Neutral Citation Number: 2011 EWHC 1606 (Pat) IN THE HIGH COURT OF JUSTICE CHANCERY DIVISION PATENTS COURT MR JUSTICE FLOYD - - - - - - - - - - - - - - - - - - - - - Between: WARNER-LAMBERT COMPANY LLC Claimant (1) TEVA UK LIMITED (2) PHOENIX HEALTHCARE DISTRIBUTION LIMITED (3) AAH PHARMACEUTICALS LIMITED Defendants - - - - - - - - - - - - - - - - - - - - -Digital
- A |
J |K |
U |V |
Jcmm-118.qxdJ. Cell. Mol. Med. Vol 11, No 5, 2007 pp. 1-4 Journal on Cellular and
Christian de Duve was born in 1917 in the South Molecular Medicine is an appropriate stage for a
of England, where his family had found refuge from tribute to Professor C. de Duve on his 90th birthday.
the first invasion of Belgium by German troops in Indeed, the work of Christian de Duve led to an 1914. He grew up in the French-speaking upper- explosion in cell biology, with the discovery of lyso- class atmosphere of Antwerp, an affluent city open to somes and peroxisomes and of their function. From the world, while benefiting from a solid classical the deciphering of the physiopathology of lysosomes greco-latin education. No doubt this familial, cultural followed the first molecular explanation of an intracel- and educational background took a great part in fos- lular genetic disorder, Pompe’s glycogenosis, the tering a rich blend of intellectual qualities: open- prototype of lysosomal storage diseases. In turn, this mindedness with unlimited curiosity, dedication to basic knowledge paved the way to rational molecular hard work yet leaving due place for culture (de Duve medicine, with the first effective cure of another is a talented pianist and a music lover), thorough inborn lysosomal disorder, Gaucher’s disease, by quantitative analysis with uncompromising intellectu- replacement therapy with recombinant glucocere- al rigor, enterprising spirit with social responsibility, brosidase, now a current practice. How did this story not to mention a unique style! Fascinated by experi- develop and what does the example of de Duve tell us? mental medicine and the example of Claude Journal compilation 2007 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd Bernard, Christian de Duve obtained his MD at the approach that had been recently developed by catholic University of Louvain in 1941 and immedi- another Belgian scientist, Albert Claude. ‘Tissue frac- ately moved to research on insulin action in the lab- tionation studies’ was the beginning title of not less oratory of physiology, awarded with a Masters than 18 classical papers contributed by C. de Duve degree in chemical sciences (thus anticipating the and his team, a story summarized in the Nobel lec- future MD PhD programme). This integrated biomed- ture review ‘Exploring cells with a centrifuge’, still ical education was strengthened by two additional enjoyable to read . In these investigations, acid years of training abroad, first in biophysics at the phosphatase, whose function was unknown, served Medical Nobel Institute in Stockholm with Prof. Hugo as a control. Quite unexpectedly, instead of vanishing Theorell, then in biological chemistry at Washington with time due to proteolysis or denaturation, the University with Profs. Carl and Gerty Cori (and by the activity of acid phosphatase paradoxically increased same token, enjoying mentorship by three Nobel when sub-cellular fractions were ageing. Rather than discounting this incidental observation as a mere With this unusually broad expertise, Christian de anecdote distracting from the main project, de Duve Duve was ready to return to his alma mater and to and his colleagues went on to show that the effect of create, in 1947, his own laboratory dedicated to ageing was mimicked by mechanical disruption, physiological chemistry, primarily aimed at decipher- freezing-thawing and detergents, indicating that ing the mechanism of insulin action.yet led to the enzymatic latency was due to sequestration by a serendipitous discovery of lysosomes, then peroxi- membrane impermeable to the substrate. Moreover, somes! The quality of this laboratory rapidly attracted this property was shared by other hydrolases, all with a large team of brilliant young minds: to name a few, an optimal activity at acidic pH. Combined with the Jacques Berthet and Henri Beaufay, with whom the integrated and rigorous analysis of the differential theory and practice of analytical sub-cellular fraction- sedimentation profiles of more than 40 enzymes in ation was developed; Gery Hers, who mainly contin- rodent liver contributed by several laboratories world- ued on the regulation of carbohydrate metabolism wide, these three lines of evidence led to a new con- and identified the first lysosomal disease by elucidat- cept of cytoplasmic compartmentation, that is gath- ing a familial glycogen-storage disorder (Pompe’s ering of all acid hydrolases in acidified vesicles, disease); Robert Wattiaux and Pierre Baudhuin, accessible to substrates only by membrane fusion associated with the story of lysosomes and peroxi- and serving as the cell’s stomach .
somes, and many others. Their lasting collaboration To prove the existence of the putative lytic body, and the establishment of several new ones was a named ‘lysosome’, required its isolation in pure frac- tions. This was first a puzzle, as ‘lysosomal’ enzymes Pasteur once wrote ‘chance favours prepared co-sedimented with mitochondria. However, naked- minds’. Let us take the discovery of lysosomes as an eye inspection of the conventional rat liver ‘mitochon- example of how de Duve’s mind helped him to be drial’ fraction revealed a stratification, with a yellow favoured by chance. It needed curiosity, freedom, (lipofuchsin-rich) layer over the red (cytochrome-rich) consistency, integration and vision. Let also this mitochondrial pellet. The separate collection of the example continue to inspire scientific committees two populations was sufficient to resolve lysosomes and maintain the same freedom for truly original sci- from mitochondria . Further purification by density entists, driven by curiosity and long-term challenges, centrifugation after loading with an undigestible low- despite inevitable fierce competition for limited density compound allowed large-scale isolation for resources (but also avoidable pollution by evaluation functional studies. Nevertheless, for many scientists, on short-term results and blind ‘scientometry’). To ‘seeing is believing’. Although a biochemist, de Duve address the mechanism of insulin action on the liver managed to acquire the first electron microscope for by a biochemical approach, de Duve and his team the Belgian scientific community and, in collaboration measured in liver extracts a series of phosphatase with Alex Novikoff, formally established lysosomes activities, such as glucose 6-phosphatase, and as the well known, yet so far obscure pericanalicular attempted to identify where these activities were bodies . Final evidence was provided with the cyto- localized based on sub-cellular fractionation, an chemical demonstration of acid phosphatase by Journal compilation 2007 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd electron microscopy, in collaboration with Marilyn Experimental medicine, Endocrinology and Microbiology) from the Faculty of Medicine at the University of The significance of lysosomes was systematically Louvain, which provided strong support ever since explored in other tissues and contexts. A comprehen- while allowing independent direction. The Institute sive review  paved the way to the integration of was reinforced by autonomous fund raising, the cre- lysosomes with (i) pinocytosis, that blossomed with ation of new laboratories (such as a Tropical dis- the discovery of receptor-mediated endocytosis and eases unit) and a special training program for foreign the elucidation of low-density lipoprotein processing post-docs (long before the Curie fellowships). The and cholesterol homeostasis by Goldstein and Institute further attracted Thierry Boon and his Brown ; (ii) phagocytosis, anticipated a century team to create the Brussels branch of the Ludwig ago by Metchnikoff; (iii) autophagy, a still elusive Institute for Cancer Research, an association of process; (iv) genetic lysosomal diseases, with the tremendous mutual benefit. In this branch, the first elucidation by Gery Hers of the origin of Pompe’s human tumoural antigen was cloned and several glycogenosis ; (v) acquired lysosomal diseases, important discoveries on tumour immunity continue such as foam cells in atherosclerosis  and (vi) pharmacology, illustrated by the anti-malaria agent, Having completed these two outstanding success stories, de Duve did not limit his ambitions to a well- A similar approach, based on the identification of deserved retirement. Instead, he enjoys writing text- another group of enzymes catalyzing oxidation reac- books of remarkable clarity on cell biology, both on tions and sharing a distinct distribution, unravelled structures  and biochemical machineries , the existence of peroxisomes and ignited active and took on his extraordinary abilities as an indefati- research with Paul Lazarow and others on their still gable speaker of infectious enthusiasm, to spread intriguing biogenesis. Thus, the development and scientific knowledge and combat the ‘intelligent application of the same rigorous methodology led to design’ theory. Indeed, his favourite activity has the unexpected discovery (almost a pleonasm) of focused on the origin of life, pursuing on scientific two major, totally unrelated sub-cellular compart- grounds his previous debate challenging the view of the late Jacques Monod, that life is too complex ever International recognition was soon to come, with to occur elsewhere in the universe . Over the last joint tenure at the catholic University of Louvain and decade, de Duve has been extensively assembling the Rockefeller Institute in New York since 1962, and and integrating lessons from pre-biotic chemistry, culminating with the Nobel Prize of Medicine in 1974, evidence on early forms of life on earth and astro- shared by Christian de Duve, Albert Claude and nomical data on the conditions compatible with the George Palade for their discoveries on the structural emergence of life in the cosmos. He convincingly and functional organization of the cell (see ). In argues that life is far from a most improbable, single response to this highest of scientific honours (and chance event. To the contrary, because it obeys the the challenge it conveys), de Duve took on a second laws of chemistry, life should by necessity emerge direction in his professional life. He harnessed his whenever adequate conditions are provided, which fame to create the International Research Institute of are inevitably to be repeated given the immense time Cellular and Molecular Pathology in Brussels, origi- duration and multiplicity of galaxies of our universe: nally called the ICP (and renamed this year ‘de Duve ‘life is a cosmic imperative’ [13, 14].
Institute”). From its origin, the ambitious goal set to Whatever aspect one may speculate on in an the Institute was to exploit multidisciplinary exceptional destiny, it is clear to those who have had approaches in order to better understand diseases the privilege of closely interacting with Professor and to derive rational therapies, with a motto «Mieux Christian de Duve, that an admirable blend of intel- comprendre pour mieux guérir», and a logo inter- lectual freedom, self-confidence, leadership and twining the DNA double helix with the staff of immense scientific culture likely explains how he Aesculapius (Fig. 2). Under de Duve’s strong vision could encompass in one professional career three and leadership, a core Institute was generated by distinct, yet equally successful scientific lives: first, merging the four leading laboratories (Biochemistry, as primary investigator and head of one, then two Journal compilation 2007 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd laboratories at the forefront of biochemistry and cell de Duve C, Wattiaux R. Functions of lysosomes.
biology on both sides of the Atlantic ocean; second, Annu Rev Physiol. 1966; 28: 435–92.
as founder and first director of a multidisciplinary Brown MS, Goldstein JL. A receptor-mediated
international research institute in Brussels; and third, pathway for cholesterol homestasis. Science. 1986;232: 34–47.
as a free-thinking mind actively pursuing bold studies Van Hoof F, Hers HG. The ultrastructure of the liver
on the origin of life and committed to fight dogmatic in various thesaurismoses. Rev Int Hepatol. 1967; 17: theories, dangerous for the choices of mankind.
de Duve C, de Barsy T, Poole B, Trouet A, Tulkens
P, Van Hoof F. Lysosomotropic agents. Biochem
Tribute to Professor George E. Palade. J Cell Mol
de Duve C. Exploring cells with a centrifuge. Science
de Duve C. A Guided Tour of the Living Cell (two vol-
de Duve C., Berthet J. The use of differential cen-
umes). 1984; Scientific American Books, pp 423.
trifugation in the study of tissue enzymes. Int Rev de Duve C. Blueprint for a Cell. 1991; Neil Patterson
Publishers, Carolina Biological Suppl, pp 353.
Beaufay H, de Duve C, Novikoff AB. Electron
Monod J. Le Hasard et la Nécessité. Essai sur la
microscopy of lysosome-rich fractions from rat liver. J Philosophie Naturelle de la Biologie Moderne. 1970; Biophys Biochem Cytol. 1956; 2: Suppl.4: 179–84.
Farquhar MG, Bainton DF, Baggiolini M, de Duve
de Duve C. Vital Dust. Life as a Cosmic Imperative.
C. Cytochemical localization of acid phosphatase
activity in granule fractions from rabbit polymor- de Duve C. The origin of eukaryotes: a reappraisal.
phonuclear leukocytes. J Cell Biol. 1972; 54: 141–56.
Pierre Courtoy, MD PhD,
Comments by J. Berthet, L. Hue, M. Rider and E.
van Schaftingen have been much appreciated.
Journal compilation 2007 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
Culver-Stockton College Study Abroad Program Introduction “Travel if fatal to prejudice, bigotry and narrow mindedness…broad, wholesome, charitable views…cannot be acquired by vegetating on one’s little corner of earth.” Mark Twain knew what he was talking about. During his life h traveled extensively in Europe and the Middle East. Since Twain’s times, the world has