Researchers had used brain organoids to study how Zika virus affects brain development in the embryo and causes small-sized brain called microcephaly. This study would have been nearly impossible using human brain at the embryo stage for obvious ethical reasons.
On October 21, at the Society for Neuroscience’s 49th meeting Neuroscience 2019 held in Chicago, two neuroscientists warned the gathering that fellow neuroscientists are “perilously close” to crossing the ethical red line of growing mini-brains or organoids in the lab that can perceive or feel things.
In some cases, scientists have already transplanted such lab-grown brain organoid into adult animals. The transplanted organoid had integrated with the animal brain, grown new neuronal connections and responded to light. Similarly, lung organoid transplanted into mice was able to form branching airways and early alveolar structures. These are seen as a step towards potential “humanisation” of host animals.
What is an organoid?
Organoids are group of cells grown in labs into three-dimensional, miniature structures that mimic the cell arrangement of a fully-grown organ. They are tiny (typically the size of a pea) organ-like structures that do not achieve all the functional maturity of human organs but often resemble the early stages of a developing tissue. Most organoids contain only a subset of all the cells seen in a real organ, and most importantly organoids lack blood vessels to make them fully functional.
In the case of brain organoids, scientists have been able to develop neurons and even make specific brain regions such as the cereberal cortex that closely resemble the human brain. The largest brain organoids that have been grown in the lab are about 4 mm in diameter.
How are organoids grown in the lab?
Organoids are grown in the lab using stem cells that can become any of the specialised cells seen in human body, or stem cells taken from the organ or adults cells that been induced to behave like stem cells, scientifically called induced pluripotent stem cells (iPSC). The stem cells are provided with nutrients and other specific molecules to grow and become cells resembling a specific organ. The growing cells are capable of self-organising into cellular structures of a specific organ and can partly replicate the complex functions — physiological processes to regeneration and disease — of mature organs.
Organoid of retina. — Photo: David Gamm, University of Wisconsin-Madison
Organoids of which organs have already been developed?
Organoids of the brain, small intestine, kidney, heart, stomach, eyes, liver, pancreas, prostate, salivary gland, skin, and inner ear to name a few have already been developed in the lab.
Why are scientists excited about organoids?
Since use of embryonic stem cells to grow organs of interest has been mired in controversy leading to a ban on such research, researchers have turned to generating organoids using stem cells taken from an organ or adult cells that have been induced to behave like stem cells.
Researchers have been successful in generating organoids of increasing “complexity and diversity”. Since the organoids closely resemble mature tissues, it opens up new vistas. These include, studying the complex arrangements and interactions of cells in three-dimensions, studying the function of cells in more detail and understanding how cells assemble into organs, which has been nearly impossible so far especially in tissues such as brain.
Organoids can be used to study safety and efficacy of new drugs and also test the response of tissues to existing drugs. Since organoids mimic the original tissue in the lab, they provide an ideal platform for tissue engineering studies.
Since the use of animals during drug development studies is becoming increasing difficult the focus has been on refining, reducing and replacing the use of animals in research. While scientists have been increasingly using human cell lines and other methods, such alternatives have some inherent limitations — they cannot mimic the whole organ system. Organoids are a far superior alternative to cell lines.
Generating organoids in the lab brings precision medicine closer to reality. Growing organoids using the patient’s own cells help in studying microscopic anatomy (histology) and gene landscape of the diseased organ. Organoids will particularly be helpful in identifying patient-specific treatment strategies by studying which drugs the patient is most sensitive to. This becomes particularly useful in the case of cancer, where many patients suffer from drug resistance.
How have organoids helped in our understanding of diseases?
Organoids are already being used to understand and study diseases. Organoids offer new opportunities to study the proteins and genes that are critical for the development of an organ. This helps in knowing how a mutation in a specific gene causes a disease or disorder. Using intestinal organoids of six patients with an intestine disorder, it became possible to identify the mutation in a gene that prevented the formation of healthy intestine. Researchers had used brain organoids to study how the Zika virus affects brain development in the embryo and causes small-sized brain called microcephaly. This study would have been nearly impossible using human brain at the embryo stage for obvious ethical reasons.
Researchers have used brain organoids to investigate neurodevelopmental alterations that are seen in people with autism spectrum disorders or schizophrenia.
Scientists are already using stem cells taken from tumours to grow organoids that are poised to develop cancer. The ability to grow organoids using cancer stem cells allows researchers to study the genes, proteins and signalling pathways that cancer cells use to develop and grow. They are also using healthy organoids to identify and verify the gene mutations that cause cancer.
Can organoids be grown for organ transplantation?
The current focus is on developing organoids of more human organs and to make the organoids to become more representative of actual organs in terms of all specialised cells. While organoids might become a source for cell therapies, lab-grown organoids for organ transplantation is currently too distant in the future, if at all. But growing organoids that closely resemble actual organs in some aspects is the first step in that direction.
In the foreseeable future, organoids might be grown using patient-specific stem cells for the purpose of cell therapy. Towards that goal scientists are already evaluating the safety and reliability of organoids by transplanting them into animals.
What are the ethical challenges of growing organoids?
In an opinion piece in Nature, scientists argue that the largest brain that has been grown in the lab is only 4 mm in diameter and contain only 2-3 million cells. In comparison, an adult human brain is 1,350 cubic centimetres, and has 86 billion neurons and another 86 billion non-neuronal cells. The authors argue that organoids do not have sensory inputs and sensory connections from the brain are limited. Isolated regions of the brain cannot communicate with other brain regions or generate motor signals. “Thus, the possibility of consciousness or other higher-order perceptive properties [such as the ability to feel distress] emerging seems extremely remote,” they write.
With organoids transplanted into mice exhibiting neural activity when activated with light, the future possibility of sensory input and output increasing is real as organoids become increasingly complex. Arguing that transplanting brain organoids into animals is allow blood supply so organoids can grow bigger, they say that the “size of rodent models restricts the degree to which human brain organoids can grow within them”.
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