Novartis Foundation Bulletin
Issue 15, May 2003
Welcome to the 15th edition of the Novartis Foundation's e-mail Bulletin.
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This issue features reports on:
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Bursar's report—Cancer and inflammation
Chromatin, cancer and the histone code
Considering that 2m of DNA is contained within a nucleus of 10µm diameter, it is not surprising that the organization of the genetic code within the nucleasome of histone and non-histone proteins has a huge impact on gene expression and protein translation. As early as 1954 Professor VG Allfrey suspected that "acetylation of histones diminishes their capacity to inhibit RNA synthesis in the nucleus". Today it is common knowledge that the normal 'ground state' for eukaryotic chromatin is non-permissive to transcription. Furthermore, many modulators which can bind to chromatin 'silencing' it such that transcription is potentiated, have recently been characterized.
Such modulators effect post-translational changes on histones including acetylation, deacetylation, phosphorylation, methylation and ubiquitination. Broadly speaking, acetylation of histone tails corresponds to transcriptional activation, whereas deacetylation causes repression of gene expression. Dalia Cohen
(Novartis Institute for Biomedical Research, Cambridge, MA) was the proposer of a recent meeting at the Novartis Foundation in London on reversible acetylation. Her work focuses on the role of HDACs (histone deacetylases) in transcriptional regulation specifically in regard to the therapeutic use of HDAC inhibitors as a cancer treatment.
Integral to the development of cancer are both the over-expression of oncogenes and under-expression of tumour suppressor genes, the latter often being caused by histone acetylation and DNA hypermethylation. Several classes of HDAC inhibitor are currently in clinical trials. Stephen Baylin
(Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore) points out the importance of the interaction between DNA hypermethylation in conjuction with histone deacetylation. His research has shown that HDACs alone aren't enough to reverse aberrant silencing in cancer cells. So it is proposed that DNA methyltransferases (DNMTs) or other demethylating agents could thus potentially be used in conjuction with HDACs to treat cancers.
Whilst one holds out hope for improvements in the treatment of a disease which has a worldwide incidence of between 5 and 10%, it also seems likely that the fundamental nature of chromatin-based epigenetics will have an impact on X-inactivation, imprinting, developmental reprogramming of cell lineages and the plasticity of stem cells. Thus, the implications for human biology and disease, including cancer and ageing, are far-reaching.
David Allis's laboratory (Rockefeller University, New York) favours the general view that histone proteins are major carriers of epigenetic information. The 'histone code' predicts that different histone modifications can influence
each other either synergistically or antagonistically, providing a mechanism to generate and stabilize specific imprints. How different male and female genomes are in regard to histone methylation patterns is not yet known, but imprinting mechanisms may use marks outside of DNA methylation and in some instances, histone methylation and DNA methylation are intimately linked. Almost complete removal of histones is known to occur during vertebrate spermatogenesis, hinting at the possibility of reprogramming potential male marks in the germ line.
Because chromatin is the physiological template of eukaryotic cells, Allis wonders if genomes are programmed to 'open' and 'close' on demand by enzyme complexes that evolved to respond directly to metabolic cues. He proposes that, if so, further insights will arise from systematic investigation of chromatin changes during different physiological and pathological states.
Brona McVittie—Assistant Editor, Novartis Foundation, London
'Reversible protein acetylation' will be published in January 2004 by John Wiley & Sons, Chichester, UK
Psyche on sickness
"A happy man will not catch the plague" ran a popular saying in 18th century England. Today, we chuckle at such simplistic thinking, knowing full well that a bacterium has no preference for the bad-tempered guys. Yet bizarrely, in many other health situations, we still believe this to be true.
While most people readily admit that a positive outlook won't protect you from the HIV virus, they intuit that a depressive nature can bring on heart disease. And indeed, the
latest epidemiological studies have confirmed that depression and heart attacks are associated.
But to many scientists, this is dangerous nonsense. Look back to 1951, says George Davey-Smith, an epidemiologist
(University of Bristol) and you will find a paper published in reputable journal asking, "Is baldness psychological?" At the time, a tense scalp was thought to prompt hair loss, but today the suggestion is laughable.
For Davey-Smith and legions of biomedical researchers, illness has little to do with our psyche and more to do with a conspiracy of genetic predisposition, infections and external triggers. And for those mystery conditions, it's merely a case of uncovering the causal agents involved. Take gastric ulcers, for example. It wasn't so long ago that the notion that stress causes gastric ulcers was taken as gospel. When
H.pylorii came into the limelight, clinicians quickly dropped their 'change-your-lifestyle' mantra in favour of prescribing an antibiotic.
But why are the skeptics so ferociously opposed to the psychological touch? What's wrong with a little pep-talk or a course of cognitive behavioural therapy to get you out of a rut? Because there is a dark side to this approach, says Davey Smith. Blame and false expectations. If someone is diagnosed with breast cancer, for example, they may assume the blame rests on their shoulders, when, in reality, there is little they could have done to prevent it.
In contrast, many medics and psychiatrists, are not convinced that psychological events have no bearing on disease. The proof stares them in the face in the clinic when they see patients with no diagnosable disease but whose lives are disabled by pain and suffering often coinciding with adverse life events, sudden loss or chronic adversity. To gastroenterologist Doug Drossman
(University of North Carolina), the association between gastrointestinal disorders and a history of trauma and sexual abuse is clear. In research soon to be published, he sees that in patients with irritable bowel syndrome who have also been abused there is an effect on cingulated cortex activation and these patients respond best to both drugs and CBT.
Stafford Lightman (Bristol Royal Infirmary) believes that inflammation, and in particular cytokines, are responsible for leaving a neuroanatomical imprint on the brain, providing biological evidence for the relationship between stress and disease.
But as scientists continue to debate whether psychological events are driving disease, cognitive behavioural therapy can be a powerful tool for managing established disease. As Kate Lorig
(Stanford School of Medicine) has shown, cognitive behavioral therapy can reduce pain, dependency and fatigue, even with disparate conditions such as diabetes type II, asthma, and arthritis. The disease progression may be unaffected but quality of life improves dramatically. Here is where psychology shows its worth.
Dr Lisa Melton—Science Writer, Novartis Foundation, London
(Based on presentations given at Novartis Foundation Symposium 256, 'Cancer and inflammation' which was held in London on 12-14 November 2002)
Bursar's report
In addition to attending the symposium on Cancer and inflammation, The Novartis Foundation funded
a 12-week stay for me at Professor Fran Balkwill's lab, The Translational Oncology Laboratory at Barts and The London Queen Mary's School of Medicine & Dentistry at the John Vane Science Centre. Professor Balkwill's group are working on the interaction of
tumour cells and host immune cells, especially the macrophages, using a great variety of biochemical, biophysical, immunochemical, molecular and cell biology approaches. They have extensively studied the role of the chemokines and their receptors and TNF-alpha. These studies have revealed new insights about the 'the dark side of immune system'.
When I arrived in London, I joined Stephen Robinson who was already working on this subject. During my stay, I established the co-culture model that I developed in Germany and we did a lot of new
experiments, especially inhibitor and neutralizing antibody studies under the supervision of PhD Stephen Robinson and Professor Balkwill. I profited a lot from working in Professor Balkwill's lab, as I learned new techniques that will further my projects in the future. I highly appreciated the friendly atmosphere in the lab. Everybody was always ready to help. Besides scientific issues, I learned how beautiful London and the surrounding environment is as well as enjoying several tours with colleagues from the lab.
Participating in the Novartis Foundation Symposium with experts in the field of cancer and inflammation from all over the world was a very exciting experience for me. I thank the administrators and trustees of the Novartis Foundation for sponsoring a wonderful symposium. I feel very fortunate to participate in discussions with these established investigators from the basic science and clinical areas on this topic and instilled within me an enthusiasm for the future of the field.
Professor Balkwill arranged for me to spend time discussing contemporary research and clinical issues with her research team and at the regular symposia at Lincoln's Inn Fields. However, being able to discuss methodologies, theoretical development of key issues, and future directions for immunology research in detail was an invaluable and exciting experience.
I am indebted to the Novartis Bursary hosts for their enthusiastic encouragement of my current research and future research plans and for enabling me to participate in an exciting symposium and to work in a lab that is scientifically outstanding and which is home to such friendly researchers. I would particularly like to thank Fran Balkwill and Stephen Robinson for being much more than just a host for 12 weeks, but last but not least Allyson Brown and Jane Dempster from the Novartis Foundation who enthusiastically supported me from the very start.
The Novartis Foundation Bursary was an extremely rewarding experience from the interaction and exchange of ideas during the paper discussions to the simple questions we pursued in the short set of experiments performed. I fully appreciate the Foundation's support in providing young investigators a view of what the craft of multidisciplinary research should be about, as well as the opportunity to network and establish collaborations that would be critical to a career in academic science.
Since my return to Germany, I have remained in contact with my newly acquainted research colleagues, and we started a very powerful collaboration.
Thorsten Hagemann—Department of Hematology and Oncology, University of Göttingen
Dr Hagemann has also published a report of his experiences on the New Wave website called Meet the Who's Who of your field at http://intl-nextwave.sciencemag.org/cgi/content/full/2003/02/26/11
'Cancer and inflammation' will be published in November 2003 by John Wiley & Sons, Chichester, UK
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 'Osteoarthritic joint pain' will take place on
4th July 2003 in London
Other forthcoming open meetings include:
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Pathological pain: from molecular to clinical aspects (Japan) Friday 3rd October 2003
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
London on 6-8 May 2003 entitled 'Reversible protein acetylation'. Chaired by
Eric Verdin, Gladstone Institute of Virology and Immunology, University of
California, San Diego.
Discussion meetings:
The next discussion meetings to take place are:
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Evolution and environmental change: so is there a link?
(with the Royal Society) Friday 30th May
Publications
We are pleased to announce the imminent publication of:
Development of the cardiac conduction system
(Novartis Foundation Symposium 250)
For details of this, and other recently published books and how to order see:
http://www.novartisfound.org.uk/nbook.htm
Book Sale 2003
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.
Publicity
‘Oestrogen on the brain: Lisa Melton looks at work to extend the beneficial effects of the female hormone oestrogen to men as well as women’ by Dr Lisa Melton, published in Chemistry in Britain, March 2003, Vol 39, No 3, p 41-43
‘On the trail of SNPs. Extracting useful data from the human genome sequences is a major challenge. Lisa Melton examines the early steps towards personal genotyping.' by Lisa Melton in Nature, 24 April 2003, Vol 422, p 917-923
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
2003 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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