The Oxford Science Lecture Series

Professor Dame Janet Thornton  FRS FMedSci

European Bioinformatics Institute

“From molecules to medicine”

 Dorothy Hodgkin Memorial Lecture 2017

Somerville College, Oxford, 10th March 2017

Dame Janet Thornton studied physics at the University of Nottingham, followed by a master’s degree in biophysics at King’s College London leading to her PhD at the National Institute of Medical Research at Mill Hill, on the outskirts of London. She commented that, as a married woman, her PhD grant was less than anyone else’s! She then moved to Oxford and was a young post-doc when Dorothy Hodgkin was there. Dame Janet remembers her as a gentle but determined woman who asked penetrating questions at seminars. Dorothy’s presence meant that female crystallographers never felt that they weren’t as good as the men.

In her lecture, Dame Janet presented a personal view of the field of crystallography. She started by studying nicotinamide adenine dinucleotide (NAD) but as she was a physicist she knew no biology. She learnt how to program a computer to work out whether NAD molecules stacked so that the aromatic rings came together. When she finished her PhD in 1973, there were no jobs in computing so she got a job as a systems administrator in a lab working on protein structures. It was not long after Dorothy had solved the structure of insulin and a time when people were only beginning to understand what protein structures were. She was in the lab in Oxford when David Phillips solved the crystal structure of triose phosphate isomerase, which was exquisitely symmetrical and prompted the question of how proteins folded. For the first ten years of Dame Janet’s work she didn’t care what the proteins did, just their structure. During this time she had two children and worked two days a week. She then won a half-time fellowship to go to Birkbeck College in the ‘80s, when more and more protein structures were being solved. Some of the published structures were incorrect, so Dame Janet developed tools to clean up the structures. Her paper on this programme, ProCheck, is one of the most cited papers. She also realised that the field needed a way to classify shapes of proteins, and so developed a method akin to that used to classify plants.

Dame Janet went on to discuss how protein structures became important for target and drug discovery and she formed a company to predict protein structures for structure activity relationships (the relationship between the 3D structure of a molecule and its biological activity). She moved to EMBL as Director in 2001, by which time over 10,000 protein structures had been solved. The European Bioinformatics Institute now has over 700 employees, a big change from the ‘70s when there were no jobs in protein structures. However the downside of becoming Director was that she had to spend over 50% of her time doing administration! In the same year, the human genome was sequenced, and this transformed the world of biological research. Dame Janet commented that in 2003 the cost of sequencing DNA was comparable to the cost of one of the more expensive houses in London, now it is the cost of a football season ticket! The UK has led the way and plans to sequence 100,000 genomes, particularly in areas of cancer, pathogens, childhood diseases and hospital infections. This needs a huge amount of information to be stored and interpreted but can be extremely beneficial. The genome of MRSA is only little and takes less than an hour to sequence. As MRSA passes from one person to another, it changes its sequence and so it is possible to track the progress of the infection by studying these mutations.

It is probable that in the future everyone will have their genome sequenced and this will affect medicine. Dame Janet went on to discuss how knowledge of variants in DNA translate to medical diagnosis and treatment. Variants in DNA sequence can lead to changes in the amino acids within a protein and thus to the protein structure, which will affect how well the protein will work. By studying variants in the insulin gene, you can map out the structure and determine how particular variants can lead to diabetes, so Dorothy Hodgkin’s original work is still yielding valuable information. If you know you have a DNA variant that is strongly linked to a specific disease, you can take steps to prevent development of that disease, as shown by actress Angelina Jolie choosing to have a mastectomy to prevent her getting breast cancer. In addition, it is possible to design personalised drugs, for example Vemurafenib works on one variant of melanoma, and will clear up all the tumours in patients with that variant, whilst patients with other variants are not affected.

Dame Janet described how the Deciphering Developmental Disorders project is looking at the genes of children with developmental disorders. By comparing the DNA of the child with that of their parents, they can discover spontaneous variants and link these to protein structures that may not be working properly. Dame Janet’s team are also looking at changes that occur with ageing. They have found a variant in the insulin signalling pathway in the worm that can extend lifetime. Moreover the variants are additive and they now have worms that live six times longer than normal! Using bioinformatics to combine data from worms, flies and mice they can translate discoveries to humans and look for ways to delay the onset of disease.

Dame Janet finished her fascinating lecture with a few personal observations. She said that research is great fun and that there has been astounding progress in the field of proteins structures over her lifetime. It is hard work and it doesn’t get any easier. She said that it had been a great privilege to lead the staff at EMBL and added that women in leadership are needed at all stages of their careers. She said that women shouldn’t wait for someone to give them leadership, they should not be reluctant and should take it when they saw the opportunity, commenting that she has never been conscious of negative discrimination during her own career, probably due to the influence of Dorothy Hodgkin. The leader of a group or a department is extremely important, a scientific group is like a family, and Dame Janet commented that being a mother is good training for being a group leader! She finished by saying that it is possible to have a good work-life balance in scientific research, although the scales tip from one side to the other over the years depending on the challenge!

Prof. Carolyn Carr, Associate Professor of Biomedical Science, University of Oxford.

Honorary Senior Research Fellow, Imperial College