Scientific discovery as a combinatorial optimisation problem: How best to navigate the landscape of possible experiments?

Kell, Douglas B.

doi:10.1002/bies.201100144

Cited by 46 publications

(47 citation statements)

References 109 publications

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“…Computational approaches are increasingly being viewed as critical for knowledge discovery in the natural sciences (Kell 2012). On one hand this may be addressed by using "big data" to reduce the space of possible solutions (Hey et al 2009).…”

Section: Discussion and Related Workmentioning

confidence: 99%

Identification of biological transition systems using meta-interpreted logic programs

Bain

Srinivasan

2018

Mach Learn

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We adopt the principal idea from Plotkin's Structural Operational Semantics (SOS), in which computation by a system is to be understood using: (a) a signature of configurations, ; (b) a binary relation (→) defined over × ; and (c) a meta-interpreter for general transition systems, defined at the level and →. Using specific definitions for configurations and transition rules, the meta-interpreter generates an operational explanation of a system's behaviour in the form of the stepwise computations (transitions) involved. This setting is of special interest to inductive logic programming (ILP), given recent developments in meta-interpretive learning. We focus here on the specific application of obtaining automatically Petri net models of biological system behaviour. Using a simple logic program as a meta-interpreter with a metarule for guarded transitions we show that using definitions of biologically-known transitions, proofs constructed by the meta-interpreter allow us, just as in SOS, to explain system behaviour as stepwise transitions in Petri nets. In the meta-interpretive learning setting, the proofs identify hypotheses that together with the metainterpreter and domain-knowledge logically entail the observed behaviour. Meta-interpretive learning enables us to go beyond the explanations available in SOS, which are purely deductive, since the meta-interpreter is allowed abductive steps in the proof. This enables us to "invent" transitions which have not been specified in domain-knowledge. We use this facility to deal with noisy data by constructing first a hypothesis that includes abduced transitions, followed by the use of a Viterbi-style computation to find the most likely sequence of transitions for a system with a specified initial and final state. Extensive experiments with some well-known biological systems show that this approach can reliably identify the correct set of transitions even with fairly high levels of noise and with moderate amount of missing values.

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Section: Discussion and Related Workmentioning

confidence: 99%

Identification of biological transition systems using meta-interpreted logic programs

Bain

Srinivasan

2018

Mach Learn

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“…In the past, and partly because of the enormous number of possible sequences [374][375][376] this was done rather empirically, using methods such as error-prone PCR (ePCR) [377][378][379] to introduce mutations. Although showing the utility of the general directed evolution strategy, this had three highly undesirable consequences: (i) there was no control over which mutations were made, (ii) the search could only be local, as high mutation rates necessarily introduced stop codons [379,380], and (iii) the reliance on selection of local 'winners' as starting points for the next generation inevitably meant that search was soon trapped in local minima from which it was impossible to escape (as was evident from many published studies showing a lack of further improvement after 3 or so generations, despite quite poor k cat values) [324].…”

Section: Synthetic Biology For Efflux Transporter Engineeringmentioning

confidence: 99%

Control of metabolite efflux in microbial cell factories: current advances and future prospects

Kell¹

2018

Preprint

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The yield and ease of purification of biotechnological products are typically greatly enhanced if they can be secreted into the external medium. Although not universally appreciated, however, small molecule biotechnological products do not ‘float across’ the phospholipid bilayer portion of biological membranes, and thus they need transporters to assist their passage into the extramembrane and extracellular spaces. Some of these transporters may be reversible, equilibrative transporters that might more normally be used for uptake, while others may have an efflux directionality imposed on them via suitable energy coupling mechanisms. Despite the energetic costs of small molecule synthesis, natural evolution does in fact provide a number of mechanisms by which the secretion of such products can actually enhance fitness. Where available these provide useful starting points, and assaying for such activities is crucial. In particular, in a systems biology approach, we first need to identify such/suitable activities before we can seek to increase them. They may then be improved through promoter engineering, via manipulation of control elements, or by directed evolution of the transporter proteins themselves. Modern methods of synthetic biology provide enormous opportunities for all kinds of efflux transporter engineering; they are just beginning to be realised.

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“…This can therefore increase dramatically the rate of knowledge-based navigation of the relevant search space (Fox and Huisman, 2008; Kell, 2012; Romero et al , 2013) for functional screening, and coupled with efficient synthesis and expression in E. coli or any other preferred host can provide a platform for the potential screening of millions of sequence variants in a single generation.…”

Section: Discussionmentioning

confidence: 99%

SpeedyGenes: an improved gene synthesis method for the efficient production of error-corrected, synthetic protein libraries for directed evolution

Currin

Swainston

Day

et al. 2014

Protein Engineering, Design and Selection

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The de novo synthesis of genes is becoming increasingly common in synthetic biology studies. However, the inherent error rate (introduced by errors incurred during oligonucleotide synthesis) limits its use in synthesising protein libraries to only short genes. Here we introduce SpeedyGenes, a PCR-based method for the synthesis of diverse protein libraries that includes an error-correction procedure, enabling the efficient synthesis of large genes for use directly in functional screening. First, we demonstrate an accurate gene synthesis method by synthesising and directly screening (without pre-selection) a 747 bp gene for green fluorescent protein (yielding 85% fluorescent colonies) and a larger 1518 bp gene (a monoamine oxidase, producing 76% colonies with full catalytic activity, a 4-fold improvement over previous methods). Secondly, we show that SpeedyGenes can accommodate multiple and combinatorial variant sequences while maintaining efficient enzymatic error correction, which is particularly crucial for larger genes. In its first application for directed evolution, we demonstrate the use of SpeedyGenes in the synthesis and screening of large libraries of MAO-N variants. Using this method, libraries are synthesised, transformed and screened within 3 days. Importantly, as each mutation we introduce is controlled by the oligonucleotide sequence, SpeedyGenes enables the synthesis of large, diverse, yet controlled variant sequences for the purposes of directed evolution.

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Scientific discovery as a combinatorial optimisation problem: How best to navigate the landscape of possible experiments?

Cited by 46 publications

References 109 publications

Identification of biological transition systems using meta-interpreted logic programs

Identification of biological transition systems using meta-interpreted logic programs

Control of metabolite efflux in microbial cell factories: current advances and future prospects

SpeedyGenes: an improved gene synthesis method for the efficient production of error-corrected, synthetic protein libraries for directed evolution

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