Photos by Michael Chiabaudo COMMON SCENTS Following a less-traveled path has led Hans-Jürgen Fülle to the sense responsible for the cellular beginnings of mother and infant bonding.
by Lori OliwensteinHans-Jürgen Fülle, M.D., is taking the road less traveled. Rather than follow others down the already-paved paths leading to surefire scientific gold, this biochemist turned physician turned pharmacologist turned cell biologist chose an unmarked trail, looking for a bit of research terrain to claim for his own. Fülle's pioneering spirit led him to the relative wilderness of the nose. And what he has found may shed new light on the biochemical basis of the mysterious, instinctual connection between a newborn infant and its mother.
Olfaction-as the sense of smell is more properly called-has long been vision's poor relation, receiving mere fractions of the attention heaped on studies of its more visible kin. "It's only in the past couple of years that researchers have started detailing what happens in the nose in much the same way they've done for the eye," says Fülle, assistant professor of cell and neurobiology and ophthalmology.
And yet, it is in the nose-or, more specifically, the specialized nerve cells that pick up and interpret the odors that continually waft into the nostrils-where Fülle's disparate interests have come together. "From the beginning, I was fascinated by how much of medicine is based on our abilities as scientists to modify cellular behaviors and structures," he confides. "In medicine and pharmacology we attempt to redirect cells' efforts in a certain way-but we need to understand just how we can manipulate the system to the benefit of the patient."
It was this sort of intellectual curiosity that prompted Cheryl Craft, Ph.D., the Mary D. Allen Chair in Vision Research and chair of the Department of Cell and Neurobiology, to offer funding from a Howard Hughes Medical Institute resources grant to lure Fülle from the University of Texas Southwestern Medical Center at Dallas to the Keck School of Medicine.
At the Keck School, Fülle's attention was quickly drawn to what is one of the hottest fields of scientific inquiry today: signal transduction, the process by which a signal from outside the cell gets inside. In the nose, these signals are the odors themselves, which settle into specialized receptors that stud the surface of the olfactory nerve cells in the nose. Fülle likens these receptors to radio or television antennas: They pick up the signals floating through the air, allowing them to be interpreted.
Once an olfactory cell's receptor has snared an odorant, it sets off a chain reaction; the signal travels over the cell's membrane, is passed from protein to protein and turns into an electrical signal that is transmitted along the cell's axon to the portion of the brain called the olfactory bulb. But just how this signal gets passed along-and which odors settle into which receptors-is still not fully understood.
The most common receptor found on the olfactory cell is named the 7-transmembrane domain (7TD) receptor because it snakes back and forth across the membrane seven times. But instead of focusing on this most-widely studied protein, Fülle is marking new terrain by concentrating on a receptor that he only recently discovered while still at Texas Southwestern. That receptor populates less than one-tenth of one percent of all olfactory cells.
The receptor, called guanylyl cyclase D (GCD), is unique for several reasons. "The 7TD receptor binds a signal molecule like an odorant and then sends a message to one protein, which acts as an enzyme, which binds to another protein, and so on," Fülle explains. "What makes guanylyl cyclase D special is that it does it all: it combines all of this in one protein. It binds the signal, gets it across the membrane and acts as an enzyme."
But perhaps even more intriguing is what Fülle, along with collaborators at the University of Washington in Seattle, found when they followed the snaking axons of the small number of GCD-containing olfactory nerve cells to the brain. They all connected to one small area of the olfactory bulb-a special region known to be specifically involved in the suckling behavior of newborn mice and rats.
Scientists have long known that these blind, deaf and helpless nurslings find their way to their mother's teat based solely on its smell, Fülle explains. For the first five days of their lives, it is this sense that guides them to the source of the nutrition that will keep them alive. Wash mom's teats with soap, and her pups will starve to death; they will even refuse the odorless teat if placed directly on it.
In humans, the sense plays a similar, though less dire, role. Here, notes Fülle, instinct is mixed with learning and environmental influences. Still, many studies of humans have found that the bond between mother and child grows ever tighter because of the sense of smell. After all, a baby feeding at its mother's breast is continually rubbing its nose in the scent glands that circle the nipple. And it has been shown that oftentimes both baby and mother can recognize one another based solely on scent.
How does all this tie in to a rare protein receptor? Fülle's hypothesis is that since signals from all cells with GCD receptors wind up in this one small region of the brain, the GCD receptor may be a pheromone receptor-the place where those behavior-inducing substances kick off the chain of events that results in a newborn mouse's instinctual suckling at its mother's teat, or a human baby's innate recognition of its mother.
"The idea that these receptors are picking up and processing pheromone information is extremely seductive," he says. "But as scientists, we need to be open to all possibilities. We need to prove or disprove our hypothesis."
The best way to do that, Fülle explains, is to get down to the level of the genes, where it all begins. He and his colleagues are attempting to create a so-called knockout mouse, in which the genes that code for the GCD receptors are missing or inactivated. If a mouse without a GCD receptor were unable to nurse properly, that would provide strong scientific evidence that this protein is of critical importance in controlling the suckling phenomenon.
To cover all the bases, Fülle, along with Nori Kashara, M.D., Ph.D., assistant professor of pathology and biochemistry at the USC Institute for Genetic Medicine, and electrophysiologist Stuart Firestein, Ph.D., at Columbia University in New York, is also working on creating mice that are simply overflowing with guanylyl cyclase D. "Because so few of the olfactory cells express GCD receptors, it's hard find a single cell to isolate and watch how it responds to various odors," he explains. "Overexpression gives us a better chance to do that."
Once the cells are chock-full of GCD, the researchers will send puffs of more than 500 different odors at the cells in an attempt to determine which of the odors prompts an electrical response from the cells-in other words, which of the odors gloms onto the receptor and kicks the cell into action. If that odor happens to be a pheromone, so much the better.
In addition, Fülle wants to make sure that the pheromone is not perhaps binding to another receptor entirely, one that they are not even considering as part of this whole equation. To that end, medical student Chris Walz is doing a genetic analysis of the GCD cells that will create what Fülle calls a "catalog of receptors." Fülle is also modifying bacteria so that they carry the part of the GCD protein that sticks out of the cell-the antenna portion, if you will. By then analyzing the types of molecules that attach to that antenna, he may be able to get a better idea of just what types of molecules bind to GCD, and if they resemble pheromones at all.
Finally, he is adding the GCD protein to specially-modified cells that actually light up when activated. He can then expose those cells to an infinite number of different substances-including pheromones. "Then, if any of the cells light up, we can harvest them and analyze them to see what turned them on," he explains.
"We are doing all of this to find out what activates these cells that send their axons to that one specific region of the olfactory bulb. This is a basic science question: How does smell work? We know that the 7TD receptor is not the whole story. But we still don't know what the rest of the story is."
Fülle may have found his niche, but that does not mean he is staying on one path. His eclectic scientific tastes and basic curiosity simply wouldn't allow that. So, in addition to his smell research, he is teaching courses in medical pharmacology, neuropharmacology, neurophysiology and cell biology. And he is an active contributor to the Keck School's flourishing vision research program, looking for the types of genetic mutations that lead to inherited blindness. "The machinery is the same in vision and olfaction," he says. "It's just combined in different ways and adapted to different needs. In vision, however, the basic research-how we see-has mostly already been done. In olfaction, it's still wide open. And that's exciting to me."
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