Brain organoids, consciousness, ethics and moral status.

Advances in the field of human stem cells are often a source of public and ethical controversy. Researchers must frequently balance diverse societal perspectives on questions of morality with the pursuit of medical therapeutics and innovation. Recent developments in brain organoids make this challenge even more acute. Brain organoids are a new class of brain surrogate generated from human pluripotent stem cells (hPSCs). They have gained traction as a model for studying the intricacies of the human brain by using advancements in stem cell biology to recapitulate aspects of the developing human brain in vitro. However, recent observation of neural oscillations spontaneously emerging from these organoids raises the question of whether brain organoids are or could become conscious. At the same time, brain organoids offer a potentially unique opportunity to scientifically understand consciousness. To address these issues, experimental biologists, philosophers, and ethicists united to discuss the possibility of consciousness in human brain organoids and the consequent ethical and moral implications.

Setting ethical limits on human gene editing after the fall of the somatic/germline barrier.

The ethical debate about what is now called human gene editing (HGE) has gone on for more than 50 y. For nearly that entire time, there has been consensus that a moral divide exists between somatic and germline HGE. Conceptualizing this divide as a barrier on a slippery slope, in this paper, I first describe the slope, what makes it slippery, and describe strong barriers that arrest the slippage down to the dystopian bottom of pervasive eugenic enhancement. I then show how the somatic/germline barrier in the debate has been weakened to the level of ineffectiveness, with no replacement below. I examine a number of possible barriers on the slope below the somatic/germline barrier, most of which lack sufficient strength. With the exception of the minority of people in the HGE debate who see the eugenic society as utopia, the majority will need a barrier on the slope to stop the slide to dystopia.

Power and jurisdiction.

In response to Flamm and Kodish, I argue that our misunderstanding or disagreement is primarily the result of different definitions of power. I also disagree with them and claim that they are indeed using the public's ethics. Finally, I argue that there is no reason to think that bioethicists cannot have the same sort of influence in the boardroom that they have in the clinic.

Defending the jurisdiction of the clinical ethicist.

In this essay I suggest that the bioethics profession's jurisdiction over healthcare ethics consultation is in need of reinforcement. I argue that as the profession becomes more successful, competitors will challenge the profession to justify its ethical claims and ask whose ethics the profession represents. This challenge will come more quickly as the profession tries to influence the ethics of healthcare organizations. I propose a method of bolstering jurisdiction that will make the profession less vulnerable to challenge in the future.

Response to Callahan and Winslade.

I respond to commentaries by Daniel Callahan and William J. Winslade on my article, "Defending the Jurisdiction of the Clinical Ethicist," all of which are in this issue of JCE.

Scientism, trust, value alignment, views of nature, and U.S. public opinion about gene drive mosquitos.

Gene drive could be a powerful tool for addressing problems of conservation, agriculture, and human health caused by insect and animal pests but is likely to be controversial as it involves the release of genetically modified organisms. This study examined the social determinants of opinion of gene drive. We asked a representative sample of the U.S. public to respond to a description of a hypothetical application of a gene-drive mosquito to the problem of malaria and examined the relationship of these responses with demographic and ideological beliefs. We found strong general approval for the use of gene-drive mosquitos to address malaria, coinciding with the concern about a possible environmental impact of modified mosquitos and that gene drives represent "too much power over nature." Among the determinants we measured, respondent acceptance of scientism and trust that scientists are advancing the public's interest were the greatest predictors of views of gene drive.

Translational Bioethics and Public Input.

Translational science is justified as advancing the public's interests but has no mechanism for determining these interests. Standard social science approaches would produce either unrepresentative descriptions or a cacophony of data not easily condensed into a concrete conclusion about moving forward with a translational-science project. Here, I propose that the simplifying and structuring ethics employed by institutional review boards (IRBs) be used to create social science reports of the four to six most prominent values or principles of the public regarding a biotechnology. A board of bioethicists would weigh and balance these values to conclude whether the public supports a given translational-science innovation.

Patient narratives of hope in stem cell technologies: Trust in biomedicine and the body's natural ability to heal itself.

The scholarship on patient hope in biomedical technologies describes two narratives of hope: the biomedical and the individual. The biomedical narrative represents patients' beliefs that the institution of science will eventually produce treatment for their disease, whereas the individual narrative represents patients' beliefs that they can alter their prognosis through affective and behavioral modifications. The distinct analytical categories of "biomedical" and "individual," however, fail to account for the fact that patient hope has been found to be much more complex. Building upon extant literature, we contribute to the understanding of the complexity of patient hope in biomedical technologies by examining a case that highlights interdependencies between the biomedical and individual narratives: hope in stem cell technologies (SCTs). We draw upon interviews with patients with Parkinson's Disease, and find two narratives of hope: a biomedical narrative, as captured above, and an additional hybrid narrative, which we call a nature narrative. The nature narrative reflects patients' beliefs that scientists will eventually create SCTs that will allow their individual body to naturally heal itself, which combines a biomedical and an individual narrative.

Neurocheck Frequency: Determining Perceptions and Barriers to Implementation of Evidence-Based Practice.

BACKGROUND: Following acute brain injury, patients in the intensive care unit often undergo hourly or every-other-hour exams ("neurochecks") to monitor for neurodeterioration. We assessed health care provider attitudes towards neurocheck frequency and evaluated providers' ideal neurocheck frequency. METHODS: This was a cross-sectional, online survey distributed in Spring 2021 at a tertiary care academic medical center. Providers from multiple intensive care unit and neuroscience clinical specialties including attending faculty, medical trainees, advanced practice providers, and bedside nurses were invited to participate. RESULTS: Among 177 participants, 61 (34%) and 116 (66%) were self-identified as ordering and performing providers, respectively. The survey response rate was 58% among physicians and 51% among bedside nurses with neurological expertise. The most common medical and non-medical reasons for ordering hourly neurochecks were "a specific diagnosis with anticipated course" and "standard of care," respectively. Compared with ordering providers, performing providers felt guidelines regarding neurocheck frequency ( P <0.01) and duration ( P <0.01) should be proscriptive. Conversely, ordering providers felt hourly neurochecks were detrimental to patients with acute brain injury ( P =0.02) and believed they would not utilize hourly neurochecks if there was another mode of monitoring available ( P =0.03). Performing providers identified multiple patient-related factors impacting the difficulty of and their willingness to perform frequent neurochecks, and only 70% of neurochecks were perceived to be performed as ordered. Both ordering and performing providers preferred every-other-hour neurochecks following acute brain injury. CONCLUSIONS: This survey revealed clinically relevant differences in ordering versus performing provider attitudes about frequent neurochecks. Providers preferred every-other-hour rather than hourly neurochecks.

Saccharomyces cerevisiae strains used industrially for bioethanol production.

Fuel ethanol is produced by the yeast Saccharomyces cerevisiae mainly from corn starch in the United States and from sugarcane sucrose in Brazil, which together manufacture ∼85% of a global yearly production of 109.8 million m3 (in 2019). While in North America genetically engineered (GE) strains account for ∼80% of the ethanol produced, including strains that express amylases and are engineered to produce higher ethanol yields; in South America, mostly (>90%) non-GE strains are used in ethanol production, primarily as starters in non-aseptic fermentation systems with cell recycling. In spite of intensive research exploring lignocellulosic ethanol (or second generation ethanol), this option still accounts for <1% of global ethanol production. In this mini-review, we describe the main aspects of fuel ethanol production, emphasizing bioprocesses operating in North America and Brazil. We list and describe the main properties of several commercial yeast products (i.e., yeast strains) that are available worldwide to bioethanol producers, including GE strains with their respective genetic modifications. We also discuss recent studies that have started to shed light on the genes and traits that are important for the persistence and dominance of yeast strains in the non-aseptic process in Brazil. While Brazilian bioethanol yeast strains originated from a historical process of domestication for sugarcane fermentation, leading to a unique group with significant economic applications, in U.S.A., guided selection, breeding and genetic engineering approaches have driven the generation of new yeast products for the market.

Evidence that opioids may have toll-like receptor 4 and MD-2 effects.

Opioid-induced proinflammatory glial activation modulates wide-ranging aspects of opioid pharmacology including: opposition of acute and chronic opioid analgesia, opioid analgesic tolerance, opioid-induced hyperalgesia, development of opioid dependence, opioid reward, and opioid respiratory depression. However, the mechanism(s) contributing to opioid-induced proinflammatory actions remains unresolved. The potential involvement of toll-like receptor 4 (TLR4) was examined using in vitro, in vivo, and in silico techniques. Morphine non-stereoselectively induced TLR4 signaling in vitro, blocked by a classical TLR4 antagonist and non-stereoselectively by naloxone. Pharmacological blockade of TLR4 signaling in vivo potentiated acute intrathecal morphine analgesia, attenuated development of analgesic tolerance, hyperalgesia, and opioid withdrawal behaviors. TLR4 opposition to opioid actions was supported by morphine treatment of TLR4 knockout mice, which revealed a significant threefold leftward shift in the analgesia dose response function, versus wildtype mice. A range of structurally diverse clinically-employed opioid analgesics was found to be capable of activating TLR4 signaling in vitro. Selectivity in the response was identified since morphine-3-glucuronide, a morphine metabolite with no opioid receptor activity, displayed significant TLR4 activity, whilst the opioid receptor active metabolite, morphine-6-glucuronide, was devoid of such properties. In silico docking simulations revealed ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. An in silico to in vitro prediction model was built and tested with substantial accuracy. These data provide evidence that select opioids may non-stereoselectively influence TLR4 signaling and have behavioral consequences resulting, in part, via TLR4 signaling.

Self-Interested and Altruistic Motivations in Volunteering for Clinical Trials: A More Complex Relationship.

Empirical studies have found that altruism and self-interest are the two primary motivations for enrollment in clinical trials. Some studies have shown that in some cases these two motivations are contingent upon each other, which complicates our understanding of motivation. In this study, we interviewed 27 people with Parkinson's disease about their willingness to enroll in a hypothetical clinical trial. Through inductive, grounded theory analysis of the interview transcripts, we find four different contingent relationships between altruism and self-interest. It is important for ethicists to be aware of these more complex motivations because some are ethically problematic and others not. Moreover, practitioners need to be aware of these contingent relationships so that they can understand the motivations of the research participants.

Reactions to the National Academies/Royal Society Report on Heritable Human Genome Editing.

In September 2020, a detailed report on Heritable Human Genome Editing was published. The report offers a translational pathway for the limited approval of germline editing under limited circumstances and assuming various criteria have been met. In this perspective, some three dozen experts from the fields of genome editing, medicine, bioethics, law, and related fields offer their candid reactions to the National Academies/Royal Society report, highlighting areas of support, omissions, disagreements, and priorities moving forward.

The contribution of spatial cues to memory: direction, but not cue, changes support response reversal learning.

In four experiments, rats were trained on a response problem followed by three reversals. Rats that changed rooms between acquisition and reversals learned the reversals in fewer trials than rats that remained in the same room, even when distal visual cues were limited. Changes in orientation, even in the same room, also facilitated response reversal learning. The advantage observed with changes in orientation across reversals does not appear to be due to differences in local views or to different start positions. Direction changes, but not cue changes, may support response reversal learning by taking advantage of the natural interaction between responses and direction when one map is used.

Specific translocation of protein kinase Calpha to the plasma membrane requires both Ca2+ and PIP2 recognition by its C2 domain.

The C2 domain of protein kinase Calpha (PKCalpha) controls the translocation of this kinase from the cytoplasm to the plasma membrane during cytoplasmic Ca2+ signals. The present study uses intracellular coimaging of fluorescent fusion proteins and an in vitro FRET membrane-binding assay to further investigate the nature of this translocation. We find that Ca2+-activated PKCalpha and its isolated C2 domain localize exclusively to the plasma membrane in vivo and that a plasma membrane lipid, phosphatidylinositol-4,5-bisphosphate (PIP2), dramatically enhances the Ca2+-triggered binding of the C2 domain to membranes in vitro. Similarly, a hybrid construct substituting the PKCalpha Ca2+-binding loops (CBLs) and PIP2 binding site (beta-strands 3-4) into a different C2 domain exhibits native Ca2+-triggered targeting to plasma membrane and recognizes PIP2. Conversely, a hybrid containing the CBLs but lacking the PIP2 site translocates primarily to trans-Golgi network (TGN) and fails to recognize PIP2. Similarly, PKCalpha C2 domains possessing mutations in the PIP2 site target primarily to TGN and fail to recognize PIP2. Overall, these findings demonstrate that the CBLs are essential for Ca2+-triggered membrane binding but are not sufficient for specific plasma membrane targeting. Instead, targeting specificity is provided by basic residues on beta-strands 3-4, which bind to plasma membrane PIP2.

Mechanical Function of the Nucleus Pulposus of the Intervertebral Disc Under High Rates of Loading.

STUDY DESIGN: Bovine motion segments were used to investigate the high-rate compression response of intervertebral discs (IVD) before and after depressurising the nucleus pulposus (NP) by drilling a hole through the cranial endplate into it. OBJECTIVE: To investigate the effect of depressurising the NP on the force-displacement response, and the energy absorption in IVDs when compressed at high strain rates. SUMMARY OF BACKGROUND DATA: The mechanical function of the gelatinous NP located in the center of the IVDs of the spine is unclear. Removal of the NP has been shown to affect the direction of bulge of the inner anulus fibrosus (AF), but at low loading rates removal of the NP pressure does not affect the IVD's stiffness. During sports or injurious events, IVDs are commonly exposed to high loading rates, however, no studies have investigated the mechanical function of the NP at these rates. METHODS: Eight bovine motion segments were used to quantify the change in pressure caused by a hole drilled through the cranial endplate into the NP, and eight segments were used to investigate the high-rate response before and after a hole was drilled into the NP. RESULTS: The hole caused a 28.5% drop in the NP pressure. No statistically significant difference was seen in peak force, peak displacement, or energy-absorption of the intact, and depressurized NP groups under impact loading. The IVDs absorbed 72% of the input energy, and there was no rate dependency in the percentage energy absorbed. CONCLUSION: These results demonstrate that the NP pressure does not affect the transfer of load through, or energy absorbed by, the IVD at high loading rates and the AF, rather than the NP, may play the most important role in transferring load, and absorbing energy at these rates. This should be considered when attempting surgically to restore IVD function. LEVEL OF EVIDENCE: N/A.