Artificial intelligency can bring speed and reliability to drug discovery process. It represents an additional intelligence, which in any case can replace the strategic and logic creative insight of the medicinal chemist who remains the architect and molecule master designer. In terms of drug design, artificial intelligency, deep learning machines, and other revolutionary technologies will match with the medicinal chemist’s natural intelligency, but for sure never go beyond. This manuscript tries to assess the impact of the artificial (...) intelligency on drug discovery today. (shrink)

ADP‐ribosylation is a post‐translational modification catalyzed by writer enzymes – ADP‐ribosyltransferases. The modification is part of many signaling events, can modulate the function and stability of target proteins, and often results in the recruitment of reader proteins that bind to the ADP‐ribosyl groups. Erasers are integral actors in these signaling events and reverse the modification. ADP‐ribosylation can be targeted with therapeutics and many inhibitors against writers exist, with some being in clinical use. Inhibitors against readers and erasers are sparser and (...) development of these has gained momentum only in recent years. Drug discovery has been hampered by the lack of specific tools, however many significant advances in the methods have recently been reported. We discuss assays used in the field with a focus on methods allowing efficient identification of small molecule inhibitors and profiling against enzyme families. While human proteins are focused, the methods can be also applied to bacterial toxins and virus encoded erasers that can be targeted to treat infectious diseases in the future. (shrink)

Chance and accidents play important roles in scientific discoveries, but they are not blind luck. Serendipity is not merely stumbling on things unsought for, it is the ability to see significances and find values in the things stumbled upon. Without this ability, accidents do not lead to discoveries, as Pasteur observed: “Chance favors the prepared mind.” What are the characteristics of a prepared mind in science? How do chance and serendipity work in scientific research in general and drug (...) class='Hi'>discovery in particular? (shrink)

Drug discovery traditionally has occurred behind closed doors in for-profit corporations hoping to develop best-selling medicines that recoup initial research investment, sustain marketing infrastructures, and pass on healthy returns to shareholders. Only corporate Pharma has the man- and purchasing-power to synthesize the thousands of molecules needed to find a new drug and to conduct the clinical trials that will make the drug legal. Against this view, individual physician-scientists have suggested that the promise of applied genomics work (...) calls for a new form of social organization in order to speed the generation and understanding of new therapeutics. Recent successes in open source drug discovery show it is possible to produce valuable, empirically adequate, and sustainable collective beliefs without secrecy, proprietary attitudes, initial cooperation from Pharma, or outsized monetary incentives. After reviewing and differentiating these successes, I diagnose the source of this healthy new epistemic strategy. (shrink)

Clinical research under the usual regulatory constraints may be difficult or even impossible in a public health emergency. Regulators must seek to strike a good balance in granting as wide therapeutic access to new drugs as possible at the same time as gathering sound evidence of safety and effectiveness. To inform current policy, I reexamine the philosophical rationale for restricting new medicines to clinical trials, at any stage and for any population of patients (which resides in the precautionary principle), to (...) show that its objective to protect public health, now or in the future, could soon be defeated in a pandemic. Providing wider therapeutic access and coordinating observations and natural experiments, including service delivery by cluster (wedged cluster trials), may provide such a balance. However, there are important questions of fairness to resolve before any such research can proceed. (shrink)

Drug development regularly has to deal with complex circumstances on two levels: the local level of pharmacological intervention on specific target proteins, and the systems level of the effects of pharmacological intervention on the organism. Different development strategies in the recent history of early drug development can be understood as competing attempts at coming to grips with these multi-level complexities. Both rational drug design and high-throughput screening concentrate on the local level, while traditional empirical search strategies as (...) well as recent systems biology approaches focus on the systems level. The analysis of these strategies reveals serious obstacles to integrating the study of interventive and systems complexity in a systematic, methodical way. Due to some fairly general properties of biological networks and the available options for pharmaceutical intervention, drug development is captured in an obstinate methodological dilemma. It is argued that at least in typical cases, drug development therefore remains dependent on coincidence, serendipity or plain luck to bridge the gap between development methodology and actual therapeutic success. (shrink)

The conventional paradigm for developing new treatments for disease mainly involves either the discovery of new drug targets, or finding new, improved drugs for old targets. However, an ion channel found only in invertebrates offers the potential of a completely new paradigm in which an established drug target can be re‐engineered to serve as a new candidate therapeutic agent. The L‐glutamate‐gated chloride channels (GluCls) of invertebrates are absent from vertebrate genomes, offering the opportunity to introduce this exogenous, (...) inhibitory, L‐glutamate receptor into vertebrate neuronal circuits either as a tool with which to study neural networks, or a candidate therapy. Epileptic seizures can involve L‐glutamate‐induced hyper‐excitation and toxicity. Variant GluCls, with their inhibitory responses to L‐glutamate, when engineered into human neurons, might counter the excitotoxic effects of excess L‐glutamate. In reviewing recent studies on model organisms, it appears that this approach might offer a new paradigm for the development of candidate therapeutics for epilepsy. (shrink)

The potential of the folic acid biosynthesis pathway as a target for the development of antibiotics has been acknowledged for many years and validated by the clinical use of several drugs. Recently, the crystal structures of all but one of the enzymes in the pathway from GTP to dihydrofolate have been determined. Given that structure‐based drug design strategies are now widely employed, these recent developments have prompted a re‐evaluation of the potential of each of the enzymes in the pathway (...) as a target for development of specific inhibitors. Here, we review the current knowledge of the structure and mechanism of each enzyme in the bacterial folic acid biosynthesis pathway from GTP to dihydrofolate and draw conclusions regarding the potential of each enzyme as a target for therapeutic intervention. BioEssays 24:637–648, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Proteolysis-targeting chimeric molecules represent an emerging technique that is receiving much attention for therapeutic intervention. The mechanism is based on the inhibition of protein function by hijacking a ubiquitin E3 ligase for protein degradation. The hetero-bifunctional PROTACs contain a ligand for recruiting an E3 ligase, a linker, and another ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate “undruggable” protein targets, such as transcription factors and non-enzymatic proteins, which are not limited to physiological (...) substrates of the ubiquitin-proteasome system. These findings indicate great prospects for PROTACs in the development of therapeutics. However, there are several limitations related to poor stability, biodistribution, and penetrability in vivo. This review provides an overview of the main PROTAC-based approaches that have been developed and discusses the promising opportunities and considerations for the application of this technology in therapies and drug discovery. The hetero-bifunctional PROTAC molecules contain a ligand for recruiting an E3 ligase linked with a ligand to bind with the protein targeted for degradation. Thus, PROTACs have profound potential to eliminate “undruggable” disease-causing proteins, which are not limited to physiological substrates of the ubiquitin-protease system, suggesting great prospects for therapeutic development. (shrink)

A considerable number of areas of bioscience, including gene and drug discovery, metabolic engineering for the biotechnological improvement of organisms, and the processes of natural and directed evolution, are best viewed in terms of a ‘landscape’ representing a large search space of possible solutions or experiments populated by a considerably smaller number of actual solutions that then emerge. This is what makes these problems ‘hard’, but as such these are to be seen as combinatorial optimisation problems that are (...) best attacked by heuristic methods known from that field. Such landscapes, which may also represent or include multiple objectives, are effectively modelled in silico, with modern active learning algorithms such as those based on Darwinian evolution providing guidance, using existing knowledge, as to what is the ‘best’ experiment to do next. An awareness, and the application, of these methods can thereby enhance the scientific discovery process considerably. This analysis fits comfortably with an emerging epistemology that sees scientific reasoning, the search for solutions, and scientific discovery as Bayesian processes. (shrink)

In this article I attempt to examine the justification for the mandatory drug testing of employees. The justification commonly assumes the form of the productivity argument which states that an employer has a proprietary right to regulate the purchased time of the employee. Since the employer may be rightfully concerned with the employee''s productive output, so this argument goes, the employer retains the right to motivate production. By extension, the employee''s behavior outside of the workplace which affects his or (...) her productive capacity may also be regulated, including drug use which may affect this capacity. Thus it is claimed that the employer has the right to test employees for drug use and to impose sanctions when it is discovered.I argue that the implications of the productivity argument lead to unacceptable consequences and thus must be rejected. The productivity argument can be examined in light of a thought-experiment in which the reader is asked to imagine the discovery of two drugs, both of which enhance employee productivity. Calling these drugs hedonine and pononine, I imagine the first to be pleasurable to the employee while the second is accompanied by a degree of pain and discomfort. Since the mandated use of both of these imagined drugs would be consistent with the productivity argument, I maintain that the productivity argument thereby fails and so must be rejected. As employee drug testing is justified by this argument, it must also be rejected. (shrink)

Patient-driven drug development is an emerging approach to pharmaceutical research that is forged in rare-disease communities and patient advocacy networks. Patients and their advocates increasingly engage in drug discovery and influence early-stage drug research as clinical trial participants or through compassionate-use programs. Some advocacy groups and patients also influence which therapies are developed by financing promising treatments that otherwise would not secure funding. Though some critics of patient-driven drug development worry about the ethical and scientific (...) implications of this new approach to research, it also has several advantages over the current system. In this essay I argue that patient-driven drug development is morally permissible. (shrink)

We present some ideas on logical process descriptions, using relations from the DIO (Drug Interaction Ontology) as examples and explaining how these relations can be naturally decomposed in terms of more basic structured logical process descriptions using terms from linear logic. In our view, the process descriptions are able to clarify the usual relational descriptions of DIO. In particular, we discuss the use of logical process descriptions in proving linear logical theorems. Among the types of reasoning supported by DIO (...) one can distinguish both (1) basic reasoning about general structures in reality and (2) the domain-specific reasoning of experts. We here propose a clarification of this important distinction between (realist) reasoning on the basis of an ontology and rule-based inferences on the basis of an expert’s view. (shrink)

In the last years there has been a great improvement in the development of computational methods for combinatorial chemistry applied to drug discovery. This approach to drug discovery is sometimes called a “rational way” to manage a well known phenomenon in chemistry: serendipity discoveries. Traditionally, serendipity discoveries are understood as accidental findings made when the discoverer is in quest for something else. This ‘traditional’ pattern of serendipity appears to be a good characterization of discoveries where “luck” (...) plays a key role. In this sense, some initial failures in combinatorial chemistry are frequently attributed to a naïf appropriation of a “serendipity model” for discovery (a “serendipity mistake”). In this paper we try to evaluate this statement by criticizing its foundations. It will be suggested that the notion of serendipity has different aspects and that the criticism to the first attempts could be understood as a “serendipity mistake.” We will suggest that “serendipity” strategies, a kind of blind search, can be seen sometimes as a “genuine part” of scientific practice. A discussion will ensue about how this characterization can give us a better understanding of some aspects of serendipity discoveries. (shrink)

The US government supports drug innovation. It is therefore crucial that it distinguish between high-value and low-value innovation in purchasing expensive prescription drugs and medical devices and ensure the continued discovery of transformative drugs and that patient and taxpayer funds are not wasted.

The role of mechanistic evidence tends to be under-appreciated in current evidencebased medicine (EBM), which focusses on clinical studies, tending to restrict attention to randomized controlled studies (RCTs) when they are available. The EBM+ programme seeks to redress this imbalance, by suggesting methods for evaluating mechanistic studies alongside clinical studies. Drug approval is a problematic case for the view that mechanistic evidence should be taken into account, because RCTs are almost always available. Nevertheless, we argue that mechanistic evidence is (...) central to all the key tasks in the drug approval process: in drug discovery and development; assessing pharmaceutical quality; devising dosage regimens; assessing efficacy, harms, external validity, and cost-effectiveness; evaluating adherence; and extending product licences. We recommend that, when preparing for meetings in which any aspect of drug approval is to be discussed, mechanistic evidence should be systematically analysed and presented to the committee members alongside analyses of clinical studies. (shrink)

A biochemical pathway is a sequence of chemical reactions in a biological organism. Such pathways specify mechanisms that explain how cells carry out their major functions by means of molecules and reactions that produce regular changes. Many diseases can be explained by defects in pathways, and new treatments often involve finding drugs that correct those defects. This paper presents explanation schemas and treatment strategies that characterize how thinking about pathways contributes to biomedical discovery. It discusses the significance of pathways (...) for understanding the nature of diseases, explanations, and theories. (shrink)

In the last few years, annexins have been discovered in several nematodes and other parasites, and distinct differences between the parasite annexins and those of the hosts make them potentially attractive targets for anti‐parasite therapeutics. Annexins are ubiquitous proteins found in almost all organisms across all kingdoms. Here, we present an overview of novel annexins from parasitic organisms, and summarize their phylogenetic and biochemical properties, with a view to using them as drug or vaccine targets. Building on structural and (...) biological information that has been accumulated for mammalian and plant annexins, we describe a predicted additional secondary structure element found in many parasite annexins that may confer unique functional properties, and present a specific antigenic epitope for use as a vaccine. (shrink)

The history of drug/vaccine development has included major advances guided primarily by risk/benefit analyses concerning the innovative agent, not by evidence-based clinical trials (Phase I–IV). Because the approval for new drugs is hindered under the present process, the system requires restructuring. The Phase I/II study period should be more flexible, using the “environment of knowledge” about the new agent, plus risk/benefit assessments. Phase III, as presently constructed, does not add new adverse events data, it provides a narrower profile of (...) drug efficacy than properly done Phase II studies, and placebo-controlled trials continue to raise unresolved ethical and social issues. Phase III studies should be abandoned for most drugs, and substituted with properly powered Phase II doseranging studies plus careful post-marketing surveillance. Phase III should be a penalty for poor drug development, not a regulatory requirement. (shrink)

In psychiatry, pharmacological drugs play an important experimental role in attempts to identify the neurobiological causes of mental disorders. Besides being developed in applied contexts as potential treatments for patients with mental disorders, pharmacological drugs play a crucial role in research contexts as experimental instruments that facilitate the formulation and revision of neurobiological theories of psychopathology. This paper examines the various epistemic functions that pharmacological drugs serve in the discovery, refinement, testing, and elaboration of neurobiological theories of mental disorders. (...) I articulate this thesis with reference to the history of antipsychotic drugs and the evolution of the dopamine hypothesis of schizophrenia in the second half of the twentieth century. I argue that interventions with psychiatric patients through the medium of antipsychotic drugs provide researchers with information and evidence about the neurobiological causes of schizophrenia. This analysis highlights the importance of pharmacological drugs as research tools in the generation of psychiatric knowledge and the dynamic relationship between practical and theoretical contexts in psychiatry. (shrink)

In all domains of life, transmembrane proteins from the ATP‐binding cassette (ABC) transporter family drive the translocation of diverse substances across lipid bilayers. In pathogenic fungi, the ABC transporters of the pleiotropic drug resistance (PDR) subfamily confer antibiotic resistance and so are of interest as therapeutic targets. They also drive the quest for understanding how ABC transporters can generally accommodate such a wide range of substrates. The Pdr5 transporter from baker's yeast is representative of the PDR group and, ever (...) since its discovery more than 30 years ago, has been the subject of extensive functional analyses. A new perspective of these studies has been recently provided in the framework of the first electron cryo‐microscopy structures of Pdr5, as well as emergent applications of machine learning in the field. Taken together, the old and the new developments have been used to propose a mechanism for the transport process in PDR proteins. This mechanism involves a “flippase” step that moves the substrates from one leaflet of the bilayer to the other, as a central element of cellular efflux. (shrink)

The discovery and development of new therapeutics has always been central to improving health worldwide. However, there is ongoing concern regarding the current state of medical innovation. Output from the pharmaceutical industry has been criticized for not being “transformative,” that is, offering substantial improvements in patient outcomes over existing therapeutics. While the cost of drug development continues to rise, breakthrough therapies remain elusive and one half of Phase 3 studies fail. Venture capital, a traditional source of funding for (...) new breakthrough biomedical innovations, has decreased investment by 30% in the biotechnology and medical device sectors from 2007 to 2013. Stakeholders question whether the new drugs approved each year by the FDA —many criticized as marginal improvements over existing therapies — justify the enormous investment. (shrink)

By age 85, most adults manifest some degree of motor impairment. However, in most individuals a specific etiology for motor decline and treatment to modify its inexorable progression cannot be identified. Recent clinical-pathologic studies provide evidence that mixed-brain pathologies are commonly associated with late-life motor impairment. Yet, while nearly all older adults show some degree of accumulation of Alzheimer’s disease and related dementias pathologies, the extent to which these pathologies contribute to motor decline varies widely from person to person. Slower (...) or faster than expected motor decline in the presence of brain injury and/or pathology has been conceptualized as more or less “resilience” relative to the average person This suggests that other factors, such as lifestyles or other neurobiologic indices may offset or exacerbate the negative effects of pathologies via other molecular pathways. The mechanisms underlying neural motor resilience are just beginning to be illuminated. Unlike its cousin, cognitive resilience which is restricted to neural mechanisms above the neck, the motor system extends the total length of the CNS and beyond the CNS to reach muscle and musculoskeletal structures, all of which are crucial for motor function. Building on prior work, we propose that by isolating motor decline unrelated to neuropathologies and degeneration, investigators can identify genes and proteins that may provide neural motor resilience. Elucidating these molecular mechanisms will advance our understanding of the heterogeneity of late-life motor impairment. This approach will also provide high value therapeutic targets for drug discovery of therapies that may offset the negative motor consequences of CNS pathologies that are currently untreatable. (shrink)

Recent research shows that a faulty or sub‐optimally operating metabolic network can often be rescued by the targeted removal of enzyme‐coding genes – the exact opposite of what traditional gene therapy would suggest. Predictions go as far as to assert that certain gene knockouts can restore the growth of otherwise nonviable gene‐deficient cells. Many questions follow from this discovery: What are the underlying mechanisms? How generalizable is this effect? What are the potential applications? Here, I approach these questions from (...) the perspective of compensatory perturbations on networks. Relations are drawn between such synthetic rescues and naturally occurring cascades of reaction inactivation, as well as their analogs in physical and other biological networks. I specially discuss how rescue interactions can lead to the rational design of antagonistic drug combinations that select against resistance and how they can illuminate medical research on cancer, antibiotics, and metabolic diseases. Editor's suggested further reading in BioEssaysThe evolutionary context of robust and redundant cell biological mechanisms AbstractReprogramming cell fates: reconciling rarity with robustness Abstract. (shrink)

Side effects are a concern in medical decision making and a robust area of biomedical research. However, there is relatively little philosophical investigation into side effects as such, especially given that side effects are appealed to for various applications in philosophy of medicine. In addition, health authorities like the FDA, CDC, and WHO have contrary definitions of ‘side effect.’ Moreover, these definitions have clear counterexamples. This dissertation aims to provide a complete account of what side effects are. I posit that (...) an account of side effects ought to draw clean conceptual lines between side effects and related treatment outcomes. I contend that an account of side effects must address two components: the reasons behind an intervention that produced the side effect, and the causal powers of the intervention that brought about that effect. With this account in mind, I address contemporary philosophical models that distinguish placebo effects from side effects. These arguments, respectively in chapters 2 and 3, yield a more complete, less problematic account of side effects than previous accounts. The dissertation then turns to the process of discovering side effects, specifically in the post-market context. Given the paucity of external validity in pre-market drug trials, chapter 4 argues that post-market ‘phase IV’ trials blur the received distinction of ‘confirmatory’ versus ‘exploratory’ experimentation in philosophy of science. The other component of post-market drug research is spontaneous reporting, or the voluntary reporting of a suspected side effect to a regulatory body. Chapter 5 uses the framework of risks and values in science to examine why clinicians underreport, which hinders our ability to prevent drug-related harms. Chapter 6 looks at how patients could mitigate underreporting and develops a social-epistemic, pragmatic, and ethical framework which can evaluate proposals to engage patients to spontaneously report their suspected side effects. In short, this dissertation aims to firstly address the conceptual problems in how we define ‘side effect’ and relate it to other treatment outcomes, and secondly it addresses issues that hinder the scientific investigation of side effects. (shrink)

Mammalian synthetic biology holds the promise of providing novel therapeutic strategies, and the first success stories are beginning to be reported. Here we focus on the latest generation of mammalian transgene control devices, highlight state‐of‐the‐art synthetic gene network design, and cover prototype therapeutic circuits. These will have an impact on future gene‐ and cell‐based therapies and help bring drug discovery into a new era. The inventory of biological parts that are essential for life on this planet is becoming (...) increasingly complete. The postgenomic era has provided encyclopedic information on gene‐function correlations and systems biology is now delivering comprehensive details on the dynamics of biochemical reaction networks in living organisms. The time has come to reassemble these catalogued items and design new biological devices and systems with novel and useful functionality in a rational and systematic manner. This is the premise of synthetic biology, a constructive systems biology discipline likely to become the life science revolution of the 21st century. (shrink)

In The Ethics of Food, Gregory E. Pence brings together a collection of voices who share the view that the ethics of genetically modified food is among the most pressing societal questions of our time. This comprehensive collection addresses a broad range of subjects, including the meaning of food, moral analyses of vegetarianism and starvation, the safety and environmental risks of genetically modified food, issues of global food politics and the food industry, and the relationships among food, evolution, and human (...) history. (shrink)

Children who experience well-being are engaging more confidently and positively with their caregiver and peers, which helps them to profit more from available learning opportunities and support current and later life outcomes. The goodness-of-fit theory suggests that children’s well-being might be a result of the interplay between their temperament and the environment. However, there is a lack of studies that examined the association between children’s temperament and well-being in early childhood education and care, and whether this association is affected by (...) ECEC process quality. Using a multilevel random coefficient approach, this study examines the association between toddlers’ temperament and well-being in Norwegian ECEC and investigates whether process quality moderates this association. Results reveal an association between temperament and well-being. Staff-child conflict moderates the association between shyness and well-being, and between activity and well-being. Moreover, high emotional behavioral support moderates the association between activity and well-being. Extra attention should be paid by the staff to these children’s needs. (shrink)

How can new drug lead suggestions beinferred from neurophysiological models? This paperaddresses this question based on a case study ofresearch into Parkinson''s disease at the GroningenUniversity Department of Pharmacy. It is argued thatneurophysiological box-and-arrow models can beunderstood as qualitative differential equationmodels. An inference task is defined to helpunderstand and possibly aid the discovery andexplanation of new drug lead suggestions.

The ability to convert human somatic cells into induced pluripotent stem cells (iPSCs) is allowing the production of custom‐tailored cells for drug discovery and for the study of disease phenotypes at the cellular and molecular level. IPSCs have been derived from patients suffering from a large variety of disorders with different severities. In many cases, disease related phenotypes have been observed in iPSCs or their lineage‐specific progeny. Several proof of concept studies have demonstrated that these phenotypes can be (...) reversed in vitro using approved drugs. However, several challenges must be overcome to take full advantage of this technology. Here, we highlight recent advances in the field and discuss the main challenges associated with this technology as it applies to disease modelling. (shrink)

Rather than seek to distinguish hype from legitimate promise, it may be more helpful to think about personalised medicine as embodying a promissory economy which serves both to mobilize resources for research and — partly at least — to determine the ends to which that research is directed. Personalised medicine is a development of the larger promissory economy of medical biotechnology. As such, it systematically conflates public benefit with the pursuit of commercial and especially pharmaceutical interests. Consequently, research and development (...) in personalised medicine tends to favour the production of expensive new treatments over unprofitable forms of prevention or more effective use of older therapies. A rebalancing of research priorities is needed to favour the pursuit of public benefit, even when it does not deliver private profits. This will in turn require sustained reflection, self-criticism and often self-denial on the part of public research funders and the scientists they support. (shrink)

This book is the first systematic, detailed treatment of the approaches to ethical issues taken by biotech and pharmaceutical companies. The application of genetic/genomic technologies raises a whole spectrum of ethical questions affecting global health that must be addressed. Topics covered in this comprehensive survey include considerations for bioprospecting in transgenics, genomics, drug discovery, and nutrigenomics, as well as how to improve stakeholder relations, design ethical clinical trials, avoid conflicts of interest, and establish ethics advisory boards. The expert (...) authors represent multiple disciplines including law, medicine, bioinformatics, pharmaceutics, business, and ethics. (shrink)

Healthcare systems across the globe are struggling with increasing costs and worsening outcomes. This presents those responsible for overseeing healthcare with a challenge. Increasingly, policymakers, politicians, clinical entrepreneurs and computer and data scientists argue that a key part of the solution will be ‘Artificial Intelligence’ (AI) – particularly Machine Learning (ML). This argument stems not from the belief that all healthcare needs will soon be taken care of by “robot doctors.” Instead, it is an argument that rests on the classic (...) counterfactual definition of AI as an umbrella term for a range of techniques that can be used to make machines complete tasks in a way that would be considered intelligent were they to be completed by a human. Automation of this nature could offer great opportunities for the improvement of healthcare services and ultimately patients’ health by significantly improving human clinical capabilities in diagnosis, drug discovery, epidemiology, personalised medicine, and operational efficiency. However, if these AI solutions are to be embedded in clinical practice, then at least three issues need to be considered: the technical possibilities and limitations; the ethical, regulatory and legal framework; and the governance framework. In this article, we report on the results of a systematic analysis designed to provide a clear overview of the second of these elements: the ethical, regulatory and legal framework. We find that ethical issues arise at six levels of abstraction (individual, interpersonal, group, institutional, sectoral, and societal) and can be categorised as epistemic, normative, or overarching. We conclude by stressing how important it is that the ethical challenges raised by implementing AI in healthcare settings are tackled proactively rather than reactively and map the key considerations for policymakers to each of the ethical concerns highlighted. (shrink)

The development and deployment of artificial intelligence (AI) is and will profoundly reshape human society, the culture and the composition of civilisations which make up human kind. All technological triggers tend to drive a hype curve which over time is realised by an output which is often unexpected, taking both pessimistic and optimistic perspectives and actions of drivers, contributors and enablers on a journey where the ultimate destination may be unclear. In this paper we hypothesise that this journey is not (...) dissimilar to the personal journey described by the Kubler-Ross change curve and illustrate this by commentary on the potential of AI for drug discovery, development and healthcare and as an enabler for deep space exploration and colonisation. Recent advances in the call for regulation to ensure development of safety measures associated with machine-based learning are presented which, together with regulation of the rapidly emerging digital after-life industry, should provide a platform for realising the full potential benefit of AI for the human species. (shrink)

Table of contentsI1 Proceedings of the 4th World Conference on Research IntegrityConcurrent Sessions:1. Countries' systems and policies to foster research integrityCS01.1 Second time around: Implementing and embedding a review of responsible conduct of research policy and practice in an Australian research-intensive universitySusan Patricia O'BrienCS01.2 Measures to promote research integrity in a university: the case of an Asian universityDanny Chan, Frederick Leung2. Examples of research integrity education programmes in different countriesCS02.1 Development of a state-run “cyber education program of research ethics” in (...) KoreaEun Jung Ko, Jin Sun Kwak, TaeHwan Gwon, Ji Min Lee, Min-Ho LeeCS02.3 Responsible conduct of research teachers’ training courses in Germany: keeping on drilling through hard boards for more RCR teachersHelga Nolte, Michael Gommel, Gerlinde Sponholz3. The research environment and policies to encourage research integrityCS03.1 Challenges and best practices in research integrity: bridging the gap between policy and practiceYordanka Krastev, Yamini Sandiran, Julia Connell, Nicky SolomonCS03.2 The Slovenian initiative for better research: from national activities to global reflectionsUrsa Opara Krasovec, Renata SribarCS03.3 Organizational climate assessments to support research integrity: background of the Survey of Organizational Research Climate and the experience with its use at Michigan State UniversityBrian C. Martinson, Carol R. Thrush, C.K. Gunsalus4. Expressions of concern and retractionsCS04.1 Proposed guidelines for retraction notices and their disseminationIvan Oransky, Adam MarcusCS04.2 Watching retractions: analysis of process and practice, with data from the Wiley retraction archivesChris Graf, Verity Warne, Edward Wates, Sue JoshuaCS04.3 An exploratory content analysis of Expressions of ConcernMiguel RoigCS04.4 An ethics researcher in the retraction processMichael Mumford5. Funders' role in fostering research integrityCS05.1 The Fonds de Recherche du Québec’s institutional rules on the responsible conduct of research: introspection in the funding agency activitiesMylène Deschênes, Catherine Olivier, Raphaëlle Dupras-LeducCS05.2 U.S. Public Health Service funds in an international setting: research integrity and complianceZoë Hammatt, Raju Tamot, Robin Parker, Cynthia Ricard, Loc Nguyen-Khoa, Sandra TitusCS05.3 Analyzing decision making of funders of public research as a case of information asymmetryKarsten Klint JensenCS05.4 Research integrity management: Empirical investigation of academia versus industrySimon Godecharle, Ben Nemery, Kris Dierickx5A: Education: For whom, how, and what?CS05A.1 Research integrity or responsible conduct of research? What do we aim for?Mickey Gjerris, Maud Marion Laird Eriksen, Jeppe Berggren HoejCS05A.2 Teaching and learning about RCR at the same time: a report on Epigeum’s RCR poll questions and other assessment activitiesNicholas H. SteneckCS05A.4 Minding the gap in research ethics education: strategies to assess and improve research competencies in community health workers/promoteresCamille Nebeker, Michael Kalichman, Elizabeth Mejia Booen, Blanca Azucena Pacheco, Rebeca Espinosa Giacinto, Sheila Castaneda6. Country examples of research reward systems and integrityCS06.1 Improving systems to promote responsible research in the Chinese Academy of SciencesDing Li, Qiong Chen, Guoli Zhu, Zhonghe SunCS06.4 Exploring the perception of research integrity amongst public health researchers in IndiaParthasarathi Ganguly, Barna Ganguly7. Education and guidance on research integrity: country differencesCS07.1 From integrity to unity: how research integrity guidance differs across universities in Europe.Noémie Aubert Bonn, Kris Dierickx, Simon GodecharleCS07.2 Can education and training develop research integrity? The spirit of the UNESCO 1974 recommendation and its updatingDaniele Bourcier, Jacques Bordé, Michèle LeducCS07.3 The education and implementation mechanisms of research ethics in Taiwan's higher education: an experience in Chinese web-based curriculum development for responsible conduct of researchChien Chou, Sophia Jui-An PanCS07.4 Educating principal investigators in Swiss research institutions: present and future perspectivesLouis Xaver Tiefenauer8. Measuring and rewarding research productivityCS08.1 Altimpact: how research integrity underpins research impactDaniel Barr, Paul TaylorCS08.2 Publication incentives: just reward or misdirection of funds?Lyn Margaret HornCS08.3 Why Socrates never charged a fee: factors contributing to challenges for research integrity and publication ethicsDeborah Poff9. Plagiarism and falsification: Behaviour and detectionCS09.1 Personality traits predict attitude towards plagiarism of self and others in biomedicine: plagiarism, yes we can?Martina Mavrinac, Gordana Brumini, Mladen PetrovečkiCS09.2 Investigating the concept of and attitudes toward plagiarism for science teachers in Brazil: any challenges for research integrity and policy?Christiane Coelho Santos, Sonia VasconcelosCS09.3 What have we learnt?: The CrossCheck Service from CrossRefRachael LammeyCS09.4 High p-values as a sign of data fabrication/falsificationChris Hartgerink, Marcel van Assen, Jelte Wicherts10. Codes for research integrity and collaborationsCS10.1 Research integrity in cross-border cooperation: a Nordic exampleHanne Silje HaugeCS10.3 Research integrity, research misconduct, and the National Science Foundation's requirement for the responsible conduct of researchAaron MankaCS10.4 A code of conduct for international scientific cooperation: human rights and research integrity in scientific collaborations with international academic and industry partnersRaffael Iturrizaga11. Countries' efforts to establish mentoring and networksCS11.1 ENRIO : a network facilitating common approaches on research integrity in EuropeNicole FoegerCS11.2 Helping junior investigators develop in a resource-limited country: a mentoring program in PeruA. Roxana Lescano, Claudio Lanata, Gissella Vasquez, Leguia Mariana, Marita Silva, Mathew Kasper, Claudia Montero, Daniel Bausch, Andres G LescanoCS11.3 Netherlands Research Integrity Network: the first six monthsFenneke Blom, Lex BouterCS11.4 A South African framework for research ethics and integrity for researchers, postgraduate students, research managers and administratorsLaetus OK Lategan12. Training and education in research integrity at an early career stageCS12.1 Research integrity in curricula for medical studentsGustavo Fitas ManaiaCS12.2 Team-based learning for training in the responsible conduct of research supports ethical decision-makingWayne T. McCormack, William L. Allen, Shane Connelly, Joshua Crites, Jeffrey Engler, Victoria Freedman, Cynthia W. Garvan, Paul Haidet, Joel Hockensmith, William McElroy, Erik Sander, Rebecca Volpe, Michael F. VerderameCS12.4 Research integrity and career prospects of junior researchersSnezana Krstic13. Systems and research environments in institutionsCS13.1 Implementing systems in research institutions to improve quality and reduce riskLouise HandyCS13.2 Creating an institutional environment that supports research integrityDebra Schaller-DemersCS13.3 Ethics and Integrity Development Grants: a mechanism to foster cultures of ethics and integrityPaul Taylor, Daniel BarrCS13.4 A culture of integrity at KU LeuvenInge Lerouge, Gerard Cielen, Liliane Schoofs14. Peer review and its role in research integrityCS14.1 Peer review research across disciplines: transdomain action in the European Cooperation in Science and Technology “New Frontiers of Peer Review ”Ana Marusic, Flaminio SquazzoniCS14.2 Using blinding to reduce bias in peer reviewDavid VauxCS14.3 How to intensify the role of reviewers to promote research integrityKhalid Al-Wazzan, Ibrahim AlorainyCS14.4 Credit where credit’s due: professionalizing and rewarding the role of peer reviewerChris Graf, Verity Warne15. Research ethics and oversight for research integrity: Does it work?CS15.1 The psychology of decision-making in research ethics governance structures: a theory of bounded rationalityNolan O'Brien, Suzanne Guerin, Philip DoddCS15.2 Investigator irregularities: iniquity, ignorance or incompetence?Frank Wells, Catherine BlewettCS15.3 Academic plagiarismFredric M. Litto16. Research integrity in EuropeCS16.1 Whose responsibility is it anyway?: A comparative analysis of core concepts and practice at European research-intensive universities to identify and develop good practices in research integrityItziar De Lecuona, Erika Löfstrom, Katrien MaesCS16.2 Research integrity guidance in European research universitiesKris Dierickx, Noémie Bonn, Simon GodecharleCS16.3 Research Integrity: processes and initiatives in Science Europe member organisationsTony Peatfield, Olivier Boehme, Science Europe Working Group on Research IntegrityCS16.4 Promoting research integrity in Italy: the experience of the Research Ethics and Bioethics Advisory Committee of the Consiglio Nazionale delle Ricerche Cinzia Caporale, Daniele Fanelli17. Training programs for research integrity at different levels of experience and seniorityCS17.1 Meaningful ways to incorporate research integrity and the responsible conduct of research into undergraduate, graduate, postdoctoral and faculty training programsJohn Carfora, Eric Strauss, William LynnCS17.2 "Recognize, respond, champion": Developing a one-day interactive workshop to increase confidence in research integrity issuesDieter De Bruyn, Bracke Nele, Katrien De Gelder, Stefanie Van der BurghtCS17.4 “Train the trainer” on cultural challenges imposed by international research integrity conversations: lessons from a projectJosé Roberto Lapa e Silva, Sonia M. R. Vasconcelos18. Research and societal responsibilityCS18.1 Promoting the societal responsibility of research as an integral part of research integrityHelene IngierdCS18.2 Social responsibility as an ethical imperative for scientists: research, education and service to societyMark FrankelCS18.3 The intertwined nature of social responsibility and hope in scienceDaniel Vasgird, Stephanie BirdCS18.4 Common barriers that impede our ability to create a culture of trustworthiness in the research communityMark Yarborough19. Publication ethicsCS19.1 The authors' forum: A proposed tool to improve practices of journal editors and promote a responsible research environmentIbrahim Alorainy, Khalid Al-WazzanCS19.2 Quantifying research integrity and its impact with text analyticsHarold GarnerCS19.3 A closer look at authorship and publication ethics of multi- and interdisciplinary teamsLisa Campo-Engelstein, Zubin Master, Elise Smith, David Resnik, Bryn Williams-JonesCS19.4 Invisibility of duplicate publications in biomedicineMario Malicki, Ana Utrobicic, Ana Marusic20. The causes of bad and wasteful research: What can we do?CS20.1 From countries to individuals: unravelling the causes of bias and misconduct with multilevel meta-meta-analysisDaniele Fanelli, John PA IoannidisCS20.2 Reducing research waste by integrating systems of oversight and regulationGerben ter Riet, Tom Walley, Lex Marius BouterCS20.3 What are the determinants of selective reporting?: The example of palliative care for non-cancer conditionsJenny van der Steen, Lex BouterCS20.4 Perceptions of plagiarism, self-plagiarism and redundancy in research: preliminary results from a national survey of Brazilian PhDsSonia Vasconcelos, Martha Sorenson, Francisco Prosdocimi, Hatisaburo Masuda, Edson Watanabe, José Carlos Pinto, Marisa Palácios, José Lapa e Silva, Jacqueline Leta, Adalberto Vieyra, André Pinto, Mauricio Sant’Ana, Rosemary Shinkai21. Are there country-specific elements of misconduct?CS21.1 The battle with plagiarism in Russian science: latest developmentsBoris YudinCS21.2 Researchers between ethics and misconduct: A French survey on social representations of misconduct and ethical standards within the scientific communityEtienne Vergès, Anne-Sophie Brun-Wauthier, Géraldine VialCS21.3 Experience from different ways of dealing with research misconduct and promoting research integrity in some Nordic countriesTorkild VintherCS21.4 Are there specifics in German research misconduct and the ways to cope with it?Volker Bähr, Charité22. Research integrity teaching programmes and their challengesCS22.1 Faculty mentors and research integrityMichael Kalichman, Dena PlemmonsCS22.2 Training the next generation of scientists to use principles of research quality assurance to improve data integrity and reliabilityRebecca Lynn Davies, Katrina LaubeCS22.3 Fostering research integrity in a culturally-diverse environmentCynthia Scheopner, John GallandCS22.4 Towards a standard retraction formHervé Maisonneuve, Evelyne Decullier23. Commercial research and integrityCS23.1 The will to commercialize: matters of concern in the cultural economy of return-on-investment researchBrian NobleCS23.2 Quality in drug discovery data reporting: a mission impossible?Anja Gilis, David J. Gallacher, Tom Lavrijssen, Malwitz David, Malini Dasgupta, Hans MolsCS23.3 Instituting a research integrity policy in the context of semi-private-sector funding: an example in the field of occupational health and safetyPaul-Emile Boileau24. The interface of publication ethics and institutional policiesCS24.1 The open access ethical paradox in an open government effortTony SavardCS24.2 How journals and institutions can work together to promote responsible conductEric MahCS24.3 Improving cooperation between journals and research institutions in research integrity casesElizabeth Wager, Sabine Kleinert25. Reproducibility of research and retractionsCS25.1 Promoting transparency in publications to reduce irreproducibilityVeronique Kiermer, Andrew Hufton, Melanie ClyneCS25.2 Retraction notices issued for publications by Latin American authors: what lessons can we learn?Sonia Vasconcelos, Renan Moritz Almeida, Aldo Fontes-Pereira, Fernanda Catelani, Karina RochaCS25.3 A preliminary report of the findings from the Reproducibility Project: Cancer biologyElizabeth Iorns, William Gunn26. Research integrity and specific country initiativesCS26.1 Promoting research integrity at CNRS, FranceMichèle Leduc, Lucienne LetellierCS26.2 In pursuit of compliance: is the tail wagging the dog?Cornelia MalherbeCS26.3 Newly established research integrity policies and practices: oversight systems of Japanese research universitiesTakehito Kamata27. Responsible conduct of research and country guidelinesCS27.1 Incentives or guidelines? Promoting responsible research communication through economic incentives or ethical guidelines?Vidar EnebakkCS27.3 Responsible conduct of research: a view from CanadaLynn PenrodCS27.4 The Danish Code of Conduct for Research Integrity: a national initiative to promote research integrity in DenmarkThomas Nørgaard, Charlotte Elverdam28. Behaviour, trust and honestyCS28.1 The reasons behind non-ethical behaviour in academiaYves FassinCS28.2 The psychological profile of the dishonest scholarCynthia FekkenCS28.3 Considering the implications of Dan Ariely’s keynote speech at the 3rd World Conference on Research Integrity in MontréalJamal Adam, Melissa S. AndersonCS28.4 Two large surveys on psychologists’ views on peer review and replicationJelte WichertsBrett Buttliere29. Reporting and publication bias and how to overcome itCS29.1 Data sharing: Experience at two open-access general medical journalsTrish GrovesCS29.2 Overcoming publication bias and selective reporting: completing the published recordDaniel ShanahanCS29.3 The EQUATOR Network: promoting responsible reporting of health research studiesIveta Simera, Shona Kirtley, Eleana Villanueva, Caroline Struthers, Angela MacCarthy, Douglas Altman30. The research environment and its implications for integrityCS30.1 Ranking of scientists: the Russian experienceElena GrebenshchikovaCS30.4 From cradle to grave: research integrity, research misconduct and cultural shiftsBronwyn Greene, Ted RohrPARTNER SYMPOSIAPartner Symposium AOrganized by EQUATOR Network, Enhancing the Quality and Transparency of Health ResearchP1 Can we trust the medical research literature?: Poor reporting and its consequencesIveta SimeraP2 What can BioMed Central do to improve published research?Daniel Shanahan, Stephanie HarrimanP3 What can a "traditional" journal do to improve published research?Trish GrovesP4 Promoting good reporting practice for reliable and usable research papers: EQUATOR Network, reporting guidelines and other initiativesCaroline StruthersPartner Symposium COrganized by ENRIO, the European Network of Research Integrity OfficersP5 Transparency and independence in research integrity investigations in EuropeKrista Varantola, Helga Nolte, Ursa Opara, Torkild Vinther, Elizabeth Wager, Thomas NørgaardPartner Symposium DOrganized by IEEE, the Institute of Electrical and Electronics EngineersRe-educating our author community: IEEE's approach to bibliometric manipulation, plagiarism, and other inappropriate practicesP6 Dealing with plagiarism in the connected world: An Institute of Electrical and Electronics Engineers perspectiveJon RokneP7 Should evaluation of raises, promotion, and research proposals be tied to bibliometric indictors? What the Institute of Electrical and Electronics Engineers is doing to answer this questionGianluca SettiP8 Recommended practices to ensure conference content qualityGordon MacPhersonPartner Symposium EOrganized by the Committee on Freedom and Responsibility in the Conduct of Science of ICSU, the International Council for ScienceResearch assessment and quality in science: perspectives from international science and policy organisationsP9 Challenges for science and the problems of assessing researchEllen HazelkornP10 Research assessment and science policy developmentCarthage SmithP11 Research integrity in South Africa: the value of procedures and processes to global positioningRobert H. McLaughlinP12 Rewards, careers and integrity: perspectives of young scientists from around the worldTatiana Duque MartinsPartner Symposium FOrganized by the Online Resource Center for Ethics Education in Engineering and Science / Center for Engineering, Ethics, and Society of the National Academy of EngineeringP13 Research misconduct: conceptions and policy solutionsTetsuya Tanimoto, Nicholas Steneck, Daniele Fanelli, Ragnvald Kalleberg, Tajammul HusseinPartner Symposium HOrganized by ORI, the Office of Research Integrity; Universitas 21; and the Asia Pacific Research Integrity NetworkP14 International integrity networks: working together to ensure research integrityPing Sun, Ovid Tzeng, Krista Varantola, Susan ZimmermanPartner Symposium IOrganized by COPE, the Committee on Publication EthicsPublication without borders: Ethical challenges in a globalized worldP15 Authorship: credit and responsibility, including issues in large and interdisciplinary studiesRosemary ShinkaiPartner Symposium JOrganized by CITI, the Cooperative Institutional Training InitiativeExperiences on research integrity educational programs in Colombia, Costa Rica and PeruP16 Experiences in PeruRoxana LescanoP17 Experiences in Costa RicaElizabeth HeitmanP18 Experiences in ColumbiaMaria Andrea Rocio del Pilar Contreras NietoPoster Session B: Education, training, promotion and policyPT.01 The missing role of journal editors in promoting responsible researchIbrahim Alorainy, Khalid Al-WazzanPT.02 Honorary authorship in Taiwan: why and who should be in charge?Chien Chou, Sophia Jui-An PanPT.03 Authorship and citation manipulation in academic researchEric Fong, Al WilhitePT.04 Open peer review of research submission at medical journals: experience at BMJ Open and The BMJTrish GrovesPT.05 Exercising authorship: claiming rewards, practicing integrityDésirée Motta-RothPT.07 Medical scientists' views on publication culture: a focus group studyJoeri Tijdink, Yvo SmuldersPoster Session B: Education, training, promotion and policyPT.09 Ethical challenges in post-graduate supervisionLaetus OK LateganPT.10 The effects of viable ethics instruction on international studentsMichael Mumford, Logan Steele, Logan Watts, James Johnson, Shane Connelly, Lee WilliamsPT.11 Does language reflect the quality of research?Gerben ter Riet, Sufia Amini, Lotty Hooft, Halil KilicogluPT.12 Integrity complaints as a strategic tool in policy decision conflictsJanneke van Seters, Herman Eijsackers, Fons Voragen, Akke van der Zijpp and Frans BromPoster Session C: Ethics and integrity intersectionsPT.14 Regulations of informed consent: university-supported research processes and pitfalls in implementationBadaruddin Abbasi, Naif Nasser AlmasoudPT.15 A review of equipoise as a requirement in clinical trialsAdri LabuschagnePT.16 The Research Ethics Library: online resource for research ethics educationJohanne Severinsen, Espen EnghPT.17 Research integrity: the view from King Abdulaziz City for Science and TechnologyDaham Ismail AlaniPT. 18 Meeting global challenges in high-impact publications and research integrity: the case of the Malaysian Palm Oil BoardHJ. Kamaruzaman JusoffPT.19 University faculty perceptions of research practices and misconductAnita Gordon, Helen C. HartonPoster Session D: International perspectivesPT.21 The Commission for Scientific Integrity as a response to research fraudDieter De Bruyn, Stefanie Van der BurghtPT. 22 Are notions of the responsible conduct of research associated with compliance with requirements for research on humans in different disciplinary traditions in Brazil?Karina de Albuquerque Rocha, Sonia Maria Ramos de VasconcelosPT.23 Creating an environment that promotes research integrity: an institutional model of Malawi Liverpool Welcome TrustLimbanazo MatandikaPT.24 How do science policies in Brazil influence user-engaged ecological research?Aline Carolina de Oliveira Machado Prata, Mark William NeffPoster Session E: Perspectives on misconductPT.26 What “causes” scientific misconduct?: Testing major hypotheses by comparing corrected and retracted papersDaniele Fanelli, Rodrigo Costas, Vincent LarivièrePT.27 Perception of academic plagiarism among dentistry studentsDouglas Leonardo Gomes Filho, Diego Oliveira GuedesPT. 28 a few bad apples?: Prevalence, patterns and attitudes towards scientific misconduct among doctoral students at a German university hospitalVolker Bähr, Niklas Keller, Markus Feufel, Nikolas OffenhauserPT. 29 Analysis of retraction notices published by BioMed CentralMaria K. Kowalczuk, Elizabeth C. MoylanPT.31 "He did it" doesn't work: data security, incidents and partnersKatie SpeanburgPoster Session F: Views from the disciplinesPT.32 Robust procedures: a key to generating quality results in drug discoveryMalini Dasgupta, Mariusz Lubomirski, Tom Lavrijssen, David Malwitz, David Gallacher, Anja GillisPT.33 Health promotion: criteria for the design and the integrity of a research projectMaria Betânia de Freitas Marques, Laressa Lima Amâncio, Raphaela Dias Fernandes, Oliveira Patrocínio, and Cláudia Maria Correia Borges RechPT.34 Integrity of academic work from the perspective of students graduating in pharmacy: a brief research studyMaria Betânia de Freitas Marques, Cláudia Maria Correia Borges Rech, Adriana Nascimento SousaPT.35 Research integrity promotion in the Epidemiology and Health Services, the journal of the Brazilian Unified Health SystemLeila Posenato GarciaPT.36 When are clinical trials registered? An analysis of prospective versus retrospective registration of clinical trials published in the BioMed Central series, UKStephanie Harriman, Jigisha PatelPT.37 Maximizing welfare while promoting innovation in drug developmentFarida LadaOther posters that will be displayed but not presented orally:PT.38 Geoethics and the debate on research integrity in geosciencesGiuseppe Di Capua, Silvia PeppoloniPT.39 Introducing the Professionalism and Integrity in Research Program James M. DuBois, John Chibnall, Jillon Van der WallPT.40 Validation of the professional decision-making in research measureJames M. DuBois, John Chibnall, Jillon Van der Wall, Raymond TaitPT.41 General guidelines for research ethicsJacob HolenPT. 42 A national forum for research ethicsAdele Flakke Johannessen, Torunn EllefsenPT.43 Evaluation of integrity in coursework: an approach from the perspective of the higher education professorClaudia Rech, Adriana Sousa, Maria Betânia de Freitas MarquesPT.44 Principles of geoethics and research integrity applied to the European Multidisciplinary Seafloor and Water Column Observatory, a large-scale European environmental research infrastructureSilvia Peppoloni, Giuseppe Di Capua, Laura BeranzoliF1 Focus track on improving research systems: the role of fundersPaulo S.L. Beirão, Susan ZimmermanF2 Focus track on improving research systems: the role of countriesSabine Kleinert, Ana MarusicF3 Focus track on improving research systems: the role of institutionsMelissa S. Anderson, Lex Bouter. (shrink)

Alzheimer's disease (AD) is the most common cause of dementia, and there is currently no cure. The “β‐amyloid cascade hypothesis” of AD is the basis of current understanding of AD pathogenesis and drug discovery. However, no AD models have fully validated this hypothesis. We recently developed a human stem cell culture model of AD by cultivating genetically modified human neural stem cells in a three‐dimensional (3D) cell culture system. These cells were able to recapitulate key events of AD (...) pathology including β‐amyloid plaques and neurofibrillary tangles. In this review, we will discuss the progress and current limitations of AD mouse models and human stem cell models as well as explore the breakthroughs of 3D cell culture systems. We will also share our perspective on the potential of dish models of neurodegenerative diseases for studying pathogenic cascades and therapeutic drug discovery. (shrink)

In this study a combination of computer tools for coupling and virtual screening is detailed, in 108 active molecules and 3620 decoys to find stabilizers for G quadruplex. To have more precise results, combinations of coupling programs with fifteen energy scoring functions were applied. The validation and evaluation of the metrics was done with the CompScore genetic algorithm. The results showed an increase in BEDROC and EF of 50% compared to other strategies, as well as reflecting early recognition of active (...) molecules. From these results it is possible to work with the molecules that showed a good early recognition and evaluate their effect as G4 stabilizers. This ensures more efficient and accurate results in the preclinical stage for the development of anticancer drugs. Keywords: Enrichment metrics; telomere; G quadruplex ; CompScore. References [1]M. Porru, P. Zizza, M. Franceschin, C. Leonetti and A. Biroccio. «EMICORON: A multi-targeting G4 ligand with a promising preclinical profile» 2017. Biochimica et Biophysica Acta - General Subjects, 1861, 1362–1370. [Online]. Available: https://doi.org/10.1007/s00294-018-0836-6. [2]K. Tomita. «How long does telomerase extend telomeres? Regulation of telomerase release and telomere length homeostasis». Current Genetics, 64, 1177–1181. 2018. [Online]. Available: https://doi.org/10.1016/j.bbagen. 2016.11.010. [3]M. Jafri, S. Ansari, M. Alqahtani and J. Shay. «Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies. Genome Medicine., 2016. [Online]. Available: https://doi.org/10.3390/ijms19020482. [4]J. Huppert and S. Balasubramanian. «G-quadruplexes in promoters throughout the human genome». 35, 406–413. 2007. [Online]. Available: https://doi.org/10.1016/j.bbapap.2017.06.012. [5]S. Joy, Vijayakumar, S. Choi and H. Sunhye. «Role of computer-aided drug design in modern drug discovery». Archives of Pharmacal Research. 2015. [Online]. Available: https://doi.org/10.1007/s12272-015-0640-5. [6]S. Asamitsu, S. Obata, Z. Yu, T. Bando and H. Sugiyama. «Recent Progress of Targeted G-Quadruplex-Preferred Ligands Toward Cancer Therapy». Molecules, 24, 429. 2019. [En línea]. Available: https://doi.org/10.3390/molecules24030429. [7]R. Monsen and J. Trent. «Biochimie G-quadruplex virtual drug screening : A review». Biochimie, 152, 134–148. 2018. [Online]. Available: https://doi.org/10.1039/c9cc06748e. [8]J. Beauvarlet, P. Bensadoun, E. Darbo, G. Labrunie, E. Richard, I. Draskovic and M. Djavaheri-mergny. «Modulation of the ATM / autophagy pathway by a G-quadruplex ligand tips the balance between senescence and apoptosis in cancer cells». 1–18. 2019. [Online]. Available: https://doi.org/10.1093/nar/gkz095. [9].Z. Crees, J. Girard, Z. Rios, G. Botting, K. Harrington and C. Shearrow. « Oligonucleotides and G-quadruplex stabilizers: targeting telomeres and telomerase in cancer therapy».2014. [Online]. Available: https://doi.org/10.2174/1381612820666140630100702. [10].M. Meier, A. Moya-torres, N. Krahn, M. Mcdougall, L. Orriss, E. Mcrae and T. Patel. «Structure and hydrodynamics of a DNA Gquadruplex with a cytosine bulge»., 1–13. 2018. [Online]. Available: https://doi.org/10.1093/nar/gky307. (shrink)

Animal models play a crucial role in fundamental and medical research. Progress in the fields of drug discovery, regenerative medicine and cancer research among others are heavily dependent on in vivo models to validate in vitro observations, and develop new therapeutic approaches. However, conventional rodent and large animal experiments face ethical, practical and technical issues that limit their usage. The chick embryo represents an accessible and economical in vivo model, which has long been used in developmental biology, gene (...) expression analysis and loss/gain of function experiments. It is also an established model for tissue/cell transplantation, and because of its lack of immune system in early development, the chick embryo is increasingly recognised as a model of choice for mammalian biology with new applications for stem cell and cancer research. Here, we review novel applications of the chick embryo model, and discuss future developments of this in vivo model for biomedical research. (shrink)