Novartis Foundation Bulletin
Issue 24, March 2005
Welcome to the 24th edition of the Novartis Foundation's
electronic Bulletin.
This issue features reports on:
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Epithelial anion transport (NF273)
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Cannabis and ecstasy (DM 546)
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Cryopreserved follicles (NF265)
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Bursar's report (NF258)
(Based on presentations given at Novartis Foundation Symposium 273 'Epithelial anion transport in health and disease: the role of the SLC26 transporters in health and disease' held in London on 1-3 March 2005)
Meeting report by the proposer
Our understanding of
epithelial anion transport was greatly hampered by the lack of knowledge
of the molecular identity of the transporters that mediate luminal
chloride, bicarbonate, iodide, oxalate, formate and sulfate transport.
This was changed with the identification of the family of the SLC26A
transporters. Furthermore, identification of the family shed light on well
known human diseases and is very likely to impact on our understanding of
other diseases associated with aberrant anion transport that are not yet
associated with members of the SLC26A transporters family, such as cystic
fibrosis (CF).
The SLC26A is a new family of anion transporters that came of age in the
era of the genome. The founding member of the family, SLC26A1, was
identified by standard expression-cloning as a hepatic sulfate transporter
that we know now is expressed in multiple tissues. Soon afterwards the
gene mutated in chondrodysplasias was identified as SLC26A2, which was
followed by identification of
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SLC26A3, mutation of which causes congenital chloride diarrhoea
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SLC26A4, mutation in which results in Pendred syndrome and deafness; and
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SLC26A5, mutations in which are associated with non-syndromic hearing impairment.
Analysis of the human and mouse
genomes that followed resulted with identification of a total of 11 genes
that form the family.
Initial characterization of the transporters revealed that all transport
anions. Additional key findings were that many of the transporters are
expressed in the luminal membrane of various epithelial cells and that
they can transport several anions including chloride, bicarbonate, iodide,
oxalate, formate and sulfate. This allowed a new approach to understanding
cellular homeostasis of these anions in epithelial and non-epithelial
cells and led to a better understanding of the underlying mechanisms of
the associated diseases. Furthermore, characterization of chloride and
bicarbonate transport by several members of the family (SLC26A3, SLC26A4
and SLC26A6) solved a riddle that remained obscure for many years, which
is the molecular identity of the major luminal Cl-/HCO3- exchangers in
epithelia.
Understanding the physiological role of the SLC26A transporters is still
in its infancy, but significant strides are being made with the
development of mouse lines with mutations in SLC26A2, SLC26A3, SLC26A4,
SLC26A5 and SLC26A6 and characterization of the transport properties of
several members of the family. In addition to establishing their role in
specific functions associated with the diseases, gene deletions in mice
reveal unexpected roles of the transporters, such as a role for SLC26A4 in
renal acid-base transport and hypertension.
As we learn more about them, it is highly likely that the SLC26A
transporters will be found to be linked to other human diseases caused by
aberrant epithelial anion transport and fluid and electrolyte secretion.
Examples include chronic pancreatitis, reduced or lack of fertility, and
CF. This is exemplified in the case of CF in which organs that express the
protein mutated in CF, the Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR), absorb chloride and secrete copious amounts of
bicarbonate. It turns out that the SLC26A transporters interact with CFTR to
cause mutual activation of both transporters. The interaction is mediated
by the R domain of CFTR and the STAS domain present in the C terminal of
all SLC26A transporters. It would not be surprising to find that mutations in CFTR or the SLC26A transporters that perturb their
interaction are associated with CF or other diseases of epithelial
anion transport.
A recent Novartis Foundation symposium discussed the function of this new
family of anion transporters and highlighted the enormous potential that
they offer in understanding human disease and epithelial physiology.
Shmuel Muallem—Department of Physiology, University of Texas South Western Medical Center, Dallas, USA
The book on "Epithelial anion transport in health and disease: the role of the SLC26 transporters in health and disease" will be published by Wiley, Chichester in November 2005
(Based on contributions from a recent Novartis Foundation Discussion meeting on MDMA/Ecstasy: the human and animal research interface held in London on 3 December 2004)
Cannabis mix really does make you a dope
Students who regularly mix ecstasy and cannabis could be exposing themselves to an unforeseen risk: poor academic results. The real toll of ecstasy may not show up in brain scans but in students' grades, according to a Spanish study
“What does it mean to you in your life to consume these drugs? This is the important message to deliver,” Dr Rafael de la Torre, the leader of the study, said at a Novartis Foundation meeting last December.
Dr de la Torre’s team (Municipal Institute for Medical Research,
Barcelona) in Spain, followed 120 ecstasy and cannabis users over three years as they
attended university. Their preliminary results suggest that drug users attained half the performance of students in a control group who did not take drugs.
Ecstasy has been demonized as a brain-crippling drug. Yet the scientific camp remains divided about its impact: while few endorse the idea that the drug is harmless, there is no consensus on how dangerous it really is.
Ecstasy is taken by an estimated eight million people world-wide. Clubbers love it because it floods their brain with the mood-enhancing compound serotonin. The surge in serotonin induces feelings of euphoria. But this feel-good experience comes at a price, because ecstasy causes memory problems.
Brain imaging data from previous research suggested that people who stick to ecstasy alone have worse memory problems than those who combine it with cannabis or other drugs. Users were asked to perform short-term memory tests while in the brain scanner, and found that the activation patterns in the hippocampus area of the brain were altered to a greater extent in those using pure ecstasy compared with polydrug users.
Andy Parrott, at the University of Wales, Swansea, has found that people who use ecstasy and cannabis combined report higher positive moods and greater well-being, than those who take ecstasy by itself.
The explanation for this counter-intuitive finding could be that cannabis has an antioxidant effect, quenching the neurotoxic free radicals that are generated by ecstasy.
Dr de la Torre said that the combination of ecstasy and cannabis could affect users for the rest of their lives. He stressed that for a young person the prospect of failing to make the grade could act as the strongest deterrent yet.
Dr Lisa Melton—Science Writer, Novartis Foundation, London
Originally published in The Times Higher, January 28 2005
(Based on presentations given at Novartis Foundation Symposium 265, 'Stem cells: nuclear reprogramming and therapeutic applications' held in London, 2-4 March 2004)
Cryopreserved follicles
Around 6% of embryos created in the UK through in-vitro fertilization have been donated to research between 1991 and 2003. The fate of human IVF embryos is currently a hot topic of debate. Hundreds of thousands of cryopreserved balls of cells—potential human beings—exist across the globe, paused. The great majority of these will never become human beings.
IVF costs hopeful couples thousands of pounds with no guarantee of success. Every attempt generates a number of embryos which may be frozen for future use, donated to another infertile couple or used for research purposes. The fate of spare embryos is subject to the wishes of the couple, but also the policy of the clinic. Research on both viable and non-viable embryos has the potential
to help us better understand and treat a range of genetic diseases.
A recent Australian survey showed that only 30% of couples were willing to donate spare embryos to research. So we’re willing to wager huge resources on potential future generations, but not necessarily to share the leftovers with our neighbour. But are we really so selfish?
If people aren’t willing to donate embryos to scientific research, perhaps fear and uncertainty are more to blame than selfishness. To donate an embryo to a friend or family presents the couple with the possibility that their own flesh and blood be raised by strangers, or stranger still, close friends that have fertility problems. Donating embryos to scientific research provides couples with the opportunity to assist in the research of genetic disease. The decision rests on their perception of the embryo. Is the human born at the fertilized egg stage or the implantation stage?
Even if a couple is happy to donate to research, the policies of their clinic may stand in the way. In the USA, the fate of spare embryos is influenced by state law. There is no federal law against reproductive or therapeutic cloning, although there is no federal funding for such research. In some cases, where IVF clinics have offered the option for couples to donate spare embryos to scientific research, state law has not permitted this. What’s more, owing to the government’s position on reproductive cloning, all funding for embryonic stem-cell research must be acquired privately.
Spain provides an interesting example of people power on embryonic stem-cell research policy. Bernat Soria
(Miguel Hernandez University, Alicante, Spain) received a grant to research possible therapies for diabetes in the late
1990s. He was told that he could not use the money because he wanted to use stem cells from spare human embryos. So Bernat tried to arrange to do the research abroad, where regulations might permit the work. Meanwhile a pressure group consisting of diabetic patients managed to generate a petition against the ban on Soria’s work. Despite respected doctors and scientists’ appeals to the government the only thing that changed their policy was the prospect of losing 1.5 million votes.
So what will happen to these hundreds of thousands of spare embryos across the globe? A legal framework for their use is crucial to the scientific research of diseases with a genetic basis. Using embryonic stem cells to treat diabetes or Parkinson’s is preferable to using
islet cells from dead individuals or neurons from aborted
foetuses.
Brona McVittie—Assistant
Editor, Novartis Foundation, London
The Novartis Foundation’s latest book on
Stem
cells offers insights into the nature of stem cells, where they can be found, and what we can do with them. Read the revealing discussions between leading scientists in the field, including
• Ian Wilmut (Roslin Institute, Scotland), head of the team that created Dolly
• John Gurdon (Welcome Trust/Cancer Research UK, Cambridge)
who developed the technology underlying cloning
• Rudolf Jaenisch (Whitehead Institute, Cambridge, MA),
pioneer of mouse models of human disease
• Irving Weissman (Stanford University Medical Center, USA),
pioneer in stem-cell generation
• Davor Solter (Max Planck Institute of Immunobiology, Germany),
pioneer of gene imprinting
• Martin Evans (Cardiff School of Biosciences, UK),
who first demonstrated gene therapeutic cure of the deficit in Cystic Fibrosis in the whole animal
This book was published by Wiley, Chichester, in March 2005
(Based on presentations given at Novartis Foundation Symposium 258, 'Mammalian TRP channels as molecular targets', held in London on 25-27 March 2003)
Bursar's report
In January 2003 I was awarded a Novartis Foundation symposium bursary for the ‘Mammalian TRP channels as molecular targets’ meeting in March later that year, in London. On this small-scale symposium the crème de la crème of the TRP ion channel research field was present, giving me an excellent opportunity to mingle with the big shots, whom I only knew by name from their publications.
The meeting itself was an excellent example of how a truly informative meeting should be organized. A thirty minute talk was followed by an even more thorough discussion of the same length, making it possible to get to the bottom of things in an efficient manner. Thus, all the main issues and controversies in the TRP field were discussed without (obvious) reservations, making this the most informative and rewarding meeting in my field I ever attended to date.
Also, the mix of academic researchers and people from private research and development facilities, such as Novartis and Glaxo-Smithkline, provided a great opportunity to point to the different needs and urges these two groups of researchers have, and how they could be better aligned to each other. The atmosphere at the meeting was quite relaxed, leaving room for humour during the talks, and friendly conversations at the breakfast, lunch and dinner table. I was absolutely honored to be part of this meeting, since this was the kind of atmosphere among top-researchers you rarely are able to experience, being a relative fresh-man like myself.
The bursary period which was included in the scholarship I received, I’ve taken up at the lab of Professor Bernd Nilius in Leuven, Belgium in the fall of 2004. Bernd Nilius is one of the world leaders in the electrophysiological characterization of members of the TRP family of ion channels. I went to this lab planning to characterize ionic currents in isolated primary cells from transgenic mice using the patch-clamp technique and Fura-2 imaging. Overall, I may say that my stay was quite successful. The data gathered in this period are currently being used as a starting point to further characterize the phenotype of the transgenic mice in question, which I hope to report on in a publication in the summer of 2005.
Working in this lab was a really exciting experience. Bernd Nilius is a very inspiring man, with an infectious enthusiasm. The chemistry between him and his co-workers creates in this lab a swirling drive which I’ve rarely experienced. Thus, I have to admit that I’ve seldom worked in a more efficient manner than these two months I’ve spent in Leuven. And furthermore, Leuven is a really great city, with beautifully restored 15th century buildings. Definitely worth a visit in a summer weekend!
I would like to thank the Novartis Foundation for their generous support during my stay in Leuven, and for giving me the chance to be part of a top-class scientific meeting. Especially, I would like to mention Ms. Allyson Brown, the bursary scheme administrator at the Novartis Foundation, who patiently guided me through all the practical issues concerning this trip.
Rudi Vennekens—Institut fur
Pharmakologie und Toxikologie, Universitat des Saarlandes, Hamburg,
Germany
Mammalian TRP channels was published by Wiley, Chichester, in March 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 'Heart failure: molecules,
mechanisms and therapeutic targets' will take place on 29 April 2005 at
The Geological Society, London W1 in collaboration with the RSM and
PhysSoc.
To book your place at the meeting please register
here by 22nd April, or contact Sharan
Gallagher at the Royal Society of Medicine, Academic Conference
Department, 1 Wimpole Street, London, W1G 0AE:
Tel: +44 (0) 20 7290 3946
Fax: +44 (0) 20 7290 2977
email: events@rsm.ac.uk
Website: http://www.rsm.ac.uk
Other forthcoming open meetings include:
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Understanding nicotine and tobacco addiction (20 May 2005)
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 1-3 March entitled 'Epithelial
anion transport in health and disease: the role of SLC26 transporter
family'. Chaired by Michael Welsh, Howard Hughes Medical Institute,
Iowa, USA.
Discussion meetings:
The next discussion meetings to take place are:
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Sex determinants of pain: myth versus reality and implications for therapies Mon/Tues 4/5 Apr
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Insights into evolution from post-genomics bioinformatics Weds 6 Apr
Publications
We are pleased to announce the publication over the last few months of:
Nuclear
organization in development and disease
(Novartis Foundation Symposium 264)
Stem
cells: nuclear reprogramming and therapeutic applications
(Novartis Foundation Symposium 265)
For details of this, and other recently published books and how to order see:
http://www.novartisfound.org.uk/nbook.htm
Book Sale 2005
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
Dr Lisa Melton, in-house science writer has recently published:
'There's more to heredity than
genes' in The Mill Hill Essays 2004
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
2005 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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