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2 The Science of Human Neural Organoids, Transplants, and Chimeras
Pages 19-44

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From page 19...
... First, the brain is by far the most complex of human organs, with nearly 100 billion neurons (plus an even larger number of glial cells) comprising thousands of distinct types, interconnected in complex circuits, with some neurons making or receiving thousands of synaptic connections (see Box 2-1)
From page 20...
... The spinal cord receives inputs from the sensory division of the peripheral nervous system and sends commands to muscles and viscera through the motor and autonomic divisions. In simple cases, such as the knee-jerk reflex or withdrawal from intense heat, it mediates the entire transaction, but for more complex computations, including all conscious sensation and willed movement, it must exchange messages with the brain.
From page 21...
... . These and other differences limit the value of model organisms for research aimed at understanding the human brain, and are likely to account at least in part for the frequent failure of potential therapies developed in current animal neurological disease models to translate effectively to humans (King, 2018; Sierksma et al., 2020)
From page 22...
... or obtained postmortem. Slices of such ex vivo brain tissue have been used for analyses of neural activity and molecular composition of defined regions and cell types but are severely limited in quality and quantity.
From page 23...
... As discussed in Chapter 1, three sets of model systems have been developed that allow scientists to analyze human neural cells in powerful new ways: neural organoids, neural cell transplants, and neural chimeras. In this report we refer to these three systems according to the following definitions: • Neural organoids are three-dimensional cultures derived from pluripotent stem cells that have been treated in ways that lead them to generate neu rons and glia (see Figure 1-1 in Chapter 1)
From page 24...
... Transplanted glia can also interact with host cells. Cells in neural cell transplants vary in where and how they interact with the recipient's brain, but they seldom if ever contribute to other host tissues or organs.
From page 25...
... IMAGE SOURCE: Maria Diaz de la Loza, Ph.D. The distinction between a neural cell transplant and a neural chimera rests largely on whether the introduced cells remain limited to the nervous system or contribute substantially to other organs.
From page 26...
... Ethical and moral issues are discussed in Chapter 3, and regulatory and oversight mechanisms in Chapter 4. HUMAN NEURAL ORGANOIDS Organoids are three-dimensional cell cultures in which multiple cell types are arranged in patterns that recapitulate some features of the corresponding organ in vivo.
From page 27...
... Both ESCs and iPSCs can be maintained and expanded in culture, and treated to differentiate into neural progenitor cells. The progenitors can be induced to differentiate into specific neural cell types in monolayer cultures or organoids (see Figure 1-1)
From page 28...
... and to recapitulate key features of brain development, such as neurogenesis from progenitor zones, patterns of gene activity, migration of specific cell types, aspects of neural circuitry, and generation of spontaneous and induced electrical activity (Le Bail et al., 2020; Pasca, 2018; Quadrato et al., 2017)
From page 29...
... For example, while major cell classes are represented, neural organoids do not display the full diversity of individual cell types found in the brain, nor do they exhibit patterns of organization, lamination, and precise connectivity observed in vivo (Bhaduri et al., 2020; Velasco et al., 2020)
From page 30...
... Vessels are generated from nonneural cells, so they are not present in organoids formed from neural stem cells. Researchers are working to integrate synthetic vasculature into the three-dimensional matrix used for organoid formation (Karzbrun and Reiner, 2019)
From page 31...
... . HUMAN NEURAL TRANSPLANTS There is a long history of transplanting neural progenitors from one animal into the brain of another.
From page 32...
... One possible explanation is that the human astrocytes were better able than their mouse counterparts to support the neuronal functions responsible for the behaviors. HUMAN NEURAL CHIMERAS Transplants vary markedly in the number and type of human neural cells introduced and the stage at which they are introduced into the nonhuman host.
From page 33...
... One major impediment is that maturation times of human and mouse neurons are roughly proportional to the gestation times of the species, which differ by more than 10-fold, and the temporal mismatch persists when human neural cells are transplanted into mouse brain (Linaro et al., 2019; Masaki and Nakauchi, 2017; Rayon et al., 2020)
From page 34...
... For neural transplants and chimeras, synaptic connections with the host imply that the introduced neurons could respond to sensory inputs, influence motor outputs, and participate in sophisticated computations. As discussed in Chapter 3, some ethical concerns about human neural organoids, transplants, and chimeras require further scientific knowledge to address, and some do not.
From page 35...
... This situation may change as the circuitry required to experience pain becomes better understood, but at present neuroscientists would not be able to recognize neural circuits that confer the potential for pain in an organoid even if they existed. Thus, two related but logically distinct concerns about pain in human neural transplants, chimeras, and organoids might be raised: that the entity actually experiences pain, and that the entity has the capacity to experience pain (or the potential to develop that capacity)
From page 36...
... The adoption of a working definition of consciousness is necessary for specifying ethical issues involved in research with human neural organoids, transplants, and chimeric animals. Once specified, ethical judgments could be critically informed by knowledge of underlying neural mechanisms.
From page 37...
... Higher levels of subjective experience are almost always studied in human subjects, who are able to report their experiences verbally. That does not mean, however, that consciousness is confined to humans.
From page 38...
... sibilities of conscious experience in human neural organoids, transplants, and chimeras. Research in this area has proceeded on two fronts.
From page 39...
... presents subliminal stimuli to subjects and asks which brain regions are activated by those that make the subject consciously aware of a stimulus that would otherwise not reach consciousness. The other front for neurobiological research involves determining which brain regions house the highest levels of consciousness.
From page 40...
... Likewise, transplants of human neural cells into nonhuman animals currently involve far too few cells to generate any capacity approaching consciousness. Chimeras, in contrast, raise distinct issues, which are considered in Chapter 3.
From page 41...
... For other measures of complexity, however, some metrics exist. Human Neural Organoids At present, neural organoids lack complex and precise circuitry, are missing critical diversity among cell types, and do not include more than very limited representations of the multiple brain regions and long-range circuitry thought to underlie consciousness (Alves et al., 2019; Zirui et al., 2020)
From page 42...
... , can be used to assess gene expression of many thousands of single cells per organoid. These methods are increasingly being applied to postmortem samples of developing and adult human brains, making it possible to compare gene expression patterns in organoids with those in vivo.
From page 43...
... They come closer than traditional methods to harmonizing the scales of behavioral and physiological measures, and therefore improve the ability to assess possible consequences of augmenting nonhuman brains with human neurons. Researchers have also developed behavioral metrics for other types of awareness or emotional capabilities that range from whether nonhuman animals feel pain (e.g., learned avoidance of painful stimuli)


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