Read more - Centre for Molecular Medicine and Therapeutics

cpa-june-09:Layout 1 6/2/2009 12:06 PM Page 6
DÉVELOPPEMENT PRÉCOCE DU CERVEAU
Scientist identifies genetic roots of extreme violence in mice
humans. “It turns out the NR2E1
gene is one of the most similar genes
between human and mouse,” she
explains. “It is expressed similarly in
the development of the brain, both in
the fetus and in the continued development of the adult brain, as well as
in the stem cell areas of the brain.”
by Jadranka Bacic
T
he link between genetics,
brain development and
behaviour has always
fascinated Elizabeth Simpson.
The senior scientist and associate
professor at the University of British
Columbia’s Centre for Molecular
Medicine and Therapeutics has
enlisted mice in her quest to understand the genetics involved in certain
brain and behaviour disorders,
particularly extreme violence and
aggression.
“The overall goal of my research program is to use genetically engineered
mouse models to understand and
improve treatments for brain and
behaviour disorders,” says Dr.
Simpson. “My approach is to study
the genetics, behaviour, neurogenesis
and genome-wide transcription in
mouse models of brain disorders.”
Her lab was the first to find that the
human gene NR2E1 can correct
violent behaviour in a mouse modeling pathological aggression. NR2E1 is
the nuclear receptor involved in
controlling stem cells in the brain.
The gene has also been linked to
bipolar disorder since it overlaps with
a chromosome that is associated with
the psychiatric illness.
The discovery, like many scientific
experiments, was a complete fluke.
Her research team genetically
engineered a strain of mice to be
missing a specific gene with the
Une scientifique
identifie les racines
génétiques de la
violence extrême
chez les souris
par Jadranka Bacic
L
e lien entre les gènes, le
développement du cerveau et le
comportement a toujours
intéressé Elizabeth Simpson.
Scientifique principale et professeure
agrégée au Centre for Molecular
Medicine and Therapeutics de
l’Université de la ColombieBritannique, la docteure Simpson
utilise des souris dans ses recherches
pour comprendre les gènes associés à
certains troubles du cerveau et du
comportement, en particulier la
violence et l’agressivité extrêmes.
Missing gene in
aggressive lab mice
could unlock potential
of gene therapy for
mental illnesses
expectation that it would result in a
spermatogenesis problem. “Instead,”
she says. “We accidentally created a
delusion of a gene that we didn’t
know anything about.”
The mouse lacking the NR2E1 gene
was called “fierce” because it was
highly aggressive. Mice, like humans,
are social animals that normally live
in extended families and develop close
bonds. The “fierce” mouse, however,
displays dramatic behavioural
problems. Males are extremely
violent, often injuring or killing their
siblings or intended mates. Females
may not kill other mice, but they
show increased aggression. What is
even more startling to Dr. Simpson is
that the females don’t seem to possess
any strong maternal instincts. The
mother may be strong and her litter
healthy, but 50 per cent will abandon
their pups shortly after birth.
“It makes sense now, in retrospect,
that the stem cells are defective in
‘fierce mice’,” she says. “The cells
don’t divide as often as they should
and they don’t differentiate the way
they should, which means the forebrain and limbic regions of the brain
are abnormal. It is those abnormalities
that presumably lead to the behaviour
problems that result in ‘fierce’ mice.”
The discovery of a single gene that
could produce such a dramatic
change in behaviour was both exciting
and controversial for the field of
aggression research, according to
Dr. Simpson.
Once the damaged gene was isolated
and identified as NR2E1, the first
Her next step was to determine if
these findings were relevant to
peut corriger un comportement
violent d’une souris montrant une
agressivité pathologique. Le gène
NR2E1 est un récepteur nucléaire
impliqué dans le contrôle des cellules
souches du cerveau. Le gène a aussi
été lié au trouble bipolaire puisqu’il
chevauche un chromosome associé à
la maladie psychiatrique.
santé, mais 50 % d’entre elles abandonnent leurs nouveaux nés.
Comme plusieurs expériences
scientifiques, la découverte résulte d’un
pur hasard. Son équipe de chercheurs a
délibérément supprimé un gène dans
une série de souris génétiquement
modifiées dans l’espoir que cela entraîne
un problème de spermatogenèse.
« Au lieu de cela, dit-elle, nous avons
créé une illusion d’un gène qui nous
était tout à fait inconnu. »
La souris déficiente en gène NR2E1 a
été baptisée «la violente » en raison de
sa grande agressivité. Les souris sont
des animaux sociaux qui, à l’instar des
humains, vivent habituellement au sein
« L’objectif global de mon programme de familles élargies et qui développent
de recherche est d’utiliser des modèles des liens étroits. Toutefois, la souris
de souris génétiquement modifiées
« violente » présente des problèmes de
pour comprendre et améliorer les
comportement radicaux. Les mâles sont
traitements pour les troubles du
extrêmement violents et, souvent,
cerveau et du comportement »,
blessent ou tuent leurs frères et sœurs
précise-t-elle. « Mon approche
ou leurs partenaires destinées. Les
consiste à étudier les gènes, le comfemelles peuvent s’abstenir de tuer
portement, la neurogenèse et les
d’autres souris, mais elles démontrent
facteurs de transcription sur tout le
une agressivité croissante. Ce qui surgénome des modèles de souris
prend davantage la docteure Simpson,
montrant des troubles du cerveau. »
c’est que l’instinct maternel est presque
nul chez les femelles. Les mères
Son laboratoire a été le premier à
découvrir que le gène humain NR2E1 peuvent être fortes et leurs bébés en
6 Canadian Psychiatry Aujourd’hui, June 2009 Juin
member of a new subclass of nuclear
receptors, Dr. Simpson’s lab could
take a closer look at its function and
learned that the gene is expressed in
the brain and involved in stem cell
development.
Dès que le gène endommagé a été
isolé et identifié comme étant le
NR2E1, le premier membre d’une
nouvelle sous-catégorie de récepteurs nucléaires, les chercheurs ont
pu examiner sa fonction sous la
loupe et ont appris que le gène
s’exprime dans le cerveau et est
impliqué dans le développement des
cellules souches.
« En rétrospective, il est évident que
les cellules souches des souris
« violentes » sont déficientes, » dit la
docteure Simpson. « Les cellules ne
se divisent pas aussi souvent qu’elles
le devraient et leur capacité de
différenciation n’est pas suffisante, ce
qui veut dire que l’avant cerveau et
les régions limbiques du cerveau sont
anormales. Ce sont ces anormaux
qui entraînent des problèmes de
comportement engendrant des souris
« violentes ». »
Selon la docteure Simpson, pour les
spécialistes du domaine de la
recherche de l’agressivité, la découverte d’un gène unique pouvant
produire un changement de
comportement aussi radical était à la
fois stimulante et controversée.
Sa prochaine étape consistait à déterminer si ces résultats s’appliquaient
aux humains. « Il ressort que le gène
NR2E1 est l’un des gènes les plus
similaires entre les humains et les
With this first hint that the gene
worked the same in both mouse and
human, Dr. Simpson and her research
team went to work on placing a
human version of the gene into a
“fierce” mouse. Their 2005 study
showed that pathological aggression
in “fierce” mice could be corrected by
the human version of the nuclear
receptor.
“It was fabulous. Their brains underwent normal development,” she
recalls. “We could see from the time
they were weaned that their behaviour was completely normal, and as
they got older, they mated normally
and raised their litters normally.”
But do these genes work the same in
humans? Dr. Simpson says it’s too
early to tell. Studies have shown a
link between genes, brain development and mental illness. Her own
work in 2008 found an association
between the NR2E1 gene and bipolar
disorder. Her lab has since been funded by the U.S. National Institutes of
Health to introduce the mutations
found in bipolar humans back into
mice to see if the mice would develop
behaviours similar to bipolar disorder.
“Fierce” mice continued on p 7
souris, » explique-t-elle. « Ce gène
s’exprime de façon similaire dans le
développement du cerveau, du fœtus
jusqu’à l’âge adulte, et dans les
cellules souches du cerveau. »
Forte de cette première indication
que le gène fonctionnait de la même
façon chez les souris que chez les
êtres humains, la docteure Simpson
et ses collaborateurs ont poursuivi
leur recherche en imprégnant une
version humaine du gène dans la
souris « violente ». Les résultats de
leur étude de 2005 montrent que la
version humaine du récepteur
nucléaire peut corriger l’agressivité
pathologique chez les souris
« violentes ».
« Quelle veine, » dit-elle. « Les
cerveaux se sont développés normalement. Nous avons constaté que les
souris étaient complètement normales
depuis leur sevrage et, en grandissant,
elles se sont accouplées normalement
et ont eu des familles normales. »
Mais ces gènes fonctionnent-ils de la
même façon chez les êtres humains?
Selon la docteure Simpson, il est
encore trop tôt pour l’affirmer. Les
résultats des études montrent qu’il
existe un lien entre les gènes, le
développement du cerveau et la
maladie mentale. Son ouvrage de
2008 indique un lien entre le gène
NR2E1 et le trouble bipolaire.
« La violente » suite à la page 7
cpa-june-09:Layout 1 6/2/2009 12:06 PM Page 7
EARLY BRAIN DEVELOPMENT
MRIs link pedophilia to
early brain development
by Jadranka Bacic
I
s a pedophile born or made?
James Cantor, a clinical
psychologist at the Centre for
Addiction and Mental Health
(CAMH) in Toronto, has been trying
to answer this question for years and
what he has learned could potentially
yield strategies for preventing the
development of pedophilia.
Dr. Cantor believes the roots of
pedophilia lie in the wiring of the
brain. He has spent years studying the
neurobiological make-up of hundreds
of pedophiles at CAMH’s Kurt Freund
Laboratory with the help of brain
scanning technologies.
His groundbreaking discovery began
with a standardized assessment of over
1,000 men being evaluated for
pedophilia or other sexual disorders at
the Kurt Freund Laboratory in
Toronto between 1995 and 2006.
Dr. Cantor says patterns began to
emerge. He found that pedophiles are
more likely to have lower IQs and
have failed grades in school, are more
likely to have suffered brain injuries as
children, are shorter on average than
non-pedophilic sexual offenders, and
are three times more likely to be lefthanded. They were also more likely
to have mothers who suffer or have
suffered from a psychiatric illness.
“There was clue after clue that something was different about these men,”
says Dr. Cantor. “And much of it
seemed to be related to early brain
development.”
While he admits that some of these
findings could be explained by
external psychosocial factors, there is
no known environmental influence
that would affect a person’s handedness. “That is something that is determined entirely by brain organization
and established before birth,” explains
Dr. Cantor. “If being left-handed is
related to being pedophilic, then there
has to be some chain of events that
leads all the way back to the womb.”
« La violente » suite de la page 6
Depuis, son laboratoire a reçu des
fonds de la U.S. National Institutes of
Health pour poursuivre cette
recherche. L’objectif : réintroduire
dans les souris les mutations
trouvées dans des personnes
atteintes de la maladie bipolaire pour
voir si les souris développeront un
trouble bipolaire semblable.
La docteure Simpson espère que ses
découvertes ouvriront une voie
potentielle à la mise au point d’un
traitement amélioré pour les personnes atteintes de maladies mentales.
« Mieux vous comprenez la biologie
naturelle d’une maladie, plus vous
êtes en mesure de trouver des façons
de la traiter – en développant de
meilleurs médicaments ou par le
Pedophilia, according to Dr. Cantor,
appears to be just one of a constellation of characteristics which point to
a problem with the development of
the brain in the womb, such as being
left-handed, having a low IQ and
being shorter in stature than the
average male.
His next step was to look more
directly at the brains of pedophiles
versus those of non-sexual offenders
with the help of magnetic resonance
imaging (MRI) technologies. A total
of 127 men participated in this
follow-up study.
“The results surprised me and my
entire team,” says Dr. Cantor. There
were two schools of thought on where
the differences in the brain would be
located, he explains. Some researchers
believed the differences would be
found in the frontal lobe; the
emotional control centre of the brain
housing impulse control. Others
believed distinctions would be found
deep in the limbic system of the
temporal lobe; the area of the brain
that controls sexual behaviour and
urges.
“We kept re-running the analyses
because we had trouble believing our
own results,” says Dr. Cantor.
“It turned out that the differences
weren’t in either the frontal or
temporal lobe. Instead, we found
variations existed in the white matter
tissue that connects all regions of the
brain. There was significantly less of it
in the brains of male pedophiles.”
The eureka moment came when
Dr. Cantor glanced over at a paper
evaluating which parts of the brain
respond to sexual stimuli. It was
sitting on his desk next to the pile of
results from his own MRI study. It
showed that the areas of the brain
which light up in response to sexual
stimuli were the same in both
pedophiles and non-pedophiles. Even
more important was that these areas
were the ones where variations were
found in the connective white matter.
dépistage des facteurs génétiques du
risque. »
Avec une subvention de 10,2
millions de dollars de Génome
Canada, la docteure Simpson est en
voie de dresser la carte complète des
racines neurobiologiques des troubles
du cerveau les plus sérieux. « Il se
peut que plusieurs maladies mentales
soient causées par des problèmes
de développement des cellules
souches, » conclut-elle. « Je crois
que la thérapie génétique constitue
un nouvel horizon pour les maladies
mentales. Certes, ce n’est pas pour
demain, mais en en axant nos traitements des troubles du cerveau sur la
thérapie génétique, nous ouvrirons
une grande et nouvelle porte
thérapeutique. » 
“It seems the brain doesn’t have a sex
centre, but instead the brain has a
network that together serves to identify in the environment what stimuli are
potentially sexual stimuli,” explains
Dr. Cantor. “The research seems to
suggest that there is a problem in the
wiring of the brain of a pedophile.
There is something wrong with the
way that circuitry connects the
sexually responsive parts of the brain.”
In 2008, Dr. Cantor has received a
$1 million operating grant to expand
his research program from the
Canadian Institutes for Health
Research (CIHR). His team will be
repeating the MRI scans from his
previous study, but will also be using
two newer MRI technologies:
diffusion tensor imaging (DTI) and
magnetization transfer.
These two cutting edge MRI
technologies will give more specialized
and focused information about white
matter that Dr. Cantor says isn’t
captured by the regular MRI.
“My greatest hope for this line of
research is to give us an idea of how
and when to engage in the primary
prevention of pedophilia,” says
Dr. Cantor. “If we can figure out why
someone has a sexual attraction to
children, we can figure out a way to
remove the motivation a person may
have to commit a sexual offense
against a child.”
While Dr. Cantor’s research suggests
early brain development may be the
key to what makes a person a
“Fierce” mice continued from p 6
Dr. Simpson hopes her findings will
translate into better treatment for
people with mental illness. “The
better you understand the natural
biology of a disease, the better you are
able to think of ways to treat it – like
developing new and better drugs or
screening for genetic risk factors,” she
says.
With a $10.2 million grant from
Genome Canada, Dr. Simpson is on
pedophile, it is too early in the
research to pinpoint when before
birth or what before birth caused the
neurological variance.
“It could be something as simple as
poor prenatal nutrition, or some toxin
in the environment, or the mother
may have been exposed to some sort
of virus that interferes with normal
and optimal fetal growth in the
womb,” says Dr. Cantor. “It’s too early
to rule anything out, but it seems
there is something in the wiring of the
brain that causes the behaviour, along
with the development of certain
physical and intellectual characteristics like being left-handed and
having a low IQ.”
Dr. Cantor is quick to point out that
there is nothing in his research to
suggest there is a magic pill or therapy
that will turn a pedophile into a nonpedophile, but it does underscore the
types of treatments that are probably
most effective are those that involve
medications to dial down the sex drive
and counseling techniques to teach
pedophiles to manage their sexual
interests and exercise self-control.
“The MRI scans suggest early brain
development may be the key to what
makes a person a pedophile, but
despite the biological link, there is
nothing in this research to suggest
that pedophiles are not responsible
for their actions,” says Dr. Cantor.
“I think the strongest implications of
these findings is that we need to do
everything we can to help people
control their own behaviours.” 
course to help map out the neurobiological roots of some devastating
brain disorders. “It may be that many
mental illnesses occur due to
problems with stem cell development,” says Dr. Simpson. “I think
gene therapy is a new horizon for
mental illnesses. “I think it’s still quite
far away, but by moving towards stem
cell gene-based therapy for brain
disorders we are opening a huge new
therapeutic door.” 
Canadian Psychiatry Aujourd’hui, June 2009 Juin 7