Small but mighty: In mice, around ten million olfactory sensory neurons analyze incoming air for promising odors. The corresponding figure for humans has not been identified, but it is assumed to be significantly lower. 32 MaxPlanckResearch 3 | 09 FOCUS_Olfaction The Genetic Story behind a Good Nose Peter Mombaerts is as familiar with the world of molecules, genes and cellular signals as he is with the world of odors. The Belgian, who is now Director at the Max Planck Institute of Biophysics in Frankfurt/Main, is one of the researchers who have clarified what pathway odors take through the nose and brain – or at least the basic principles of it. TEXT KLAUS WILHELM he importance of the world of But many of the questions in olfactory through the nose and the brain. It is olfaction for humans, and research remain “baffling,” Mombaerts also surprising in view of the fact that even more so for other mam- notes. There are several reasons for this. women, in particular, strongly affirm mals like dogs, cats and mice, For one thing, the secrets of olfactory that their partners must “smell good” is immediately obvious to any- processing in mammals can be decod- to be attractive. There is hardly any- T one who thinks about it. But the genet- ed only by carrying out complex and thing more repellent to us than a bad ics and biochemistry that underlie the time-consuming animal experiments in smell. Biologists, physicians and psy- sense of smell are beyond most people’s which the olfactory receptor genes are chologists are well aware of just how imaginations. Depending on the mam- genetically modified in a specific way loaded natural smells are with informa- malian species in question, between 300 using increasingly finely-tuned meth- tion – for humans and, to an even and 1,200 genes form the basis of the ods. Faster experiments using cell cul- greater extent, for other mammals. ability to discriminate between the tures do not work. For another, only a When a dog sniffs the urine of another unquantifiable abundance of existing small, select group of researchers have member of its species, it can, without odors. These olfactory receptor genes taken up this difficult scientific chal- seeing the other animal, immediately contain the instructions for proteins lenge. Peter Mombaerts estimates that identify its gender. When a mouse that recognize the various structures of there are only “around a thousand peo- breaks out in a cold sweat, it sends out odorant molecules. Moreover – and in ple” working on olfaction throughout a warning to the other animals in the Mombaerts’s view this is the most signif- the world. group. The teat secretion of a mouse icant of his many findings – they also guides the sucking behavior of her control the navigation of axons from A SMELL SAYS MORE THAN pups. As Peter Mombaerts stresses, the olfactory sensory neurons to the A THOUSAND WORDS there is no doubt that “olfaction is the brain. The entire procedure of olfactory most elementary and fleeting of all processing takes a good 200 millisec- When we consider that Germans alone senses.” An ideal detector of body and onds. Researchers like Andreas Schäfer, spend billions of euros every year on environmental chemistry, the sense of who heads an Independent Junior Re- the pleasure of surrounding themselves smell is almost impossible to mislead. search Group at the Max Planck Insti- with scents like vanilla, rose and musk, Mombaerts became enamored with tute for Medical Research in Heidelberg, it may come as a surprise to learn the science of olfaction back in 1991. take a stopwatch in their hands when that so few scientists are involved in At that time, a new era in olfactory Photo: fotolia they put mice on the trail of a smell. researching the pathway odors take research had just begun. Prior to this 3 | 09 MaxPlanckResearch 33 FOCUS_Olfaction » Since the breakthrough of 1991, it has gradually become clear how an odor literally rushes to the brain and is assessed, decoded, and stored there. date, the nose was viewed as the most genetic abundance corroborates the im- mysterious of the sensory organs. This mense significance of olfaction. With- was clearly due to the nature of the out it, the sense of taste would be beast: hearing, for example, is based on helpless – not only in mice, but also in a linear system of sound waves that can humans. The final say on all culinary be detected by a biological structure creations – be it tuna steak, hamburger, with relative ease and transformed into pasta, or wine – goes to the olfactory sensory impressions. Similarly, sight is epithelium. also based on the detection of wave- The family of olfactory receptor lengths that can be understood in genes is remarkable in a number of re- numerical ranges – for red, green and spects. Unlike almost all other genes, blue. But how can a mammal, with its these genes are not interrupted by so- limited genetic resources, discriminate called introns – DNA segments that do between the hundreds of thousands of not encode information about the odorant molecules with different chem- structure of a protein. This intronless ical structures? “From today’s perspec- gene structure probably made it easier tive, there were some bizarre ideas for the olfactory receptor genes to pro- floating around the scientific world liferate with new variants in the ge- back then,” remembers the Max Planck nome over the course of evolution and researcher, such as the theory relating to become such a huge family of genes. The images show the two olfactory bulbs of to the existence of seven “primary” Moreover, in all of the mammals stud- a mouse: The olfactory sensory neurons in odors, similar to the primary colors in ied so far, the genes appear to be locat- the olfactory epithelium are stimulated here by butenal. The degree of neuronal activity the visual system. ed seemingly haphazardly on all chro- is shown using different colors (bottom). mosomes. “There’s no identifiable logic A HUGE FAMILY OF OLFACTORY here,” says Mombaerts. The team work- RECEPTOR GENES ing with the scientist succeeded in demonstrating that the control areas An article published in 1991 revolu- for gene expression are “inconceivably tionized the field of olfactory research. small,” even in terms of genetic dimen- American biologists Richard Axel and sions. Such control areas determine Linda Buck, who have since been when and where a gene is activated and awarded a Nobel Prize, reported to their how its information is ultimately im- stunned colleagues that there are more plemented in a protein. than 1,000 genes for the detection of Since the breakthrough in 1991, it odors in the genome of rats. “The larg- has gradually become clear how an est family of genes in mammals over- odor literally rushes to the brain and is all,” says Mombaerts. Of the approxi- assessed, decoded, and stored there. All mately 30,000 genes in mice and rats, smelly living creatures or things release around 1,000 are involved in olfaction. volatile molecules that are almost al- This figure is lower in humans, but ways complex mixtures. Smells consist at 350, significant nonetheless. This of hundreds of chemical components Photos: Peter Mombaerts (2) 34 MaxPlanckResearch 3 | 09 that waft into the nose and collide there with the olfactory epithelium. This patch of tissue is located within the olfactory mucosa and is more or less the size of a postage stamp in humans, but much larger in dogs and mice relative to their body size. The ol- factory epithelium consists of three cell types: the supporting cells, which pro- vide important assistance in olfaction, the olfactory sensory neurons, and the basal cells – adult stem cells that replace the olfactory sensory neurons and thus above A pioneer in the realm of the senses: Flemish scientist Peter Mombaerts is one of the researchers who have clarified what pathway odors take ensure “the strongest neurogenesis of through the nose and brain. all in the adult body,” says Mombaerts. below Cross-section of the vomeronasal organ of a mouse. The different colors show that the epithelium consists of two types of neurons. RECEPTORS FISH FOR ODORANT MOLECULES Approximately ten million olfactory sensory neurons in the mouse “ap- praise” the incoming air; the number of neurons in humans is unknown. Around 20 fine sensory hairs, known as the cilia, protrude into the nasal mu- cosa. Their cell membrane houses all of the molecular components that ensure that humans can perceive several mil- lion smells, even in low concentrations, and can discriminate between thou- sands of them – despite having only 350 types of molecular receptors that are encoded by the olfactory receptor genes. In the olfactory epithelium of mice and dogs, around 1,200 different types of receptor proteins scan the incoming odorant molecules. “The olfactory receptors are the basis of olfactory perception in mam- mals,” stresses Mombaerts. The recep- Photos: Christophe VanderEecken (top)/Tomohiro Ishii tor proteins, which consist of around 3 | 09 MaxPlanckResearch 35 FOCUS_Olfaction 320 amino acids, are similar in overall during their maturation, but ultimate- structure; they traverse the cell mem- ly opt for a single receptor type. Such brane of the olfactory sensory neurons details are important for Mombaerts, as seven times. Certain parts of the he wants to understand how and why receptors display the greatest diversity: a cell chooses only one olfactory recep- the binding pocket, the area where tor gene for expression and – while “in the interaction between the odorant biology nothing is really perfect” – why molecule and receptor takes place, is the mechanism appears to be so good.