The Donation of Human Biological Material for Brain Organoid Research: The Problems of Consciousness and Consent.

Human brain organoids are three-dimensional masses of tissues derived from human stem cells that partially recapitulate the characteristics of the human brain. They have promising applications in many fields, from basic research to applied medicine. However, ethical concerns have been raised regarding the use of human brain organoids. These concerns primarily relate to the possibility that brain organoids may become conscious in the future. This possibility is associated with uncertainties about whether and in what sense brain organoids could have consciousness and what the moral significance of that would be. These uncertainties raise further concerns regarding consent from stem cell donors who may not be sufficiently informed to provide valid consent to the use of their donated cells in human brain organoid research. Furthermore, the possibility of harm to the brain organoids raises question about the scope of the donor's autonomy in consenting to research involving these entities. Donor consent does not establish the reasonableness of the risk and harms to the organoids, which ethical oversight must ensure by establishing some measures to mitigate them. To address these concerns, we provide three proposals for the consent procedure for human brain organoid research. First, it is vital to obtain project-specific consent rather than broad consent. Second, donors should be assured that appropriate measures will be taken to protect human brain organoids during research. Lastly, these assurances should be fulfilled through the implementation of precautionary measures. These proposals aim to enhance the ethical framework surrounding human brain organoid research.

The Ethics of Human Brain Organoid Transplantation in Animals.

In this paper, we outline how one might conduct a comprehensive ethical evaluation of human brain organoid transplantation in animals. Thus far, ethical concerns regarding this type of research have been assumed to be similar to those associated with other transplants of human cells in animals, and have therefore not received significant attention. The focus has been only on the welfare, moral status, or mental capacities of the host animal. However, the transplantation of human brain organoids introduces several new ethical issues. Many of these are related to uncertainty regarding whether or not brain organoids might be conscious. While these concerns might not be immediately relevant, they warrant closer scrutiny. We discuss how various ethical issues are relevant to different stages of human brain organoid transplantation and can guide the ethical evaluation of research. Our examination would broaden the horizons of the debate on the transplantation of brain organoids.

The legal personhood of human brain organoids.

Research using three-dimensional neural tissues derived from human pluripotent stem cells-known as 'human brain organoids'-has progressed rapidly in recent years. Although related ethical issues have been intensively discussed, legal issues have only been sparsely examined compared with the related ethical issues. In this paper, we explore a fundamental issue concerning the legal status of human brain organoids: whether they can be considered legal persons. We clearly distinguish between two types of legal personhood: 'natural person' as a human legal person and 'juridical person' as a nonhuman legal person. By examining natural and juridical personhood separately, we point out the bias and confusion in the remarks on the legal personhood of human brain organoids and provide a more comprehensive picture of the problem.

The importance of accurate representation of human brain organoid research.

Representations of brain organoids in the media are often negatively or positively exaggerated without appropriate discussion. Here, we examine two topics (the possibility of consciousness and medical applications) and call on scientists, ethicists, and the media to represent brain organoid research and its ethical issues more accurately.

Peptide-nucleic acids (PNAs) with pyrimido[4,5-d]pyrimidine-2,4,5,7-(1H,3H,6H,8H)-tetraone (PPT) as a universal base: their synthesis and binding affinity for oligodeoxyribonucleotides.

Peptide-nucleic acids (PNAs) including pyrimido[4,5-d]pyrimidine-2,4,5,7-(1H,3H,6H,8H)-tetraone (PPT) as a nucleobase were synthesized, and their binding affinity for the complementary oligodeoxyribonucleotides was investigated. We found that PNAs with one or two PPT(s) and natural nucleobases (i.e., adenine, cytosine, guanine, or thymine) have excellent binding affinity for oligodeoxyribonucleotides with complementary bases at the positions facing the natural nucleobases, and with adenine, cytosine, guanine, and thymine at the positions opposite PPT in PNAs. The binding affinity of the PPT-containing PNA is higher than or comparable to that of a PNA consisting of all complementary natural nucleobases, viz. a PNA with a suitable natural nucleobase in place of PPT in the PPT-containing PNA. Consequently, it was concluded that PPT serves as a useful universal base that can recognize all natural nucleobases.

Binding affinity of a peptide nucleic acid containing pyrimido[4,5-d]pyrimidine-2,4,5,7-(1H,3H,6H,8H)-tetraone as a nucleobase for oligonucleotides.

In order to examine the potentiality as a universal nucleobase of pyrimido[4,5-d]pyrimidine-2,4,5,7-(1H,3H,6H,8H)-tetraone (PPT) incorporated in a peptide-nucleic acid (PNA), we synthesized a PNA with PPT, that is H-Gly-CCT(PPT)TCC-Lys-NH2, and investigated the duplex-formation ability of this PNA for the oligodeoxyribonucleotide, (5')GGAXAGG(3') (X = A, G, C or T) on the basis of the Tmvalue of a 1:1 mixture of the PNA and the oligonucleotide. As a result, we found that H-Gly-CCT(PPT)TCC-Lys-NH2 has good binding affinity for all the tested oligonucleotides, i.e., (5')GGAAAGG(3'), (5')GGAGAGG(3'), (5')GGACAGG(3') and (5')GGATAGG(3') and forms stable duplexes with these nucleotides. Thus, it was revealed that PPT serves as an excellent universal base in PNA to discriminate all natural nucleobases.

The evaluation of whole-body plethysmography as a semiautomated method for analysis of emesis in the house musk shrew (Suncus murinus).

We analyzed the cisplatin-induced emetic responses of Suncus murinus by observation of both videorecorded behavior and changes in peak expiratory flow (PEF) as monitored by whole-body plethysmography. Analysis of the PEF data by use of a macro program revealed emesis-related changes in PEF. Cisplatin dose-response curves obtained by both methods showed similar emesis profiles. In addition, our PEF-based analytical method could be used to assess emesis changes induced by various other emetogens (veratrine hydrochloride, nicotine bitartrate, and copper sulfate) and confirmed the efficacy of the antiemetic drugs ondansetron, metoclopramide, and GR205171 in the cisplatin-induced emesis model. These results demonstrate that the use of whole-body plethysmography to follow changes in PEF was an effective semiautomated method of assessing emetic responses in Suncus murinus. This novel semiautomated method may provide an objective, sensitive, and efficient way to study emesis in animal models.

A ribonucleoside with pyrimido[4,5-d]pyrimidine-2,4,5,7-(1H,3H,6H,8H)-tetraone as a nucleobase, which universally binds to natural nucleosides.

A ribonucleoside with pyrimido[4,5-d]pyrimidine-2,4,5,7-(1H,3H,6H,8H)-tetraone, which is expected to serve as a universal base, was synthesized and binding affinity of this artificial nucleoside to natural nucleosides was investigated by UV analysis. As the result, it was revealed that the artificial derivative universally forms a base pair with four kinds of natural deoxyribonucleosides.

Synthesis of a peptide nucleic acid oligomer with pyrimido[4,5-d]pyrimidine-2,4,5,7-(1H,3H,6H,8H)-tetraone as a nucleobase.

A peptide nucleic acid (PNA) oligomer containing pyrimido[4,5-d]pyrimidine-2,4,5,7-(1H,3H,6H,8H)-tetraone (PPT) as a nucleobase, which is expected to serve as a universal base, was synthesized.

Pyrimido[4,5-d]pyrimidine-2,4,5,7-(1H, 3H, 6H, 8H)-tetraone as a novel universal base.

A derivative of pyrimido[4,5-d]pyrimidine-2,4,5,7-(1H,3H,6H,8H)-tetraone (PPT), which may form various keto-enol tautomers suitable for forming base pairs with all natural bases, and is thus expected to serve as a universal base, was synthesized. The ability of PPT to form base pairs with natural bases was evaluated by UV analysis.

Internucleotide-linkage formation via the phosphoramidite method using a carboxylic acid as a promoter.

This paper describes utility of a carboxylic acid, such as 2,4-dinitrobenzoic acid, as a promoter for internucleotide-linkage formation via the phosphoramidite method.

Effect of heparinoid on the production of tissue inhibitor of metalloproteinases (TIMP)-3 in rheumatoid synovial fibroblasts.

Heparinoid is one of the major contents of Mobilat widely used as an antirheumatic drug. To clarify the precise mechanisms of the antirheumatic effect of heparinoid, we investigated its effects on the production of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) from rheumatoid synovial fibroblasts stimulated (or not) with interleukin-1 alpha (IL-1alpha) at 100 units mL(-1). The expression of TIMP-3 mRNA was also investigated in a similar manner. The production of both MMPs and TIMPs and the expression of TIMP-3 mRNA were investigated by western-blot analysis and northern-blot hybridization, respectively. Under the stimulation of IL-1alpha, heparinoid increased the production of TIMP-3 in a concentration-dependent manner, but not TIMP-1, TIMP-2, MMP-1 or MMP-3. Heparinoid did not affect the expression of TIMP-3 mRNA that was increased by the stimulation of IL-1alpha. These findings suggest that the anti-rheumatoid effect of heparinoid may be due to increased production of TIMP-3. This increase in TIMP-3 may help redress the imbalance between the amounts of MMPs and TIMPs as observed in the joint tissues of rheumatoid arthritis and osteoarthritis patients.

Utility of Porous Glass with a new long-chain alkylamine spacer arm as a solid support for synthesis of oligodeoxyribonucleotides via the phosphoramidite method.

Porous Glass with an [[N-(2-aminoethyl)aminomethyl]phenyl]ethylsilyl spacer arm serving as a useful solid support in the synthesis of oligodeoxyribonucleotides via the phosphoramidite strategy.