Matching up people in need of organ grafts with immuno-compatibledonors is a dicey business.

A quarter century ago, the president of Sloan-Kettering CancerCenter, Lewis Thomas, suggested in all seriousness the followinggame plan to seek out individuals with rare kidney immunotypes:

Train a keen-nosed tracking dog to memorize the body odor of thepatient on the waiting list for a donor kidney. Then send that canineforth among the multitudes of humanity to smell out the one personemitting the identical scent.

This seemingly senseless stratagem reflects the only recentlyrecognized molecular connection between the sense of smell _olfaction _ and the mammalian immune system. Both operate asfingerprints, olfactory or immune, to distinguish self from non-self.Thomas regarded the immune system, and by extension, the olfactoryone, as the most varied and complex arrangement in nature.

He observed that if a wild-type pregnant mouse smells thepheromones from another male, she loses her fetus, and becomessexually receptive again [the "Bruce effect"]. Not so the inbredmouse, which cannot sense the "strangeness" of the second male. "Isit possible," Thomas mused, "that the HL-A antigen has an odor allits own?"

Laboratory technicians at Sloan-Kettering, taking care of laboratorymice, had noticed that these animals seemed to smell each other outwith care, and chose their mates accordingly, based on the set ofgenes they carried.

"Their odor types differ from mouse to mouse," says biopsychologistGary Beauchamp, director of the Monell Chemical Senses Center inPhiladelphia. "We think it's their cue for maintaining heterozygosity,and avoiding inbreeding."

Beauchamp is first author of a paper in the current Proceedings of theNational Academy of Sciences (PNAS) dated March 28. Its title:"Evidence suggesting that the odor types of pregnant women are acompound of maternal and fetal odor types."

Trained Rodents Get Whiffs Of Human Odor Clues

To verify this suggestion, he and his co-authors recruited fourpregnant women and four educable rats.

They trained and tested these animals in a computer-controlledcontrivance seemingly inspired by Rube Goldberg. In the odorchamber of this "automated olfactometer," rats respond to specificsmells by touching a bar with their nose. "Correct" responses arerewarded by a measured dollop of drinking water. Each snoutmovement interrupts a photoelectric beam, and registers on thecomputer.

The source of these olfactory stimuli is an adjacent odor deliverysystem containing a battery of urine samples. These are individuallyselected, or mixed, for wafting to the rats' odor chamber.

After boot-camp training to manipulate the system, and discriminatebetween rewarded and unrewarded odors in unrelated inbred mousestrains, the rats went on to learn to recognize urine effluvia from oneof four women at various stages of pregnancy, and from theirneonatal offspring.

In their very first trial, the animals scored 16 out of 16 correct calls,distinguishing prenatal from postnatal odors in all four mothers.

Part two of the final exam aimed to see whether the geneticallydetermined odor type, and hence genotype, of the fetus contributed tothe altered scent of a pregnant women's urine. Shortly after birth,neonatal urine from either her own offspring or another baby wasadded to the maternal sample. The rats preferred the mother's owninfant odor, which implies a molecular "self" relatedness.

As Beauchamp wrote in PNAS, "We believe that odor types arecomposed mainly of normal metabolites that happen to be odorous,and whose outputs are subject to genetic variation." He comparedthis olfactory differentiation of individual smells to "the visualindividuality of all humans except identical twins."

"What's remarkable here," Beauchamp told BioWorld Today, is thatthe individual odor types, the genetically controlled odor of thefetuses, is apparently expressed in the mother's secretions.

Not So Much Paternity Testing As Disease Detection

"To the extent that they reflect the half of the genes contributed bythe father," he added, "it's obviously possible that the father can beidentified, based on the odor of the fetus."

Neither paternity nor forensic testing of odor DNA is a part of theMonell Center's agenda, Beauchamp made clear, but he did observethat, "It's likely that a mouse could sniff a pregnant female and tellnot only that she was pregnant, but who the father of the litter was,based on her odor being similar to that of the father."

Furthermore, he pointed out, "in a non-pregnant human female, herfather's contribution to her odor consists of genetic material in themajor histocompatibility complex [MHC]." This is the chromosomalregion whose genes encode proteins that regulate interactions amongcells of the immune system.

"To use the handle we have in the MHC genes," Beauchamp said,"provided for us so nicely and exquisitely by the immunologists, wedon't have to do the genetics. They've done it for us, from 3-Dmolecular structure to genes to proteins to odor. But we still don'tunderstand the genetic code for odor, or its pathway to and in thebrain, or its chemical character. We are now working on these aspectswith sophisticated bioassays. In mice we can show that a single DNAchange produces a change in odor."

He also noted that a skilled physician's diagnostic tools include asense of smell for detecting the characteristic odors of certain diseasestates.

"Our big purpose," he concluded, "is to try to understand howanimals and people regulate their behavior and physiology, and whatrole odors play in that. It plays a bigger role in people than peoplebelieve." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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