Restoring Scents

Betty (not her real name) remembers the day 9 years ago when she fully experienced an orange. As she split the fruit’s skin, citrus scents sprayed into the air and the 51-year-old woman experienced a sensory epiphany: “Whoa! This is an orange. My God, this is what an orange smells like.”

Even now, she says, recalling that day “makes me tear up because that orange was the very first thing I smelled.” Ever.

“There are probably around 25 million people in this country who have some olfactory problem,” observes Barry Davis, who directs the taste and smell program at the National Institute on Deafness and Other Communication Disorders in Bethesda, Md.

Few people lack all sense of smell. Among these, Davis notes, only a tiny share were either born that way, as Betty was, or lost olfaction so early that they can’t recall being able to smell.

More common is a gradual diminution of olfaction among seniors, notes Beverly J. Cowart, a sensory psychologist at the Monell Chemical Senses Center in Philadelphia. By age 70, she says, “some degree of smell loss will be close to universal.”

Smell loss can also follow head trauma, arise as a complication of respiratory or brain disease, or signal pollutant poisoning of nasal cells.

Many research programs are not only probing what underlies loss of the sense of smell, but also investigating ways to restore it. Strategies to achieve that goal include drug therapy, sniff training, and even reseeding the nasal lining with stem cells.

Prodding the research is recognition that good olfaction can be a lifesaver, enabling people to detect gas leaks or pick up putrid warnings from spoiled food.

But for Betty, the main benefit has been an improved quality of life. She’s building an inventory of identifiable scents—from the fragrances of new-mown grass and roses, to the odor of a cat box. “I love that I can smell them all,” she gushes. “Well, maybe not the cat box.”

Taste versus flavor

Jason Feifer, an associate editor at Boston magazine, can’t smell a thing. However, he wasn’t aware of this sensory deprivation until he was in college and a girlfriend began constantly asking for his opinions on foods. It didn’t take long for him to realize that she was responding to cues that he couldn’t even vaguely detect.

“My taste buds work fine,” Feifer points out. “So I can detect sweet, salty, sour, and bitter.” Add in color, texture, and mouth feel—such as the smoothness of high-fat fare—and he could easily explain why he preferred some foods over others.

But blindfolded, he says, “I can’t tell the difference between mint and peanut butter–cup ice creams.” Fruits are sweet to Feifer, but with eyes closed, he can only guess their identity on the basis of texture and acidity.

He now suspects that when he can see what he’s eating, “my mind fills in some level of sensation that helps me differentiate between foods.”

“In fact, what most people call taste is really flavor,” a combination of the taste buds’ input with tactile impressions and scents, explains neurologist Robert I. Henkin, director of the Taste and Smell Clinic in Washington, D.C. Eliminate scents, Henkin says, and cherry, mint, and butterscotch candies all taste the same.

Smell killers

Feifer divulged a scary anecdote about the seriousness of his sensory deficit in the Nov. 1, 2005, Washington Post. While he was in the kitchen, his girlfriend called to him from another room to ask whether something was burning. “I said no,” Feifer recalls, and when his girlfriend asked if he was sure, he replied emphatically, “Yes, ma’am.”

In fact, a malfunctioning electric grill just inches away from him had begun spewing stinky, black smoke.

The episode prompted Feifer to get a thorough checkup at the taste and smell clinic of the University of Connecticut in Farmington. The good news: He got a clean bill of health—no brain tumor, serious congenital disease, or other detectable source of smell loss. But those negative findings also implied that he could expect no cure.

A host of conditions can trigger smell loss. Indeed, the olfactory system is fairly vulnerable, as it’s the only one of the human senses involving nerves from the brain that make contact with the outside world—on the inside of the nose.

Those thin, spaghettilike nerves run from the nose through an opening in a skull segment called the cribiform plate. Head trauma can sever the nerves, or if an injury shatters the plate, its aperture may close as the bone mends.

Severed olfactory nerves have the capacity to regenerate. If they reconnect to the brain, smell can return, notes James E. Schwob of the Tufts University School of Medicine in Boston. But if their conduit through the cribiform plate closes, smell loss will be irreversible.

Other major reasons for smell loss are respiratory infections and allergies. In rare cases, Schwob says, germs can move up the nerve and into the olfactory bulb, a relay station through which nerve signals enter the brain. If germs damage that bulb, scent data may not reach the tissues able to interpret them.

But the most common causes of smell loss in middle age, says Davis, are chronic inflammation of the nose due to infections and obstructions by growths called polyps. The latter can be surgically removed to restore smell. Steroids, which turn off inflammation, may also bring a rapid return of smell.

However, Davis notes, “sometimes chronic nose infections lead to permanent damage.” In those cases, scent receptors in the nasal lining may disappear. Local stem cells should replenish those receptor nerves—except that the stem cells may also disappear. When this happens, he says, “there’s no hope” of smell restoration—at least not yet.

Smell factors

Despite the generally grim prognosis for many smell-deprived individuals, there are emerging glimmers that some long-time sufferers will, like Betty, be cured.

Olfactory cells in the nasal lining, or epithelium, don’t proliferate by dividing. Instead, individual cells live for a while, then die on command, Henkin explains. Signaling agents such as tumor-necrosis factors (TNFs) give nasal olfactory cells the death sentence. Other signaling compounds known as growth factors then tell stem cells to wake up and divide, creating what will become new scent-sensing cells.

In May, at the Experimental Biology meeting in Washington, D.C., Henkin described his studies of these life-or-death signals in 273 patients, most with profound smell loss or no smell at all. He found that the amounts of two pivotal signal-messenger compounds, cyclic-AMP and cyclic-GMP, in nasal mucus correlated with the ability to smell. The poorer an individual’s olfaction, the lower the concentrations of these messenger molecules.

He also reported that the worse an individual’s sense of smell, the greater the ratio of death-signaling agents to growth factors in that person’s mucus.

For more than a decade, Henkin has been treating a small group of smell-deprived patients with a prescription form of theophylline, a caffeinelike stimulant that’s abundant in tea. Doctors typically prescribe theophylline for asthma, but Henkin reasoned that it might help his patients because the drug inhibits the breakdown of cyclic-AMP and cyclic-GMP. He also stumbled upon an additional benefit—the drug substantially ratchets down concentrations of death factors in nasal mucus.

At the Washington meeting, Henkin reported new data on 25 patients treated with theophylline. It didn’t help everyone, but Betty and 13 other patients responded.

Among such responders, growth-factor concentrations in nasal mucus skyrocketed. In some cases, concentrations had started at 0.5 percent of normal values. After treatment, concentrations “didn’t quite reach normal, but got close to it,” Henkin told Science News. Death-factor concentrations also fell to near-normal values.

Henkin cautions that it can take a long time before patients see a difference. Betty can attest to that. Every 3 months after her daily theophylline treatment began, she performed a battery of sniff tests. Henkin offered her three scents, one after another, then asked which smell was different from the other two. “I’d have no clue,” Betty says. “So, I’d just guess.”

Over the course of a year, her guesses became increasingly accurate, Henkin told her. “But I had to trust him on that,” she says, because she could not consciously tell that she was smelling anything at all.

Then came the day she smelled that orange. With continuing drug therapy, her olfaction has steadily improved, but her threshold for detecting odors remains high. She still can’t smell coffee brewing in an adjoining room.

Sniffs and more

Nancy E. Rawson of the Monell Center has been investigating a few other treatments. One that looked quite promising—vitamin A therapy—has turned disappointing.

Vitamin A has anti-inflammatory and skin-regenerating benefits. After learning that doctors would occasionally prescribe it to treat smell loss, Rawson and her team launched a pilot study in animals. A day after severing the olfactory nerves of mice, the researchers began administering vitamin A. To their amazement, it halved the animals’ smell-recovery time, when compared with recovery periods in untreated animals.

In repeated experiments since that first trial in 1999, the “findings hold up quite robustly,” Rawson says.

Several physicians who read the studies wanted to try vitamin A on their patients. Because excess vitamin A can be toxic, especially to a fetus, the Monell group recommended prescribing beta-carotene, the orange pigment in carrots. The body converts beta-carotene into vitamin A but shuts down the process before an excess builds up.

The treatment didn’t work. Cowart now suspects that far higher vitamin A doses may be needed—ones higher than the body will make from beta-carotene.

For now, Monell scientists have changed tack and are teaming with Thomas Hummel’s unit at the University of Dresden Medical School’s Smell and Taste Clinic in Germany to investigate sniff training. Patients with smell deficiencies sniff from each of several canisters of scented chemicals daily. Although some people initially smell nothing, each volunteer is told the source of the scent—lemon, for example—and asked to think about it as he or she takes in whiffs for 5 to 10 seconds.

In one preliminary trial in Germany, 47 people with partial or total smell loss took part in this sniff training; another 15 with similar smell problems did not. At the end of a 3-month program, “using highly sophisticated tools, we could measure an improvement of more than 15 percent” in the ability of people in the trained group to detect and identify scents, Hummel says. “In addition, this group was able to recognize odors that it hadn’t before.”

The treatment may train the brain to pick out scent signals from what had been olfactory noise, Rawson speculates.

Or, Hummel says, it might be that the strong scents he used also helped stimulate the regeneration of nasal sensory cells. In test-tube studies, such cells grow better when exposed to scents.

Tufts scientists are among several groups exploring a far more ambitious therapy: growing nasal-epithelium stem cells in the lab so that they can be grafted into noses devoid of them. In animals, Schwob says, “we have taken [nasal stem] cells from one animal, engrafted them into another, and they’ll divide, differentiate, and make new neurons.” Moreover, he says, those new nerves make connections to the brain.

Working the same trick with human-olfactory stem cells has proved challenging, however. Recognizing such cells in a donor’s nasal tissue is not easy, Schwob says, and the stem cells don’t grow well in the lab.

Indeed, Henkin says that there’s much to learn about the environment that the cells of faulty sniffers need in order to regenerate. But the payoff for success, he says, is watching patients come alive to the scents around them.

In particular, Betty says, “I’ve learned how wonderful foods can smell and taste.” It’s something that her husband no doubt appreciates: He’s a chef.

Of course, there can be one weighty side effect of gaining smell. “When I first was beginning to smell things, I became ravenous,” Betty says. “I don’t know if food tasted better or the new scents just stimulated my appetite. But I [temporarily] gained 30 pounds over the first couple years.”

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Beyond the Nose

Smell studies may offer nonolfactory benefits

Smell loss may be an early diagnostic symptom of Alzheimer’s disease, new data indicate. Ten years ago, scientists at Rush University Medical Center in Chicago recruited more than 1,000 area seniors, all about 80 years old, into the hospital’s Memory and Aging Project. At enrollment, the volunteers took scratch-and-sniff tests of their ability to recognize such familiar odors as turpentine, soap, and lemon.

After the recruits die, Robert S. Wilson and his colleagues at Rush compare data from those smell-recognition tests with autopsy analyses of cell-fiber tangles in the brain—one hallmark of Alzheimer’s disease.

Data from the first 129 individuals show that the more trouble a person had identifying smells accurately, the greater the number of tangles that showed up in the brain’s olfactory area. This link was strong even in people “with no cognitive impairment” when the smell testing took place, Wilson told Science News, suggesting “that problems in smell ability may be a very early sign of [Alzheimer’s] disease.” His team’s findings appeared in the January Journal of Neurology, Neurosurgery, and Psychiatry.

In the early stages of Alzheimer’s, nerve connections between the nose and brain may work fine, Wilson says. The problem may lie in the inability of brain tissue riddled with tangles to make sense of odor signals.

A new tool developed by Robert A. Frank and his colleagues of the University of Cincinnati may help researchers such as Wilson continue their smell analyses in people with Alzheimer’s, other dementias, Parkinson’s disease, or olfactory loss alone. Frank’s team devised canisters that open when people stick their noses into them and inhale. The more quickly a person notices an odor, the smaller the sniff he or she takes. Computers monitor each inhalation’s length and intensity, thereby gauging ability to smell in people who may not be able to speak or even think clearly, says Frank.

Wilson adds that smell testing may one day help identify patients with Alzheimer’s and other neurological conditions before dementia or other crippling symptoms set in—a time when therapy can be most effective.