Transplantation of Human Brain Organoids: Revisiting the Science and Ethics of Brain Chimeras.

Recent demonstrations of human brain organoid transplantation in rodents have accentuated ethical concerns associated with these entities, especially as they relate to potential "humanization" of host animals. Consideration of established scientific principles can help define the realistic range of expected outcomes in such transplantation studies. This practical approach suggests that augmentation of discrete brain functions in transplant hosts is a more relevant ethical question in the near term than the possibility of "conscious" chimeric animals. We hope that this framework contributes to a balanced approach for proceeding with studies involving brain organoid transplantation and other forms of human-animal brain chimeras.

Surgical, ethical, and psychosocial considerations in human head transplantation.

Transplanting a head and brain is perhaps the final frontier of organ transplantation. The goal of body-to-head transplantation (BHT) is to sustain the life of individuals who suffer from terminal disease, but whose head and brain are healthy. Ideally BHT could provide a lifesaving treatment for several conditions where none currently exists. BHT is no ordinary experiment, to transfer a head to another body involves extraordinarily complex medical challenges as well as ethical and existential dilemmas that were previously confined to the imagination of writers of fiction. The possibility of replacing an incurably ill body with a healthy one tests not only our surgical limits, but also the social and psychological boundaries of physical life and alters what we recognize life to be. The purpose of this target article, the complementary manuscript focused on immunological issues in BHT, and the accompanying Commentaries by scholars and practitioners in medicine, immunology, and bioethics is to review major surgical and psychosocial-ethical and immunological considerations surrounding body-to-head transplantation. We hope that together these ideas will provide readers with a comprehensive overview of the possibilities and challenges associated with BHT and initiate professional discussion and debate through which this new frontier in medicine is considered and approached.

Unintended changes in cognition, mood, and behavior arising from cell-based interventions for neurological conditions: ethical challenges.

The prospect of using cell-based interventions (CBIs) to treat neurological conditions raises several important ethical and policy questions. In this target article, we focus on issues related to the unique constellation of traits that characterize CBIs targeted at the central nervous system. In particular, there is at least a theoretical prospect that these cells will alter the recipients' cognition, mood, and behavior-brain functions that are central to our concept of the self. The potential for such changes, although perhaps remote, is cause for concern and careful ethical analysis. Both to enable better informed consent in the future and as an end in itself, we argue that early human trials of CBIs for neurological conditions must monitor subjects for changes in cognition, mood, and behavior; further, we recommend concrete steps for that monitoring. Such steps will help better characterize the potential risks and benefits of CBIs as they are tested and potentially used for treatment.

The cellular repair of the brain in Parkinson's disease--past, present and future.

Damage to the central nervous system was once considered irreparable. However, there is now growing optimism that neural transplant therapies may one day enable complete circuit reconstruction and thus functional benefit for patients with neurodegenerative conditions such as Parkinson's disease (PD), and perhaps even those with more widespread damage such as stroke patients. Indeed, since the late 1980s hundreds of patients with Parkinson's disease have received allografts of dopamine-rich embryonic human neural tissue. The grafted tissue has been shown to survive and ameliorate many of the symptoms of the disease, both in the clinical setting and in animal models of the disease. However, practical problems associated with tissue procurement and storage, and ethical concerns over using aborted human fetal tissue have fuelled a search for alternative sources of suitable material for grafting. In particular, stem cells and xenogeneic embryonic dopamine-rich neural tissue are being explored, both of which bring their own practical and ethical dilemmas. Here we review the progress made in neural transplantation, both in the laboratory and in the clinic with particular attention to the development of stem cell and xenogeneic tissue based therapy.

Medical ethics in the neurosciences.

Doctors in India are heirs to a long tradition of ethics from their own forebears and from those from the West. This paper discusses ethical aspects of topics of relevance to neurological scientists such as brain death, neural transplant and whole brain transplant. Many other topics such as ethics in research, patients with AIDS, patients in a persistent vegetative state and euthanasia deserve similar consideration and debate.

Transplantation of human adult astrocytes: efficiency and safety requirements for an autologous gene therapy.

Ex vivo gene therapy is emerging as a promising approach for the treatment of neurodegenerative diseases and central nervous system (CNS) trauma. We have shown previously that human adult astrocytes can be expanded in vitro and can express various therapeutic transgenes (Ridet et al. [1999] Hum. Gene Ther. 10:271-280; Serguera et al. [ 2001] Mol. Ther. 3:875-881). Here, we grafted normal and lentivirally-modified human adult astrocytes into the striatum and spinal cord of nude mice to test whether they are suitable candidates for ex vivo CNS gene therapy. Transplanted cells survived for at least 2 months (longest time analyzed) and sustained transgene expression. Importantly, the absence of proliferating cell nuclear antigen (PCNA) staining, a hallmark of cell division, ascertains the safety of these cells. Thus, adult human astrocytes are a promising tool for human CNS repair; they may make autologous ex vivo gene transfer feasible, thereby avoiding the problems of immunological rejection and the side effects of immunosuppressors.

Clinical neurotransplantation: core assessment protocol rather than sham surgery as control.

Basic neurotransplantation research evoked clinical trials of restorative brain surgery. Parkinson's disease was the first and primary test bed for this putative new therapeutic method. Various centers performed the grafting surgery and the behavioral evaluations in different ways, and observed a varying degree of symptomatic relief. This led to a plea for double blind placebo-controlled clinical trials, which have since been performed and of which the first outcomes were recently published. In the present paper this approach of experimental neurotransplantation in brain diseases is discussed and rejected. Neural grafting in the central nervous system is irreversible and is therefore not suitable for experimental approaches originally designed for and best suited to drug studies. For Parkinson's disease in particular, the technique is far from optimized to perform large-scale studies at this stage. Moreover, previous negative results of adrenal medulla tissue implantation in the brain of patients make placebo effects rather unlikely. Moral arguments concerning the validity of the informed consent, therapeutic misconception, and the risk/benefit ratio can be added in the plea against this control surgery. Finally, a recommendation is made for study designs that apply a disease-dedicated core assessment protocol (CAP) that can evaluate the period from pre-operative to post-convalescent stages quantitatively, and therefore, unbiased. The strength of these CAPs is that they allow comparisons of different grafting techniques, of results between centers and of other types of interventions and invasive treatments such as deep brain stimulation. On ethical grounds, it is unacceptable not to use a study design that circumvents sham or imitation surgery. It is a challenge for the neuroscience community to develop CAPs for brain diseases that are eligible for neurotransplantation in the future.

Sham surgery controls: intracerebral grafting of fetal tissue for Parkinson's disease and proposed criteria for use of sham surgery controls.

Sham surgery is a controversial and rarely used component of randomised clinical trials evaluating surgical interventions. The recent use of sham surgery in trials evaluating efficacy of intracerebral fetal tissue grafts in Parkinson's disease has highlighted the ethical concerns associated with sham surgery controls. Macklin, and Dekkers and Boer argue vigorously against use of sham surgery controls. Macklin presents a broad argument against sham surgery controls while Dekkers and Boer present a narrower argument that sham surgery is unnecessary in the specific setting of fetal tissue engraftment for Parkinson's disease. I defend sham surgery controls against both these criticisms. Appropriate clinical trial design, sometimes including sham surgery, is needed to ensure that false positive trial results do not occur and endanger public safety. Results of a completed trial of fetal tissue grafting for Parkinson's disease are used to illustrate the potential benefits of, and problems associated with, sham surgery controls. Sham surgery controls, however, should be employed only when absolutely necessary. I suggest criteria for appropriate use of sham surgery controls.