Kelvin J. A. Davies - Biography
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Education and Academic Posts
Kelvin Davies was born and raised in London, UK and educated at Liverpool and Lancaster Universities. He received an M.Sc. degree from the University of Wisconsin (1976) and his C.Phil and Ph.D. degrees in Physiology and Biochemistry from the University of California at Berkeley (1979/1981). Following post-doctoral work in the Physiology Dept. at Harvard Medical School, and a junior faculty position at Harvard University, he became Assistant then Associate Professor of Biochemistry & Molecular Biology, and Physiology & Toxicology at the University of Southern California. Davies was next recruited to Albany Medical College as Chairman of the Department of Biochemistry & Molecular Biology, John Muntz University Professor, and Distinguished Professor of Molecular Medicine. In 1996 Davies moved back to the University of Southern California as James E. Birren Endowed Professor of the Biology of Aging, and as Professor of Molecular and Computational Biology, and Professor of Biochemistry & Molecular Biology (Medicine). He was Associate Dean of Research at USC's Leonard Davis School of Gerontology (1996-2006), then Associate Dean (2008-2011), and is now Dean of Faculty and Dean of Research (2012-Now).
Honorary Degrees, Fellowships & Awards
Davies has been awarded seven honorary doctoral degrees from European, South American, and Chinese Universities. He has won numerous medals, prizes, distinguished/lifetime scientific achievement awards, and mentoring awards; and has been elected a Fellow of no less than eight national and international scientific societies. Davies has been Visiting Professor or Distinguished Visiting Professor at the following universities: Cambridge, Camerino, Ancona, Pisa, Padova, Moscow, Rennes, and the European University of Brittany. Kelvin Davies has held visiting professor positions at many European Universities including, Rennes, European University of Brittany, Pisa, Padova, Ancona Camerino, Cambridge and Sienna. Davies is a Fellow of eight national/international societies, including the American Association for the Advancement of Science, the Royal Society of Biology, the Royal Society of Medicine, the Royal Society of Chemistry, and the Academy of Europe (Academia Europaea) . He was given the Lifetime Scientific Achievement Award of the Society for Free Radical Biology & Medicine in 2006. He has received various medals and honorary doctoral degrees from several European and American Universities, and was knighted as a Chevalier de l’Ordre National du Mérite de France in 2012.
Professional Activities/Scientific Societies
Building on the strong free radical chemistry background that already existed, Davies became a key player in establishing the Free Radical Biology & Medicine field and its major scientific journal. Kelvin Davies was a founding member of the UK Society for Free Radical Research, and of the US Oxygen Society. He was also a founding member of the Society for Free Radical Biology & Medicine, its first Secretary General in 1987, and its President in 2002. From 1988-1990 he spearheaded efforts, with colleagues in Europe (especially UK, France, Italy, Germany) to create the International Society for Free Radical Research (SFRR International). Davies was Secretary General of SFRR International (2002-2004) and then President (2006-2008). He started the first scientific journal in the field, Free Radical Biology & Medicine, in 1985 and has now been Editor-in-Chief for 30 years. He has also been Editor-in-Chief of the journals, Biochemistry & Molecular Biology International and IUBMB Life and an associate editor or editorial board member for numerous other scientific journals including the Biochemical Journal.
In 2012/2013 Davies organized negotiations between the European Society for Free Radical Research and the (American) Society for Free Radical Biology & Medicine such that both societies joined together in adopting the journal Free Radical Biology & Medicine as their official print journal, and the two societies jointly launched a new open access journal called Redox Biology; these affiliations have greatly increased both the scientific and financial standing of the two societies.
Kelvin Davies has been a Council Member of the Research Council of New Zealand (1988-Now), the International Union of Biochemistry and Molecular Biology (1995-1999), the Gordon Research Conferences (1995-2000, 2007-2010), the National Institute of Environmental Health Sciences (2003–2006), the American Federation for Aging Research (2003-Now), and the National Heart, Lung, and Blood Institute (2005–2009). He has organized or co-organized scientific meetings and conferences in France (four in Paris), Germany, Italy, Greece, Spain, Israel, India, Malaysia, and Argentina; as well as some 15 meetings in America. He has also chaired three Gordon conferences, Free Radicals, Oxidative Stress & Disease, and Ageing.
Davies was the founding President of the California Philharmonic Orchestra, and the CalPhil Orchestra Foundation. He is now President Emeritus of both organizations. He also was the founding Director of the S.T.A.R. program (Student Tutoring And Research), a cooperative agreement between the University of Southern California and the Los Angeles County Schools District. This program introduces children from disadvantaged neighborhoods to potential careers in science, medicine, dentistry, and the allied health professions.
Davies has mentored some 28 former graduate (M.Sc. and Ph.D.) students, as well as 30 post-doctoral fellows. He has won Mellon mentoring awards for his work with undergraduate students, with graduate students, and with junior faculty.
Scientific Career & Research Accomplishments
Kelvin Davies pioneered the study of protein oxidation and the selective proteolysis of oxidized proteins, establishing that oxidation is a major factor in mammalian protein turnover by Proteasome and the mitochondrial Lon protease: discoveries that at first met with significant resistance but which have now been incorporated within mainstream biochemistry. He demonstrated the importance and universality of transient and reversible oxidative stress-adaptation via coordinated patterns of gene expression, and the role of the Nrf2 signal transduction pathway. He discovered six oxidative-stress genes, including RCAN1 which favorably regulates the activity of calcineurin in stress, but is associated with Alzheimer disease and Down syndrome when chronically overexpressed. He played a major role in uncovering age-related declines in Proteasome and Lon inducibility, and declining shock & stress gene adaptive-responses in ageing.
Kelvin Davies most highly cited research concerns the genes encoding enzymes that selectively degrade oxidatively damaged proteins, and his laboratory has made contributions to our understanding of this subject over the past thirty five years. His research is focused on the regulation of damage removal and repair genes that minimize the toxic effects of environmental oxidants, and the apparent decline of such systems during ageing. His work involves biochemical, molecular biology, and genetic studies of both normal ageing processes, and age-associated pathologies such as Parkinson, Alzheimer, and Huntington diseases.
During ageing, and in several age-related disease processes, vital cellular proteins are damaged by free radicals produced by environmental toxicants, metabolism, chronic inflammation, radiation, smoke, and by many foods and drugs. These oxidized and non-functional proteins must be removed before they aggregate, cross-link, and become permanent cellular inclusion bodies that propagate damage. Several years ago, the Davies lab. discovered that the Proteasome recognizes and selectively degrade such damaged proteins in the cytoplasm, endoplasmic reticulum, and nucleus, while the Lon protease performs the same function with intramitochondrial proteins, thus minimizing aggregate formation and allowing the synthesis of replacement proteins.
More recently, the Davies lab. discovered that expression of the mitochondrial Lon Protease, the Proteasome, the Immunoproteasome, and the Pa28αβ and Pa200 Proteasome regulators are all increased during adaptation to oxidative stress (hormesis), that the Nrf2/EpRE signal transduction pathway appears to play a significant role in, at least part, of this adaptive response, and that phosphorylation of the 26S Proteasome may regulate its disassembly (into free 20S Proteasomes and 19S regulators bound to HSP70) during oxidative stress; thus temporarily supplying more 20S Proteasomes to degrade oxidized proteins. The group has also recently discovered that not only does Lon and Proteasome activity decline in ageing, but Lon and Proteasome inducibility may be impaired, making older individuals more prone to toxicity from environmental oxidants, and the deterioration and diseases associated with the accumulation of damaged protein aggregates. The mechanisms by which such damaged protein aggregates, Lon and the Proteasome, may contribute to age-related increases oxidative toxicity and diseases is now a major topic of interest for the Davies group. They have also recently discovered that the mitochondrial Lon Protease is a bona fide human shock or stress protein, whose levels are increased by more than seven-fold during adaptation to oxidative stress. Interestingly lon mRNA levels barely increase during stress adaptation, raising the possibility that lon is under translational control during stress; this is a possibility we now plan to test. Additionally, they have now shown that Lon inducibility by stress declines with senescence in animal and human cells. This raises the possibility that diminished Lon inducibility may contribute to age-related declines in stress adaptability. The mechanism of Lon induction during stress, and the loss of this capability in ageing are major questions for their future research.
While one half of the Davies laboratory works on proteins, the other half is studying the genetic basis of adaptation to oxidative stress, and has discovered seven new genes that contribute to stress resistance. One of these genes, called RCAN1, unfortunately seems to have a dual nature; a Jeckyll and Hyde gene? The RCAN1 gene consists of seven exons that undergo differential splicing to encode a family of proteins, called the RCAN1 proteins, that inhibit the serine/threonine phosphatase, Calcineurin. When expressed transiently, RCAN1’s seem to promote a strong and protective adaptive response to stress by preventing calcineurin from turning the stress response off. When RCAN1 is expressed chronically, however, it seems to promote hyperphosphorylation of the tau protein and the formation of neurofibrillary tangles, which are common features of both Down syndrome and Alzheimer disease. Importantly, the group has shown (in vitro) that RCAN1-induced hyperphosphorylation of the tau protein makes it a very poor substrate for degradation by the proteasomal pathway that is normally responsible for tau turnover. In postmortem studies, the Davies group has found very high levels of RCAN1 expression in the brains of Alzheimer and Down patients. The group is now trying to determine whether or not RCAN1 is actually a causal factor in the progression of neurodegenerative diseases.
Other Activities
Davies was the founding President of the California Philharmonic Orchestra, and the CalPhil Orchestra Foundation. He is now President Emeritus of both organizations. He also was the founding Director of the S.T.A.R. program (Student Tutoring And Research), a cooperative agreement between the University of Southern California and the Los Angeles County Schools District. This program introduces children from disadvantaged neighborhoods to potential careers in science, medicine, dentistry, and the allied health professions.
Citation History, H Index & Selected Publications
According to a Google Scholar search on the 15th of January 2015, Kelvin J. A. Davies has an overall H index of 96. Below are a selection of 15 publications out of over 300 since 1982. The number of actual citations for each paper below (in blue) was also determined by a Google Scholar search. Kelvin J. A. Davies has a total of 27 Citation Classics (defined as papers with 300 or more citations), his Total Citations = 28,304, and he has an i10 index of 175.
1. Davies, K.J.A., Quintanilha, A.T., Brooks, G.A., and Packer, L. (1982) Free radicals and tissue damage produced by exercise. Biochem. Biophys. Res. Commun. 107, 1198 - 1205 (1,673 Citations).
2. Davies, K.J.A. (1987) Protein damage and degradation by oxygen radicals: I-IV. J. Biol. Chem. 262, 9895 - 9920 (total 3,222 Citations for papers I-IV).
3. Zhang, Y., Marcillat, O., Giulivi, C., Ernster, L., and Davies, K.J.A. (1990) The oxidative inactivation of mitochondrial electron transport chain components and ATPase. J. Biol. Chem. 265, 16330-16336 (623 Citations).
4. Davies, K.J.A. (1995) Oxidative Stress: the paradox of aerobic life. Biochem. Soc. Symp. 61, 1-31 (919 Citations).
5. Grune, T., Reinheckel, T., and Davies, K.J.A. (1995) Protein degradation in cultured liver epithelial cells during oxidative stress: role of the multicatalytic proteinase complex, proteasome. J. Biol. Chem. 270, 2344-2351 (383 Citations).
6. Grune, T., Reinheckel, T., and Davies, K.J.A. (1995) Degradation of oxidized proteins in mammalian cells. FASEB. J. 11, 526-534 (715 Citations).
7. Ullrich, O., Reinheckel, T., Sitte, N., Haass, G., Grune, T., and Davies, K.J.A. (1999) Poly-ADP-ribose-polymerase activates nuclear proteasome to degrade oxidatively damaged histones. Proc. Natl. Acad. Sci. (USA) 96, 6223-6228 (183 Citations).
8. Cadenas, E. and Davies, K.J.A. (2000) Mitochondrial free radical production, oxidative stress, and aging. Free Radic. Biol. Med. 29, 222-2230 (1,825 Citations).
9. Davies, K.J.A. (2001) Degradation of oxidized proteins by the 20S proteasome. Biochimie 83, 301-310 (572 Citations).
10. Bota, D. and Davies, K.J.A. (2002) Lon protease preferentially degrades oxidized mitochondrial aconitase by an ATP-stimulated mechanism Nature Cell Biol. 4, 674-680 (333 Citations).
11. Shringarpure, R., Grune, T., and Davies, K.J.A. (2003) Ubiquitin-conjugation is not required for the degradation of oxidized proteins by proteasome. J. Biol. Chem. 278, 311-318 (329 Citations).
12. Costa V., Giacomello M., Hudec R., Lopreiato R., Ermak G., Lim D., Malorni W., Davies K.J.A., Carafoli E., and Scorrano L. (2010) Mitochondrial fission and cristae disruption increase the response of cell models of Huntington's disease to apoptotic stimuli. EMBO Molecular Medicine. 2, 490-503 (86 Citations).
13. Pickering, A.M., Koop, A.L., Teoh, C.Y., Ermak, G., Grune, T., and Davies, K.J.A. (2010) The immunoproteasome, the 20S proteasome and the PA28 proteasome regulator are oxidative-stress-adaptive proteolytic complexes. Biochem. J. 432:585-594 (106 Citations).
14. Ermak, G., Sojitra, S., Yin, F., Cadenas, E., Cuervo, A.M., and Davies, K.J.A. (2012) Chronic expression of RCAN1-1L induces mitochondrial autophagy and a metabolic shift from oxidative phosphorylation to glycolysis in neuronal cells. J. Biol. Chem. 287, 14088-14098 (21 Citations)
15. Pickering, A.M, Linder, R.A., Zhang, H., Forman, H.J., and Davies, K.J.A. (2012) Nrf2 dependent induction of proteasome and Pa28αβ regulator is required for adaptation to oxidative stress. J. Biol. Chem. 287, 10021-10031 (61 Citations)
