Novartis Foundation Bulletin
Issue 17, October 2003
Welcome to the 17th edition of the Novartis Foundation's
E-Bulletin.
This issue features reports on:
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Growth hormones and health (NF262)
Print the PDF bulletin
(Based on presentations given at Novartis Foundation Symposium 262, 'Biology of IGF-1: it's interaction with insulin in health and malignant states' which was held in London on 14-16 October 2003)
Growth hormones and health
"It has been estimated that more than half of the growth hormone sold in North America is not used for the treatment of individuals with documented deficiency in the growth hormone-IGF-1 axis", informs Michael Pollak
(McGill University, Montreal, Canada). This is suggestive that wealth and health do not correlate closely, and recent growth hormone treatment
fads—an attempt to increase longevity and youthfulness by raising
IGF-1 levels—may cause more harm than good despite individuals paying thousands of dollars. While there may be short-term increases in muscle-mass associated with growth hormone supplementation, to date there has been no hard evidence that boosting serum
IGF-1 beyond the age-specific normal range over the long term will result in prolonged life. In fact, the available data suggest that chronic elevated levels of IGF may actually promote cellular proliferation and may increase the risk of cancer.
A recent Novartis Foundation Symposium on the Biology of IGF-1 assessed the current knowledge on the complex biology of the IGF signalling system. A much clearer picture of the regulation of IGF and related peptide hormones has emerged and Pollak affirms that "several labs working on experimental
models ranging from yeast to mice have observed that an increase in longevity may be possible by decreasing IGF receptor signalling". His recent study on human protein intake in relation to IGF-1
showed that IGF-1 levels may be pertinent not only to ageing but also to health in general. The
study
found that elevated IGF-1 levels correlated with higher levels of protein (milk, fish, poultry, vegetable protein but not red meat) intake, evidencing the close relationship between this hormone and diet.
Jeff Holly (Bristol University, UK) corroborates this view highlighting his research that shows that milk consumption causes a very significant increase in serum IGF-1, and this is evidenced by cohort studies globally. Holly explains that physiologically the IGF signalling system is quite unusual in that total blood concentrations of IGF are around 1000 times higher than most peptide hormones, although our cells are stimulated by relatively tiny amounts. Indeed most of this is not biologically active, being held in check by IGFBPs (binding proteins) that circulate in the blood and prevent IGFs from stimulating cells.
90% of serum IGF-1 is transported bound to IGFBP-3 (IGF binding-protein-3), and only liberated by the action of specific IGFBP proteases, which in turn are regulated by individual inhibitors that have yet to be characterized. The
actions of IGF are exerted by means of binding to cell-surface receptors, although the affinity for IGFBPs is so much higher than that for cell-surface IGF and insulin receptors, that the biological activity of IGF is only unleashed when the proteases break down these binding-proteins. Thus anything that enhances the activity of these proteases could increase biologically active IGF with significant effects on health and physiology.
Whilst classical definitions of IGF-related disease were characterized by extremely low IGF (stunting growth) or high IGF levels (causing gigantism), the current realization within the scientific community is that altered 'normal' levels of IGF can have huge influences on health and disease. Broadly speaking, across the normal range of IGF expression, the emerging trend suggests that lower levels of IGF-1 are a risk for insulin resistance, cardiovascular disease and osteoporosis, and that higher levels might predispose to cancers including prostate, breast and colorectal.
Brona McVittie—Assistant Editor, Novartis
Foundation, London
(top)
NF262 Biology of IGF-1: it's interaction with insulin in health and
malignant states will be published by John Wiley & Sons in July 2004
(Based on presentations given at Novartis Foundation Symposium 262, Pathological pain: from molecular to clinical
aspects held on 30 September-1 October in collaboration with the Novartis Foundation in Tsukuba, Japan)
When pain is more than nerve deep
For all the analgesics and opioids consumed worldwide to tackle everything from headaches to post-surgical pain, when the pain is rooted in the nervous system, it remains notoriously hard to treat. People with nerve damage often endure years of agonizing pain, with little respite from traditional pain-killers.
Fortunately, anticonvulsants have stepped in as powerful agents in alleviating neuropathic pain, and scientists are beginning to understand the mechanisms by which they work. A recent
Novartis Foundation Symposium in Japan brought basic researchers and neurologists together to discuss the ins and outs of these and other pathological pain phenomena with the sights set firmly on novel pharmacological solutions.
Scientists now understand that anti-depressants can have an analgesic effect on top of any mood effect. Despite the knowledge accumulated over the last decade, today doctors rarely suspect nerve damage, and prescribe traditional painkillers that have little or no effect. An anti-epileptic drug may seem a bizarre solution, but in the last decade, scientists have begun to understand why these compounds work for mysterious pain conditions that involve nerve trauma.
Neuropathic pain can result from injury following accidents or surgery, viral infections such as shingles and HIV, as well as diabetes. "Not all people with nerve trauma or injury develop neuropathic
pain" points out Dr Steve Allen, a consultant in Pain Management (Royal Berkshire hospital,
Reading, UK). "But for the many who do, it's a huge problem. The symptoms can be very
distressing." In Britain, there are more than half a million people suffering from this type of pain. For some people with neuropathic pain, even the slightest touch or the pressure of clothing or sheets can be unbearable.
Today anticonvulsants have become the drugs of choice for many pain clinicians. "We have something that works," comments an upbeat Dr Allen. Why tricyclic anti-depressants and anti-epileptics are effective in nerve pain is something that researchers have only recently figured out. Nerves don't work in isolation - they are connected to the spinal cord and the brain. When a nerve is injured and the trauma persists, the brain and spinal cord become hyperexcitable, and every signal is amplified resulting in more pain. "Some people come in and say: 'cut my arm off, doctor,' but the pain isn't coming from the bit that hurts, it's central by that time," explains Dr Allen. Anticonvulsants and antidepressants block the mechanisms that lead to such hyperexcitability and dampen the excessive nervous activity.
New formulation anti-convulsants and promising compounds such as cannabinoids are undergoing the last stages of clinical trials. As scientists gain a foothold on the different mechanisms that trigger neuropathic pain, the possibility of designing drugs to help alleviate and even reverse such conditions is becoming a firm possibility. "The future is looking very bright," enthuses Dr Allen.
Dr Lisa Melton—Science Writer, Novartis
Foundation, London
This article has been abstracted from a forthcoming Times T2 publication
by Dr Lisa Melton.
(top)
NF261 Pathological pain: from molecular to clinical aspects will be
published by John Wiley & Sons in June 2004
(Based on presentations given at Novartis Foundation Symposium 259, Reversible protein acetylation held in London on
6-8 May 2003)
Bursary report
I was very lucky to be selected to attend Novartis Foundation Symposium 259. The meeting was chaired by Dr. Eric Verdin, and the topics addressed covered virtually all aspects of the field, from basic research on the modification of histone and nonhistone proteins to their relevance to the human disease. Each talk was followed by a stimulating and informative 30-minute discussion. I came away from the meeting with a considerable amount of new knowledge and lots of ideas to apply to my own work. I also got the chance to meet almost all the 'big names' in the field. The connections I made with these scientists will definitely benefit my research in the future. This was the best meeting I ever attended!
After the symposium, I returned to San Francisco to complete the second part of my bursary in the laboratory of my mentor, Dr. Warner
Greene (Gladstone Institute of Virology and Immunology and the University of California, San
Francisco, USA) Dr. Greene's laboratory focuses on the regulation of
NF-kappaB/Rel family of transcription factors-the 'master regulators' of the immune and inflammatory responses-and on the pathogenic interplay of the human retrovirus HIV-1 and the disease it causes, AIDS. During this period, I extended my studies on the regulation of
NF-kappaB by reversible acetylation by developing in vitro and in vivo systems to investigate the functional relations between acetylation and phosphorylation of
NF-kappaB. My work was greatly facilitated by weekly group meetings with Dr. Greene and by weekly joint meetings with the laboratory of Dr. Eric Verdin, which focuses on the role of Tat acetylation in transactivation of the HIV long terminal repeat and on the biochemistry and function of histone deacetylases.
With support from Dr. Greene and with discussions and help from my colleagues in the Greene and Verdin labs, I made several interesting findings. Currently, I am writing a manuscript about this work, continuing my research, and beginning my search for an independent research position.
Now that my bursary has come to an end, I want to thank the Novartis Foundation for this wonderful experience to strengthen my professional experience and future career development. I would also like to thank Miss Allyson Brown for her wonderful help in arranging my bursary. Finally, I would like to thank Dr. Greene for his support and mentorship during the bursary period.
The Novartis Foundation bursary provides an outstanding opportunity for young scientists to participate in discussions on the frontiers of science, to interact and establish connections with leading investigators in the field, to learn new techniques, and to broaden their scientific expertise. I am most grateful for the experience.
Lin-Feng Chen—Gladstone Institute of
Virology and Immunology, UCSF, USA
(top)
NF259 Reversible protein acetylation will be published by John
Wiley & Sons in February 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 Inflammatory bowel disease—crossroads
of microbes, epithelium and immune systems will take place on 28
November 2003 at the Clore Management Centre, Birkbeck College, Malet Street,
WC1 in collaboration with the Royal Society of Medicine and the
Physiological Society.
To book your place at the meeting please register
online or 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:
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Nuclear organization in development of disease on 30 January 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 NF262 Biology of IGF-1: it's interaction with
insulin in health and malignant states took place on 14-16 October
2003 at the Novartis Foundation, London.
Chaired by Professor Derek LeRoith, Bethesda, USA.
Discussion meetings:
The next discussion meeting to take place is:
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Drugs for developing world diseases: translating new molecular targets into candidates for development (with NIMS) Friday 3 November 2003
Publications
We are pleased to announce the recent publication of:
Generation and effector functions of regulatory lymphocytes
(Novartis Foundation Symposium 252)
Molecular clocks and light signalling
(Novartis Foundation Symposium 253)
Immunoinformatics: bioinformatic strategies for better understanding of
immune function
(Novartis Foundation Symposium 254)
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
Dr Lisa Melton, the Foundation's Science writer has recently published:
Bringing heads together in the Novartis Journal, Pathways,
October/December 2003
She was also quoted in the Argentine Newpaper, La Nacion, on her
writings about the obesity epidemic in France.
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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