A fragrance assessment for science

One of the more perplexing COVID-related symptoms is the diminished sense of smell, which can linger long after the virus has subsided. Based on studies from Mass Eye and Ear, over 20 million COVID sufferers lost their ability to smell or taste in 2021 alone. Approximately 27 percent of these individuals showed little to no recovery.

For those experiencing olfactory dysfunction (partial inability to smell) or anosmia (complete or near-complete inability to smell), the consequences can be severe. The lack of smell can dull food flavors, render cooking hazardous, and increase concerns about gas leaks and fires. It may even trigger depression in up to one-third of patients. Though some individuals regain partial function over time, effective therapies remain scarce.

A Harvard researcher aims to alter that.

“As I transitioned from medical school to residency, into otolaryngology, and learned about cochlear implants — devices for hearing — it was always a consideration,” stated Eric Holbrook, director of the Division of Rhinology at Mass Eye and Ear and an associate professor of otolaryngology at Harvard Medical School. “Could we replicate that for the sense of smell?”

In 2019, Holbrook published findings exploring that question. He utilized small electrodes implanted in the brains of five patients to determine if he could stimulate the sense of smell. In three of the cases, it was successful — evidence, according to Holbrook, that olfactory implants can restore the sense of smell. Meanwhile, Dan Coelho and Richard Costanzo, both affiliated with Virginia Commonwealth University, were investigating the use of electrode stimulation on the olfactory system in mice. The trio of scientists soon collaborated, culminating in an informal gathering at a Dubai conference for otolaryngologists — the first global meeting, as Holbrook noted, dedicated to assistive devices for smell.

“Numerous individuals were indeed demonstrating that they were progressing towards this,” he remarked. “It was essentially about understanding what others were working on in Europe, Japan, and similar locations. We had no idea they were also advancing this concept.”

Last month, Holbrook, Coelho, Costanzo, and international colleagues published an international consensus paper on nascent olfactory implant technologies in the journal Rhinology.

The evolution of olfactory implants poses a bewildering array of challenges. In a functioning olfactory system, odor molecules adhere to chemoreceptors in the olfactory epithelium — layers of thin, mucus-covered tissue within the nasal cavity. There, nerves relay signals to the olfactory bulb, which effectively “maps” scents by linking specific chemoreceptors to specific spherical structures known as glomeruli. Each scent activates multiple receptor types, illuminating various parts of the bulb simultaneously.

This intricacy makes it significantly more complicated to replicate smell than hearing, where sound frequencies align neatly along the cochlea.

Nonetheless, the potential is enticing. The current strategy involves placing an electrode array adjacent to the olfactory bulb, bypassing damaged nasal neurons to directly stimulate the brain. Similar to a cochlear implant, an external receiver, possibly concealed within glasses or a headpiece, would connect with an internal electrode through magnetic coupling.

Safety concerns are considerable. The olfactory bulb is located within the skull, meaning any device must protect against infection, particularly meningitis. Additionally, early stimulation tests indicate that indiscriminate activation of various receptor pathways at once can create unpleasant or phantom scents — hardly the enhancement to quality of life that patients desire. Designing a method to induce specific odors will necessitate much experimentation.

“Utilizing machine learning, one could have an implanted electrode array select areas at random for stimulation and inquire about the person’s experience,” Holbrook stated. “Over time, you are progressively approaching the capability to generate recognizable scents.”

Operational, long-term implanted devices are likely several years away, but Holbrook and his associate Mark Richardson, a neurosurgeon at Mass General, aspire to make a significant impact sooner. Richardson sometimes temporarily implants electrodes into the brains of seizure patients. With the consent of the patients, Holbrook and Richardson intend to place electrodes on the surface of the olfactory bulb during Richardson’s procedures, when the patients are conscious, and electrically stimulate areas on the bulb to determine if patients perceive a smell without a fragrance being present.

The path to dependable implants will not be swift or simple, according to Holbrook, but he envisions hope for those whose quality of life has been diminished due to a loss of smell.

“If you speak to someone who had COVID, and they find everything they eat flavorless now because they cannot smell it, they would most likely prefer coffee over a strawberry. That would be a significant improvement for them.”