Computational biology of the heart: from structure to function.

摘要: The last two or three decades have been a spectacular success for biological research in its reductive mode. Molecular mechanisms, such as the gating of ionic channels and transporters, drug-receptor interactions, control protein expression regulation, that could only be treated ‘black boxes’ by cell biophysics 1960s 1970s now revealed not terms detailed molecular sequences structures but also, many cases, relation to their genetic coding. With end-point Human Genome Project already sight, it might seem excitement will soon over, leaving our successors continue long task filling details widening range applications. That would, however, profound misunderstanding both nature approach what next major challenge must be. First, has depended on blind mechanical application very powerful techniques rather using these answer questions known relevant functional interpretation at cell, organ organism levels. search bases voltage channels, example, was regarded important became highly focussed because plays crucial role functioning excitable cells. Functional properties identified higher levels ensured sequencing proteins just stamp collecting. Similar arguments apply genome. Hence demand development is becoming genomics. great majority genome cries out that, present, we do have. Second, so much information cellular there an increasing need re-integrate this detail into understanding how mechanisms interact regulated way produce normal pathological functioning. Most physiological functions occur level. Consider, origin cardiac rhythm. There no oscillator responsible this. Cardiac pacemaker activity emerges property interaction number separate transporters No single one can, itself, generate study arrhythmias, some which cannot even studied level; they require interactions large numbers cells connected networks. It may well also take account gross- micro-anatomy. This kind complex regulated, susceptible purely qualitative study. However accurate about individual unless represented quantitatively then integrated computational work designed reproduce thinking function largely armchair hand-waving. We can expect like pacemaking level, logic living systems are organised become evident studying whole name systems. called Physiology which, after all, means ‘logic systems’. title book (The Logic Life, Boyd & Noble, OUP, 1993) celebrated 1993 International Congress Physiological Sciences. Yet, simply genetics, identify emerging quantitative physiology necessary all through function. Some opted call discipline ‘Computational Physiology’. Computation necessary, course, studies computational. mathematical insight. This reason why us coin word ‘Physiome’, deliberate linguistic echo ‘Genome’. yet firm settled definition certain form part domain. And, concept led (or other round?), idea Physiome leading Project. subject recently small workshop held 1997 IUPS St Petersburg. little doubt time ripe integrative complement successes approaches. Indications others same legion (see, reports Banbury Conference, AW Cowley, Physiologist, October 1997). spirit informed recent NOVARTIS Foundation symposium London Limits Reductionism Biology (NOVARTIS 213, Editors GR Bock J Goode, Wiley, 1998). Within Physiome, sub-projects concerned with organs And foremost amongst Cardiome. simple. Computational far more advanced case heart than any organ. Thus, over 90% papers issue Chaos, Solitions Fractals Nonlinear Phenomena Excitable Systems (see volume 5, nos 3/4, 1995) were heart. The not, limited excitability, exciting though is! prospect integrating aspects organ, including biochemistry, mechanics, circulation etc exciting. context decided hold June San Diego entitled “Computational Heart: From Structure Function”. brought together teams field provided extremely valuable opportunity between those working different discuss together. Although question publication initial motivation, delighted when Progress Biophysics chose first issues. journal totally appropriate work. Much seminal modelling past published journal, notably A. F. Huxley's model sliding filament mechanism muscle contraction (Huxley, 1957, see 7 Biophysics). The articles forming actual presentations made Diego. Each author invited contribute article based presentations, taking make material accessible readers review journal. hope believe result up-to-date present state art Cardiome, basis further greater progress future. The Supercomputer Center support National Biomedical Resource, NIH national resource aims improve access biomedical scientists high-performance computing. Workshop co-sponsors included Medtronic Inc. (Minneapolis, MN); Alliance Pharmaceutical Corporation (La Jolla, CA); UCSD Institute Engineering; Mechanics Materials; Advanced Science Engineering. The topics covered meeting here anatomy structure, myocardial mechanics growth, ventricular fluid dynamics valves, electromechanical metabolism energetics, currents nonlinear dynamics, propagation waves vortices throughout heart, conduction defibrillation, imaging visualization processes. Participants discussed develop hierarchy models from level contractile ion channel, tissue, organism, envisaged proposed “Human Project”: complete, integrated, hierarchical complexity. span scales organization body, touching diverse functions, chemical metabolic electrical. The editorial committee formed members organising (Andrew McCulloch, Jim Bassingthwaighte Peter Hunter) permanent editor (Denis Noble). took responsibility refereeing editing articles.