David Roth works in immunology research and development. Here he talks to us about the complexity of the body’s defence system and how we’re working to unlock its hidden secrets to help bring new medicines to patients.
It’s incredible that every moment of every day, our immune system works tirelessly to defend our bodies from attack. As a clinical nephrologist by training, the exquisite complexity of the body’s defence system continues to amaze me. There is something beautiful about the way our immune system silently protects us while we go about our daily lives.
This desire to unlock the hidden secrets of the immune system inspired me to pursue a career in immunology and so I started my journey by going to med school. In my second year, I remember having tremendous trouble with a pathophysiology course on the functional changes that occur in the body as a result of disease. I just couldn’t understand why the immune system worked in the way it did.
After a while, I realised there was nothing wrong with my understanding – there just wasn’t very much known. Scientists were still unravelling the role of B cells, T cells and the many other elements of the immune system that come together like instruments in a symphony.
These huge gaps in our knowledge meant there was a lot left to discover about the immune system and after 22 years at GSK, I am proud to help continue to uncover important parts of the puzzle.
I am particularly motivated by the need to understand what happens when the immune system goes wrong, when this incredible defence system starts to turn on itself and cause disease. Take lupus for example. Instead of seeking out foreign invaders to protect the body from infection, B cells turn rogue and produce antibodies that start attacking healthy tissues leading to symptoms such as joint pain and stiffness, extreme tiredness, kidney and other major organ involvement and skin rashes.
What happens when your body's defence system turns on itself?
We've made a lot of progress in understanding the pathophysiology of lupus and how the immune system is disrupted in this challenging autoimmune condition. When I learned about lupus in medical school, we were taught it was the prototypical B cell/antibody-mediated disease. No other parts of the immune system were deemed to be important for lupus to occur. When I was training in nephrology at the University of Pennsylvania, my division chief, Eric Neilson, as well as others, demonstrated that actually T cells could be involved in the pathogenesis of the disease as well.
Now it is becoming apparent that other parts of the immune system, including neutrophils, are also involved. What this is saying to us is that assessing autoimmune disease by looking only at one component of the immune system, is like hearing Mozart’s Jupiter Symphony by only listening to the violins. That is not to say that the violins are not important, but the complexity comes from the interplay of the different instruments.
Even when we look at a single cytokine involved in lupus, B cell activating factor (BAFF), we now understand that it has effects beyond just B cells. Despite our increased understanding, there is still a long way to go in uncovering the subtypes of lupus and how they differ pathophysiologically and revealing other diseases affected by these pathways.
Unlike traditional R&D, where we first choose a disease and then develop a drug to treat it, we take an unblinkered approach. We look at what the science is showing us, without bias, and challenge ourselves to look deeply at the data to make sure we are thinking broadly enough and don’t miss any opportunities. This ‘disease-agnostic’ approach can lead to interesting surprises and disease areas we weren’t previously thinking about.
For instance, earlier this year we held a B Cell Summit in New York, which brought together world-leading experts in rheumatology, dermatology, nephrology and many other fields. Instead of a traditional advisory board, we took a unique approach by sharing all our basic and clinical findings with the external experts and in turn listening to their data presentations on the B cell pathway. Then we asked the question of where it makes sense to look next? This resulted in a tremendous exchange of scientific ideas. As a direct result of the B Cell Summit, a number of supported studies are being progressed in various indications including inflammatory bowel disease, autoimmune hepatitis, chronic lymphocytic leukemia and a whole range of other diseases.
By following the science, we hope to reduce the industry-wide failure rate for drugs in development, which currently stands at over 90%. This just isn’t a sustainable number from an industry perspective, or a patient care perspective, and it means there aren’t enough treatments coming through. If we could bring that rate down, even just a little, it would have an enormous impact on patients.
I’m very excited about our pipeline and our ability to make better risk-based decisions earlier on by linking certain pathways with specific diseases. Bringing new medicines to patients with autoimmune conditions requires many different functions and so collaborations are vital both at GSK and with external partners.
Just like in my own project team, I like to think of us all working together as an organism or, indeed like the immune system itself. Our shared goal of helping as many patients as possible holds us together and I’m excited for what the future holds as we reveal the beautiful complexity of the immune system.
This blog is part of our A view from the lab… series, sharing insights from scientists around our company. It was originally published on David's LinkedIn profile
