Address to the Assembled Faculties of Charles University, Prague. ****************************************************************************************** * Address to the Assembled Faculties of Charles University, Prague. ****************************************************************************************** Introduction “Rector Magnificus, Dean Spectabilis, Academicians and Scholars, vázeni hosté, dámy a páno velkou cti, ze mohu oslovit toto slovutné shromázdeni.” I hope, Rector, that you will permit me to revert to my native tongue, as I am not anxious misunderstanding that might lead to defenestration – a subtle expression of disapproval es these Hallowed Halls. Charles University As a graduate of University College London – an institution founded as recently as 1826 – understand my admiration and esteem for your University, founded here some 500 years earli the King of Bohemia, the Holy Roman Emperor Charles IV. Charles University has a long and distinguished history of scholarship and its alumni and luminaries such as Jan Hus, Bernard Bolzano, Jan Purkyne, Tomas Masaryk, Albert Szent-Györ Ferdinand and Gerty Cori, Albert Einstein and Jaroslav Heyrovsky. Szent-Györgyi, the Coris, Einstein and Heyrovsky were recipients of Nobel Prizes for their formulated his General Theory of Relativity whilst teaching here in Prague, and Heyrovsky of polarography) forms a link between our institutions, as his postgraduate studies were a College with Sir William Ramsey and Frederick Donnan. I had the privilege of knowing Alber personally, and benefitted from his wisdom in the field of free radical reactions. The strong tradition of research and teaching has made Charles University an international institution of Higher Education and, in addition to its distinguished scholastic history, acknowledged as a contemporary centre of excellence. In conferring on me an honorary doctorate I am indeed deeply honoured and I am greatly pri numbered among such notable and distinguished previous recipients such as James Watson, Pa Cech, Günter Blöbel, Richard Ernst and my UCL colleague, Salvador Moncada. Of course, science is not a solitary undertaking and I consider the recognition awarded to solely my modest contribution to the advancement of knowledge, but celebrates a wider ambi the work of many colleagues with whom I have had the privilege to collaborate in the field biology. I gladly acknowledge the debt that I owe to them – notably my friends and support today. Pigment Cell Research As well as its major contributions in other disciplines, Charles University is one of the centres in the world of work on pigmentation and pigment cells. It was the famous Czech ph Evangelista Purkyne, who began pigment cell research here in Prague. In 1833 he was the fi neuromelanin granules in the substancia nigra of the human brain. Twentyfive years later ( lecturer in the Faculty of Medicine, Bohumil Eiselt, described the occurrence, in patients of melanogenuria (that is the presence in the urine of colourless precursors of the dark p And in 1932 Heinrich Waelsch analysed the pigment in the retinas of horses and concluded t melanins were complexed with protein – so-called melanoprotein – a view that we now know t 1954 Antonin Felix Richter and Jiri Duchon were able to show that natural melanins were co fractions (which were subsequently classified as sulphur-containing pheomelanins and eumel  In the 1960s Jiri Duchon went on to found here at Charles University a centre for researc biosynthesis of melanins. With the collaboration of several young colleagues, including St Bohuslav Matous and Jiri Vachtenheim,  the first reports were published on the identity of metabolites of melanogenic intermediates, which were to become important metabolic markers Duchon was also closely involved in the identification of the intracellular organelles in synthesis occurs (now called melanosomes) and, with Jan Borovansky and Petr Hach demonstra internal structure of these particles. Also, Milan Elleder characterised the phenomenon of of melanin. Not only has Charles University spawned this rich seam of fundamental work in pigment cell continues to this day, but several important clinical aspects have emerged from here inclu of Jiri Trapl on the histological classification of melanoma and the well-known descriptio of albinism associated with haemorrhagic diathesis by Hermansky and Pudlak in 1959. The pre-eminence of Charles University in this field has been recognised by the pigment ce Prague has hosted many International meetings devoted to melanin and melanogenesis includi 3rd European Workshop on Melanin Pigmentation in 1981, the symposium on Cancer at the 14th the International Union of Biochemistry in 1988, the 8th meeting of the European Society f Research in 1998 (commemorating the 650th anniversary of Charles University), and the symp and Melanosomes at the recent successful 34th FEBS Congress (2009), presided over by your Dean, Tomas Zima. Acknowledgements All of us who have laboured in the field of pigment cell research owe a debt of gratitude emergent from Charles University and I would like especially to acknowledge the important Duchon (now sadly no longer with us), Jan Borovansky, and Stanislav Pavel. I should also like to take this opportunity to acknowledge my indebtedness to the colleagu shaped my career as a pathologist including Claude Rimington, Peter Sutton, and the late T who was so influential in guiding my work on free radicals. And no listing of acknowledgem complete without mention of my wife, Christine, whose constant and uncomplaining support h in my professional career. Research My interest in pigment cells arose from some early studies in the laboratory of Arthur Jar which is a condition in which there is loss of cutaneous pigmentation in a segmental distr identified an industrial depigmentation in tannery workers due to rubber gloves as a possi the pathogenesis. The component of the rubber gloves which was responsible for the loss of an antioxidant – the monbenzyl ether of hydroquinone. The formation of melanin involves ox the aminoacid tyrosine and it had been thought that the anti-oxidant might inhibit this pr turned out that the monobenzyl ether of hydroquinone was converted by the melanin-forming toxic quinone product which eliminated the pigment cells in the affected areas. It seemed our hands a potential means of specifically targeting pigment cells, and thus a possible w chemotherapy to malignant cells of the pigment cell lineage, and much effort has been dire this approach. I have to tell you that, regrettably, we have not yet succeeded in subduing metastasis, but novel initiatives are still being developed. Another area that we have explored which has turned out to be very exciting is the strong exhibited by melanins. This is one of the properties of melanins discovered here at Charle and described in a series of major publications by Jan Borovansky. Jan and I were able to significant collaborative studies with the aid of grants from the British Council and we h work together under the auspices of the Quintox Group (with some financial support from th on biochemical aspects of melanogenesis. Recently we co-edited the first monograph on mela will shortly be published. Ontology and Epistemology As I have intimated, the general advancement of knowledge is not a singular achievement an engaged in a search for a true understanding of the world. I was fortunate to graduate fro when it was full of brilliant men. One of my mentors, Sir Peter Medawar, made an interesti between ‘truth’ by definition (what he called apodictic truth) and truth by comparison wit Ontologically we may argue that there is a external reality, but its nature is epistomolog because (as another of my teachers, J.B.S.Haldane, pointed out) we are part of it, and sel excludes axiomatic provability (as demonstrated by Kurt Gödel). However, we can construct analogue arguments which are comprehensible to us, and test the behaviour between the analogy and the real world. This idea of the basis of knowledge seem continuous development through Kant, Hegel, Descartes, Hume to Popper. I was introduced by Richard Spearman to the philosophy of science promulgated by Karl Popper, and I believe th of the ‘vulnerability of theory to disproof’ is the most useful approach to understanding. two corollaries to this. One is that it is the hypothesis and not the proposer that is vul it is quite in order to be wrong! Secondly, to be capable of  refutation a hypothesis must process that can be tested and thus must posit a mechanism. This requirement overcomes the fallacy of non-mechanistic statements such as ‘All swans are white’ since ‘whiteness’ is n mechanistically linked to ‘swan-ness’. To us, the possibility of the existence of black sw from an understanding of the mechanism of pigmentation. Conclusion The generation of knowledge involves the arrangement and organization of categories of dat consists of more than this. It requires an imaginative ability to devise a system of the w be represented by the observed reality (insofar as we are able to perceive it) Within this greater order may be conceived and tested against the ultimate reality of our amazing Univ In this noble tradition I have tried to make a genuine contribution to knowledge in my sma am conscious of the short way we have progressed and, as expressed so eloquently by Isaac long path ahead: Magnus Oceanus Veritatis totus ignotus adhuc ante nos iacet.