get here they have to propose a creative research programme that is going to bring forward high quality discoveries.”

Once accepted, a group leader will work on a project for six years, during which time Prof O’Garra will ensure they receive the necessary mentoring. Between the fifth and sixth years, their progress is reviewed. “If they have done well, they can stay for another six years. After that, they have to move on to positions elsewhere so we can continue to develop the next generation of leaders.”

The skills they pick up along the way are fundamental. “They have to be able to lead a team effectively as well as drive the project forward and produce high quality papers for publication. Publishing papers is a scientist’s passport: sharing new work with the wider scientific community allows you to create new collaborations and helps gain future funding. It is what you are all about, because in the end we want to go out into the world and have a positive impact on human health.”

Beyond the post-doctoral stage, the number of women participating in scientific research drops off alarmingly, and having been the chair of a previous Athena Swan award—an initiative set up to promote gender equality in science, technology, engineering, maths and medicine—Prof O’Garra is deeply invested in ensuring that more women become leaders in their fields.

Professor Anne O’Garra

Widening the net
The figures show how much work needs to be done: for PhD level researchers, the gender split is 60% female, 40% male; for post-doctoral researchers it is 50% each; and at the level of research group leaders it is 20% female, 80% male. “The question we are asking is how are we going to fix this,” she says with feeling. “The talent is clearly there—it is just not getting through.”

One approach has been to cast the recruitment net much more widely, while offering support to women who apply. “We do not do affirmative action, because research excellence is our aim, but we do have targets about how many women need to be interviewed and then asked back for second interviews. The talent is out there, and simply by widening the net we are identifying more excellent female scientists who are making their way through the system. We have the same approach for people from black and ethnic minority backgrounds.”

As one of the world’s leading immunologists, Prof O’Garra certainly provides an example to which other female researchers can aspire. But although she is responsible for running her own research programmes at the Crick, even eminent scientists like her cannot depend upon a guaranteed place, such is the institute’s commitment to excellence. “Every five years we have to write a review paper to justify our place here,” she explains. “I have to detail the papers we have produced, show where they have been taken up by others and give examples of where our work has led directly to research programmes being set up elsewhere. I also have to detail how we plan over the next five years to build on the work we have done.”

Alongside her research into the workings of the immune system at cellular level, the professor is involved in an effort to fight the scourge that is tuberculosis. “I wanted to tackle one of the diseases that are devastating parts of the world, and one of the reasons I chose TB is that there was an overlap with the immunological work I was doing, through a type of protein called a cytokine. It meant that I knew this was an area where potential progress could be made.”

Making headway
Progress is certainly needed. According to the World Health Organisation’s 2017 global tuberculosis report, TB is the ninth leading cause of death worldwide and the leading cause from a single infectious agent. Specific targets set out in the WHO End TB Strategy call for a 90% reduction in TB deaths and an 80% reduction in new cases per year by 2030, compared with 2015. While some headway has been made, the current rates of reduction will miss this target, so a great deal of work is still needed.

This is not an issue confined to distant shores. Contrary to what many believe, TB has not been eradicated here at home—in fact, the UK recently This is not an issue confined to distant shores. Contrary to what many believe, TB has not been eradicated here at home—in fact, the UK recently

Prof O’Garra’s mission is to find a way of identifying people who are at risk of becoming seriously ill from the disease. “I am investigating what is happening at the very early stages of TB,” she explains. “A third of all people in the world are estimated to have been infected with Mycobacterium tuberculosis (Mtb), but remain what we call latent, which means they show no symptoms. Only 10% of those who are latent will go on to develop TB. All we can say is that they are positive when tested for reactivity to Mtb, but we can’t currently tell who will develop the disease and who will not. As part of our research, we have a collaboration with our colleagues at Leicester University who are collecting blood as early as they can after the infection has occurred and before any symptoms appear.”

Volunteers are tested to establish their TB status. They are then monitored extremely closely, with blood samples taken every week and examined at a cellular level. “We are looking for anything that occurs in those who develop symptoms, in the hope of finding something that could become the basis of a diagnostic test. We are also looking at cells in the lung to see what type of changes may be occurring there, as this might show us what is happening with the infection.”

The fight against TB
Alongside this, the professor’s core work as an immunologist also has implications for the fight against TB. “I run the Laboratory of Immuno-regulation and Infection, and my work in the lab is on the regulation of proteins called cytokines, which are a category of small proteins that are important in cell-to-cell signalling. We are investigating their role in the immune response. I am particularly looking at the role of a cytokine called Interleukin 10. This is what we call a negative regulatory molecule, because its role is to stop an over-exuberant response from the immune system, which can cause diseases such as colitis,” the professor explains. “However, too much Interleukin 10 can also contribute to chronic infections and we have shown that it is over-expressed in active tuberculosis.”

Prof O’Garra and her colleagues are trying to obtain information that will allow the development of ‘prognostic markers’—biomarkers that help to determine infected people’s risks of going on to develop the disease. But the information they are uncovering is also being used to improve the experimental models used in research into human disease by scientists who are trying to understand the pathways different molecules take that lead to the immune system either protecting from or causing disease.

“The holy grail, and we are definitely making progress, is to be able to tell someone who is infected that they are in the category of people with a high risk of developing the disease. If you can do that, you can then put them into a clinical situation which will either prevent the disease or mitigate the disease when it arrives,” Prof O’Garra enthuses. “For example, at the moment, with a grant from the technological research institute BIOASTER, we are working with BioMérieux, which is a French company that specialises in diagnostics in infectious diseases.

“The aim of this collaboration is to improve treatment monitoring when measuring the effectiveness of new drugs for fighting TB. The current test looks for a change in sputum Mycobacterium load, which, for a variety of reasons, can be very difficult to conduct. A test based on blood samples, which may come out of our work with our colleagues in Leicester, could be powerful, and BioMérieux is helping us develop these tests.”

Future diagnosis
Prof O’Garra’s teams are also examining the complex data they are gathering in relation to tuberculosis and comparing it to other lung diseases. “We are seeing similarities and examining how we can best identify the set of genes that are going to be most specific to a particular disease. Knowing this will give the highest sensitivities to any future diagnosis tests we develop.”

With one foot in pure research and the other in applied research, Prof O’Garra’s work pretty much sums up the ethos of The Francis Crick Institute: the drive for cutting edge, collaborative investigations that end in real world solutions. Geneticist Sir Paul Nurse, who was jointly awarded a Nobel Prize in 2001, is the director and chief executive of the Crick and was one of the driving forces behind its creation. He described the aim of the institute as “understanding the fundamental biology underlying health and disease” and “helping to understand why disease develops and find ways to prevent, diagnose and treat illnesses”. Essentially, he wants the institution’s researchers to find ways to help eradicate serious human illness.

It is a huge task, which at the moment looks like a tiny light at the end of a very long tunnel. But with scientists like Prof O’Garra and her colleagues making full use of the collaborative environment The Francis Crick Institute provides, that lofty goal might just be a little more attainable than it once was.