'The ethics approval took 20 months on a trial which was meant to help terminally ill cancer patients. In the end we had to send the funding back': a survey of views on human research ethics reviews.

BACKGROUND: We conducted a survey to identify what types of health/medical research could be exempt from research ethics reviews in Australia. METHODS: We surveyed Australian health/medical researchers and Human Research Ethics Committee (HREC) members. The survey asked whether respondents had previously changed or abandoned a project anticipating difficulties obtaining ethics approval, and presented eight research scenarios, asking whether these scenarios should or should not be exempt from ethics review, and to provide (optional) comments. Qualitative data were analysed thematically; quantitative data in R. RESULTS: We received 514 responses. Forty-three per cent of respondents to whom the question applied, reported changing projects in anticipation of obstacles from the ethics review process; 25% reported abandoning projects for this reason. Research scenarios asking professional staff to provide views in their area of expertise were most commonly exempted from ethics review (to prioritise systematic review topics 84%, on software strengths/weaknesses 85%); scenarios involving surplus samples (82%) and N-of-1 (single case) studies (76%) were most commonly required to undergo ethics review. HREC members were 26% more likely than researchers to require ethics review. Need for independent oversight, and low risk, were most frequently cited in support of decisions to require or exempt from ethics review, respectively. CONCLUSIONS: Considerable differences exist between researchers and HREC members, about when to exempt from review the research that ultimately serves the interests of patients and the public. It is widely accepted that evaluative research should be used to reduce clinical uncertainties-the same principle should apply to ethics reviews.

Research approvals iceberg: helping it melt away.

BACKGROUND: In their paper "Research approvals iceberg: how a 'low-key' study in England needed 89 professionals to approve it and how we can do better" Petrova and Barclay highlight concerns with the health research regulatory environment in the UK. DISCUSSION: As long-standing chairs of NHS research ethics committees, researchers, and also academics in research ethics, we are also often frustrated with the regulatory process in the UK. However, we think that Petrova and Barclay's analysis is misleading because it conflates research ethics with governance and funding processes, thus failing to adequately distinguish between the national coordinating function of the Health Research Authority, local research governance processes, and interactions with research sponsors and/or the Clinical Research Network.

Interaction of serum amyloid P component with hexanoyl bis(D-proline) (CPHPC).

Under physiological conditions, the pentameric human plasma protein serum amyloid P component (SAP) binds hexanoyl bis(D-proline) (R-1-{6-[R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl}pyrrolidine-2-carboxylic acid; CPHPC) through its D-proline head groups in a calcium-dependent interaction. Cooperative effects in binding lead to a substantial enhancement of affinity. Five molecules of the bivalent ligand cross-link and stabilize pairs of SAP molecules, forming a decameric complex that is rapidly cleared from the circulation by the liver. Here, it is reported that X-ray analysis of the SAP complex with CPHPC and cadmium ions provides higher resolution detail of the interaction than is observed with calcium ions. Conformational isomers of CPHPC observed in solution by HPLC and by X-ray analysis are compared with the protein-bound form. These are discussed in relation to the development of CPHPC to provide SAP depletion for the treatment of amyloidosis and other indications.

Trapping of palindromic ligands within native transthyretin prevents amyloid formation.

Transthyretin (TTR) amyloidosis is a fatal disease for which new therapeutic approaches are urgently needed. We have designed two palindromic ligands, 2,2'-(4,4'-(heptane-1,7-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (mds84) and 2,2'-(4,4'-(undecane-1,11-diylbis(oxy))bis(3,5-dichloro-4,1-phenylene)) bis(azanediyl)dibenzoic acid (4ajm15), that are rapidly bound by native wild-type TTR in whole serum and even more avidly by amyloidogenic TTR variants. One to one stoichiometry, demonstrable in solution and by MS, was confirmed by X-ray crystallographic analysis showing simultaneous occupation of both T4 binding sites in each tetrameric TTR molecule by the pair of ligand head groups. Ligand binding by native TTR was irreversible under physiological conditions, and it stabilized the tetrameric assembly and inhibited amyloidogenic aggregation more potently than other known ligands. These superstabilizers are orally bioavailable and exhibit low inhibitory activity against cyclooxygenase (COX). They offer a promising platform for development of drugs to treat and prevent TTR amyloidosis.

Ethics, Legality, and Safety for Geneticists.

Never before have we had the methods to edit or manipulate genes and genomes in the way we can today. This volume has described technologies that, a generation ago, were unthinkable. But such power raises broader issues on how we wield it. These concerns are relevant at a number of levels, from basic safety, through the importance of scientific reproducibility and transparency, to Ethical, Philosophical, or even Political considerations. But why should this matter to a laboratory scientist - surely results are the main aim of experiments? However, such a view misses the important point that alongside our research generating new information, experience gained conducting research can also be used for influence far beyond the lab bench. Indeed, how research is conducted can be as important as the results themselves because our actions also reflect and inform the values that society and us as individuals view as important. Rather than focusing on the details of policy or legislation, this chapter therefore seeks to reflect on how Ethics, Legality, and Safety impact the molecular biologist, and why researchers need to view these not as bureaucracy, but rather as a critical part of their wider scientific identity and task.

The trinity of good research: Distinguishing between research integrity, ethics, and governance.

The words integrity, ethics, and governance are used interchangeably in relation to research. This masks important differences that must be understood when trying to address concerns regarding research culture. While progress has been made in identifying negative aspects of research culture (such as inequalities in hiring/promotion, perverse incentives, etc.) and practical issues that lead to research waste (outcome reporting bias, reproducibility, etc.), the responsibility for addressing these problems can be unclear due to the complexity of the research environment. One solution is to provide a clearer distinction between the perspectives of "Research Integrity," "Research Ethics," and "Research Governance." Here, it is proposed that Research Integrity should be understood as focused on the character of researchers, and consequently the responsibility for promoting it lies primarily with researchers themselves. This is a different perspective from Research Ethics, which is focused on judgments on the ethical acceptability of research, and should primarily be the responsibility of research ethics committees, often including input from the public as well as the research community. Finally, Research Governance focuses on legal and policy requirements, and although complementary to research integrity and ethics, is primarily the responsibility of expert research support officers with the skills and experience to address technical compliance.

Ranking Research Methodology by Risk - a cross-sectional study to determine the opinion of research ethics committee members.

BACKGROUND: When reviewing a protocol, research ethics committees (RECs, equivalent to institutional review boards - IRBs) have the responsibility to consider whether the proposed research is justified. If research is not justified, it can waste participants' time, researchers' time and resources. As RECs are not constituted to cover all areas of scientific or academic expertise, it can be difficult for RECs to decide whether research is scientifically or methodologically justified especially in the absence of authoritative (often in the form of systematic) reviews. Where such reviews are absent, some have argued that RECs should insist on a new review of existing evidence as a condition of the REC favourable opinion. However, as RECs review a wide range of research, such requests must be proportionate to the type, and extent, of proposed projects. Risk is one factor that may influence the extent of evidence need for a REC to determine that the new project is justified, but not the only factor. The aim of the work described here was to determine whether REC members and researchers specifically link risk to the type of research methodology, and if so, whether this link could be used to help guide the need for systematic, or other, types of reviews. METHOD: We conducted a cross-sectional study, gathering data between November 2020 and January 2021, to examine whether proposed research methodologies impact how RECs perceive risk to participants. We presented 31 research methodologies to REC members and researchers in the form of an international survey. RESULTS: We collected 283 responses that included both qualitative and quantitative data as to how research methodology impacts perceptions of risk to participants. We used the data to conclude that RECs did see a link between risk and type of research. We therefore constructed a hierarchy of risk with Phase 1 and 2 clinical trials, and clinical psychology/psychiatry intervention studies, at the top (i.e. viewed as most risky). CONCLUSIONS: We discuss whether this hierarchy is useful for guiding RECs as to the level of scientific justification that they should seek when reviewing proposed research protocols, and present a one-page guidance sheet to help RECs during their reviews.

Targeting C-reactive protein for the treatment of cardiovascular disease.

Complement-mediated inflammation exacerbates the tissue injury of ischaemic necrosis in heart attacks and strokes, the most common causes of death in developed countries. Large infarct size increases immediate morbidity and mortality and, in survivors of the acute event, larger non-functional scars adversely affect long-term prognosis. There is thus an important unmet medical need for new cardioprotective and neuroprotective treatments. We have previously shown that human C-reactive protein (CRP), the classical acute-phase protein that binds to ligands exposed in damaged tissue and then activates complement, increases myocardial and cerebral infarct size in rats subjected to coronary or cerebral artery ligation, respectively. Rat CRP does not activate rat complement, whereas human CRP activates both rat and human complement. Administration of human CRP to rats is thus an excellent model for the actions of endogenous human CRP. Here we report the design, synthesis and efficacy of 1,6-bis(phosphocholine)-hexane as a specific small-molecule inhibitor of CRP. Five molecules of this palindromic compound are bound by two pentameric CRP molecules, crosslinking and occluding the ligand-binding B-face of CRP and blocking its functions. Administration of 1,6-bis(phosphocholine)-hexane to rats undergoing acute myocardial infarction abrogated the increase in infarct size and cardiac dysfunction produced by injection of human CRP. Therapeutic inhibition of CRP is thus a promising new approach to cardioprotection in acute myocardial infarction, and may also provide neuroprotection in stroke. Potential wider applications include other inflammatory, infective and tissue-damaging conditions characterized by increased CRP production, in which binding of CRP to exposed ligands in damaged cells may lead to complement-mediated exacerbation of tissue injury.

Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component.

New therapeutic approaches in Alzheimer's disease are urgently needed. The normal plasma protein, serum amyloid P component (SAP), is always present in cerebrospinal fluid (CSF) and in the pathognomonic lesions of Alzheimer's disease, cerebrovascular and intracerebral Abeta amyloid plaques and neurofibrillary tangles, as a result of its binding to amyloid fibrils and to paired helical filaments, respectively. SAP itself may also be directly neurocytotoxic. Here, in this unique study in Alzheimer's disease of the bis(d-proline) compound, (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), we observed depletion of circulating SAP and also remarkable, almost complete, disappearance of SAP from the CSF. We demonstrate that SAP depletion in vivo is caused by CPHPC cross-linking pairs of SAP molecules in solution to form complexes that are immediately cleared from the plasma. We have also solved the structure of SAP complexed with phosphothreonine, its likely ligand on hyperphosphorylated tau protein. These results support further clinical study of SAP depletion in Alzheimer's disease and potentially other neurodegenerative diseases.

The mitochondrial activity of leukocytes from Artibeus jamaicensis bats remains unaltered after several weeks of flying restriction.

Bats are the only flying mammals known. They have longer lifespan than other mammals of similar size and weight and can resist high loads of many pathogens, mostly viruses, with no signs of disease. These distinctive characteristics have been attributed to their metabolic rate that is thought to be the result of their flying lifestyle. Compared with non-flying mammals, bats have lower production of reactive oxygen species (ROS), and high levels of antioxidant enzymes such as superoxide dismutase. This anti-oxidative vs. oxidative profile may help to explain bat's longer than expected lifespans. The aim of this study was to assess the effect that a significant reduction in flying has on bats leukocytes mitochondrial activity. This was assessed using samples of lymphoid and myeloid cells from peripheral blood from Artibeus jamaicensis bats shortly after capture and up to six weeks after flying deprivation. Mitochondrial membrane potential (Δψm), mitochondrial calcium (mCa2+), and mitochondrial ROS (mROS) were used as key indicators of mitochondrial activity, while total ROS and glucose uptake were used as additional indicators of cell metabolism. Results showed that total ROS and glucose uptake were statistically significantly lower at six weeks of flying deprivation (p < 0.05), in both lymphoid and myeloid cells, however no significant changes in mitochondrial activity associated with flying deprivation was observed (p > 0.05). These results suggest that bat mitochondria are stable to sudden changes in physical activity, at least up to six weeks of flying deprivation. However, decrease in total ROS and glucose uptake in myeloid cells after six weeks of captivity suggest a compensatory mechanism due to the lack of the highly metabolic demands associated with flying.

Ethics review of COVID-19 human challenge studies: A joint HRA/WHO workshop.

This report of a joint World Health Organization (WHO) and United Kingdom (UK) Health Research Authority (HRA) workshop discusses the ethics review of the first COVID-19 human challenge studies, undertaken in the midst of the pandemic. It reviews the early efforts of international and national institutions to define the ethical standards required for COVID-19 human challenge studies and create the frameworks to ensure rigorous and timely review of these studies. This report evaluates the utility of the WHO's international guidance document Key criteria for the ethical acceptability of COVID-19 human challenge studies (WHO Key Criteria) as a practical resource for the ethics review of COVID-19 human challenge studies. It also assesses the UK HRA's approach to these complex ethics reviews, including the formation of a Specialist Ad-Hoc Research Ethics Committee (REC) for COVID-19 Human Challenge Studies to review all current and future COVID-19 human challenge studies. In addition, the report outlines the reflections of REC members and researchers regarding the ethics review process of the first COVID-19 human challenge studies. Finally, it considers the potential ongoing scientific justification for COVID-19 human challenge studies, particularly in relation to next-generation vaccines and optimisation of vaccination schedules. Overall, there was broad agreement that the WHO Key Criteria represented an international consensus document that played a powerful role in setting norms and delineating the necessary conditions for the ethical acceptability of COVID-19 human challenge studies. Workshop members suggested that the WHO Key Criteria could be practically implemented to support researchers and ethics reviewers, including in the training of ethics committee members. In future, a wider audience may be engaged by the original document and potential additional materials, informed by the experiences of those involved in the first COVID-19 human challenge studies outlined in this document.

Structural basis of ligand specificity in the human pentraxins, C-reactive protein and serum amyloid P component.

The normal physiological roles of the phylogenetically conserved human plasma proteins C-reactive protein (CRP) and serum amyloid P component (SAP) are not known. Novel drugs targeting their ligand specificities are in clinical development as both proteins have significant pathophysiological effects, SAP in promoting amyloidosis and CRP in exacerbating ischemic injury. Both proteins bind to phosphoethanolamine and we show here that, under physiological conditions, phosphoethanolamine is bound with higher affinity by human SAP than by human CRP. An explanation is provided by X-ray crystal structures that show SAP residue Tyr74 allowing additional hydrophobic protein-ligand interactions compared with the equivalent Thr76 of CRP. Docking simulations show many more low energy positions for phosphoethanolamine bound by CRP than by SAP and are consistent with the crystallographic and functional binding results. These fundamental observations on structure-activity relationships will aid the design of improved pentraxin targeting drugs.

Drug targets for amyloidosis.

The amyloid hypothesis indicates that protein misfolding is at the root of many neurodegenerative disorders. Small molecules targeting the formation, clearance, aggregation to toxic oligomers or SOD (superoxide dismutase)-like activities of Abeta (amyloid beta-peptide) 1-42 have provided encouraging candidates for AD (Alzheimer's disease) medicines in animal models, although none have yet proved to be effective in human trials. We have been investigating approaches to treat systemic amyloidoses, conditions that show common features with some CNS (central nervous system) disorders. For TTR (transthyretin) amyloidosis, we are seeking small molecule compounds that stabilize the amyloidogenic protein and either prevent its structural transition to the crossed beta fibres deposited in diseased tissues, or promote its clearance from circulation. Effective stabilizer compounds that simultaneously bind to both thyroxine-binding sites have been developed. A more generic approach involves targeting the plasma glycoprotein SAP (serum amyloid P component). This protein recognizes the misfolded polypeptide structures of amyloid deposits wherever they occur, and acts as a powerful anti-opsonin. We have developed a bivalent drug called CPHPC {(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]-pyrrolidine-2-carboxylic acid} that cross-links pairs of pentameric SAP molecules and causes their rapid elimination from the circulation. This strategy raises the prospect of encouraging natural mechanisms to clear amyloid and recent work suggests that this approach extends to the CNS.

Structure of human porphobilinogen deaminase at 2.8 A: the molecular basis of acute intermittent porphyria.

Mutations in the human PBGD (porphobilinogen deaminase) gene cause the inherited defect AIP (acute intermittent porphyria). In the present study we report the structure of the human uPBGD (ubiquitous PBGD) mutant, R167Q, that has been determined by X-ray crystallography and refined to 2.8 A (1 A=0.1 nm) resolution (Rfactor=0.26, Rfree=0.29). The protein crystallized in space group P2(1)2(1)2 with two molecules in the asymmetric unit (a=81.0 A, b=104.4 A and c=109.7 A). Phases were obtained by molecular replacement using the Escherichia coli PBGD structure as a search model. The human enzyme is composed of three domains each of approx. 110 amino acids and possesses a dipyrromethane cofactor at the active site, which is located between domains 1 and 2. An ordered sulfate ion is hydrogen-bonded to Arg26 and Ser28 at the proposed substrate-binding site in domain 1. An insert of 29 amino acid residues, present only in mammalian PBGD enzymes, has been modelled into domain 3 where it extends helix alpha2(3) and forms a beta-hairpin structure that contributes to a continuous hydrogen-bonding network spanning domains 1 and 3. The structural and functional implications of the R167Q mutation and other mutations that result in AIP are discussed.

Determining the level of data sharing, and number of publications, from research databases that have been given a favourable opinion by UK research ethics committees.

OBJECTIVE: To determine data sharing and number of publications coming from research databases that have been given a favourable opinion by UK National Health Service (NHS) Research Ethics Committees (RECs). DESIGN: Cohort study. INCLUSION CRITERIA & SETTING: All research databases listed on the UK Health Research Authority's Assessment Review Portal (HARP) that had received a favourable ethics opinion as of January 2018. MAIN OUTCOME MEASURES: Publications and data access requests are either listed on HARP or notified through subsequent email correspondence. RESULTS: Out of 354 eligible databases, 34% had granted access requests and 40% had produced at least one peer-reviewed paper or conference abstract/talk. We could not establish contact with 9% of databases, and 19% reported no access requests or publications. Only 9% of databases were up to date with all annual reports. Email responses from database owners showed a range of attitudes towards data sharing. CONCLUSION: Less than half of research databases that have received a favourable opinion from NHS research ethics committees share their data and produce publications. There is also considerable variability in the operation of research databases and understanding of the purpose of research databases. This work was hampered by incomplete records due mainly to researchers not submitting annual reports.

Registration audit of clinical trials given a favourable opinion by UK research ethics committees.

OBJECTIVE: To determine levels of public registration for a cohort of clinical trials reviewed and given a favourable opinion by research ethics committees in the United Kingdom. STUDY DESIGN: Audit of records. SETTING: Clinical trials receiving a favourable ethics opinion between 1 January 2016 and 30 June 2016. MAIN OUTCOME MEASURES: Correlation between trials on the UK research ethics committee database and any primary registry entry on the WHO International Clinical Trials Registry Platform or clinicaltrials.gov as of 29 August 2017 (14 to 20 months after the favourable ethics committee opinion). RESULTS: Over the study period 1014 trials received a favourable ethics opinion, with 397 (39%) registered on the European Union Drug Regulating Authorities Clinical Trials database, and 18 with an agreed clinical trial registration deferral. Excluding these trials, the total number subsequently requiring registration was 599, and of these 405 (40% of total) were found to be registered. Follow-up with the 194 investigators or sponsors of trials not found to be registered produced 121 responses with a further 10 (1%) trials having already registered, 55 commitments to register and a variety of other responses. The overall registration rate was therefore 80%. CONCLUSIONS: Despite researchers and sponsors being reminded that registration of clinical trials is a condition of the research ethics committee (REC) favourable opinion, one-fifth of clinical trials either had not been registered, or their registration could not easily be found, 14 to 20 months after receiving the favourable opinion letter. The methodology trialled here proved effective, and although there are positive indications of a culture change towards greater registration, our results show that more still needs to be done to increase trial registration.

Virus Control of Cell Metabolism for Replication and Evasion of Host Immune Responses.

Over the last decade, there has been significant advances in the understanding of the cross-talk between metabolism and immune responses. It is now evident that immune cell effector function strongly depends on the metabolic pathway in which cells are engaged in at a particular point in time, the activation conditions, and the cell microenvironment. It is also clear that some metabolic intermediates have signaling as well as effector properties and, hence, topics such as immunometabolism, metabolic reprograming, and metabolic symbiosis (among others) have emerged. Viruses completely rely on their host's cell energy and molecular machinery to enter, multiply, and exit for a new round of infection. This review explores how viruses mimic, exploit or interfere with host cell metabolic pathways and how, in doing so, they may evade immune responses. It offers a brief outline of key metabolic pathways, mitochondrial function and metabolism-related signaling pathways, followed by examples of the mechanisms by which several viral proteins regulate host cell metabolic activity.