Transcriptional Science

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Transctriptional Science aims to re-evaluate existing data in the context of the translational sciences paradim in order to secure reliability and validity of data used for hypothesis generation, project design and decision making at a highest possible level of confidence

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Transcriptional Science

  1. 1. Transcriptional Science: an essential prerequisite to enable translational sciences developed by: Thomas Wilckens, MD, PhD
  2. 2. “ Science Business”, Gari P. Pisano, Harvard Business School Press, 2007 Can Science be a business? It would appear that the answer, based on the experience to date would be no. This answer is, however, only correct, if we take existing organizational and institutional arrangements and existing management technologies as given. Transcriptional Sciences: a building block for Symbiotic Innovation: Reshaping value creation in concert with Translational Sciences Academia cannot replace early stage R&D but must establish essential fundaments. Lessons from biotech should guide the creation of novel anatomies. Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens
  3. 3. SI:Overcoming the challenges of early stage drug discovery Implementing Translational Sciences and new value creation concepts <ul><li>Transcriptional Sciences: </li></ul><ul><ul><ul><li>Obstacles and challenges for translational sciences </li></ul></ul></ul><ul><ul><ul><li>The Cortisol Story: an example par excellence for perpetuated dogmas </li></ul></ul></ul><ul><ul><ul><li>TS essential prerequisite for Translational Sciences </li></ul></ul></ul><ul><li>Summary and conclusions </li></ul>Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens
  4. 4. Translational research connecting basic research to patient care: The wealth of data need rigorous evaluation by putting human biology back in the center of discovery Translational Research - © Dr. Thomas Wilckens Cells/animals molecules genes Health Clinical Research Basic Research human research Participants Populations Societies Heal care systems Mechanism Markers Drugs Devices Interventions T1 or TR T2 or TM1 Bench to Bedside Laboratory to Human Bedside to Community Experience to Practice Caveat: Research & funding need to be arranged around and along scientific/medical problems rather then aligning existing infrastructures and organisations in order create increased revenue to academic institutions; i.e. disease areas, pathologies, target-families T3 or TM2 Barriers Feasibility Strategy Effectiveness Safety Post-marketing Obeservatios Off-label-use GP obeservations
  5. 5. Translational Sciences are endangered by the way we conduct research itself: Provoking thoughts Perpetuated errors & dogmas Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens Disregard of our “ignorance” <ul><li>How much do we actually know? </li></ul><ul><li>Dominating mainstream concepts </li></ul><ul><li>No open questions allowed </li></ul>Lack of global thinking <ul><li>How often must the same experiment be repeated with minimal change </li></ul><ul><li>www enables new research anatomies to generate optimal value from science </li></ul>Lack of disputation culture <ul><li>Scientific disputations are not fostered as an art and measure to improve critical thinking </li></ul>Lack of critical design assessment <ul><li>Are the experiments relevant with respect to a physiological context </li></ul><ul><li>The older a dogma the stronger </li></ul>Funding culture <ul><li>Submit for studies that you have already completed and be sure to get the next grant </li></ul><ul><li>Conflicting theories get little support </li></ul>Lack of general discussions <ul><li>Translational Sciences enable for the first time in biomedical history that the current approach to research is under critical review </li></ul>Too much data Too little content Publish or parish: impact factor
  6. 6. On-Ko-Chi-Shin “ The new idea resides within the old.” What about the old data & overcome experimental designs ; i.e. compare the “cortisol story” In consequence a third field for research seems required to enable Translational Sciences . Translational Sciences (Research & Medicine): forward directed measures A critical analysis of our approach to science should allow optimal use of old and emerging studies and data Transcriptional Science: Securing contemporary experimental designs and data’s reliability and validity Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens
  7. 7. SI: Overcoming the challenges of early stage drug discovery Implementing Translational Sciences and new value creation concepts <ul><li>Transcriptional Sciences: </li></ul><ul><ul><ul><li>Obstacles and challenges for Translational Sciences </li></ul></ul></ul><ul><ul><ul><li>The Cortisol Story: an example par excellence for perpetuated dogmas </li></ul></ul></ul><ul><ul><ul><li>TS essential prerequisite for Translational Sciences </li></ul></ul></ul><ul><li>Summary and conclusions </li></ul>Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens
  8. 8. <ul><li>Selected differences affecting function: </li></ul><ul><li>Cortisol binding globulin </li></ul><ul><li>Metabolism by 11 β -HSD </li></ul><ul><li>Binding to GR (5 “isoforms”), MR (2) </li></ul><ul><li>Intracellular activation/recycling </li></ul><ul><li>GR/MR dimer formation: immense potential for heterodimer formation </li></ul><ul><li>Receptor affinity </li></ul><ul><li>Receptor/ligand co-activator, repressor assembling </li></ul><ul><li>Rransrepression/transactivation (differences between all GR-ligands) </li></ul><ul><li>Ligand-dependent change of conformation and related effects </li></ul>Endogenous glucocorticoids orchestrate inflammation & immunity Endogenous cortisol differs from synthetic ligands at almost every step along the activation pathways Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens MR (b) dimerisation
  9. 9. The majority (at least 2/3) of our knowledge on glucocorticoids is based on DEX: Physiological functions of endogenous cortisol are poorly understood and exploited <ul><li>Google Schoolar search hits (April 2009): </li></ul><ul><li>(immune OR immunology OR immunity OR inflammation OR inflamed OR inflammatory; Text) </li></ul><ul><li>AND rat AND ( dexamethasone ; text): 68.700 </li></ul><ul><li>AND rat AND corticosterone ; text): 23.900 </li></ul><ul><li>AND mice AND dexamethasone ; text): 64.400 </li></ul><ul><li>AND mice AND corticosterone ; text): 21.600 </li></ul><ul><li>AND rat AND corticosterone NOT dexamethasone ; abstract): 18.200 </li></ul><ul><li>AND rat AND dexamethasone NOT corticosterone ; abstract): 59.500 </li></ul><ul><li>AND mice AND corticosterone NOT dexamethasone ; abstract): 15.900 </li></ul><ul><li>AND mice AND dexamethasone NOT corticosterone ; abstract): 57.500 </li></ul><ul><li>A microarray analysis showed from 300 genes only 25 are regulated identical by dex, cortisol and corticosterone (M. Cidlowski, pers. Communication) </li></ul><ul><li>Disregarding the inherent differences between the species GC system may still hamper progress; i.e. human mature osteoblast express MR not GR : Eplerenone may show benefit in RA and osteoporosis </li></ul><ul><li>Most drug discovery programs of the last decades on pathways affect by GC have been launched on results obtained with dexamethasone and not on the basis of physiological functions (SEGRAs, new slow release formulations,… </li></ul>Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens
  10. 10. Cortisol: the master of homeostasis and host defence : Cortisol exploits complex receptor interactions to assure optimal adaptation to “stress” Cortisol follows a circadian rhythm superimposed by adaptations to stressors occupying GR and MR, A, B, C Aldosterone shows no circadian rhythm and reacts to changes in volume and/or minerals Cort/Aldo undulation is not synchronous like sinus/cosinus resulting in complex dynamic GR/MR interactions MR activation is associated with tissue damage in CVD, stroke and related inflammation (activation of NfkB) 11- β -HSD-1 11- β -HSD-1/2 catabolism activation
  11. 11. Chaos & control of cortisol actions: stochastic induction of disease non-linear dynamics impact on biological systems and side effect potential Linear correlation analyses may not translate to real world biology and therapeutic constellations Mathematic models support the identification of “ therapeutic windows ” and experimental designs Circadian rhythms of GR and MR ligands interfere with “natural stress” responses Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens Homeostatic model” without” perturbations; i.e. equally long parts of a pendulum result already in a highly complex pattern; the animation shown represent individual variations
  12. 12. <ul><li>Cortisol research: back to the future </li></ul><ul><li>An example for Transcriptional Science </li></ul><ul><li>A teleological view based on literature analysis back to 1945 proposed: </li></ul><ul><li>“ Endogenous cortisol defends homeostasis and orchestrates adaptations to acute (trauma, shock, injury, acute inflammation…) and chronic stressors (fasting, infection, unresolved inflammation, …), which also includes induction of pro-inflammatory genes .” </li></ul><ul><li>(T. Wilckens, 1995, Wilckens and DeRijk1997): </li></ul>General lesson: All published data must be continuously, critically evaluated with respect to their physiological relevance and relation to human biology before being used in virtual models, data bases, experimental designs,…, and their translation in clinical development plans Implementing Transcriptional Science: Establish database comparing GC-effects on bone on a molar basis for all GC-ligands for the identification of discrete differences that may allow delineation of new therapeutic concepts; i.e. use Eplerone in rheumatoid arthritis Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens
  13. 13. SI: Overcoming the challenges of early stage drug discovery Implementing Translational Sciences and new value creation concepts <ul><li>Transcriptional Sciences: </li></ul><ul><ul><ul><li>Obstacles and challenges for Translational Sciences </li></ul></ul></ul><ul><ul><ul><li>The Cortisol Story: an example par excellence for perpetuated dogmas </li></ul></ul></ul><ul><ul><ul><li>TS essential prerequisite for Translational Sciences </li></ul></ul></ul><ul><li>Symbiotic Innovation & Translational Sciences </li></ul><ul><ul><ul><li>Lack of ROI and selected challenges </li></ul></ul></ul><ul><ul><ul><li>Collective learning and a team/project strategy </li></ul></ul></ul><ul><ul><ul><li>The creation of Symbiotic Innovation and the www. </li></ul></ul></ul><ul><ul><ul><li>Impact on organisational measure and long term value creation </li></ul></ul></ul><ul><li>Summary and conclusions </li></ul>Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens
  14. 14. Transcriptional Sciences: an essential prerequisite for Translational Sciences Incorporation of semantic computational technologies with individual manual content ranking; G o o g l e Source: InnVentis <ul><li>Transcriptional Sciences: </li></ul><ul><li>Ensures reliability and validity </li></ul><ul><li>Ensures physiological context </li></ul><ul><li>Identification & elimination of dogmas </li></ul><ul><li>New views and theories </li></ul><ul><li>New uses for existing compounds </li></ul><ul><li>Enables success of translational science </li></ul>The immanent risk that could invalidate Translational Sciences a priori including financial investment Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens Repetition of key experiments under physiological conditions Identification of physiologically irrelevant data Identification of physiologically relevant data Definition of standardized translational/physiological experimental designs Validated physiological relevant databases for Translational Sciences Neglecting a re-evaluation of the fundaments will result in building translational sciences on sand
  15. 15. TS: reduces risks, costs, time and increases the chance for success Successful product development will require sustainable support combined with iterative project evaluation ‘ It is not the strongest of the species that survives, nor the most intelligent, but the one most responsive to change’ Charles Darwin Imagine, what happened, if we additionally used our intelligence and resources optimally to adopt? P. Talaga in Drug Discovery Today 9/2009, Share or die!: Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens
  16. 16. Thank you for your attention: Could anybody please ask why I am convinced that SI works! I have a nice slide! Can Science be a business? Facing the opportunities of the www, the transitions that take place, innovation & value creation for society and industry appears a feasible goal SI: Fostering Transcriptional & Translational Sciences Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens Transcriptional Science Translational Medicine Translational Research Symbiotic Innovation

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