Novartis Foundation Bulletin

Welcome to the eighth edition of the Novartis Foundation's e-mail Bulletin. This issue features reports on:

• Make your own Valium
• Nobel Laureates honour Foundation
• Anorexia in ageing
• News from the Foundation
  • Meetings
  • Publications
  • Hospitality
  • Personalia

Make your own Valium

(Based on presentations given at the Novartis Foundation symposium: Ion channels: from atomic resolution physiology to functional genomics, held in London 12-14 June 2001)

Locked inside your brain is the most powerful sedative, anti-anxiety drug and pain-killer all rolled into one. The magical compound derives from the sex hormone progesterone and, if medicinal chemists get it right, it may soon lead to an analgesic to rival morphine.

Scientists have known since the 1940s that progesterone--the female hormone we usually associate with the Pill and making babies--is also an incredibly potent sedative. Today, researchers know that it is the breakdown products of natural progesterone that have such a potent anaesthetic and analgesic effect. 'During pregnancy, for example, as a woman comes close to term, the levels of these breakdown products of progesterone are extremely high,' says Jeremy Lambert, a neuropharmacologist at the University of Dundee in Scotland.

Fortunately, this natural analgesia and anxiolysis is not exclusive to women. There are enzymes in the brain and spinal cord of both men and women that produce similar compounds, neurosteroids, from cholesterol or progesterone.

Neurosteroids target the gamma-amino-butyric acid (GABA) type A receptor and, as a result, dampen neuronal activity. GABA is the brain's most important inhibitory neurotransmitter and sedative drugs, like benzodiazepines (Valium and Librium) and barbiturates, all enhance its calming effects. By fine-tuning GABA, Lambert explained at last year's Ion channels symposium, progesterone metabolites may promote sleep, keep anxiety at bay and, in mounting doses, act as analgesics, anticonvulsants and even anaesthetics.

Researchers are now intent on harnessing these effects. The trick is to untangle one neurosteroid action from another: to induce pain-relief without knocking you unconscious and without the sexual side effects. Colin Goodchild an anaesthesiologist at Monash University in Victoria, Australia may have already hit on a compound--alphadolone--that can do exactly that. 'It can work as a pain-relieving drug without causing sedation,' says Goodchild.

Goodchild hopes that alphadolone may eventually replace opioids, such as morphine, or at least reduce their usage. Progesterone metabolites might also lead to an 'all natural' sleeping pill and anti-epileptic, with few--if any--side effects. 'I think neurosteroids are going to be the pharmaceuticals of the future,' says Goodchild.

Lisa Melton is Science Writer at the Novartis Foundation (top)

This article first appeared in the New Scientist 19 January 2002, p 32-37 http://www.newscientist.com

‘Ion channels: from atomic resolution physiology to functional genomics’ is due to be published by Wiley in May 2002

Nobel Laureates honour Foundation

In October this year, two British scientists scooped the Nobel Prize in Medicine for their seminal discoveries on how cells work--findings that may eventually lead to new treatments for cancer and other diseases. Only a year earlier, these top-class researchers spent three days secluded at the Novartis Foundation in London. But why did they abandon their labs? To brainstorm on the subject closest to their hearts: the cell cycle.

Sir Paul Nurse, Director-General of the Imperial Cancer Research Fund in London, and Dr Tim Hunt, an associate at the same charity, shared science's top prize with US researcher Professor Lee Hartwell. Their pioneering work, which identified key molecules with a role in regulating how cells grow, divide and multiply is important in every field of biology but especially in medicine: defects in cell cycle control can lead to the alterations seen in many cancer cells.

In April 2000, the Novartis Foundation invited these Laureates-to-be and 28 other experts from around the world to a symposium entitled 'The cell cycle and development'. The idea was to discuss not only how cells divide to replace others that are dying but also what keeps these cycling cells in check when the embryo is developing from a single cell (the fertilized egg) into a fully formed being.

As chair of the meeting, Sir Paul Nurse praised the Foundation's work in his opening remarks: 'Without any reservation I can say that the Novartis Foundation symposia are amongst the best discussion meetings held throughout the world, and I am sure that this will be yet another excellent meeting.' His links with the Novartis Foundation are close--not only has he attended similar meetings in the past but he is also member of the Foundation's Executive Council.

The Foundation shares everyone's delight at the awards.

Lisa Melton (top)

‘The cell cycle and development’ was published by Wiley in May 2001

Anorexia in ageing

(A Report from the bursar of the Novartis Foundation symposium: Endocrine facets of ageing, held in London 30 January-1 February 2001)

***The symposium bursary scheme enables young scientists from any country to attend symposia as active discussants and then spend up to 12 weeks in the laboratory of one of the participants. This scheme has attracted over 1500 applications from 20 countries. In all, more than 100 bursaries have been awarded***

In January last year I had the pleasure and the honour as a young scientist to take part in the Novartis Foundation Symposium Endocrine facets of ageing, along with a highly qualified group of experts from all over the world. The scientific presentations of every speaker and the ensuing discussions were extremely interesting, and of great benefit for my scientific training.

Over the last few years I have been increasingly interested in the regulation of the somatotropic axis during ageing. Growth hormone (GH) secretion declines with ageing in mammals, including humans. GH-deficient non-elderly subjects were shown to have reduction in lean body mass, expansion of adipose mass, diminution in renal function, and in the rate of cell division; blood lipid profiles that favour the development of vascular diseases, and increased overall mortality. It has therefore been proposed that this reduced GH secretion may be a cause of the metabolic and physiological changes that denote ageing. This has led to the idea that stimulation of endogenous GH secretion in a physiological pulsatile manner may help to counter structural and functional alterations related to somatotrop deficiency in the elderly.

Opportunities to test this proposition have been provided by the recent discovery of GH-secretagogues (GHSs), a series of peptidic and non-peptidic synthetic molecules endowed with a strong GH-releasing and orexigenic activity. In addition the cloning of a GHS receptor (GHS-R), present in the hypothalamus and the pituitary, lead to the isolation of the endogenous ligand of GHS-R ghrelin, a 28-amino acid peptide whose main source is the stomach.

GHSs are very effective at enhancing GH secretion in elderly subjects, but long-term studies are needed to assess their safety and the true biological impact of GHS replacement therapy in ageing. Therapeutic use of GHSs can also be envisaged to restore, via GH-independent mechanisms, other functional and structural age-related alterations, such as anorexia of ageing.

Many neuropeptides, like neuropeptide Y (NPY) and ghrelin, possess both neuroendocrine and orexigenic actions. These neuropeptides might play a role in the pathogenesis of anorexia of ageing. For this reason I decided it was important to study this interesting research topic.

I spent my bursary period at Professor Aubert's laboratory, at the Fondation pour la Recherche Medicale, University of Geneva, Switzerland. Here, I could greatly improve my technical and scientific background, working on new experimental approaches, and using techniques of molecular biology applied to neuroendocrinology. Particular emphasis was given to the neuromodulation exerted by NPY in the control of food intake, energy balance, gonadotropic and somatotropic axis and glucose metabolism.

I am extremely grateful to the Novartis Foundation for giving me the opportunity to attend an outstanding Symposium in London and for generously supporting my bursary period in Geneva. My sincere thanks to all the staff of the Novartis Foundation in London and to Prof. Aubert and his collaborators, in particular Dr. Paula Raposihno, at Geneva.

Dr Antonello Rigamonti, MD--Department of Medical Pharmacology, University of Milan, Italy (top)

‘Endocrine facets of ageing' was published Wiley in January 2002

For abstracts from the symposium see http://www.novartisfound.org.uk/fp242.htm

For details the bursary scheme and forthcoming bursaries see http://www.novartisfound.org.uk/bursary.htm

The Novartis Foundation bursary scheme

The aim of the bursary scheme is to enable young scientists to attend Novartis Foundation symposia and, immediately following the meeting, 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. It is essential that they be actively engaged in research on the topic covered by the symposium. They should not already have accepted an invitation to participate in that symposium.

The award includes:
(a) travel expenses to symposium and host laboratory
(b) board and lodging for the duration of the bursary

For more details see http://www.novartisfound.org.uk/bursary.htm
or email bursary@novartisfound.org.uk 

News from the Foundation

Meetings
Open Meetings:
The next Novartis Foundation Open meeting on Mucus hypersecretion, will be held on Friday 1st March 2002 in collaboration with The Royal Society of Medicine, at The Science Societies Lecture Theatre, New Burlington Place, Off Saville Row, London, W1X 1AB.

To book your place at the meeting please contact Sharan Gallagher at The Royal Society of Medicine academic department:
telephone: +44 (0) 20 7920 3946
fax: +44 (0) 20 7290 2977
email:events@rsm.ac.uk
Or complete the registration form at: http://www.rsm.ac.uk/novartisfoundation

Other forthcoming open meetings include:
* Tissue engineering of cartilage and bone, on Friday 12 April 2002
* Development of the cardiac conduction system, on Friday 24 May 2002
* Autism: neural basis and treatment possibilities, on Friday 21 June 2002
* Functions of regulatory lymphocytes, on Friday 12 July 2002

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 from the 27-29 November, entitled: 'In silico' simulation of biological processes
Chaired by Professor Denis Noble, University Laboratory of Physiology, University of Oxford

Discussion meetings:
Two discussion meetings were held at the Foundation over recent months:
The costs and contents of neuronal signals
Chaired by Professor Andrew Derrington, on Friday 7 December 2001
Wildlife population growth rates: current analyses and future options, Chaired by Jim Hone, on Friday 8 January 2002.
Both meetings were organised in collaboration with the Royal Society.

Hospitality
Details of all conference facilities and accommodation available at the
Foundation can be found at http://www.novartisfound.org.uk/hosp.htm

Personalia
The end of last year saw one change of staff in the Accounts Department. Maria Kyprou resigned her post after almost 23 years' loyal service and we welcomed Sara Tyler in her stead as Accountant. We extend to Maria our grateful thanks and very best wishes for the future. Sara has an ONC in Business and Finance and gained her accountancy experience within the manufacturing and service industry.

Our congratulations are once again extended to Professor Steve Ley FRS (Chair of the Foundation's Executive Council and President, Royal Society of Chemistry) who was appointed CBE for services to Chemistry in the New Year's Honours list.

We were pleased to welcome Executive Council members to the 212th Council meeting at the end of last month followed by an informal dinner held at the Foundation at which they were joined by trustees and members of the scientific and senior staff.

The dinner provided an opportunity to welcome the Foundation's new honorary accountant Mr Michael Fahey who joined the council at the beginning of this year. Commencing his career with KPMG in Sydney, Australia in 1987, Michael qualified as a Chartered Accountant before joining Sandoz Australia in 1991. He has held a number of international finance positions, firstly with Sandoz, then Novartis in Switzerland, Singapore and now the UK.

The retirement of five members of our international Scientific Advisory Panel was announced at the end of last year: Dr R Gamez (Costa Rica), Professor V L Chopra (one of two advisers for India), Professor Lim Pin (Singapore), Professor A Garcia-Bellido (Spain) and Dr P A Pulido (Venezuela). We are grateful to these scientists for their help and support and are very pleased to welcome, as new members, Professor Dr Georg Stingl (Austria), Professor W Stalmans (Belgium), Professor J M Gershoni (Israel) Professor Milan Profant (Slovak Republic) and Professor Margarita Salas (Spain).

Full details of personalia and activities at the Novartis Foundation can also be
found in the Foundation's 2001 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