Kelleher’s organoid NAMs are an advanced in vitro system, an experiment performed outside of a living organism in a dish or test tube, that enables extended propagation of primary uterine cells. After the cultures expand within extracellular matrix droplets, they’re biobanked or preserved in ultra-low temperatures, allowing them to be stored long term and distributed to collaborators across the country.
He added once the cells are thawed out, they can be refreshed with new media and survive for long periods of time.
“This allows for consented patient samples to go much further in the research community,” Kelleher said.
Three prominent types of NAMs — organoids, computational models and microphysical systems — offer options for a variety of research.
While organoids have been effective in answering Kelleher’s early research questions, the questions still need animal models or human clinical trials to confirm results. Even development of the organoid models needs further assessment using animal cells. This is to preserve “precious human samples” in troubleshooting new cell culture models, Kelleher said.
“I think these models are extremely useful,” Kelleher said about NAMs. “But I do think it’s premature to say that they will bypass animal models; the complexity of the 3D organoid models is not at the complexity of an organism.”
Daniel Davis, co-director of the Animal Modeling Core at Mizzou, utilizes another type of NAM called induced pluripotent stem cells (iPSCs), as well as humanized mouse models to study diseases and test therapeutics.
With the use of skin or blood samples, researchers like Davis reprogram cells into pluripotent stem cells — cells which can be morphed into any cell type in the body.
“Researchers in our team treat those iPSCs with specific reagents to turn them into whatever type of cell we want,” Davis said. “They can be turned into heart cells, muscle cells, brain cells, virtually any cell type relevant to the disease we are studying.”
Davis is part of a team that uses iPSCs to study a rare neurological disease, Baker-Gordon Syndrome, and collects skin or blood samples from patients affected by the disease. The cells from these samples are later converted into iPSCs, which can then be turned into a model of the patient’s neurons, cells in the central nervous system that control human functions like movement and thought.
“We turn iPSCs into neurons so that we can study patient cells that are relevant to the disease we are working on and it is too invasive to go into a patient’s brain and take their neurons out directly.” Davis said.
Davis added that his team tests therapies to treat patients with Baker-Gordon Syndrome on the iPSCs-turned-neurons, but determining the success of treatment for the disease doesn’t stop at NAMs.
Genetically engineered mouse models with human patient mutations, and what Davis calls a “patient avatar,” are then used to further vet the safety and effectiveness of therapies for human use.
“A lot of human genes are 99% conserved in mice, so it’s very easy to recapitulate most of the human diseases in the mouse model,” Davis said.
iPSC-converted neurons in a dish don’t interact with other cells that would also be in the brain, and Davis said this is why further testing with mouse models is important to see how the therapies respond on a system-level within a living organism.
“When you’re testing a drug, you shouldn’t be testing it in only a mouse model, and you shouldn’t solely be testing it in a NAM,” Davis said.
He added that researchers should test their therapies across multiple avenues to reap the benefits of each system. This approach to answering preliminary research questions yields “more promising and translatable data to move into clinical trials with.”
Scientists who have primarily focused on animal models might feel a degree of apprehension when asked to move towards new methodologies, but Lorson sees various NAMs as an opportunity.
“NAMs are not about abandoning our core research questions, rather we are simply upgrading some of the tools we use to answer them,” Lorson said.
That upgrade effectively reduces the time it takes to go from an initial research discovery to its clinical application and allows for precision medicine approaches across Kelleher’s research.
Invariably, these methods will continue to get more complex and better simulate human physiology with the creation of models made for more human cell types, like mesenchymal stromal cells and immune cells.
“I think the innovation is going to continue,” Kelleher said. “Because everyone always wants to build better model systems.”
Have you used an interesting NAMs approach in your lab? Share your experience with our communications team by emailing muresearch@missouri.edu.