Civil Servant and Expert Perspectives on Drivers, Values, Challenges and Successes in Adopting Systems Thinking in Policy-Making

The use of systems thinking (ST) to handle complexity and wicked policy problems is gaining traction in government and the Civil Service, but policy-makers and civil servants can encounter several challenges in practice. How best to support them in understanding and applying ST in policy-making is not well understood. This study aims to explore civil servant and expert perspectives on the drivers and values of ST and the challenges, successes and solutions for its adoption in policy-making. We conducted semi-structured interviews with 31 civil servants across 17 UK government departments, agencies and public bodies, and 5 experts skilled in supporting ST use in policy-making. Via thematic analysis, we identified the values, challenges and successes interviewees experienced when implementing ST and their definitions of the term systems thinking. Civil servants were drawn into an ST approach by their academic training and exposure to it in their previous role(s), workshops, networking events and apprenticeships and through appreciating its values. Civil servants provided various interpretations of ST concepts and values with a strong emphasis on ‘complexity’ and ‘interrelationship’. Our analysis identified eight challenge themes for the implementation of ST in policy-making, including (i) ST language and interpretation, (ii) the policy landscape, (iii) government structure and operation, (iv) methodology and technical aspects, (v) capacity and expertise, (vi) conceptualisation, expectations and buy-in, (vii) stakeholders, engagement and collaboration and (viii) evaluation and evidence. Despite the high interest in ST among civil servants across different policy areas within the UK government and the Civil Service, implementation is challenging. Recommendations for implementation include ST language in policy, systems leadership, policy-specific capacity development and evaluation processes for collecting evidence of impacts

Civil servant and expert perspectives on drivers, values, challenges and successes in adopting systems thinking in policy making

The use of systems thinking (ST) to handle complexity and wicked policy problems is gaining traction in government and the Civil Service, but policy makers and civil servants can encounter several challenges in practice. How best to support them in understanding and applying ST in policy making is not well understood. This study aims to explore civil servant and expert perspectives on the drivers and values of ST and the challenges, successes and solutions for its adoption in policy making. We conducted semi-structured interviews with 31 civil servants across 17 UK government departments, agencies and public bodies, and 5 experts skilled in supporting ST use in policy making. Via thematic analysis, we identified the values, challenges and successes interviewees experienced when implementing ST and their definitions of the term systems thinking. Civil servants were drawn into an ST approach by their academic training and exposure to it in their previous role(s), workshops, networking events and apprenticeships and through appreciating its values. Civil servants provided various interpretations of ST concepts and values with a strong emphasis on ‘complexity’ and ‘interrelationship’. Our analysis identified eight challenge themes for the implementation of ST in policy making, including (i) ST language and interpretation, (ii) the policy landscape, (iii) government structure and operation, (iv) methodology and technical aspects, (v) capacity and expertise, (vi) conceptualisation, expectations and buy-in, (vii) stakeholders, engagement and collaboration and (viii) evaluation and evidence. Despite the high interest in ST among civil servants across different policy areas within the UK government and the Civil Service, implementation is challenging. Recommendations for implementation include ST language in policy, systems leadership, policy-specific capacity development and evaluation processes for collecting evidence of impacts

Soluble Aβ aggregates can inhibit prion propagation

Mammalian prions cause lethal neurodegenerative diseases such as Creutzfeldt–Jakob disease (CJD) and consist of multi-chain assemblies of misfolded cellular prion protein (PrPC). Ligands that bind to PrPC can inhibit prion propagation and neurotoxicity. Extensive prior work established that certain soluble assemblies of the Alzheimer's disease (AD)-associated amyloid β-protein (Aβ) can tightly bind to PrPC, and that this interaction may be relevant to their toxicity in AD. Here, we investigated whether such soluble Aβ assemblies might, conversely, have an inhibitory effect on prion propagation. Using cellular models of prion infection and propagation and distinct Aβ preparations, we found that the form of Aβ assemblies which most avidly bound to PrP in vitro also inhibited prion infection and propagation. By contrast, forms of Aβ which exhibit little or no binding to PrP were unable to attenuate prion propagation. These data suggest that soluble aggregates of Aβ can compete with prions for binding to PrPC and emphasize the bidirectional nature of the interplay between Aβ and PrPC in Alzheimer's and prion diseases. Such inhibitory effects of Aβ on prion propagation may contribute to the apparent fall-off in the incidence of sporadic CJD at advanced age where cerebral Aβ deposition is common

The cellular prion protein traps Alzheimer's A beta in an oligomeric form and disassembles amyloid fibers

This work was supported by a Wellcome Trust project grant (093241/Z/10/Z) and UK Biotechnology and Biological Sciences Research Council Quota studentships. The authors thank Harold Toms (Queen Mary, University of London) and the UK National Institute for Medical Research for NMR support, and Graham McPhail for assistance with TEM

Distinguishing closely related amyloid precursors using an RNA aptamer

Although amyloid fibrils assembled in vitro commonly involve a single protein, fibrils formed in vivo can contain multiple protein sequences. The amyloidogenic protein human ?2-microglobulin (h?2m) can co-polymerize with its N-terminally truncated variant (?N6) in vitro to form hetero-polymeric fibrils that differ from their homo-polymeric counterparts. Discrimination between the different assembly precursors, for example by binding of a biomolecule to one species in a mixture of conformers, offers an opportunity to alter the course of co-assembly and the properties of the fibrils formed. Here, using h?2m and its amyloidogenic counterpart, ??6, we describe selection of a 2'F-modified RNA aptamer able to distinguish between these very similar proteins. SELEX with a N30 RNA pool yielded an aptamer (B6) that binds h?2m with an EC50 of ?200 nM. NMR spectroscopy was used to assign the (1)H-(15)N HSQC spectrum of the B6-h?2m complex, revealing that the aptamer binds to the face of h?2m containing the A, B, E, and D ?-strands. In contrast, binding of B6 to ?N6 is weak and less specific. Kinetic analysis of the effect of B6 on co-polymerization of h?2m and ?N6 revealed that the aptamer alters the kinetics of co-polymerization of the two proteins. The results reveal the potential of RNA aptamers as tools for elucidating the mechanisms of co-assembly in amyloid formation and as reagents able to discriminate between very similar protein conformers with different amyloid propensity

Putative Mechanism for ADDL inhibition of RML propagation. from Soluble Aβ aggregates can inhibit prion propagation

Infected PK1/2 cells generate PrPSc by recruitment of PrPC which occurs at a rate faster than the cells innate clearance systems and dilutional effect of cell division, thus the cells remain chronically infected. However when ADDLs are added they bind to PrPC at the cell surface preventing conversion to PrPSc. This reduction in the conversion rate allows the PrPSc to be cleared over time, resulting in reduction in PrPSc levels and cell curing

Trisomy of human chromosome 21 enhances amyloid-beta deposition independently of an extra copy of APP

Down syndrome, caused by trisomy of chromosome 21, is the single most common risk factor for early-onset Alzheimer's disease. Worldwide approximately 6 million people have Down syndrome, and all these individuals will develop the hallmark amyloid plaques and neurofibrillary tangles of Alzheimer's disease by the age of 40 and the vast majority will go on to develop dementia. Triplication of APP, a gene on chromosome 21, is sufficient to cause early-onset Alzheimer's disease in the absence of Down syndrome. However, whether triplication of other chromosome 21 genes influences disease pathogenesis in the context of Down syndrome is unclear. Here we show, in a mouse model, that triplication of chromosome 21 genes other than APP increases amyloid-β aggregation, deposition of amyloid-β plaques and worsens associated cognitive deficits. This indicates that triplication of chromosome 21 genes other than APP is likely to have an important role to play in Alzheimer's disease pathogenesis in individuals who have Down syndrome. We go on to show that the effect of trisomy of chromosome 21 on amyloid-β aggregation correlates with an unexpected shift in soluble amyloid-β 40/42 ratio. This alteration in amyloid-β isoform ratio occurs independently of a change in the carboxypeptidase activity of the γ-secretase complex, which cleaves the peptide from APP, or the rate of extracellular clearance of amyloid-β. These new mechanistic insights into the role of triplication of genes on chromosome 21, other than APP, in the development of Alzheimer's disease in individuals who have Down syndrome may have implications for the treatment of this common cause of neurodegeneration.status: publishe