Une histoire de la recherche de substances naturelles à activités thérapeutiques

L identification d une substance naturelle, produite par un organisme vivant n est que l une des toutes premières étapes du développement d un nouveau médicament. Beaucoup de molécules à visée thérapeutique développées par des sociétés pharmaceutiques ont en fait été découvertes dans des laboratoires académiques. C est toujours un continuum de la recherche fondamentale vers la recherche appliquée, souvent de la recherche publique vers la recherche privée, qui aboutit à la mise au point d un médicament. Leur fabrication, directement à partir de substances naturelles, pose fréquemment le problème de l approvisionnement en matière première. De nombreuses équipes du monde entier se heurtent aux difficultés de synthèse de ces molécules naturelles complexes. Ce travail de thèse retrace l histoire des travaux majeurs sur la recherche de molécules naturelles d intérêt médical à travers les succès et les échecs de chercheurs ayant mis leur énergie, leur imagination, leur ténacité et leur patience au service de la science pour surmonter les obstacles et découvrir de nouvelles molécules de grand intérêt thérapeutique. Elle présente également un travail complémentaire de mise au point d une base de données regroupant un certain nombre de plantes utiles dans la lutte contre le cancer dans le cadre d un projet de vulgarisation scientifique. La discussion est consacrée à la question de la place du hasard dans les découvertes scientifiques à travers l'exemple de Pierre Potier.Identifying a natural substance produced by a living organism is only one of the very first steps towards the development of a new drug. Many molecules which were aimed at therapeutic goals and developed by pharmaceutical companies have in fact been discovered in academic research laboratories. The elaboration of a new drug is always a continuum from basic research toward applied research, and often from public research toward private research. Making these drugs straight from natural substances frequently confronts us with the problem of finding the raw materials. Numerous teams all over the world are facing the difficulties linked to the synthesis of these complex natural molecules.This PhD thesis relates the story of the milestones in the research of natural molecules for medicine through the successes and failures of scientists who put their energy, imagination, tenacity and patience into Science in order to overcome obstacles and discover new molecules for therapeutic use.It also presents a complementary work which consists in developing a database of useful plants in cancer fighting as part of a project of scientific vulgarisation. The discussion is about the part of chance in scientific discovery through the example of Pierre Potier.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Importance, but not intensity of plant interactions relates to species diversity under the interplay of stress and disturbance

The lack of clarity on how the intensity and importance of plant interactions change under the co-occurrence of stress and disturbance strongly impedes assessing the relative importance of plant interactions for species diversity. We addressed this issue in subalpine grasslands of the French Pyrenees. A natural soil moisture gradient further experimentally stretched at both ends was used and a mowing disturbance treatment was applied at each position along the soil moisture gradient. Changes in intensity and importance of plant interactions were assessed by a neighbour removal experiment using four target ecotypes. A structural equation modelling approach was used to assess the relative impact of stress, disturbance, the intensity and importance of plant interactions on diversity at both the neighbourhood and community scales. Without mowing, changes in intensity and importance of plant interactions only diverged in the dry part of the soil moisture gradient. The intensity of plant interactions linearly shifted from competition to facilitation with increasing stress, while the importance followed a hump-shaped relationship. Species diversity components were tightly related to the importance of plant interactions only, both the neighbourhood and community scales. Mowing disturbance strongly reduced the importance of facilitation along the soil moisture gradient, and suppressed the relationship between the importance of plant interactions and diversity components. Together, our results highlight that 1) the importance is the best predictor of variations in species diversity in this subalpine herbaceous system, and 2) that fine-scale processes such as plant interactions can affect the entire plant communities. Finally, our results suggest that high level of constraints due to co-occurring stress and disturbance can inhibit the effects of plant interactions on species diversity, highlighting their potential role in regulating diversity and the maintenance/extinction of plant communities. The co-occurrence of stress (i.e. factors such as drought limiting plant growth, sensu Grime 1973) and disturbance (drastic events such as mowing removing plant biomass) can lead to a rapid loss of diversity. Co-occurring negative effects of stress and disturbance on diversity and ecosystem functioning are specific to severe environments such as alpine grasslands or dry steppes OIKOS How plant interactions change along environmental gradients is an unsolved debate, particularly when both stress and disturbance interact. This lack of clarity explains why the relative impact of plant interactions (intensity and importance) on species diversity has been rarely assessed. Using an experimental approach, we found that the importance of plant interactions highly contributed to variation in species diversity, confirming that neighbourhood scale processes such as plant interactions can affect the entire plant communities. The co-occurrence of stress and disturbance inhibited the effects of plant interactions, highlighting that plant interactions may regulate drops of diversity and the maintenance/ extinction of plant communities. Synthesi

The relationships between soil seed bank, aboveground vegetation and disturbances in old embanked marshlands of Western France

The study deals with the influence of land use and abandonment on species composition of vegetation and seed bank in grasslands and oldfields. We wanted to explore: (1) How the seed bank changes when agricultural practices cease? In convergence with proposals in the literature, we addressed in particular the following two questions that have been proposed by Symonides (1986), Pickett & McDonnell (1989) and Roberts & Vankat (1991) for seed bank characteristics under secondary succession: (i) Does species richness and species diversity in the soil seed bank decrease during succession? (ii) Does the density of buried seed decline during succession? (2) What is the role played by seed bank in the recolonisation of plots disturbed by experimental disturbances ? We studied species composition of vegetation and seed bank in an experiment with grassland and oldfield plots in old embanked marshlands (called "Marais Poitevin"). In these wetlands, artificial disturbances (mowing) and natural disturbances (cattle, roebucks, coypus, voles) are very frequent. In order to mimic disturbances, experimental disturbances were generated in spring after the end of the winter flooding and emerged seedlings counted three months later. Data about the seed bank, the undisturbed vegetation and seedlings emerging in disturbed quadrats were sampled. Detrended Correspondence Analysis (DCA) of the undisturbed quadrats, disturbed quadrats and seed bank samples showed significant differences of species composition. Similarity between seed bank and undisturbed aboveground vegetation was low and not very different between grassland and oldfield. Very few seedlings emerged in the undisturbed vegetation both in grassland and oldfield, which potentially indicates the importance of gaps for seed bank expression. In Marais Poitevin, the seed bank contributed very little to the seedling flora, and vegetative regrowth clearly predominated recolonisation after disturbances. In the seed bank, few species lost after succession from grassland to oldfield vegetation were still present as seeds in the soil, but in most cases species lost were not recorded in the seed bank. The results have shown that species richness and species diversity in the seed bank decrease during succession. On the other hand, the density of buried seeds did not decrease significantly from grassland to oldfiel

Does disturbance drive the collapse of biotic interactions at the severe end of a diversity–biomass gradient?

It has been recently proposed that the decrease in diversity towards the severe end of the humped-back diversity–biomass model of Grime was driven by a collapse of facilitation due to extreme conditions of either stress or physical disturbance. In order to test the hypothesis that disturbance is the primary direct factor driving the collapse of interactions occurring along environmental severity gradients, we conducted a removal experiment in the highly stressed French coastal dunes along a gradient of disturbance due to sand burial. Four dune species were used as targets and transplanted with and without neighbours in four communities along the gradient. The experiment was conducted twice, a dry and an average year. Results of the experiment showed that during the dry year the effect of the environment was prominent and only one species was facilitated for survival in the least disturbed community. During the average year, interactions for growth were important only in the same community, with positive or negative responses depending on the natural position of the target species within the coastal dune gradient. In accordance with our hypothesis, most interactions for both survival and growth were observed in the least disturbed community exhibiting the highest diversity. There were no interactions in the most disturbed community with the lowest diversity

Germination responses of a Saharan species Henophyton deserti Coss. & Durieu to temperature and water stress

Henophyton deserti Coss. & Durieu, is an endemic Saharan plant of the Brassicaceae family. Experiments were conducted to assess the effects of temperature and water stress on seed germination. The germination responses of the seeds of H. deserti in complete darkness were determined over a wide range of temperatures (10°C, 15°C, 20°C, 25°C, 30°C, 35°C) and different water potentials (−0.2, −0.6, −0.8, −1.0, −1.2, −1.4, −1.6, −2.0 MPa) induced by polyethylene glycol (PEG-6000) in order to verify their resistance to drought conditions. Germination was inhibited by either an increase or decrease in temperature from the optimal temperature (20°C) and decreased with a decrease in water potential at all temperatures. An interaction between water potential and temperature yielded no germination at −2 MPa. An understanding of these factors is crucial for successful regeneration and recruitment of these long lived Saharan plant species

Influence des conditions édaphiques sur la réponse des communautés alpines au changement global

National audienceLes effets du réchauffement climatique et de l'augmentation de la sécheresse estivale sur la composition et la diversité des communautés alpines ont été largement étudiés. Cependant le rôle modulateur des facteurs locaux tels que la roche mère, la mésotopographie et l'enneigement, est encore mal connu. Dans cette étude nous ré-échantillonnons la végétation d'un site de l'alpin inférieur des Alpes dauphinoises (France) étudié en 1997 et où se juxtaposent des variations importantes de roches mères (calcaire et siliceuse), de mésotopographie et d'enneigement susceptibles de moduler la réponse des communautés alpine au changement climatique. 112 relevés effectués en 1997 et 2017 et précisément géo-référencés, sont analysés par Analyse Factorielle des Correspondances. La végétation a très sensiblement évolué en 20 ans et montre une tendance vers la xérophilisation et l'oligotrophisation. La xérophilisation s'observe le long de l'axe 1 de l'AFC par déplacement de la position des relevés vers un pôle caractérisé par des sols superficiels calcaires à disponibilité en eau réduite, qui s'oppose à un autre pôle représenté par des sols acides développés sur roche siliceuse ou sur matériau mixte. Cet effet est particulièrement sensible au milieu du gradient de disponibilité en eau, en bordure de combes à neige. L'oligotrophisation, est probablement due à une baisse du pâturage et s'observe principalement le long de l'axe 2 de l'AFC, par déplacement de la position des relevés vers un pôle caractérisé par des sites exposés à déneigement précoce (mésotopographie convexe) sur sols siliceux. La richesse spécifique de l'ensemble des communautés décroit en moyenne de 15%, très probablement sous l'effet de l'augmentation de la compétition par les ligneux induite par la baisse du pâturage. Nos résultats montrent que les facteurs édaphiques locaux peuvent limiter la remontée altitudinale des espèces telle qu'elle est prédite par les principaux modèles de niche, la plupart des espèces pouvant trouver à la même altitude des refuges microclimatiques leur permettant d'éviter les effets du changement climatique

Acacia tortilis (Forssk.) subsp. raddiana (Savi) Brenan as a foundation species: a test from the arid zone of Tunisia

The geographic distribution of Acacia tortilis (Forssk.) Hayne subsp. raddiana (Savi) Brenan in Tunisia, is limited to the Bou-Hedma region (Bled Talah) where the National Park of Bou-Hedma, a UNESCO (1986) biosphere reserve, is located. We have tested the hypothesis that A. tortilis acts as a foundation species as a result of the improvement of soil conditions under its canopy (soil water availability and nutrient enrichment). The herbaceous community (floristic composition, species density, species richness) and soil characteristics (soil nutrients and soil water) were sampled using the quadrat method beneath and between 16 adult trees of A. tortilis with both northwards and southwards (south and north sides) and eight open areas among the trees. Results showed that A. tortilis trees improve soil water availability, the nutrient status of soil (organic matter, total carbon, total nitrogen, extractable phosphorus), and has a positive effect on the understorey vegetation under arid conditions. No significant differences in species richness were observed between the north subhabitats and the south subhabitats

Végétation et gradients écologiques dans les salines abandonnées de l'ouest de la France

International audienceLes marais salés le long de la Côte atlantique française ont été convertis en salines depuis le 7e siècle. La production de sel décline fortement depuis le 18e siècle, menant à l'abandon nombre de ces salines. La forte salinité du sol est une rémanence de la production salicole d'origine et varie d'une saline à l'autre selon la date d'abandon, le régime d'inondation et les conditions de drainage. Les relations entre les communautés de plantes et sept variables environnementales ont été analysées par analyse canonique des correspondances. La durée d'inondation, la conductivité électrique et la sodicité du sol sont le plus fortement corrélées avec les variations dans la végétation. L'Heleocharo-Hippuridetum vulgaris et le Caricetum ripariae occupe les salines au sol peu salé et inondées pendant la plus longue période ; le Scripetum-Maritimi compacti fréquente les salines au sol salé et longtemps submergées ; l'Alopecuro-Juncetum perennis n'est jamais submergé et n'occupe que les sols peu salés. La salinité du sol et la durée de submersion fournissent une explication satisfaisante des variations de la composition spécifique dans les anciennes salines abandonnées mais les pratiques agricoles, spécialement le pâturage, doivent être prises en compte pour comprendre de manière précise leur composition floristique

Seed germination responses of the Saharan plant species Ephedra alata ssp. alenda to fungicide seed treatments in the laboratory and the field

Given its importance in the functioning of arid ecosystems, Ephedra alata ssp. alenda has drawn some attention and appeared to be suitable for desert re-vegetation. An experimental study has been carried out on the germination properties of seeds of this strictly Saharan species. Analyses of temperature effects, and fungicide seed treatments in the laboratory and the field enabled to determine the optimum germination conditions. The predominant microorganisms isolated from the E. alata ssp. alenda seeds before treatment were Alternaria alternata and Rhizopus spp. The germination capacity was significantly greater between 20 and 25 °C. Captab (61.1 %) and propiconazole (53.2%) fungicides significantly increased the germination of E. alata seeds. These results are confirmed by experiments in the field where all treatments (except treatments with NaOCl and benomyl) significantly increased the emergence percentage. None of the treatments (except benomyl) affected the shoot and root length of the plants. Benomyl treatment resulted in a significant decrease in the shoot and root length