Changing the face of medical technology with organoid based treatment

By Easha Vigneswaran

Most of our understanding about how we test novel medical treatments is based on our use of animal models. Whilst this has been successful for most treatments and drug testing trials, there are obvious problems with using animals as opposed to true human tissue. With the fast developments in lab-based stem cell generation, scientists have been able to culture cells under artificial conditions to create organoids. Having been named method of the year in 2017, these artificial cultures help to improve scientific understanding of human organ systems. These tissues can now be monitored to better understand genetic disorders, cancer, and disease pathogenesis. 

Until stem cell technologies had been successfully established for drug trial use, the easiest way to test such therapeutics was through animal models. Its important to note this still is the most common way as alternate model systems are yet to be fully functioning. Anatomical and physiological similarities between animals and humans meant that it was easier for researchers to test drug therapies and achieve a reasonable certainty that the treatments would have similar effect when implemented into humans (Barre-Sinnoussi & Mintaguelli, 2015). However, it is an undeniable fact there are also numerous stark differences between humans and animals. The need to accurately test in-vitro processes prompted scientists to create more organ like systems for testing purposes.

One of the first examples of creating organs outside of the human body was done by culturing cells on a microphysiological device called ‘Organ-on-Chips’. These are microdevices that were biologically engineered to have human cells that mimic an organ system. These were created with the aim to simulate the similar physiological system of cells for use in drug testing in pre-clinical trial (Low et al., 2020). Whilst these appear to show some benefit, the technology has only shown some successes.

Breakthrough discoveries were made using these newly developed technologies – organoids. Organoids are defined as 3D structures similar to organs. The organoid should possess similar functions to the organ being replicated and can work both in vivo and in vitro. These specific technologies are also able to self-organise (Lancaster & Knoblich, 2014). Organoids are derived from pluripotent stem cells and adult stem cells. Recently, the use of adult stem cells has gained popularity because they were found to possess self-renewing capabilities and they can differentiate into cell types specifically found in adults but still maintain stability in their genetic makeup (Koo & Huch, 2015). Thus far some of the major developments in organoid research have produced the gut, liver, kidney, brain, and the retina in vitro (Lancaster & Knoblich, 2014). 

One extraordinary use of organoid generation was done by two research groups whose aim was to understand the effect of the Zika Virus on the brain. At the time the research was conducted, there was a growing concern as to the impact the virus had on foetal brains specifically observed in south America.  Using induced pluripotent stem cells (iPSC) the team generated the specific regions of the brain into cerebral organoid form. A mini bioreactor was developed to create these organoids; the organoids had numerous features including human cortical development, neurogenesis and most importantly a human outer radial glial cell layer. These specific types of cells are not found in great abundance in mouse models which is what made the organoids considerably more beneficial. Using these organoids, the teams were able to assess the effects of the Zika Virus in neural tissue. Some observations included increased lumen size of ventricular structures of the brain that had similarly been observed in foetuses infected with the virus. The virus was also seen to preferentially attack the forebrain and showed reduction in neuronal layer thickness. This supported existing knowledge of the virus’ pathogenesis specifically in early foetal development. The research conducted by the team proves the invaluable benefits organoids hold for the ways in which we treat and further look to understand how different neurological condition impact the human body (Qian et al., 2016)

Another example in which organoids have revolutionised how scientists understand disease in the human body is with liver cells. It is no surprise to anyone there are vast numbers of liver related diseases including but not limited to hepatitis b and c, liver cirrhosis due to excessive alcohol consumption and other autoimmune liver diseases. Whilst animal models have been used to study these diseases, they are far more costly and more time consuming due to the added maintenance (Akbari et al., 2019). Organoid technology has been used to develop two major liver cells: hepatocytes and cholangiocytes. From these successful developments, some of these chronic diseases have been modelled allowing further study of how these cells are affected in the body (Sun & Hui, 2020). Some organoid cultures have shown response to ethanol demonstrating they are viable test subjects to understanding alcohol induced liver diseases (Wang et al., 2019).

Organoids also allow for research in line with precision medicine. Being able to synthesise organs in vitro provides an opportunity to identify specific drug treatment for various conditions. One disease that has been explored is to treat the genetic disorder cystic fibrosis (CF). This specific disease is caused by a mutation that results in the loss of function of the CTFR gene. At present there are drugs that have been extensively used to treat these mutations however one of the major issues is that the mutation is not the same in all sufferers of CF meaning that these drugs do not always prove effective. Using organoid technology and biopsies there is a possibility more specific drug targeting methods can be engineered for people with more rare mutations, with the aim of finding specific drugs to treat their individual condition (Kim et al., 2020).

Much like the issues observed with treating cystic fibrosis, cancer also poses a similar challenge for finding affective therapies. Cancer heterogeneity means that one drug treatment for one cancer patient may not necessarily work for another patient with the same cancer (Fan et al., 2019). In recent years, studies have shown the same response to cancer drugs was observed in both the patients’ organoid culture as well as the patient themself in 90% of cases (Kim et al., 2020). These two successes prove exciting for the potential of personalised medicine in the future for medical therapeutics.

In conclusion, the research potential for organoid developments is huge and proves very exciting for the ways in which we look to understand how personalised drug treatments can revolutionise the world of medicine. Its an undeniable fact there are still large amounts of research needed to establish this line of treatment as fully functional. However, alongside all the other rapidly developing medical technologies it is likely we will see fewer animal models being used in the future and more testing done in organoids.


References:

Barré-Sinoussi, F. & Montagutelli, X. (2015) Animal models are essential to biological research: issues and perspectives. Future Science OA. 1 (4), FSO63. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28031915. Available from: doi: 10.4155/fso.15.63. 

Low, L. A., Mummery, C., Berridge, B. R., Austin, C. P. & Tagle, D. A. (2020) Organs-on-chips: into the next decade. Nature Reviews. Drug Discovery. 1-17. Available from: https://search.proquest.com/docview/2441613971. Available from: doi: 10.1038/s41573-020-0079-3. 

Lancaster, M. A. & Knoblich, J. A. (2014) Organogenesis in a dish: modeling development and disease using organoid technologies. Science (New York, N.Y.). 345 (6194), 1247125. Available from: doi: 10.1126/science.1247125. Available from: https://science.sciencemag.org/content/345/6194/1247125.long. [Accessed Feb 15, 2021]. 

Huch, M. & Koo, B. (2015) Modeling mouse and human development using organoid cultures. Development (Cambridge, England). 142 (18), 3113-3125. Available from: doi: 10.1242/dev.118570. Available from: https://pubmed.ncbi.nlm.nih.gov/26395140/ [Accessed Feb 15, 2021]. 

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Akbari, S., Arslan, N., Senturk, S. & Erdal, E. (2019) Next-Generation Liver Medicine Using Organoid Models. Frontiers in Cell and Developmental Biology. 7 Available from: https://www.frontiersin.org/articles/10.3389/fcell.2019.00345/full#B119. Available from: doi: 10.3389/fcell.2019.00345. [Accessed Feb 15, 2021]. 

Sun, L. & Hui, L. (2020) Progress in human liver organoids. Journal of Molecular Cell Biology. 12 (8), 607-617. Available from: https://doi.org/10.1093/jmcb/mjaa013. Available from: doi: 10.1093/jmcb/mjaa013. [Accessed Feb 15, 2021]. 

Wang, S., Wang, X., Tan, Z., Su, Y., Liu, J., Chang, M., Yan, F., Chen, J., Chen, T., Li, C., Hu, J. & Wang, Y. (2019) Human ESC-derived expandable hepatic organoids enable therapeutic liver repopulation and pathophysiological modeling of alcoholic liver injury. Cell Research. 29 (12), 1009-1026. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31628434. Available from: doi: 10.1038/s41422-019-0242-8. 

Kim, J., Koo, B. & Knoblich, J. A. (2020) Human organoids: model systems for human biology and medicine. Nature Reviews. Molecular Cell Biology. 21 (10), 571-584. Available from: https://search.proquest.com/docview/2474990570. Available from: doi: 10.1038/s41580-020-0259-3. 

Fan, H., Demirci, U. & Chen, P. (2019) Emerging organoid models: leaping forward in cancer research. J Hematology & Oncolology. 12, 142. https://doi.org/10.1186/s13045-019-0832-4 . [Accessed Feb 15, 2021]. 

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