Towards understanding the myometrial physiome: approaches for the construction of a virtual physiological uterus
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Premature labour (PTL) is the single most significant factor contributing to neonatal morbidity in Europe with enormous attendant healthcare and social costs. Consequently, it remains a major challenge to alleviate the cause and impact of this condition. Our ability to improve the diagnosis and treatment of women most at risk of PTL is, however, actually hampered by an incomplete understanding of the ways in which the functions of the uterine myocyte are integrated to effect an appropriate biological response at the multicellular whole organ system. The level of organization required to co-ordinate labouring uterine contractile effort in time and space can be considered immense. There is a multitude of what might be considered mini-systems involved, each with their own regulatory feedback cycles, yet they each, in turn, will influence the behaviour of a related system. These include, but are not exclusive to, gestational-dependent regulation of transcription, translation, post-translational modifications, intracellular signaling dynamics, cell morphology, intercellular communication and tissue level morphology.
We propose that in order to comprehend how these mini-systems integrate to facilitate uterine contraction during labour (preterm or term) we must, in concert with biological experimentation, construct detailed mathematical descriptions of our findings. This serves three purposes: firstly, providing a quantitative description of series of complex observations; secondly, proferring a database platform that informs further testable experimentation; thirdly, advancing towards the establishment of a virtual physiological uterus and in silico clinical diagnosis and treatment of PTL.
KeywordsPreterm Labour Myometrial Cell Intensive Care Admission Myometrial Contractility Detailed Mathematical Description
'The challenge to interpret this vast volume of data at the genomic and proteomic level in terms of function at higher levels is exactly what modern physiology is about.' .
The development of improved methods of diagnosis and treatment of preterm labour (PTL) is the major task facing obstetric research in this new millennium. PTL accounts for 6–8% of all births across Europe (~6% in the UK) . Of even greater significance is that 75% of neonatal deaths, and most neonatal intensive care admissions, arise from preterm babies born before 32 weeks of pregnancy . Oft-overlooked is the realisation that the impact of PTL is long-lasting; prematurely born children face a high risk of disability and life-long ill health. In a recent follow-up study of 308 UK children born prematurely (<26 weeks), the rates of severe, moderate and mild disability at 6 years of age were 22%, 24% and 34% respectively . The short- and long-term economic consequences of preterm birth also place a considerable burden on society as a whole . It is, therefore, a considerable cause of concern that the prevention of PTL, or the treatment of established PTL, remains seriously inadequate; in fact, the rates of PTL have not declined in the last 20 years. It is paramount, therefore, that we advance our understanding of uterine physiology, in all its complexities, in order to improve our diagnosis and treatment of PTL.
There is an overall goal underpinning our wish to combine theoretical and empirical approaches to understanding uterine physiology and pathophysiology. That is, to eventually establish a comprehensive and rigorous model of integrated gravid uterine function that enables the application of non-invasive in silico tools for predicting the physiological impact of any new treatment regimens for women at the risk of preterm labour. In other words, the creation of a virtual physiological uterus. Similar approaches have been exceptionally successful in the last 15 years at informing us of the function (and dysfunction) of isolated cardiac cells, specialised cardiac regions or the heart as a whole .
A final consideration concerns establishing meaningful access to the divergent datasets related to PTL for computational modelling purposes by the academic community of biologists, chemists, mathematicians and clinicians. Certainly this requires a web-based forum for the storage, and continued supplementation, of datasets in a standardized, well-defined and cross-referenced manner with open access to software tools allowing for model developments and data analysis [11, 19].
This paper was supported by funding from Action Medical Research (MJT, AB), Wellcome Trust (MJT), EU Network of Excellence BioSim (AVH) and the EU SAFE Network of Excellence (LSHB-CT-2004-503243). Publication costs were supported by Ferring, Serono and Perkin Elmer. Written consent was obtained from the patient or their relative for publication of this study.
This article has been published as part of BMC Pregnancy and Childbirth Volume 7, Supplement 1, 2007: Proceedings of the First and Second European Workshops on Preterm Labour of the Special Non-Invasive Advances in Fetal and Neonatal Evaluation (SAFE) Network of Excellence. The full contents of the supplement are available online at http://www.biomedcentral.com/1471-2393/7?issue=S1.
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