Remembering Smell (20 page)

These neuroanatomical black holes can have bizarre effects. Patients try to cover up their memory deficits by confabulating, making up information to fill in the gaps in their memories. One Korsakoff's patient was described in Oliver Sacks's "The Lost Mariner." This man had no short-term memory and had "misplaced" almost thirty years of his life. Another Korsakoff's victim inspired a film that starred the comic actor Peter Sellers; in it, the protagonist embellishes (beyond recognition) his former medical career. Interestingly, victims of Korsakoff's can't tell odors apart or recognize faces, and they often suffer debilitating depression.

Patients with Huntington's chorea follow a similar emotional and olfactory path. First they lose the ability to express visually (for example, with a curled lip) their revulsion for unpleasant odors. Soon after they lose the sense of smell. Psychiatric symptoms of this congenital disease, which eventually destroys the nervous system, include anxiety and depression, compulsive and addictive behaviors, and problems recognizing others' emotional responses.

The same year that Richard Axel took his Nobel home to Columbia, a team of neuroscientists and pathologists at Johns Hopkins raised hopes that Lou Gehrig's disease might one day be curable through gene therapy. The researchers had prolonged the lives of diseased mice by transplanting adult stem cells from the olfactory bulbs of healthy mice. The adult human olfactory bulb is now regarded as a potential nonembryonic source of stem cells to help those who've lost nerve cells due to injury or diseases like ALS and Parkinson's.

In 2007 a group of researchers in New Zealand happened upon what they called a cell "superhighway," a pathway that conducts stem cells from the olfactory bulb to the rest of the limbic system, apparently dropping some off via exit ramps throughout the brain. Their findings (inspired by a 1998 discovery of neurogenesis in rats and brought about by a decision to slice the brain in such a way that the pathway was immediately discernible) challenged the long-standing assumption that cells in the brain—other than olfactory cells—can't replace themselves. The lead New Zealand scientist believes that most new neurons are diverted before they reach the olfactory cortex, making them available for other brain repair.

In an interview on National Public Radio in February 2007, Richard Faull, who is an expert on brain diseases at the University of Auckland, described his team's extraordinary discovery. "It's like the freeway from Boston to Washington, D.C. It's actually got off-ramps going off to New York and all the rest of it. And we are seeing hints that cells are leaving this pathway well before the end of it."

Writer and former memory researcher Jonah Lehrer thinks the new cells are going to places involved in more important functions, like memory or motion. "These new brain cells may be vital to keeping these parts of the brain working." Story Landis, director of the National Institute of Neurological Disorders and Stroke, is hopeful that researchers can use the pathway to repair damage caused by the spectrum of neurological disorders, from Parkinson's and Alzheimer's to stroke.

I'd been without smell for fully five months. What had begun as a casual interest in smell was now an obsession.
Casual
is the wrong word. I was obsessed from day one—that being the day I started smelling things that weren't there, back in October. Internet browsing was being replaced by long phone conversations with important scientists. I'd even managed to arrange to visit the famous Axel lab at Columbia University.

I was greeted in the first-floor reception area by one of Axel's postdocs. Dan Stettler handed me a security badge, took me up in a tiny elevator to the tenth floor of the Julius and Armand Hammer Health Services Center, and ushered me into the lab, apologizing for the "awful stench." I didn't bother to remind him I couldn't smell it.

Dan admitted he was "a little OCD." He'd scrubbed down the entire lab the first week he'd worked there. It had been pretty disgusting, he said. Labs like this one wear their slovenliness like a badge of honor. Chemicals are smelly, especially the ones in a smell-science lab. In the postdoc's "office" (too glamorous a word for what consisted of a long counter with a computer on it), a graduate student was applying special dyes to the olfactory bulb of an anesthetized mouse. Dan bumped her arm and then apologized profusely. No harm done, she assured him.

Soon the sleeping mouse was ready for the trip to the two-photon microscope. Colors emanating from the mouse's olfactory bulb and olfactory cortex lit up as the mouse sniffed various fragrances: camphor, banana. (Humans, interestingly, don't experience odor sensation during sleep, but lower mammals do, presumably for the same reason that lower mammals smell more acutely than we do—their survival depends on being in a constant state of high alert against predators.)

The colors represent patterns of neuron activity, Dan said. He was in a good mood. Just the day before, after many false starts, he'd figured out how to display these same color arrays on a computer screen for his boss's PowerPoint presentations. These days, Axel relies on funding from various foundations to keep the lab supplied with postdocs, lab assistants, and two-photon microscopes; visuals are the bells and whistles for his presentations, but the "red meat," as scientists like to say, is the talk of medical breakthroughs.

Smell research is reaping unexpected rewards in the meat department. The study of all types of infectious diseases, neurological disorders, mental illnesses, and even cancers will certainly benefit from the work going on in this and other smell labs as scientists learn more about the mysterious ways in which environmental factors can trigger chain reactions that make us sick.

Yale researchers created the world's first olfactory map. They found a mutant fruit fly that had an olfactory neuron lacking an attached odor receptor; that neuron didn't respond to any smells. Using genetic engineering, the researchers created several mutant flies that each had a different odor receptor attached to the previously receptorless neuron. They then tested each fly and established a receptor-to-neuron map. The scientists are hoping the map will serve as a model for the smell systems of insects that transmit disease, such as mosquitoes, as well as for smell systems of more complex organisms, including humans. Related studies with fruit flies published in 2007 showed how two genes allow flies to follow the scent of carbon dioxide; work on the molecular characteristics of odor perception in frogs may shed light on how malaria-spreading mosquitoes detect host odors.

Richard Axel frequently invokes the M-word. And why not? It's a jungle out there. Bill Gates isn't the first zillionaire philanthropist bent on eradicating disease. Centuries from now, the late Howard Hughes may be remembered not as an eccentric oil man who loved airplanes but as the man whose foundation, the Howard Hughes Medical Institute, funded the United States' top scientists. Richard Axel and Linda Buck, the biologist who shared the 2004 Nobel with him, both belong to this elite group. Howard Hughes investigators have access to more than money—they get to swap ideas with the best and brightest.

Not all are thrilled by the growing emphasis on "translational" research—where the focus is on tangible scientific consequences (breakthroughs, applications, products)—some want to get back to basic science. Caltech neurobiologist and HHMI investigator David J. Anderson, a former Axel postdoc, raised eyebrows when he abruptly shifted from mice to fruit flies in his quest to understand the connection between olfaction and behavior. Flies are an essential tool in biology labs because of their structural simplicity. Says Anderson, "In over four hundred million years of evolution, the same neural circuit organization has been conserved, even when the molecules themselves have not. And if this circuitry has been conserved, perhaps emotional responses have been as well." Anderson wants to know if, for example, the avoidance behavior of a fly to the smell of carbon dioxide represents an emotional response. This begs the question: What is emotion? And how did the earliest instinctive survival responses evolve into feelings?

Surely mice, being more like us than insects are, can provide solutions to medical problems more readily than flies can. To defend Anderson's work, some have suggested that a new type of antidepressant could come out of it. But to Anderson, that's a pretty big leap, and not his objective. The beauty of being an HHMI investigator, he says, is that the institute supports basic research. People like himself, Axel, Buck, and others interested in smell genetics can pursue any line of research that might lead to a better understanding of the brain. Switching from mice to flies in his lab required a huge learning curve for Anderson, one Axel also undertook when he brought fruit flies into his lab a few years back. "I feel like a graduate student again," Anderson says. He now thinks the structure of flies' wing positions may indicate their mood (for example, whether they want to avoid danger or mate).

Anderson and Axel have joined forces, applying their knowledge of fruit flies and mice to better understand how such behaviors evolved. Genes don't control behavior, but they design the neurons that do. By comparing similarities and differences between vertebrates and invertebrates, the scientists are hoping to figure out how and why their evolutionary paths diverged and what genetic mechanisms were at work.

Axel has found similar structural schemes in both mice and fruit flies. This indicates that all neurons that express a common olfactory receptor in these species have axons that converge on a single point in the brain.

Radically new treatments for a range of disorders may be on the horizon thanks to smell research. To find out about one new treatment, I didn't have to look much farther than my own backyard. University of Minnesota physician and smell researcher William Frey runs an Alzheimer's research center out of Regions Hospital in St. Paul. He and colleagues in Germany successfully implanted stem cells in the brains of rats and mice by a method they call snorting. The rodents are trained to sniff hard. Frey says one in ten cells makes it up the nasal cavity, through the skull, up the fluids in the olfactory pathways, all the way to the cerebral cortex, and finally out to the cerebellum. The farther the journey, the fewer the cells that show up in scans of the rodents' brains, but Frey believes he can improve the odds and that his technique will one day be the gold standard for stem cell implantation in the brain. Snorting is less likely than surgery to cause inflammation and other problems that could interfere with the cells' success in restoring brain function to damaged regions. Snorting is easier on the stem cells themselves and on the patients. And, unlike rats, people don't have to be trained to inhale sharply.

Northwestern's Jay Gottfried has nothing against smell research but deplores the lack of attention paid to smell itself. He complains that olfaction gets little attention in neurology textbooks and that this is a glaring omission. Why? Because smell dysfunction is a valuable diagnostic tool.

In other words, smell-dysfunction research itself is of minimal consequence unless it sheds light on how a toxin disturbs the olfactory system on its way to more "important" regions. Collateral damage. As I mined the medical literature for links between smell dysfunction and other diseases, it was all too obvious where priorities lay. Anosmia and phantosmia were side effects, symptoms, clues. They were not considered serious illnesses.

I seemed to have come full circle, for the truly serious illnesses were the very same disorders I'd imagined I had in the fall—Parkinson's, MS, schizophrenia, Alzheimer's. I could now toss in Lou Gehrig's disease, Huntington's disease, and Korsakoff's syndrome. With so many calamitous possibilities out there, how could I
not
have one? Or at the very least, some minor and heretofore undocumented variation?

Don't go there.

I took it as a sign of recovery that I didn't go there. My mood was unquestionably on the mend, even if my nose wasn't. Was it the SSRI I'd been taking since Christmas? Was Lexapro finally kicking in?

O
NE REASON WHY
the nose has been neglected is that smell dysfunction is relatively rare. In humans, the sense of smell actually
outlasts
vision and hearing. Before you counter that your grandmother sees just fine but can't smell a thing, think about those glasses she's wearing. While the nose makes a dandy perch, nothing gives
it
a boost later in life. We're so tuned in to vision that we don't see bifocals as signaling the onset of our inevitable (if we live long enough) blindness. Note the use of the word
see
in that sentence. We esteem vision so highly that we've come to say
see
when we mean "think."

Hearing begins to deteriorate earlier than olfaction too. A 2008 study found that 8.5 percent of people in their twenties have some hearing loss.

You have to search hard to find an anosmic that young. Two percent of the population below sixty-five is essentially smell-blind; a quarter of that 2 percent was born without smell. Smell declines precipitously in old age; half of all eighty-year-olds report diminished smell. An estimated half a million people annually see a doctor about olfactory problems.

Gerontologists invariably blame depression for their patients' poor appetites, even though depression is actually less common in the elderly than in the general population—unless the elderly person is anosmic.

It's not simply because hearing and vision problems show up earlier in life than smell problems that medical science has made a sizable investment in hearing aids and eyeglasses. Bias against smell is expressed by the AMA in its impairment assessment. Deafness is taken so seriously that parents who've passed deafness on to a child feel pressured to give the child the gift of hearing—a cochlear implant. (Understandably, many such parents want their children to hear the way they do, through sign language.) A ninety-five-year-old California man who'd gone deaf managed to persuade his insurance company to cover his expensive implant because he said it would improve his health (lower his risk of a stroke or heart attack) by assuaging his loneliness.