Engineering simulations for cancer systems biology

Computer simulation can be used to inform in vivo and in vitro experimentation, enabling rapid, low-cost hypothesis generation and directing experimental design in order to test those hypotheses. In this way, in silico models become a scientific instrument for investigation, and so should be developed to high standards, be carefully calibrated and their findings presented in such that they may be reproduced. Here, we outline a framework that supports developing simulations as scientific instruments, and we select cancer systems biology as an exemplar domain, with a particular focus on cellular signalling models. We consider the challenges of lack of data, incomplete knowledge and modelling in the context of a rapidly changing knowledge base. Our framework comprises a process to clearly separate scientific and engineering concerns in model and simulation development, and an argumentation approach to documenting models for rigorous way of recording assumptions and knowledge gaps. We propose interactive, dynamic visualisation tools to enable the biological community to interact with cellular signalling models directly for experimental design. There is a mismatch in scale between these cellular models and tissue structures that are affected by tumours, and bridging this gap requires substantial computational resource. We present concurrent programming as a technology to link scales without losing important details through model simplification. We discuss the value of combining this technology, interactive visualisation, argumentation and model separation to support development of multi-scale models that represent biologically plausible cells arranged in biologically plausible structures that model cell behaviour, interactions and response to therapeutic interventions

Physical portrayal of computational complexity

Computational complexity is examined using the principle of increasing entropy. To consider computation as a physical process from an initial instance to the final acceptance is motivated because many natural processes have been recognized to complete in non-polynomial time (NP). The irreversible process with three or more degrees of freedom is found intractable because, in terms of physics, flows of energy are inseparable from their driving forces. In computational terms, when solving problems in the class NP, decisions will affect subsequently available sets of decisions. The state space of a non-deterministic finite automaton is evolving due to the computation itself hence it cannot be efficiently contracted using a deterministic finite automaton that will arrive at a solution in super-polynomial time. The solution of the NP problem itself is verifiable in polynomial time (P) because the corresponding state is stationary. Likewise the class P set of states does not depend on computational history hence it can be efficiently contracted to the accepting state by a deterministic sequence of dissipative transformations. Thus it is concluded that the class P set of states is inherently smaller than the set of class NP. Since the computational time to contract a given set is proportional to dissipation, the computational complexity class P is a subset of NP.Comment: 16, pages, 7 figure

Transparency in Complex Computational Systems

Scientists depend on complex computational systems that are often ineliminably opaque, to the detriment of our ability to give scientific explanations and detect artifacts. Some philosophers have s..

Distributed Computing with Adaptive Heuristics

We use ideas from distributed computing to study dynamic environments in which computational nodes, or decision makers, follow adaptive heuristics (Hart 2005), i.e., simple and unsophisticated rules of behavior, e.g., repeatedly "best replying" to others' actions, and minimizing "regret", that have been extensively studied in game theory and economics. We explore when convergence of such simple dynamics to an equilibrium is guaranteed in asynchronous computational environments, where nodes can act at any time. Our research agenda, distributed computing with adaptive heuristics, lies on the borderline of computer science (including distributed computing and learning) and game theory (including game dynamics and adaptive heuristics). We exhibit a general non-termination result for a broad class of heuristics with bounded recall---that is, simple rules of behavior that depend only on recent history of interaction between nodes. We consider implications of our result across a wide variety of interesting and timely applications: game theory, circuit design, social networks, routing and congestion control. We also study the computational and communication complexity of asynchronous dynamics and present some basic observations regarding the effects of asynchrony on no-regret dynamics. We believe that our work opens a new avenue for research in both distributed computing and game theory.Comment: 36 pages, four figures. Expands both technical results and discussion of v1. Revised version will appear in the proceedings of Innovations in Computer Science 201