Lab-grown mini human organs may play key role in COVID-19 drug development: Scientists

An emerging technique that uses lab-grown tiny human organs to study viral diseases can accelerate research on the novel coronavirus, and pave the way for new COVID-19 therapies, leading scientists say. "Organoids, are lab-grown organs, which closely resemble human tissues that are relevant for disease,” Josef Penninger, Director, Life Science Institute at the University of British Columbia (UBC) in Canada, told PTI.

In these human organ-like structures, Penninger said, scientists are beginning to perform more experiments to explore how the SARS-CoV-2 virus replicates in hosts, or even test vaccines and drugs against COVID-19. Cultured from undifferentiated cells in the human body called stem cells, he said, these tiny organs contain cells which are also present in a "real" human organ.

For instance, organoids of blood vessels are perfect mini versions of the vascular tissue, made up of an empty cavity, cells that stabilise it, and a membrane wrapped around and keeping it all together, Penninger explained. Similarly, the scientist said, kidney organoids have multiple cell types found in a normal kidney, including those expressing the ACE2 receptor which acts as an entry gate for SARS-CoV-2.

According to Penninger, research using organoids can open new doors for studying COVID-19 symptoms. The tiny organs have previously helped scientists understand how the Zika virus, an emerging mosquito-borne pathogen, causes smaller head size, and intellectual disability in developing newborns. Infection of brain organoid models with Zika virus revealed which cells were affected, and resulting neurological disorders, noted a study published last year in the journal Viruses.

But even now, preliminary experiments on viral infection use only mouse models or lab-grown animal or human tissues, which do not possess the complexity seen in human organs, Penninger said.

"For studying infectious diseases, the commonly used lab models are vero cell lines which are derived from monkey kidneys, and colon cancer cell lines, but these do not fully capture what happens in humans," Shuibing Chen, stem cell biologist from Cornell University in the US, told PTI. While scientists also study SARS-CoV-2 infection in mice, Chen said the rodents do not have the same human version of ACE2 -- the SARS-CoV-2 'gateway' receptor.

Organoids can help overcome these limitations, she said, adding that they can change how scientists understand and test potential COVID-19 therapeutics. For instance, Penninger and his colleagues recently found that a trial drug could block early stages of COVID-19 in a study involving blood vessel and kidney organoids. Another study, published in the pre-print server bioRxiv, screened 1,280 drugs already approved by the US Food and Drug Administration against novel coronavirus infection of the intestines.

The researchers, who studied these drugs on large intestine organoids, said there is an urgent need to create standard models of these tiny organs to study COVID-19.
"In colon, we have more than 10 different cell types like nutrient absorbing cells, and cells which produce hormones," Chen explained. Since using just one human cell line over-simplifies studies, she said there is a growing number of COVID-19 research using organoids to "capture the complexity of infection".

Citing an example, Chen mentioned a study published in the journal Science, which showed how SARS-CoV-2 infects intestinal cells. Joep Beumer, co-author of this study from Hubrecht Institute in the Netherlands, told PTI that organoid experiments revealed which cells in the outer layer of the intestine are infected by the virus, likely contributing to gut-related COVID-19 symptoms like diarrhea.

The scientists led by Hans Clevers had previously developed a new method to grow snake venom gland cells as organoids. The first pathogen-organoid cultures were done only a few years ago, and since then these studies have been increasing, with COVID-19 likely accelerating this further, Beumer said.

Penninger too believes that several COVID-19 puzzles -- such as how the virus lives inside cells, and how it can be blocked from entering them -- can be pieced together via organoid studies. He said tricking the virus, and preventing it from finding the ACE2 entry gate, is "probably the most rationale therapy possible for COVID-19." "Many groups in the world have followed our example, and are using or developing organoids for COVID-19 studies, also in tissues like the heart, and especially the lung," Penninger added.

Some scientists also caution that organoids may not capture the whole reality of diseases. "Organoids are certainly better than cell culture, but they are missing the immune system and the endocrine system," Saisubramanian N, Professor of microbiology at SASTRA School of Chemical & Biotechnology in Tamil Nadu, told PTI. In order to overcome this limitation, special versions of the tiny organs in which the virus, organoids, and immune cells are co-cultured can be used, Beumer noted.

Commenting on the affordability of organoid studies in developing countries, Penninger said, "this is still relatively expansive work, but we work on making it much cheaper, and at numbers that allow testing of new drugs and combinations in thousands of experiments." Beumer said growing these mini organs requires equipment like culture hoods and 37 degree Celsius incubators, along with the supply of patient biopsies as a source for the organoid culture. "Once this infrastructure is developed, organoids can be grown for years," he added.