COVID is inspiring smell scientists to explore exciting new frontiers

Just over five years ago, while listening to some friends gripe about the overwhelming aroma of a nearby lemon candle, it struck me that not only could I not smell that scent, I couldn’t recall the last time I’d smelled any citrus. In fact, I couldn’t remember what citrus was meant to smell like.

Fairly jarred, I decided to start making little, surreptitious notes day-to-day about what I smelled versus what other people said they could smell. I soon realized I was slowly losing my sense of smell. I’m still not sure why. (Smell loss is a possible yet under-studied symptom of a progressive neurological disorder I’ve lived with since childhood, though I have yet to firmly establish that link.) But whatever the cause, as my smell has worsened I've gradually come to appreciate that olfactory disorders are not just a minor inconvenience. They're a major disruption to the way that I and many other people experience and navigate the world around us.

At its most mundane, smell loss disrupts our ability to appreciate pleasant aromas, or the flavor of food. In fact, many people with smell loss lose interest in food altogether, describing eating as a dull chore. Chrissi Kelly, a fellow smell loss sufferer and founder of the smell disorder patient advocate group AbScent, adds that the effects of olfactory issues can be even more profound. “Smell is closely aligned with our sense of self,” she tells Mic. “Think of the smell of your house, your bed, your children. Without smell, our experience of existence is flattened.” As such, it’s easy, after losing some or all of your smell, to fall into a general depressive spiral.

Smell loss has historically been hard to manage because medical experts have long viewed chronic and severe olfactory disorders as relatively rare — most common among the elderly and those with much more pressing health concerns. So for decades now, few researchers have dug into, and few medical care providers have received meaningful education in, smell loss and its cascading effects on people’s lives.

But in the first days of 2020, the world’s small clutch of smell scientists started getting tons of calls and emails from doctors all over, reporting a massive spike in patients suffering sudden and severe olfactory issues, and asking for help in figuring out what was going on and how to handle it. Fast forward two years, and we now know smell loss is one of the most distinctive and prevalent symptoms of COVID-19. Recent surveys suggest that at least half of everyone with symptomatic Covid experiences it to some degree. Often, it’s the first clear sign, or the only major symptom, people get of the disease.

For most people, this wave of smell loss is just one more line in the litany of pandemic pain and suffering. But many smell scientists see a silver lining within this mass misfortune: The dire public health need to understand the dynamics of this unprecedented and likely enduring problem has generated a surge of interest in — and new funding for — their long-neglected field of research. And the size and nature of the Covid patient pool has opened up novel and promising research opportunities.

“Obviously, it’s not good that anyone has had to lose their sense of smell,” stresses Alan Hirsch, a doctor at the Smell and Taste Treatment and Research Foundation in Chicago. “But as a result of this pandemic, we may develop a much better perspective on the mechanisms of smell, and how to treat smell loss overall.” Including, potentially, my own odd olfactory issues.

These patients all know exactly when and why they lost their sense of smell. So, using them as a test population for treatments new and old may yield particularly robust results.

Although people with smell loss have historically felt like isolated aberrations, even in the pre-Covid era olfactory issues were actually fairly common. Smell loss is a typical symptom of respiratory viruses like the common cold, and a hallmark of early-stage Alzheimer’s, Parkinson’s, and other neurodegenerative disorders. Head trauma, nasal polyps, and aging can all cause some degree of smell loss, too.

However, Pamela Silberman of the Smell and Taste Association of North America, another smell loss patient advocacy group, points out that doctors don’t regularly monitor olfaction. And while people often register anosmia, a total and often sudden loss of smell, and report it to doctors, they are far less likely to bring up hyposmia, piecemeal smell loss, especially if it’s minor or comes on gradually. Yet by all accounts hyposmia is far more common than anosmia. So, we’ve never been able to get a clear and meaningful snapshot of the scope and scale of the issue.

Smell lost to viruses also tends to return as nasal congestion and inflammation fade. Likewise, smell lost to polyps and other obstructions usually returns after a simple procedure to remove the blockage. These easy apparent resolutions, combined with a lack of active smell monitoring, have long made it easy for many medical experts to underestimate the prevalence of smell loss overall, and to write off chronic and severe cases in particular as relatively rare.

“Our society tends to view smell as a lesser sense,” adds Hirsch. We’re rarely as aware of it as we are of sight, hearing, and touch. We also discount smell as our least-developed sense, convinced that it’s more important for snout-y animals like dogs. (Our noses work actually about as well as most animals’. Most people just fail to hone or utilize their latent sensory capacity.)

Smell has “historically been a very fringe subject to investigate,” Hirsh says. “Not many people spend their lives on it.” And those who do often struggle to secure funding for their research.

The research that smell scientists have managed to conduct over the last two decades has mainly revealed that olfaction is far more complex than most of us might expect. Sure, it seems simple: Receptors in our nose and the back of our throat pick up on odor molecules in the air and use just one nerve to send a signal to our brains, which translates that information into our sense of smell. But we’ve learned, for instance, that high versus low concentrations of the same molecule can read as radically different smells. That our brains don’t just mix together diverse odor molecules like a paint blend, but instead translate them into seemingly unrelated smells. And that the order in which smell receptors pick up on odor molecules can have a huge effect on what we actually smell. Diverse genetic and environmental factors, as well as personal experience, also lead each of us to develop unique sensitivities to or interpretations of particular smells.

These insights explain why, say, a musty old shirt may smell subtle and sweet to you, but reek of rancidity to everyone else. They also explain why even two people who develop partial smell loss (which usually affects our ability to detect or interpret specific odors as opposed to dampening our ability to smell across the board) for the same reason may have very different experiences.

Our understanding of smell is so anemic that experts are actually still debating how many distinct odors humans are actually physically capable of detecting. Some researchers say it’s around 10,000, while others say it’s more like 1 trillion.

But the numerous remaining gaps in our understanding of the mechanisms of smell perception leave us with few concrete insights on how to address diverse, often idiosyncratic, experiences of smell loss. A 2020 conference on this topic noted that there are few established treatments for long-term and severe olfactory issues — and those that exist aren’t actually backed by much robust and meaningful research data. Our understanding of smell is so anemic that experts are actually still debating how many distinct odors humans are actually physically capable of detecting. Some researchers say it’s around 10,000, while others say it’s more like 1 trillion.

Past attempts to dig deeper into the nuts and bolts of varied smell issues, and investigate viable means of treating them, often hit a frustrating logistical wall, explains Jay Piccirillo, a professor of otolaryngology at the Washington University School of Medicine in St. Louis. “The patients we work with often didn’t know exactly when they lost, or started losing, their sense of smell. My past research focused on the loss of smell following a viral infection. But we rarely knew exactly what type of virus had affected each individual. So, our patients were a hodgepodge.”

“Clinical research has been on autopilot” for years, argues Avery Gilbert, an independent smell researcher. “Almost no recent studies have illuminated the mechanisms of smell, or explored possible [novel] treatments for smell loss.”

In early 2020, as smell scientists started to recognize the impact of Covid on olfaction, they got to talking about how they might be able to coordinate efforts and resources to start digging into the issue. Valentina Parma of the Monell Chemical Senses Center, one of the few notable hubs for olfactory research, says she initially expected some short-term dialogue between 50 leading specialists. But by February, these conversations coalesced into a formalized collaboration, the Global Chemosensory Research Consortium, looping in folks from external but relevant fields like neurobiology to push forward rapid research on Covid’s effects on smell, taste, and more.

“We have people talking every single day, sharing what they know,” says Parma. They currently have over 700 active members, “really trying to work across fields to make things happen.”

As the connection between Covid and smell loss solidified throughout 2020 — and especially as it became clear that a notable portion of patients seem to suffer enduring, potentially permanent olfactory issues even after their initial recovery from Covid — new funds started to flow into the field as well.

The experts Mic spoke with estimate that 10 to 20 percent of people who develop olfactory Covid symptoms will have some lingering smell loss. It may take years to tabulate firm numbers on permanent damage, as researchers know that sensory recovery can be a slow game of inches. But no matter how things shake out, Hirsh notes that the birth of “a huge new group of people — many young people with long lives ahead of them — who may respond to new medications that address chronic smell loss,” has also caught the eye of big pharma, with its deep pockets and drug development expertise.

“When people have developed, or witnessed, a problem for themselves, they become more empathetic to it” - Alan Hirsch

The fragrance and food industries are also reportedly starting to explore new research into tools and techniques that could help them reach hyposmic and anosmic shoppers. Although it is not clear how much these industries will invest in the issue, they add a substantial source of dollars, and a distinct set of expertise, to the pandemic era upsurge in olfactory research efforts.

Most research initiated in the wake of the pandemic is unsurprisingly focused on unpacking how the novel coronavirus specifically affects the olfactory system, what happens to patients over time, and what treatments this particular population responds to. Gilbert is skeptical about how much good this research will actually do, whether for Covid patients or in general. And Parma acknowledges that “there are a ton of people who became so-called ‘experts’ in the field overnight,” mainly to position themselves to sell dubious cures to this huge and often desperate patient population based on at times flimsy data. “Day in and day out, people I’ve never heard of proposing to sell kits contact us, seeking evidence to support their products,” she says.

But most smell scientists believe Covid-centric research will yield insights on the mechanisms of smell writ large — and new approaches to treating a wide array of olfactory issues. Notably, scientists still aren’t absolutely sure how Covid causes smell loss; the disease may actually be doing several things at once with the potential to affect smell, all in slightly different ways. However, emerging consensus holds that many cases of Covid-related smell loss are not the result of direct damage to smell receptors, or the olfactory nerve, but instead to the cells that provide structural support to them. Damage those cells hard enough or long enough, and you may end up permanently damaging receptors and the nerves themselves. Although perhaps a little wonky to an outside eye, that’s a striking new insight into how our smell system works — and into a mode of smell loss that few if any researchers had ever considered beforehand.

The rush to cure Covid-related smell loss has also subjected established but under-examined approaches to treating other olfactory issues to rigorous analysis. Piccirillo and his colleagues, for example, are digging into the efficacy of “smell training,” an approach pioneered over a decade ago in which smell loss patients take big, regular whiffs of concentrated odors, like peppermint oil, to try to stimulate their smell system, strengthening what’s left of it or spurring regeneration. It’s the go-to treatment for people with all sorts of olfactory issues — but the few small tests of the technique to date have shown inconsistent results at best. Other institutions have also started to explore novel treatments, like using omega-3 fatty acids to accelerate nasal cell healing. Even if they’re not successful, Piccirillo points out, some of these explorations may offer further insights into how our smell system works — and how we could potentially turbo charge it in the future.

“Covid-19 patients do not pose the same issues we’ve faced in previous studies,” Piccirillo notes. These patients all know exactly when and why they lost their sense of smell. So, using them as a test population for treatments new and old may yield particularly robust results.

On a more fundamental level, Parma adds, researchers have started to talk about how to address their limited ability to measure smell loss in individuals, given the lack of a clear baseline for their unique olfactory capabilities before Covid hit them in the nasal cavity. The Monell Center, among other institutions, are trying to use these conversations, and the general improvement of clinical awareness of smell loss and its effects on patients, to launch what they call SCENTinel, a program that would incorporate a rapid smell test into people’s annual physicals, slowly building up a rich body of data for reference in treating individuals — if not for the study of smell overall.

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“Most studies in our field take several years to complete,” Hirsch cautions. “We don’t move as fast as some other fields.” He believes it will take at least five years of concentrated research on Covid’s effects, and subjects branching off of this immediate concern, to start yielding notable insights into the science of smell, and how to treat all kinds of smell loss more effectively.

Gilbert and a handful of other researchers doubt that interest in and funding for smell science will last this long — especially as Covid and its symptoms hopefully start to fade from the headlines in the coming months and years. If that’s the case, then the substantial potential within the current mini-renaissance of pandemic era smell research may end up largely squandered.

But Parma says researchers are taking a proactive stance to try to keep smell loss in the public eye. A handful of them recently launched World Taste and Smell Day, which they intend to observe every September 14th, hopefully drawing industry, public, and press attention to the topic as they do. The pandemic has also energized and expanded patient advocacy groups, which intend to help marshal funding, logistical support, and public interest in ongoing research efforts.

“When people have developed, or witnessed, a problem for themselves, they become more empathetic to it,” adds Hirsch. Even if acute awareness fades, he believes the pandemic will leave fertile ground behind for activists to do their work, and researchers to ply their trade. So, he’s confident that this minor research renaissance will last long enough to yield major results. Or, put another way, that the horrors of Covid will revolutionize our understanding of smell — and our ability to help millions who’ve long coped with smell loss alone, with no hope in sight. Myself included.

“Hopefully, we’ll never have this opportunity again in our lifetimes,” Piccirillo adds. “We really should take advantage of it, in order to help Covid patients, and others in the future.”