User login password Gerjo van Osch K bS6qRGSf Eric Farrell

User login password Gerjo van Osch K001451 bS6qRGSf Eric Farrell
mY5FmTSh Yvonne Bastiaansen k001460 xK892MPE Roberta Tasso k001463 nK4QG7aa Daniel Kelly k001414 pG4jE7a9 Frank Zaucke k001452 wX59594j Bent Brachvogel k001454 aB3YHHv9 Andrew Pitsillides k001455 dA9n2mnu John Gleeson k001416 nC3z5pyS Linda Kock k001446 xH8uyhpw Nienke Klomp k xQ3wQsfK Kaveh Memarzadeh k001456 mU2cDUwy Arash Angadji k001459 yJ7MX6g8 User login password Yannick Nossin k001447 tC88SseF Cansu Gorgun k001464 kW7eG8AS Kathrin Maly k001445 uW9ESN3A Mengije Zhu k qA6WwjFQ Claudio Intini k001450 vL482EEr Enrique Andres Sastre k001462 rJ9dfUGw Farhad Chariyev Prinz k001444 bR4mSDLR Edoardo Andreini k001453 bF9VvUCY Soraia Silva k001457 zU8mgYn3 Astrid Novicky k001415 tV3XXpks reserve k001461 sH2aWdCB k001465 uD3HBBjG June 27, 2019

In vivo, in vitro … in silico
Liesbet Geris

Analysis & experiments
In vivo, in vitro … Literature Existing knowledge Set-up Tools & concepts Execution Efficient methods Validation Analysis & experiments 27/06/2019 All rights reserved © 2014

In vivo, in vitro … in silico
Literature Existing knowledge Modelling Tools & concepts Simulation Efficient algorithms Validation Analysis & experiments 27/06/2019 All rights reserved © 2014

The 3 R’s Reduction Better planning of experiments Refinement
Extrapolate experimental data using models Replacement … and translation from animal to human 27/06/2019 All rights reserved © 2014

Outline Introduction Fixing the radio - analogy Models General How to?
CARBON applications (Raphaelle) + DIY exercises! 27/06/2019 All rights reserved © 2014

Introduction From linear pathways...
Protein-protein interaction, protein modifications & small signaling molecules Facilitated through availability of robust readouts of pathway activation Kestler et al., BioEssays, 2008 27/06/2019 All rights reserved © 2014

Introduction To feedback loops... Negative or positive
Positive feedback allows ultrasensitive activation & bistable behavior Negative feedback limit strength or duration of signal or lead to stable oscillations Kestler et al., BioEssays, 2008 27/06/2019 All rights reserved © 2014

Introduction And signaling networks.
Overlap between different signaling cascades Cross talk with other pathways Kestler et al., BioEssays, 2008 27/06/2019 All rights reserved © 2014

Introduction A system is more than the sum of its parts
Nakhleh, COMP 572, 2011 27/06/2019 All rights reserved © 2014

Fixing the radio - analogy
Lazebnik, Cancer Cell, 2002 Radio Conceptually similar to signal transduction pathway (convert signal from one form into another) Many components > comparable to number of molecules in reasonably complex signal transduction pathway Info: radio is a box that is supposed to play music 27/06/2019 All rights reserved © 2014

Broken radio – biologists approach Secure funds to obtain large supply of identical functioning radios to dissect & compare to broken one Open radio: find objects of various shape, color, size 27/06/2019 All rights reserved © 2014

Approach 1: describe & classify according to their appearance Family of square metal objects, of round brightly colored objects with 2 legs, of ... Changing of colors > only attenuating effect Approach 2: remove components one at a time or shoot radio at close range with metal particles, after which radios that malfunction (phenotype) are selected & components identified 27/06/2019 All rights reserved © 2014

Approach 2 Removing of some components: attenuating effect Accidental discovery of wire whose deficiency will stop music completely: ‘Seredipitously Recovered Component (Src)’ Wire connects rest of radio to long extendable object, object named ‘Most Important Component (Mic)’ another lab: other unmissable object (graphite, no influence of length) + evidence that Mic is not necessary for radio to work > object named ‘Really Important Component (Ric)’ 27/06/2019 All rights reserved © 2014

Approach 2: Mic vs Ric Accumulating evidence that some radios require Mic and others (apparently identical ones) Ric Discovery of switch whose state determines whether Mic or Ric is required: undoubtedly Most Important Component (U-Mic) 27/06/2019 All rights reserved © 2014

Approach 3: crush radio into small pieces identify components that are on each of pieces Provide evidence for interaction between components Eventually: all components cataloged, connections described & consequences of removing each component or combinations documented Can we now fix radio? Sometimes... 27/06/2019 All rights reserved © 2014

However... if radio has tunable components, outcome is not so promising Radio might not work because several components are not tuned properly which is not reflected in appearance or connections Who might fix radio? Engineer Trained repairman Difference? Use of formal language! 27/06/2019 All rights reserved © 2014

Objections to use of formal language Cell is too complex for engineering approaches Engineering approaches not applicable to cells because cells are fundamentally different from other engineering objects Too little is known to analyze cells as systems Experiments provide ‘real data’ 27/06/2019 All rights reserved © 2014

Models: general Modeling is a subjective and selective procedure
A model represents only specific aspects of reality that are relevant to the question under consideration How detailed a model is does not make it right or wrong; it just determines whether the model is appropriate to the problem to be solved “Essentially, all models are wrong, but some are useful.” (George E.P. Box) 27/06/2019 All rights reserved © 2014

Models: general Mathematical modeling and computer simulations can help us understand the internal nature and dynamics of processes and to arrive at predictions about their future development and the effect of interactions with the environment Modeling drives conceptual clarification Modeling highlights gaps in knowledge or understanding Modeling can assist experimentation Model results can often be presented in precise mathematical terms that allow for generalization Modeling allows for making well-founded and testable predictions 27/06/2019 All rights reserved © 2014

Models: vocabulary Some vocabulary... Model scope
Models consist of mathematical elements (variables, parameters, constants) A model describe certain aspects of the system, and simplifies/neglects all others 27/06/2019 All rights reserved © 2014

Models: vocabulary System state
The state of a system is a snapshot of the system at a given time The state is described by the set of variables that must be kept track of in a model 27/06/2019 All rights reserved © 2014

Models: vocabulary Variables, parameters, and constants
A constant is a quantity with a fixed value Parameters are quantities that have a given value Variables are quantities with a changeable value for which the model establishes relations 27/06/2019 All rights reserved © 2014

Models: vocabulary Model behavior
Two fundamental factors that determine the behavior of a system are influences from the environment (input) processes within the system Measurements of the system output often do not suffice to choose between alternative models, as different system structures may still produce similar system behavior 27/06/2019 All rights reserved © 2014

Models: vocabulary Model classification
A structural or qualitative model specifies the interactions among model elements. A quantitative model assigns values to the elements and to their interactions In a deterministic model, the system evolution through all following states can be predicted from the knowledge of the current state. Stochastic descriptions give instead a probability distribution for the successive states. 27/06/2019 All rights reserved © 2014

Models: vocabulary Model classification
The nature of values that time, state, or space may assume distinguishes a discrete model (where values are taken from a discrete set) from a continuous model (where values belong to a continuum) 27/06/2019 All rights reserved © 2014

Models: vocabulary PHENOMENOLOGICAL DATA-DRIVEN
MECHANISTIC HYPOTHESIS DRIVEN Gene/protein Cell Tissue Statistics (clustering, PLSR) Boolean models Agent based systems Ordinary differential equations Partial differential equations 27/06/2019 All rights reserved © 2014

Empirical models empirical, data driven identification of set of biomarkers critical for certain outcome no identification of underlying mechanistic principles USE: relate in vitro to in vivo determine critical in vitro parameters 27/06/2019 All rights reserved © 2014

Boolean networks large number of genes/proteins in one network
interactions absence of complex biochemical mechanisms absence of true temporal & quantitative information USE: investigate stability identify missing links in network 27/06/2019 All rights reserved © 2014

Mechanistic models quantitative and time dependent behaviour
robustness can be used as a model criterion model complexity (e.g. extensive parameter set) USE: conceptual test hypoteses in silico experiments 27/06/2019 All rights reserved © 2014

Models: How to? Example: network models GRN: gene regulatory network
A network structure (topology) is first defined, typically using information from databases and/or literature To complete the network definition the interactions between components must be defined Determine which components interact with each other, as well as the kinetics of these interactions GRN: gene regulatory network 27/06/2019 All rights reserved © 2014

Graph representation Nakhleh, COMP 572, 2011 27/06/2019

Kinetics, dynamics Biochemical kinetics is based on the mass action law The law states that the reaction rate is proportional to the probability of a collision of the reactants This probability is in turn proportional to the concentration of the reactants to the power of the molecularity, that is the number in which they enter the specific reaction 27/06/2019 All rights reserved © 2014

Kinetics, dynamics Nakhleh, COMP 572, 2011 27/06/2019

Kinetics, dynamics

Kinetics, dynamics And further...
simple signaling pathways can be embedded in networks using positive and negative feedback to generate more complex behaviors which are the basic building blocks of the dynamic behavior shown by non- linear control systems. Buzzer Sniffer Switch Oscillator Tyson et al, Curr Op Cell Bio, 2003 27/06/2019 All rights reserved © 2014

User login password Gerjo van Osch K001451 bS6qRGSf Eric Farrell
mY5FmTSh Yvonne Bastiaansen k001460 xK892MPE Roberta Tasso k001463 nK4QG7aa Daniel Kelly k001414 pG4jE7a9 Frank Zaucke k001452 wX59594j Bent Brachvogel k001454 aB3YHHv9 Andrew Pitsillides k001455 dA9n2mnu John Gleeson k001416 nC3z5pyS Linda Kock k001446 xH8uyhpw Nienke Klomp k xQ3wQsfK Kaveh Memarzadeh k001456 mU2cDUwy Arash Angadji k001459 yJ7MX6g8 User login password Yannick Nossin k001447 tC88SseF Cansu Gorgun k001464 kW7eG8AS Kathrin Maly k001445 uW9ESN3A Mengije Zhu k qA6WwjFQ Claudio Intini k001450 vL482EEr Enrique Andres Sastre k001462 rJ9dfUGw Farhad Chariyev Prinz k001444 bR4mSDLR Edoardo Andreini k001453 bF9VvUCY Soraia Silva k001457 zU8mgYn3 Astrid Novicky k001415 tV3XXpks reserve k001461 sH2aWdCB k001465 uD3HBBjG June 27, 2019

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