Perspective: Dimensions of the scientific method

The scientific method has been guiding biological research for a long time. It not only prescribes the order and types of activities that give a scientific study validity and a stamp of approval but also has substantially shaped how we collectively think about the endeavor of investigating nature. The advent of high-throughput data generation, data mining, and advanced computational modeling has thrown the formerly undisputed, monolithic status of the scientific method into turmoil. On the one hand, the new approaches are clearly successful and expect the same acceptance as the traditional methods, but on the other hand, they replace much of the hypothesis-driven reasoning with inductive argumentation, which philosophers of science consider problematic. Intrigued by the enormous wealth of data and the power of machine learning, some scientists have even argued that significant correlations within datasets could make the entire quest for causation obsolete. Many of these issues have been passionately debated during the past two decades, often with scant agreement. It is proffered here that hypothesis-driven, data-mining–inspired, and “allochthonous” knowledge acquisition, based on mathematical and computational models, are vectors spanning a 3D space of an expanded scientific method. The combination of methods within this space will most certainly shape our thinking about nature, with implications for experimental design, peer review and funding, sharing of result, education, medical diagnostics, and even questions of litigation.

[1]  Jaeyun Sung,et al.  Molecular signatures from omics data: From chaos to consensus , 2012, Biotechnology journal.

[2]  Preethi L. Chandran,et al.  An engineering design approach to systems biology. , 2017, Integrative biology : quantitative biosciences from nano to macro.

[3]  Francisco J. Ayala,et al.  Darwin and the scientific method , 2009, Proceedings of the National Academy of Sciences.

[4]  M A Savageau,et al.  Effect of overall feedback inhibition in unbranched biosynthetic pathways. , 2000, Biophysical journal.

[5]  M A Savageau,et al.  A theory of alternative designs for biochemical control systems. , 1985, Biomedica biochimica acta.

[6]  Eberhard O Voit,et al.  New insights into the complex regulation of the glycolytic pathway in Lactococcus lactis. II. Inference of the precisely timed control system regulating glycolysis. , 2016, Molecular bioSystems.

[7]  J. Platt Strong Inference , 2007 .

[8]  K. Popper,et al.  Conjectures and refutations;: The growth of scientific knowledge , 1972 .

[9]  E. Voit Design principles and operating principles: the yin and yang of optimal functioning. , 2003, Mathematical biosciences.

[10]  S. Tu,et al.  The scientific method: pillar and pitfall of cancer research , 2014, Cancer medicine.

[11]  Jason E. Stewart,et al.  Minimum information about a microarray experiment (MIAME)—toward standards for microarray data , 2001, Nature Genetics.

[12]  B. Palsson,et al.  A protocol for generating a high-quality genome-scale metabolic reconstruction , 2010 .

[13]  J. Lopreato,et al.  General system theory : foundations, development, applications , 1970 .

[14]  D. Paustenbach Scientific Method Questioned , 2006, International journal of occupational and environmental health.

[15]  C. Frevert,et al.  Revisiting the scientific method to improve rigor and reproducibility of immunohistochemistry in reproductive science† , 2018, Biology of Reproduction.

[16]  Maria João Fonseca Scientific Method in Brief , 2015 .

[17]  K. Popper,et al.  Conjectures and refutations;: The growth of scientific knowledge , 1972 .

[18]  T. Kuhn,et al.  The Structure of Scientific Revolutions. , 1964 .

[19]  Daniel A. Beard,et al.  Strong Inference for Systems Biology , 2009, PLoS Comput. Biol..

[20]  C. Begley,et al.  Drug development: Raise standards for preclinical cancer research , 2012, Nature.

[21]  Nathan D. Price,et al.  Metabolic Constraint-Based Refinement of Transcriptional Regulatory Networks , 2013, PLoS Comput. Biol..

[22]  Jamie Schwendinger-Schreck,et al.  A First Course in Systems Biology , 2012, The Yale Journal of Biology and Medicine.

[23]  Christophe G. Lambert,et al.  Learning from our GWAS mistakes: from experimental design to scientific method , 2012, Biostatistics.

[24]  E. Lander Array of hope , 1999, Nature Genetics.

[25]  James Ladyman,et al.  Understanding Philosophy of Science , 2001 .

[26]  D. Kell,et al.  Here is the evidence, now what is the hypothesis? The complementary roles of inductive and hypothesis-driven science in the post-genomic era. , 2004, BioEssays : news and reviews in molecular, cellular and developmental biology.

[27]  David B. Searls,et al.  The Linguistics of DNA , 1992 .

[28]  On John Allen's critique of induction , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[29]  J. Wagensberg On the Existence and Uniqueness of the Scientific Method , 2014, Biological theory.

[30]  Jens Nielsen,et al.  Integrated Network Analysis Reveals an Association between Plasma Mannose Levels and Insulin Resistance. , 2016, Cell metabolism.

[31]  Helen Beebee,et al.  Philosophy of science and the diagnostic process. , 2013, Family practice.

[32]  Markus J. Herrgård,et al.  Integrating high-throughput and computational data elucidates bacterial networks , 2004, Nature.

[33]  Percy Williams Bridgman,et al.  Reflections of a Physicist , 1956 .

[34]  Albert Sorribas,et al.  Special issue on biological design principles. , 2011, Mathematical biosciences.

[35]  Robert V Blystone,et al.  WWW: the scientific method. , 2006, CBE life sciences education.

[36]  Richard Bonneau Learning biological networks: from modules to dynamics. , 2008, Nature chemical biology.

[37]  Sauro Succi,et al.  Big data: the end of the scientific method? , 2018, Philosophical Transactions of the Royal Society A.

[38]  K. Popper Objective Knowledge: An Evolutionary Approach , 1972 .

[39]  R. Swinburne OBJECTIVE KNOWLEDGE: AN EVOLUTIONARY APPROACH , 1973 .

[40]  Rudiyanto Gunawan,et al.  Parameter estimation of kinetic models from metabolic profiles: two-phase dynamic decoupling method , 2011, Bioinform..

[41]  Nathan D. Price,et al.  Data-driven integration of genome-scale regulatory and metabolic network models , 2015, Front. Microbiol..

[42]  James F. Allen,et al.  In silico veritas , 2001, EMBO reports.

[43]  Luís L. Fonseca,et al.  A model of Plasmodium vivax concealment based on Plasmodium cynomolgi infections in Macaca mulatta , 2017, Malaria Journal.

[44]  M. Norton,et al.  A Guide to Parallel Paragraph and Page References in Oxford University Press Editions of Hume's Enquiry concerning Human Understanding , 2002, Hume Studies.

[45]  J. Allen Hypothesis, induction and background knowledge. Data do not speak for themselves. Replies to Donald A. Gillies, Lawrence A. Kelly and Michael Scott , 2001 .

[46]  Charles Anderson,et al.  The end of theory: The data deluge makes the scientific method obsolete , 2008 .

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

[48]  R. May,et al.  Stability and Complexity in Model Ecosystems , 1976, IEEE Transactions on Systems, Man, and Cybernetics.

[49]  Eberhard O Voit,et al.  New insights into the complex regulation of the glycolytic pathway in Lactococcus lactis. I. Construction and diagnosis of a comprehensive dynamic model. , 2016, Molecular bioSystems.

[50]  T. C. Chamberlin The Method of Multiple Working Hypotheses: With this method the dangers of parental affection for a favorite theory can be circumvented. , 1965, Science.

[51]  Eberhard O Voit,et al.  Inference of cancer mechanisms through computational systems analysis. , 2017, Molecular bioSystems.

[52]  Anthony Spalding Colour, humour and scientific method , 2010, Clinical & experimental optometry.

[53]  M J Sternberg,et al.  Application of machine learning to structural molecular biology. , 1994, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[54]  Cynthia A. Welsh,et al.  Learning the scientific method using GloFish. , 2012, Zebrafish.

[55]  Mark D. Wilkinson,et al.  SADI, SHARE, and the in silico scientific method , 2010, BMC Bioinformatics.

[56]  David Hunter,et al.  Just the Facts , 2010 .

[57]  F. Weiling Lotka, A. J.: Elements of Mathematical Biology. Dover Publications Inc., New‐York 1956; XXX + 465 S., 72 Abb., 36 Tabellen und 4 Übersichtstabellen im Anhang, Preis $ 2,45 , 1965 .

[58]  J F Allen,et al.  Bioinformatics and discovery: induction beckons again , 2000, BioEssays : news and reviews in molecular, cellular and developmental biology.

[59]  Gary James Jason,et al.  The Logic of Scientific Discovery , 1988 .

[60]  Donald A. Gillies Popper and computer induction , 2001, BioEssays : news and reviews in molecular, cellular and developmental biology.

[61]  Roger E Bumgarner,et al.  Integrated genomic and proteomic analyses of a systematically perturbed metabolic network. , 2001, Science.

[62]  Mark P. Styczynski,et al.  Metabolic modeling helps interpret transcriptomic changes during malaria. , 2017, Biochimica et biophysica acta. Molecular basis of disease.

[63]  Michela Noseda,et al.  Where did the scientific method go? , 2008, Nature Biotechnology.

[64]  J. Bennett,et al.  Enquiry Concerning Human Understanding , 2010 .

[65]  The influence of funding sources on the scientific method. , 2016, Molecular plant pathology.

[66]  K. F. Tipton,et al.  Biochemical systems analysis: A study of function and design in molecular biology , 1978 .

[67]  Ludwig von Bertalanffy,et al.  Der Organismus als physikalisches System betrachtet , 1940, Naturwissenschaften.

[68]  Jason A. Papin,et al.  Integrated Experimental and Computational Analyses Reveal Differential Metabolic Functionality in Antibiotic-Resistant Pseudomonas aeruginosa. , 2019, Cell systems.

[69]  Steven Gimbel Exploring the scientific method : cases and questions , 2011 .

[70]  Sriram Chandrasekaran,et al.  A Protocol for the Construction and Curation of Genome-Scale Integrated Metabolic and Regulatory Network Models. , 2019, Methods in molecular biology.

[71]  Graham Priest,et al.  Can Theories Be Refuted , 1976 .

[72]  Savageau Ma,et al.  A theory of alternative designs for biochemical control systems. , 1985 .

[73]  Susan Michie,et al.  Specifying and reporting complex behaviour change interventions: the need for a scientific method , 2009, Implementation science : IS.