"We wanted to develop an easy-to-use model so that non-stem cell biologists and those working in labs with limited resources could use it to better understand how olfactory neurons regenerate and what happens that causes that process to diminish or fail completely," Lin says.
Next Step: A Human Organoid
While the mouse-tissue model has provided invaluable insights, the ultimate objective of the Tufts team is to translate these findings into human health applications. The next major milestone on their horizon is the development of a human olfactory organoid.
The advantages of organoids in medical research are significant. They allow for pre-clinical trials that are faster, less expensive, and often more accurate than traditional animal testing or two-dimensional cell cultures. Because organoids mimic the 3D architecture of real human tissue, they provide a much better environment for screening potential drugs. While organoids have already been successfully developed for organs like the lungs and kidneys, the human olfactory system has proven to be a more difficult challenge.
The primary hurdle lies in the collection of pure tissue. "It’s challenging to get pure olfactory tissue from humans," Lin notes. Currently, the process of collecting these cells involves anesthetizing a patient and using a tool similar to a COVID-19 testing wand, which is pushed deep into the nasal cavity to reach the olfactory epithelium.
However, unlike the relatively controlled environment of the mouse model, the samples collected from humans are often a "mixed bag" of different cell types. Specifically, human respiratory stem cells and olfactory stem cells are frequently gathered together, and they are notoriously difficult to separate. For an organoid to be effective as a drug-screening tool, it must be composed of the correct, specific cell types.
The research team’s next challenge is to refine a simple and cost-effective technique for isolating these human olfactory stem cells. Once they can successfully separate these cells and coax them to grow into 3D structures in the lab, the door will open to a new era of sensory medicine.
The potential applications are vast. A human olfactory organoid could be used to test regenerative drugs for COVID-19 "long-haulers," explore the early sensory markers of neurodegenerative diseases like Parkinson’s and Alzheimer’s—where loss of smell is often one of the earliest symptoms—and develop therapies for the millions of elderly individuals who suffer from age-related anosmia.
As the team at Tufts continues to refine their models, their work serves as a reminder that even the most "dormant" parts of our biology may hold the key to our most vital functions. By unlocking the secrets of the nose’s regenerative engine, they are paving the way for a future where the loss of a sense is no longer an inevitable consequence of illness or age.
