Gene patents still alive and kicking: their impact on provision of genetic testing for long QT syndrome in the Canadian public health-care system.

PurposeAlthough the Supreme Court of the United States limited their availability in Association for Molecular Pathology v. Myriad Genetics, gene patents remain important around the world. We examine the situation in Canada, where gene patents continue to exist, in light of recent litigation relating to familial long QT syndrome (LQTS).MethodsWe conducted in-depth semistructured interviews with 25 stakeholders across five Canadian provinces and supplemented this with a case analysis of the litigation.ResultsThe majority of LQTS testing was carried out outside Canada. Rising costs prompted several provinces to attempt to repatriate testing. However, LQTS gene patents stymied efforts, particularly in provinces where testing was more centralized, increasing costs and lowering innovation. It was in this context that a hospital launched a test case against the LQTS patents, resulting in a novel agreement to free Canadian hospitals from the effects of patents.ConclusionOur analysis reveals a rapidly evolving genetic test provision landscape under pressure from gene patents, strained budgets and poor collaboration. The litigation resulted in a blueprint for free public use of gene patents throughout Canada's health-care system, but it will only have value if governments are proactive in its use.

Non-invasive Prenatal Testing and the Unveiling of an Impaired Translation Process.

Non-invasive prenatal testing (NIPT) is an exciting technology with the potential to provide a variety of clinical benefits, including a reduction in miscarriages, via a decline in invasive testing. However, there is also concern that the economic and near-future clinical benefits of NIPT have been overstated and the potential limitations and harms underplayed. NIPT, therefore, presents an opportunity to explore the ways in which a range of social pressures and policies can influence the translation, implementation, and use of a health care innovation. NIPT is often framed as a potential first tier screen that should be offered to all pregnant women, despite concerns over cost-effectiveness. Multiple forces have contributed to a problematic translational environment in Canada, creating pressure towards first tier implementation. Governments have contributed to commercialization pressure by framing the publicly funded research sector as a potential engine of economic growth. Members of industry have an incentive to frame clinical value as beneficial to the broadest possible cohort in order to maximize market size. Many studies of NIPT were directly funded and performed by private industry in laboratories lacking strong independent oversight. Physicians' fear of potential liability for failing to recommend NIPT may further drive widespread uptake. Broad social endorsement, when combined with these translation pressures, could result in the "routinization" of NIPT, thereby adversely affecting women's reproductive autonomy. Policymakers should demand robust independent evidence of clinical and public health utility relevant to their respective jurisdictions before making decisions regarding public funding for NIPT.

SOCIO-ETHICAL ISSUES IN PERSONALIZED MEDICINE: A SYSTEMATIC REVIEW OF ENGLISH LANGUAGE HEALTH TECHNOLOGY ASSESSMENTS OF GENE EXPRESSION PROFILING TESTS FOR BREAST CANCER PROGNOSIS.

OBJECTIVES: There have been multiple calls for explicit integration of ethical, legal, and social issues (ELSI) in health technology assessment (HTA) and addressing ELSI has been highlighted as key in optimizing benefits in the Omics/Personalized Medicine field. This study examines HTAs of an early clinical example of Personalized Medicine (gene expression profile tests [GEP] for breast cancer prognosis) aiming to: (i) identify ELSI; (ii) assess whether ELSIs are implicitly or explicitly addressed; and (iii) report methodology used for ELSI integration. METHODS: A systematic search for HTAs (January 2004 to September 2012), followed by descriptive and qualitative content analysis. RESULTS: Seventeen HTAs for GEP were retrieved. Only three (18%) explicitly presented ELSI, and only one reported methodology. However, all of the HTAs included implicit ELSI. Eight themes of implicit and explicit ELSI were identified. "Classical" ELSI including privacy, informed consent, and concerns about limited patient/clinician genetic literacy were always presented explicitly. Some ELSI, including the need to understand how individual patients' risk tolerances affect clinical decision-making after reception of GEP results, were presented both explicitly and implicitly in HTAs. Others, such as concern about evidentiary deficiencies for clinical utility of GEP tests, occurred only implicitly. CONCLUSIONS: Despite a wide variety of important ELSI raised, these were rarely explicitly addressed in HTAs. Explicit treatment would increase their accessibility to decision-makers, and may augment HTA efficiency maximizing their utility. This is particularly important where complex Personalized Medicine applications are rapidly expanding choices for patients, clinicians and healthcare systems.

Whole genome scanning: resolving clinical diagnosis and management amidst complex data.

Momentum around the era of genomic medicine is building, and with it, anticipation of the benefits that whole genome analysis (personalized or individualized genomics) will bring for the provision of health care. These technologies have the potential to revolutionize genetic diagnosis; however, the expansive data generated can lead to complex or unexpected findings, sometimes complicating clinical utility and patient benefit. Here, we use our experience with whole genome scanning microarrays, an early instance of whole genome analysis already in clinical use, to highlight fundamental challenges raised by these technologies and to discuss their medical, ethical, legal and social implications. We discuss issues that physicians and healthcare professionals will face, in particular, as the resolution of testing further increases toward full genome sequence determination. We emphasize that addressing these issues now, and starting to evolve our healthcare systems in response, will be pivotal in avoiding harms and realizing the promise of these new technologies.

An open toolkit for tracking open science partnership implementation and impact.

Serious concerns about the way research is organized collectively are increasingly being raised. They include the escalating costs of research and lower research productivity, low public trust in researchers to report the truth, lack of diversity, poor community engagement, ethical concerns over research practices, and irreproducibility. Open science (OS) collaborations comprise of a set of practices including open access publication, open data sharing and the absence of restrictive intellectual property rights with which institutions, firms, governments and communities are experimenting in order to overcome these concerns. We gathered two groups of international representatives from a large variety of stakeholders to construct a toolkit to guide and facilitate data collection about OS and non-OS collaborations. Ultimately, the toolkit will be used to assess and study the impact of OS collaborations on research and innovation. The toolkit contains the following four elements: 1) an annual report form of quantitative data to be completed by OS partnership administrators; 2) a series of semi-structured interview guides of stakeholders; 3) a survey form of participants in OS collaborations; and 4) a set of other quantitative measures best collected by other organizations, such as research foundations and governmental or intergovernmental agencies. We opened our toolkit to community comment and input. We present the resulting toolkit for use by government and philanthropic grantors, institutions, researchers and community organizations with the aim of measuring the implementation and impact of OS partnership across these organizations. We invite these and other stakeholders to not only measure, but to share the resulting data so that social scientists and policy makers can analyse the data across projects.

Identifying the challenges in implementing open science [version 1; peer review: 2 approved].

Areas of open science (OS) policy and practice are already relatively well-advanced in several countries and sectors through the initiatives of some governments, funders, philanthropy, researchers and the community. Nevertheless, the current research and innovation system, including in the focus of this report, the life sciences, remains weighted against OS. In October 2017, thought-leaders from across the world gathered at an Open Science Leadership Forum in the Washington DC office of the Bill and Melinda Gates Foundation to share their views on what successful OS looks like. We focused on OS partnerships as this is an emerging model that aims to accelerate science and innovation. These outcomes are captured in a first meeting report: Defining Success in Open Science. On several occasions, these conversations turned to the challenges that must be addressed and new policies required to effectively and sustainably advance OS practice. Thereupon, in this report, we describe the concerns raised and what is needed to address them supplemented by our review of the literature, and suggest the stakeholder groups that may be best placed to begin to take action. It emerges that to be successful, OS will require the active engagement of all stakeholders: while the research community must develop research questions, identify partners and networks, policy communities need to create an environment that is supportive of experimentation by removing barriers. This report aims to contribute to ongoing discussions about OS and its implementation. It is also part of a step-wise process to develop and mobilize a toolkit of quantitative and qualitative indicators to assist global stakeholders in implementing high value OS collaborations. Currently in co-development through an open and international process, this set of measures will allow the generation of needed evidence on the influence of OS partnerships on research, innovation, and critical social and economic goals.

Defining Success in Open Science.

Mounting evidence indicates that worldwide, innovation systems are increasing unsustainable. Equally, concerns about inequities in the science and innovation process, and in access to its benefits, continue. Against a backdrop of growing health, economic and scientific challenges global stakeholders are urgently seeking to spur innovation and maximize the just distribution of benefits for all. Open Science collaboration (OS) - comprising a variety of approaches to increase open, public, and rapid mobilization of scientific knowledge - is seen to be one of the most promising ways forward. Yet, many decision-makers hesitate to construct policy to support the adoption and implementation of OS without access to substantive, clear and reliable evidence. In October 2017, international thought-leaders gathered at an Open Science Leadership Forum in the Washington DC offices of the Bill and Melinda Gates Foundation to share their views on what successful Open Science looks like. Delegates from developed and developing nations, national governments, science agencies and funding bodies, philanthropy, researchers, patient organizations and the biotechnology, pharma and artificial intelligence (AI) industries discussed the outcomes that would rally them to invest in OS, as well as wider issues of policy and implementation. This first of two reports, summarizes delegates' views on what they believe OS will deliver in terms of research, innovation and social impact in the life sciences. Through open and collaborative process over the next months, we will translate these success outcomes into a toolkit of quantitative and qualitative indicators to assess when, where and how open science collaborations best advance research, innovation and social benefit. Ultimately, this work aims to develop and openly share tools to allow stakeholders to evaluate and re-invent their innovation ecosystems, to maximize value for the global public and patients, and address long-standing questions about the mechanics of innovation.

Defining Success in Open Science [version 2; peer review:2 approved].

Mounting evidence indicates that worldwide, innovation systems are increasing unsustainable. Equally, concerns about inequities in the science and innovation process, and in access to its benefits, continue. Against a backdrop of growing health, economic and scientific challenges global stakeholders are urgently seeking to spur innovation and maximize the just distribution of benefits for all. Open Science collaboration (OS) - comprising a variety of approaches to increase open, public, and rapid mobilization of scientific knowledge - is seen to be one of the most promising ways forward. Yet, many decision-makers hesitate to construct policy to support the adoption and implementation of OS without access to substantive, clear and reliable evidence. In October 2017, international thought-leaders gathered at an Open Science Leadership Forum in the Washington DC offices of the Bill and Melinda Gates Foundation to share their views on what successful Open Science looks like. Delegates from developed and developing nations, national governments, science agencies and funding bodies, philanthropy, researchers, patient organizations and the biotechnology, pharma and artificial intelligence (AI) industries discussed the outcomes that would rally them to invest in OS, as well as wider issues of policy and implementation. This first of two reports, summarizes delegates' views on what they believe OS will deliver in terms of research, innovation and social impact in the life sciences. Through open and collaborative process over the next months, we will translate these success outcomes into a toolkit of quantitative and qualitative indicators to assess when, where and how open science collaborations best advance research, innovation and social benefit. Ultimately, this work aims to develop and openly share tools to allow stakeholders to evaluate and re-invent their innovation ecosystems, to maximize value for the global public and patients, and address long-standing questions about the mechanics of innovation.

Motivating participation in open science by examining researcher incentives.

Support for open science is growing, but motivating researchers to participate in open science can be challenging. This in-depth qualitative study draws on interviews with researchers and staff at the Montreal Neurological Institute and Hospital during the development of its open science policy. Using thematic content analysis, we explore attitudes toward open science, the motivations and disincentives to participate, the role of patients, and attitudes to the eschewal of intellectual property rights. To be successful, an open science policy must clearly lay out expectations, boundaries and mechanisms by which researchers can engage, and must be shaped to explicitly support their values and those of key partners, including patients, research participants and industry collaborators.

Retinoid receptor antagonists alter the pattern of apoptosis in organogenesis stage mouse limbs.

Exposure of murine limbs in vitro to vitamin A (retinol) induces limb reduction defects and apoptosis. To assess the relative roles of the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), embryonic-day-12 murine limbs were cultured with selective RAR or RXR antagonists in the presence or absence of teratogenic concentrations of retinol. Both antagonists alone impaired limb development; in the presence of teratogenic concentrations of retinol, both attenuated limb malformations. Abnormal limb morphology, whether caused by excessive or attenuated retinoid signaling by retinol or either antagonist, respectively, was correlated with increased apoptosis after 24 h of drug exposure. We conclude that, in the developing limb, antagonists selective for either member of the RAR/RXR heterodimer attenuate retinoid signaling and block the teratogenic signaling of excess retinol. Improvements in limb morphology in the presence of either the RAR or the RXR antagonist coincided with restoration of the extent and localization of limb bud apoptosis to control patterns.

Novel retinoid targets in the mouse limb during organogenesis.

Bioactive retinoids are potent limb teratogens, upregulating apoptosis, decreasing chondrogenesis, and producing limb-reduction defects. To target the origins of these effects, we examined gene expression changes in the developing murine limb after 3 h of culture with teratogenic concentrations of vitamin A. Embryonic day 12 CD-1 limbs were cultured in the absence or presence of vitamin A (retinol acetate) at 1.25 and 62.5muM (n = 5). Total RNA was used to probe Atlas 1.2 cDNA arrays. Eighty-one genes were significantly upregulated by retinol exposure; among these were key limb development signaling molecules, extracellular matrix and adhesion proteins, oncogenes, and a large number of transcriptional regulators, including Eya2, Id3, Snail, and Hes1. To relate these expression changes to teratogenic outcome, the response of these four genes was assessed after culture with vitamin A and retinoid receptor antagonists that are able to rescue retinoid-induced malformations; expression levels were correlated with limb malformations. Lastly, pathways analysis revealed that a large number of the genes significantly affected by retinoid treatment are functionally linked through direct interactions. Several regulatory gene cascades emerged relevant to morphogenesis, cell-fate, and chondrogenesis; moreover, members of these cascades crosstalk with one other. These results indicate that retinoids act in a coordinated fashion to disrupt development at multiple levels. In sum, this work proposes several unifying mechanisms for retinoid-induced limb malformations, identifies novel retinoid targets, and highlights Eya2, Id3, Snail, and Hes1 as potential key teratogenic effectors.

Sino-Canadian collaborations in stem cell research: a scientometric analysis.

BACKGROUND: International collaboration (IC) is essential for the advance of stem cell research, a field characterized by marked asymmetries in knowledge and capacity between nations. China is emerging as a global leader in the stem cell field. However, knowledge on the extent and characteristics of IC in stem cell science, particularly China's collaboration with developed economies, is lacking. METHODS AND FINDINGS: We provide a scientometric analysis of the China-Canada collaboration in stem cell research, placing this in the context of other leading producers in the field. We analyze stem cell research published from 2006 to 2010 from the Scopus database, using co-authored papers as a proxy for collaboration. We examine IC levels, collaboration preferences, scientific impact, the collaborating institutions in China and Canada, areas of mutual interest, and funding sources. Our analysis shows rapid global expansion of the field with 48% increase in papers from 2006 to 2010. China now ranks second globally after the United States. China has the lowest IC rate of countries examined, while Canada has one of the highest. China-Canada collaboration is rising steadily, more than doubling during 2006-2010. China-Canada collaboration enhances impact compared to papers authored solely by China-based researchers This difference remained significant even when comparing only papers published in English. CONCLUSIONS: While China is increasingly courted in IC by developed countries as a partner in stem cell research, it is clear that it has reached its status in the field largely through domestic publications. Nevertheless, IC enhances the impact of stem cell research in China, and in the field in general. This study establishes an objective baseline for comparison with future studies, setting the stage for in-depth exploration of the dynamics and genesis of IC in stem cell research.

The use of race, ethnicity and ancestry in human genetic research.

Post-Human Genome Project progress has enabled a new wave of population genetic research, and intensified controversy over the use of race/ethnicity in this work. At the same time, the development of methods for inferring genetic ancestry offers more empirical means of assigning group labels. Here, we provide a systematic analysis of the use of race/ethnicity and ancestry in current genetic research. We base our analysis on key published recommendations for the use and reporting of race/ethnicity which advise that researchers: explain why the terms/categories were used and how they were measured, carefully define them, and apply them consistently. We studied 170 population genetic research articles from high impact journals, published 2008-2009. A comparative perspective was obtained by aligning study metrics with similar research from articles published 2001-2004. Our analysis indicates a marked improvement in compliance with some of the recommendations/guidelines for the use of race/ethnicity over time, while showing that important shortfalls still remain: no article using 'race', 'ethnicity' or 'ancestry' defined or discussed the meaning of these concepts in context; a third of articles still do not provide a rationale for their use, with those using 'ancestry' being the least likely to do so. Further, no article discussed potential socio-ethical implications of the reported research. As such, there remains a clear imperative for highlighting the importance of consistent and comprehensive reporting on human populations to the genetics/genomics community globally, to generate explicit guidelines for the uses of ancestry and genetic ancestry, and importantly, to ensure that guidelines are followed.

Admixture mapping: from paradigms of race and ethnicity to population history.

Admixture mapping is a whole genome association strategy that takes advantage of population history-or genetic ancestry-to map genes for complex diseases. However, because it uses racial/ethnic groupings to examine differential disease risk, admixture mapping raises ethical and social concerns. While there has been much theoretical commentary regarding the ethical and social implications of population-based genetic research, empirical data from stakeholders most closely involved with these studies is limited. One of the first admixture mapping studies carried out was a scan for Multiple Sclerosis (MS) risk factors in an African-American population. Applying qualitative research methods, we used this example to explore developing views, experiences and perceptions of the ethical and social implications of admixture mapping and other population-based research-their value, risks and benefits, and the future prospects of the field. Additionally, we sought to understand how social and ethical risks might be mitigated, and the benefits of this research optimized. We draw on in-depth, one-on-one interviews with leading population geneticists, genome scientists, bioethicists, and African-Americans with MS. Here we present our findings from this unique group of key informants and stakeholders.

Race and ancestry in biomedical research: exploring the challenges.

The use of race in biomedical research has, for decades, been a source of social controversy. However, recent events, such as the adoption of racially targeted pharmaceuticals, have raised the profile of the race issue. In addition, we are entering an era in which genomic research is increasingly focused on the nature and extent of human genetic variation, often examined by population, which leads to heightened potential for misunderstandings or misuse of terms concerning genetic variation and race. Here, we draw together the perspectives of participants in a recent interdisciplinary workshop on ancestry and health in medicine in order to explore the use of race in research issue from the vantage point of a variety of disciplines. We review the nature of the race controversy in the context of biomedical research and highlight several challenges to policy action, including restrictions resulting from commercial or regulatory considerations, the difficulty in presenting precise terminology in the media, and drifting or ambiguous definitions of key terms.

Caspase-3 mediates retinoid-induced apoptosis in the organogenesis-stage mouse limb.

BACKGROUND: Caspases are key mediators in the regulation and execution of apoptosis, a crucial part of the morphogenetic process during limb development. Caspase-8 and -9 are upstream caspases. Caspase-8 mediates the extrinsic pathway of apoptosis triggered by signaling through TNF-R1 family receptors. Caspase-9 is activated during the intrinsic pathway downstream of mitochondria. Caspase-3 is an effector caspase that initiates degradation of the cell in the final stages of apoptosis. Vitamin A is a potent teratogen that causes limb reduction defects in embryos exposed during organogenesis. Previous in vitro studies have shown that exposure of the organogenesis-stage murine limb to vitamin A results in excessive levels of apoptosis. The goal of this work was to characterize the involvement of caspase-3, -8, and -9, as well as cytochrome-c release from the mitochondria, in the apoptotic cascade induced by vitamin A. METHODS: Limb buds from gestational day 12 CD-1 mice were cultured in a chemically defined medium in the absence or presence of vitamin A. Cultures were terminated after 6 days to examine the effect of the drug on gross morphology. Apoptosis was detected by TUNEL staining after culture for 24 hr. Caspase activation was determined by Western blotting and localized by immunohistochemistry of control and treated limbs. The release of cytochrome-c into the cytoplasm was assessed by Western blotting after cell-fractionation. RESULTS: Limbs cultured in the presence of vitamin A showed a dose-dependent growth reduction and dysmorphogenesis of the cartilaginous anlagen. Apoptosis was increased in the interdigital, anterior, and posterior marginal zones and in the apical ectodermal ridge. Western-blotting confirmed the presence of activated caspase-3 that increased with time in culture and vitamin A concentration. Cleaved caspase-3 immunoreactivity colocalized with TUNEL stained limb regions and increased dramatically with increasing drug concentrations. In contrast, procaspase-8 and -9 were not activated. Exposure to high concentrations of vitamin A did, however, increase cytoplasmic cytochrome-c, suggesting mitochondrial involvement. CONCLUSIONS: Caspase-3 is a key effector caspase in the apoptotic pathway induced by Vitamin A. While caspases-8 and -9 are not responsible for the activation of caspase-3 in response to the drug, cytochrome-c release from mitochondria may play an upstream role.