Pheromone Research
Chemical communication being studied at IU’s Institute for
Pheromone Research
By Hal Kibbey
Novotny
An IU chemist’s laboratory identified the first definitive
mammalian pheromones in the house mouse in the late 1980s.
Before then, the term \'pheromones\' was largely confined to the
world of insects. In a recent issue of \'Nature,\' Milos Novotny
and Harvard colleagues explore \'semiochemicals\' in mammals.
All it takes is a few molecules of a certain chemical to enable
mammals to smell their own species up to a half-mile away, says
Milos Novotny, Distinguished Professor of chemistry and
director of the Institute for Pheromone Research at Indiana
University Bloomington.
The chemicals, called pheromones, are detected by the
vomeronasal organ (VNO) in the animal\'s nose. Unlike the part of
the nose that detects ordinary smells, this super-sensitive organ
is connected directly to the mid-brain.
\"This is the shortest organ-to-brain distance in mammalian
biology,\" Novotny said. \"A cascade of biochemical processes can
be triggered quite selectively by specific olfactants such as
pheromones at incredibly small quantities. Studies of mammalian
pheromones can have a significant effect on pest control,
promoting endangered species, and, perhaps above all, for
understanding our own sense of smell and associated behaviors.\"
Signals from a mammal\'s nose caused by normal smells called
odorants go to various places in the cortex, in the upper part of
the brain, which is why humans are conscious of smells. But
pheromone signals go directly to the mid-brain, without being
processed by the conscious brain. What happens after that is
not completely clear, but there is a lot of evidence that the
animal\'s behavior and hormonal levels are influenced.
In a paper published July 12 in the journal Nature, Novotny and
co-workers at Harvard Medical School in Boston headed by
Linda Buck reported that the vomeronasal organ can actually
detect both odorants and pheromones. The VNO detected
odorants classified as animalic, camphoraceous, citrus, floral,
fruity, green/minty, musky, sweet or woody. Like pheromones,
these odorants were detected at extremely small
concentrations.
\"This suggests that in mammals, as in insects, odorous
compounds released from plants or other animal species may act
as \'semiochemicals\'--signaling molecules that elicit behaviors
that are advantageous to the sender or the receiver,\" Novotny
said.
\"The house mouse provides a classic example of an elaborate
pheromone communication system: to signal inter-male
aggression and dominance, to show readiness for mating, to slow
down or accelerate the onset of puberty as needed, or to signal
stress to the other members of a colony,\" he said. \"Other
mammals, including possibly humans, use structurally diverse
substances for pheromone signaling.\"
The established view is that mammals detect odorants in the
olfactory epithelium (OE) of the nose and detect pheromones in
the vomeronasal organ. OE signals are relayed to various areas
in the cortex of the brain, while VNO signals are targeted to
areas of the mid-brain that control instinctive drives,
neuroendocrine responses and innate behaviors. The findings by
Novotny and his collaborators demonstrate that the VNO and
OE do not, in fact, detect mutually exclusive sets of chemicals.
Novotny\'s laboratory identified the first definitive mammalian
pheromones in the house mouse in the late 1980s, including their
chemical structure, synthesis and biological effects. Before
then, the term \"pheromones\" was largely confined to the world
of insects. Since then, he has identified pheromones in rats and
hamsters as well.
His current emphasis is on the neurochemistry of neurons in the
VNO and OE. He is the leader of interdisciplinary studies that
bridge the physical sciences, life sciences and social sciences,
including chemistry, neurobiology, psychobiology, biochemistry,
wildlife ecology, medical sciences, and animal physiology and
behavior.
The Institute for Pheromone Research at IU is a center of
excellence in the rapidly developing areas of chemical
communication (semiochemistry) and biochemical aspects of
olfactory perception. It promotes interdisciplinary collaborations
between IU scientists and a worldwide network of researchers
in chemical communication.
Both smells and pheromones may arouse instinctive behaviors in
mammals
July 16, 2001
BLOOMINGTON, Ind. -- Ever notice how male dogs come from
the other side of the neighborhood when a female dog is in heat?
All it takes is a few molecules of a certain chemical to enable
mammals to smell their own species up to a half-mile away, said
Milos Novotny, Distinguished Professor of Chemistry and
director of the Institute for Pheromone Research at Indiana
University.
The chemicals, called pheromones, are detected by the
vomeronasal organ (VNO) in the animal\'s nose. Unlike the part of
the nose that detects ordinary smells, this super-sensitive organ
is connected directly to the mid-brain.
\"This is the shortest organ-to-brain distance in mammalian
biology,\" Novotny said. \"A cascade of biochemical processes can
be triggered quite selectively by specific olfactants such as
pheromones at incredibly small quantities. Studies of mammalian
pheromones can have a significant effect on pest control,
promoting endangered species, and, perhaps above all, for
understanding our own sense of smell and associated behaviors.\"
Signals from a mammal\'s nose caused by normal smells called
odorants go to various places in the cortex, in the upper part of
the brain, which is why humans are conscious of smells. But
pheromone signals go directly to the mid-brain, without being
processed by the conscious brain. What happens after that is
not completely clear, but there is a lot of evidence that the
animal\'s behavior and hormonal levels are influenced.
In a paper published July 12 in the journal Nature, Novotny and
co-workers at Harvard Medical School in Boston headed by
Linda Buck reported that the vomeronasal organ can actually
detect both odorants and pheromones. The VNO detected
odorants classified as animalic, camphoraceous, citrus, floral,
fruity, green/minty, musky, sweet or woody. Like pheromones,
these odorants were detected at extremely small
concentrations.
\"This suggests that in mammals, as in insects, odorous
compounds released from plants or other animal species may act
as \'semiochemicals\' -- signaling molecules that elicit behaviors
that are advantageous to the sender or the receiver,\" Novotny
said.
\"The house mouse provides a classic example of an elaborate
pheromone communication system: to signal inter-male
aggression and dominance, to show readiness for mating, to slow
down or accelerate the onset of puberty as needed, or to signal
stress to the other members of a colony,\" he said. \"Other
mammals, including possibly humans, use structurally diverse
substances for pheromone signaling.\"
The established view is that mammals detect odorants in the
olfactory epithelium (OE) of the nose and detect pheromones in
the vomeronasal organ. OE signals are relayed to various areas
in the cortex of the brain, while VNO signals are targeted to
areas of the mid-brain that control instinctive drives,
neuroendocrine responses and innate behaviors. The findings by
Novotny and his collaborators demonstrate that the VNO and
OE do not, in fact, detect mutually exclusive sets of chemicals.
Novotny\'s laboratory identified the first definitive mammalian
pheromones in the house mouse in the late 1980s, including their
chemical structure, synthesis and biological effects. Before
then, the term \"pheromones\" was largely confined to the world
of insects. Since then, he has identified pheromones in rats and
hamsters as well.
His current emphasis is on the neurochemistry of neurons in the
VNO and OE. He is the leader of interdisciplinary studies that
bridge the physical sciences, life sciences and social sciences,
including chemistry, neurobiology, psychobiology, biochemistry,
wildlife ecology, medical sciences, and animal physiology and
behavior.
The Institute for Pheromone Research at IU is a center of
excellence in the rapidly developing areas of chemical
communication (semiochemistry) and biochemical aspects of
olfactory perception. It promotes interdisciplinary collaborations
between IU scientists and a worldwide network of researchers
in chemical communication.
Novotny can be reached at 812-855-4532 or novotny@indiana. (\"novotny@indiana.\")
edu
(Hal Kibbey, 812-855-0074, hkibbey@indiana.edu) (\"hkibbey@indiana.edu)\")
---------------------------------------------------------------------
Monday August 28, 2000
Researchers find gene that may open door to pheromone
By The Associated Press
Scientists have identified the first human gene that may be
linked to pheromones, odorless molecules that in other animals
trigger primal urges including sex, defense and kinship.
Experts describe the discovery as possibly opening a new door
into the role of pheromones in human development.
In animals, researchers have documented how pheromones trace
complex neurological paths to stimulate parts of the brain that
are deeply rooted in instinct.
Researchers have long believed that humans also communicate
through pheromones, but until now they had been unable to find
any of the equipment needed to detect these potent molecules.
Now, in experiments at Rockefeller University and Yale,
neurogeneticists have isolated a human gene, labeled V1RL1, that
they believe encodes for a pheromone receptor in the mucous
lining of the nose. A receptor is a patch on the surface of a cell
that binds with specific molecules, like a lock that accepts only a
specific key.
\'\'This is the first convincing identification of a human pheromone
receptor,\'\' said University of Colorado biochemist Joseph Falke.
Humans share the V1RL1 gene with rodents and other mammals
that rely heavily on pheromone cues to survive.
However, it has not been determined whether the gene is active
in humans or which pheromone-induced behavior the gene might
induce.
\'\'The ultimate test will be to find a pheromone that binds to the
receptor and triggers a measurable physiological response,\'\'
Falke said.
The research was published in the September issue of the
journal Nature Genetics.
Researchers took samples from a gene bank and scanned them
for matches to the rodent genes from the V1r family. They
found eight matches in human genetic material.
Further testing showed that seven of the eight human V1r genes
are inoperative. The potentially functional gene, called V1RL1,
subsequently was found in 11 out of 11 randomly chosen people
from varying ethnic backgrounds, researchers said.
While rodents and other creatures essentially are reactive
animals that depend heavily on pheromones for behavioral cues,
humans use their larger brains to rely more on judgment and
complex sensory cues, such as vision.
\'\'In mice, we think there are more than 100 functioning genes in
the V1r family,\'\' said Ivan Rodriguez of Rockefeller University,
lead author of the study. \'\'But in humans, V1RL1 may very well
be the sole functioning gene in the family.\'\'
\'\'Why has it hung around all this time?\'\' said Charles Wysocki of
the Monell Chemical Senses Center in Philadelphia. \'\'It must be
very important if it has outlived all of its predecessors.\'\'
Scientists aren\'t sure what happened to the other 99 genes.
\'\'It\'s unheard of that a family of 100 genes in mice is reduced
to a single gene in humans,\'\' said the study\'s senior author,
Peter Mombaerts.
In most mammals, pheromones usually are detected by a
specialized organ inside the nose or mouth called the
vomeronasal organ, or VNO. Nerves connect it to parts of the
brain involved in reactions rather than cognition.
In humans, the organ appears in embryos with its nerve cells
extending into the developing brain. For several weeks, it serves
as a pathway for hormones vital to sexual development and
maturity. However, the VNO in humans shrinks and stops
working before birth.
Researchers have long suspected that humans communicate with
pheromones. But how pheromones are produced and how they
are detected across a room, or even greater distances, is poorly
understood.
One 1998 study at the University of Chicago demonstrated that
pheromones in underarm sweat prompt women living in close
quarters to synchronize their menstrual cycles.
Some companies put pheromones in perfumes. Chemical makers
bait insect traps with pheromones.
Mombaerts said it is too early to tell whether the gene discovery
might lead to pheromone-based medicines.
However, the potential for pheromone misuse worries some
researchers and bioethicists.
\'\'Safeguards will be needed to prevent the manipulation of
human behavior,\'\' Falke said. \'\'We won\'t want pheromones
showing up in magazine ads, or pumped through ventilation
systems at the mall.\'\'
----------------------------------------------------------------------
Brief Communication
Nature, 12 July 2001
Nature ,Volume 412, No. 6843, page 142 © Macmillan
Publishers Ltd.
Neuropharmacology: Odorants may arouse instinctive
behaviours*
Mehran Sam*, Sadhna Vora*, Bettina Malnic*, Weidong Ma,
Milos V Novtny, Linda B Buck*
* Howard Hughes Medical Institute, Department of
Neurobiology, Harvard Medical School, Boston, Massachusetts
02115, USA
Institute for Pheromone Research, Department of Chemistry,
Indiana University, Bloomington, Indiana 47405, USA
e-mail: lbuck@hms.harvard.edu (\"lbuck@hms.harvard.edu\")
The prevailing view of the mammalian olfactory system is that
odorants are detected only in the nasal olfactory epithelium,
whereas pheromones are generally detected in the vomeronasal
organ. Here we show that vomeronasal neurons can actually
detect both odorants and pheromones. This suggests that in
mammals, as in insects, odorous compounds released from plants
or other animal species may act as \'semiochemicals\' -- signalling
molecules that elicit stereotyped behaviours that are
advantageous to the emitter or to the receiver.
*Reproduced with permission of Nature © Macmillan Pub. Ltd
2001 Reg. No. 785998 England.
---------------------------------------------------------------------
Office of Development and Alumni Programs |
Table of Contents
The College Magazine Home
Chemical Attractions
In his acceptance speech at the College of Arts and Sciences
banquet where he was presented with the 1999 Distinguished
Faculty Award, Milos Novotny recalled the journey that brought
him to Indiana University. Born in Czechoslovakia, he earned his
doctorate in biochemistry from the University of Brno in 1965.
He left Czechoslovakia for a research post in Stockholm,
Sweden, just weeks before Russian tanks moved in to repress
the brief flowering of freedom known as the Prague Spring.
Since 1971 he has been on the faculty at IU, but his
international ties remain important to him. Science, he says, is an
international discipline whose practitioners owe their first
allegiance to the pursuit of knowledge. \"I don’t think you can
stop people from discovering,\" says Novotny. \"It’s our basic
human nature. We are curious. And of course we try to put our
discoveries to good uses.\"
Anyone who has ever leafed through a copy of Vogue or
Mademoiselle is probably already familiar with the concept of
pheromones. In the world of these magazines, pheromones are
the mysterious substances that act subconsciously to produce
sudden paroxysms of lust, adding their je-sais-exactly-quoi to
expensive perfumes. Less sexily, they cause masses of women
living together, as in dorms, to have their periods at the same
time.
Well, the magazines don’t have it entirely wrong, but they don’t
have it right, either. Pheromones—the real thing—are much less
well understood and much more complex than the popular
picture of sexual telepathy implies. They are also much more
interesting.
Milos Novotny, James H. Rudy Professor of bioanalytical
chemistry, has devoted a good part of the last twenty years or
so to studying pheromones. His reaction to the notion that a dash
of human pheromones in a bottle of perfume can spice up your
sex life is a dismissive chuckle. All the same, there is clearly a
note of passion in his voice when he discusses the subject.
\"In the mid 1970s I became aware of pheromone communication
in mammals,\" he says. Many studies had already been done on
their effects on insects; Japanese beetle traps, for example,
developed as a result of research done in the 60s, use
pheromones to lure the beetles to their deaths. But even now,
very few people are doing work with mammals. Novotny is one of
the few. \"Some people refer to me as the chemist in this field,\"
he says, with some chagrin. \"It’s nice to have something that is
your own, but I wish more people were involved, to develop the
field more quickly.\"
Novotny is drawn to research with mammals because their
complexity is so great. There is, he says, \"more plasticity to the
behavior of the mammal,\" while insects respond in very
consistent and predictable ways to chemical cues. \"You
synthesize pheromones in the lab, then there is a big danger all
the ants in the building will come to that place,\" says Novotny. \"
Insects will follow slavishly a trail, animals think a little more.\"
Initially inspired by Marvin Carmack, professor emeritus of
organic chemistry, Novotny began developing techniques for
separating pheromones from the complex substances, such as
urine, that carry them. He has worked mainly with mice and
nocturnal animals whose poor vision demands that they rely
heavily on the sense of smell.
\"We have been able to reproduce the biological effect,\" Novotny
says. \"We can put man-made chemical on the skin of mice and
cause them to fight.\"
In addition to inducing aggression, pheromones are linked to the
following behavioral phenomena: Acceleration of puberty,
dominance, synchronization of estrus, and, yes, sexual
attraction.
It is hard to tell, in such a young field, where the research might
lead. Pest control, as mentioned above, is one practical
application, but there will certainly be many more. Novotny is
particularly intrigued by the neurobiological aspects of his work
\"I’d like to see pheromone research leading to a better
understanding of the sense of smell,\" he says. \"The nose is the
shortest possible route to our brain.\"
Although his interest in pheromones is longstanding, Novotny’s
work in the 70s, when he first came to IU, was quite a different
kettle of fish. On a bookshelf in his office in the chemistry
building he keeps a memento,\"“for sentimental reasons,\" of those
earlier efforts. It looks like a sprung Slinky that’s gone down the
steps a few too many times. On closer examination, it turns out
to be made of glass. Coiled, it’s easy to hold in your hand, but
fully extended, Novotny says, breaking off a few expendable
inches at the end for emphasis, it’s 50 yards long. This inelegant
object turns out to be a highly sophisticated measuring device, a
chromatogram. The glass is flecked inside with chemicals. When
a substance to be analyzed is put in at one end, as it travels the
length of the tube these chemicals react with different
components of the unknown substance, ultimately reducing it
from its sum into its parts.
It seems surprising, somehow, that in the era of the Internet
and space travel, scientific advancement should be dependant on
something so apparently simple as making a long enough, thin
enough tube. \"It all goes hand in hand,\" says Novotny. \"This,\" he
says, grasping a metal version of the chromatogram, \"went to
analyze Martian soil [as part of the 1975 Viking Lander mission].
High technologies click into \"low\" very well. These tubes can be
attached to a computer that can distinguish, quantify, and
compare the results.\"
The link between this early work and his current research into
pheromones and glycans, or sugars—the two areas that Novotny
says are closest to his heart—is his lifelong interest in
understanding the workings of those most complex biological
systems, human beings. \"The human body I view as one big
chemical reactor,\" he says. \"My guiding philosophy for doing
science is that I’m interested in some kinds of natural
phenomena and it’s much easier to develop methodologies for
what I’m interested in.\"
Even as a child, growing up in Czechoslovakia, Novotny knew he
was going to be a scientist. At first, he wanted to do something
biologically oriented. “My father was a botanist, so he really
introduced me to nature,” he says. \"At 15, I just happened to
run into a medical student—he rented an apartment in my aunt’s
house. I would have him explain things to me, and when he was
studying for his exams, he used me as a sounding board.\"
Not surprisingly, Novotny aspired to study medicine himself, but
he was \"prevented by politics from doing this.\" Under
communism, he says, \"the system decided for you what you
should do. I didn’t have a sufficiently politically friendly profile
to pursue anything as socially prestigious as being a doctor.
However, if I cannot do one thing, I try to do the next.\" And
thus the chemist was born.
That willingness to try the next thing is a hallmark of Novotny’s
work as well as his life. The themes that come up over and over
again in his colleague’s commendations are his tenacity and his
creativity. Both in the laboratory and in the classroom, he is
constantly looking for new problems to be solved, and new ways
to solve them.
Novotny himself finds the creativity of a scientist to be an
unknown quanitity Where does it come from? And how does a
teacher cultivate it? Novotny’s approach to these problems
derives from his own experience. To become a creative scientist,
a student needs to begin with boundless curiosity and then to
train that curiosity with rigor. \"Creativity in science is a subject
that intrigues me,” he says. \"I try to instill this in my students.
Not just creativity, though. There has to be discipline in
following through. One of my colleagues once said, ‘in science
you have to be reckless,’ not intimidated by authority. I think we
are like artists in that way.\"
400 E. 7th Street. Bloomington, IN 47405
Phone: (812) 855-6494
Publication date: August 31, 2001
Comments: homepgs@indiana.edu (\"homepgs@indiana.edu\")
Copyright 2000, The Trustees of Indiana University
PHEROMONE RESOURCES
www.cnn.com/HEALTH/9803/11/pheromones/ (\"http://www.cnn.com/HEALTH/9803/11/pheromones/\")
www.nature.com/dynasearch/app/dynasearch.taf (\"http://www.nature.com/dynasearch/app/dynasearch.taf\")
Cutler WB (1998) Pheromonal Modulation of Brain and Behavior
in Hormonal Modulation of Brain and Behavior, American
Psychiatric Press, ed. U Halbreich, MD American Psychiatric
Press in press.
Cutler WB, Genovese-Stone E (1998) Wellness in Women After
40 Years of Age: The Role of Sex Hormones and Pheromones
Disease-A-Month, 44:423-546
Cutler WB, McCoy NL, Friedmann E (1998) Pheromonal
Influences on Sociosexual Behavior: Response to Wysocki and
Preti, Archives of Sexual Behavior 27:629-634.
Cutler W (1999) Human Sex-Attractant Pheromones: Discovery,
Research, Development, and Application in Sex Therapy.
Psychiatric Annals 1999; 29:54-59.
Cutler WB, Genovese-Stone E (2000) Wellness in Women After
40 Years of Age: The Role of Sex Hormones and Pheromones:
Part 1 The Sex Hormones, Adrenal Sex Hormones and
Pheromonal Modulation of Brain and Behavior. Current Problems
in Obstetrics, Gynecology and Fertility 23:1:1-32.
Cutler WB, Genovese-Stone E (2000) Wellness in Women After
40 Years of Age: The Role of Sex Hormones and Pheromones:
Part II Hormone Replacement Therapy; Part III Hysterectomy.
Current Problems in Obstetrics, Gynecology and Fertility 23:1:
33-88.
www.nel.edu/22_5/NEL220501R01_Review.htm (\"http://www.nel.edu/22_5/NEL220501R01_Review.htm\")
www.cnn.com/HEALTH/women/9906/25/sexuality.scent/www (\"http://www.cnn.com/HEALTH/women/9906/25/sexuality.scent/www\")
.findarticles.com/cf_0/m1042/7_48/54141345/print.jhtml
-------------------------------------------------------------------
PHEROMONE RESOURCES
www.cnn.com/HEALTH/9803/11/pheromones/ (\"http://www.cnn.com/HEALTH/9803/11/pheromones/\")
www.nature.com/dynasearch/app/dynasearch.taf (\"http://www.nature.com/dynasearch/app/dynasearch.taf\")
Cutler WB (1998) Pheromonal Modulation of Brain and Behavior
in Hormonal Modulation of Brain and Behavior, American
Psychiatric Press, ed. U Halbreich, MD American Psychiatric
Press in press.
Cutler WB, Genovese-Stone E (1998) Wellness in Women After
40 Years of Age: The Role of Sex Hormones and Pheromones
Disease-A-Month, 44:423-546
Cutler WB, McCoy NL, Friedmann E (1998) Pheromonal
Influences on Sociosexual Behavior: Response to Wysocki and
Preti, Archives of Sexual Behavior 27:629-634.
Cutler W (1999) Human Sex-Attractant Pheromones: Discovery,
Research, Development, and Application in Sex Therapy.
Psychiatric Annals 1999; 29:54-59.
Cutler WB, Genovese-Stone E (2000) Wellness in Women After
40 Years of Age: The Role of Sex Hormones and Pheromones:
Part 1 The Sex Hormones, Adrenal Sex Hormones and
Pheromonal Modulation of Brain and Behavior. Current Problems
in Obstetrics, Gynecology and Fertility 23:1:1-32.
Cutler WB, Genovese-Stone E (2000) Wellness in Women After
40 Years of Age: The Role of Sex Hormones and Pheromones:
Part II Hormone Replacement Therapy; Part III Hysterectomy.
Current Problems in Obstetrics, Gynecology and Fertility 23:1:
33-88.
www.nel.edu/22_5/NEL220501R01_Review.htm (\"http://www.nel.edu/22_5/NEL220501R01_Review.htm\")
www.cnn.com/HEALTH/women/9906/25/sexuality.scent/www (\"http://www.cnn.com/HEALTH/women/9906/25/sexuality.scent/www\")
.findarticles.com/cf_0/m1042/7_48/54141345/print.jhtml
Pheromone Receptors Need \"Escorts\"
\"This association opens all sorts of possibilities for the
mechanism of pheromone detection,\" said HHMI investigator
Catherine Dulac.
-----------------------------------------------------------------
March 7, 2003— Howard Hughes Medical Institute (HHMI)
researches and their colleagues have discovered that escort
molecules are required to usher pheromone receptors to the
surface of sensory neurons where they are needed to translate
chemical cues.
In an interesting twist, the researchers found that the escort
molecules belong to a family of proteins, called the major
histocompatibility complex (MHC), which plays an important role
in the immune system. The researchers speculate that in addition
to being escort molecules, the MHC proteins might actively
modulate an animal\'s response to pheromones. Modulation of
pheromone activity might aid in the recognition of other animals.
The studies in mice add “a novel and unexpected layer of
complexity to the process of pheromone detection,” the
researchers wrote in an article published in the March 7, 2003,
issue of the journal Cell. The article was published online on
March 4, 2003. The findings also suggest that, similarly, escort
molecules, although of a different kind, may be important in
smell and taste receptors.
HHMI investigators Catherine Dulac at Harvard University and
Kirsten Fischer Lindahl at the University of Texas Southwestern
Medical Center led the research teams that collaborated on the
studies.
The pheromone communication system, which is found in a wide
range of mammals, involves detection of chemical odorants
released by animals. Detection of pheromones takes place in a
specialized structure, called the vomeronasal organ (VNO).
Although the VNO resides in the nasal cavity, the pheromone
sensory system is distinct from the sense of smell, as are the
chemical receptors involved. In animals possessing a pheromone
sensory system — including mice, dogs, cats and elephants — the
system governs a range of genetically preprogrammed mating,
social ranking, maternal, and territorial defense behaviors.
According to Dulac, untangling the complexity of the pheromone
system has been a daunting task for researchers. “For example,
if you compare the number of receptors, which ranges between
two hundred and four hundred, and the number of behaviors
they trigger, which ranges up to a dozen, there is a huge
discrepancy,” she said. “So, you can either postulate that there
are hundreds of behaviors not yet described, or more likely a
given behavior involves the activation of multiple receptors.”
To begin sorting out the functions of the multitude of
pheromone receptors, Dulac and her colleagues decided to study
a subpopulation of sensory neurons in the VNO. The researchers
knew they could distinguish neurons that expressed one family
of receptors, called V2R, from another family, called V1R, so
they used a technique called “subtractive differential screening
of single cell cDNA libraries” to compare the genes that are
switched on in neurons bearing the two different types of
pheromone receptor.
Their comparisons — as well as sequencing of the discovered
genes and searches of gene databases — yielded evidence that
two families of MHC genes called M1 and M10 were
preferentially activated in these neurons, said Dulac. The finding
was surprising because MHC proteins commonly function on the
surface of immune cells to present foreign proteins to the
immune system to trigger destruction of invading pathogens. The
M10 proteins found in the VNO were different in structure and
obviously in function from other such molecules.
Dulac\'s and Fischer Lindahl\'s research teams set out to explore
the structure and function of the M10 type of MHC proteins
that the genes produced. Their studies revealed that the MHC
genes were exclusively expressed in the VNO and in no other
tissue. And within the VNO, they were only expressed in V2R-
positive VNO neurons. The researchers observed that each type
of V2R receptor apparently had a specific type of M10 protein
associated with it.
“So, we found that there is a population of neurons in which each
neuron expresses only one type of pheromone receptor gene,”
said Dulac. “We also were able to show that these individual
neurons express only one type of M10 gene. This told us there
was some type of logic in that association.”
Additional studies showed that the M10 gene was activated only
after birth, which suggested that M10 only functions in
pheromone sensing in the adult animal. The researchers showed
that the M10 proteins, like the pheromone receptor proteins,
were localized to the tips of neurons, called dendrites, where
chemical reception takes place.
Their studies showed that the M10 protein, as well as an “
accessory” molecule, beta2-microglobulin, that accompanies such
M10 proteins, directly interacted with the pheromone receptor
molecule. Finally, they found that the M10 protein and its
accessory molecule were necessary for the pheromone receptor
to reach the surface of the neuron.
The researchers also explored the effects of knocking out the
key M10 accessory molecule, beta2-microglobulin, in mice. They
found that the beta2-microglobulin-knockout male mice lacked
V2R receptors in their VNOs and also failed to exhibit the
normal aggressive behavior toward other males.
According to Dulac, the scientists\' findings show that M10 plays
a crucial escort role for pheromone receptors, but it might well
have a modulatory role. “The fact that the receptor needs M10
to go to the surface, doesn\'t prove it\'s the exclusive role of the
protein,” she said. “We do know that each time researchers have
described an association between a particular receptor and
another molecule at the cell surface, it has always been the case
that the specificity of the original receptor is being modified. So,
we have found new molecular players, if you will, in the game of
pheromone detection.”
Dulac said that the newly discovered MHC molecule involvement
could have important implications for understanding the
pheromone system. “This association opens all sorts of
possibilities for the mechanism of pheromone detection, because
we know the animal can modulate its behavior according to the
sex of another animal, its genetic background and the elements
that make up the identity of an animal.”
The discovery of escort molecules in the pheromone system
could have implications for understanding the molecular
machinery involved in smell and taste, Dulac said. Researchers
knew that in cell cultures, olfactory and taste receptors seemed
to require additional molecules to reach the surfaces of cells.
That observation hints at the need for still-undiscovered escort
molecules for those receptors, as well as for the V1R-
expressing class of pheromone receptors, she said.
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CATS COMFORTED BY SYNTHETIC CHEMICAL, RESEARCH
SUGGESTS
COLUMBUS, Ohio - Have an anxious cat? A synthetic chemical
may be what it takes to put kitty at ease in unfamiliar territory,
a new study suggests.
Researchers at Ohio State University found that when stressed
cats were exposed to a synthetic form of a feline facial
pheromone (FFP), they ate more and seemed more comfortable
in a hospital than did cats not exposed to the pheromone.
FFP is one of a variety of pheromones, chemicals that animals
use to communicate with others of the same species. FFP seems
to signal comfort and amicability.
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\"The increases in grooming, interest in food and food intake
suggest that FFP had an anxiety-reducing effect on some cats,\"
Buffington said.
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Changing a cat\'s behavior by introducing a synthetic pheromone
to its environment is a unique solution to helping agitated cats,
said Tony Buffington, co-author of the study and professor of
clinical nutrition at Ohio State\'s College of Veterinary Medicine.
\"Veterinarians are so used to putting something in or on an
animal that we\'ve never really thought of altering the animal\'s
environment,\" he said. \"Using pheromones may be an effective
way of calming cats.\"
The study appears in a recent issue of the Journal of the
American Veterinary Medical Association. Buffington conducted
the study with Cerissa Griffith, a veterinary student at Ohio
State, and Elizabeth Steigerwald, of Parke-Davis Pharmaceutical
Research.
In one study, 20 cats were housed in stainless steel cages 3
feet high by 4 feet wide at Ohio State\'s veterinary teaching
hospital. The cages included a litter pan, food and water bowls
and a clean towel. Enough space was left between the litter box
and the back of the cage to allow the cat to hide in this area.
When faced with new surroundings, especially in a hospital with
other animals, cats tend to show signs of stress and fear, such
as hiding or becoming hyper-vigilant, Buffington said. Common
behaviors, such as exploring their surroundings and playing, are
often suppressed.
In this study, 10 cats (four healthy, six ill) were exposed to
synthetic FFP while the rest of the cats (three healthy, seven ill)
were exposed to towels that had been sprayed with ethanol (the
ethanol, which acted as a placebo, evaporated before the
animals were placed in the cage with the towels.) The
researchers applied FFP or ethanol to the towels 30 minutes
before placing the towels in each cage. The researchers
videotaped the cats for 125 minutes. They then recorded cat
behavior and food intake for 18 five-minute intervals that began
35 minutes after the cat was placed in the cage with the towel.
\"The effects of FFP tend to kick in about a half-hour after
exposure,\" Buffington said. Once the FFP kicked in, though, the
cats exposed to the pheromone exhibited more episodes of
typical feline behavior, such as lying in the cage, sitting, grooming
and eating. Three cats in the FFP group ate during the
observation period, compared to only one cat in the control
group; the cats in the FFP group that did eat consumed nearly
10 grams of food during the observation period, compared to 0
.2 grams in the non-exposed group.
What was key with these findings was that cats exposed to the
pheromone exhibited more \"calming behaviors,\" Buffington said.
\"The increases in grooming, interest in food and food intake
suggest that FFP had an anxiety-reducing effect on some cats,\"
Buffington said. \"The cats responded to the synthetic FFP by
increased episodes of facial rubbing, which meant they released
more FFP onto objects in the cage.\" Cats release FFP via glands
in their face.
In a second study, researchers looked at another environmental
factor that may help calm anxious cats. The researchers
exposed 20 cats - all different than those in the first study - to
FFP and placed cat carriers in half of the cages. They wanted to
know if having a place to hide - the carrier - would have an
effect on their food intake. For this study, the researchers
recorded the 24-hour food intake of each group.
Adding the carrier caused cats to eat significantly more,
Buffington said. These cats consumed an average of 26 grams
of food during the 24-hour period, while the cats without the
carrier consumed about 9 grams of food. (26 grams is
equivalent to about half of a cat\'s daily food intake needs.)
\"The increase in food intake in this group suggests that other
features of the environment may affect a cat\'s response to
FFP,\" Buffington said.
Synthetic FFP is currently available from veterinarians,
Buffington said. Cat owners can use it to make their pet feel
more comfortable at home or to control fearful behavior.
\"It\'s a lot easier for an owner to spray a pheromone around the
home than it is to stick a pill down a cat\'s throat,\" Buffington
said.
Abbott Laboratories provided support for thiBoth smells and
pheromones may arouse instinctive behaviors in mammals
July 16, 2001
BLOOMINGTON, Ind. -- Ever notice how male dogs come from
the other side of the neighborhood when a female dog is in heat?
All it takes is a few molecules of a certain chemical to enable
mammals to smell their own species up to a half-mile away, said
Milos Novotny, Distinguished Professor of Chemistry and
director of the Institute for Pheromone Research at Indiana
University.
The chemicals, called pheromones, are detected by the
vomeronasal organ (VNO) in the animal\'s nose. Unlike the part of
the nose that detects ordinary smells, this super-sensitive organ
is connected directly to the mid-brain.
\"This is the shortest organ-to-brain distance in mammalian
biology,\" Novotny said. \"A cascade of biochemical processes can
be triggered quite selectively by specific olfactants such as
pheromones at incredibly small quantities. Studies of mammalian
pheromones can have a significant effect on pest control,
promoting endangered species, and, perhaps above all, for
understanding our own sense of smell and associated behaviors.\"
Signals from a mammal\'s nose caused by normal smells called
odorants go to various places in the cortex, in the upper part of
the brain, which is why humans are conscious of smells. But
pheromone signals go directly to the mid-brain, without being
processed by the conscious brain. What happens after that is
not completely clear, but there is a lot of evidence that the
animal\'s behavior and hormonal levels are influenced.
In a paper published July 12 in the journal Nature, Novotny and
co-workers at Harvard Medical School in Boston headed by
Linda Buck reported that the vomeronasal organ can actually
detect both odorants and pheromones. The VNO detected
odorants classified as animalic, camphoraceous, citrus, floral,
fruity, green/minty, musky, sweet or woody. Like pheromones,
these odorants were detected at extremely small
concentrations.
\"This suggests that in mammals, as in insects, odorous
compounds released from plants or other animal species may act
as \'semiochemicals\' -- signaling molecules that elicit behaviors
that are advantageous to the sender or the receiver,\" Novotny
said.
\"The house mouse provides a classic example of an elaborate
pheromone communication system: to signal inter-male
aggression and dominance, to show readiness for mating, to slow
down or accelerate the onset of puberty as needed, or to signal
stress to the other members of a colony,\" he said. \"Other
mammals, including possibly humans, use structurally diverse
substances for pheromone signaling.\"
The established view is that mammals detect odorants in the
olfactory epithelium (OE) of the nose and detect pheromones in
the vomeronasal organ. OE signals are relayed to various areas
in the cortex of the brain, while VNO signals are targeted to
areas of the mid-brain that control instinctive drives,
neuroendocrine responses and innate behaviors. The findings by
Novotny and his collaborators demonstrate that the VNO and
OE do not, in fact, detect mutually exclusive sets of chemicals.
Novotny\'s laboratory identified the first definitive mammalian
pheromones in the house mouse in the late 1980s, including their
chemical structure, synthesis and biological effects. Before
then, the term \"pheromones\" was largely confined to the world
of insects. Since then, he has identified pheromones in rats and
hamsters as well.
His current emphasis is on the neurochemistry of neurons in the
VNO and OE. He is the leader of interdisciplinary studies that
bridge the physical sciences, life sciences and social sciences,
including chemistry, neurobiology, psychobiology, biochemistry,
wildlife ecology, medical sciences, and animal physiology and
behavior.
The Institute for Pheromone Research at IU is a center of
excellence in the rapidly developing areas of chemical
communication (semiochemistry) and biochemical aspects of
olfactory perception. It promotes interdisciplinary collaborations
between IU scientists and a worldwide network of researchers
in chemical communication.
Novotny can be reached at 812-855-4532 or novotny@indiana. (\"novotny@indiana.\")
edu
(Hal Kibbey, 812-855-0074, hkibbey@indiana.edu) (\"hkibbey@indiana.edu)\")
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Pinning Down Pheromones
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Challenge
Many bacteria release chemicals called pheromones to monitor
their population density. The bacteria use this information to
regulate the transcription of certain genes such as those that
cause luminescence or biofilms. Scientists hope that by pinning
down precisely how pheromones control gene behavior, they can
learn how to manipulate them (with pharmaceuticals, for
example) to prevent diseases in humans, such as cystic fibrosis,
as well as diseases that affect our agricultural resources.
Argonne\'s Response
A team of Argonne bioscientists has been the first to observe
the three-dimensional structure of a pheromone captured in the
act of binding to a gene\'s regulatory element. The pheromone-
DNA-transcription-factor complex they analyzed is from
Agrobacterium tumefaciens, a bacterium that causes tumors in
crops (Figure 1). Learning about the pheromone\'s structural
convolutions and its binding sites helps scientists deduce how the
pheremone functions on the molecular level. They can then
hypothesize how similar systems may work in other pathogenic
bacteria.
Approach
The Argonne-solved structure is the first transcriptionally active
complex combining pheromone with transcription-factor protein
and DNA to be captured in three dimensions. Researchers used
the world\'s most powerful x-rays the Structural Biology Center
beams at Argonne\'s Advanced Photon Source. The x-rays
diffract from (and scatter off) the crystallized molecule, and
the intensities of the diffracted beams are read by a computer
that feeds these data into advanced structure determination
programs (Figure 2). The structure was determined at a
resolution of 1.66 angstroms allowing scientists to detect the
details of the structure. (To give some perspective: 10 million
angstroms make up 1 millimeter.)
Figure 1. Three-dimensional visualization of the structure of a
pheromone-DNA-transcription factor, as delineated by Argonne
bioscientists using the Structural Biology Center at the
Advanced Photon Source. Blue = DNA, red = pheromone, shades
of red and blue = subunit-interaction sites and RNA polymerase
activation sites on transcription factor protein.
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Figure 2. Diagram of x-ray-scattering analysis at Argonne\'s
Advanced Photon Source, where scientists use the world\'s
brightest x-ray beams to study nanoscale structures.
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Results
By discovering the pheromone-binding site, Argonne scientists
have determined that the A. tumefaciens pheromone works
indirectly, by making the transcription-factor protein more
stable and forming molecule pairs that are asymmetrical and
activate gene transcription (Figure 3). They have also confirmed
that the pheromone provides a necessary \"scaffold\" for
formation of the molecule pairs, and that the asymmetry of the
molecule pairs is likely to be significant in activating gene
transcription. These structure-function relationships can be
considered prototypes for similar pheromones.
Future Research
Work is under way to expand this research by:
Looking at the binding sites of pheromone analogs,
Creating structural mutations in the A. tumefaciens transcription
factor to study their effects on DNA binding and on activation
of gene transcription, and
Determining the three-dimensional structure of the molecule
pair complexed with RNA polymerase — catching it in the act of
gene activation
Figure 3. Argonne bioscientists determined the details of
pheromone binding, at 1.66-angstrom resolution, of a TraR
transcription-factor protein from A. tumefaciens bacteria. The
protein interacts with pheromone and a water molecule (light
blue).
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Contact
Andrzej Joachimiak
Biosciences Division and Structural Biology Center
Phone: 630/252-3926
Fax: 630/252-6126
andrzejj@anl.gov (\"andrzejj@anl.gov\")
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R-5 — 8/2002 Printable PDF version
Collaborators
Cornell University
Monsanto Company
Sponsors
U.S. Department of Energy, Office
of Biological and Environmental Research
National Institutes of Health
Contact: Tony Buffington, (614) 292-7987; Buffington.1@osu. (\"Buffington.1@osu.\")
edu
Written by Holly Wagner, (614) 292-8310; Wagner.235@osu. (\"Wagner.235@osu.\")
edu
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PSC Synchronin Project
Background
At its inception, Pheromone Sciences Corp. set its sights on the
development of commercially viable human pheromone
compounds. The first of these, a synthesized pheromone
product based on compounds found in female human sweat, was
named PSC Synchronin™.
Pheromones are behavior-modifying hormones transmitted
between both insects and animals by scent or by contact. The
knowledge of insect pheromones is considerable, research in
recent years having been driven by a market demand for safer
pesticides. The use of insect pheromone compounds can achieve
pest control by confusing normal insect behavior and preventing
reproduction. Pheromones are good for human health and the
environment because they pose fewer risks than traditional
chemical pesticides. Some brand-name pharmaceutical
companies, through their AgChem divisions, are now developing or
producing biopesticides that are based on insect pheromone
compounds.
Up until the mid-1990s, when Pheromone Sciences Corp. made its
first discoveries in the field, the pheromones of humans had
been less well studied than those of insects, although the
evidence for human pheromones had been building for some
time. Much of the attention to human pheromones had focused
on attempting to identify male-secreted compounds, such as
steroids in sweat responsible for human body odour, thought to
potentially influence the menstrual cycles and/or sexual
behavior of females. However, this approach is not consistent
with what has been observed in nature. Adult males secrete
steroids in their apocrine sweat somewhat continuously, and
therefore could not be expected to provide a time signal that
would synchronize a female partner\'s cycle. Further, it has been
known since the early 1970s that women who live in close
quarters such as college dormitories often become synchronized
in their menstrual cycles. This phenomenon suggested that some
possible pheromone-type factor that manifests itself between
women had the capability of lengthening or shortening their
cycles.
Dr. Martha McClintock, an American researcher, observed cycle
synchronization in female rats, and proposed a coupled-
oscillator hypothesis whereby cycle-shortening pheromones were
presumed to be released in the late follicular stage (the time
prior to ovulation) and cycle-lengthening pheromones at the time
of ovulation. She and Dr. Jeffrey Schank later tested this
hypothesis. In 1998, Dr. McClintock suggested that the same
coupled-oscillator hypothesis for cycle synchronization is in
operation in human females, and provided evidence for this by
stimulating changes in women\'s menstrual cycle length by
exposing them to armpit sweat from women collected in their
follicular or ovulatory phases.
As to the method of transmission, recent genetic studies have
discovered a pheromone receptor in humans, found to be
expressed in the main olfactory bulb---the same organ that
gives us our sense of smell.
PSC\'s early scientific research built on the body of work by the
American researchers, adding observations about the effects
female human pheromones have on males-including libido
enhancement and mood elevation.
The Company\'s first evidence of effects on males came when it
was observed that women in their follicular phase appeared to
release a substance that affected electrolyte metabolism (anti
-diuretic activity) in their male partners. Subsequently, it was
found that this affect could be transferred to certain men by
simply exposing them to sweat extracts from the women.
Experiments with males found that certain subjects exhibited
consistent elevations in certain urinary hormone levels observed
after exposure to these female extracts. These sweat extracts
have been subjected to biochemical investigation to determine
their precise chemical makeup, as well as the timing and
mechanisms for their release.
In our drive to isolate these compounds, an examination was
undertaken as to their effects on sex drive in males. In pilot
experiments over the past years, a procedure was carried out to
track the changes in the male subjects\' urinary hormone levels.
Subjective impressions on mood and libido were also observed
and recorded. Based on research to date, we have synthesized
12 chemical analogues that resemble the PSC compounds found
in the active fractions isolated from female subjects.
Clinical Testing
In 2001, the Company initiated a small-scale placebo-controlled
trial to test for pharmacological activity of these isolates on
male libido and mood. Under the direction of Dr. Sidney
Radomski, Toronto Hospital, Western Division, this study was
undertaken for obtaining a better understanding of the
pharmacological activity of these isolates as well as the best
manner for testing and documenting their activity. If successful,
PSC hopes to use this research to develop new pharmacological
agents applicable to libido enhancement in men. However,
because of the small sample sizes to date, the results cannot be
considered conclusive until more extensive trials are undertaken
with larger groups of subjects.
The company has decided to hold off of any further
investments in this project until the funds from sales of the PSC
Fertility Monitor in North America and Europe materialize. This
step will permit the company to stay focussed on projects which
will generate revenues sooner as opposed to later.
Intellectual Property
It is anticipated that patent applications of the structure and
synthesis of pheromone analogues will be filed upon completion
of the tests using the synthesized analogues of PSC
Synchronin™.
Market Potential
Pheromone\'s continuing research into how both the natural
pheromones and the PSC Synchronin affect human physiology is
bringing new knowledge about the hormonal control of libido.
Pheromone intends to use this new data in the future to develop
both drug and perhaps cosmetic applications for its pheromone
based product.
The Future
A new era of pharmacological development is dawning, and
Pheromone Sciences is poised to be at the leading edge with
these new therapeutic agents.
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Pheromones in Humans: Myth or Reality?
(c) 1992 David Wolfgang-Kimball
The Senses
Dr. Goldsmith
Pheromones are volatile, odorous substances which are released
by one animal and detected by another, causing some sort of
physiological reaction. These reactions can manifest themselves
in a variety of different ways: some pheromones modulate
sexual activity, some affect aggression, some play roles in
territory marking, and other pheromones have similarly diverse
effects on the target animal. Pheromones have been
demonstrated in a very large number of organisms ranging from
amoebas to fish to mammals, including primates. However, the <br /
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