Calculating life? Duelling discourses in interdisciplinary systems biology

A high profile context in which physics and biology meet today is in the new field of systems biology. Systems biology is a fascinating subject for sociological investigation because the demands of interdisciplinary collaboration have brought epistemological issues and debates front and centre in discussions amongst systems biologists in conference settings, in publications, and in laboratory coffee rooms. One could argue that systems biologists are conducting their own philosophy of science. This paper explores the epistemic aspirations of the field by drawing on interviews with scientists working in systems biology, attendance at systems biology conferences and workshops, and visits to systems biology laboratories. It examines the discourses of systems biologists, looking at how they position their work in relation to previous types of biological inquiry, particularly molecular biology. For example, they raise the issue of reductionism to distinguish systems biology from molecular biology. This comparison with molecular biology leads to discussions about the goals and aspirations of systems biology, including epistemic commitments to quantification, rigor and predictability. Some systems biologists aspire to make biology more similar to physics and engineering by making living systems calculable, modelable and ultimately predictable-a research programme that is perhaps taken to its most extreme form in systems biology's sister discipline: synthetic biology. Other systems biologists, however, do not think that the standards of the physical sciences are the standards by which we should measure the achievements of systems biology, and doubt whether such standards will ever be applicable to 'dirty, unruly living systems'. This paper explores these epistemic tensions and reflects on their sociological dimensions and their consequences for future work in the life sciences.     

Causality in Complex Systems

Systems involving many interacting variables are at the heart of the natural and social sciences. Causal language is pervasive in the analysis of such systems, especially when insight into their behavior is translated into policy decisions. This is exemplified by economics, but to an increasing extent also by biology, due to the advent of sophisticated tools to identify the genetic basis of many diseases. It is argued here that a regularity notion of causality can only be meaningfully defined for systems with linear interactions among their variables. For the vastly more important class of nonlinear systems, no such notion is likely to exist. This thesis is developed with examples of dynamical systems taken mostly from mathematical biology. It is discussed with particular reference to the problem of causal inference in complex genetic systems, systems for which often only statistical characterizations exist.     

The autonomy of the visual systems and the modularity of conscious vision.

Anatomical and physiological evidence shows that the primate visual brain consists of many distributed processing systems, acting in parallel. Psychophysical studies show that the activity in each of the parallel systems reaches its perceptual end-point at a different time, thus leading to a perceptual asynchrony in vision. This, together with clinical and human imaging evidence, suggests strongly that the processing systems are also perceptual systems and that the different processing-perceptual systems can act more or less autonomously. Moreover, activity in each can have a conscious correlate without necessarily involving activity in other visual systems. This leads us to conclude not only that visual consciousness is itself modular, reflecting the basic modular organization of the visual brain, but that the binding of cellular activity in the processing-perceptual systems is more properly thought of as a binding of the consciousnesses generated by each of them. It is this binding that gives us our integrated image of the visual world.     

Cation transport in Escherichia coli. VIII. Potassium transport mutants

Analysis of K transport mutants indicates the existence of four separate K uptake systems in Escherichia coli K-12. A high affinity system called Kdp has a Km of 2 muM, and Vmax at 37 degrees C of 150 mumol/g min. This system is repressed by growth in high concentrations of K. Two constitutive systems, TrkA and TrkD, have Km's of 1.5 and 0.5 mM and Vmax's of 550 and 40 at 37 and 30 degrees C, respectively. Mutants lacking all three of these saturable systems take up K slowly by a process, called TrkF, whose rate of transport is linearly dependent on K concentration up to 105 mM. On the whole, each of these systems appears to function as an independent path for K uptake since the kinetics of uptake when two are present is the sum of each operating alone. This is not true for strains having both the TrkD and Kdp systems, where presence of the latter results in K uptake which saturates at a K concentration well below 0.1 mM. This result indicates some interaction between these systems so that uptake now has the affinity characteristic of the Kdp system. All transport systems are able to extrude Na during K uptake. The measurements of cell Na suggest that growing cells of E. coli have very low concentrations of Na, considerably lower than indicated by earlier studies.     

Fuzzy systems vegetation theory

Fuzzy systems vegetation theory is a comprehensive framework for the expression of vegetation theory and conceptual models, as well as the development of vegetation analyses. It is applicable to vegetation/environment relations, vegetation dynamics, and the effects of environmental dynamics on vegetation composition. Fuzzy systems vegetation theory is a fuzzy set generalization of dynamical systems theory and incorporates a formal logic and mathematics. This paper presents the elements of fuzzy systems vegetation theory and discusses the relationship of the fuzzy systems theory to the geometric concepts generally employed in vegetation theory.     

A comparison of phosphorus immobilization in sediments of freshwater and coastal marine systems

The extent to which sediments of aquatic systems immobilize or release phosphorus can affect dramatically the P content of overlying waters. Data from 48 different aquatic systems suggests that there may be a major difference between fresh- and salt-water systems in this immobilization. Under oxic conditions (water overlying sediments had dissolved oxygen > 0.5 mg/L) P is strongly immobilized in sediments of most fresh-water systems. In sediments of most salt-water systems P is released from sediments and behaves, essentially, as a conservative tracer of benthic decomposition. This difference in P cycling is large enough to have an influence on the often cited difference in phytoplankton nutrient limitation between fresh- and salt-water systems.     

LCA of food products and production systems

This article is a summary of my dissertation in which LCA was applied to food products and production systems. The overall objectives were: (1) to learn more about the feasibility and limitations of LCAs of systems for the production and consumption of foods (food systems); and (2) to generate information on the environmental impact of such systems. Case studies of tomato ketchup and white bread were carried out. The main conclusion is that LCA is very valuable for incorporating environmental aspects in the development of more sustainable food systems. One of the major problems encountered was the great scarcity of environmental data. It was found that there is a need for simplified methods that can be used as a compass to show the direction towards sustainability. Accordingly, the feasibility of combinng the concept of sustainabiliry principles and LCA for product development was examined and discussed. This combination was found to yield a simplified method well suited for screening analysis and product development.     

Unique features of hepatitis C virus capsid formation revealed by de novo cell-free assembly

The assembly of hepatitis C virus (HCV) is poorly understood, largely due to the lack of mammalian cell culture systems that are easily manipulated and produce high titers of virus. This problem is highlighted by the inability of the recently established HCV replicon systems to support HCV capsid assembly despite high levels of structural protein synthesis. Here we demonstrate that up to 80% of HCV core protein synthesized de novo in cell-free systems containing rabbit reticulocyte lysate or wheat germ extracts assembles into HCV capsids. This contrasts with standard primate cell culture systems, in which almost no core assembles into capsids. Cell-free HCV capsids, which have a sedimentation value of approximately 100S, have a buoyant density (1.28 g/ml) on cesium chloride similar to that of HCV capsids from other systems. Capsids produced in cell-free systems are also indistinguishable from capsids isolated from HCV-infected patient serum when analyzed by transmission electron microscopy. Using these cell-free systems, we show that HCV capsid assembly is independent of signal sequence cleavage, is dependent on the N terminus but not the C terminus of HCV core, proceeds at very low nascent chain concentrations, is independent of intact membrane surfaces, and is partially inhibited by cultured liver cell lysates. By allowing reproducible and quantitative assessment of viral and cellular requirements for capsid formation, these cell-free systems make a mechanistic dissection of HCV capsid assembly possible.     

Comprehensive DNA microarray analysis of Bacillus subtilis two-component regulatory systems.

It has recently been shown through DNA microarray analysis of Bacillus subtilis two-component regulatory systems (DegS-DegU, ComP-ComA, and PhoR-PhoP) that overproduction of a response regulator of the two-component systems in the background of a deficiency of its cognate sensor kinase affects the regulation of genes, including its target ones. The genome-wide effect on gene expression caused by the overproduction was revealed by DNA microarray analysis. In the present work, we newly analyzed 24 two-component systems by means of this strategy, leaving out 8 systems to which it was unlikely to be applicable. This analysis revealed various target gene candidates for these two-component systems. It is especially notable that interesting interactions appeared to take place between several two-component systems. Moreover, the probable functions of some unknown two-component systems were deduced from the list of their target gene candidates. This work is heuristic but provides valuable information for further study toward a comprehensive understanding of the B. subtilis two-component regulatory systems. The DNA microarray data obtained in this work are available at the KEGG Expression Database website (http://www.genome.ad.jp/kegg/expression).     

Temperature acquisition as a function of the computer-based biofeedback system utilized: An exploratory analysis

Thermal biofeedback is widely used to treat various clinical disorders. Given its widespread utility, and the variability among the biofeedback systems currently on the market, it is important to investigate which systems are most effective for training various skills. This study compared the performance of normal subjects on two different computer-biofeedback systems. Results indicated a significant difference in subject performance between the two systems. Limitations and implications of these findings are discussed.     

Absolute Sustainability‐Based Life Cycle Assessment (ASLCA): A Benchmarking Approach to Operate Agri‐food Systems within the 2°C Global Carbon Budget

Given the increasing environmental impacts associated with global agri‐food systems, operating and developing these systems within the so‐called absolute environmental boundaries has become crucial, and hence the absolute environmental sustainability concept is particularly relevant. This study introduces an approach called absolute sustainability‐based life cycle assessment (ASLCA) that informs the climate impacts of an agri‐food system (on any economic level) in absolute terms. First, a global carbon budget was calculated that is sufficient to limit global warming to below 2°C. Next, a share of the carbon budget available to the global agri‐food sector was estimated, and then it was shared between agri‐food systems on multiple economic levels using four alternative methods. Third, the climate impacts of those systems were calculated using life cycle assessment methodology and were benchmarked against those carbon budget shares. This approach was used to assess a number of New Zealand agri‐food systems (agri‐food sector, horticulture industries and products) to investigate how these systems operated relative to their carbon budget shares. The results showed that, in 2013, the New Zealand agri‐food systems were within their carbon budget shares for one of the four methods, and illustrated the scale of change required for agri‐food systems to perform within their carbon budget shares. This method can potentially be extended to consider other environmental impacts with global boundaries; however, further development of the ASLCA is necessary to account for other environmental impacts whose boundaries are only meaningful when defined at a regional or local level.     

A model management systems approach to manufacturing systems design

Manufacturing systems design involves the solution of a complex series of interrelated problems. This complexity will increase in the future as manufacturing practices change to meet increased global competition. Research within manufacturing systems design has mainly been focused on finding improved models for solving particular problems, or extending existing modeling techniques. This has resulted in numerous modeling tools being available to support manufacturing systems design. However, little research work has been carried out into consolidating the existing theories and models. As a result, a large body of this work has not been applied in industry. Model management has evolved as a research area which investigates methods for storing, modifying, and manipulating models. This article describes a prototype model management system for manufacturing systems design. The objective here is not to develop “another” decision support system for manufacturing design, but to illustrate, through the development of a prototype system, a number of key ideas of how concepts from the area of model management systems can be used to support manufacturing systems design. The prototype model management system utilizes the structured modeling framework and uses an extended version of the structured modeling language. An important aspect of the prototype model management system is the incorporation of the model development task, thus allowing the system to be easily updated and adapted. The prototype system was evaluated using a range of queueing network models for manufacturing systems design.     

Recombinant expression systems: the obstacle to helminth vaccines?

The need for alternative ways to control helminth parasites has in recent years led to a boost in vaccination experiments with recombinant antigens. Despite the use of different expression systems, only a few recombinants induced high levels of protection against helminths. This is often attributed to the limitations of the current expression systems. Therefore, the need for new systems that can modify and glycosylate the expressed antigens has been advocated. However, analysis of over 100 published vaccine trials with recombinant helminth antigens indicates that it is often not known whether the native parasite antigen itself can induce protection or, if it does, which epitopes are important. This information is vital for a well-thought-out strategy for recombinant production. So, in addition to testing more expression systems, it should be considered that prior evaluation and characterization of the native antigens might help the development of recombinant vaccines against helminths in the long term.     

The numerical solution of stiff differential equations

This paper first discusses the conditions in which a set of differential equations should give stable solutions, starting with linear systems assuming that these do not differ greatly in this respect from non-linear systems. Methods of investigating the stability of particular systems are briefly discussed. Most real biochemical systems are known from observation to be stable, but little is known of the regions over which stability persists; moreover, models of biochemical systems may not be stable, because of inaccurate choice of parameter values.The separate problem of stability and accuracy in numerical methods of approximating the solution of systems of non-linear equations is then treated. Stress is laid on the consistently unsatisfactory results given by explicit methods for systems containing "stiff" equations, and implicit multistep methods are particularly recommended for this class of problem, which is likely to include many biochemical model systems. Finally, an iteration procedure likely to give convergence both in multistep methods and in the steady-state approach is recommended, and areas in which improvement in methods is likely to occur are outlined.     

Autonomy and hypersets

This paper has two primary aims. The first is to provide an introductory discussion of hyperset theory and its usefulness for modeling complex systems. The second aim is to provide a hyperset analysis of several perspectives on autonomy: Robert Rosen's metabolism-repair systems and his claim that living things are closed to efficient cause, Maturana and Varela's autopoietic systems, and Kauffman's cataytically closed systems. Consequences of the hyperset models for Rosen's claim that autonomous systems have non-computable models are discussed.     

Cation chelators and their utilization in the preparation of low concentrations of calcium. Caution of use in biological systems with high affinity to calcium

Ethylene glycol bis (beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA)-calcium buffer is widely used in various calcium-dependent reactions where free calcium concentrations of 1 microM or less are desirable. The free calcium concentration is calculated from the association constant of EGTA . Ca2- and serves as the true available calcium in systems devoid of a constituent with high affinity to Ca2+ other than EGTA. But, it is conceivable that in systems with high affinity to Ca2+ (comparable to that of EGTA) this is not the case, because such systems will compete with EGTA for the total calcium content in the medium, so that the true available calcium for these systems is greater than that calculated from the EGTA buffer. This hypothesis was tested in three different Ca+-modulated systems: Quin 2 fluorescence, Ca2+-ATPase, and adenylate cyclase, in which the response of the system to calcium was compared between EGTA-free media, containing known amounts of added calcium, and the EGTA-Ca2+ buffer media. In all three systems, the amount of available calcium in the EGTA-Ca2+ buffer medium was much greater than the calculated free Ca2+ concentration. This indicates that in systems with high affinity to Ca2+, preparation of available Ca2+ in concentrations of 1 microM or less must account for both the EGTA and the system capacities for calcium.     

Acid tolerance of gastrointestinal pathogens

The ability of pathogenic bacteria to survive in the face of host defense systems is intimately linked to virulence. This is exemplified by gastrointestinal pathogens that must survive exposure to extreme acid conditions within the stomach and organic acid conditions within the small intestine. These organisms have evolved complex systems to respond to acid stress, and recent work has revealed new genetic components involved in survival and virulence. Here, we review recent work on four gastrointestinal pathogens, focusing on studies that reveal both acid-inducible resistance systems and inherent (basal state) acid-resistance systems.