Novartis Foundation Bulletin
Issue 12, October 2002
Welcome to the 12th edition of the Novartis Foundation's Bulletin.
This issue features reports on:
(Based on presentations given at Novartis Foundation Symposium 252 'Generation and effector functions of regulatory lymphocytes' held in London on 9-11 July 2002)
Crackdown on
persistent infections imminent
Crafty pathogens such as Mycobacterium tuberculosis, HIV and
Trypanosoma gondii cause chronic, often deadly infections by
hoodwinking their host's immune surveillance. But at a Novartis Foundation
Symposium recently held in London, scientists declared it soon may be
possible to manipulate the immune system to eliminate these infectious
agents for good. Their main target is a type of lymphocyte known as a 'T
suppressor' or 'T regulatory' cell that is currently causing a furore in
immunological circles.
These suppressor cells are not exactly newcomers. Their existence was
proposed more than 30 years ago, but it was only in 1995 that Shimon
Sakaguchi (Kyoto University, Kyoto, Japan) showed they were a
distinct lineage of CD4+ T cells with a common marker on their surface:
CD25. Since then, the excitement surrounding these cells has been
mounting.
Normally, regulatory lymphocytes are involved in the laudable task of
suppressing autoreactive cells that cause autoimmune disease. But in
chronic infections, these immunosuppressive T cells may actually be
helping the pathogens to avoid detection. Kim Hasenkrug (National
Institute of Allergy and Infectious Diseases, NIH, Hamilton, MT, USA)
points out that "these microorganisms may be using T suppressor cells
as a window of escape."
To investigate ways to eliminate chronic infection, Hasenkrug has focused
his studies on mice persistently infected with Friend leukaemia virus.
These animals are clearly immunosuppressed: their CD4+CD25+ T cells shoot
up to twice the normal percentage, and they are unable to reject
transplanted tumours.
"Once the virus establishes persistence it is hard to get rid
of," he admits. However, injecting antibodies that block TGFb
and IL-10 receptors—molecules thought to be key in suppression—has
been a success. The numbers of suppressor cells fall and the mice regain
their capacity to reject tumours. "This is a feasible treatment
approach for virus-induced immunosuppression; it is very short but with
long term effects," he enthuses.
There are a number of persistent infections where immunosuppressive T
cells have been detected; for instance, infections with Borrelia
burgdorferi (the causative agent of Lyme disease), Bordetella
pertussis, Schistosomiasis mansoni and in infections with human
immunodeficiency and hepatitis C viruses.
Skin infections with the parasite Leishmania major, also reveal an
abundance of CD4+CD25+ cells. "It's a beautiful system," remarks
Ethan Shevach (NIAID Laboratory of Immunology, Bethesda, MD, USA).
"After you infect the ear, the number of parasites plummets and you
are left with 6000 parasites that live happily ever after."
At the healed site of infection, there is also an abundance of
immunosuppressive T cells. "Half of these are CD4+CD25+ cells,"
says Shevach. "They are contributing to the survival and
proliferation of the parasites by suppressing and killing Leishmania-specific
effector T cells." These effector lymphocytes would normally clear
the parasite but they are kept back by the regulatory lymphocytes. In the
chronically infected skin, suppressor and effector T cells are engaged in
a delicate balancing act.
To eliminate parasites or other persistent infections, one solution is to
expand T effector cells. Vaccines have the potential to do this but the
response is often too weak. "It would be great to get rid of
CD4+CD25+ cells, at least transiently, for vaccination purposes,"
Shevach concludes. No doubt immunologists already have some options up
their sleeves.
Dr Lisa Melton—Science writer, Novartis Foundation, London
This article was published in
the Lancet Infectious Diseases 2:514, September 2002
'Generation and effector functions of regulatory lymphocytes' is due to
be published by John Wiley & Sons, Chichester, UK in April 2003
(Based on presentations given at Novartis Foundation Symposium 251 'Autism: neural basis and treatment possibilities' held in London on 18-20 June 2002)
What's in a
face?
What does a face mean to you? How easily can you recognize fear when you
see it? Scientists have pinpointed certain areas of the brain involved in
face recognition and fear recognition through neurological research.
People with autism have a specific deficit in face recognition and they
find it difficult to recognize expressions of emotion. Brain scans in
normal individuals show that an area the size of a broad bean, within the
fusiform gyrus at the back of the brain, is activated during face
recognition. This so-called fusiform face area (FFA), points out Rob
Schultz (Yale University Child Study Center), is not activated in
individuals with autism when they see faces. Neural activation in these
people is observed in a different region normally associated with object
recognition.
This led Chris Frith (Wellcome Department of Imaging Science), at a
recent Novartis Foundation Symposium on autism, to raise the question,
which Schultz had dealt with in an earlier publication, as to whether
people with autism might be treating faces as objects. The answer is clouded by
the fact that in normal individuals the FFA is activated in response to seeing
certain objects. This might be the case for a camera lover when he sees
his favourite lens. Perhaps faces are not as interesting for individuals
with autism as they are for normal people.
In light of findings suggesting that the FFA is not selective for faces,
Schultz proposes that persons with autistic spectrum disorders are less
socially motivated and therefore disinterested in the face. He believes
that an expertise for face processing develops gradually in normal
socially motivated individuals possibly through interactions between the
FFA and the amygdala. Recent studies indicate that the amygdala plays an
important role in processing facial expressions in collaboration with
other brain regions.
The amygdala of autistic individuals is abnormal. It has been shown that
the human amygdala (situated near the fusiform gyrus) is engaged in
processing fearful expressions on faces. David Amaral (UC Davis Center
for Neuroscience) has studied monkeys with damage to the amygdala.
These monkeys were curiously unafraid of frightening stimuli including
snakes but appeared to be capable of normal social interaction. Hitherto
it had been proposed that abnormal amygdalas in people with autism were
associated with altered social functioning. However, Amaral advises that
"If the amygdala is pathological in subjects with autism, it may
contribute to their abnormal fears and increased anxiety rather than their
abnormal social behaviour".
Individuals with Turner's syndrome are females and, like males, have a
substantially higher rate of autistic-like conditions than normal females;
most notably Turner's females have enlarged amygdalas. Turner's females
have only one X-chromosome unlike their normal female counterparts who
have two Xs, one from each parent. In order to explain why males are
statistically at least 4 times more likely to suffer from autistic
spectrum disorders, David Skuse (Institute of Child Health, London)
argues that one or more X-linked genetic loci are associated with the
expression of autistic characteristics. Two different genetic mechanisms
could explain male vulnerability. First, males (like
Turner's females) have a single X-chromosome, therefore a lower level of
X-linked product for any gene that is needed in two copies in normal
females.
Second, males (whose single X-chromosome is always inherited from their
mothers) may lack expression of an imprinted X-linked gene, which is
active only if inherited from the father (as in normal females). Both
putative mechanisms could provide protection from autism for females by
increasing the threshold at which other autism-predisposing genes
influence behaviour and cognition. This explanation for male vulnerability
is plausible despite the fact that genome wide screens haven't revealed
strong X-linkage to autism. Skuse points out that "a complex
multiallelic pattern of vulnerability would be necessary for phenotypic
expression". To date, linkage studies have had insufficient power to
detect this.
With a limited success in drug treatment and/or intervention studies there
is a greater need for genetic predictors and understanding of the
pathology of autism. However, as alluded to above, this will not
necessarily result from genome-wide screens until we understand how genes
interact with one another and how post-translational modifications (like
methylation) impact on the phenotype. There is a very large picture to
complete before we approach a full understanding of the aetiology and
therefore potentially successful treatment of autistic spectrum disorders.
Francesca Happé (Institute of Psychiatry, London) feels that given
the complexity of such disorders, it would be more profitable to search
for the biological basis of the characteristic social and non-social
deficits rather than the aetiology of autism per se. It would
certainly be interesting to pinpoint the genes associated with neural
development, specifically the development of the fusiform face area and
the amygdala in relation to this spectrum of disorders.
Brona McVittie—Assistant Science Editor,
Novartis Foundation, London
(top)
'Autism: neural basis and treatment possibilities' is due to be
published by John Wiley & Sons, Chichester, UK in March 2003
(Based on presentations given at Novartis Foundation Symposium 251 'Autism: neural basis and treatment possibilities' held in London on 18-20 June 2002)
Bursar's
report
The opportunity to attend the three-day-symposium on Autism: neural
basis and treatment possibilities symposium chaired by Sir Michael
Rutter, and attended by a select group of world leaders in the area,
constituted the highlight of my research career to date. In addition to
this great opportunity, the Novartis Foundation funded a six week study
tour enabling me to spend time at Cambridge University, the Institute of
Psychiatry, and the University of Oxford.
The first leg of my bursary period at Cambridge University (Centre for
Autism Research) was spent with Dr. Patrick Bolton, a leader in the
field of the genetics, neurobiology, and psychiatry of child developmental
disorders. Dr. Bolton arranged for me to spend time discussing
contemporary research and clinical issues with his large research team of
epidemiologists, psychiatrists, and experimental psychologists. I had read
much of the ground breaking research to emerge from Cambridge over the
last decade. However, being able to discuss methodologies, theoretical
development of key issues, and future directions for autism research in
detail was an invaluable and exciting experience. At the end of my
two-weeks at Cambridge, I left having made key contacts with fellow
researchers, who in addition to sharing their intellect, went out of their
way to show me their beautiful university town, arranging tours of the
colleges, punting, and of course a pint in the famous Cambridge Pub where
Watson & Crick's pioneering contribution to the discovery of DNA took
place.
For the second part of my bursary period I was hosted by Dr. Francesca
Happe at the Institute of Psychiatry (Social, Genetic and Developmental
Psychiatry Research Centre). This was a particular highlight for me,
as I have based much of my own research on Dr. Happe's cutting-edge
'central coherence' theories of autism. I had the opportunity to present
my own research work at the Institute and receive valuable feedback from
Dr. Happe and her research colleagues. Dr. Happe's passion and drive to
understand the cognitive underpinnings of autism was inspirational.
The last two-weeks of my bursary period were spent with Professor Dorothy
Bishop at the University of Oxford (Department of Experimental
Psychology). Professor Bishop is a world leader in childhood language
disorders, and has made a huge contribution to our understanding of
language delays and deficits in children with autism. Through my
discussions with Professor Bishop, I was inspired to 'think outside the
square' about my research and directed to look more closely at the
interplay between the cognitive, motor, and language features of autism.
It was an honour to be able to discuss and share ideas with a scholar as
eminent as Professor Bishop.
I am indebted to the Novartis Bursary hosts for their enthusiastic
encouragement of my current research and future research plans. Since
returning to Australia, I have remained in contact with my newly
acquainted research colleagues, and look forward to catching up with them
again in person during the Autism World Congress which will be held in
Melbourne later this year [see http://www.autismcongress.com].
Dr. Nicole J. Rinehart—Department of Psychology, Monash University, Australia
The Novartis Foundation bursary scheme
The aim of the bursary scheme is to fund young scientists to attend Novartis Foundation
Symposia and subsequently spend up to 12 weeks in the department of one of the symposium participants. Applicants (of any nationality) must be aged between 23-35 years on the closing date for application. They must be actively engaged in research on the topic covered by the symposium and should not already have accepted an invitation to participate in that symposium.
For details of the bursary scheme and forthcoming bursaries see:
http://www.novartisfound.org.uk/bursary.htm
or contact the bursary scheme administrator:
E-mail: bursary@novartisfound.org.uk
Meetings
Open meetings:
The next Novartis Foundation Open meeting is on 'Novel
chemotherapeutic strategies in cancer treatment' will take place
on 15 November 2002 at Scientific Societies' Lecture Theatre, New
Burlington Place, London W1
To book your place at the
meeting please contact Stanley Langer at the Royal Society of Chemistry,
Burlington House, Piccadilly, London W1J 0BA by 8 November 2002
tel: +44 (0) 20 7440 3325
fax: +44 (0) 20 7734 1227
Email: langers@rsc.org
Other forthcoming meetings include:
-
Anaphylaxis, Friday 28 February 2003
-
Mammalian TRP channels as molecular targets, Friday 28 March 2003
-
Reversible acetylation of chromatin and non-histone proteins: biology and relevance to human disease, Friday 9 May 2002
To book your place at these
meetings please contact the open meetings organizer
tel: +44 (0) 20 7636 9456
fax: +44 (0) 20 7436 2840
Email: openmtg@novartisfound.org.uk
Full details of Novartis
Foundation Open Meetings can be found at:
http://www.novartisfound.org.uk/open.htm
Symposia:
The most recent symposium took place in Baltimore 21-23 Oct 2002 entitled
'Retinal dystrophies: functional genomics to gene therapy'. Chaired
by Shomi Bhattacharya
Discussion meetings:
The next discussion meetings to take place are:
-
31 Oct/1 Nov 2002: The biophsychosocial model within medicine: luxury or necessity? (in collaboration with One Health)
-
15 Nov 2002: Self-assembled nanostructures in physics, chemistry and biology (in collaboration with the Royal Society)
-
6 Dec 2002: Transgene flow in flowering plants (in collaboration with the Royal Society)
-
21 Feb 2003: Epigenesis versus preformation in mammalian development (in collaboration with the Royal Society)
Publications
We are pleased to announce the imminent publication of:
'In silico'
simulation of biological processes
(Novartis Foundation Symposium 247)
http://www.novartisfound.org.uk/nbook.htm#247
and
Mucus hypersecretion in respiratory disease
(Novartis Foundation Symposium 248)
http://www.novartisfound.org.uk/nbook.htm#248
For details of other publications see: http://www.novartisfound.org.uk/nbook.htm
Book
sale 2002
Many of our out-of-print symposium volumes are available at vastly reduced
prices in this year's book sale.
Please see: http://www.novartisfound.org.uk/booksale.htm
for details and how to order or email: bulletin@novartisfound.org.uk
Publicity
Resident science writer, Dr Lisa Melton has recently published the
following:
'Immunotherapy comes in from the cold' in The Lancet 360:697,
31 August 2002
'Crackdown on persistant infections imminent' in The Lancet
Infectious Diseases 2:514, September 2002
'How to conquer incontinence' in The Times T2, p 14-15, 17
September 2002
Hospitality
Details of all conference facilities and accommodation available at the
Foundation can be found at: http://www.novartisfound.org.uk/hosp.htm
Personalia
The Foundation would like to congratulate Kurt Wüthrich who was recently
awarded the Nobel Prize for Chemistry 2002, along with John B. Fenn and
Koichi Tanaka. Professor Wüthrich received the award for his
development of nuclear magnetic resonance spectroscopy for determining the
three-dimensional structure of biological macromolecules in
solution.
The Foundation welcomes Dr Panjab Singh, Director General of the Indian
Council of Agricultural Research, New Dehli, as joint scientific advisor
for India.
Full details of personalia and activities at the Novartis Foundation can
also be found in the Foundation's 2002 Annual Report and Handbook.
If you would like to receive a copy of the handbook, please send an email
including postal details to: bulletin@novartisfound.org.uk
(back to top)