Novartis Foundation Bulletin
Issue 19, March 2004
Welcome to the 19th edition of the Novartis Foundation's e-mail Bulletin.
You may print the bulletin from this PDF
This issue features reports on:
-
The importance of a lamin (NF264)
-
Richard Pumphrey on Anaphylaxis (NF257)
-
Bursar's report (NF263)
The importance of a lamin
Around 1 in every 3500 boys is born with Duchenne muscular dystrophy (DMD). This X-linked neuromuscular disease is characterized by severe muscle degeneration affecting sufferers early in life. DMD is caused by a defect in a single gene on the X-chromosome, which produces a protein called dystrophin. Dystophin is required inside muscle cells for structural support, anchoring elements of the internal cytoskeleton to the surface membrane. Defects in this protein cause the cell membrane to become permeable, so that extracellular components enter the cell, increasing the internal pressure until the muscle cell explodes and dies. The subsequent immune response can add to the damage.
Nuclear organization is critical to normal cellular structure and function and scientists’ understanding of the ‘nuts and bolts’ of the nucleus and their role in disease is growing rapidly in the wake of the molecular biological revolution. The nuclear envelope is composed of the nuclear lamina, nuclear pore complexes and nuclear membranes. The outer membrane is similar to the rough endoplasmic reticulum, and the inner nuclear membrane is associated with
heterochromatin and the nuclear lamina. The lamina is a meshwork of intermediate filament proteins called lamins. Defects in these proteins give rise to the laminopathies, a recognized group of disorders caused by mutation in the lamin A
(LMNA) gene. Autosomal dominant Emery-Dreifuss muscular dystrophy, for example, is caused by a mutation in lamin A coupled with a loss of
emerin.
Lamin A mutations also give rise to lipodystrophies, cardiomyopathies and premature ageing, namely Hutchison-Gilford progeria (HGPS), which affects children and Werner syndrome (WS), which affects adults. At a recent
Novartis Foundation Symposium on nuclear organization Junko Oshima
(University of Washington, Seattle, USA) explained that HGPS is mainly caused by a recurrent
de novo mutation in
LMNA, which results in an in-frame deletion of 50 amino acids, including endoproteolytic sites required for the processing of prelamin A to mature lamin A.
Classical WS (see http://www.wernersyndrome.org for more information) is caused by mutation of the
WRN gene that encodes a multifunctional nuclear protein possessing both helicase and exonuclease functions and which may participate in optimizing DNA repair/recombination. WS is characterized by the early onset of common age-related disorders including diabetes mellitus type 2, ocular cataracts, osteoporosis, hypogonadism, atherosclerosis and malignancies.
Around 8 out of the 10 genetic disorders caused by mutations in nuclear
envelope proteins are linked to LMNA mutation. These include dilated cardiomyopathy type 1A (DCM1A), limb-girdle muscular dystrophy type 1B (LGMD1B), Charcot-Marie-Tooth disease type 2 (CMT2), Dunnigan-type familial partial lipodystrophy (FPLD), and mandibuloacral dysplasia (MAD). It is not yet known why mutations in
LMNA are able to cause such a large variety of disorders, although Colin Stewart
(NIC at Frederick, Frederick Maryland, USA) has developed mouse lines that are defective in
LMNA. The lamin A gene is highly conserved between human and mouse, and Stewart has generated mice with different
LMNA mutations causing progeria, muscular dystrophy and dilated cardiomyopathy. He confirms that “these mouse lines are providing novel insights into how changes to the nuclear lamina affect cell signalling, such as the NF-kappaB pathway, gene expression patterns, cell proliferation and survival, cellular functions that, when disrupted, may be the basis of such diseases”.
This meeting was based on a proposal made by Colin Stewart and was chaired by Professor Bob Goldman
(Northwestern University, Chicago, USA). The resultant book will feature contributions from
many leading scientists including Kay Davies
(University of Oxford, UK), Susan Gasser (University of Geneva,
Switzerland) and Wayne Giles (Whitaker Institute of Biomedical
Engineering, UCSD, La Jolla, USA). A very informative review co-authored by Juliet
A. Ellis
(King’s College, London, UK) who attended this symposium, covering the range of genetic diseases arising from disruptions in nuclear organization is available
here.
NF264 Nuclear organization in development and disease, will be published by Wiley, Chichester in September 2004.
Brona McVittie—Assistant Editor, Novartis Foundation, London
Based on presentations given at Novartis Foundation Symposium
257,
'Anaphylaxis' which was held in
London on 25-27 February 2003)
Anaphylaxis
Allergic disease is becoming more common in all the developed countries of the world. Anaphylaxis, the most severe type of acute allergic reaction, was the focus for the Novartis Symposium 257, held
25-27 February 2003. The 15 presentations ranged widely over all aspects of anaphylaxis including its history, experimental systems, epidemiology and other clinical characteristics of anaphylaxis to a wide range of allergens, recommendations for its management and ending with the patient’s perspective.
There was discussion over the nomenclature and classification of anaphylaxis. Different pathological processes may lead to a variety of acute illness with similar outward appearances: calling all these different phenomena “anaphylaxis” may hinder optimal diagnosis and management but diagnosing the specific mechanism is often impossible before treatment has to be given.
Discussion of the pathophysiology of anaphylaxis centred around IgE antibodies, mast cells and the influence of other factors such as interleukin-4 on mast cell activation. At the end of the meeting there was a feeling that further discussion of genetic factors and the effect of other classes of antibodies might be helpful.
Epidemiology of fatal anaphylaxis revealed risk factors for life-threatening reactions; asthmatic reactions were most common in food allergy and shock reactions were most common in sting and drug anaphylaxis. Shock was in some cases related to volume redistribution, in others due to the direct effect of anaphylactic mediators on the heart. Food allergy is the commonest cause of anaphylaxis outside hospital, and optimal management of patients with food allergy relies on accurate diagnosis of the cause. Accidental re-exposure was considered inevitable and treatment plans essential in the coping strategy.
Desensitization offers an effective cure for sting anaphylaxis, but three quarters of those dying from sting anaphylaxis had not previously reacted to stings. Drug reactions during anaesthesia
have been most commonly to muscle relaxants and antibiotics and were most commonly IgE-mediated, though other mechanisms are more likely for some agents. The mechanism for contrast media reactions remains obscure.
Epinephrine (adrenaline) remains the first-line treatment for anaphylactic reactions. Although it is widely available in the community, it is not necessarily given in a timely manner when required. Early intramuscular administration is essential for optimal action and epinephrine may be ineffective for established anaphylactic shock. Cure would be better than rescue and hopeful results of a trial of monoclonal anti-IgE in peanut allergy were reported to the meeting. Until such time as the cause of the rise in food allergy is found and removed, or a cure for the sensitivity becomes widely available, avoidance is the mainstay of management. Inadvertent re-exposure seems inevitable and improvements in food labelling are needed both for packaged foods and commercial catering.
Richard Pumphrey—Immunology Department, St Marys Hospital, Manchester, UK
Participants from the Anaphylaxis symposium
This book arises from a symposium proposal from Johannes Ring (Technical
University, Munich, Germany) and was chaired by Steve Galli (Stanford
University, USA). It features contributions from Richard Pumphrey and many
other scientists in the field including Frank Austen (Brigham and
Women's Hospital, Boston, USA), David Golden (Johns Hopkins Asthma
and Allergy Center, Baltimore, USA) and Henry Metger (NIAMS/NIH,
Bethesda, USA).
NF257
Anaphylaxis was published in January 2004, and is available to buy
from the Foundation or Wiley,
Chichester.
Based on presentations given at Novartis Foundation Symposium
263,
'Inflammatory bowel disease—crossroads of
microbes, epithelium and the immune system' which was held in
London on 25-27 November 2004)
Bursar's report
The Novartis Foundation arranged a bursary period to be spent with Professor Sander van Deventer
(Academic Medical Centre, Amsterdam). This followed a symposium in London chaired by Professor Derek Jewell
(Nuffield Department of Medicine, University of Oxford, UK) which explored
the interactions between microbes, the epithelium and immune systems in relation to inflammatory bowel
disease.
A greater knowledge of the biochemical nature of bacterial–epithelial, bacterial–immune and bacterial–bacterial interactions will be important in understanding how microbes regulate the inflammatory state of the gut in health and in inflammatory bowel diseases. This is an exciting area of research in which modification of the internal environment to prevent disease or restore health is already being used in the clinical setting. Controlled clinical trials using probiotics have demonstrated efficacy in the treatment of some inflammatory bowel diseases, in particular
pouchitis.
The Academic Medical Centre in Amsterdam has evolved from a long and impressive medical tradition, underlined by Rembrandt’s famous painting of “the Anatomy Lesson of Dr. Nicolaes
Tulp” in 1632. It is an internationally renowned centre for patient care in addition to scientific research, with strong connections between the two.
This link between clinical and scientific research is highlighted by a current trial which is underway at the Academic Medical Centre to assess the effects of the organism
Lactococcus lactis, engineered to release IL10 locally within the gut, in patients with active Crohn’s disease and explore potential immunomodulatory mechanisms. The trial aims to recruit 12 patients with Crohn’s disease and administer these genetically-modified organisms orally for one week.
State- of- the- art techniques allowing description of the genome, transcriptome and proteome are being developed and used in both animal models of intestinal inflammation and human tissue. These research tools hold great promise for studies on inflammatory bowel diseases. I was privileged to spend time with the scientists working with these techniques and gain an understanding of their application.
I was also delighted to gain exposure to some new endoscopic techniques. In particular, narrow band imaging, magnification and chromoendoscopy are being developed, to assist in selecting areas
for biopsy, to improve early detection of dysplasia in patients with longstanding ulcerative colitis.
I would like to thank the Novartis Foundation for enabling me to participate in a stimulating symposium. I would like to thank Professor Sander van Deventer and his team of enthusiastic and friendly clinicians and scientists for the subsequent enjoyable and rewarding time at the Academic Medical Centre in Amsterdam.
Ailsa Hart—Physiology Unit, St Marks Hospital, Harrow, UK
(top)
This meeting was co-proposed
by Bill Roediger (Queen Elizabeth Hospital, Adelaide, Australia) and Derek Jewell (pictured below with Ailsa Hart).
The resultant book on inflammatory bowel disease will be published by
Wiley, Chichester in August 2004
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
News from the Foundation
Meetings
Open Meetings:
The next Novartis Foundation Open meeting on 'hERG cardiac potassium
channel: structure, function and drug-induced long QT syndrome' will take place on
Friday 7 May 2004 at The Geological Society,
Burlington House, Piccadilly, London W1
To register, use the online
form, or please contact:
Sharan Gallagher
Academic Conference Department
Royal Society of Medicine
1 Wimpole Street
London W1G 0AE
fax: 020 7290 2977
tel: 020 7290 3946
e-mail: events@rsm.ac.uk
Other forthcoming open meetings include:
-
Genetics of autoimmunity 25 June 2004
-
Molecular mechanisms influencing aggressive behaviours 23 July 2004
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
e-mail: 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 at the Foundation 2-4 March entitled 'Stem
cells: nuclear reprogramming and therapeutic applications'. Chaired by
John Gearhart, Johns Hopkins School of Medicine, Baltimore, USA.
Discussion meetings:
The next discussion meetings to take place are:
-
Biology of the trophoblast 18-19 March 2004
-
Energy landscapes in biomolecules 21 April 2004
Publications
We are pleased to announce the publication over the last few months of:
Mammalian
TRP channels as molecular targets
(Novartis Foundation Symposium 258)
For details of this, and other recently published books and how to order 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.
See http://www.novartisfound.org.uk/booksale-03.htm
for details of the titles and how to order them or e-mail bulletin@novartisfound.org.uk
for more details.
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
(back to top)