19 March 0214 - Great British bioscience pioneers – Professor Dame Janet Thornton
In the third in a series of articles on Great British bioscience pioneers, Professor Dame Janet Thornton, Director of the European Bioinformatics Institute (EMBL-EBI) highlights advances in the understanding of protein structure, function and evolution that underpin life.
How did your bioscience career first begin?
"When I was studying as a physics undergraduate at the University of Nottingham, I realised that although I loved the understanding and rigorous approaches employed in physics, my real interests lay in understanding biology and life. I applied for a PhD at the National Institute for Medical Research in London where I enrolled for a master's conversion course. This was a lifeline since I had a lot to learn.
"I started to become more and more involved in computational work on molecules produced by living organisms. I studied them in three dimensions on the new computer screen, changing their conformation and calculating the associated energies. After my PhD, I went to Oxford Biophysics where the focus of the lab was determining and understanding the 3D structures of proteins. I had found my niche."
What are you working on now?
"There are two strands in my laboratory. The first is 'understanding how proteins, especially enzymes change their sequences and structures through small and large scale variations, and so evolve new functions'.
"We have recently had a breakthrough in being able to compare reactions computationally using our EC-BLAST algorithm - software that makes it easier to develop novel enzymes. This has allowed us to study quantitatively how function changes with sequence. Combining this with the measurable change in sequence and structure during evolution allows for quick and efficient analysis of enzyme evolution in different protein families. This reveals the complexities of the function of evolution, where small changes or whole domain changes can lead to a change of function.
"The second strand is 'computational analysis to help elucidate the molecular basis of ageing.' This delightful collaboration with experimental colleagues in London demonstrates the challenge of moving from the molecular level to the organismal phenotype and back again. Linking molecular changes in biochemistry and pathways with changes in lifespan so that we understand cause and effect remains challenging and continues to keep me busy.
"At EBI, we are also celebrating our 20th Anniversary this year, looking back on a remarkable two decades of growth and discovery, sharing ideas about the future of bioinformatics."
What advances have you seen in your chosen field in the last 20 years?
"In some areas there have been tremendous advances, but in others our understanding has developed more slowly.
"When I started looking at protein structures, there were only 20 which had been determined. Now there are nearly 100,000 in the Protein Data Bank. Our understanding of the structure and architecture of proteins has advanced dramatically, and with this has come a 3D understanding of how molecules perform biological processes which is elegant and very satisfying.
"However the more basic theoretical challenges such as predicting protein structure from sequence remain unsolved, except by comparison to homologous proteins. The original dreams of the ab initio 'from the beginning' prediction do not diminish."
What are the 5 key bioscience milestones that you've been part of?
- 1980's: Characterising the elements of protein structures
- 1993: Improving Protein Structure Validation using known structures to define expectations for the stereochemistry of new structures
- 1994: Protein Structure Classification (CATH)
- 2001: Understanding more about how proteins evolve new functions
- 2014: Successful comparison of enzyme reactions – EC-BLAST A fully automated computational approach to compare enzyme reactions
How has BBSRC supported you throughout your career
"In the early part of my career, BBSRC (then part of the Science Research Council) funded my part-time independent fellowship at Birkbeck (1980-1985), my first proper job as a part-time lecturer (1985), my involvement in the Protein Engineering Club which introduced me to many colleagues in industry and my first grant panel.
"Since BBSRC was founded, I have received over 15 grants. Of these were the usual three year research grants, studentships, grants contributing to developing centres at UCL and grants involving industrial partners. The subjects covered basic research such as protein folding, neural network predictions, work with industry on genome annotation and core support for the bioinformatics and structural biology centre at UCL.
"BBSRC has also provided generous support for many of the core resources at EBI in collaboration with colleagues in academia around the UK. This forward-looking strategic goal to support bioinformatics services has been critical in providing excellent bioinformatics services from the UK."
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