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The current lack of organisation in the physical distribution of relevant genes, especially within neural organoids, limits the use of organoids in a clinical setting.
More accurately patterned brain organisation is needed for use in accurate disease diagnoses.

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On the other hand, in a study conducted by Sloane et al. 2017 where astrocytes taken from the brain, showed an accurate transformation from fetal to early postnatal development. After this period the rate of phagocytosis steadily declined, however.

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bop

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OUR PROCESS

FIRST IDEAS: ideal anatomy/physiology for living in space, ideal anatomy/physiology for a predator, organoids

NARROWING IT DOWN: organoids were our main interest since they combined most of the concepts we wanted to investigate.

WHY BRAIN ORGANOIDS:

OUR TEAMWORK:

- prioritizing other coursework, but consistently met to discuss new ideas and offer suggestions
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Now, there is a far reaching and relatively accepted theory of consciousness, called the Integrated Information Theory of Consciousness (IIT).

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However, this falls short when considering machine learning and AI, whereby software and machinery can reach higher intellect than humans without having a consciousness (of course, presumably, though this may change in the future and is a main point of contention amongst scientists and philosophers, and essentially all of mankind).

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Moral significance of consciousness is also highly relevant, since the meaning of consciousness is debated.

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This aims to make it possible to transplant organs while overcoming problems of scarcity, compatibility, and rejection.

Though incredible, it is also a central debate topic for cerebral organoids specifically.

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- living beings aren’t destroyed/impaired
- scientific reliability may be higher than model organism
- may be a more acceptable way to test hypotheses and carry out brain research, when compared to human fetuses, animals, or even voluntary adults
- may very well be cheaper than certain large scale trials

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Some schools of thought argue that intelligence is the key aspect of ‘humanity’, ie. the individual’s functional capacity of the subject in performing tasks.

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Epistemologically, some experts argue that the logic used for comatose patients should be applied to organoids.
However, this is highly diminutive, and many argue that there needs to be a developed, objective index of brain-based consciousness that doesn't rely on motor outputs, sensory processing, or executive functions.

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Potential Benefits, Dangers & Additional Dilemmas 

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Potential Benefits, Dangers & Additional Dilemmas 

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Ethical Considerations of Brain Organoids

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Ethical Considerations of Brain Organoids

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OVERVIEW OF CONSIDERATIONS:

Defining Consciousness & its Importance

Machines vs. Organoids

The Holy Grail of Medical Science

Potential Dangers & Additional Dilemmas

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Human cerebral organoids and the various brain regions marked by genetic markers.

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Anatomy of the inside of the brain, showing the pineal and pituitary glands, optic nerve, ventricles (with cerebrospinal fluid shown in blue), and other parts of the brain.

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Organoids self organise during development through 'cell sorting' and 'spatially restricted lineage commitment'.

At different periods of time, different types and volumes of cells develop e.g primarily neurons are generated during early development, versus glial cells during later stages [3].

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https://www.youtube.com/watch?v=9ksLuRoEq6A&ab_channel=NewScientist

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Human brain cells in a dish learn to play Pong

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Summary for cellular composition and tissue type in brain organoid

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would you beat a brain organoid at pong?

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would you beat a brain organoid at pong?

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Consisting of around 800,000 neurons, a group of researchers managed to make a cerebral organoid capable of playing Pong! [1]

Using electrodes, the electrical signals and subsequent cellular changes were converted into a visual representation, shown in the video linked.

It's a long way away from the 80-100 billion neurons of a human, but it is a promising step towards developing more complex brains, or even developing more advanced AI!

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Another aspect of such is in regenerative medicine where organoids can be used be to heal or replace damaged or scarred tissue within the body, more specifically in the digestive system with the potential to treat short bowel syndrome or human inflammatory bowel disease by using organoids to develop functional tissue to be reintroduced into the patient for effective function(1)(Updated as of 06/03/23).. Applications of Organoids (news-medical.net)

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Cerebral organoids were used because the cerebral cortex and spinal cord have similar physiological properties. [6]

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Matured cerebral organoids were used to repair small sections of the spinal cord.

Cerebral organoids were transplanted to the spinal cord sections. The cerebral organoids fused with the spinal cord tissue.

Research showed that successful fusion between tissues is selective. The cortical organoids were more likely to fuse with the spinal cord organoids compared to the skeletal muscle organoids. [6]

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Spinal cord injury treatment can be trialled via organoids, which can be used to visualise the effects of used biomaterials.

Spinal cord spheroids can be differentiated into dorsal, intermediate and ventral spinal cord units by restricting the direction of differentiation. [5]

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Research has been conducted on mice but there is limited correlation between mice and human mutations. [7]

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During development, the spinal cord is formed via neurulation. Errors during early neurulation can lead to neural tube defects (NTDs). Use of organoids can lead to better understanding of human development. [7]

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They can’t undergo full patterning, have high variability in formed organoids and high tissue heterogeneity. [8]

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It can partly recapitulate DV and AP patterning of the neural tube. [8]

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Throughout development, various cell types begin to differentiate. These include astrocytes, oligodendrocytes, glutamatergic neurons and various others.

In addition, synapses and dendritic spines, structural traits of mature neurons, were also found around 8 months into development, suggesting that the mature brain organoid can be used to investigate more advanced nervous functions [7].

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Research was carried out on organoids with functional neuromuscular junctions, which were then exposed to different ALS subgroups. This allowed identification of different structures such as motor neurons and skeletal muscle. [4]

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Cerebral organoids show brain regionalisation

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Cerebral organoids show brain regionalisation

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During development, extracellular signalling at different stages can dictate development of specific regions [4].

These regions include the choroid plexus, hippocampus and frontal brain. Photosensitive cells can be developed, mimicking a structure similar to the retina.

Genetic markers can be added to outline certain regions [6] to see how the organoid develops.

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To generate a cerebral organoid, embryonic stem cells are used. In normal embryonic development, the nervous system develops from ectoderm.

Hence, the stem cells are placed in neuroectoderm encouraging broth, grown in a gel scaffold, spun in a bioreactor to distribute O2 and nutrients to maintain viability.
Rich populations of radial glial cells are present during growth, helping increase the number of developing neurons [2].

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The cellular composition of the spinal cord organoids were investigated through immunostaining at different stages. As the organoids matured, an apical-to-basal patterning was seen. [2]

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Usually, neurotoxicity is dependent on animal models, which has several disadvantages. This includes differences in anatomy, ethical concerns and costs.

Advancements of neural organoids allow testing of chemicals that can affect human CNS development. Using spinal cord organoids has helped visualise the potential risk of neural tube defects. [8]

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Spinal cord organoids can be used for toxicology screening.

The effects of antiepileptic drugs (AEDs) were trialled on spinal cord organoid models. The models were treated with 3 concentrations of 6 selected AEDs. Results showed that two types of AEDs resulted in neural tube closure failure after 8 days of treatment. These results were consistent with clinical risks of AEDs. [7]

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Neural organoids could be developed further in the future by incorporating vascularization as this would mimic the in vivo environment of a real life brain.Recently, researchers have developed microglia- containing human brain organoids (MC-HBOs) as microglia play a key role as the immune defence in the central nervous system.This allows researchers to study diseases using a more reproducible,accurate  model which encapsulates the main features of the human brain.

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Application of organoids on the pharmaceutical industry

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Application of organoids on the pharmaceutical industry

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Drug Discovery:

Neural organoids or organoids have been used and tested in mice against cancer with personalised drug treatment as the organoid will closely mimic the genetics of the mouse and can be used to see what drug or treatment would be best to cure or cope with different condition whilst mitigating as many side effects as possible to make the treatment ‘safe’ and through recent development it will be used to curate medicine in humans against disease.(1) (Updated as of 06/03/23)Applications of Organoids (news-medical.net)

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Fused in sarcoma (FUS) is a protein that is involved in regulating transcription and processing RNA.

ALS patients usually have mutated FUS in the cytoplasm of affected neurons.

Reducing levels of FUS in a spinal cord organoid decreased neural proliferation and differentiation, suggesting that FUS is important for those roles. [9]

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Studying Brain Development:

The development of neural organoids has allowed researchers to gain a deeper understanding of the functioning of the human brain during development (1). Since neural organoids are similar to the human brain at a molecular and cellular level, researchers can study the mechanisms underlying brain development which will then allow them to understand how certain neurological disorders arise (1).

(1) -  Qian X, Song H, Ming G. Brain organoids: advances, applications and challenges.Development.2019; 146 (8).https://journals.biologists.com/dev/article/146/8/dev166074/19861/Brain-organoids-advances-applications-and ( Accessed 20/03/23)

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ALS affects motor neurons, resulting in progressive muscle weakness. The condition has an average survival rate of about 3 years after symptoms onset. [3]

Organoids derived from patients with ALS have shown irregular neuromuscular junctions. [4]

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This disorder is caused by mutations affecting levels of spinal motor neurons. This can result in paralysis or death in extreme cases.

Spinal organoid models can be derived to observe development of the patient’s motor neurons and for testing what small molecules can help increase motor neuron levels. [2]

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specifically the distribution of cells in cortical layers being in multiple rosettes, instead of continuous layers as typical of the human brain.

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Does not accurately reflect the developmental events of typical human growth, occurring more rapidly than normal, especially relating to neural organoids.

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History/development of organoids - TIMELINE

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History/development of organoids - TIMELINE

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Open to view timeline
Alot of progress has been made with the development of organoids with now having produced  we have organoids like gut, brain and lung organoids. We now even have bioreactors printing

References
1. Corrò C, Novellasdemunt L, Li VSW. A brief history of organoids. American Journal of Physiology-Cell Physiology. 2020 Jul 1;319(1):C151–65 (accessed 01/02/2023).
2.

Yu J, Wang K, Zheng D. Brain organoids for addressing COVID-19 challenge. Frontiers in Neuroscience [Internet]. 2022 Nov 29  ;16:1055601.  (accessed 16/02/2023)

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Specificity of gene expression are not yet perfectly replicated in organoid-derived cells

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Defining Consciousness & its Importance  

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Defining Consciousness & its Importance  

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Limitations include:

High-fidelity cell types

Limited maturation

Atypical physiology

Lack of arealization

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brain

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Examining the morphogenesis of an organ can provide useful insight in their development and how they function at a cellular level and with this understanding disease mechanisms can be understood and treatments can be curated.(1). Applications of Organoids (news-medical.net)

Immunological and pharmacological.

https://www.stemcell.com/technical-resources/area-of-interest/organoid-research/neural-organoids/overview.html(2)

Due to difficulties in accessing patient brain tissue, the majority of knowledge regarding PD pathology was originally obtained from the study of postmortem brains

https://www.stemcell.com/forms/wallchart-brain-organoids.html(3)

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Spinal cord organoids can be formed by combining induced pluripotent stem cells (iPSCs), derived neural and non-neural cells. This can form a replica of a mature human spinal cord. [1]