Defining Biomarkers in Stem Cell-Derived Tissue Constructs for Drug and Disease Screening.

The development of stem cell-derived tissue constructs (SCTCs) for clinical applications, including regenerative medicine, drug and disease screening offers significant hope for detecting and treating intractable disorders. SCTCs display a variety of biomarkers that can be used to understand biological mechanisms, assess drug interactions, and predict disease. Although SCTCs can be derived from patients and share the same genetic make-up, they are nevertheless distinct from human patients in many significant ways, which can undermine the clinical significance of measurements in SCTCs. This study defines biomarkers, how they apply to SCTCs, and clarifies specific ethical issues associated with the use of SCTCs for drug and disease screening.

Definition of Implanted Neurological Device Abandonment: A Systematic Review and Consensus Statement.

Importance: Establishing a formal definition for neurological device abandonment has the potential to reduce or to prevent the occurrence of this abandonment. Objective: To perform a systematic review of the literature and develop an expert consensus definition for neurological device abandonment. Evidence Review: After a Royal Society Summit on Neural Interfaces (September 13-14, 2023), a systematic English language review using PubMed was undertaken to investigate extant definitions of neurological device abandonment. Articles were reviewed for relevance to neurological device abandonment in the setting of deep brain, vagal nerve, and spinal cord stimulation. This review was followed by the convening of an expert consensus group of physicians, scientists, ethicists, and stakeholders. The group summarized findings, added subject matter experience, and applied relevant ethics concepts to propose a current operational definition of neurological device abandonment. Data collection, study, and consensus development were done between September 13, 2023, and February 1, 2024. Findings: The PubMed search revealed 734 total articles, and after review, 7 articles were found to address neurological device abandonment. The expert consensus group addressed findings as germane to neurological device abandonment and added personal experience and additional relevant peer-reviewed articles, addressed stakeholders' respective responsibilities, and operationally defined abandonment in the context of implantable neurotechnological devices. The group further addressed whether clinical trial failure or shelving of devices would constitute or be associated with abandonment as defined. Referential to these domains and dimensions, the group proposed a standardized definition for abandonment of active implantable neurotechnological devices. Conclusions and Relevance: This study's consensus statement suggests that the definition for neurological device abandonment should entail failure to provide fundamental aspects of patient consent; fulfill reasonable responsibility for medical, technical, or financial support prior to the end of the device's labeled lifetime; and address any or all immediate needs that may result in safety concerns or device ineffectiveness and that the definition of abandonment associated with the failure of a research trial should be contingent on specific circumstances.

How I became myself after merging with a computer: Does human-machine symbiosis raise human rights issues?

Novel usages of brain stimulation combined with artificially intelligent (AI) systems promise to address a large range of diseases. These new conjoined technologies, such as brain-computer interfaces (BCI), are increasingly used in experimental and clinical settings to predict and alleviate symptoms of various neurological and psychiatric disorders. Due to their reliance on AI algorithms for feature extraction and classification, these BCI systems enable a novel, unprecedented, and direct connection between human cognition and artificial information processing. In this paper, we present the results of a study that investigates the phenomenology of human-machine symbiosis during a first-in-human experimental BCI trial designed to predict epileptic seizures. We employed qualitative semi-structured interviews to collect user experience data from a participant over a six-years period. We report on a clinical case where a specific embodied phenomenology emerged: namely, after BCI implantation, the patient reported experiences of increased agential capacity and continuity; and after device explantation, the patient reported persistent traumatic harms linked to agential discontinuity. To our knowledge, this is the first reported clinical case of a patient experiencing persistent agential discontinuity due to BCI explantation and potential evidence of an infringement on patient right, where the implanted person was robbed of her de novo agential capacities when the device was removed.

First Organoid Intelligence (OI) workshop to form an OI community.

The brain is arguably the most powerful computation system known. It is extremely efficient in processing large amounts of information and can discern signals from noise, adapt, and filter faulty information all while running on only 20 watts of power. The human brain's processing efficiency, progressive learning, and plasticity are unmatched by any computer system. Recent advances in stem cell technology have elevated the field of cell culture to higher levels of complexity, such as the development of three-dimensional (3D) brain organoids that recapitulate human brain functionality better than traditional monolayer cell systems. Organoid Intelligence (OI) aims to harness the innate biological capabilities of brain organoids for biocomputing and synthetic intelligence by interfacing them with computer technology. With the latest strides in stem cell technology, bioengineering, and machine learning, we can explore the ability of brain organoids to compute, and store given information (input), execute a task (output), and study how this affects the structural and functional connections in the organoids themselves. Furthermore, understanding how learning generates and changes patterns of connectivity in organoids can shed light on the early stages of cognition in the human brain. Investigating and understanding these concepts is an enormous, multidisciplinary endeavor that necessitates the engagement of both the scientific community and the public. Thus, on Feb 22-24 of 2022, the Johns Hopkins University held the first Organoid Intelligence Workshop to form an OI Community and to lay out the groundwork for the establishment of OI as a new scientific discipline. The potential of OI to revolutionize computing, neurological research, and drug development was discussed, along with a vision and roadmap for its development over the coming decade.

Ethical and regulatory issues of stem cell-derived 3-dimensional organoid and tissue therapy for personalised regenerative medicine.

BACKGROUND: Regenerative medicine has the potential to treat genetic disorders and replace damaged or missing tissue. The use of donor or animal tissue raises many well-known issues, including limited tissue availability, the possibility of rejection and patient infection. Stem cell therapy raised hope of overcoming these issues, but created new risks including tumour formation and limited benefit if the desired target tissue does not form. The recent development of 3-dimensional tissues, including organoids, allows the creation of more complex tissues for personalised regenerative medicine. METHODS: This article details the potential health risks of 3-dimensional organoid and tissue therapy versus dissociated stem cell therapy. The current ethical and regulatory issues surrounding 3-dimensional organoid and tissue therapy are presented with a focus on the highly influential FDA and International Society of Stem Cell Research (ISSCR) guidelines. CONCLUSIONS: The potential use of 3-dimensional organoid and tissue therapy may deliver greater patient benefits than other regenerative medicine approaches, but raises new health and ethical risks. Preclinical testing of these therapies will not mitigate some of their risks; they may only be understood after first-in-human trials. The potential irreversibility and high risk of these therapies affects how clinical trials should be structured, including post-trial care for participants.

Investigating the feasibility and ethical implications of phenotypic screening using stem cell-derived tissue models to detect and manage disease.

Stem-cell-derived tissue models generated from sick people are being used to understand human development and disease, drug development, and drug screening. However, it is possible to detect disease phenotypes before a patient displays symptoms, allowing for their use as a disease screening tool. This raises numerous issues, some of which can be addressed using similar approaches from genetic screenings, while others are unique. One issue is the relationship between disease disposition, biomarker detection, and patient symptoms and how tissue models could be used to define disease. Other issues include decisions of when to screen, what diseases to screen for, and what treatment options should be offered.

Restoring vision using optogenetics without being blind to the risks.

Retinit is pigmentosa is an incurable degenerative disease that causes loss of light-sensitive cells in the retina and leads to severe vision impairment. The development of optogenetics has created great hype around its potential to treat retinitis pigmentosa by the introduction of light-sensitive proteins into other neural cells in the retina. The first-in-human studies of optogenetic treatment for this disease have recently been reported (NCT02556736 and NCT03326336). The treatment involves irreversible gene therapy and requires access to specially designed goggles to deliver light to the treated eye. These highly innovative and high-profile clinical trials raise numerous ethical issues that must be addressed during the early phases of research and clinical testing to ensure trial participants are treated fairly and can provide appropriate informed consent.

Invasive experimental brain surgery for dementia: Ethical shifts in clinical research practices?

The increasing dementia prevalence worldwide is driving the testing of novel therapeutic approaches, such as invasive brain technologies, despite limited clinical evidence and the risk of accelerating cognitive decline. Our manuscript (a) reviews the NIH Clinicaltrials.gov database for deep brain stimulation, stem cell implantation, and gene therapy trials on people with dementia; (b) discusses issues on beneficence, nonmaleficence, and autonomy associated with these trials; and (c) proposes nine recommendations that build on elements from the Declaration of Helsinki. We found 49 preregistered high-risk trials from nine countries planning to or involving 11,801 people with Alzheimer's or Lewy body dementia or dementia secondary to Parkinson's or Huntington's disease. Most of the people with Alzheimer's who are in these trials are from North America and East Asia. There is substantial heterogeneity in the enrolment criteria, even for trials recruiting only those with Alzheimer's disease. Although most trials enrol people in mild to moderate stages of Alzheimer's disease, trials in China enrol people who have severe Alzheimer's. Our findings highlight a pressing need to review and refine the enrolment criteria for invasive neural trials in people with dementia, considering risks, potential benefits, and capacity for informed consent. As a multidisciplinary team from Australia, the USA, Canada, and Germany with expertise in neurology, neuroscience, and ethics, we examine how it is essential to balance the risks of invasive neural research in a vulnerable population with limited capacity to provide informed consent to help advance the body of knowledge regarding a disease with limited therapeutic options.

Ethical examination of deep brain stimulation's 'last resort' status.

Deep brain stimulation (DBS) interventions are novel devices being investigated for the management of severe treatment-resistant psychiatric illnesses. These interventions require the invasive implantation of high-frequency neurostimulatory probes intracranially aiming to provide symptom relief in treatment-resistant disorders including obsessive-compulsive disorder and anorexia nervosa. In the scientific literature, these neurostimulatory interventions are commonly described as reversible and to be used as a last resort option for psychiatric patients. However, the 'last resort' status of these interventions is rarely expanded upon. Contrastingly, usages of DBS devices for neurological symptoms (eg, Parkinson's disease, epilepsy or dystonia) have paved the way for established safety and efficacy standards when used earlier in a disease's timeline. As DBS treatments for these neurological diseases progress to have earlier indications, there is a parallel ethical concern that early implementation may one day become prescribed for psychiatric illnesses. The purpose of this article is to build off contemporary understandings of reversible neurostimulatory interventions to examine and provide clarifications on the 'last resort' status of DBS to better address its ethically charged use in psychiatric neurosurgery. To do this, evaluative differences between DBS treatments will be discussed to demonstrate how patient autonomy would be a paramount guiding principle when one day implementing these devices at various points along a psychiatric disease's timeline. In presenting the clarification of 'last resort' status, the ethical tensions of early DBS interventions will be better understood to assist in providing psychiatric patients with more quality of life years in line with their values.