Alessandro Blasimme

Cell Reprogramming Requires Silencing of a Core Subset of Polycomb Targets

Transcription factor (TF)–induced reprogramming of somatic cells into induced pluripotent stem cells (iPSC) is associated with genome-wide changes in chromatin modifications. Polycomb-mediated histone H3 lysine-27 trimethylation (H3K27me3) has been proposed as a defining mark that distinguishes the somatic from the iPSC epigenome. Here, we dissected the functional role of H3K27me3 in TF–induced reprogramming through the inactivation of the H3K27 methylase EZH2 at the onset of reprogramming. Our results demonstrate that surprisingly the establishment of functional iPSC proceeds despite global loss of H3K27me3. iPSC lacking EZH2 efficiently silenced the somatic transcriptome and differentiated into tissues derived from the three germ layers. Remarkably, the genome-wide analysis of H3K27me3 in Ezh2 mutant iPSC cells revealed the retention of this mark on a highly selected group of Polycomb targets enriched for developmental regulators controlling the expression of lineage specific genes. Erasure of H3K27me3 from these targets led to a striking impairment in TF–induced reprogramming. These results indicate that PRC2-mediated H3K27 trimethylation is required on a highly selective core of Polycomb targets whose repression enables TF–dependent cell reprogramming.

Mapping the translational science policy 'valley of death'

Translating the knowledge from biomedical science into clinical applications that help patients has been compared to crossing a valley of death because of the many issues that separate the bench from the bedside and threaten to stall progress. But translation is also inhibited by a science policy environment with its own impediments. Mapping these policy impediments give a more complete picture of the valley of death. Stem cell science is one example where success in moving from the bench to the bedside has confronted policy challenges generating difficulties as challenging as those facing scientists and clinicians. We highlight some of the characteristics and challenges of the science policy valley of death common to the U.S. and Europe, illustrate them with a recent example from stem cell science, and describe some promising strategies for traversing the valley.

Becoming partners, retaining autonomy: ethical considerations on the development of precision medicine

Precision medicine promises to develop diagnoses and treatments that take individual variability into account. According to most specialists, turning this promise into reality will require adapting the established framework of clinical research ethics, and paying more attention to participants’ attitudes towards sharing genotypic, phenotypic, lifestyle data and health records, and ultimately to their desire to be engaged as active partners in medical research.Notions such as participation, engagement and partnership have been introduced in bioethics debates concerning genetics and large-scale biobanking to broaden the focus of discussion beyond individual choice and individuals’ moral interests. The uptake of those concepts in precision medicine is to be welcomed. However, as data and medical information from research participants in precision medicine cohorts will be collected on an individual basis, translating a participatory approach in this emerging area may prove cumbersome. Therefore, drawing on Joseph Raz’s perfectionism, we propose a principle of respect for autonomous agents that, we reckon, can address many of the concerns driving recent scholarship on partnership and public participation, while avoiding some of the limitations these concept have in the context of precision medicine. Our approach offers a normative clarification to how becoming partners in precision is compatible with retaining autonomy.Realigning the value of autonomy with ideals of direct engagement, we show, can provide adequate normative orientation to precision medicine; it can do justice to the idea of moral pluralism by stressing the value of moral self-determination: and, finally, it can reconcile the notion of autonomy with other more communitarian values such as participation and solidarity.

Familial Alzheimer's disease sustained by presenilin 2 mutations: Systematic review of literature and genotype–phenotype correlation

Familial Alzheimers disease (FAD), despite representing a rare condition, is attracting a growing interest in the scientific community. Improved phenotyping of FAD cases may have a relevant impact both in clinical and research contexts. We performed a systematic review of studies describing the phenotypic features of FAD cases sustained by PSEN2 mutations, the less common cause of monogenic AD. Special attention was given to the clinical manifestations as well as to the main findings coming from the most commonly and widely adopted diagnostic procedures. Basing on the collected data, we also attempted to conduct a genotype-phenotype correlation analysis. Overall, the mutations involving the PSEN2 gene represent an extremely rare cause of FAD, having been reported to date in less than 200 cases. They are mainly associated, despite some peculiar and heterogeneous features, to a typical AD phenotype. Nevertheless, the frequent occurrence of psychotic symptoms may represent a potential distinctive element. The scarcity of available phenotypic descriptions strongly limits the implementation of genotype-phenotype correlations.

Regulation of Cell-Based Therapies in Europe: Current Challenges and Emerging Issues

Europe is ready to deploy its immense capital of knowledge into the development of effective cell-based therapies and delve into the global race for translating stem cell science into regenerative medicine. But what are the challenges and the emerging issues that lay ahead the realization of Europes enormous potential in this field? Both researchers and industrial stakeholders tend to impute the slow pace of translation to specific suboptimal features of the regulatory environment in Europe. At the same time, a host of new issues are emerging as testified by a recent public controversy regarding the provision of unproven cell therapy in Italy. We will review this topic and suggest some solutions to foster the responsible development of innovative cell-based therapies in Europe.

Biomedical Big Data: New Models of Control Over Access, Use and Governance

Empirical evidence suggests that while people hold the capacity to control their data in high regard, they increasingly experience a loss of control over their data in the online world. The capacity to exert control over the generation and flow of personal information is a fundamental premise to important values such as autonomy, privacy, and trust. In healthcare and clinical research this capacity is generally achieved indirectly, by agreeing to specific conditions of informational exposure. Such conditions can be openly stated in informed consent documents or be implicit in the norms of confidentiality that govern the relationships of patients and healthcare professionals. However, with medicine becoming a data-intense enterprise, informed consent and medical confidentiality, as mechanisms of control, are put under pressure. In this paper we explore emerging models of informational control in data-intense healthcare and clinical research, which can compensate for the limitations of currently available instruments. More specifically, we discuss three approaches that hold promise in increasing individual control: the emergence of data portability rights as means to control data access, new mechanisms of informed consent as tools to control data use, and finally, new participatory governance schemes that allow individuals to control their data through direct involvement in data governance. We conclude by suggesting that, despite the impression that biomedical big data diminish individual control, the synergistic effect of new data management models can in fact improve it.

From Evidence to Action: Promoting a Multidimensional Approach to Mild Cognitive Impairment.

To the Editor: Mild cognitive impairment (MCI) is commonly indicated as an intermediate state between normal cognitive functioning and dementia, and represents the object of growing scientific and clinical interest.1 This entity was originally proposed for research purposes, in particular for allowing the detection of early pathophysiological modifications responsible for subsequent dementia. It has rapidly been acquiring clinical value and is today widely regarded as a specific nosographic entity (as also confirmed by the formulation of specific diagnostic criteria2). Nevertheless, despite robust supporting evidence, some key aspects of this construct are frequently neglected, thus resulting in a biased and unbalanced use of it. To date, particularly in neurology settings, MCI is largely considered as the manifestation of an incipient neurodegenerative process (ie, early stage of Alzheimer disease or another neurological disorder). Accordingly, major efforts have been devoted to the identification of clinical and biological factors predictive of its progression to dementia.3,4 Adopting a broader viewpoint, MCI may also represent the “cognitive” expression of concurrent and underlying pathological conditions not merely confined to the nervous system. Evidence clearly shows that nutritional deficiencies, affective disturbances, physical frailty, sleep disorders, and multiple medical conditions can directly or indirectly sustain an objective decline of cognitive performance.1,5 This means that MCI should be considered the manifestation of a global homeostatic disruption and, as such, approached using a broader, more flexible, and holistic assessment. Such framework may easily find support in the proven effectiveness of interventions apparently targeting specific domains of the health status (eg, physical activity, cardiovascular care, social engagement), but capable of exerting more systemic benefits to the individual, including to his or her cognitive function.1 Describing MCI as an age-related pathological condition6 implies the necessity of abandoning the traditional approach simply limiting it to a synonym of incipient neurodegeneration. The onset of cognitive impairment should be multidimensionally explored so as to identify underlying conditions explaining the cognitive disturbances and serve as targets for person-tailored preventive/ therapeutic interventions. The cognitive impairment sustained by non-neurodegenerative conditions may likely benefit from different interventions compared with the one determined by neurodegeneration.7 This means improving the personalization of care and promoting the design of more effective interventions. It is noteworthy that better differentiating the etiopathogenesis of the MCI will in parallel allow to potentially increase the effect size of the available specific treatments for individuals with clear neurodegenerative conditions. Substantial evidence shows that individuals with MCI present an increased risk of incident dementia. However, most affected individuals do not experience significant cognitive worsening over time (even over the long term).8 Moreover, a sizeable proportion of cases may revert back to normal cognition.9 The bidirectional modifications of MCI should induce a careful thinking about the risk of incorrect diagnosis of cognitive impairment in individuals with normal cognition and the often underestimated reversibility of MCI. The still too limited study of characteristics explaining the reversion from MCI to normal cognition may have important practical implications. Improved identification of individuals with a favorable cognitive trajectory will allow better allocation of health care resources and avoid misdiagnoses in individuals with MCI. It is noteworthy that by enlarging the target population from patients with dementia to individuals with MCI, research is surely going toward early phases of neurodegenerative diseases but is also exposed to the risk of a higher number of false-positive cases. In fact, the larger the population of interest, the more heterogeneous it will be. This means that clinical research in individuals with MCI may not necessarily facilitate the identification of clear pathophysiological mechanisms as the basis of the neurodegenerative conditions. This paradigm is valid only if a rigid and clear selection of individuals with MCI is made up front so as to limit the recruitment to those who will most likely develop dementia in the future. Finally, the ethical aspects of an MCI diagnosis should be always clearly present to clinicians because potentially affecting the psychological well-being of the patient and his or her proxies. In fact, an individual receiving an MCI diagnosis may easily incur in a number of potentially harmful consequences, such as discrimination, stigmatization, and overmedicalization.10 In conclusion, MCI should not be primarily/exclusively thought of as the prelude to unavoidable future dementia, but regarded as a condition presenting equal (if not higher) potential for being reversed to normality. MCI should be multidimensionally approached because it represents a heterogeneous risk factor, and not be considered as a disease. A more cautious and conservative approach will probably minimize the negative consequences of “labeling” an individual as affected by an undefined condition, and promote the personalization of care.

Open sharing of genomic data: Who does it and why?

We explored the characteristics and motivations of people who, having obtained their genetic or genomic data from Direct-To-Consumer genetic testing (DTC-GT) companies, voluntarily decide to share them on the publicly accessible web platform openSNP. The study is the first attempt to describe open data sharing activities undertaken by individuals without institutional oversight. In the paper we provide a detailed overview of the distribution of the demographic characteristics and motivations of people engaged in genetic or genomic open data sharing. The geographical distribution of the respondents showed the USA as dominant. There was no significant gender divide, the age distribution was broad, educational background varied and respondents with and without children were equally represented. Health, even though prominent, was not the respondents’ primary or only motivation to be tested. As to their motivations to openly share their data, 86.05% indicated wanting to learn about themselves as relevant, followed by contributing to the advancement of medical research (80.30%), improving the predictability of genetic testing (76.02%) and considering it fun to explore genotype and phenotype data (75.51%). Whereas most respondents were well aware of the privacy risks of their involvement in open genetic data sharing and considered the possibility of direct, personal repercussions troubling, they estimated the risk of this happening to be negligible. Our findings highlight the diversity of DTC-GT consumers who decide to openly share their data. Instead of focusing exclusively on health-related aspects of genetic testing and data sharing, our study emphasizes the importance of taking into account benefits and risks that stretch beyond the health spectrum. Our results thus lend further support to the call for a broader and multi-faceted conceptualization of genomic utility.

Issues about the use of subjective cognitive decline in Alzheimer's disease research

Recently, Jessen et al. [1] have described the conceptual framework for “subjective cognitive decline” (SCD) in Alzheimer’s disease (AD) research. SCD has been indicated as a possible risk factor for incident cognitive impairment and dementia [2], and pathophysiological commonalities have been reported between subjects with SCD and AD [3]. The hypothesis that SCD might represent a preliminary stage of the dementia cascade has already brought to the development of specific preventive trials targeting individuals with subjective cognitive complaints [4]. Nevertheless, to date, the study of SCD is hampered by the lack of a shared and agreed terminology. Thus, SCD has so far been differently defined, screened, and measured [5]. By proposing a new lexicon for SCD, Jessen et al. [1] address an important gap in the field. The authors proposed the core criteria for defining SCD and recommendations for its adoption as a preclinical model of AD in research. The article indeed poses itself as a possible cornerstone for future research in the field. However, we would like to point out some issues that we believe should have been better considered and discussed by the authors. The course of SCD over time is quite unstable (and often unpredictable), so that it can progress toward overt cognitive impairment and revert to a subjective experience of normal mental efficiency [6,7]. Interestingly, despite being commonly described, the reversion to normal cognition has also been frequently neglected in other predementia conditions, including mild cognitive impairment (MCI) [8]. Moreover, because all the assessment tools we use in clinics and research for objectively defining cognitive abnormalities present methodological and accuracy limitations, the risk of misclassification across these conditions is present and enhanced by the limited knowledge about them. The possible inversion of the SCD trajectory can be easily explained when the condition is sustained/influenced by temporary reversible clinical conditions (e.g., pain, depressive symptoms, fatigue). To operationalize the novel construct, Jessen et al. proposed to exclude any “psychiatric

Tailored-to-You: Public Engagement and the Political Legitimation of Precision Medicine

With the launch of the Precision Medicine Initiative (PMI) in January 2015, the White House granted a high degree of federal support to an emerging biomedical paradigm. What explains this level of political recognition? Based on literature and policy analysis, we reconstruct the scientific and the legislative paths that led to the political endorsement of precision medicine. First, we describe the proliferation of personalized approaches to therapy ignited by the discovery of hemoprotein cytochrome P450 polymorphism in 1988. Then, we analyze the legislative history of precision medicine, from the unsuccessful introduction of Genomics and Personalized Medicine Acts in the second half of the last decade, to the highly acclaimed PMI. However, scientific progress and political contingency alone do not explain the upheaval of precision medicine as an institutionally supported initiative. On examination, the launch of a Precision Medicine Research Cohort and the incorporation of a participatory ethos into the fabric of the PMI proved to be crucial determinants of the political support for precision medicine. Weaving together the scientific and legislative antecedents of precision medicine, we illuminate how the mutual constitution of science and social order generates political recognition for innovative biomedical paradigms.