Science and research have always relied on using animals to understand various human diseases. The primarily reasons have been the genetic similarity between animals and humans (mice share 98% of DNA with us), and that we have developed tools to edit genes in various animals. We can edit a gene out in mice to try to understand its role in progression of human cancer. These “animal models” are supposed represent a window to further study and understand human diseases.
An animal model for a particular disease should fulfil two criteria. It should be able to “catch” that infection (in case of infectious diseases) and show the clinical outcomes and altered physiology that accompanies the disease. Many animals do not fulfil the second criteria. Amyotrophic Lateral Sclerosis (ALS) is a fatal disease that leads to loss of neurons that control our motor functions, leading to wasting of muscles, paralysis and death. While mice models of this disease also show wasting of muscles, the cause of death is blockage in the gut. Thus, drug targets that would prevent these mice from dying would be irrelevant in humans.
Road blocks
These systemic issues are coming to the fore with scientists trying to find the elusive vaccine/drug by attempting to cure experimentally infected lab mice, rats, hamsters and rhesus monkeys. However, they are faced two roadblocks. Mice, the most widely used “models” to understand human diseases, cannot be infected with SARS-CoV-2. If you imagine the virus to be a lock, it needs a “key” (usually a protein) on the surface of a cell to enter. The “key” is present in humans, rhesus monkeys, to a lesser extent in hamsters, ferrets and cats, but not in mice. Scientists are now creating genetically altered mice that express this “key”, as larger animals pose additional difficulties of housing, handling and are expensive.
This leads us to our second roadblock that an animal model should also reflect the clinical features. Apart from fever, sore throat, cough, pneumonia, COVID-19 infection in humans is also known to affect the heart, kidneys, intestine, and brain. While ferrets, hamsters, cats, rhesus monkeys and genetically modified mice could get infected with SARS-CoV-2, all of these develop only mild lung infection, most do not show fever, and they recover within seven–nine days. Many of them do not show the virus in organs other than the lungs, and exhibit contradictory results. A study in cats showed that the infection was more severe in kittens versus older cats. This is opposite to humans where older infected population has a higher risk for death.
Those critical roadblocks bring some questions on how much these models will be able to help the scientists to find a cure, if they are able to self-limit the disease. Thus, there is need for systems and approaches that can “model” human diseases to a greater extent.
Mini organs
Scientists are now creating miniature 3D organ-like-structures, called “organoids” that aim to replicate a human organ. These mini organs, created using stem cells, are 200 microns (width of two human strands of hair) to a few millimetres in size. They have similar three-dimensional structure and cellular composition as human organs, and thus, are better reflective of human biology compared to animal models. Infection of mini-lungs with SARS-CoV-2 showed that virus triggers a massive immune response, similar to what has been observed clinically in humans. Four compounds were able to reduce viral levels in mini-lungs, and one of them is registered in three clinical trials. Scientists were also unclear on how the virus travels to various organs inside the body, till a study found that SARS-CoV-2 could infect blood vessel organoids. This indicates that the virus could travel via the blood stream to various organs, such as kidney, heart, etc (which also express “key” for the virus to enter).
Despite their potential, many of these mini-organs currently do not have blood supply, resident microbes or immune cells. Also, it is difficult to understand the holistic response based on individual organs. Scientists are currently battling these limitations by creating multiple interconnected mini-organs, and growing different types of cell (blood cells, immune cells) together.
It is unlikely that we would get all the answers on how the virus affects humans using one system or model. Thus, we also need to invest in computational or AI-based approaches to integrate information from different organ systems or models to create a systems body of information.
A study by Tufts Centre estimated that seven out of eight drugs that enter the clinical pipeline fail indicating the low translatability of the current paradigm. With many drugs, like Remdesivir failing to show statistically significant clinical benefits in COVID-19 trials, use of new methodologies that are more relevant to human biology coupled with further innovation to address their limitations could hold the key to find potent therapeutic targets for this healthcare crisis.
(Surat Parvatam is senior research associate, Centre for Predictive Human Model Systems, Atal Incubation Centre–Centre for Cellular and Molecular Biology (AIC-CCMB), Hyderabad)
