Volume 6, Issue 44 May 2009
On the Scent of Smell
John Ngai is the Coates Family Professor of Neuroscience and Director of the Functional Genomics Laboratory at UC Berkeley. Photo credit: Kirstie Tweed (courtesy UC Berkeley University Relations)
The next time you stop to smell the roses, take a moment to consider how you are able to enjoy their perfume. Sniff the velvet petals, and a cocktail of aromatic molecules wafts across odor receptors within your nasal cavity. Each is located on an olfactory neuron that extends into the brain. Chemical compounds that tumble past will bind to and activate a variety of receptors and their neurons. Your brain decodes this pattern as the unmistakable fragrance of a rose.
The neurons that link olfactory receptors to the brain are laid down according to a precise developmental blueprint, says Berkeley professor of neurobiology John Ngai. "When you and I smell a lemon, the same olfactory sections of the brain light up in the same pattern. There is a spatial representation of chemical sensation in the brain that is stereotyped from person to person."
The nose contains more than 5 million olfactory neurons, each of which expresses just one of more than 1,000 possible receptor types. Neurons bearing the same receptor types all extend their axons to the same areas of the brain's olfactory bulb. For the system to work, each neuron must connect to precisely the right bulb sections.
Ngai wants to know how the body controls this monumental wiring job. To that end, his lab is identifying the genetic and molecular cues involved in olfactory system development. This work is yielding new ways to control neural growth and direct stem cell development. Meanwhile, their analyses of olfactory receptors promise a tastier future for food.
The head of a zebrafish embryo showing the olfactory sensory neurons and their axonal projections (green) innervating the olfactory bulb (red) of the brain. Photo credit: Shannon DeMaria, MCB graduate student
To understand how olfactory neurons reach their targets, Ngai is searching for the molecular cues they follow. Just last year, his graduate student Jonathan Scolnick reported that growing olfactory neurons express receptors for a molecule called insulin-like growth hormone, or IGF. These receptors enable neurons to find their way to the olfactory bulbs. In mouse mutants lacking IGF signaling, it prevented an important symmetry from forming within the bulb. The discovery establishes IGF as one of a handful of axon guidance molecules known to help neurons establish brain connections.
Ngai is studying the genes regulating this process with the help of DNA microarrays. These gene chips indicate which genes are active at any given moment within a cell. Some of the proteins produced during neural growth are likely involved in steering neural axons.
The olfactory system may also provide insights into regenerative medicine. While most neurons grow only during development, the olfactory system keeps producing replacement neurons throughout life. These arise from a population of neural stem cells that multiply and then differentiate into mature olfactory neurons.
Using a computational model of a goldfish olfactory receptor to screen novel odorants, John Ngai discovered that goldfish can smell the bacterial metabolite diaminopimelic acid (DAP). In the fish's natural environment, DAP be a cue for the presence of food. Photo credit: Jake Osborne, University of Minnesota
"It's a possible model for understanding how neural stem cells in general regenerate," Ngai says. "If we understand how this process is regulated in the nose, the closer we are to being able to use neural stem cells to treat diseases" such as spinal cord injuries and Parkinson's disease.
Ngai's group is characterizing both the genes and molecules driving this process. By surveying all the genes that are expressed in olfactory stem cells, they are identifying the genes that regulate neuronal stem cell maintenance and differentiation. The information should help advance stem cell science toward future medical therapies.
Another important aspect of smell is how chemical odorants interact with olfactory receptors. Collaborating with colleagues at the University of Paris and the Accelrys company, Ngai uses detailed three-dimensional computer models to observe how well odorants fit a given receptor. "We look for common features of a chemical's structure that the receptor must like, to determine what makes that chemical a good odorant," Ngai says.
A molecular model of the binding pocket of the goldfish DAP olfactory receptor. The ligand binds in the cleft and the wings close around it. The image shows arginine, one of the receptor's natural ligands, docked in the binding pocket. Photo credit: Hugues-Olivier Bertrand, Accelrys
As a proof of concept, Ngai performed this analysis on an amino acid receptor in the fish nose. "It looks like a Venus flytrap — instead of catching and holding a fly in its binding pocket, it docks an amino acid," he says. This receptor shares many structural similarities to human receptors for the amino acid glutamate, which include receptors for neurotransmitters in the brain and for the flavor enhancer monosodium glutamate on the tongue.
After using a computational program to search over 1 million chemical structures, Ngai discovered one, di-amino pimelic acid, or DAP, that is present in rivers at concentrations fish can smell. DAP is a metabolite only found in certain types of bacteria. "A high local concentration of DAP probably signals high local concentrations of bacteria. That means the bacteria must be eating something. So DAP could be a proxy for available fish food," Ngai says
Much of our sense of taste depends on our sense of smell. So Ngai is now screening vast computer databases to find other ligands that bind to DAP-type receptors found in tongue taste buds. He hopes to identify flavorings that could, for example, increase the palatability of bland, restricted-calorie diets. These could help address the twin epidemics of obesity and diabetes-and keep us all enjoying the roses over long, healthy lives.