The Jewish Perspectives on Xenotransplantation.

Xenotransplantation represents a viable solution to meet the great need to provide organ donors at a time when there are not enough human organ donors. A lot of clinical studies have focused on using genetically engineered pigs as the prime source for organ transplantation. However, several religions, such as Judaism and Islam, have restrictions on the use of pigs for food or in business. In this article, we review the Jewish perspectives on xenotransplantation. Overall, the preservation of human life trumps most of the potential religious concerns associated with xenotransplantation. However, there are religious nuances related to xenotransplantation that are highlighted here, and that must be addressed by rabbinical scholars.

CRISPR Technology: A Jewish Legal Perspective.

Clustered regularly interspaced short palindromic repeats (CRISPR) gene editing is an innovative and potentially game-changing biotechnology that can potentially reverse DNA mutations in a tissue-specific manner. In addition, CRISPR is being targeted for xenotransplantation, for increasing human longevity, in animal breeding, and in plant science. However, there are many ethical challenges that emerge from CRISPR technology. This article discusses several positions that relate to these ethical challenges from a Jewish legal perspective. In addition, we present several other applications of CRISPR technology that lack a defined Jewish legal precedent and require rabbinical scholars to address and resolve them in the future.

Will CRISPR Germline Engineering Close the Door to an Open Future?

The bioethical principle of autonomy is problematic regarding the future of the embryo who lacks the ability to self-advocate but will develop this defining human capacity in time. Recent experiments explore the use of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 for germline engineering in the embryo, which alters future generations. The embryo's inability to express an autonomous decision is an obvious bioethical challenge of germline engineering. The philosopher Joel Feinberg acknowledged that autonomy is developing in children. He advocated that to reserve this future autonomy, parents should be guided to make ethical decisions that provide children with open futures. Here, Feinberg's 1980 open future theory is extended to the human embryo in the context of CRISPR germline engineering. Although the embryo does not possess the autonomous decision-making capacity at the time of germline engineering, the parental decision to permanently change the unique genetic fabric of the embryo and subsequent generations disregards future autonomy. Therefore, germline engineering in many instances is objectionable considering Feinberg's open future theory.

Outer Limits of Biotechnologies: A Jewish Perspective.

A great deal of biomedical research focuses on new biotechnologies such as gene editing, stem cell biology, and reproductive medicine, which have created a scientific revolution. While the potential medical benefits of this research may be far-reaching, ethical issues related to non-medical applications of these technologies are demanding. We analyze, from a Jewish legal perspective, some of the ethical conundrums that society faces in pushing the outer limits in researching these new biotechnologies.

A Consensus Definitive Classification of Scavenger Receptors and Their Roles in Health and Disease.

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of nonself or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. This classification was discussed at three national meetings and input from participants at these meetings was requested. The following manuscript is a consensus statement that combines the recommendations of the initial workshop and incorporates the input received from the participants at the three national meetings.

Influence of pigments and protein aging on protein identification in historically representative casein-based paints using enzyme-linked immunosorbent assay.

A systematic study on the influence of pigments and sample aging on casein identification was performed on 30 reconstructed paints. The protein in all the paints was extracted into solution for analysis. The amount of protein that can be retrieved for solution-based analysis in each of the reconstructed paints was studied with a well-developed NanoOrange method before and after artificial aging. The results showed that in the paints with calcium phosphate (in bone black) and copper carbonate, hydroxide, or acetate (in verdigris and azurite), the amount of protein that can be retrieved for liquid-phase analysis is much smaller than the other paints, indicating that the protein degradation was accelerated significantly in those paints. Carbon (in vine black), calcium carbonate (in natural chalk), and calcium sulfate (terra alba gypsum and ground alabaster) did not affect much the amount of protein that can be retrieved in the paints compared to non-pigmented binder, meaning that the protein degradation rate was not affected much by those pigments. Artificial aging was observed to decrease the amount of retrievable protein in all the reconstructed paints that were studied. The enzyme-linked immunosorbent assay (ELISA) method was applied to the 28 reconstructed paints (except two verdigris paints) to assess the protein identification. The ELISA responses from the different paints were compared at fixed protein concentrations. Natural chalk, bone black, raw sienna, stack lead white, and cochineal red-violet lake had the lowest ELISA signal in this study, which indicated that the binding sites (epitopes) on the target protein in these paints are likely to deteriorate more than those in the other paints. Artificial aging did not influence the ELISA response as much as the pigments when the protein concentration was kept the same for the paints that were studied.

Mitochondrial Replacement Therapy: Halachic Considerations for Enrolling in an Experimental Clinical Trial.

The transition of new biotechnologies into clinical trials is a critical step in approving a new drug or therapy in health care. Ethically recruiting appropriate volunteers for these clinical trials can be a challenging task for both the pharmaceutical companies and the US Food and Drug Administration. In this paper we analyze the Jewish halachic perspectives of volunteering for clinical trials by focusing on an innovative technology in reproductive medicine, mitochondrial replacement therapy. The halachic perspective encourages individuals to volunteer for such clinical trials under the ethical principles of beneficence and social responsibility, when animal studies have shown that health risks are minimal.

The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis.

In contrast to microbially triggered inflammation, mechanisms promoting sterile inflammation remain poorly understood. Damage-associated molecular patterns (DAMPs) are considered key inducers of sterile inflammation following cell death, but the relative contribution of specific DAMPs, including high-mobility group box 1 (HMGB1), is ill defined. Due to the postnatal lethality of Hmgb1-knockout mice, the role of HMGB1 in sterile inflammation and disease processes in vivo remains controversial. Here, using conditional ablation strategies, we have demonstrated that epithelial, but not bone marrow-derived, HMGB1 is required for sterile inflammation following injury. Epithelial HMGB1, through its receptor RAGE, triggered recruitment of neutrophils, but not macrophages, toward necrosis. In clinically relevant models of necrosis, HMGB1/RAGE-induced neutrophil recruitment mediated subsequent amplification of injury, depending on the presence of neutrophil elastase. Notably, hepatocyte-specific HMGB1 ablation resulted in 100% survival following lethal acetaminophen intoxication. In contrast to necrosis, HMGB1 ablation did not alter inflammation or mortality in response to TNF- or FAS-mediated apoptosis. In LPS-induced shock, in which HMGB1 was considered a key mediator, HMGB1 ablation did not ameliorate inflammation or lethality, despite efficient reduction of HMGB1 serum levels. Our study establishes HMGB1 as a bona fide and targetable DAMP that selectively triggers a neutrophil-mediated injury amplification loop in the setting of necrosis.

Neuroinflammation in Parkinson's disease animal models: a cell stress response or a step in neurodegeneration?

The motor symptoms of Parkinson's disease are due to the progressive degeneration of dopaminergic neurons in the substantia nigra. Multiple neuroinflammatory processes are exacerbated in Parkinson's disease, including glial-mediated reactions, increased expression of proinflammatory substances, and lymphocytic infiltration, particularly in the substantia nigra. Neuroinflammation is also implicated in the neurodegeneration and consequent behavioral symptoms of many Parkinson's disease animal models, although it is not clear whether these features emulate pathogenic steps in the genuine disorder or if some inflammatory features provide protective stress responses. Here, we compare and summarize findings on neuroinflammatory responses and effects on behavior in a wide range of toxin-based, inflammatory and genetic Parkinson's disease animal models.

Neuronal MHC-I expression and its implications in synaptic function, axonal regeneration and Parkinson's and other brain diseases.

Neuronal expression of major histocompatibility complex I (MHC-I) has been implicated in developmental synaptic plasticity and axonal regeneration in the central nervous system (CNS), but recent findings demonstrate that constitutive neuronal MHC-I can also be involved in neurodegenerative diseases by playing a neuroinflammtory role. Recent reports demonstrate its expression in vitro and in human postmortem samples and support a role in neurodegeneration involving proinflammatory cytokines, activated microglia and increased cytosolic oxidative stress. Major histocompatibility complex I may be important for both normal development and pathogenesis of some CNS diseases including Parkinson's.

MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration.

Subsets of rodent neurons are reported to express major histocompatibility complex class I (MHC-I), but such expression has not been reported in normal adult human neurons. Here we provide evidence from immunolabel, RNA expression and mass spectrometry analysis of postmortem samples that human catecholaminergic substantia nigra and locus coeruleus neurons express MHC-I, and that this molecule is inducible in human stem cell-derived dopamine (DA) neurons. Catecholamine murine cultured neurons are more responsive to induction of MHC-I by gamma-interferon than other neuronal populations. Neuronal MHC-I is also induced by factors released from microglia activated by neuromelanin or alpha-synuclein, or high cytosolic DA and/or oxidative stress. DA neurons internalize foreign ovalbumin and display antigen derived from this protein by MHC-I, which triggers DA neuronal death in the presence of appropriate cytotoxic T cells. Thus, neuronal MHC-I can trigger antigenic response, and catecholamine neurons may be particularly susceptible to T-cell-mediated cytotoxic attack.

Standardizing scavenger receptor nomenclature.

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a variety of ligands, including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the U.S. National Institute of Allergy and Infectious Diseases, National Institutes of Health to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of non-self or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. The discussion and nomenclature recommendations described in this report only refer to mammalian scavenger receptors. The purpose of this article is to describe the proposed mammalian nomenclature and classification developed at the workshop and to solicit additional feedback from the broader research community.

Creating a three-parent child: an educational paradigm for the responsible conduct of research.

The field of assisted reproduction is renowned for its remarkable advances and constant pushing forward of research boundaries in an effort to offer innovative and effective methods for enhancing fertility. Accompanying these advances, however, are physiological, psychological, and bioethical consequences that must be considered. These concomitant advances and consequences make assisted reproduction an excellent educational paradigm for inculcating responsible conduct in both research and clinical practice. Ultimately, responsible conduct rests on the ethical researcher and clinician. Here, we present the as-yet unapproved, contentious assisted reproductive technology of mitochondrial replacement transfer (MRT) as an ideal educational platform to foster the responsible conduct of research by advancing dialogue among multi-disciplinary scholars, researchers, and students. Using a likely future case, we present the basic science, legal, and ethical considerations, and the pedagogical principles and strategies for using MRT as an effective educational paradigm. Society will benefit when the ethical issues inherent in creating children with three genetic parents as well as germline interference are discussed across multiple academic levels that include researchers, legal experts, bioethicists, and government-appointed commissions. Furthermore, undergraduate and graduate students should be included because they will likely determine the ethical fates of these biotechnologies. While emerging assisted reproduction technologies such as MRT are highly complex and will take years to be readily available for patients in need, now is the time to consider their scientific, legal, ethical, and cultural/religious implications for ensuring the responsible conduct of research.

Lessons learned from undergraduate students in designing a science-based course in bioethics.

Columbia University offers two innovative undergraduate science-based bioethics courses for student majoring in biosciences and pre-health studies. The goals of these courses are to introduce future scientists and healthcare professionals to the ethical questions they will confront in their professional lives, thus enabling them to strategically address these bioethical dilemmas. These courses incorporate innovative pedagogical methods, case studies, and class discussions to stimulate the students to think creatively about bioethical issues emerging from new biotechnologies. At the end of each course, each student is required to submit a one-page strategy detailing how he or she would resolve a bioethical dilemma. Based on our experience in teaching these courses and on a qualitative analysis of the students' reflections, we offer recommendations for creating an undergraduate science-based course in bioethics. General recommendations include: 1) integrating the science of emerging biotechnologies, their ethical ramifications, and contemporary bioethical theories into interactive class sessions; 2) structuring discussion-based classes to stimulate students to consider the impact of their moral intuitions when grappling with bioethical issues; and 3) using specific actual and futuristic case studies to highlight bioethical issues and to help develop creative problem-solving skills. Such a course sparks students' interests in both science and ethics and helps them analyze bioethical challenges arising from emerging biotechnologies.

Surface acoustic waves enhance neutrophil killing of bacteria.

Biofilms are structured communities of bacteria that play a major role in the pathogenicity of bacteria and are the leading cause of antibiotic resistant bacterial infections on indwelling catheters and medical prosthetic devices. Failure to resolve these biofilm infections may necessitate the surgical removal of the prosthetic device which can be debilitating and costly. Recent studies have shown that application of surface acoustic waves to catheter surfaces can reduce the incidence of infections by a mechanism that has not yet been clarified. We report here the effects of surface acoustic waves (SAW) on the capacity of human neutrophils to eradicate S. epidermidis bacteria in a planktonic state and within biofilms. Utilizing a novel fibrin gel system that mimics a tissue-like environment, we show that SAW, at an intensity of 0.3 mW/cm(2), significantly enhances human neutrophil killing of S. epidermidis in a planktonic state and within biofilms by enhancing human neutrophil chemotaxis in response to chemoattractants. In addition, we show that the integrin CD18 plays a significant role in the killing enhancement observed in applying SAW. We propose from out data that this integrin may serve as mechanoreceptor for surface acoustic waves enhancing neutrophil chemotaxis and killing of bacteria.