Novartis Foundation Bulletin

Issue 25 July 2005

Welcome to the 25th edition of the Novartis Foundation's e-mail Bulletin.

This issue features reports on:

 

News from the Foundation

Heat, light and a case of vintage reserve 
by Lisa Melton. This piece was published in the Times Higher Educational Supplement, 17 June 2005

(Based on presentations given at Novartis Foundation Discussion meeting in London on 'Cognitive Reserve', held on 12 November 2004.)

The threat hung in the air. Ian Deary, one of the UK’s top researchers into intelligence and ageing, had become disgruntled at the lack of original ideas and could not contain himself any longer. “Please say something else or I'll catch an early train back to Edinburgh,” he snapped. Several of his peers laughed awkwardly. Deary, professor of differential psychology at Edinburgh University and organizer of the remarkable meeting, had hit a nerve amid an already charged atmosphere.

The respected clinicians, epidemiologists, geneticists, and psychologists were leaders in their fields, gathered in London at the Novartis Foundation to discuss the contentious concept of cerebral reserve. But now the very person who had summoned them all to share their thoughts seemed to be angling to walk out.

The focus of their attentions was undeniably challenging. Cerebral reserve, a notional quality that gives individuals differing levels of mental resilience, is a proposal that has all the ingredients needed to stoke a controversy - intelligence, genes, social status, education and health. Behind it all is a set of widely accepted scientific results that suggest that people with high intelligence and superior education cope better with the progress of Alzheimer’s disease and other forms of dementia and recover more rapidly from stroke, head injuries, depression and even intoxication than the average. And while mental faculties always decline with age, there are marked differences in the rate at which the years dull the mind. Cerebral reserve was dreamt up to explain such anomalies.

Sir Michael Marmot, the epidemiologist whose ground-breaking Whitehall studies of civil servants showed how social standing affects life expectancy, was in the chair at the meeting back in November 2004. In typically understated manner, he had opened proceedings by acknowledging the depressing truth that age brings about cognitive degeneration. But he wondered about the growing body of evidence that education might soften the blow of advanced years. “Is that what we mean by cognitive reserve?” Marmot prodded his audience. “Does it relate to something basic in the brain structure, something crude about brain size or is it something to do with the software?” And so it started.

The group had been hand-picked. Meetings held at the Novartis Foundation’s 18th century London headquarters are generally invitation only and numbers are deliberately limited to between 20 and 30 experts to encourage interaction. Participants sit in comfortable chairs in a plain room, with no distractions other than a projector. And, in a complete departure from the usual format for scientific meetings, equal time is dedicated to discussion as to presentations. Delegates are there to comment, critique and collude. Exchanges can become heated, yet scientists relish the opportunity to exchange ideas with their scientific peers. The Foundation is renowned for generating scientific ruckus of the highest calibre and always attracts scientific luminaries to take part in the intellectual free-for-all.

Please continue reading the article by clicking here

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Full Article

 

Understanding nicotine and tobacco addiction
by Lisa Melton

(Based on presentations given at Novartis Foundation Symposium 275 'Understanding nicotine and tobacco addiction' held in London, May 2005.)

Why is it that despite therapies to help smokers quit some individuals simply cannot give up? They may have their genes to blame. Scientists at the University of Oxford have uncovered new evidence that individuals with the ankyrin 1 (ANKK1) gene variant are more prone to addiction and have more trouble in kicking the habit. Testing people for this genetic variant could help clinicians tailor interventions to help all smokers quit.

This was one of the findings presented at a symposium in London last week, when an elite group of researchers, psychologists and clinicians met at the Novartis Foundation for a three-day brain-storming session on ‘Nicotine and tobacco addiction’. 

With molecular tools at their disposal, researchers are now digging deep into the pathways involved in nicotine addiction. And as brain imaging uncovers the details of how smoking affects the human brain, new treatment avenues are opening up.

If tobacco addiction is all about nicotine, then why isn’t nicotine replacement therapy (NRT) 100 per cent effective? Scientists at Queen Mary’s School of Medicine and Dentistry, London, UK believe NRT fails because it is too weak or too slow. Patches, nasal sprays, and gum lack the nicotine rush that smokers find so rewarding. 

But would it be safe to bump up the nicotine dose? Faster, higher dose products would not be more dangerous than drinking tea or coffee, say the researchers. Unfortunately, the idea persists that smoking while wearing a nicotine patch, or combining nicotine therapies, is risky, despite being proven safe.

Better understanding of how smokers’ brains work could result in improved treatments for tobacco dependence. At the University of California, Los Angeles, smokers were scanned as they watched videos of people taking a puff. The aim of these brain imaging studies was to localize the pathways activated in craving. The limbic and paralimbic brain regions light up in response to these cues, although treatment dampens this activation, a reassuring sign that people’s cravings for nicotine are assuaged. The scientists also found that heavy smokers had lower grey matter volume in areas associated with sustained attention and reward seeking behaviour than non-smokers. 

Short-circuiting the addiction centres in the brain offers another opportunity to influence a person’s drug-taking habits. It has long been known that the mesolimbic dopamine system – the brain’s reward region – plays a key role in addictions, and in particular the dopamine D3 receptor. Researchers at GlaxoSmithKline Pharmaceuticals in Verona, Italy are testing compounds that block D3 as a new strategy for smoking cessation. So far these antagonists have been effective in a host of animal studies for nicotine, alcohol, cocaine, heroin and cannabis, and the compounds will soon be entering clinical trials.

But while some researchers focus on the brain, others believe that it is nicotine metabolism that hinders people’s efforts to give up. People are genetically predisposed to being slow or fast metabolizers depending on the levels of the activating enzyme CYP2A6. Slow metabolizers, with one copy of the CYP2A6 gene have sluggish rates of nicotine inactivation, which means that nicotine hangs around the bloodstream for longer. They are less likely to smoke and if they do, they puff at 7–10 fewer cigarettes a day than people with higher metabolic rates, and what’s more, their risk of lung cancer is low. The fast metabolizers with two copies of the CYP2A6 gene, however, smoke more and find it difficult to give up. The hunt is now on for a compound to block the CYP2A6 enzyme which could be turned into an oral pill. Such a treatment would be a godsend, as it could transform avid smokers into indifferent consumers more likely to kick the habit. 

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Bursar's symposium report: Molecular mechanisms influencing aggressive behaviours

(The bursar attended the Novartis Foundation Symposium 268 'Molecular mechanisms influencing aggressive behaviours' held in London, July 2004)

In July 2004 I attended the Symposium on Molecular Mechanisms of Aggression.  This was probably the most unique meeting I have ever attended as the organizers brought prominent researchers from many different fields.  In general there is relatively little contact between neuroscientists, clinicians and social scientists.  I thought that the discussions after each presentation were especially valuable.  Post-docs can often get lost in the crowd at large meetings such as the Society for Neuroscience.  I thought the symposium was a great opportunity to meet prominent faculty members who have made important contributions to the study of aggressive behavior.  The meeting has definitely inspired me to take a more integrative approach with my own research.

After the Symposium I joined Dr. Randy Nelson’s lab at The Ohio State University.  One major theme at the Symposium was the importance of gene and environment interactions in the modulation of aggression.  I have been investigating the neuronal bases of aggression in the beach mouse, which shows increased aggression levels only in short photoperiods, which are coincident with winter.  The beach mouse is an interesting model system for human aggressive behavior because in common with humans, beach mice do not undergo reproductive suppression during short days.  Studies of human behavior have showed seasonal cycles in aggression, although the bases for this variation remain unclear.  I am currently investigating whether changes in neuronal steroid receptor protein and mRNA are associated with the differences in aggression observed in long days and short days.  These studies should be important complements to studies of steroid receptor knock-out mice, which have suggest that steroid receptors have important effects on aggressive behavior in mice.

I’d like to thank the Novartis Foundation for giving me the opportunity to attend the symposium on the Molecular Mechanisms of Aggression and for my bursary period in Dr. Nelson’s laboratory.  I think that these experiences will influence my research and career for years to come.

by Brian Trainor, The Ohio State University

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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 symposium participants. Applicants (of any nationality) must be aged between 25–35 years of age 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 click here

or contact the bursary scheme administrator:
Email: bursary@novartisfound.org.uk
News from the Foundation

Meetings

Open meetings:

28-30 Sept 2005
Dengue and dengue haemorrhagic fever: the search for a cure
To be held at: The Novartis Institute for Tropical Diseases in Singapore

30 Nov - 2 Dec 2005 
Innate immunity in the lung
To be held at: Institute for Infectious Disease & Molecular Medicine, University of Cape Town. This is a joint EMBO, Novartis Foundation & Medical Research Council workshop

For further information regarding Open meetings:
Email: openmtg@novartisfound.org.uk

Full details of Novartis Foundation Open Meetings can be found at:
http://www.novartisfound.org.uk/open.htm

Symposia: 
 Recently held symposia:

June 05
Purinergic signalling in neuron-glia interactions 
 Chaired by Douglas Fields

May 05
 Understanding nicotine and tobacco addiction
 Chaired by William Corrigall

April 05 
 Heart failure: molecules, mechanisms and therapeutic targets
Chaired by Seigo Izumo 

Discussion meetings:
The next discussion meetings to take place are:

28 Sept 05
Reconciling fossil dates and molecular trees and rates of evolution; limitations and utility of the clock concept with respect to early cell evolution

16 Nov 05
Computational approaches to H-transfer

Publications:

We are pleased to announce the publication of:

The hERG cardiac potassium channel: structure, function and long QT syndrome
(Novartis Foundation Symposium 266)

Genetics of autoimmunity
(Novartis Foundation Symposium 267)

Book Sale: 

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

Dr Lisa Melton, in-house science writer has recently published:

'Snoring suspects: free radicals may set off sleep apnea's cardio dangers', published in Scientific American, June 2005, p16. 
This was based on the Novartis Foundation symposium 272 'Signalling pathways in acute oxygen sensing'.

'Heat, light and a case of vintage reserve' published in the Times Higher Education Supplement (THES), 17 June 2005. 
This was based on the discussion meeting on Cognitive Reserve held on 12 November 2004.
Hospitality

Details of all conference facilities and accommodation available at the Foundation can be found here 

Personalia

We take great pleasure in welcoming new members of the Foundations' Scientific Advisory Panel:

Barbara Imperiali is a Class of 1922 Professor of Chemistry and Professor of Biology at the Massachusetts Institute of Technology (MIT). Research in the Imperiali group is concerned with diverse aspects of protein structure, function and design. One area of investigation focuses on co-translational protein glycosylation, including asparagine-linked glycosylation. A second programme is targeted at the design and implementation of new chemical probes into the study of complex biological systems. This comprises research on the use of oligopeptide motifs for metal ion and kinase sensing, and as minimal biophysical probes for structural and functional proteomics.

Professor Imperiali is the recipient of a Sloan Fellowship (1993), a Dreyfus Teacher-Scholar Award (1993) and the Caltech Feynman Prize for Excellence in Teaching (1998). In 2004 she was named a Fellow of the Royal Society of Chemistry.

Frank Grosveld received his Ph.D in Biochemistry from McGill University in 1976, where he studied the primary structure of bacteriophage S13 genome. One of his postdoctoral positions began in 1979, with the Flavell group at the MRC National Institute for Medical Research, Mill Hill in London, UK, achieving Head of Division in 1982. In 1993 he became Professor of Cell Biology and Genetics and head of the Department of Cell Biology at Erasmus MC in Rotterdam, Netherlands. His work has primarily focused on the regulation of transcription of the human beta-globin genes, but he also has an active interest in developmental biology with emphasis on the haematopoietic and nervous systems.

Robin Lovell-Badge is Head of the Division of Developmental Genetics at the MRC National Institute for Medical Research, Mill Hill in London, UK. He is also a Visiting Professor in the Biochemistry department of the University of Hong Kong and an Honorary Professor in the Department of Anatomy and Developmental Biology at University College London. He carried out postdoctoral research in the Department of Genetics, University of Cambridge and at the Institute Jacques Monod in Paris. He worked as Staff Scientist at the MRC Mammalian Development Unit in London, before moving to the NIMR in 1988. He has had long-standing interests in the biology and uses of embryonic stem cells, in how genes work in the context of development and how decisions of cell fate are reached during embryogenesis. Major themes of his current work include sex determination, development of the nervous system and stem cells in the embryo.

He is a member of EMBO and was elected a Fellow of the Academy of Medical Sciences in 1999 and a Fellow of the Royal Society in 2001. He received the 1995 Louis Jeantet Prize for Medicine and the Amory Prize in 1996 for his work on sex determination. 

Full details of personalia and activities at the Novartis Foundation can also be found in the Foundation's 2005 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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