We stood around the body planning our autopsy strategy. A scalpel, we realized, was not going to be the appropriate implement for this corpse, so we made our decision.
It took all three of us to muscle the slippery black bulk of the pilot whale into the screaming blur of the band-saw blade.
The whale had died of natural causes, after a distinguished military tenure conducting deep-sea operations for the U.S. Navy, which sends marine mammals to places where humans cannot safely go. In death, it was going to perform one more service—provide us with information about its magnificent brain. The navy had invited researchers at the Scripps Institution of Oceanography in La Jolla, Calif., to come to its base in San Diego in the mid-1980s, and I had joined them. Dressed like fishmongers in black rubber smocks and boots, anatomist Leo S. Demski, then visiting from the University of Kentucky, veterinarian Sam H. Ridgway, now at the National Marine Mammal Foundation, and I sought to unravel a scientific mystery. It was imperative that we learn whether the whale had a certain cranial nerve—for reasons that will soon become apparent.
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Every picture of the human brain you have seen is wrong. Something is missing, and the omission is not trivial. The dirty little secret is a tiny, relatively unstudied nerve sprouting from the base of the brain whose function is only now becoming clear: subliminal sexual attraction. Many scientists believe that pheromones, those silent chemical messages exchanged by members of the opposite sex in search of mates, relay subconscious signals to the brain through this obscure nerve. Others are skeptical. How can a little-studied nerve be involved in activities with such important implications for human behavior—especially when anatomists have scrutinized every minute detail of the human body for centuries? Could there be more to choosing a mate than we consciously realize? Researchers like us have been working to find out.
Tracking this mysterious cranial nerve brought me to the pilot whale, as a model for understanding our fellow mammals. For reasons that I will explain, it was particularly important to find out if this nerve exists in whales.
Most nerves enter the brain through the spinal cord, but some—the cranial nerves—enter the brain directly. The existence of some of the cranial nerves, if not their precise function, has been known since the time of Greek philosopher and physician Galen (who lived circa a.d. 129–210). Today we understand that they provide the vital senses of smell, sight, hearing, taste and touch; they are also involved in the movement of the eyes, jaw, tongue and face. Cranial nerves emerge from the floor of the brain in pairs, like a multilegged centipede. As medical students know, each nerve pair is numbered in sequence from the front of the brain (closest to the forehead) to the back (near the spinal cord).
Cranial nerve one is the olfactory nerve. All scents enter our brain through this nerve. Next, immediately behind the olfactory nerve, is cranial nerve two, the optic nerve. The optic nerve connects the eyes to the brain. The pairs continue in sequence to the 12th cranial nerve, which extends from the tongue and enters the brain near the spinal cord. Each pair was carefully identified, numbered and studied in detail. Then, in the late 1800s, neuroanatomists had their tidy understanding of cranial nerves attacked, so to speak, by a shark.
In 1878 German scientist Gustav Fritsch noticed a slender cranial nerve entering the brain of a shark just ahead of all the known nerves. No one had noticed it before. Even today countless anatomy students dissect dogfish sharks, but few detect the nerve because it is still not in the textbooks.
The discovery put anatomists in a predicament. Because it was located in front of the olfactory nerve, the new nerve should have been named cranial nerve one. But renumbering all the cranial nerves at this point was impossible because their identities were deeply entrenched in the medical vocabulary. The solution was to christen this new find “nerve zero,” the “terminal nerve.” Most people forgot about it altogether. It just did not fit within the 12-nerve curriculum. And anyway, all five senses were accounted for by the other cranial nerves. How important could this little nerve be?
It would have been easier to overlook this inconvenient discovery if nerve zero were present only in sharks. But over the next century anatomists found the wispy nerve springing from the brain just in front of the olfactory nerve in almost all vertebrates (animals with backbones). To their chagrin, they found the nerve in humans, too, in 1913. Usually it is ripped away during dissection when the tough membranes that wrap the brain are peeled off, but if one knows where to look and is especially careful, the little nerve is always there. What is its purpose?
One clue comes from how it is connected in the brain. Like the olfactory nerve, nerve zero sends its endings to the nose. Perhaps, some researchers argue, this nerve is simply a frayed strand of the olfactory nerve and not a separate cranial nerve at all. The dead pilot whale, my colleagues and I realized, was a perfect opportunity to examine that notion by looking directly to an example from nature.
Whales and dolphins are unique in having a blowhole on the top of their head. Whales evolved from aquatic mammals that breathed through nostrils in the front of the face. Over the course of millions of years of evolution, the nostrils gradually migrated to the top of their head. In the process, whales and dolphins gave up the sense of smell, and they lost their olfactory nerve. We realized that if nerve zero were also involved in the sense of smell—as just a twig branching off of the olfactory nerve—it, too, would have been abandoned in the evolutionary exchange of nostrils for blowhole. But if, as we suspected, nerve zero did something else, it might still be present in whales.
Before I relate the results of our autopsy, you must have a look at some of the evidence that raised our suspicions that nerve zero connects the sense of smell to sex.
Smell and Pheromones
Smell is the most ancient of all the senses—even the lowly bacterium must discern the difference between nutritious and noxious substances by sniffing (detecting chemicals in) its environs. Humans, who have a weak sense of smell compared with most mammals, nonetheless have 347 different types of sensory neurons in the olfactory epithelium, where cells for smell reside in the nose. Each one detects a different type of odor, and all the varied aromas and stenches we know result from mixtures of responses of these 347 types of receptor cells. In comparison, every color we see results from signal combinations of only three types of sensory neurons in the retina (red-, green- or blue-sensitive cones), vision's sensing layer at the back of the eyes.
Animals rely heavily on the sense of smell and other nonverbal cues for communication. From frenzied June beetles to tomcats pursuing a queen in heat, pheromones are important for selecting mates and stimulating reproduction throughout the animal kingdom. A stallion curls its upper lip and inhales deeply to snuffle pheromones from a mare in heat, a behavior called flehming. Many animals also rely on the sense of smell to determine sex, social rank, territories, reproductive status and even identity of specific individuals, such as their own mates or offspring.
In humans, mate selection and sexual reproduction are far more complex, but there are indications that people do exchange such secret pheromone messages. Pheromones differ in two important ways from the chemicals that excite our sense of smell. For a smell to waft a distance from its source, the odor-producing molecules must be very small and volatile (able to float great distances in the air). Not so for pheromones, which can be large molecules passed between the noses of individuals during intimate contact, such as kissing.
Second, not all pheromones have an odor. If pheromones were to excite nerve endings that convey their signals directly to brain regions controlling sexual reproduction, bypassing the cerebral cortex where consciousness arises, they could act like an unseen olfactory cupid—putting a romantic twinkle in the eye of a certain member of the opposite sex—and we would never know it.
As it turns out, nerve zero's connections in the brain leave open that very possibility. To explain how requires a more detailed look at the circuitry for the sense of smell and for a special structure in the nose of many animals that detects pheromones, called the vomeronasal organ.
The olfactory nerve connects sense cells in our nose to the olfactory bulb inside our skull. This neural bulb is a massive relay point containing a nest of synapses. Raw incoming sensory information from the 347 kinds of odor receptors is first sorted here, then processed to analyze and discriminate among the universe of odors. The signals next pass to the olfactory cortex for finer discrimination and conscious perception of the odor.
For many animals that rely on pheromones for sexual communication, the key place for sensing these chemicals is a specialized area inside the vomeronasal organ. This organ, in turn, is connected to a tiny “accessory” olfactory bulb, next to the main olfactory bulb involved in the sense of smell. From there, nerves connect to areas of the brain involved in sexual arousal (such as the amygdala) rather than to the olfactory cortex. In rodents, for example, stimulating the vomeronasal organ with pheromones can release a flood of sex hormones into the blood.
Acting through the vomeronasal organ, pheromones influence the frequency of estrus and stimulate sexual behavior and ovulation in animals. The wrong pheromones can even terminate a pregnancy. In 1959 Hilda M. Bruce of the National Institute for Medical Research in London reported that an embryo will not implant in the uterus of a recently mated female mouse if she is exposed to the smell of urine from an unfamiliar male. Instead the embryo will be aborted, and the female will return to estrus. In contrast, the smell of urine from her mate does not prevent implantation and pregnancy.
In research published in 2006, Nobel laureate Linda Buck and her colleague Stephen Liberles, both then at the Fred Hutchinson Cancer Research Center in Seattle, identified 15 members of a new family of receptor proteins. These receptors, found in the mouse nose, exist on the surface of sense cells that detect pheromones, lending credence to the idea of a separate pathway for pheromones in mammals. These cells are different from the receptors that detect odors. Each of the TAARs (trace amine-associated receptors) responds selectively to specific nitrogen-containing molecules in mouse urine. The concentration of one of these chemicals increases in mouse—and human—urine under the stresses associated with mating behavior, such as those involving dominance and submission. Two of the TAARs are excited by compounds found exclusively in the urine of male mice, but only after puberty, also suggesting a sex link. Incidentally, behavioral researchers had previously identified one of these compounds and found that it accelerated the onset of puberty in female mice.
We now have an understanding of pheromones in mice that extends from molecules to sexual behavior, but what about pheromones in humans? Intriguingly, Buck found that humans have the genes to make at least six of the same pheromone receptors present in mice.
Nerve Zero's Role
Although some scientists claim to have detected an operational vomeronasal organ in humans as well, most believe that it appears to be vestigial. As is the case with gill slits, we possess vomeronasal organs only during our fetal lives, after which they atrophy. So if pheromones are sending sexual signals to human brains, they are not relying on the vomeronasal organ to relay them. Instead nerve zero might be stepping into the breach.
Consider the following anatomical features of nerve zero. Like its olfactory cousin, nerve zero has its endings in the nasal cavity, but remember that it sends its nerve fibers to the hot-button sex regions of the brain: the medial and lateral septal nuclei and preoptic areas. These regions of the brain are concerned with the “nuts and bolts” of reproduction. They control release of sex hormones and other irresistible urges such as thirst and hunger. The septal nucleus can act on and be influenced by the amygdala, hippocampus and hypothalamus. Damage to the septal nuclei causes behavioral changes in sexual behavior, feeding, drinking and rage reactions. Thus, in connecting the nose to the reproductive centers of the brain, nerve zero completely bypasses the olfactory bulb.
Cutting the olfactory nerve or removing the vomeronasal organ will disrupt normal mating behavior in rodents, suggesting that the olfactory nerve transmits pheromone messages from the vomeronasal organ. But in the past two decades researchers have come to understand that nerve zero also sends fibers to the vomeronasal organ—and that nerve zero's fibers run extremely close to the fibers of the olfactory nerve. As a result, in experiments in which the olfactory nerve was deliberately severed, investigators may have inadvertently cut through nerve zero as well.
In 1987 neuroscientist Celeste Wirsig, then at Baylor College of Medicine, carefully severed the nerve zero of male hamsters, leaving the olfactory nerve unscathed (as shown by the fact that hamsters with a severed nerve zero could find a hidden cookie just as fast as control animals could). The hamsters with a severed nerve zero failed to mate.
Similarly, in 1980 neuroscientists observed that electrically stimulating the olfactory nerve could trigger sexual responses in fish and other animals. But could this sexual behavior actually result from a stimulated nerve zero, which runs close to the olfactory nerve for most of its length? Neuroanatomists R. Glenn Northcutt, then at the University of Michigan (now at the University of California, San Diego), and Demski, then at Kentucky (now at the New College of Florida), suspected as much. They also knew that on their way to the brain, some fibers in nerve zero took an unexpected side trip and sent branches to the retinas of the eyes. This may seem odd until you realize that for most plants and animals, reproduction is seasonal—and day length is the most accurate way to gauge time of year. Many scientists suspect that a nerve involved in mating and reproduction might also connect to the retina to keep a constant check on the calendar.
Regardless of function, this place was where nerve zero and the olfactory nerve parted company, so Northcutt and Demski were able to apply a mild electric shock to goldfish nerve zero fibers in this site without stimulating the olfactory nerve at the same time. When they did, the male goldfish responded instantly by releasing sperm.
Therefore, in addition to the anatomical evidence that nerve zero connected the nose to parts of the brain controlling sexual reproduction, strong physiological evidence now existed that—in fish at least—nerve zero might be a sensory system for responding to sex pheromones and regulating reproductive behavior. Another lead pointing to a sexual role for nerve zero would come from my own research, again on a creature from the sea.
In 1985, while studying nerve zero of a stingray using the electron microscope, I saw something peculiar: many of its axons (nerve fibers) were stuffed with what looked like minuscule black spheres. They turned out to be peptide hormones packed tightly together like pellets in a shotgun shell. And at the tips of some of these nerves, I observed the release of these hormones and their uptake by tiny blood vessels—suggesting that nerve zero may in fact be a neurosecretory organ, meaning that it regulates reproduction by releasing hormones in much the same way as the pituitary gland does. This new clue that the terminal nerve released sex hormones, together with the knowledge that it connected the nose to parts of the brain controlling sexual reproduction, triangulated on one conclusion: pheromones.
Yet skeptical scientists have credited arousal exclusively to the olfactory nerve, still arguing that nerve zero is not a separate cranial nerve at all but simply a frayed strand of the olfactory nerve. So when Demski and I heard that a pilot whale had just died at the San Diego Naval Base, we jumped at the chance to examine it. This animal could show us whether nerve zero was truly autonomous and might even help illuminate its function.
Whale of a Find
Back in the lab at Scripps, Demski reached into a plastic bucket with gloved hands and withdrew the pilot whale's brain that we had removed from the immense carcass. It was about the size of a soccer ball and resembled a human brain, except that its cerebral cortex had tighter and more numerous convolutions—almost kinky in comparison to the wavy folds of a human cortex.
After turning over the whale brain for a look at its underside, we were struck by the strangeness of seeing a mammalian brain devoid of its olfactory nerves. (Remember that whales lost their sense of smell in exchange for blowholes.) Demski carefully peeled away the membranes from the area in which we expected to find a pair of nerve zeros, assuming they had not been lost along with the olfactory nerves. With the surprise of unwrapping a present, we found them: two slender white nerves headed toward the whale's blowhole.
Our postmortem on the pilot whale had proved that nerve zero was a distinct neural entity, not just a fragment of the olfactory nerve. And for whales and dolphins, which had sacrificed their sense of smell and the olfactory nerves that made it possible, whatever nerve zero did was too precious to survival for evolution to abandon.
Despite the intriguing findings, nerve zero's role in the sexual behavior of humans remains unclear. Research in mice has revealed the presence of certain sensory neurons that are not associated with the vomeronasal organ but that respond to pheromone stimulation. So even without a functioning vomeronasal organ, our noses may nonetheless contain sensory neurons capable of responding to pheromones.
How much of this labor is split between the olfactory nerve and nerve zero is not yet worked out. Obviously, nerve zero is doing something different with the information it is receiving from the nose because it does not connect to the olfactory bulb where smells are analyzed. Moreover, it connects to parts of the brain controlling reproduction, and it releases a powerful sex hormone (GnRH) into the blood.
Nerve zero develops very early in embryos, and studies show that all the neurons in the forebrain that produce GnRH use the fetal nerve zero as a pathway to migrate along to find their proper place in the brain. When this embryonic pathway is disrupted, Kallmann's syndrome is the result. This disorder not only impairs people's sense of smell, it leaves them unable to mature sexually beyond puberty. Undoubtedly, nerve zero has other functions in addition to reproduction—most cranial nerves transmit sensory and motor (related to body movement) traffic. Electrical impulses have been detected traveling out from the brain through nerve zero, but what the outgoing messages do is puzzling.
One of the most intriguing things about the story of nerve zero is the suggestion that signals in the environment control our brain and behavior. This notion clashes with our passionate belief in free will, but the evidence continues to mount.
A study by Denise Chen, now at Baylor College, and her colleagues found that people performed better on cognitive tests while sniffing sweat collected from individuals who had been watching a scary movie than they did while smelling the sweat of people who had been watching a happy movie. The test takers said they could not tell the difference between the two types of sweat, but they were more cautious and accurate while inhaling the sweat of fearful moviegoers. In many animals stress and fear produce lifesaving chemical warning signals—humans, it seems, are no different.
Functional magnetic resonance imaging is also providing a fascinating window into pheromone stimulation of the human brain. A study by Valerie Treyer and her colleagues at University Hospital Zurich revealed that an odorless pheromone extracted from swine sweat (5a-Androst-16-en-3-one) stimulates neural activity in the same “pleasure/reward” region of the human brain activated by smelling roses—something to keep in mind the next time your guy shows up with an expectant smile and a fist full of flowers.
Many animals have specialized scent glands for releasing pheromones, but so do people. The dark area surrounding a mother's nipple, called the areola, warms suddenly at the sound of a crying infant, and pheromones are released from the bumpy skin glands that ring the area. A team led by Benoist Schaal, now at the University of Burgundy in Dijon, France, found that these pheromones speed the time it takes a newborn infant to locate the breast and begin suckling. Infants of mothers who are blessed with more of these scent glands latch on faster and gain weight quicker than infants born to women with fewer glands.
Nerve zero undermines not only our confidence in free will but also our faith in our own senses. Research on animals shows that impulses from nerve zero change how the environment is perceived. Neuropeptides released from the endings of nerve zero in the nose modify the sense of smell by adjusting the sensitivity of olfactory neurons. In the same way, fibers from nerve zero that enter the retina of a fish's eye alter processing of visual information in response to olfactory signals stimulating the nerve. In fish, at least, nerve zero may provide a biological basis for the adage that “love is blind.”
Chemical Messages
What is it about sexual attraction that can instantly draw two people together? Could pheromones be a factor for human couples, as they are for other animals? Research on molecules that protect us from infections offers intriguing clues.
In many animals, the nose can determine sex and reproductive status by sensing trace hormones and other compounds in urine and sweat. A different class of molecules provides information about the individual identity of a mate. Such macromolecules, called major histocompatibility complex (MHC) proteins, sit on the surface of cells to allow the immune system to distinguish the body’s own cells from foreign ones.
Here is how it works. MHC molecules are huge proteins equipped with bird beak–like appendages that snatch small protein fragments inside cells and poke them through the cell membrane for guard patrols called T cells to inspect. If the protein fragments are foreign, the immune system attacks.
Some studies suggest that people can discern whether someone has different MHC genes. Biologist Claus Wedekind, then at the University of Bern in Switzerland, reported in the mid- 1990s that in one study women preferred the odor of T-shirts worn two nights by men who had different MHC genes from their own; men had the same ability to distinguish MHC genes by smell. In a 1997 study geneticist Carole Ober of the University of Chicago and her colleagues reported that people avoid mating with individuals carrying the type of MHC genes most similar to those of their own mothers.
It makes good evolutionary sense to mate with someone who has a different set of MHC genes, because doing so increases the arsenal of immune system genes in your children and thus allows them to better resist infection. It is also biologically important to diminish sexual arousal toward one’s own family members, who are most likely to share your variety of MHC genes. The Wedekind and Ober studies suggest that an individual’s odor is affected by the particular variety of MHC genes he or she has. This effect may come about because differences in an individual’s immune system alter the body’s bacterial � ora and, in turn, the resulting odors created by the breakdown of sweat and apocrine gland secretions by these bacteria. But would nature leave such a vital process as mate selection under the control of microbes, which can change with infections and other environmental in� uences?
As it turns out, it is not the MHC protein itself that is the pheromone. Research indicates that it is the small protein fragment clutched in the jaws of the MHC molecule. In 2004 neurobiologist Trese Leinders-Zufall, now at the Saarland University Medical Center in Germany, and her colleagues found that when synthetic protein fragments that are more readily picked up by classes of MHC proteins in unfamiliar mice were added to the urine of the female mouse’s mate, pregnancy was blocked just as if she had been exposed to urine from an unfamiliar male mouse. —R.D.F.