Debra J. H. Mathews

The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities

Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.

Scientific and ethical issues related to deep brain stimulation for disorders of mood, behavior, and thought

CONTEXT A 2-day consensus conference was held to examine scientific and ethical issues in the application of deep brain stimulation for treating mood and behavioral disorders, such as major depression, obsessive-compulsive disorder, and Tourette syndrome. OBJECTIVES The primary objectives of the conference were to (1) establish consensus among participants about the design of future clinical trials of deep brain stimulation for disorders of mood, behavior, and thought and (2) develop standards for the protection of human subjects participating in such studies. RESULTS Conference participants identified 16 key points for guiding research in this growing field. CONCLUSIONS The adoption of the described guidelines would help to protect the safety and rights of research subjects who participate in clinical trials of deep brain stimulation for disorders of mood, behavior, and thought and have further potential to benefit other stakeholders in the research process, including clinical researchers and device manufactures. That said, the adoption of the guidelines will require broad and substantial commitment from many of these same stakeholders.

Medicine on the Fringe: Stem Cell-Based Interventions in Advance of Evidence

Stem cell‐based interventions (SCBIs) offer great promise; however, there is currently little internationally accepted, scientific evidence supporting the clinical use of SCBIs. The consensus within the scientific community is that a number of hurdles still need to be cleared. Despite this, SCBIs are currently being offered to patients. This article provides a content analysis of materials obtained from SCBI providers. We find content that strains credulity and almost no evidence of SCBIs being delivered in the context of clinical trials. We conclude that until scientific evidence is available, as a general rule, providers should only offer SCBIs in the context of controlled clinical trials. Clients should be aware that the risks and benefits of SCBIs are unknown, that their participation is unlikely to advance scientific knowledge, and they are likely to become ineligible to participate in future clinical trials of SCBIs. We recommend steps to promote patient education and enhance global oversight. STEM CELLS 2009;27:2312–2319

CELL-BASED INTERVENTIONS FOR NEUROLOGIC CONDITIONS: ETHICAL CHALLENGES FOR EARLY HUMAN TRIALS

Background: Attempts to translate basic stem cell research into treatments for neurologic diseases and injury are well under way. With a clinical trial for one such treatment approved and in progress in the United States, and additional proposals under review, we must begin to address the ethical issues raised by such early forays into human clinical trials for cell-based interventions for neurologic conditions. Methods: An interdisciplinary working group composed of experts in neuroscience, cell biology, bioethics, law, and transplantation, along with leading disease researchers, was convened twice over 2 years to identify and deliberate on the scientific and ethical issues raised by the transition from preclinical to clinical research of cell-based interventions for neurologic conditions. Results: While the relevant ethical issues are in many respects standard challenges of human subjects research, they are heightened in complexity by the novelty of the science, the focus on the CNS, and the political climate in which the science is proceeding. Conclusions: Distinctive challenges confronting US scientists, administrators, institutional review boards, stem cell research oversight committees, and others who will need to make decisions about work involving stem cells and their derivatives and evaluate the ethics of early human trials include evaluating the risks, safety, and benefits of these trials, determining and evaluating cell line provenance, and determining inclusion criteria, informed consent, and the ethics of conducting early human trials in the public spotlight. Further study and deliberation by stakeholders is required to move toward professional and institutional policies and practices governing this research.

Pluripotent Stem Cell-Derived Gametes: Truth and (Potential) Consequences

An emerging body of data suggests that pluripotent stem cells may be able to differentiate to form eggs and sperm. We discuss the state of the science and the potential social implications and offer recommendations for addressing some of the ethical and policy issues that would be raised by the availability of stem cell-derived gametes.

The role of animal models in evaluating reasonable safety and efficacy for human trials of cell-based interventions for neurologic conditions.

Progress in regenerative medicine seems likely to produce new treatments for neurologic conditions that use human cells as therapeutic agents; at least one trial for such an intervention is already under way. The development of cell-based interventions for neurologic conditions (CBI-NCs) will likely include preclinical studies using animals as models for humans with conditions of interest. This paper explores predictive validity challenges and the proper role for animal models in developing CBI-NCs. In spite of limitations, animal models are and will remain an essential tool for gathering data in advance of first-in-human clinical trials. The goal of this paper is to provide a realistic lens for viewing the role of animal models in the context of CBI-NCs and to provide recommendations for moving forward through this challenging terrain.

Geneticists' views on science policy formation and public outreach.

Though much research about the publics views of scientists, genetic research and its moral, ethical, and social implications exists, little has been done to investigate how scientists view their own role(s) in public discussions and policy formation related to genetic research and technologies. We interviewed 20 academic geneticists in the United States about their perceptions of the roles they and others (e.g., professional societies, the public, ethicists, and elected officials) do and should play in the formation of science policy, the communication of science to the public, and the public discussions of moral and ethical issues raised by scientific advances. The participants in our study thought that scientists should be more actively involved in public outreach and science policy formation, but frequently they felt ill‐equipped and unsupported by their peers and institutions to pursue these activities. Furthermore, many were skeptical of or did not trust elected officials—who they consider uninformed about the issues and too driven by political agendas—to formulate sound science policy. They do, however, have faith in the ability of scientific societies to influence policy effectively, and some thought that societies should play a larger role, both in science policy and as a liaison between scientists and the public. Finally, participants offered suggestions for increasing the involvement and influence of scientists in science‐policy formation and public discourse.

Access to Stem Cells and Data: Persons, Property Rights, and Scientific Progress

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Beyond consent in research. Revisiting vulnerability in deep brain stimulation for psychiatric disorders.

Vulnerability is an important criterion to assess the ethical justification of the inclusion of participants in research trials. Currently, vulnerability is often understood as an attribute inherent to a participant by nature of a diagnosed condition. Accordingly, a common ethical concern relates to the participants decisionmaking capacity and ability to provide free and informed consent. We propose an expanded view of vulnerability that moves beyond a focus on consent and the intrinsic attributes of participants. We offer specific suggestions for how relational aspects and the dynamic features of vulnerability could be more fully captured in current discussions and research practices.

Deep brain stimulation, personal identity and policy

A range of implantable brain-interfacing devices (IBIDs) is currently in use and development for the treatment of movement disorders and disorders of mood, behaviour and thought. These include cochlear implants, deep brain stimulation (DBS), prosthetic limbs, and optogenetic interventions (the combined use of genetics and optics to control individual cells). While implantable non-brain devices, such as implantable cardioverter defibrillators, began receiving US Food and Drug Administration approval in 1980, the development of IBIDs is recent, with the approval of DBS for Parkinsons disease in 1997. The expansion in use of IBIDs from neurological to psychiatric conditions is even more recent, with current trials underway for a range of disorders including depression, OCD, addiction, Alzheimers disease and Tourettes syndrome. Emerging applications of existing IBIDs and new devices in development differ from currently approved devices and applications in two potentially crucial ways: 1) They target conditions traditionally seen as psychiatric; and/or 2) They target and modify functions or traits tied closely to agency, personal identity and personhood. As such, understanding patients’ and caregivers’ conceptions of personal identity in the context of disease and treatment is important not only for the informed consent process, but also for questions of public policy.