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Denis Noble

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This article is about the British biologist. For the British baritone, see Dennis Noble.

Denis Noble
CBE FRS FMedSci MAE
Born (1936-11-16) 16 November 1936 (age 87)[2]
NationalityBritish
EducationEmanuel School
Alma materUniversity College London (BSc, MA, PhD)
Spouse
Susan Jennifer Barfield
​
​
(m. 1965)​
[2] Died 2015
Children2[2]
Awards
Scientific career
Fields
InstitutionsBalliol College, University of Oxford
ThesisIon conductance of cardiac muscle (1961)
Doctoral advisorOtto Hutter
Website

Denis Noble CBE FRS FMedSci MAE[3] (born 16 November 1936) is a British physiologist and biologist who held the Burdon Sanderson Chair of Cardiovascular Physiology at the University of Oxford from 1984 to 2004 and was appointed Professor Emeritus and co-Director of Computational Physiology. He is one of the pioneers of systems biology and developed the first viable mathematical model of the working heart in 1960.[4][5][6][7][8] Noble established The Third Way of Evolution (TWE) project with James A. Shapiro which predicts that the entire framework of the modern synthesis will be replaced.[9]

Education

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Noble was educated at Emanuel School and University College London (UCL).[2][4] In 1958 he began his investigations into the mechanisms of heartbeat. This led to two seminal papers in Nature in 1960[10][11] giving the first experimentally-based mathematical simulation of the electrical rhythm of the heart,[12] extensively developed with Richard Tsien in 1975,[13] and with Dario DiFrancesco in 1985.[14] All three articles form the foundations of modern electrophysiology of the heart. The 1985 article was included in 2015 in the Royal Society's 350 year celebration of the publication of Philosophical Transactions.[15]

From this work it became clear that there was not a single oscillator which controlled heartbeat, but rather this was an emergent property of the feedback loops involving the various ion channels. In 1961 he obtained his PhD working under the supervision of Otto Hutter at UCL.[16][17]

Research

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Noble's research focuses on using computer models of biological organs and organ systems to interpret function from the molecular level to the whole organism. Together with international collaborators, his team has used supercomputers to create the first virtual organ, the virtual heart.[18][19]

As secretary-general of the International Union of Physiological Sciences 1993–2001, he played a major role, together with Sir Peter Hunter, in launching the Physiome Project, an international project to use computer simulations to create the quantitative physiological models necessary to interpret the genome, and he was elected president of the IUPS at its world congress in Kyoto in 2009.[20]

Noble is also a philosopher of biology, with many publications in journals and books of philosophy.[21][22][23]

His books The Music of Life, Dance to the Tune of Life and Understanding Living Systems challenge the foundations of current biological sciences, question the central dogma, its unidirectional view of information flow, and its imposition of a bottom-up methodology for research in the life sciences[24]

Reductionism

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His 2006 book The Music of Life examines some of the basic aspects of systems biology, and is critical of the ideas of genetic determinism and genetic reductionism. He points out that there are many examples of feedback loops and "downward causation" in biology, and that it is not reasonable to privilege one level of understanding over all others. He also explains that genes in fact work in groups and systems, so that the genome is more like a set of organ pipes than a "blueprint for life". His 2016 book Dance to the Tune of Life sets these ideas out in a broad sweep from the general principle of relativity applied to biology, through to the role of purpose in evolution and to the relativity of epistemology.[citation needed]

He contrasts Dawkins's famous statement in The Selfish Gene ("Now they [genes] swarm ... safe inside gigantic lumbering robots ... they created us, body and mind; and their preservation is the ultimate rationale for our existence") with an alternative view: "Now they [genes] are trapped in huge colonies, locked inside highly intelligent beings, moulded by the outside world, communicating with it by complex processes, through which, blindly, as if by magic, function emerges. They are in you and me; we are the system that allows their code to be read; and their preservation is totally dependent on the joy we experience in reproducing ourselves. We are the ultimate rationale for their existence". He then suggests that there is no empirical difference between these statements, and says that they differ in "metaphor" and "sociological or polemical viewpoint".[25]

He argues that "the paradigms for genetic causality in biological systems are seriously confused" and that "The metaphors that served us well during the molecular biological phase of recent decades have limited or even misleading impacts in the multilevel world of systems biology. New paradigms are needed if we are to succeed in unravelling multifactorial genetic causation at higher levels of physiological function and so to explain the phenomena that genetics was originally about."[26]

The Third Way of Evolution

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Noble has called for an extended evolutionary synthesis, and more controversially a replacement for the modern synthesis known as The Third Way of Evolution (TWE).[9][27][28]

He has argued that from research in epigenetics, acquired characteristics can be inherited and in contrast to the modern synthesis, genetic change is "far from random" and not always gradual. He has also claimed that the central dogma of molecular biology has been broken as an "embodiment of the Weismann Barrier",[29] and a new synthesis will integrate research from physiology with evolutionary biology.[30][31][32][33][34]

Noble and James A. Shapiro established The Third Way of Evolution (TWE) project in 2014. The TWE which is also known as the "Integrated Synthesis" shares many similarities with the extended evolutionary synthesis but is more extreme in its claims.[9] The TWE consists of a group of researchers who provide a "Third Way" alternative to creationism and the modern synthesis. The TWE predicts that the modern synthesis will be replaced with an entirely new evolutionary framework. Similar to the extended evolutionary synthesis (EES), advocates cite examples of developmental bias, genetic assimilation, niche construction, non-genetic inheritance, phenotypic plasticity and other evolutionary processes.[9] Shapiro's natural genetic engineering, a process described to account for novelty created in biological evolution is also important for the TWE.[33][34][35] The difference between the extended synthesis and the TWE is that the latter calls for an entire replacement of the modern synthesis rather than an extension.[9]

In 2022, the HowTheLightGetsIn Festival at Hay-on-Wye featured Noble and Richard Dawkins in a "conversation" on evolution.[36] In 2024 he was featured in Forbes with a video and associated article. He has now (2024) published more than 50 articles and books on evolutionary biology. THETHIRDWAYOFEVOLUTION has now edited 8 special issues of Journals or Book Series, comprising over 100 articles.

In 2023, evolutionary biologist Erik Svensson commented that "to date, there are few leading evolutionary biologists who have openly embraced the TWE" and it is unlikely that an entire replacement of the modern synthesis will occur as there has been little visibility of such a forthcoming paradigm shift during the past decade.[9]

Principles of Systems Biology

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Denis Noble at a meeting on Systems Biology at Chicheley Hall, August 2013

Noble has proposed Ten Principles of Systems Biology:[37][38]

  1. Biological functionality is multi-level
  2. Transmission of information is not one way
  3. DNA is not the sole transmitter of inheritance
  4. The theory of biological relativity: there is no privileged level of causality
  5. Gene ontology will fail without higher-level insight
  6. There is no genetic program
  7. There are no programs at any other level
  8. There are no programs in the brain
  9. The self is not an object
  10. There are many more to be discovered; a genuine 'theory of biology' does not yet exist

Career

[edit]
  • 1961–1963 – Assistant lecturer in Physiology, University College London
  • 1961–1963 – Vice-warden of Connaught Hall (University of London)[39]
  • 1963–1984 – Fellow and tutor, Balliol College, Oxford. University Lecturer in Physiology
  • 1967–2024 – Editor-in Chief of Progress in Biophysics and Molecular Biology[40]
  • 1969–1970 – Visiting professor and visiting scientist of the Canadian MRC
  • 1971–1989 – Head (praefectus) of the Balliol College Graduate Centre at Holywell Manor
  • 1975–1985 – Leader of MRC Programme Grant team
  • 1983–1985 – Vice-master of Balliol College
  • 1986 – co-founder of Save British Science, now the Campaign for Science and Engineering
  • 1984–2004 – Burdon Sanderson Professor of Cardiovascular Physiology, Oxford University
  • 1984–2004 – Professorial fellow, Balliol College
  • From 2004 – Emeritus professor of Cardiovascular Physiology, Oxford University
  • From 2004 – Emeritus fellow of Balliol College, Oxford
  • From 2004 – Director of Computational Physiology, Oxford
  • 2003–2007 – Adjunct professor, Xi’an Jiaotong University, Shaanxi province, China
  • From 2005 – Visiting professor, Osaka University, Japan
  • 2009–2017 – President, International Union of Physiological Sciences[41]
  • From 2009 – Co-founder and editor-in-chief of Voices from Oxford[42]
  • 2011–2017 – Editor in chief of Interface Focus[43][44][45]
  • From 2014 – Member and co-founder of The Third Way of Evolution[46]
  • From 2021 – Co-Founder Oxford Longevity Project[47]

Publications

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Noble has published over 700 articles in academic journals,[1][19] including Nature,[10][11][48][49][50][51] Science,[52][53] PNAS,[54] Journal of Physiology,[55][56][57][58][59] Progress in Biophysics & Molecular Biology;[60] Many articles in national press. He is the author or editor of many books, including:

Awards and honours

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His major invited lectures include the Darwin Lecture for the British Association in 1966,[61] the Nahum Lecture at Yale in 1977 and the Ueda lecture at Tokyo University in 1985 and 1990. He was President of the Medical Section of the British Science Association 1991–92. Many further invited lectures during his election as Secretary-General (1993-2001) and President (2009-2017) of IUPS.

In 1979 he was elected a Fellow of the Royal Society. His nomination for the Royal Society reads:

Distinguished for the discovery of slowly activated potassium currents in the heart and a quantitative analysis of their role in controlling repolarization and pacemaker activity; the discovery of the ionic mechanisms by which adrenaline increases heart rate. He has shown that therapeutic levels of cardiac glycosides may increase, rather than decrease, potassium gradients in the heart, and has published an analytical treatment of membrane excitation theory and cable theory that provides a modern basis for the concepts of safety factor, liminal length, excitation time constants and the phenomenon of repetitive firing.[3]

He was elected an Honorary Member of the Royal College of Physicians in 1988 and an Honorary Fellow in 1994, an Honorary Member of the American Physiological Society in 1996 and of the Physiological Society of Japan in 1998. In 1989 he was elected a Member of the Academia Europaea. In 1998, he also became a founding Fellow of the Academy of Medical Sciences.[62] In 1998 he was awarded a CBE.[63] In 2021 he was elected a Fellow of the IUPS Academy. In 2022 he was elected a Fellow of The Linnean Society (FLS)

He has honorary doctorates from the University of Sheffield (2004),[64] the Université de Bordeaux (2005) and the University of Warwick (2008).[65]

He is an Honorary Foreign Member of the Académie Royale de Médecine de Belgique (1993),[66] of the Istituto Lombardo Accademia di Scienze e Lettere, and received the Pavlov Medal of the Russian Academy of Sciences (2004). In 2022 he was elected Foreign Member of the Russian Academy of Sciences and was also awarded the Lomonosov Gold Medal.[67]

Personal life

[edit]

Noble was born in London in 1936 to working-class tailors, George and Ethel Noble."George Noble". The family lost its home in London when a high explosive bomb, probably intended for Clapham Junction, destroyed several houses in nearby Lavender Sweep."Lavender Sweep High Explosive bomb". As a teenager, he was trained as a magician by a stage performer, Tommy Dee, who may have been a model for the famous TV magician, Tommy Cooper.[citation needed] He plays classical guitar and sings Occitan troubadour and folk songs (Oxford Trobadors[68]). In addition to English, he has lectured in French on YouTube, Italian on YouTube, Performance with Nadau & Peiraguda Occitan,[69][70] Japanese and Korean.[71]

References

[edit]
  1. ^ a b Denis Noble publications indexed by Google Scholar
  2. ^ a b c d Anon (2014). "Noble, Prof. Denis". Who's Who (online Oxford University Press ed.). Oxford: A & C Black. doi:10.1093/ww/9780199540884.013.U29605. (Subscription or UK public library membership required.)
  3. ^ a b "EC/1979/28: Noble, Denis". London: The Royal Society. Archived from the original on 30 May 2014. Retrieved 30 May 2014.
  4. ^ a b Biography Archived 25 April 2006 at the Wayback Machine, Denis Noble homepage.
  5. ^ Music of Life lecture in Maribor 2012 on YouTube
  6. ^ Lecture on Evolution IUPS Opening plenary 2013 on YouTube
  7. ^ Noble, D. (2013). "Physiology is rocking the foundations of evolutionary biology". Experimental Physiology. 98 (8): 1235–1243. doi:10.1113/expphysiol.2012.071134. PMID 23585325. S2CID 19689192.
  8. ^ Ten Tusscher, K. H. W. J. (2003). "A model for human ventricular tissue". AJP: Heart and Circulatory Physiology. 286 (4): H1573–H1589. doi:10.1152/ajpheart.00794.2003. PMID 14656705.
  9. ^ a b c d e f Svensson, E.I. (2023). The Structure of Evolutionary Theory: Beyond Neo-Darwinism, Neo-Lamarckism and Biased Historical Narratives About the Modern Synthesis. In: Dickins, T.E., Dickins, B.J. (eds) Evolutionary Biology: Contemporary and Historical Reflections Upon Core Theory. Springer. pp. 173–217. ISBN 978-3-031-22027-2
  10. ^ a b Noble, Denis (1960). "Cardiac action and pacemaker potentials based on the Hodgkin-Huxley equations". Nature. 188 (4749): 495–7. Bibcode:1960Natur.188..495N. doi:10.1038/188495b0. PMID 13729365. S2CID 4147174.
  11. ^ a b Hutter, Otto F.; Noble, Denis (1960). "Rectifying properties of heart muscle". Nature. 188 (4749): 495. Bibcode:1960Natur.188..495H. doi:10.1038/188495a0. PMID 13717088. S2CID 4273708.
  12. ^ Noble, Denis (1962). "A modification of the Hodgkin—Huxley equations applicable to Purkinje fibre action and pacemaker potentials". The Journal of Physiology. 160 (2): 317–352. doi:10.1113/jphysiol.1962.sp006849. PMC 1359535. PMID 14480151.
  13. ^ McAllister, Eric; Noble, Denis; Tsien, Richard (2022). "Reconstruction of the electrical activity of cardiac Purkinje fibres". Journal of Physiology. 251 (1): 1–59. doi:10.1113/jphysiol.1975.sp011080. PMC 1348375. PMID 1185607.
  14. ^ DiFrancesco, Dario; Noble, Denis (2022). "A model of cardiac electrical activity incorporating ionic pumps and concentration changes". Philosophical Transactions of the Royal Society B. 307 (1133): 353–398. doi:10.1098/rstb.1985.0001. PMID 2578676.
  15. ^ Partridge, Linda (2015). "Celebrating 350 years of Philosophical Transactions: life sciences papers". Philosophical Transactions of the Royal Society B. 370 (1666). doi:10.1098/rstb.2014.0380. PMC 4360128. PMID 25750243.
  16. ^ Noble, Denis (1962). Ion conductance of cardiac muscle (PhD thesis). University College London.(subscription required)
  17. ^ Dennis Noble (2006). The Music of Life, ISBN 0-19-929573-5
  18. ^ All systems go article in The Economist 25-Oct-2007 discussing Noble's work
  19. ^ a b Denis Noble's publications indexed by the Scopus bibliographic database. (subscription required)
  20. ^ "Auckland Bioengineering Institute - The University of Auckland". www.Auckland.ac.nz. Retrieved 15 April 2019.
  21. ^ Noble, Denis (1967). "Charles Taylor on Teleological Explanation". Analysis. 27 (3): 96–103. doi:10.2307/3326802. JSTOR 3326802.
  22. ^ Noble, Denis (1993). "The logic of life: the public perception of science and its threat to the values of society". Science and Public Policy. doi:10.1093/spp/20.3.187.
  23. ^ Noble, Raymond; Noble, Denis (2022). "Can reasons and values influence action: how might intentional agency work physiologically?". Journal for General Philosophy of Science. 52 (2): 277–295. doi:10.1007/s10838-020-09525-3. S2CID 228947493.
  24. ^ Werner, E. (2007). "SYSTEMS BIOLOGY: How Central is the Genome?". Science. 317 (5839): 753–754. doi:10.1126/science.1141807. S2CID 82065292.
  25. ^ The Music of Life, pp. 12-14
  26. ^ Noble, D. (September 2008). "Genes and causation". Philosophical Transactions of the Royal Society of London. Series A, Mathematical and Physical Sciences. 366 (1878): 3001–3015. Bibcode:2008RSPTA.366.3001N. doi:10.1098/rsta.2008.0086. ISSN 1364-503X. PMID 18559318. S2CID 17592966.
  27. ^ "The theory of evolution has evolved". The Physiological Society.
  28. ^ "Replace the Modern Synthesis (Neo-Darwinism): An Interview With Denis Noble". HuffPost.
  29. ^ Noble, Denis (2018). "Central Dogma or Central Debate?". Physiology. 33 (4): 246–249. doi:10.1152/physiol.00017.2018. ISSN 1548-9213. PMID 29873598.
  30. ^ Noble, Denis (2013). "Physiology is rocking the foundations of evolutionary biology". Experimental Physiology. 98 (8): 1235–1243. doi:10.1113/expphysiol.2012.071134. PMID 23585325. S2CID 19689192.
  31. ^ "Physiology and the revolution in Evolutionary Biology" Archived 2 December 2015 at the Wayback Machine. Voices from Oxford.
  32. ^ Noble, D; Jablonka, E; Joyner, MJ; Müller, GB; Omholt, SW (2014). "Evolution evolves: physiology returns to centre stage". The Journal of Physiology. 592 (11): 2237–44. doi:10.1113/jphysiol.2014.273151. PMC 4048083. PMID 24882808.
  33. ^ a b Noble, Denis (2021). "The Illusions of the Modern Synthesis". Experimental Physiology. 107 (9): 1015–1028. doi:10.1113/EP090133. PMC 9543272. PMID 35871280. S2CID 251019199.
  34. ^ a b Noble, Denis (2022). "Modern Physiology vindicates Darwin's Dream". Experimental Physiology. 107 (9): 1015–1028. doi:10.1113/EP090133. PMC 9543272. PMID 35871280. S2CID 251019199.
  35. ^ Shapiro J, Noble D (2021). "What prevents mainstream evolutionists teaching the whole truth about how genomes evolve?". Prog Biophys Mol Biol. 165: 140–152. doi:10.1016/j.pbiomolbio.2021.04.004. PMID 33933502.
  36. ^ "The Gene Machine". iai.tv.
  37. ^ Noble, D (2008). "Claude Bernard, the first systems biologist, and the future of physiology". Experimental Physiology. 93 (1): 16–26. doi:10.1113/expphysiol.2007.038695. PMID 17951329. S2CID 3080457.
  38. ^ "Principle of Systems Biology illustrated using the Virtual Heart". videolectures.net. Retrieved 15 April 2019.
  39. ^ "Archived copy". Archived from the original on 30 July 2018. Retrieved 7 December 2013.{{cite web}}: CS1 maint: archived copy as title (link)
  40. ^ "Progress in Biophysics & Molecular Biology". Retrieved 15 April 2019 – via www.journals.elsevier.com.
  41. ^ IUPS
  42. ^ "Voices From Oxford". Voices From Oxford. Retrieved 15 April 2019.
  43. ^ Noble, D. (2011). "A theory of biological relativity: No privileged level of causation". Interface Focus. 2 (1): 55–64. doi:10.1098/rsfs.2011.0067. PMC 3262309. PMID 23386960.
  44. ^ Noble, D (2011). "Differential and integral views of genetics in computational systems biology". Interface Focus. 1 (1): 7–15. doi:10.1098/rsfs.2010.0444. PMC 3262251. PMID 22419970.
  45. ^ Noble, D (2011). "Editorial". Interface Focus. 1 (1): 1–2. doi:10.1098/rsfs.2010.0385. PMC 3262238. PMID 22419969.
  46. ^ "Home - The Third Way of Evolution". www.thethirdwayofevolution.com. Retrieved 15 April 2019.
  47. ^ "Oxford Longevity Project". www.oxfordlongevityproject.org. Retrieved 8 October 2022.
  48. ^ Blakemore, C; Dawkins, R; Noble, D; Yudkin, M (2003). "Is a scientific boycott ever justified?". Nature. 421 (6921): 314. doi:10.1038/421314b. PMID 12540875. S2CID 47249920.
  49. ^ Egan, T. M.; Noble, D; Noble, S. J.; Powell, T; Twist, V. W. (1987). "An isoprenaline activated sodium-dependent inward current in ventricular myocytes". Nature. 328 (6131): 634–7. Bibcode:1987Natur.328..634E. doi:10.1038/328634a0. PMID 2441262. S2CID 4324641.
  50. ^ Cohen, I; Giles, W; Noble, D (1976). "Cellular basis for the T wave of the electrocardiogram". Nature. 262 (5570): 657–61. Bibcode:1976Natur.262..657C. doi:10.1038/262657a0. PMID 958437. S2CID 4174864.
  51. ^ Hall, A. E.; Noble, D (1963). "Transient Responses of Purkinje Fibres to Non-Uniform Currents". Nature. 199 (4900): 1294–5. Bibcode:1963Natur.199.1294H. doi:10.1038/1991294a0. PMID 14074602. S2CID 4217721.
  52. ^ Noble, D (2002). "Modeling the heart--from genes to cells to the whole organ". Science. 295 (5560): 1678–82. Bibcode:2002Sci...295.1678N. doi:10.1126/science.1069881. PMID 11872832. S2CID 6756983.
  53. ^ Hauswirth, O; Noble, D; Tsien, R. W. (1968). "Adrenaline: Mechanism of action on the pacemaker potential in cardiac Purkinje fibers". Science. 162 (3856): 916–7. Bibcode:1968Sci...162..916H. doi:10.1126/science.162.3856.916. PMID 4386717. S2CID 23508494.
  54. ^ Noble, D (2002). "Unraveling the genetics and mechanisms of cardiac arrhythmia". Proceedings of the National Academy of Sciences. 99 (9): 5755–6. Bibcode:2002PNAS...99.5755N. doi:10.1073/pnas.102171699. PMC 122846. PMID 11983875.
  55. ^ Noble, D (1962). "A modification of the Hodgkin--Huxley equations applicable to Purkinje fibre action and pace-maker potentials". The Journal of Physiology. 160 (2): 317–52. doi:10.1113/jphysiol.1962.sp006849. PMC 1359535. PMID 14480151.
  56. ^ McAllister, R. E.; Noble, D; Tsien, R. W. (1975). "Reconstruction of the electrical activity of cardiac Purkinje fibres". The Journal of Physiology. 251 (1): 1–59. doi:10.1113/jphysiol.1975.sp011080. PMC 1348375. PMID 1185607.
  57. ^ Noble, D; Tsien, R. W. (1969). "Outward membrane currents activated in the plateau range of potentials in cardiac Purkinje fibres". The Journal of Physiology. 200 (1): 205–31. doi:10.1113/jphysiol.1969.sp008689. PMC 1350425. PMID 5761944.
  58. ^ Noble, D; Tsien, R. W. (1968). "The kinetics and rectifier properties of the slow potassium current in cardiac Purkinje fibres". The Journal of Physiology. 195 (1): 185–214. doi:10.1113/jphysiol.1968.sp008454. PMC 1557911. PMID 5639799.
  59. ^ Noble, D (1984). "The surprising heart: A review of recent progress in cardiac electrophysiology". The Journal of Physiology. 353: 1–50. doi:10.1113/jphysiol.1984.sp015320. PMC 1193291. PMID 6090637.
  60. ^ Noble, D. (2013). "Systems biology and reproduction". Progress in Biophysics and Molecular Biology. 113 (3): 355. doi:10.1016/j.pbiomolbio.2013.11.004. PMID 24314295.
  61. ^ Noble, D (1966). "The Initiation of the Heart Beat. (Darwin Lecture, British Association)". The Advancement of Science. 23: 412–418.
  62. ^ "Professor Denis Noble | the Academy of Medical Sciences". Archived from the original on 3 March 2016. Retrieved 1 May 2015.
  63. ^ "Queen's Birthday honours 1998". Independent.co.uk. 12 June 1998.
  64. ^ "Archived copy" (PDF). Archived from the original (PDF) on 29 October 2013. Retrieved 1 May 2015.{{cite web}}: CS1 maint: archived copy as title (link)
  65. ^ "Our honorary graduates". Archived from the original on 13 January 2016. Retrieved 1 May 2015.
  66. ^ "Archived copy" (PDF). Archived from the original (PDF) on 21 July 2020. Retrieved 16 February 2022.{{cite web}}: CS1 maint: archived copy as title (link)
  67. ^ Lomonosov Gold Medal 2022 (in Russian)
  68. ^ "Oxford Trobadors". www.oxfordtrobadors.com. Retrieved 15 April 2019.
  69. ^ "Oxford Trobadors". www.oxfordtrobadors.com. Retrieved 15 April 2019.
  70. ^ "Dordogne-Périgord, le Département". Facebook.
  71. ^ "Biovision Conference Programme". biovision.org. Archived from the original on 25 July 2011. Retrieved 15 April 2019.
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