Organoids aren’t science fiction anymore. Going by the advances in tissue culture techniques, it is now possible to grow 3D ‘organ buds’: lab-grown bundles of cells resembling an organ (heart, liver or intestine) which are employed to study development, test drugs and understand diseases.
Because mouse models don’t cut it
As much as 95% of drugs that yielded positive results when tested on rodents, fizzled out in the case of humans. Since human brains are so different from those of most animals, looking at how animal brains develop only gives us a crude understanding of the process in humans.
In order to attain most precise and comparable results, it’s indispensable that the cells subjected to study should be alike in various crucial aspects.
The Mini-er, the better
The first mini-brain model was created in 2013 by Knoblich and Lancaster. It was a globular structure, grown in a span of 3 months.
However, the closer-to-real and comparatively cost-effective mini-brains grown in-vitro till date have been developed by Hartung’s group at Johns Hopkins University, Baltimore.
A 2-months old mini-brain has 4 types of neurons and 2 types of support cells: astrocytes and oligodendrocytes. The astrocytes wrap around the synapses, providing cells with metabolic support and regulating signal transmission, while the oligodendrocytes go on to create myelin, which insulates the neuron’s axons and enables them to communicate faster.
Since these brains are smaller (about 350 microns across), but are easy to reproduce, bear a more diversified replication of brain cells and take lesser time (10 weeks) to develop, researchers believe that this is the most standardized model created till date, which can potentially replace animal testing on a large scale.
Making brain from skin: The miracle of stem cells
Cells from the skin of several healthy adults are used to create mini-brains. The approach is through induced pluripotent stem cells (iPSCs) technology. iPSCs are adult cells that have been genetically reprogrammed to an embryonic stem cell-like state and are then stimulated to develop into brain cells. With iPSC technology, scientists can theoretically turn back the clock in any type of mature cell, be it skin, muscle, bone, etc, and bring it to a near-embryonic state. Embryonic cells can then be coaxed to develop into any of the cell types that constitute the human body.
The answer to Parkinson’s?
The human brain is not just the highway for information but also controls auditory, eye movements, vision and body movements. The specialized neurons that produce dopamine play significant roles in executive functions, motor control, motivation, reinforcement, and reward. High levels of dopamine elevate motor activity and impulsive behavior, whereas low levels of dopamine are associated with slowed reactions and stiff movements which are the characteristics of Parkinson’s Disorder. This degenerative condition is a consequence of dramatic dip in neuromelanin production.
Being able to create mini-brains in a laboratory is a key breakthrough for studies in PD, which affects about 7–10 million people worldwide.
A preview of purview
The iPSC approach is also useful to study the effect of various pharmaceuticals on the brain by developing brains from cells extracted from people with certain genetic traits or diseases like Alzheimer’s, Parkinson’s, multiple sclerosis and even autism. Also, the mini-brain organoids may be ideal for examining fetal brain development, including microcephaly which is a condition linked with the Zika virus. Some studies confirm that Zika probably causes microcephaly by attacking the neural progenitor cells that build the brain, turning them into virus factories. The reduced number of neurons in the microcephalic models is observed to be linked to a lack of a protein named CDK5RAP2 because when this protein was added to the microcephalic organoids, the number of neurons increased.When placed on an array of electrodes, the mini-brains even displayed spontaneous electrophysiological activity, similar to an electroencephalogram. The electrical communication
When placed on an array of electrodes, the mini-brains even displayed spontaneous electrophysiological activity, similar to an electroencephalogram. The electrical communication of the neurons could be heard as the test drugs were added. This is a potential game-changer in the field of drug development.Researchers at the University of California, San Diego School of Medicine and Rady Children’s Hospital used mini-brains to study Cockayne syndrome, a rare neurodegenerative disease that causes short stature and premature aging along with problems in
Researchers at the University of California, San Diego School of Medicine and Rady Children’s Hospital used mini-brains to study Cockayne syndrome, a rare neurodegenerative disease that causes short stature and premature aging along with problems in nervous system and eyesight. There is no cure for the syndrome yet, and people afflicted with it usually die in their 20s.
At the Yale School of Medicine, mini-brains were used to comprehend the intricacies of Autism (and trace its genetic links, if any) by simulating early cerebral cortex development from skin biopsies of 4 patients. Once the stem cells grew into three-dimensional mini-brains, their gene expression, and cellular content was compared to that of family members who didn’t have autism. The study specifically looked at patients with enlarged heads (a common trait in people with severe autism) and revealed that the affected brain cells possessed much higher levels of a FOXG1 gene which led them to multiply at a faster pace.
Is this ethical?
The ethical concerns, in this case, are non-existent as there are no sensory stimuli entering the brain. So the brain is not thinking in any way.
Other concerns
Since immune cells come from a different stem cell line, they are the only elements of the real brain missing from the mini-brain model.
The pressing concern is that the mini-brains cannot live for long because, unlike real brains, they are deprived of nutrients which come through blood supply. Also, in contrast to animal models, mini-brains require a longer time to grow and can only be developed to the embryonic stage.
