Smell for Life

Smell loss has been implicated in increased mortality, Alzheimer’s, dementia, and Parkinson’s disease. Before Covid-19, it was rare for physicians to inquire about a patient’s sense of smell. Not only is our sense of smell undervalued, but smell tests have been expensive and time-consuming to administer. While there are tests that are suitable for research and in-depth clinical use, they do not meet the medical and practical needs of speed, ease, and low cost for population surveillance. The Monell Center is actively addressing this gap and, in doing so, seeks to enable a fundamental change in healthcare.

The need for diagnostic smell testing was articulated in a study from the lab of Danielle Reed and published in Chemical Senses. It revealed that while about 75% of the people studied lost their sense of smell with Covid-19, not all of them were aware of their loss. Self-reporting of smell loss was an inferior measure compared to objective smell tests. In order to harness the diagnostic value of smell testing and make tests easier to administer and more readily available, Monell set out to develop a rapid smell test.

In September 2020 Co-Principal Investigators Dr. Pamela Dalton and Dr. Valentina Parma received a competitive NIH Award to develop the SCENTinel 1.0 rapid smell test. SCENTinel is designed to be an effective, easy to use test for clinical situations to identify individuals with smell loss, including Covid-19 symptom screening. The test has been licensed by a startup company that is taking it to commercial application, moving us closer to Monell’s goal of smell and taste testing for all.

Monell researchers are making great strides on the path to understanding viral-associated smell loss. In summer of 2020, Monell had raised private funds that allowed us to issue a request for proposals to our faculty seeking new research studies. Dr. Hong Wang leads the team awarded the funding, whose work addresses how to identify changes in olfactory tissue responsible for smell loss. Dr. Wang, an associate member of the Monell faculty, is a molecular biologist who has been investigating how inflammation alters or damages tissues involved in taste and smell.

Along with her Monell collaborators – Dr. Peihua Jiang, Dr. Akihito Kuboki and Dr. Johannes Reisert – Dr. Wang infected mice with the H1N1 flu virus as part of two-year study. They discovered that both the supporting cells and olfactory receptor neurons were damaged by the flu virus. These results align with other recent studies that show the SARS-CoV-2 virus significantly damages olfactory support cells, thereby causing changes to the olfactory tissue responsible for smell loss.

In the first year of work, Dr. Wang’s team saw evidence that certain genetic mutations in viral defense mechanisms lead to more severe olfactory loss after viral infection. Inborn errors in these genes have been reported in some human patients. Potentially, such genetic errors may also contribute to long-term olfactory loss associated with respiratory viral infection. Based on promising data, the team has been awarded additional philanthropic funds to expand their research to determine the underlying mechanisms of significant loss of olfactory sensory neurons and function. The team is readying to submit a proposal to the NIH to more fully investigate how olfactory tissues recover from respiratory viral infection and what factors control whether the sense of smell is fully restored or not. Insights from these studies of the mechanisms for viral-associated smell loss will inform the development of treatments for smell loss.

Discovering which genes cause anosmia at birth could lead to gene therapies to restore the sense of smell not only for congenital anosmics, but also for others who suffer from full or partial loss of smell. The lab of Dr. Joel Mainland has been studying genetic inheritance patterns as part of a NIH grant to identify genes that cause congenital anosmia.

As of fall 2021, they have sequenced and identified more than 20,000 genes for each member in 10 families that include at least two congenital anosmics. They have now analyzed this large data set looking for patterns of gene variants that are more likely to occur in anosmic family members, both within and across different families. This research is especially challenging because researchers have identified only two genes associated with congenital smell loss, while more than 200 genes are implicated in patients born without sight and 100 altered genes have been discovered in patients born without hearing.

The Mainland group uses whole-exome sequencing, which captures all of the genes involved in protein synthesis. More than 20,000 genes are analyzed for each individual in the study. The Mainland lab has generated a list of candidate anosmia genes, and as they sequence more samples, this list will be refined to prioritize gene variants found in multiple unrelated affected individuals.

Our lack of understanding of congenital anosmia prevents many anosmics from knowing if their condition is acquired or genetic, temporary or permanent, and provides them little hope for diagnosis and treatment. The work of the Mainland lab promises to provide critical knowledge about this condition.

In one area of research, we seek to understand olfactory stem cells with an eye toward the ultimate goal of regenerative medicine — using the body’s own cells to restore functions that are otherwise lost. Taste and odor receptors normally regenerate. But disease, aging, trauma, and other factors can diminish or erase this capacity, which exacerbates smell dysfunction.

Dr. Peihua Jiang hopes to find a way to harness the regenerative ability of olfactory neurons and use it to restore the sense of smell in anosmics.

To do this, Dr. Jiang and his team are identifying physiological factors that cause olfactory stem cells to grow and differentiate into functional receptors for smell. Dr. Jiang’s group worked with different growth factors in cell culture media until they found a combination that allows mouse olfactory stem cells to replicate and differentiate into mature olfactory neurons within mini-organs (“organoids”).

Now Dr. Jiang is able to culture mouse nasal stem cells that grow into a three-dimensional olfactory organoids, which produce functional olfactory receptor neurons that respond to odors. This is a very promising finding, suggesting that growth factors used to culture olfactory stem cells in a dish might be able to stimulate stem cells in the nasal cavity of an individual to grow into functional olfactory receptors. He is currently testing whether these growth factors injected into anosmic mice produce new olfactory receptors and restore their sense of smell.

Dr. Akihito Kuboki, a research associate in Johannes Reisert’s lab, suspected that insulin might play a role in the maturation of olfactory sensory neurons (OSNs) after injury because insulin is part of the body’s repair pathway for visual neurons. But, relatively little was known about the role of insulin in the sense of smell.

The team found that insulin plays a critical role in the regeneration of OSNs after injury, particularly during their immature stage. The results were published in the journal eNeuro in April 2021.

Not only do these findings suggest that applying insulin into the nasal passage could be developed as a therapy for smell dysfunction, their work identified a critical time window for treatment. OSNs are highly susceptible to insulin deprivation-induced cell death eight to 13 days after an injury. It is during that critical stage that newly generated OSNs are dependent on insulin. When they applied insulin to the regenerating OSNs at this critical time point, the mouse’s sense of smell was restored.

The research team induced diabetes type 1 in mice to reduce levels of circulating insulin reaching the OSNs. The reduced insulin interfered with the regeneration of OSNs, resulting in an impaired sense of smell. They analyzed how the structure of the olfactory tissue in the nasal cavity and the olfactory bulb is impaired by comparing the number of mature OSNs and how well the axons of OSNs reached the olfactory bulb.

The team also recorded odorant-induced responses in the OSNs in the nasal cavity. They used an odor-guided behavioral task, in which the mice needed to find a cookie reward depending on their ability to smell, to measure olfactory function. This work shows that insulin plays a key role in preventing cell death, which can explain how diabetes contributes to smell loss.

Monell scientists Pamela Dalton, Nancy Rawson, and Stephanie Hunter are part of the research team with Thomas Jefferson University Hospital, led by Thomas Jefferson University Hospital otolaryngologist Dr. David Rosen, of a first-of-its-kind topical platelet-rich plasma (PRP) treatment for smell loss.

The new topical PRP treatment consists of monthly applications for a minimum of three months. A recent phase I clinical trial of eight patients who had at least six months of olfactory disturbance has shown preliminary success with 50 percent of participants experiencing clinically significant improvements in smell and taste. The phase II study aims to exclusively look at patients who developed long term olfactory disturbance following recovery from COVID-19 infection.

Individuals interested in learning more about this treatment or who wish to schedule a consultation can call 1-800-JEFF-NOW (1-800-533-3669), email smell@jefferson.edu, or visit JeffersonHealth.org/otolaryngology.

Under the leadership of Monell Principal Investigators Nancy Rawson and Pamela Dalton, Monell has established a multi-stakeholder working group to create a joint research agenda for taste and smell disorders. Members include Monell, the Smell and Taste Association of North America (STANA), and the Otolaryngology Department at Thomas Jefferson University Hospital in Philadelphia.

The working group will establish a shared research plan and roadmap for studying smell and taste disorders. It is made possible through a contract from the Patient Centered Outcomes Research Institute (PCORI). In addition, work conducted through the PCORI project will review and update recommendations that arose from the 2018 Identifying Treatments for Taste and Smell Disorders conference (ITTSD).

The project builds on Monell’s long-time Chemosensory Clinical Research Center with Jefferson, which operated with funding from the National Institutes of Health (NIH), from 1986 to 2009 to assess the taste and smell function of patients.

Monell is dedicated to the study of sensory nutrition, a unique and timely marriage of two disciplines: sensory science and nutrition. Building the knowledge base of this nascent but terribly important part of the human experience, sensory nutrition is a part of Monell’s strategic aims. Estimates now project that, globally, approximately 18 million people will have new and/or long-term chemosensory loss from Covid-19; hence this effort is even more relevant than when we first described it in our 2018 Strategic Plan. Studies planned include comparisons of post-acute Covid-19 patients who have recovered their taste loss and those who have not in order to determine the role of taste loss in body weight and obesity for both populations.

In other strides towards nutritional health, in August 2021, Dr. Stephanie Hunter was the first researcher to win a research grant from the patient advocacy organization AbScent for her project on food enjoyment among individuals with smell loss. This study will be of immediate help to patients grappling with nutritional health.

Shortly after launching Smell for Life, the Monell Center hosted Chrissi Kelly to do a smell training session in Philadelphia. She has since founded AbScent, a UK-registered charity funding research to end smell disorders and supporting people who are experiencing the distressing effects of smell loss.

Anosmia Awareness Day, which takes place each year on February 27th, continues to be an important gathering place for individuals with taste and smell disorders and disruptions. Founded by Daniel Schein, who spent two summers doing research at Monell, this annual reminder that millions live with smell differences has grown by leaps and bounds over the years.

In 2017, the Monell Center held a talk by Duncan Boak of Fifth Sense. Boak spoke about the founding and mission of Fifth Sense, the first UK charity that was established to provide education, information, support, advice and guidance to people and their families affected by smell and taste disorders.

Fragrance Day is an annual event of the Fragrance Foundation, the leading association for the fragrance industry, often featuring Monell scientists in the line up of expert speakers.

What happens when an award-winning scientist known for studying odor processing starts a gallery? Olfactory Art Keller, by Dr. Andreas Keller, offers a regular schedule of exhibits using scents as aesthetic experiences.

In early 2020, Monell representatives began advising a group of emerging patient advocates in the United States. From our early convenings, we are proud to announce that these patients have now established the first 501c3 organization to serve North American patients with taste and smell disorders. Called the Smell and Taste Association of North America (STANA), the organization is partnering with others worldwide to build awareness while focusing on advocacy relevant to those living in North America. STANA’s formation is quite important because patients can advocate for awareness and funding in a way that we, as researchers, cannot. In 2023, STANA launched a petition calling for universal smell and taste testing.

In 2021, the Monell Center led the effort to establish the first-ever World Taste & Smell Day. The launch took place on September 14th, 2021 featuring an online world exploratorium of taste and smell, which crowdsourced taste and smell experiences from around the world. Funds were raised to support patient advocacy efforts. WTSD is now a free-standing non-profit organization.