In the first in a series of articles, Professor Sir Tom Blundell FRS, FMedSci looks back at the highlights from his 50 year career, including the important contributions he has made to determine the first 3D structures of hormones and growth factors, and the pioneering computer-based approaches to protein modelling and prediction that he has developed.
How did your bioscience career first begin?
"I joined the multidisciplinary laboratory of Professors Dorothy Hodgkin FRS and Tiny Powell FRS in Oxford in 1964. After learning the crystallography trade and writing some computer programs to implement new techniques, I moved to work with Dorothy on the 3D structure of insulin, the hormone that lowers blood sugar and a project that she had been pursuing for around 30 years.
"In 1969 we solved the structure defining the hexameric zinc insulin; we showed that this has advantages for insulin storage in the pancreas and for the treatment of diabetes, but the monomeric form recognises its receptor – this led to papers in Nature. I followed this work up in my own group in Sussex by defining the structure of glucagon, the yin of insulin's yang in blood sugar control, thus defining the first two structures of polypeptide hormones."
What are you working on now?
"The insulin work led to an interest in the architecture and organisation of complex regulatory systems, especially of hormones and growth factors. I am now working on three interrelated topics:
- The architectures of growth factors, such as fibroblast growth factor (FGF) and hepatocyte growth factor (HGF), and their multi-protein assemblies with receptors and signalling pathways. I also study similar multi-protein assemblies of DNA double-strand break repair signalling
- Developing software and databases to predict protein structure, interactions and function, free to academics and commercialised for companies, mainly based on understanding the evolution of protein families and based on ideas developed in the '70s about insulin, relaxin and the insulin-like growth factor (IGF) superfamily
- Developing structure-guided methods of drug discovery that explore chemical space effectively – so-called fragment-based methods. Astex, the company I co-founded in 1999, has eight drugs in clinical trials. In my academic lab we target the complex regulatory system involved in metastasis involving FGFR and Met receptors. We also work on infectious disease targets, especially tuberculosis."
What advances have you seen in your chosen field in the past 20 years?
"The first structures of proteins like insulin took several decades to solve and even nerve growth factor (NGF) took my group 15 years (solved in 1990). Molecular biology and biochemistry now make proteins available in the laboratory, which are present in only tiny quantities in living organisms.
"Synchrotrons for X-ray data collection, faster computers for data processing and more powerful electron microscopes have accelerated our work, while biophysical methods like isothermal calorimetry, nuclear magnetic resonance and surface plasmon resonance have revolutionised the way we look at the dynamics and thermodynamics of macromolecular interactions.
"The increases of speed and decreases in cost due to second-generation sequencing have allowed us to investigate protein systems in humans and animals, as well as their pathogens and the resistance arising from new drugs and antibiotics. We now have a structural biology that deals with spatial and temporal aspects of individual molecules, multicomponent assemblies and subcellular systems."
What are the five key bioscience milestones that you've been part of and when did these occur?
- "Determining the first 3D structures of polypeptide hormones (1969 to 1975)
- The first uses of protein structure-guided design of new therapeutics, which has subsequently transformed early discovery in pharmaceuticals and antimicrobials in much of the industry (late '70s and early '80s)
- The first computer programs for knowledge-based protein modelling and prediction, including Composer and Modeller for comparative or homology modelling, now used worldwide in academia and industry (1985-1991)
- The definition of the architectures of complex multi-protein assemblies involved in cell signalling and regulation, including cell surface receptors that recognise growth factors (such as FGFR and Met), and DNA repair signalling involving non-homologous end joining (DNA-dependant protein kinase and DNA-ligase complexes) and homologous recombination (BRCA2 and the recombinase Rad51) (1995 and ongoing)
- The development of new relational databases, such as CREDO, to store data about proteins, nucleic acid structures and their interactions, to link these to modern sequence and structure databases and those that store biological activity like CheMBL (2005 and ongoing)."
How has BBSRC supported you throughout your career?
"The Science Research Council (until 1981) and then the Science and Engineering Research Council were critically important to my career from the mid-1960s until 1990 – funding my early work in Oxford, Sussex and Birkbeck. I took over as Director General of the Agricultural and Food Research Council in 1991 at a time of change – expressed in the Government White Paper of the time, 'Realising our Potential' – and was immediately and centrally involved in the restructuring of the research councils. This led to my appointment as the founding Chief Executive of BBSRC in 1994.
"In order to avoid conflict of interests, the Imperial Cancer Research Fund generously funded my core research in London until 1996 and then the Wellcome Trust followed in Cambridge. My roles as Chief Executive and, more recently, as Chair of BBSRC have given me a good perspective on the importance of multidisciplinary bioscience in human and animal health, biotechnology and protein engineering, and the many aspects of agri-biotech."
Tom Blundell is Director of Research and Professor Emeritus of Biochemistry at the University of Cambridge.
In 1976, after research and teaching positions in molecular biophysics at the University of Oxford and biochemistry at the University of Sussex, he was appointed Professor in Birkbeck College, University of London. In 1996 he moved to Cambridge as Sir William Dunn Professor and Head of the Department of Biochemistry until 2009. He was also Head of the School of Biological Sciences between 2003 and 2009. Tom Blundell is a member of Academia Europaea, a Fellow of the Royal Society, Fellow of the Academy of Medical Sciences and of the Third World Academy of Sciences. He has Honorary Doctorates from 15 universities.
Sir Tom was a Non-Executive Director of Celltech from 1996 to 2005 and has been involved in science advisory roles with Pfizer, UCB, SmithKlyneBeecham, Syntaxin and Isogenica over the past thirty years. He co-founded the drug discovery company Astex Therapeutics in 1999. In 2013, the company, now trading under the name Astex Pharma, was purchased for nearly $1Bn by Otsuka. It has oncology drugs in early stage clinical trials in USA and UK, and employs around 80 staff on the Science Park in Cambridge.
Sir Tom has played an active role in national science policy. In the 1980s, he was a member of the advisory group to the Prime Minister (ACOST). He was Director General of the Agricultural and Food Research Council (1991-1994) and founding Chief Executive of BBSRC (1994-1996), Chairman of the Royal Commission on Environmental Pollution (1998-2005) and President of the UK Biosciences Federation between 2004 and 2008. He has been the non-executive Chair of BBSRC Council since 2009 and President of the Science Council since 2011.