By providing a simplified, cost-effective 3D model, the Tufts team hopes to empower a broader range of scientists to contribute to the field. "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 explains.
Next Step: A Human Organoid
While the mouse-tissue model has provided invaluable insights into the fundamental biology of the nose, the researchers have their sights set on a more ambitious goal: the creation of a human olfactory organoid.
The transition from animal models to human models is a cornerstone of modern translational medicine. Organoids offer a unique advantage in this regard; they can make the pre-clinical phase of research faster, less expensive, and more ethically sound than traditional animal testing. Perhaps most importantly, human organoids can be used to screen potential drug candidates with a level of accuracy that animal tissues cannot match, as they account for human-specific genetic and molecular factors.
While organoids have been successfully developed for other major organs, including the lungs, kidneys, and brain, the human olfactory system has proven to be a difficult frontier. The primary obstacle is the difficulty of obtaining pure, high-quality tissue samples from living donors.
"It’s challenging to get pure olfactory tissue from humans," Lin explains. The current process for collecting these cells is invasive and technically demanding. It typically involves anesthetizing a patient and using a specialized brush—similar to a long COVID-19 test swab—to reach deep into the uppermost reaches of the nasal cavity.
The challenge does not end with the collection of the sample. Unlike the mouse model, where researchers can more easily isolate specific cell types, human samples collected via nasal brushing are often a mix of respiratory stem cells and olfactory stem cells. In the laboratory, these two types are notoriously difficult to separate, making it hard to grow a "pure" olfactory organoid that accurately reflects the sensory tissue.
The research team’s next major challenge is to refine the techniques used to isolate these human olfactory stem cells. They are working toward a simple, inexpensive method to separate the desired cells and "coax" them into growing into 3D structures in the lab.
If successful, the development of a human olfactory organoid could revolutionize the treatment of anosmia. It would allow clinicians to take a patient’s own cells, grow them into a model in the lab, and test various pharmacological interventions to see which ones effectively stimulate the regeneration of neurons. For the millions of people worldwide suffering from permanent or long-term smell loss, this research represents a significant step toward restoring a sense that is vital to the human experience.
