Novartis Foundation Bulletin
Issue 30, May 2007
Welcome to the 30th edition of the Novartis Foundation's e-mail Bulletin.
This issue features reports on:
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Chinese medicine goes West by Lisa Melton
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Nicotine - good, bad or ugly? by Lisa Melton
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Bursar's report by Thomas Sanger
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Bursar's report by Matthew Sabin
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Bursar's report by Derek Hausenloy
News from the Foundation
Chinese medicine goes West
By Dr Lisa Melton, Science Writer in residence at the Novartis Foundation, London
Western medicine has a long history of pharmacological prospecting from nature. And as pharma companies face shrinking pipelines and a dearth of new compounds, Chinese medicine has emerged as an invaluable source for drug discovery.
Singaporean scientist Eu Leong Yong, whose aim it is to find a herbal treatment for menopausal symptoms, has selected the ‘fine wine’ approach to ethnomedicines. “Take a bottle of Chatęau Lafitte and you can track its history, the content of tannins and alcohol: you can be confident of its quality. We want the same thing for our product.”
Yong’s exploration began seven years ago with Epimedium, a ubiquitous plant used in Asia for millennia. “Right now, the recommendation for women is no hormone replacement therapy, there are limited options” says Yong, a gynaecologist and researcher at Singapore’s National University Hospital. “Many women turn to botanical alternatives without proof of safety and efficacy.”
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Yu Leong Yong (second from left) with other symposium participants at the Novartis Foundation in London. |
In traditional chinese medicine, Epimedium is considered an aphrodisiac and internet sites advertise it as herbal ‘Viagra’. Its colloquial name is ‘horny goat’s weed’ because, it is said, male goats grazing on the herb display excessive copulating behaviours.
At first, Yong was reluctant to pursue this line of research. “I wasn’t a believer in herbs, but one of my postdocs was,” he told fellow investigators gathered at a Novartis Foundation symposium London (9-11 May 2006). Nonetheless, he encouraged the young scientist to test alcohol extracts from boiled, raw leaves on cultured cells. To his surprise, the Epimedium extract was strongly estrogenic. In cell-based assays, and in rats, the botanical preparation was as potent as estradiol itself.
Yong has now recruited a team of chemists to elucidate which compounds are doing the job. The active principal, a novel prenyl-flavone – breviflavone B, has certain similarities with other phytoestrogens. But prenyl-flavone stands out because while the isoflavone genistein from soy fails to be absorbed from the gut, the prenyl group in breviflavone B encourages its uptake into the bloodstream.
In human studies, however, the extracts have been disappointing. Improving the purification methods could improve results, Yong believes. “There is a need for blending, just like wines, to get a standardised extract”.
Epimedium is currently sold to consumers in dozens of different preparations. Because plants are harvested in the wild, lack of standardisation is a huge problem. Even in China, the material on sale is not taxonomically defined, and is frequently a mixture of species of low quality.
Yong is determined to upgrade this herb formulation to the standards expected in Western medicine. He has applied genetic and chemical profiling to classify Epimedium and is currently working with commercial partners to grow, harvest and process this herb under rigorous conditions. “We want the consumer who takes it to know it is like aspirin: a thoroughly understood product,” he adds.
Based on presentations given at the Novartis Foundation symposium 282 ‘Dietary supplements and health’ held in London, May 9–11, 2006.
The full article ‘Chinese Medicine goes West’ appears in the May issue of Chemistry World.
Nicotine—good, bad or ugly?
By Dr Lisa Melton, Science Writer in residence at the Novartis Foundation, London
In the beginning, when the assault on smoking began in earnest, it all seemed rather simple. If nicotine is the demon driving tobacco smoking, giving smokers a nicotine fix should keep their hands off the pack. Yet it is 30 years since the first nicotine gum was developed in Sweden and the road to a cigarette-free life is still littered with broken resolves and people smoking themselves to an early grave.
“One billion people around the world are doing something that, if they keep at it, will kill half of them,” said Sir Richard Peto, Professor of Medical Statistics and Epidemiology at the University of Oxford at a Novartis Foundation symposium in May 2005, Peto exhorted researchers and pharmaceutical companies to develop smoking cessation compounds to cut tobacco deaths. “There is a desperate need for treatments that work,” he insisted.
Smoking is an astonishingly hard habit to break. But if people smoke for nicotine, why are nicotine replacement therapies not more effective? The problem is that people dislike nicotine replacement therapy, though nobody is quite sure why. Perhaps the products are too slow to provide the nicotine rush they crave, or the strongly-worded labelling on the packages may be off-putting. “There is a horror reaction to nicotine, a feeling it is evil,” says Peter Hajek, Professor of Clinical Psychology at the Wolfson Institute of Preventive Medicine, London.
“We now know that for a smoker, nicotine in nicotine replacement products is absolutely safe, probably no more dangerous than drinking tea or coffee,” Hajek remarks. A more liberal use of nicotine replacement therapy, in combination, and at higher doses as recently licensed, is good news.
But David Balfour challenges the idea that nicotine alone explains why people become so highly addicted to tobacco smoke. “Nicotine alone is not a powerfully addictive compound,” explains Balfour, who is Professor of Behavioural Pharmacology at Ninewells Hospital and Medical School in Dundee, Scotland. Nobody gets ‘high’ on nicotine as they do with other common drugs of abuse. “What smokers seem to find pleasurable is the act of smoking itself, not necessarily the drug,” he explains.
Under nicotine’s spell, Balfour argues, everything a person does becomes more pleasurable. Within seconds of puffing on a cigarette, nicotine enters the brain. Acting through nicotinic receptors, it triggers a dopamine overflow in the nucleus accumbens region of the brain. Dopamine lingers and remains elevated for 30 to 60 minutes, enhancing the pleasure from every act a person engages in during that time.
So while taking nicotine helps soften withdrawal symptoms, it cannot replace the pleasure conjured up by the act of smoking a cigarette. “Somehow you have to tackle those pathways in the brain associated with behaviour to help the person quit,” says Balfour.
It may be the cigarette itself which is keeping people addicted. The irritants in smoke seem to be pleasurable and drive people to light up. A nicotine-free cigarette could be the answer. Research by Jed Rose at the University of Nebraska-Lincoln has found that smoking nicotine-free cigarettes has a rewarding value. Coupling these nicotine-free cigarettes with nicotine patches, disassociating both sources of pleasure, could be the ultimate anti-smoking strategy, some scientists believe.
‘Understanding Nicotine and Tobacco Addiction’ is published by John Wiley & Sons, 2006, Novartis Foundation symposium 275.
Bursar's report: Thomas Sanger
Washington University in St. Louis, USA.
(Bursar from Novartis Foundation Symposium 284 ‘Tinkering: mechanisms of micro-evolution’ held in London 11–13 July 2006.)
As a graduate student studying the developmental mechanisms underlying morphological evolution, the historical division of evolutionary and developmental biology often presents a significant and seemingly unnecessary obstacle to my work. On the one hand, developmental biologists have long relied on a limited number of model systems to finely dissect characters readily amenable to laboratory analyses. On the other hand, evolutionary biologists have focused on populations or groups of species exhibiting great ecological or morphological diversity. In a sense, developmental biologists have focused on character in the absence of the environment, while evolutionary biologists have focused on the organism and how it functions in the environment. With such a division, how can one go about studying ecologically relevant morphological variation in non-model systems in the context of the population? It is through symposia such as this, which bring together molecular, developmental, and evolutionary biologists that the conclusive re-synthesis of these disciplines is being forged and challenges such as these are becoming surmountable in many new and exciting systems.
While the speakers at this symposium came with a wide breadth of research interests, from statistical genetics to molecular biology to paleontology, discussions were generally centred on understanding how morphology evolves within and between closely related species. Tinkering, as suggested in the symposium title, became the unifying theme, though oddly the phrase was used to refer to both the pattern of evolutionary change and the processes by which this change occurs. Rather than slowing the conversation, this difference added additional energy to discussions aimed at uniting stories of ultimate causation, historical or evolutionary causation, with changes in a character’s development, or the proximate causation. Discussions such as these, while not novel on the surface, are a major advancement for Evolutionary Developmental Biology, which is undergoing a paradigm shift from solely addressing the “what happened” questions to the “how did it happen” questions. It is through the elimination of our historical reliance on model systems and re-focusing our attention on the microevolutionary processes influencing the ebb and flow of morphological variation that this paradigm shift is possible.
The focus of my research is aimed at understanding the developmental mechanisms underlying limb length variation in Caribbean Anolis lizards. I work closely with Drs. Jim Cheverud of Washington University in St. Louis and Jonathan Losos of Harvard University to combine quantitative and phylogenetic techniques with laboratory studies of the lizard’s skeletal growth and development. The large community of anole biologists focusing on the evolutionary biology and ecology of this group make it an ideal system for such a union because my developmental studies can easily be placed back into the context of the species’ natural history. Such systems are rare but provide the best opportunity to understand how genetic variation within a population translates to morphological variation within and between closely related species. Another unique species where a synthetic approach is possible is the Alaskan three-spine stickleback, which I chose to study for my bursary period with Dr. Mike Bell of SUNY Stony Brook.
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Mike Bell (host) and Thomas Sanger (bursar) at symposium 284 Tinkering: mechanisms of micro-evolution.. |
Associated with glacial recession, the three-spine stickleback has repeatedly invaded freshwater habitats from its ancestral saltwater environment. After several thousand years of evolution, these invasions are now a dream for biologists. Hundreds of freshwater lakes serve as natural experiments from which one can study the effects of many environmental factors on the stickleback’s biology. One such transition that has been extensively studied by developmental biologists is the reduction of lateral plates and pelvic armour associated with the loss of predatory fish in freshwater environments. Changes in the expression of a single gene have been shown to correlate with the loss of pelvic armour in many lakes, however, due to experimental limitations, not much attention has been given to the relationship of variation within and between lakes. As part of my bursary, I examined this relationship by quantifying expression levels of the genes thought to be involved in the development of pelvic armour. Can variation within and between lakes simply be explained by slight differences in the expression of major genes or are many different genes of small effect used to reach the same end point?
This is an exciting time to be embarking upon my career as an evolutionary developmental biologist. Technological advances in both evolutionary and developmental biology now make it feasible to actually study the mechanisms by which morphology evolves and diversifies. It is becoming possible to relate adaptive differences between closely related species to specific changes at the molecular level. In my opinion, innovative interdisciplinary meetings such as this will pave the way for further advances in these directions. Interactions with other symposium participants and colleagues during my bursary period have been quite influential on my career; I am grateful to the organizers and the Novartis Foundation for the remarkable opportunities that have been provided to me.
Bursar's report: Matthew Sabin
University of Bristol, UK and the Royal Children’s Hospital & Murdoch Childrens Research Institute, Melbourne, Australia
(Bursar from Novartis Foundation Symposium 286 ‘Fatty acids and lipotoxicity in obesity and diabetes', held in Beijing, China, 17–19 October 2006.)
I am extremely grateful to the Novartis Foundation for awarding me a bursary to attend this first-class symposium in Beijing. Having recently completed a PhD examining the role of fatty acids in childhood obesity and their link with type 2 diabetes (funded through a Diabetes UK Clinical Training Fellowship), the meeting was an extraordinary opportunity to listen, and talk, to world leaders in this field.
The format of the meeting was new to me, with such a small group of experts and a theme that was based more on general discussion than formal presentations, and I was surprised at the enormous benefits that this format allows. Furthermore, as I had recently read the latest literature on the subject for my PhD, it was inspiring to learn of up-to-date research findings from these world-leading research groups, and also listen to the subsequent interactive discussions that appear to steer the direction of future scientific progress.
I learnt an enormous amount from many individuals and I am extremely grateful to the organisers, and other attendees, for sharing some of their insight and knowledge with me. Specifically, I would like to thank Professors Paul Black and David Bernlohr for providing me with detailed knowledge relating to fatty acid dosing and cellular transport—an area specific to my PhD. I hope that my discussions with Professor Black will lead to a future, mutually-beneficial, collaboration.
Beijing proved to be a fascinating city to visit and specific thanks go to Professor Peng Li and Wu Cong Yang of Tsinghua University for a fabulous social program and an excellent post-symposium tour of Xi’an.
Following the symposium, and as part of the bursary scheme, the Novartis Foundation then allowed me to visit the department of Professor Stephen O’Rahilly at Addenbrooke’s Hospital (Cambridge, UK). Professor O’Rahilly and Dr Sadaf Farooqi are world leaders in the investigation of the genetics of severe obesity and mechanisms of insulin resistance, and their work in this area has been of particular interest to me for some time. I am extremely grateful to them both for their time and efforts in teaching me specific aspects relating to this research field—something, which I hope in years to come, will fit well with my developing research themes.
During my time at Cambridge I learnt an incredible amount, specifically relating to the techniques of gene expression profiling, the mechanisms of CNS sensing of nutrients and satiety, and the pathological processes that may underpin the development of insulin resistance in lipodystrophic states. I also heard about cutting-edge research techniques, such as Functional MRI, which will undoubtedly be used more in the future and that will certainly improve our knowledge of nutrient and satiety signalling in the brain. This may well lead to the development of specific therapies for obesity and consequent type II diabetes in the future.
I then travelled with Professor O’Rahilly and Dr Farooqi to the Diabetes UK Annual Professional Conference, where Professor O’Rahilly gave the Rank Nutrition Lecture and Dr Farooqi presented the 2007 RD Lawrence Lecture. This gave me a particular insight into how parallel projects in a single laboratory, by very many people, could be brought together into a common theme that, at an international scientific level, was truly inspirational.
My time at Cambridge was further rewarded by being able to learn of other projects that are in development that may, in the future, perhaps allow me the opportunity of either working with, or at least collaborating with, other research workers there.
In summary, I am extremely grateful to the Novartis Foundation for granting me such a valuable opportunity. I am certain that my bursary period has improved the way that I think about research questions and will help me in years to come in the way that I plan, and conduct, my own research in this evolving area.
Bursar's report: Derek Hausenloy
The Hatter Cardiovascular Institute, University College Hospital, London, UK.
(Bursar from Novartis Foundation Symposium 287 ‘New perspectives on mitochondrial biology', held in London, 28–30 November 2006.)
I would like to begin by first expressing my extreme gratitude to the Novartis Foundation for awarding me the bursary, which not only enabled me to attend a fascinating symposium, but also provided the opportunity for me to spend three months undertaking research in a world famous laboratory in Italy. I was fortunate to attend the Symposium entitled New Perspectives on Mitochondrial Biology at the end of November 2006. This meeting assembled the world’s leading experts in the field of mitochondrial biology to discuss, amongst other topics, the exciting subject of mitochondrial morphology, in which mitochondria as dynamic organelles are able to fragment (fission) and elongate (fusion) under the direct control of specific mitochondrial fission and fusion proteins according to the cell’s requirements. Uniquely, the organizational structure of the meeting facilitated in-depth discussion which was both intellectually stimulating and informative to a young researcher like myself.
My particular research interest lies with protecting the myocardium from ischaemia-reperfusion injury using the cardioprotective strategies of ischaemic preconditioning and postconditioning. Much of my research has focused on the pivotal role mitochondria play in myocardial protection in these settings. I was therefore extremely pleased to be given the opportunity to spend 3 months investigating mitochondrial morphology in the context of ischaemia-reperfusion injury in one of the world’s leading laboratories, situated in the beautiful Italian university city of Padova, at the Venetian Institute of Molecular Medicine (VIMM) under the tutorage of Dr Luca Scorrano.
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Luca Scorrano (host) and Derek Hausenloy (bursar) at symposium 287 New perspectives on mitochondrial biology. |
Dr Scorrano’s laboratory has led the field in mitochondrial morphology, examining mitochondrial dynamics in the context of apoptotic cell death and mitochondrial cristae restructuring. Preliminary work undertaken during my stay in Padova examined the role of Akt (a protein kinase linked to cardioprotection) on changes in mitochondrial morphology. Specifically, our preliminary data suggest that over-expressing Akt may favour mitochondrial elongation or fusion, which may contribute to the cardioprotective effect of Akt. Further ongoing collaborative work will be undertaken back at UCL in my own laboratory to investigate this relationship in more depth. In addition, I plan to investigate the role of mitochondrial dynamics in the setting of myocardial ischaemia reperfusion injury using techniques acquired whilst in Padova. Apart from the obvious academic benefits obtained from working in a reputable overseas laboratory, my experience was wholly enriched both culturally and socially from living and working in Italy.
I would like to thank Dr Luca Scorrano and all the members of his laboratory as well as the other research workers at the VIMM, who were extremely accommodating during my brief stay in Padova. Finally, I would like to commend the Novartis Foundation for providing the opportunity for young scientists to experience undertaking research abroad in world renowned laboratories.
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 symposium participants. Applicants (of any nationality) must be aged 25-35 years of age 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.
We are currently accepting applications for the following bursary:
No.
293: Understanding how gene-environment interactions work to predict
disorder: a life course approach
(7)
8-9 November 2007
Closing
date for applications: 1 August 2007
For details of the bursary scheme see http://www.novartisfound.org.uk/bursary.htm or contact the bursary scheme administrator: bursary@novartisfound.org.uk.
News from the Foundation
The 2006 Director's Report can be found on the Novartis Foundation website.
Symposia:
Three
symposia have taken place since the last bulletin. The most recent, Novel
and re-emerging respiratory viral diseases (symposium 290), took place at
in Singapore in collaboration with the Institute of Molecular and Cell
Biology. The meeting took place on 23–25 April and was chaired by Robert
Webster of the St. Jude Children's Research Hospital in Memphis, USA.
Growth factors and psychiatric disorders (symposium 289) was held at the Novartis Foundation in London on 20–22 March. The chair was Moses Chao of the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, USA.
Cortical development: genes and genetic abnormalities (symposium 288) was held at the Novartis Foundation in London on 6–8 February. The chair was John Parnavelas of University College London, UK.
Discussion
meetings:
The
next discussion meetings to take place are:
20
June 2007 The
evolution of the animals: a Linnean tercentenary celebration
Novartis
Foundation/Royal Society Discussion Meeting
Organizer:
Dr Max Telford
20
September 2007 Origin
and differentiation of the Earth: past to present
Novartis
Foundation/Royal Society Discussion Meeting
Organizer:
Professor Andrew Jephcoat
Publications
We
are pleased to announce the publication over the last few months of:
Sepsis
- new insights, new therapies
(Novartis
Foundation Symposium 280)
Published January
2007
Decoding
the genomic control of immune reactions
(Novartis
Foundation Symposium 281)
Published March 2007
Acetaldehyde-related
pathology: bridging the trans-disciplinary divide
(Novartis
Foundation Symposium 285)
Published April 2007
For details of this, and other recently published books and how to order see: http://www.novartisfound.org.uk/nbook.htm.
Book
sale
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 or email: bulletin@novartisfound.org.uk.
Publicity
‘What’s your poison? Could the damage wreaked by alcohol, tobacco, pollution, and a bad diet all be caused by the same little molecule, asks Lisa Melton’, published in New Scientist, 12 February 2007, based on symposium 285 Acetaldehyde-related pathology: bridging the trans-disciplinary divide.
‘Millionaires from antibody research: Lisa Melton finds how a Manchester husband and wife team tackled infectious diseases’, published in The Times, 19 March 2007 (section on investing in North West England).
‘A hothouse of medical research: Lisa Melton reports on the fruits of the region’s successful campaign to woo biotech firms’, published in The Times, 19 March 2007 (section on investing in North West England).
‘New formula for fit future. Baby food offering lifetime protection against obesity could be in the supermarket soon.’ by Dr Lisa Melton, in Chemistry & Industry, 23 April 2007, page 6. News.
‘Fat prophets. With over half the adult population in the developed world either overweight or obese, the search for lucrative fat-fighting drugs is gaining speed’ by Dr Lisa Melton, in Chemistry & Industry, 23 April, pps 18-20 and http://www.chemistryandindustry.com.
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
be found in the Foundation's 2007 Annual report and handbook.
If you would like to receive a copy of the 2007 handbook (available from June), please send an email including postal details to: bulletin@novartisfound.org.uk.