Models in biology: ‘accurate descriptions of our pathetic thinking’

In this essay I will sketch some ideas for how to think about models in biology. I will begin by trying to dispel the myth that quantitative modeling is somehow foreign to biology. I will then point out the distinction between forward and reverse modeling and focus thereafter on the former. Instead of going into mathematical technicalities about different varieties of models, I will focus on their logical structure, in terms of assumptions and conclusions. A model is a logical machine for deducing the latter from the former. If the model is correct, then, if you believe its assumptions, you must, as a matter of logic, also believe its conclusions. This leads to consideration of the assumptions underlying models. If these are based on fundamental physical laws, then it may be reasonable to treat the model as ‘predictive’, in the sense that it is not subject to falsification and we can rely on its conclusions. However, at the molecular level, models are more often derived from phenomenology and guesswork. In this case, the model is a test of its assumptions and must be falsifiable. I will discuss three models from this perspective, each of which yields biological insights, and this will lead to some guidelines for prospective model builders.

[1]  Francis Crick,et al.  The Genetic Code , 1962 .

[2]  Julian Lewis,et al.  From Signals to Patterns: Space, Time, and Mathematics in Developmental Biology , 2008, Science.

[3]  Lani F. Wu,et al.  Cellular Heterogeneity: Do Differences Make a Difference? , 2010, Cell.

[4]  Tinsley H. Davis Profile of Tom A. Rapoport. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Bernhard Hemmer,et al.  TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways , 2003, Nature Immunology.

[6]  Peter Davidson,et al.  Turbulence: An Introduction for Scientists and Engineers , 2015 .

[7]  J Black,et al.  Drugs from Emasculated Hormones: The Principle of Syntopic Antagonism , 1989, Science.

[8]  Luis G. Morelli,et al.  Patterning embryos with oscillations: structure, function and dynamics of the vertebrate segmentation clock , 2012, Development.

[9]  Richard Phillips Feynman,et al.  Mainly mechanics, radiation, and heat , 1963 .

[10]  Ryoichiro Kageyama,et al.  Instability of Hes7 protein is crucial for the somite segmentation clock , 2004, Nature Genetics.

[11]  David Colquhoun,et al.  The quantitative analysis of drug-receptor interactions: a short history. , 2006, Trends in pharmacological sciences.

[12]  A. Khinchin Mathematical foundations of statistical mechanics , 1949 .

[13]  J. Cooke The problem of periodic patterns in embryos. , 1981, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[14]  D. Hubble THE AUTOBIOGRAPHY OF CHARLES DARWIN , 1958 .

[15]  J. Watson Genes, Girls, and Gamow , 2001 .

[16]  J. Hopfield Kinetic proofreading: a new mechanism for reducing errors in biosynthetic processes requiring high specificity. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Jennifer Werfel,et al.  Parametric Sensitivity In Chemical Systems , 2016 .

[18]  James N. Weiss The Hill equation revisited: uses and misuses , 1997, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  R Heinrich,et al.  Metabolic regulation and mathematical models. , 1977, Progress in biophysics and molecular biology.

[20]  Julian Lewis Autoinhibition with Transcriptional Delay A Simple Mechanism for the Zebrafish Somitogenesis Oscillator , 2003, Current Biology.

[21]  J. Gunawardena Biology is more theoretical than physics , 2013, Molecular biology of the cell.

[22]  Benjamin L Turner,et al.  Supporting Online Material Materials and Methods Som Text Figs. S1 to S3 Table S1 References Robust, Tunable Biological Oscillations from Interlinked Positive and Negative Feedback Loops , 2022 .

[23]  Mark Ptashne,et al.  On the use of the word ‘epigenetic’ , 2007, Current Biology.

[24]  M. Karplus,et al.  Molecular dynamics and protein function. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[25]  Christopher R. Myers,et al.  Universally Sloppy Parameter Sensitivities in Systems Biology Models , 2007, PLoS Comput. Biol..

[26]  J. Black,et al.  A personal view of pharmacology. , 1996, Annual review of pharmacology and toxicology.

[27]  Ronald N Germain,et al.  Modeling T Cell Antigen Discrimination Based on Feedback Control of Digital ERK Responses , 2005, PLoS biology.

[28]  Samuel Glasstone,et al.  Elements of Physical Chemistry , 1993 .

[29]  Tom A. Rapoport,et al.  Generation of nonidentical compartments in vesicular transport systems , 2005, The Journal of cell biology.

[30]  Freeman Dyson,et al.  A meeting with Enrico Fermi , 2004, Nature.

[31]  J. Ferrell,et al.  Interlinked Fast and Slow Positive Feedback Loops Drive Reliable Cell Decisions , 2005, Science.

[32]  T. Ohtsuka,et al.  Intronic delay is essential for oscillatory expression in the segmentation clock , 2011, Proceedings of the National Academy of Sciences.

[33]  H. Krebs,et al.  Otto Warburg: Cell Physiologist, Biochemist, and Eccentric , 1981 .

[34]  Hiroaki Kitano,et al.  Next generation simulation tools: the Systems Biology Workbench and BioSPICE integration. , 2003, Omics : a journal of integrative biology.

[35]  N. Monk Oscillatory Expression of Hes1, p53, and NF-κB Driven by Transcriptional Time Delays , 2003, Current Biology.

[36]  M. Hoagland,et al.  Feedback Systems An Introduction for Scientists and Engineers SECOND EDITION , 2015 .

[37]  Frank Jülicher,et al.  Delayed coupling theory of vertebrate segmentation , 2008, HFSP journal.

[38]  A. Brünger Free R value: a novel statistical quantity for assessing the accuracy of crystal structures , 1992, Nature.

[39]  Julian Lewis,et al.  The elongation rate of RNA polymerase II in zebrafish and its significance in the somite segmentation clock , 2013, Development.

[40]  Jeremy Gunawardena,et al.  Some lessons about models from Michaelis and Menten , 2012, Molecular biology of the cell.

[41]  J. Pearl Causality: Models, Reasoning and Inference , 2000 .

[42]  Patricio Jeraldo,et al.  The Genetic Code , 2006 .

[43]  Andrew C Oates,et al.  Control of endogenous gene expression timing by introns , 2011, Genome Biology.

[44]  Erwin Chargaff Essays on Nucleic Acids , 1963 .

[45]  Ryoichiro Kageyama,et al.  Real-time imaging of the somite segmentation clock: Revelation of unstable oscillators in the individual presomitic mesoderm cells , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[46]  J E Ferrell,et al.  The biochemical basis of an all-or-none cell fate switch in Xenopus oocytes. , 1998, Science.

[47]  J. P. Grossman,et al.  Biomolecular simulation: a computational microscope for molecular biology. , 2012, Annual review of biophysics.

[48]  Pamela A Silver,et al.  Intron length increases oscillatory periods of gene expression in animal cells. , 2008, Genes & development.

[49]  Stanislas Leibler,et al.  Speed, dissipation, and error in kinetic proofreading , 2012, Proceedings of the National Academy of Sciences.

[50]  W. R. The Elements of Physical Chemistry , 1902, Nature.

[51]  Lily E. Kay,et al.  Who Wrote the Book of Life?: A History of the Genetic Code , 2000 .

[52]  E. C. Zeeman,et al.  A clock and wavefront model for control of the number of repeated structures during animal morphogenesis. , 1976, Journal of theoretical biology.

[53]  O. Pourquié,et al.  Avian hairy Gene Expression Identifies a Molecular Clock Linked to Vertebrate Segmentation and Somitogenesis , 1997, Cell.

[54]  T. McKeithan,et al.  Kinetic proofreading in T-cell receptor signal transduction. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[55]  S. Brenner Sequences and consequences , 2010, Philosophical Transactions of the Royal Society B: Biological Sciences.

[56]  K. Sneppen,et al.  Sustained oscillations and time delays in gene expression of protein Hes1 , 2003, FEBS letters.

[57]  Frank Jülicher,et al.  Intercellular Coupling Regulates the Period of the Segmentation Clock , 2010, Current Biology.

[58]  T. Ohtsuka,et al.  Accelerating the tempo of the segmentation clock by reducing the number of introns in the Hes7 gene. , 2013, Cell reports.

[59]  John J. Tyson,et al.  The Dynamics of Feedback Control Circuits in Biochemical Pathways , 1978 .

[60]  M. Levitt The birth of computational structural biology , 2001, Nature Structural Biology.

[61]  Julian Lewis,et al.  Setting the Tempo in Development: An Investigation of the Zebrafish Somite Clock Mechanism , 2007, PLoS biology.

[62]  E. Seibert,et al.  Fundamentals of enzyme kinetics. , 2014, Methods in molecular biology.

[63]  E. Wilson Letters to a Young Scientist , 2013 .

[64]  Frank Jülicher,et al.  Topology and Dynamics of the Zebrafish Segmentation Clock Core Circuit , 2012, PLoS biology.

[65]  Paolo Sassone-Corsi,et al.  Rhythmic transcription and autoregulatory loops: Winding up the biological clock , 1994, Cell.

[66]  O. Pourquié The Segmentation Clock: Converting Embryonic Time into Spatial Pattern , 2003, Science.

[67]  Paul François,et al.  Phenotypic model for early T-cell activation displaying sensitivity, specificity, and antagonism , 2013, Proceedings of the National Academy of Sciences.