Researchers Study Novel Coronavirus By Growing ‘Bonsai’ Organs

To test a treatment for COVID-19, a medical geneticist at the University of British Columbia in Vancouver, Josef Penninger, and his team, starting with human stem cells, have created miniature replicas of the vascular system.

These tissue bits called organoids, come in diverse varieties such as gut versions sporting the tendrils that absorb nutrients, lung mimics with air sacs, etc. They provide a way to study how viruses enter cells and cause disease,  as well as how the tissues fight back and thus are handy for vital research.

Of course, they are not the only option. Scientists have been scrambling to study infection and test treatments in as many ways as they can during the COVID-19 crisis as it’s difficult to study the viral life cycle in human beings. While there are other researchers are working with mice, and as animal responses to infections often differ from those of people, these experiments can be slow. With cells that thrive in flat layers, such as cells from human liver cancer or African green monkey kidney cells, results come faster, — but these tend to be more akin to tumors than healthy body tissues in all their

A pioneer in organoid research and coauthor of an overview of the field in the 2020 Annual Review of Pathology, and cancer and stem cell biologist at the Hubrecht Institute in Utrecht, Netherlands, Hans Clevers says, “In contrast, organoids host many of the cell types in the real tissue, organized in the right way. They provide a useful intermediate between abnormal cell lines and whole-animal studies as they are about as close as scientists can get to work on human tissues outside of actual people.

Scientists have been infecting organoids with viruses since at least 2012 and have been working on organoids for about a decade. For example, the Zika virus that caused an outbreak in 2015–16, was linked to small brains in newborns, but scientists turned to brain organoids since they couldn’t study the infection in growing fetuses. Clevers says an intestinal organoid model has also been developed recently, that they could infect with the norovirus that causes stomach flu, which should lead to the development of treatments.

Scientists already have used organoids and related systems in the case of COVID-19 and confirmed that the gut tissues are infected by SARS-CoV-2, the virus that causes the disease. In order to study other coronaviruses that have the potential to cross over into people, they have even built organoids based on the tissues of bats, the likely source of the virus.

COVID-19 in organoids, and beyond

Penninger assembled a group of collaborators to investigate the virus’s effects in diverse organoids soon after the first genetic sequence for SARS-CoV-2 came out in January. The collaborators wanted to test whether it could infect organoids of the gut, kidney, and blood vessels, the human ACE2 protein that the virus uses to enter cells is found throughout the body, though COVID-19 is primarily a respiratory disease.

The team reported in mid-May that a lab-made version of ACE2 could lure the virus away from human cells, minimizing infection of the organoids, and the virus could infect the kidney and blood vessel organoids. This decoy treatment is being tested in people with severe COVID-19 by a company founded by Penninger.

Clever’s team found that copious amounts of the virus were being produced by organoids as they were easily infected. Some people experiencing symptoms such as diarrhea and nausea can be explained by this.

To get results even closer to the real thing, models that mix tissues and copy blood flow are being developed by Don Ingber, cell biologist and bioengineer and colleagues at Harvard University’s Wyss Institute in Boston. To provide further structure to the tissues, and even make them move, Ingber’s team combines human cells with mechanical devices. For example, their lung-on-a-chip closely mimicks the actual structure of lung sacs as it has air flowing over lung cells on top, with blood vessel cells and a blood substitute on the bottom. The researchers can make the lung “breathe,” by expanding and contracting vacuum tubes along the sides of the chip.

To mimic how the influenza virus moves from person to person, Ingber’s team used their airway chip — lined with cells from the bronchial tubes on one side and vasculature on the other, in a recent study that has not yet been peer-reviewed. They used it to show how the virus mutated to resistant forms due to the constant presence of antiviral medications and also used it to test treatments.

Similar experiments related to COVID-19 were performed by the team in another preliminary paper. To make the SARS-CoV-2 spike protein that binds ACE2 to enter cells, they used other viruses engineered since their laboratory wasn’t built for dangerous pathogens. Seven FDA approved medications were tested for their infection-fighting ability.

All seven had been effective against the COVID-19 causing virus in the simple, but abnormal, monkey kidney cell model. But only two of these could strongly block the entry of the virus into the lung cells: the malaria drug amodiaquine and the breast cancer medication toremifene when they were used in the airway chip at the maximum dose people can receive. To continue to test FDA-approved medications that might be more potent against SARS-CoV-2 and to promote clinical research on those medications, Ingber is in talks with the FDA. To study how people might develop immunity to flu and SARS-CoV-2, he is also using a chip that mimics lymph nodes.

The next pandemic?

The next dangerous viruses that might infiltrate the human race could also be identified with the help of organoids. Scientists would like to predict the most dangerous viruses as there a new viruses emerging regularly from wild animal populations. Researchers are already using airway organoids to predict how infectious novel influenza strains could be in people and to test them.

For their coronaviruses for study, researchers can also use organoids made from bats in the laboratory. According to reports by researchers in Hong Kong in mid-May, based on intestinal cells of horseshoe bats that supports SARS-CoV-2 infection and replication, they had developed organoids. Clevers says that scientists may be able to identify other viruses with high potential to harm people, and thus get a head start on drug development, by growing various coronaviruses in these tissues and also testing them in human organoids. He added saying that to create an everlasting supply of organoids, it requires only one animal, be it a bat or other potential host animal. Any mammal’s internal organs can be grown.

Penninger acknowledges that though organoids can do a lot, animal models will not be replaced by this. The complex interplay between different organs is lacking in most organoids. Cells coming in from the immune system are often not included in organoids, adds Clevers.

However, the current pandemic has led numerous labs to study SARS-CoV-2 in organoids as they’re a great bet to understand how human tissues respond to infection and treatment. “This whole field of organoids is being totally exploded,” said Penninger.