Human and animal health in mutual interaction
Mini lungs to learn about animal disease
Wageningen researchers have managed to make miniature respiratory tracts from the stem cells of cows and pigs. This helps them study the behaviour of respiratory viruses without the need for lab animals.
Swine influenza and bovine respiratory disease are troublesome animal diseases that regularly affect pigs and cows. It is not easy to study how the viruses behave either, because you need live animals that you expose to the disease, which is not a desirable state of affairs for animal welfare reasons.
Now Wageningen researchers have managed to create mini respiratory tracts from the stem cells of cows and pigs. Such mini organs, termed organoids, are made from stem cells from the lungs of animals. They have the same form and function as the lungs of a live animal, but they are far smaller: one to two millimetres.
Manouk Vrieling is one of the researchers at Wageningen Bioveterinary Research who is involved in developing these ‘mini lungs’. Vrieling, who started out as a vet and microbiologist, is fascinated by how infectious diseases work in animals. “If you can figure that out, you can also come up with something to treat the animals. We hope to find a solution for troublesome animal diseases such as swine influenza and bovine respiratory disease, which occurs in calves infected with the bovine respiratory syncytial virus.”
Creating organoids involves advanced biotechnology. First, stem cells are extracted from the lungs of animals. This specimen is then used to cultivate cells, which is done by placing them in the right environment, namely one that has the necessary nutrients and growth factors and provides a surface that the cells can adhere to. There the cells grow into ‘mini lungs’.
Vrieling: “We used stem cells that are found in the bronchi that connect the windpipe to the lungs. In the organoid, we find cilia and cells that produce slime. That is good news because the closer the model is to the real world, the more valuable it is for our research. We will then be better able to simulate a virus infection.”
The mini respiratory tracts are currently used to simulate infections with the two viruses. The researchers are examining differences between viral strains: how fast do they multiply and how much damage does this cause? That indicates the severity of an infection’s progress.
‘The closer the model is to the real world, the more valuable it is for our research’
Vrieling: “Investigations using organoids mean we are better able to characterise the various strains of a virus. For example, we know that certain variants of the swine influenza virus cause more symptoms than others. We’re testing to see whether we also find these differences in infections of the mini lungs.”
The first experiments using the bovine respiratory syncytial virus (BSRV) on mini respiratory tracts from calves have looked very promising, says Vrieling. “BRSV causes a nasty disease in calves, with fever, shortness of breath and coughing. Young calves in particular can become seriously ill and die. That’s why we want to know more about this virus. But we can’t cultivate the virus in the lab because for that you need live calves that you expose to the disease. That’s a big problem in terms of animal welfare. In the future, we will hopefully be able to culture tricky viruses like these on organoids rather than having to sacrifice animals for this purpose.”
One of the strengths of the project is that the mini lungs are grown on the interface between the culture medium and air. That means the cells are exposed to air on one side during growth. Vrieling: “That is also what happens to the respiratory tract in the animal’s body. And normally the cells come into contact with viruses via the air. So this means we can simulate the natural progression of an infection rather well.”
As a professor of Infectious Diseases, Jerry Wells is also involved in the project. He is very enthusiastic about the progress that has been made, but he also sees room for improvement. “The organoids are an exciting development that let us track precisely what happens in living tissue during a virus infection. It would be good if we could manage to keep the organoids alive for longer. That’s of interest because at the moment we find we eventually lose the mini lungs: they die off within six months. We would also be able to get even closer to the real-world situation if we were able to give the mini lungs immune cells, like full-grown lung tissue has in living animals.”
‘Early identification is important in curbing large-scale outbreaks of diseases in animals and humans’
The research concentrates on existing viruses. But the method could also enable a faster, more effective response to new viruses. One hundred years ago, the world was affected by an outbreak of the Spanish flu, which was probably passed to humans via pigs. In 2020, we witnessed the outbreak of the SARS-CoV-2 virus, which caused the COVID pandemic. That virus was probably transmitted to humans via bats. The organoids offer many options for improving the response to such new viruses.
Vrieling: “Using financial support from the WUR ERRAZE programme, we have created a repository of the stem cells of many different animals in liquid nitrogen. They include pigs, cows, goats, ferrets, hamsters and dogs. If there is an outbreak of a new virus, we will be able to test whether the respiratory tract organoids of these animals can become infected. That would perhaps help us to predict which animals are susceptible to the virus and could function as a reservoir for more virus outbreaks. That is important when new viruses appear. The sooner we know what we are dealing with, the sooner we can take action to protect the health of animals – and ultimately humans too.”
Infection biologist Jerry Wells stresses that: “It’s important to be able to identify and figure out pathogens and the associated infection mechanisms early so that we can curb large-scale outbreaks of diseases in animals and humans. And there are more possibilities too. We could test medicines on organoids. And we could study genetic variations in the stem cell donors, which could be interesting in the research on hereditary lung diseases such as cystic fibrosis.”
By investing in this research as part of the Next-Level Animal Sciences (NLAS) and ERRAZE programmes, WUR is giving a significant boost to new developments. Vrieling: “I think it’s really good that WUR is doing this; we hope it will act as a catalyst for further research along these lines. Creating cell culture models of various animal species could allow us to make a significant contribution to the prevention of major outbreaks of diseases and at the same time help reduce the number of experiments with lab animals.”
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WHO Manouk Vrieling, Researcher in Molecular Microbiology
Jerry Wells, Professor of Host-Microbe Interactomics
RESEARCH Complex cell systems of airway (Airway organoïds)
TEAM Nora Gerhards, Rik de Swart
Researchers portrayed in this article: Manouk Vrieling, Rik de Swart, Nora Gerhards
MORE INFORMATION This project is part of the Next Level Animal Sciences (NLAS) innovation programme.
Participating researchers of Wageningen University & Research collaborate with various partners to develop new research methods and technologies within the field of animal sciences. NLAS consists of three research directions, namely sensor technology, complex cell systems and data and models.
