5 June 2019 – M. Madan Babu, one of two recipients of the EMBO Gold Medal 2019, talked to Rosemary Wilson about his work on G-protein coupled receptors and disordered proteins, the importance of collaboration and embracing new ideas.
What motivated you to pursue a computational approach to biological research?
Around the time I started my degree we experienced a revolution in genomics, in structural biology, and in sequencing technologies – every few years there was another wave of technological advancement and understanding. An enormous amount of data was being produced, describing various biological entities and processes from diverse organisms. It started to become clear that by understanding and integrating these diverse types of data, we can ask and answer fundamental questions. I found this cross-over between computational science and biology to be exciting and unique.
You have made some important discoveries about a medically important class of proteins called GPCRs. What insights did your work reveal?
G-protein coupled receptors sit across the cell membrane and transmit signals into the cell. There are about 800 GPCRs encoded in the human genome and they regulate virtually every aspect of human physiology. Given their central role, over one-third of all FDA-approved drugs target members of this family. In the last decade or so, more than 300 structures of different GPCRs have been published. At the same time, there has been excitement in being able to sequence entire exomes and genomes of individuals to understand natural variation in human populations.
By integrating genomics data and GPCR structure data we found that several GPCRs targeted by drugs show extensive genetic variation in the human population. We showed that this variation occurs in parts of the GPCR protein that matter for the drug response. For example, we observed polymorphisms in the GPCR targeted by morphine and painkillers, which may explain why antidotes to an opioid overdose may not always work. This is a good example of how an integrative, data-science based approach can provide new insights and potentially have an impact on society and healthcare.
Your work has changed our understanding about disordered proteins. What were the key findings of your studies?
About 40% of the proteins in eukaryotes are unlikely to adopt a defined structure on their own but are still functional. That really got our attention. Why are they so prevalent? How do they function? How are they integrated into cellular networks and contribute to different phenotypes?
We have shown that disordered proteins play a role in rewiring protein interaction networks in both space and time, for example by segregating specific proteins to one part of the cell, or ensuring that two proteins only interact at a certain time during development. Disordered proteins can therefore influence the function and health of the cell and the whole organism. We also found that cells tightly regulate the abundance of disordered proteins. This helps to explain why mutations that affect the abundance of these proteins are implicated in diseases such as cancer and neurodegeneration.
Your research encompasses many different disciplines and biological questions. How important is collaboration in your work?
Collaboration is critical on many levels. Talking to colleagues with different backgrounds really sharpens my own thinking. And, for example, we also collaborate a lot within the group. We have people working on developing computational approaches at the molecular level, systems level and at the genome level. Having everyone together is valuable as we not only identify knowledge gaps but can also offer new insights. It’s been so important to have people from different backgrounds and trainings within the group. This diversity has been a key factor for several of our projects.
What advice do you pass onto your students?
Spend time getting to know how the data was generated, and its limitations before jumping in. Frame the question clearly. This is half the problem solved and helps you from getting distracted.
I believe it is important to embrace failure. You might think you’ve lost a lot of time, but you have acquired a lot of experience and expertise understanding the data and the scientific question. That is a privileged position to be in.
Finally, have confidence in what you know but be open-minded. To push the boundaries of conventional wisdom, we have to question the basic facts and be prepared to embrace new ideas.
What does receiving the EMBO Gold Medal mean to you?
It is a great recognition of the work we are doing, which would not be possible without the past and present members of my research group and the generous, long-term funding from the Medical Research Council’s Laboratory of Molecular Biology. It is also recognition of the contribution of knowledge to the field of molecular biology that comes from computational work. That’s a great feeling.