3D Cell Culture and Organoids: Potential Tools in the Fight Against COVID-19

The following article originally appeared on December 21, 2020 in SelectScience here.

For many years cancer cells and other diseases have been studied using 2D cultures, bound by the limitations of simplified growing conditions. Researchers can now grow their own “mini-organs” or organoids using stem cells, changing the face of pathology. Chen and her team have been using this new technology to make discoveries around COVID-19 and its relationship to diabetes by teaming up with multiple labs in New York. The collaboration produced some surprising findings, with the work sparking widespread interest after recent publication in the leading science journal, Nature.

Researchers began by using different cell types each derived from human stem cells and then infected with COVID-19, to gain an understanding of which cells and organs are most likely to be affected by this virus.  In some organs, a permissive effect was expected, for example, in the lungs or colon. The pancreas was not a suspect; however, an effect was observed, specifically in the pancreatic β-cells. Speaking to endocrinologists treating COVID-19 patients, Chen found they were struggling to monitor and control blood glucose levels in COVID patients but didn’t understand why. Chen thought, “I think maybe we have an explanation for that” — a suspected link had been found between diabetes and COVID-19.

Fortunately for the researchers and endocrinologists, Chen had a specialized diabetes lab already working on pancreatic β-cells, concentrating on diabetes type 1.  They showed that the two organs involved in diabetes progression, the pancreas and liver, can both be infected by SARS-CoV-2. Endocrine cells were also seen to be susceptible to COVID re-infection. Before this investigation, it had been hypothesized that the virus may trigger type 1 diabetes in COVID patients. Therefore, to see that COVID-19 had such a permissive effect on the pancreas was an interesting discovery and added further support to this idea.  There is a follow-up study currently underway to better understand how these cells respond to COVID infection, while research published in the New England Journal of Medicine has found COVID patients often develop diabetes further down the line. It’s currently reported in China that people with diabetes have the worst outcomes and that COVID might be a cause of new onset of diabetes.

Stem cells are emerging as a favored model to predict what type of cell can be permissive to certain types of viruses, giving insight to scientists and clinicians alike and offering advantages over the limited resources of biobanks for human tissue, in vitro Petri dish cultures or animal models. “We’re always saying that we learn a lot from animals,” says Chen, “but animals are not human, so we appreciate that species differ.” A key benefit of 3D culture is that more complicated organ systems can be studied such as the lungs, heart or colon. Now, in collaboration with other labs including Cornell and Ben tenOever’s lab, a multitude of different organoids have been produced for use in a wide range of research and, in Chen’s words, “it is just a matter of time before people change from 2D to 3D.”

Though 3D cultures offer several benefits, Chen has found they are not without their challenges, such as their robustness. In 2D culture, there may be small differences vial to vial, however 3D culture is a more complicated state, capturing a whole system. The nature of 3D culture means there are many variations and like nature, this is difficult to control. Chen sums up the issue: “If you choose to differentiate two organoids, you are dealing with two different worlds.” Since you will never grow two identical organoids, people may hesitate to use them for drug screening. However, Chen believes if you know what you are looking for, it makes a big difference

3D cultures mean drug screening can begin in the mini-organs, leading to faster validation. For example, making lung or colon organoids and being able to run these in parallel can help to find common hits. Conversely, Chen has also found compounds that show inhibitory activity in only one cell.  There is still much to understand about COVID-19 drug efficacy and organ specificity, but Chen is determined and has made her decision on the best tools for the job: she turns to Corning for her 3D culture materials, such as Corning Matrigel^® Matrix. “We definitely buy all our gels from them,” says Chen. “We're very happy with their product. They keep developing new products. They understand what the biologist wants, what the scientist needs. I think that is fantastic.”

Chen hopes to find drugs that can be used or repurposed for COVID-19 patients directly. Future goals are to exploit the advantages of organoid systems and how they can explain diseases in a more human-like, biological way. So far, the organoid models have helped to further understanding of the pathology of COVID-19 by mimicking more complicated organ responses to the virus. However, the key questions still remain unanswered: Who is susceptible? And if they are infected, how can the virus be blocked? 

Other investigations will center around the COVID patient immune response such as the cytokine storm, which can be an even bigger problem than the viral infection itself, potentially killing important cells such as β-cells in the pancreas, leading to diabetic complications. So, in addition to virus-infected organoids, Chen will continue researching immune-cells in the organoid culture to see whether she can recreate the immune-response in the Petri dish. 

Chen believes people need to work together to move the field forward. She adds: “We are pretty happy we found our unique niche where we can make a different kind of organoid from human pluripotent stem cells: we can use it for disease modeling, we can make it for drug screening.” Her research aims to use this platform to develop new drugs and individual treatment plans, as Chen concludes: “Science is not one person’s journey.”