D Noble

F Crick

J Goldstein

LM Edwards

PL Greenhaff

PW Anderson

S Franklin

Extreme Physiology & Medicine

Michael P W Grocott

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Grocott Extreme Physiology & Medicine 2013, 2:9http://www.extremephysiolmed.com/content/2/1/9EDITORIAL Open AccessIntegrative physiology and systems biology:reductionism, emergence and causalityMichael P W Grocott1,2,3Systems biology. . .is about putting together rather thantaking apart, integration rather than reduction. It re-quires that we develop ways of thinking about integrationthat are as rigorous as our reductionist programmes, butdifferent.... It means changing our philosophy, in the fullsense of the term. Dennis Noble, 2006 [1].Francis Crick's ‘Central Dogma’, which states that DNAencodes mRNA (transcription) and mRNA encodes pro-tein (translation), has provided a conceptual basis for thebiomedical sciences for more than 50 years [2]. However,the limitations of this framework are increasingly clear:inherited genetic code is a necessary, but not sufficient, ex-planation of how and why cells within a living organismbehave as they do. The critical role of epigenetic changeduring life in determining the differentiation status of eachcell has added a new dimension to our understanding ofthe relationship between genotype and phenotype. Theheritability of some of these changes through mechanismsindependent of alterations in the DNA sequence of basepairs has equally profound implications. Perhaps evenmore importantly, the assumption of linear causality (fromgene via transcript to protein and thence function) implicitin Crick’s Central Dogma may in itself be flawed. Emer-gence, defined as ‘the arising of novel and coherent struc-tures, patterns and properties during the process of self-organization in complex systems’ [3], is arguably a definingcharacteristic of higher organisms: the Cartesian premisethat the whole is no more than the sum of its parts is hardto defend when considering the physiology of complex eu-karyotes. Cellular differentiation and the development ofspecific physiological functions are clearly determinist pro-cesses; the extraordinarily consistent development ofCorrespondence: mike.grocott@soton.ac.uk1Integrative Physiology and Critical Illness Group, Division of Clinical andExperimental Science, Faculty of Medicine, University of Southampton,University Road, Southampton SO17 1BJ, UK2Anaesthesia and Critical Care Research Unit, University HospitalSouthampton, NHS Foundation Trust, CE.93 Mailpoint 24, E-Level CentreBlock, Tremona Road, Southampton SO16 6YD, UKFull list of author information is available at the end of the article© 2013 Grocott; licensee BioMed Central Ltd.Commons Attribution License (http://creativecreproduction in any medium, provided the orintricate phenotypes in humans and other highly evolvedspecies cannot conceivably be the result simply of stochas-tic processes. However, the nature of these processes maynot be best explored through reductionist experimental ap-proaches. Indeed, such approaches may, by their nature,fail to identify or account for emergent phenomena. In thereductionist paradigm, the multiple interacting systems ofintact human physiology obscure the basic mechanismsunderpinning phenotypic variation: they are the physio-logical ‘noise’ obscuring the biochemical signal. Conversely,the integrative paradigm views these systems and the emer-gent phenomena that result from them as providing themore relevant signal. To quote from Anderson, ‘The abilityto reduce everything to simple fundamental laws does notimply the ability to start from those laws and reconstructthe universe. The constructionist hypothesis breaks downwhen confronted with the twin difficulties of scale andcomplexity. At each level of complexity entirely new prop-erties appear. Psychology is not applied biology, nor is biol-ogy applied chemistry. We can now see that the wholebecomes not merely more, but very different from the sumof its parts’ [4].The speed and accuracy of biochemical analyses havebeen transformed in the years since DNA was firstcharacterised as the biochemical substrate of evolution byCrick and Watson. Led by advances in genetic sequencing,the omics disciplines have opened a window on the studyof biological function (biochemistry and physiology) that isarguably comparable to the revolution in the study of bio-logical form (anatomy) that occurred in the sixteenth andseventeenth centuries with the advent of human cadaverdissection and light microscopy. Whole genome sequen-cing and high throughput transcriptomic, proteomic andmetabalomic analyses are becoming commonplace. At thesame time, the explosion in analytical power consequentupon the consistent increases in processing powerachieved by modern ‘supercomputers’ is enabling previ-ously inconceivable feats of computational biology. Thisprocessing power can be harnessed to explore the multiplehierarchical interrelationships within complex physiologicalThis is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly cited.Grocott Extreme Physiology & Medicine 2013, 2:9 Page 2 of 2http://www.extremephysiolmed.com/content/2/1/9systems and for iterative biological model generation:experimentation in silico. An additional benefit of this ana-lytical power is the capacity to examine temporal patternsof variability in putative physiological signals (rather thanthe absolute values of specific variables). Previously, wehave sought average data to identify ‘representative’ values.Now, the pattern of variability of the signal over time(time-series data) is recognised as a signal in itself. It seemslikely that the pattern of variation over time exhibited bymany physiological variables is a reflection of the robust-ness of the underlying homeostatic control systems, andthat loss of this variability is a sign of dysfunction and illhealth. For example, loss of heart rate variability isrecognised to be a risk factor for early death followingmyocardial infarction. It may be that maintenance of com-plex patterns of variability is a defining feature of beneficialadaptation to environmental stressors; conversely, loss ofsuch variability may be a signal of maladaptation.This month in Extreme Physiology & Medicine, LindsayEdwards and Ines Thiele review the application of systemsbiology methods to the study of human integrative physi-ology, with particular focus on applications relating to con-ditions of environmental stress [5]. Edwards and Thieledefine systems biology as ‘an iterative process of computa-tional model-building and experimental model-revisionwith the aim of understanding or simulating complex bio-logical systems’. Further, they highlight the limited numberof physiologically relevant perturbations that are ethicallyacceptable in humans and highlight the value of environ-mental and exertional stressors in this context.Whether there is truly a distinction between systemsbiology and integrative physiology is unclear [6]. Bothdisciplines focus on the form and function of cells andcellular systems through the study of physical and chem-ical phenomena. As has been commented previously, itis only the amount of data, and the rate of its accumula-tion, that distinguishes one from the other [7]. That isnot to say that systems biology will not yield new in-sights. The application of the tools and techniques ofcomputational biology to mega data sets incorporatingomics readouts and high-resolution phenotypic metadatamay transform our understanding of phenomena withcausation at multiple hierarchical levels within the celland organism as well as identifying the key determinantsof the development of emergent phenomena. Such in-sights may also fundamentally alter our understandingof causality in physiological systems and thereby shapeour views of the very nature of integrative physiology.Competing interestsThe author declares that he has no competing interests.AcknowledgementsThe author thanks Dr Denny Levett, Dr Andrew Murray and Professor SueWard for their valuable comments on drafts of this manuscript.Author details1Integrative Physiology and Critical Illness Group, Division of Clinical andExperimental Science, Faculty of Medicine, University of Southampton,University Road, Southampton SO17 1BJ, UK. 2Anaesthesia and Critical CareResearch Unit, University Hospital Southampton, NHS Foundation Trust, CE.93Mailpoint 24, E-Level Centre Block, Tremona Road, Southampton SO16 6YD,UK. 3The Royal College of Anaesthetists, Churchill House 35 Red Lion Square,London WC1R 4SG, UK.Received: 7 March 2013 Accepted: 7 March 2013Published: 22 March 2013References1. Noble D: The Music of Life: Biology Beyond the Genome. Oxford: OxfordUniversity Press; 2006.2. Crick F: Central dogma of molecular biology. Nature 1970, 227:561–563.3. Goldstein J: Emergence as a construct: history and issues. Emergen:Complex Org 1999, 1(1):49–72.4. Anderson PW: More is different: broken symmetry and the nature of thehierarchical structure of science. Science 1972, 177(4047):393–396.5. Edwards LM, Thiele I: Applying systems biology methods to the study ofhuman physiology in extreme environments. Extreme Physiol Med 2013, 2:8.6. Greenhaff PL, Hargreaves M: ‘Systems biology’ in human exercisephysiology: is it something different from integrative physiology?J Physiol 2011, 589(5):1031–1036.7. Franklin S, Vondriska TM: Genomes, proteomes and the central dogma.Circ Cardiovasc Genet 2011, 4(5):576.doi:10.1186/2046-7648-2-9Cite this article as: Grocott: Integrative physiology and systems biology:reductionism, emergence and causality. Extreme Physiology & Medicine2013 2:9.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color ﬁgure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submit

Integrative physiology and systems biology: reductionism, emergence and causality

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Integrative physiology and systems biology: reductionism, emergence and causality

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