Transcriptional Science

Transcriptional Science:an essential prerequisite to enable translational sciences

developed by:

Thomas Wilckens, MD, PhD

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“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

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SI:Overcoming the challenges of early stage drug discoveryImplementing Translational Sciences and new value creation concepts

Transcriptional Sciences:

Obstacles and challenges for translational sciences

The Cortisol Story: an example par excellence for perpetuated dogmas

TS essential prerequisite for Translational Sciences

Summary and conclusions


4Translational Research - © Dr. Thomas Wilckens

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

Cells/animalsmolecules

genes

HealthClinical

ResearchBasic

Research

humanresearch

ParticipantsPopulations

SocietiesHeal care systems

MechanismMarkersDrugs

DevicesInterventions

T1 or TR T2 or TM1

Bench to BedsideLaboratory to Human

Bedside to CommunityExperience 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

BarriersFeasibilityStrategy

EffectivenessSafety

Post-marketing

Obeservatios

Off-label-use

GP obeservatio

ns

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Translational Sciences are endangered by the way we conduct research itself:Provoking thoughts

Perpetuated errors &dogmas

Disregard of our “ignorance”

• How much do we actually know?• Dominating mainstream concepts• No open questions allowed

Lack of global thinking

• How often must the same experiment be repeated with minimal change

• www enables new research anatomiesto generate optimal value from science

Lack of disputation culture

• Scientific disputations are not fostered as an art and measure to improve critical thinking

Lack of critical design assessment

• Are the experiments relevant with respect to a physiological context

• The older a dogma the stronger

Funding culture

• Submit for studies that you have already completed and be sure to get the next grant

• Conflicting theories get little support

Lack of general discussions

• Translational Sciences enable for the first time in biomedical history that the current approach to research is under critical review

Too much dataToo little content

Publish or parish:impact factor


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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


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SI: Overcoming the challenges of early stage drug discoveryImplementing Translational Sciences and new value creation concepts


Obstacles and challenges for Translational Sciences





MR

(b) dimerisation

Selected differences affecting function:

• Cortisol binding globulin

• Metabolism by 11β-HSD

• Binding to GR (5 “isoforms”), MR (2)

• Intracellular activation/recycling

• GR/MR dimer formation: immense potential for heterodimer formation

• Receptor affinity

• Receptor/ligand co-activator, repressor assembling

• Rransrepression/transactivation (differences between all GR-ligands)

• Ligand-dependent change of conformation and related effects

Endogenous glucocorticoids orchestrate inflammation & immunityEndogenous cortisol differs from synthetic ligands at almost every step along the activation pathways

Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens 8

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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

Google Schoolar search hits (April 2009):

(immune OR immunology OR immunity OR inflammation OR inflamed OR inflammatory; Text)

AND rat AND (dexamethasone; text): 68.700

AND rat AND corticosterone; text): 23.900

AND mice AND dexamethasone; text): 64.400

AND mice AND corticosterone; text): 21.600

AND rat AND corticosterone NOT dexamethasone; abstract): 18.200

AND rat AND dexamethasone NOT corticosterone; abstract): 59.500

AND mice AND corticosterone NOT dexamethasone; abstract): 15.900

AND mice AND dexamethasone NOT corticosterone; abstract): 57.500

• A microarray analysis showed from 300 genes only 25 are regulated identical by dex, cortisol and corticosterone (M. Cidlowski, pers. Communication)

• 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

• 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,… Symbiotic Innovation - © Sandrine Shepard Thomas Wilckens

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catabolism

activation

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

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Chaos & control of cortisol actions: stochastic induction of diseasenon-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

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


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Cortisol research: back to the futureAn example for Transcriptional Science

A teleological view based on literature analysis back to 1945 proposed:

“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.”

(T. Wilckens, 1995, Wilckens and DeRijk1997):

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


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SI: Overcoming the challenges of early stage drug discoveryImplementing Translational Sciences and new value creation concepts

Transcriptional Sciences: Obstacles and challenges for Translational Sciences



Symbiotic Innovation & Translational Sciences

Lack of ROI and selected challenges

Collective learning and a team/project strategy

The creation of Symbiotic Innovation and the www.

Impact on organisational measure and long term value creation



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Transcriptional Sciences: an essential prerequisite for Translational Sciences

Incorporation of semantic

computational technologies with individual manual content ranking;

Google

Repetition of key experiments under

physiological conditions

Identification of physiologically irrelevant data

Identification of physiologically

relevant data

Definition of standardized translational/physiological

experimental designs

Source: InnVentis


• Ensures reliability and validity• Ensures physiological context• Identification & elimination of dogmas• New views and theories• New uses for existing compounds• Enables success of translational science

Validated physiological

relevant databases for Translational

Sciences

The immanent risk that could invalidate Translational Sciences a priori including financial investment

Neglecting a re-evaluation of the fundaments will result in building

translational sciences on sand


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TS: reduces risks, costs, time and increases the chance for successSuccessful 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!:


Thank you for your attention:

Could anybody please ask why I am convinced that SI works!

I have a nice slide!

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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

Transcriptional Science

Translational Medicine

Translational Research

Symbiotic Innovation


Documents

Transcriptional Science