Novartis Foundation Bulletin
Issue 13, December 2002
Welcome to the 13th edition of the Novartis Foundation's e-mail Bulletin.
This issue features reports on:
-
Bursar report: new therapeutic strategy for type I diabetes
-
Blocking proteases: a book review
(Based on presentations given at Novartis Foundation Symposium 247, 'In silico simulation of biological processes' which was held in London on 27-29 November 2001)
IT biology is the way to go
An urgent appeal was recently published in Nature. It read: 'Infuse more computer science in your biology curricula'. How true. However,
it is not only university lecturers
need to sit up and take note of the growing role of computers in biology. In recent years, especially with the advent of the molecular-genetics and proteomics revolution, there has been a seismic shift in how we do science and 'dry labs'
have become de rigeur.
Last November, the Novartis Foundation conducted a symposium entitled 'In silico simulation of biological
processes' to address the most salient computing systems currently being used in biological research. The book that follows this symposium has now been published by Wiley's and includes the presentations and the discussions that took place.
Leslie Loew (University of Connecticut Health Center, Farmington, USA) presented the
Virtual Cell project, an intuitive JAVA interface which allows realistic 3-D simulations of, for example, how calcium flows in intact neuroblastoma cells and Purkinje neurons. The aim is to act as a modelling tool for both the interpretation and planning of experiments.
The IUPS (International Union of Physiological Sciences) Physiome Project developed by Peter Hunter (University of Auckland, Auckland, New Zealand) has succeeded in integrating even the finer molecular details into a spectacular simulation of a whole organ, and hopefully soon the human body. These models include the nitty-gritty of ion-channel mechanisms and gap-junction densities as well as the larger scale tissue structure. The result is a technicolour simulation of a heart or a lung where it is possible to see, in real time, the potential effect of a drug, for example. Hunter envisages that in the near future, a patient's clinical diagnosis and treatment will rely heavily on pulling together information from diagnostic imaging, DNA profiling and protein expression data. And that's the job for
in silico models.
In the pharmaceutical industry, hypothesis driven discovery is already having a huge impact.
Tom Paterson (Entelos Inc, Menlo Park, CA) argues that simulations can help a company prioritise by identifying the most likely drug targets.
Using high-throughput screening data, they are able to test the outcome in a virtual patient. Entelos has had some remarkable successes with their
Virtual Patient identifying why promising drugs failed phase II and III trials as well as identifying targets for diabetes, asthma and obesity.
Denis Noble (University Laboratory of Physiology, Oxford, UK) a pioneer in the field of heart simulation, reviewed the successes and failures over the last 40 years. He also chaired the meeting and in the final discussion points to the profound influence that computational biology has had on the development of evolutionary theory in recent years. He asks, "Is it conceivable that through the process of identifying the models and the way they interact that we slowly build up the logic by which a theoretical biology could emerge?"
Dr Lisa Melton—Science Writer, Novartis
Foundation, London
'In silico simulation of biological processes' was published in
November 2002 by John Wiley &
Sons, Chichester, UK
View the abstracts
of this book
Based on presentations given at Novartis Foundation/One Health Discussion Meeting, 'The biopsychosocial model for medicine: luxury or necessity?' which was held in London on 31 October-1 November 2002)
The art of medicine
The art of medicine deals with patients as individual persons, and the science itself focuses on objective pathology. The tension between these perspectives places a strain on the
patient-physician relationship. A select group
of psychologists, psychiatrists, a surgeon, a health-sciences researcher, a philosopher
and an historian gathered together at a recent discussion meeting
organized jointly by the Novartis Foundation and One Health to discuss the place of what has been
dubbed the 'Biopsychosocial model' within medicine.
The biopsychosocial model is applicable to all illness and disease as proposed by GL Engel in 1977. It was based on systems theory which orders the world into a ladder from the most elementary particles to social phenomena and the cosmos. Such an approach to medicine incorporates the thoughts, beliefs, feelings, behaviours and social context of the patient in order to better understand and manage the pathophysiology, prognosis and disability of illness.
Why don't more healthcare professionals and patients adopt this approach? The simple answer is that most allopathic practitioners simply do not have the time in a 7-minute consultation. Adrian Furnham
(Department of Psychology, UCL) explained why many people are choosing complementary practitioners over their GP. Alternative practitioners are giving a better quality and duration of consultation and patients are dissatisfied with GP consultations and wish to make use of all the other options.
The increasingly more common choice of alternative practitioner must in part be related to the increasing reportage and/or incidence of MUS (medically unexplained symptoms) which doctors find difficult to deal with. Dr Michael von Korff
(Center for Health Studies, Group Health Cooperative, University of Washington) addressed the subject of fear and depression as remediable causes of disability. Depression, he argues, is more disabling than
common chronic conditions such as diabetes, back pain or arthritis and furthermore this relationship is
observed world-wide. So can the effect of treatment for depression reduce disability? Von Korff says that
controlled studies have shown that enhanced treatment of depression can
improve functional outcomes in general healthcare settings, including
among patients with co-morbid depression and chronic disease.
Professor Sir Michael Marmot (Department of Epidemiology and Public
Health, UCL) showed
that there was a pervasive social gradient in health.
Studies in monkeys help to understand how low social status leads
to worse health.
Removing the ovaries of a female monkey removes her protection from
atherosclerosis compared to the male.
Subordinate monkeys have higher risk than dominant monkeys.
So big is the difference that it is equivalent to the effect on
atherosclerosis of ovariectomy.
It is certainly not a new idea that disease outcomes are sometimes more related to psychological and even social factors, so why has allopathy not acknowledged this before?
When one considers that it costs approximately £600,000 for a good double-blind placebo trial of a single drug, the expense of a good multidimensional analysis of illness, for example the stress hypothesis of schizophrenia, would certainly dwarf this figure. In addition, Helge Malmgren
(Department of Philosophy, Göteberg University) points to the philosophical difficulty of supervenience which would impact on the design and analysis of any such multidimensional study.
Malmgren draws a parallel between the relationship of software to hardware and mental to physical emphasizing that one cannot determine the software state by looking at the
underlying electronic processes occurring in the hardware. Similarly, the state of mind of a schizophrenic
individual at any one point in time will be supervenient on the brain, but this does not entail
that a purely neurophysiological analysis of schizophrenia is
possible.
Whether the primary influence on the timing
of symptoms of illness is the 'psyche' or organicity, as Ed Shorter (Department
of the History of Medicine, University of Toronto) alluded to in his
historical account of the biospsychosocial model, there has been a recent
resurgence in 'hippocratic notions' and the biopsychosocial model
"will backpeddle from psychiatry and restore the lost primacy of
psychotherapy".
Brona McVittie—Assistant Editor, Novartis
Foundation, London
This discussion meeting is the result of a book proposal. The book will
be edited by Dr Peter White (Guy's, King's and St. Thomas's School of
Medicine, London) and published by OUP
(Based on presentations given at Novartis Foundation Symposium 252 'Generation and effector functions of regulatory lymphocytes' held in London on 9-11 July 2002)
A new therapeutic strategy for
type I diabetes
The WHO estimated in 1994 that the global prevalence of type I diabetes was 11.5 million.
Insulin-dependent diabetes mellitus (type I diabetes/juvenile onset diabetes) is a chronic condition in which the pancreas makes little or no insulin because the ß-cells have been destroyed. The body is then not able to use blood-glucose for energy. IDDM usually comes on abruptly, although the damage to the ß-cells may begin much earlier. The signs are a great thirst, hunger, a need to urinate often, and weight-loss. To treat the disease, sufferers must inject insulin daily, follow a diet plan, exercise daily and test blood-glucose several times a day. The condition usually occurs in children and adults under age 30, and is potentially life-threatening.
A recent Novartis Foundation Bursar, Chrystelle Asseman (La Jolla Institute for Allergy and
Immunology, San Diego) attended a symposium on the 'Generation and effector functions of regulatory
lymphocytes', after which she was funded by the Foundation to spend 7 weeks in the research laboratory of Lucienne Chatenoud (Inserm 25 Hopital Necker,
France). During this period she worked with Professor Chatenoud on a potentially new therapeutic strategy for the treatment of type I diabetes.
Type I diabetes is an autoimmune disorder, in which the CD8+ and
CD4+ lymphocytes infiltrate the pancreas and kill off insulin-producing ß-cells. NOD (non-obese diabetic) mice are a model for spontaneous diabetes, and have been shown to experience a reduction in regulatory T cells
(CD4+CD25+) as they age. Regulatory T cells (as explained by Dr Lisa Melton, in a
previous Bulletin article) are pivotal in dampening the normal immune response. This can be a help or a hindrance. In the type I diabetic scenario, where lymphocytes become unable to differentiate body cells from foreign invaders, T reg cells could potentially be very useful in reducing the numbers of such self-aggressive lymphocytes.
Dr Asseman and Professor Chatenoud reasoned that because Treg cells (CD4+CD25+)
are likely to play a role in maintaining tolerance to pancreatic ß-cells, they may be a useful therapeutic agent. The key factor in such a strategy would be to engineer such cells to specifically target the pancreatic islets, which are home to ß-cells. A clever way to help them target the pancreas is to make them specific for insulin. When the ß-cells are destroyed, insulin is released therefore injected Treg cells should migrate to the pancreas and become activated by the insulin protein. This in turn should help to reduce the levels of aggressive lymphocytes
(CD4+ and CD8+) and allow ß-cells to produce insulin.
This was modified from a report written by Dr Chrystelle Asseman—La Jolla Institute for Allergy and
Immunology, San Diego
'Generation and effector functions of regulatory lymphocytes' is due to be
published by John Wiley & Sons, Chichester, UK in April 2003
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
Book review: NM Hooper (ed) Essays in biochemistry: proteases in biology and medicine
Blocking proteases
The human body has roughly 105 different kinds of globular proteins and this represents a paucity of the total theoretically possible.
Despite this, molecular biologists and biochemists have managed to
describe the structure and function of an ever-expanding proportion. Essays in biochemistry: proteases in biology and medicine edited by NM Hooper
(Proteolysis Research Group, University of Leeds) was published this year by
Portland Press and is a very useful companion to the teacher of biochemistry or molecular biology; with helpful cross-referencing between chapters and clear diagrammatic representation of biochemical structures. It is also suitable for undergraduates pursuing biochemical explanations for and insights into the development of therapeutics.
Several chapters deal with proteases relevant to cancer. Itoh & Nagase
(Kennedy Institute of Rheumatology, London) review MMPs (Zn-metalloproteases) of which 23 known human genes are implicated in cancer. MMPs are integral in the degradation of extracellular matrix components in metastasis. Synthetic TIMPs (inhibit MMPs by chelating the
Zn2+ ion) are undergoing investigation as potential therapeutic agents in cancer. Doherty et al
(University of Nottingham Medical School) discuss the importance of the ubiquitin-proteasome pathway in cancer whilst the potential use of
anti-angiogenic compounds such as fumagillin is covered by Bradshaw & Yi
(College of Medicine, University of California). Proprotein convertases (PCs) when over-expressed can lead to tumour formation, metastasis and angiogenesis as explained by Seidah & Prat
(Clinical
Research Institute of Montreal).
Nunan & Small (Department of Pathology, Victoria, Australia) describe the current understanding of pathogenesis in Alzheimer's disease pointing to the secretase family as potential targets for therapeutic agents. They also
describe reduction of toxic amyloid ß protein by other methods such as cholinesterase treatment. Bawson
(University of Texas Southwestern Medical Center) later alludes to the importance of understanding Rip (regulated intramembrane proteolysis) in Alzheimer's disease.
In addition the book details the biochemical structures, pathways and interactions of proteases implicated in arthritis such as
MMPs, TACE which inhibits TNFα (Moss & Lambert, GlaxoSmithKline R&D, USA) and Cottrell et al
(UCSD) detail the role of PARs (protease activated receptors) in inflammation arguing for the potential therapeutic application of selected agonists/antagonists.
Brona McVittie—Assistant Editor, Novartis
Foundation, London
News from the Foundation
Meetings
Open Meetings:
The next Novartis Foundation Open meeting on 'Anaphylaxis' will take place on
28 February 2003 London. For details of the location, please refer
to http://www.novartisfound.org.uk/open.htm
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
Other forthcoming open meetings include:
-
Mammalian TRP channels as molecular targets
-
Reversible acetylation of chromatin and non-histone proteins: biology and relevance to human disease
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Signalling networks in cell shape and motility
-
Pathological pain: from molecular to clinical aspects
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 on 12-14
November 2002 entitled 'Cancer and inflammation'. Chaired by
Professor Siamon Gordon, Glaxo Wellcome Professor of Cellular Pathology,
Sir William Dunn School of Pathology, Oxford.
Discussion meetings:
Please refer to http://www.novartisfound.org.uk/disc.htm
for details on forthcoming discussion meetings
Publications
We are pleased to announce the recent publication of:
In silico simulation of biological processes
(Novartis Foundation Symposium 247)
View the abstracts
of this book
Mucus hypersecretion in respiratory disease
(Novartis Foundation Symposium 248)
For details of this, and other recently published books and how to order 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.
See http://www.novartisfound.org.uk/booksale.htm
for details of the titles and how to order them or e-mail bulletin@novartisfound.org.uk
for more details.
Publicity
Resident science writer, Dr Lisa Melton has recently published the
following:
'Riding the age wave' in Novartis Pathways Vol 3 (No 4), p
30-35
'Subduing supressor' in Scientific American, Dec 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
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
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