Louis-Jeantet Prize for Medicine 2007
The Louis-Jeantet Prize for Medicine 2007 has been awarded to two scientists working in the United Kingdom: Dr Venki RAMAKRISHNAN and Dr Stephen WEST. Dr Ramakrishnan is a researcher at the Medical Research Council’s Laboratory of Molecular Biology, Cambridge, and Dr West is a Principal Scientist at Cancer Research UK’s London Research Institute laboratory at Clare Hall in Hertfordshire. The Louis-Jeantet Prize for Medicine encourages further projects of excellence in the prize-winners’ laboratories. Venki Ramakrishnan receives the Prize for his work on determining the three-dimensional structure of the ribosome, while Stephen West receives the Prize for his pioneering work on the mechanisms of genetic recombination and DNA strand break repair. In particular, he has defined relationships between defective DNA repair processes and human diseases such as inheritable breast cancer and neurological disorders. With the Prize, Stephen West will carry out work to broaden our understanding of inheritable syndromes such as Ataxia Oculomotor Apraxia and Fanconi anemia. The Louis-Jeantet Foundation has awarded each prize-winner a sum of €400,000 to pursue their research together with a personal prize of €75,000. The awards ceremony for the Prizes will be held in Geneva (Switzerland) on Friday 27th April 2007. On hearing of the Prize Steve commented “I’m delighted to be awarded the Jeantet Prize for Medicine 2007. It is a great honour for me to know that the Jeantet Foundation has chosen to support my research program. I have been in science for 30 years, and throughout this time it has been a wonderful journey in which I have had the pleasure of interacting with some of the very best scientists. I owe this award to many people, in particular to Paul Howard-Flanders (my post-doc mentor and scientific father figure) who taught me to reach for the top and to enjoy the process of discovery, and to Tomas Lindahl who gave me the opportunity to establish my research group in the wonderful scientific environment that he created at Clare Hall, and of course to acknowledge the first-rate scientific support that I have received from the Imperial Cancer Research Fund and now Cancer Research UK. As Tomas said when he recruited me ‘if you can’t do science here, then you simply can’t do it’. He was right. Most importantly though, I owe a great debt to the many post-docs and students who have worked in my lab over the years and have contributed to the development of new ideas and directions. This Prize is a testament to their hard work, endeavors and ultimate success.” Stephen WEST biography:
Stephen West is a British citizen, born in the town of Hessle, Yorkshire, in 1952. He studied Biochemistry at Newcastle University and completed his PhD thesis in 1977 with Peter Emmerson, also at Newcastle University. He then carried out post-doctoral work with Paul Howard-Flanders in the Department of Molecular Biophysics and Biochemistry at Yale University, New Haven, USA, before becoming a Research Scientist in the Department of Therapeutic Radiology at Yale University. In 1985, he moved back to the UK to set up an independent research group at the Imperial Cancer Research Fund’s new Clare Hall Laboratories at South Mimms. Steve has remained at Clare Hall ever since, and is a Principal Scientist with Cancer Research UK. He has been awarded many distinctions, notably election to EMBO, the Royal Society, and the Academy of Medical Sciences. In 2002 he was awarded the Swiss Bridge Prize Award for Cancer Research, and presented the Leeuwenhoek Prize Lecture of the Royal Society. Stephen WEST receives the 2007 Louis-Jeantet Prize for Medicine for his pioneering work on the mechanisms of genetic recombination and DNA strand break repair. Dr West began his scientific career using model systems to define the molecular mechanisms responsible for repairing broken or damaged chromosomes. He then used this information as the basis to understand related DNA repair processes in humans. In particular, he is known for isolating and characterizing repair enzymes that play critical roles in the rejoining of DNA breaks that occur when cells replicate their DNA before cell division. A critical issue in every cell of any organism is the ability to promote the efficient repair of damaged DNA. Without effective DNA repair the genetic content of each cell will quickly become unstable, leading to changes that will affect all cellular processes and may ultimately cause tumour formation. DNA damage occurs often and with potentially catastrophic effect, especially in growing cells that need to faithfully replicate their genome prior to cell division. This is the reason why efficient DNA repair processes are so critical for cell survival. In recent years, a clear link has been established between genome instability caused by defective repair processes and cancer. Dr West’s research has focused on understanding DNA repair processes at the molecular level in order to gain new insights into human disease. The early part of Dr West’s career was spent understanding how simple organisms such as bacteria carry out the repair of DNA double-stranded breaks which arise during DNA replication, or are caused by exogenous agents such as radiation or harmful chemicals. Specifically, he set about characterizing the cellular enzymes that repair chromosome breaks by a pathway known as homologous recombination, and through detailed biochemical analyses developed in vitro systems in which the key steps of the recombinational repair reaction could be reconstituted in the test-tube. During this period, he carried out classic work with the RecA protein, showing how it promotes homologous pairing and DNA strand exchange within the context of a nucleoprotein filament. He was also the first to identify the RuvA, RuvB and RuvC proteins that promote the branch migration and resolution of Holliday junctions, which arise as intermediates during the recombination process. Dr West’s work then shifted from recombinational repair in simple organisms to develop an understanding of related processes in human cells. Although more complex, there were also some remarkable similarities, notably with the RAD51 recombinase which was found to form nucleoprotein filaments almost indistinguishable from those made by bacterial RecA. Subsequent studies of RAD51 provided a link to cancer, since a protein known as BRCA2 that regulates RAD51 activity during the cell cycle and in response to DNA damage, is known to be defective in about 10% of inheritable breast cancers. It was shown that BRCA2 interacts specifically with RAD51 and exerts both positive and negative control over its actions. When BRCA2 is defective, the repair of double-strand breaks by homologous recombination is compromised, leading to a genome instability phenotype that affects all cellular functions and ultimately sends the cell down a pathway to uncontrolled growth. For this reason, BRCA2, the regulator of RAD51, is a tumour suppressor. Most recently, work from his research group has defined the molecular defect associated with a neurological disorder known as Ataxia with Oculomotor Apraxia-1 (AOA1). It was shown that the product of the Aptx gene, Aprataxin, which is defective in individuals with AOA1, acts as a proofreader for abortive DNA ligation reactions. All cells, especially neuronal cells, are subjected to high levels of oxidative stress resulting in the formation of DNA strand breaks. When these breaks are repaired by a DNA ligase, it is not uncommon for the reaction to stall at an intermediate stage, such that ‘abortive ligation intermediates’ accumulate. It was found that Aprataxin specifically interacts with these intermediates and removes the AMP residue that ligase leaves covalently bound to the 5’-side of the unrepaired nick after abortive ligation. The loss of Aprataxin activity is particularly evident in neurological tissue that, due to its non-proliferative nature, is unable to utilize alternative (replication-associated homologous recombinational repair) mechanisms to remove these lesions. Without Aprataxin, unrepaired nicks with 5’-AMP moieties will accumulate in the neuronal tissue over a period of years until they are sufficiently numerous to pose a significant block to transcription. Many neuronal cells will then undergo apoptosis and cell death leading to the characteristic neurological features associated with the disorder AOA1. Thus, Aprataxin, like RAD51, plays a critically important cellular role in guarding the genome against DNA damages that would otherwise pose a block to normal cellular processes, again illustrating the link between defective DNA repair and human disease. The Louis-Jeantet Foundation for Medicine:
The Louis-Jeantet Foundation for Medicine was established according to the will of Louis Jeantet, a French businessman who died in Geneva in 1981. Based in Geneva, the Foundation started its activities in 1983, and awards a major scientific Prize to up to three scientists each year. The purpose of the Prize is to foster innovative biomedical research in Europe. In addition, the Louis-Jeantet Foundation encourages high quality research at the University of Geneva Medical School by endowing Professorships. Louis-Jeantet Professors are provided with funds for research and administrative personnel. The Louis-Jeantet Prize for Medicine is not intended to honour past, or already celebrated, achievements. Rather, it is awarded with a view to stimulating the highest quality of research projects. Prize-winners must be engaged in basic or clinical medical research in a member country of the Council of Europe, although they need not themselves be European Nationals. Since its inception in 1986, the Louis-Jeantet Prize for Medicine has been awarded to 64 researchers working in Europe, or which 21 were from the UK, 12 from Switzerland, 10 from Germany, 10 from France, 3 from the Netherlands, 3 from Sweden, 2 from Belgium, 2 from Finland and 1 from Austria. In total, the Foundation has awarded approximately 27 million Euros to the 64 Prize-winners to pursue their research. For additional information regarding the Louis-Jeantet Foundation contact:
Professor Bernard C. Rossier (Secretary of the Science Committee)
Louis-Jeantet Foundation for Medicine, Geneva, Switzerland
Tel: 41 21 692 53 51, secretary 50 or 60
E.mail: bernard.rossier@unil.ch
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