Novartis Foundation Bulletin
Issue 22, September 2004
Welcome to the 22nd edition of the Novartis Foundation's e-mail Bulletin.
This issue features reports on:
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Allergies and hepatitis A (NF267)
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Long QT and the hERG channel (NF266)
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Bursar's report (NF267)
(Based on presentations given at Novartis Foundation Symposium 267 "The genetics of autoimmunity" held in London on 22-24 June 2004)
Allergies and hepatitis A
Cleanliness may be next to godliness, but when it comes to allergies, it
may be possible to be too clean. Over the last two decades, allergies
including asthma, hay-fever and eczema, have soared in industrialized
countries. Many experts put the increase down to better sanitation, and an
over-hygienic lifestyle, yet so far no one has been able to pinpoint which
early infections might be building up such protection.
Now a team led by Dale Umetsu and Rosemarie Dekruyff (Stanford
University School of Medicine, USA) has uncovered one key infectious
player - the hepatitis A virus. Their findings may go some way towards
explaining why allergies are rampant in the west, but also usher in the
possibility of developing drugs that emulate a brush with the virus to
prevent or treat asthma.
The World Health Organization estimates that 150 million people worldwide
are asthmatic and the number is growing by 50% every decade. In
industrialized countries, asthma has reached epidemic proportions
affecting up to one in five people.
Nobody knows for sure what is fuelling this rise, although mounting
evidence supports the 'hygiene hypothesis' that suggests that our
sanitized existence is to blame. Children are exposed to few bacteria and
viruses, and the immune system tends to overreact to otherwise harmless
substances like pollen or dust mites.
Rather than sift through myriad microbial candidates, Umetsu chose the
genetic route. "We knew that finding a susceptibility gene for asthma
in humans would be a formidable task, so we decided to simplify the
problem and use a mouse model." Their studies threw up one gene, TIM-1,
that predisposed mice to asthma.
But the researchers got more than they bargained for. "It turned out
that TIM-1 is also the receptor used by the hepatitis A virus to infect
human cells, " Umetsu explained at a Novartis Foundation symposium in
London in June. This was a crucial discovery, since it is known that
people exposed to the hepatitis A virus have much less allergy.
The Stanford team sequenced the TIM-1 gene in humans and found that
we all carry either a long or a short variant of the gene. In a study of
375 people, they saw that those carrying the long version of TIM-1
who had also been infected with the hepatitis A virus were four times less
likely to suffer from asthma than those with the shorter version.
Protection seems to hinge on two key factors: inheriting the right version
of TIM-1 gene and succumbing to the right bug; hepatitis A.
These are tantalizing results, as they highlight the importance of our
genetics interacting with the environment as the cause for asthma. As 63%
of caucasians, 46% of Asians and 64% of African-Americans carry the
protective version of the TIM-1 gene, a dose of hepatitis A
infection would keep allergies at bay. But while in the 1970s virtually
everyone had been infected with the virus, today only 10 to 20% of people
in developed countries have been exposed, which could explain the
rocketing asthma rates.
The riddle is far from solved, however. "Exposure to hepatitis A is
one possible mechanism for how the hygiene hypothesis works. It's
interesting work but the study needs follow up," says geneticist
William Cookson (The Wellcome Trust Centre for Human Genetics in
Oxford, UK).
What is clear is that nobody would choose to go back to the bad old days
of dubious drainage and rampant infections to fend off asthma. The
Stanford team is currently testing whether vaccination will do the trick.
"We could develop a therapy to mimic the effects of hepatitis A
infection," says Umetsu.
Dr Lisa Melton—Science Writer, Novartis Foundation, London
(Based on presentations given at Novartis Foundation Symposium 266 "The hERG cardiac potassium channel: structure, function and long QT syndrome" held in London on 4-6 May 2004)
Long QT and hERG
The Guardian
recently highlighted BHF (British Heart Foundation) statistics
estimating that 3,500 apparently healthy adults die every year in England,
further to the sudden death of Cameroon soccer star Marc-Vivien Foé in
July this year during a match against Colombia. In the US it is estimated
that in excess of 300,000 annual deaths are a result of sudden cardiac
death. These statistics are certainly thought-provoking especially
considering the recent legal prosecution of Trupti Patel and other mothers
whose children have died suddenly.
Even after postmortem examination, approximately 5% of these deaths cannot
easily be explained by structural abnormalities of the heart. These
individuals are thought to have electrophysiologic abnormalities of
cardiac conduction. Conditions such as long QT syndrome, and in particular
the most common inherited form—Romano Ward syndrome—have an estimated
incidence of between 1 in 5,000-10,000 live births. These individuals are
at risk of potentially malignant forms of cardiac arrhythmias and syncope
(sudden loss of consciousness). Syncope
may result from relatively benign irregular arrhythmias or potentially
malignant forms of cardiac arrhythmia, in particular a variety known as
Torsade de Pointes (TdP), which can cause sudden cardiac death. These
events may be triggered during physical exertion or
emotional stress, but in some can occur during sleep. Thus, it is
plausible that such cardiac abnormalities could explain cases of SADS
(sudden arrhythmia death syndrome) encompassing SIDS (sudden infant death
syndrome), and it may seem sensible to consider implementing a screening
strategy, perhaps during school years, to identify those at risk. However,
this is not feasible yet because not all mutations have been identified.
In addition to the possibility of inheriting long QT, the condition can
also be drug-induced or 'acquired'. Information on the potential risk of
drug-induced long QT would be useful not only to the individuals at risk,
but to doctors prescribing a range of pharmaceuticals which might induce
life-threatening arrhythmias. Identifying these drugs early during their
development will also be of particular interest to the pharmaceutical
companies that develop such drugs. The number
of prescription medicines that prolong the QTc interval continues to
increase and they include a number of non-antiarrhythmic cardiovascular
drugs, neuroleptics and other psychoactive medicines, antihistamines and
anti-bacterial drugs to name but a few classes.
Critical to the understanding of cardiac abnormalities such as long QT
syndrome is the molecular and functional characterization of the ion
channels involved in in
initiation and propagation of cardiac impulse and induction of arrhythmias.
One such ion channel is the hERG cardiac potassium channel, the subject of
a recent Novartis Foundation Symposium, and forthcoming publication.
Mutations in the hERG channel cause inherited long QT syndrome with
increased susceptibility to arrhythmia. Many pharmaceuticals block hERG
channels, a mechanism by which TdP might arise, and thus sudden death. But
reassuringly, as Mike Sanguinetti (Department of Physiology, University
of Utah, Salt Lake City, USA)—who chaired this symposium—points
out, most pharmaceutical companies now screen for hERG channel activity
early in the drug discovery/development process. Research he has carried
out in association with John Mitcheson (Department of Cell Physiology
and Pharmacology, University of Leicester, UK), who co-proposed the
symposium, has identified drug binding site(s) by site-directed
mutagenesis, specifically uncovering the aromatic residues, Tyr652 and
Phe656, as possibly the most significant sites for interaction with
blocking drugs so far.
Rashmi Shah (Medicines and Healthcare Products Regulatory Agency, London,
UK) believes that the
hERG channel studies have a well-defined role in risk assessment. However,
the predictive value of studies that screen medicines for their hERG
activity is limited by inter-laboratory variations, a high false positive
rate and a lack of consensus on the definition of a negative hERG study.
He feels that hERG channel data by themselves may not predict the clinical
risk but that these data should be integrated with all other data to avoid
the risk of novel and valuable drugs being rejected from further
development and/or denied regulatory approval.
The publication resulting from this symposium will soon be available and
may be purchased here.
Brona McVittie—Assistant Editor, Novartis
Foundation, London
Bursar's report
The major function of the immune system is the discrimination between self
and foreign molecules. This is fundamental to the survival of the species
and the failure to establish or maintain this discrimination can lead to a
wide spectrum of autoimmune and allergic disorders. These disorders are
known to be the unfortunate result of the combined effects of
environmental triggers coupled with a background of inherited
susceptibility genes. Intense research into two major clusters is
attempting to elucidate the nature of these contributing factors.
Immunological research has taught us a lot with regard to the normal
functioning of the immune system and the editing processes by which
self-tolerance is established. Immunologic investigations of human
autoimmune diseases have indicated that patients with organ-specific
autoimmunity have activated, autoreactive T-cells specific for target
tissues. However, such conventional immunologic studies have not been
fruitful in the elucidation of the next level of pathogenesis of
spontaneous autoimmune disease, especially in humans. Therefore, there has
been great interest in investigations into the other branches of genetics,
which attempt to identify the genes that confer susceptibility to
autoimmune diseases, with the hope that this will provide valuable clues
about pathogenesis and therapeutic possibilities. However, progress in
this field has not been as rapid and clear, as initially hoped.
In order to bring the field together, a symposium was organized by the
Novartis Foundation in London to assess the current consensus on the
different aspects of autoimmune genetics. One of the co-proposers,
Professor Abul Abbas (University of California San Francisco, USA),
also chaired this meeting.
I study the genetic susceptibility of one such autoimmune disease—systemic
lupus erythematosus (SLE)—that is a chronic,
multifactorial (complex), autoimmune disease that affects 0.05% of the
Western population. Immunologically, SLE is characterized by T- and
B-lymphocyte hyperactivity and uncontrolled production of autoimmune
antibodies, leading to a loss of self-tolerance and damage of tissues and
cells. The self-reactivity affects multiple organs (systemic): the skin,
joints, kidneys, lungs, serous membranes and nervous system. SLE is
characterized by periods of illness (flares) and periods of wellness
(remission) and the disease includes everything from rather mild symptoms
to quite aggressive symptoms. SLE displays a variety of clinical and
laboratory manifestations that vary from vague constitutional symptoms to
findings of end-organ dysfunction. Despite a clear genetic component and
well-defined environmental triggers, the underlying pathogenic mechanisms
of SLE are not fully understood.
Dr Timothy Vyse's group (Rheumatology Section, Imperial College,
London, UK) has collected one of the largest body of patients for
research in SLE in the world today. Our group has collected over 80% of
all SLE patients in Finland, a very homogenous population. Together we
have studied a number of different genes of interest as potential
susceptibility genes in both patient groups using state of the art
techniques for genotyping. During the time I spent in Dr Vyse's laboratory
I had the opportunity to establish a good friendly collaborative network,
which will be of mutual benefit for both our groups for coming years of
fruitful research.
I would sincerely like to thank the Novartis Foundation for enabling me to
participate in a very stimulating symposium and for the friendly and
comfortable hospitality during my bursary period. I would also like to
express my warm gratitude to Dr Vyse and his team of enthusiastic,
excellent and friendly scientists for the enjoyable and rewarding time at
Imperial College, London, UK.
Cecilia M Lindgren—Center for
Clinical Research, Department of Biosciences at Novum, Karolinska
University Hospital, Sweden
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.
A recent
publication in the Anatomical Record resulted from research
undertaken during a bursary period pertaining to Novartis Foundation
Symposium 250 Development of the cardiac conduction system by Emil
Thomas Chuck.
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
Congratulations
Our congratulations to recent Nobel Prize winner and former Ciba
Foundation Symposiast, Linda
Buck (Howard Hughes Medical Institute, USA). Professor Buck
was awarded this year's Nobel
Prize for Medicine jointly with colleague Richard Axel. She
attended CF179 The molecular basis of smell and taste transduction
in February 1993. This book is now out of print, but a few copies are
still available directly from the Foundation in our ongoing sale.
Meetings
Open meetings:
The next Novartis Foundation Open meeting on 'Mast cells and basophils:
development, activation and roles in allergic/autoimmune disease' will
take place on 19 November 2004 at the Royal Society of Medicine,
London.
Or to book your place at the
meeting please contact Sharan Gallagher at the Royal
Society of Medicine, Academic Conference Department, 1 Wimpole Street,
London, W1G 0AE:
Tel: +44 (0) 20 7290 3946
Fax: +44 (0) 20 7290 2977
email: events@rsm.ac.uk
Website: http://www.rsm.ac.uk
Other forthcoming meetings include:
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Signalling pathways in acute oxygen sensing 28 Jan 2005
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Epithelial anion transport in health and disease: the role of the SLC26 transporters family 4 Mar 2005
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 Trieste in collaboration with the
International School for Advanced Studies (ISAS) between 1-3 October
2004 entitled 'Percept, decision, action: bridging the gaps'.
Chaired by Mathew Diamond, ISAS.
Discussion meetings:
The next discussion meeting to take place is:
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The rising tide of diabetes in children 25-26 Oct 2004
Harry Keen, Rank Foundation
Publications
We are pleased to announce the publication over the last few months of:
Biology of IGF-1: its
interaction with insulin in health and malignant states
(Novartis Foundation Symposium 262)
For details of other publications see: http://www.novartisfound.org.uk/nbook.htm
Book
sale 2004
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
Hospitality
Details of all conference facilities and accommodation available at the
Foundation can be found at: http://www.novartisfound.org.uk/hosp.htm
Personalia
Full details of personalia and activities at the Novartis Foundation can
also be found in the Foundation's 2004 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
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