Special Feature: Complex Systems: From Chemistry to Systems Biology Special Feature: Phenotypes and tolerances in the design space of biochemical systems

One of the major unsolved problems of modern biology is deep understanding of the complex relationship between the information encoded in the genome of an organism and the phenotypic properties manifested by that organism. Fundamental advances must be made before we can begin to approach the goal of predicting the phenotypic consequences of a given mutation or an organism''s response to a novel environmental challenge. Although this problem is often portrayed as if the task were to find a more or less direct link between genotypic and phenotypic levels, on closer examination the relationship is far more layered and complex. Although there are some intuitive notions of what is meant by phenotype at the level of the organism, it is far from clear what this term means at the biochemical level. We have described design principles that are readily revealed by representation of molecular systems in an appropriate design space. Here, we first describe a generic approach to the construction of such a design space in which qualitatively distinct phenotypes can be identified and counted. Second, we show how the boundaries between these phenotypic regions provide a method of characterizing a system''s tolerance to large changes in the values of its parameters. Third, we illustrate the approach for one of the most basic modules of biochemical networks and describe an associated design principle. Finally, we discuss the scaling of this approach to large systems.     

Thrombolysis risk prediction: applying the SITS-SICH and SEDAN scores in South African patients

At present, the only specific medical treatment for acute ischaemic stroke isintravenous administration of recombinant tissue plasminogen activatorwithin 4.5 hours of stroke onset. In the last year, two scores for riskstratification of intracranial haemorrhage have been derived frommulticentric European trial groups, the Safe Implementation of Treatment inStroke – Symptomatic IntraCerebral Haemorrhage risk score (SITS-SICH) andthe SEDAN score. The aim of this study was to pilot their use in a cohort ofpatients treated at a South African tertiary hospital.Prospectively collected data were used from a cohort of 41 patients whounderwent thrombolysis at Groote Schuur Hospital from 2000 to 2012.Computerised tomography brain imaging was available for review in 23 ofthese cases. The SITS-SICH and SEDAN scores were then applied and riskprediction was compared with outcomes.Two patients suffered symptomatic intracranial haemorrhage (SICH),representing 4.9% (95% CI: 0–11.5%) of the cohort. This was comparable tothe SICH rate in both the SITS-SICH (5.1%) and SEDAN (6.5%) cohorts. Patientscores in the Groote Schuur Hospital cohort appeared similar to those of thevalidation cohorts of both SITS-SICH and SEDAN.With increasing use of thrombolysis in a resource-constrained setting, thesescores represent a potentially useful tool in patient selection of thosemost likely to benefit from intravenous thrombolysis, reducing risk for SICHand with the added benefit of curtailing cost.