Novartis Foundation Bulletin
Issue 31, September 2007
Welcome to the 31st edition of the Novartis Foundation's e-mail Bulletin.
For a print version of this issue (PDF, 760 kb) please click here.
This issue features reports on:
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Fat'll fix it by Lisa Melton
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Bursar's report by Anny Fortin
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Bursar's report by Sophie Tambour
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Bursar's report by Gaëlle Friocourt
News from the Foundation
By Dr Lisa Melton, Science Writer in residence at the Novartis Foundation, London
Bulging bellies and oversized bodies, fat has become a national emergency. Yet a growing number of scientists are insisting that we should see fat as a great natural resource, one that could become the ultimate body repair kit.
Fat is rich in stem cells, and these can be coerced to grow into bone, cartilage, muscle or nerve cells. Scientists are upbeat, they predict doctors may soon be siphoning out a patient’s own fat to regenerate and repair tissues damaged by disease. Who could have imagined that the much maligned fat would become one of the hottest areas in regenerative medicine?
“Fat tissue is an underappreciated source of stem cells,” says Philippe Collas from the University of Oslo in Norway. Fat is plentiful and easy to harvest. Scores of people undergo liposuction from their buttocks, thighs and bellies to improve their looks. They are glad to get rid of the extra body fat and researchers like Collas are more than happy to take it. “It’s wonderful. We have bucketfuls of material to work with, litres and litres of liposuctioned fat.”
Researchers separate the cells trapped in the slurry by a combination of centrifugation and enzymatic treatment, no manipulation or culture necessary. The result is a precious mix of adult stem cells perfectly compatible with the donor’s tissue type, a practical source for transplants and therapy. Enthusiasts like Collas see these multitalented cells spawning a medical revolution, treating everything from Parkinson’s disease, heart attacks and bone defects, to ailing livers.
Once scientists fully understand what adipose stem cells are doing and how to manipulate them, what is now the beauty industry’s waste could become a cure for many of humanity’s ills. Far-fetched and unduly optimistic? Not necessarily. The research is moving fast. A growing number of labs and biotechnology companies are already exploiting the potential of these adult stem cells lurking in fat.
Fat blood
One group has harnessed the potential of fat-derived stem cells to heal fistulas in Crohn’s disease patients who failed to respond to any other treatment. A Spanish team injected adipose stem cells into the fistulas of 40 patients with spectacular results. The stem cells healed 71 % of patients compared
with only 4 % treated with the standard fibrin glue. Phase III trials have already begun. (Garcia-Olmo D et al 2003 Int J Colorectal Dis 18:451-454).
For patients undergoing intensive radiation therapy for cancer, cells plucked from fat could offer a source of life-saving blood stem cells for transplants. At a recent meeting (June 2007) of the Tissue Engineering and Regenerative Medicine International Society, Albert Donnenberg from the University of Pittsburgh School of Medicine reported they had made blood stem cells from human adipose tissue. The researchers took cells from fat and fed them a cocktail of bone marrow nutrients. The result was a variety of blood cells, including progenitor cells, which could serve as an alternative to bone marrow.
Fat tissue may also provide a source of muscle cells to treat diseases of the heart, gut and bladder. Researchers at the University of California Los Angeles Medical School (Rodriguez L et al 2006 PNAS 103:12167-72) reported that incubating adipose-derived stem cells with a mixture of growth factors produced cells that contracted and relaxed just like smooth muscle cells. Stem cell therapy also holds enormous hope for people who need new livers. Nagy Habib, head of liver surgery at London’s Hammersmith Hospital, is testing adipose stem cells to regenerate cirrhotic livers.
Fat skulls
Fat-derived stem cells could also rebuild bone. A team led by Michael Longaker at Stanford University, California has shown that injecting adipose-derived stem cells into mice combined with a microscopic scaffold could heal a skull fracture too large to mend by itself (Cowan CM et al 2004 Nat Biotechnol 22:560-7). And in a recent case report from Germany, a seven-year-old girl who had suffered a massive head injury had her skull repaired with a dose of adipose stem cells. In three months, a mix of bone cells supplemented with adipose cells led to new bone growth to cover a large defect.
A new bioengineered cartilage seeded with fat cells could refurbish or replace joints ravaged by age or disease, says Farshid Guilak, an orthopaedic researcher at Duke University. “The idea is to remove a bit of fat, isolate the cells, and grow them on a 3-D scaffold.” The custom-made prosthesis could replace missing cartilage or a whole joint. Guilak notes: “We don’t have a satisfactory remedy for people who suffer a cartilage-damaging injury and arthritis.” So far, the Duke researcher has tested this procedure in animals. Much additional work is needed before it can become available to patients. But Guilak is optimistic that one day this technique will become the treatment of choice for total hip and knee replacements.
Fat futures
Can fat-derived stem cells turn into every cell type to treat diseases such as Parkinson’s, diabetes and heart failure? Some say it is impossible to re-programme adult cells to become nerve cells, for example, without using embryos. Adult stem cells, such as those from fat, are thought to have more limited potential. But Collas insists that the transformation is possible. The hurdle lies not with the genes but with a cell’s epigenetic status, the subtle chemical modifications of DNA and its surrounding histone proteins.
Epigenetic marks contribute to switching genes on and off, and stem cells rely on them heavily as they divide and mature into different types of cells. The Oslo team has found that low rates of DNA methylation, for instance, boost the chances of transforming fat stem cells from one cell type into another. “Look at a cell’s epigenetic profile,” says Collas, “and you may be able to predict what that cell is likely to turn into.” Newly licensed medications that manipulate these epigenetic tags are already on the market for treating cancer and autoimmune diseases and could be used to manipulate adipose stem cells.
Even more appealing is the idea that to reprogramme fat stem cells all it takes is to expose them to the right tissue. Collas suspects that for adipose stem cells it is a case of location, location, location. They are so malleable that simply placing them in a certain environment may encourage them to take on the job of the surrounding cells. This is a key question which his lab is currently pursuing.
These epigenetic signatures on stem cells have grabbed everyone’s attention, acknowledges Ernest Arenas, from the Karolinska Institute in Stockholm, Sweden. “Scientists in the stem cell field are starting to realise that for cell manipulations to succeed they need to pay attention to their epigenetic marks. Cells can’t be pushed along to become a different cell type unless they start out with the right set of [epigenetic] conditions.”
People may soon be visiting plastic surgeons not just for aesthetic reasons, but for therapy too. In the US, several companies have been set up to allow clients to bank stem cells recovered from liposuction for future use. And since adipose stem cells taken from a young body work best, indulging in some cosmetic liposuction may not be such a bad idea.
The full article appears in Chemistry & Industry, 30 July 2007, page 19-21.
Bursar's report: Anny Fortin
Emerillon Therapeutics, Montreal, Canada
(Bursar from Novartis Foundation Symposium 281 'Decoding the genomic control of immune reactions' held at the Australian National University in Canberra, Australia, 7–9 March 2006).
Even though the trip from Montreal to Canberra seemed outrageously long to me, it was a tremendous experience to participate in the Novartis Foundation Symposium No.281 'Decoding the genomic control of immune reactions’. I am deeply thankful to the Novartis Foundation for giving me the unique opportunity to exchange knowledge with well established scientists working in the field of genetic immunology. I was particularly pleased with the intimate format of the meeting, which I believe facilitated the discussions and created a nice cohesion within the group of participants. In addition, I would like to acknowledge Dr Christopher C. Goodnow for preparing and chairing this interesting symposium.
Following the meeting, I spent a 4 week bursary period in the laboratory of Dr Jean-Laurent Casanova in Paris, becoming a member of his energetic research team. As my mother tongue is French, my integration to his lab was relatively easy, even though my French-Canadian accent sometimes caused difficulties, or amusement depending on the situation.
Dr Casanova runs the kind of laboratory where the coffee is ultra strong, and where space and equipment are always an issue: when I got to the lab, someone had to literally dig out a piece of bench for me, in front of a window, removing piles of papers, old pieces of dusty equipment and remains from numerous past lab members. The space, which was a bit hot and sunny in the morning, was nevertheless excellent because of its very nice view of the city. As soon as I started working, I realized that clearly identifying every item of my belongings was very important … not that it prevented people taking things away, but at least I was able to find them. One morning, someone even disappeared with my stool (which of course was not properly identified)! It took me half a day to steal another one….I saw this as a sign of good integration.
As well as being an excellent scientist, I discovered that Dr Casanova is a real intellectual and has great spirit. I felt particularly privileged to be able to spend time with him discussing science, in detail and in general, despite his busy schedule. In fact, during my short stay in his lab, Dr Casanova travelled back and forth to Vienna and Japan! In addition, he gave a TV interview right beside my bench (the clean lab space with the nice view of the city!), and he always looked fresh and was enthusiastic about his project. This was a really inspiring experience!
Research Conducted
Mendelian susceptibility to mycobacterial diseases (MSMD) is defined by the development of severe clinical conditions upon infection with weakly virulent mycobacterial species, such as BCG vaccine and
non-tuberculous, environmental mycobacteria (EM). Severe disease caused by Salmonella is also common in MSMD patients and is observed in nearly half the cases. Using a candidate gene based approach, the laboratory of
Dr Casanova has undertaken the identification of genes responsible for MSMD since 1994.
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(Top) Transmission electron micrograph
(TEM) of Mycobacterium tuberculosis bacilli, the causative
agent for tuberculosis. Image courtesy of CDC
/ Elizabeth
"Libby" White.
(Botton) Scanning
electron micrograph (SEM) of four Salmonella infantis bacteria.
Image courtesy of CDC
/
Janice Carr. Both images are in the public domain. |
The studies of Dr Casanova have identified IFNγR1 deficiency as one of the most common etiologies of MSMD (~39% of MSMD patients with a genetic lesion), and several mutations leading to recessive or dominant forms of IFNγR1 deficiency were identified in MSMD patients. Of particular interest was the identification of a small deletion hotspot localized within the intracellular portion of the receptor and associated with dominant susceptibility to mycobacterial infection. These patients are generally susceptible to BCG and EM, but infections with rapidly growing bacteria are rarely seen. A diagnosis of mycobacterial osteomyelitis is often associated with the dominant form of IFNγR1 deficiency.
Over the course of his research, Dr Casanova has accumulated patients with a series of different deletions across the intracellular domain of the IFNγR1 gene, including several with the 818del4 mutation, which is the most frequent deletion in the receptor. The objective of my research project was to culture transformed B-cells expressing the different mutant forms of the receptor in parallel, and compare their level of cell surface expression of the receptor, as well as their capacity to respond to IFNγ and INFα stimulation by the nuclear translocation of the STAT1 transcription factor. In parallel to this work, I was also in charge of retrieving the clinical information related to the different patients in order to get a general overview of their clinical phenotype, with the aim of correlating this with the severity of the cellular phenotype.
Overall, my results suggested that the different patients did differ with respect to both cell surface expression of the receptor and level of response to IFNγ and INFα stimulation. Patients were stratified according to their clinical phenotype using the following criteria: 1) status of BCG vaccination, 2) incidence and severity of BCG vaccination related infection and 3) onset, severity and nature of infection with EM. Based on the overall analysis, behaviour of the mutants could not be predicted by the position of the deletion, nor could the cellular phenotype be correlated with the clinical phenotype; however the number of patients per category was too low to make solid conclusions, and additional patients need to be collected.
In addition to the technical expertise I gained during my bursary period, my time in the lab of Dr Casanova gave me the opportunity to develop a new network of personal and professional contacts on which I subsequently capitalized. One such opportunity was to write a review on the host genetics of mycobacterial diseases in mouse models and in humans. This project was successfully performed in collaboration with Dr Jean-Laurent Casanova, Dr Laurent Abel, and Dr Philippe Gros, and the manuscript was recently published (Fortin A 2007 Annu Rev Genomics Hum Gene 8:163-192). Following my bursary period, I have maintained an active relationship with Dr Casanova; I recently undertook a new collaboration with him aiming to identify novel genes involved in MSMD. I am also in contact with Dr Chris Goodnow, and I am working on the development of an ENU-mutant screening effort for which he has contributed by giving expert advice. In summary, my participation at the symposium was very beneficial to the development of my research career, and I had an amazing time in Paris!
Acknowledgements
I would like to acknowledge Ariane Chapgier for valuable collaboration and supervision throughout my bursary period. I am grateful to Jean-Laurent Casanova, Laurent Abel and all their lab members for continuous friendship and support.
Bursar's report: Sophie Tambour
Département des Sciences Cognitives, University of Liege, Belgium
(Bursar from Novartis Foundation Symposium 285 ‘Acetaldehyde-related pathology: bridging the trans-disciplinary divide’, held in London, 5–7 September 2006.)
I was very happy to be selected to attend the Novartis Foundation Symposium (285) 'Acetaldehyde-related pathology: bridging the trans-disciplinary divide' held in London in September 2006. The scientific presentations and the ensuing discussions were very interesting and gave me the opportunity to expand my scientific horizons.
I spent my bursary period (10 weeks) with Professor Richard Deitrich at the Department of Pharmacology, University of Colorado Health and Science Center (UCHSC) in Denver. Professor Deitrich is internationally recognised for its contribution to the understanding of alcohol metabolism.
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Richard Deitrich (host) and Sophie Tambour (bursar). |
During my stay in Denver, I was involved in the investigation of the relationship between catalase (the key enzyme of ethanol oxidation in the brains of rodents) and ethanol sensitivity, measured by the loss of the righting reflex in some recombinant inbred mouse strains (LXS RI). The LXS set of RI strains was inbred from crosses between the ILS (Inbred Long Sleep, alcohol-sensitive) and ISS (Inbred Short Sleep, alcohol-insensitive) strains of mice. The 75 generated RI strains represent the largest set of RIs developed in mice to date. In the experiment, 20 of the 75 strains were used and I was involved in the perfusion of the animals, the spectrophotometric measure of catalase activity and the determination of protein content of the brains. The data are being analysed and will be used in continuing studies of the relationship of brain metabolism of ethanol to the central nervous system effects of ethanol.
Originally from a Belgian psychological lab, participation in this study was a great introduction to pharmacological research and gave me the opportunity to acquire new technical skills. Of course, I would like to thank the Novartis Foundation for the great opportunity they gave me and especially Céline Penfold for her work in arranging my bursary. I would also like to express my gratitude to Professor Deitrich and his research team for their patience and support during my bursary period.
Bursar's report: Gaëlle Friocourt
INSERM U613, Brest, France
(Bursar from Novartis Foundation Symposium 288 ‘Cortical development: genes and genetic abnormalities’, held in London, 6–8 February 2007.)
I am very grateful to the Novartis Foundation for giving me the opportunity to attend the symposium “Cortical development: genes and genetic abnormalities” held in London last February. I felt very fortunate to meet all the acknowledged experts in the field, from all around the world. All of the talks and following discussions were extremely interesting, and I felt very enthusiastic and motivated by the progress made in the last few years on brain development and human cortical defects.
I did my PhD in Professor Jamel Chelly’s laboratory in Paris, then did a three year post-doc with Professor John Parnavelas in London. During that time, I studied the role of doublecortin (DCX) in corticogenesis and in interneuron migration. Lately, I have became more interested in the function of ARX (aristaless-related homeobox gene) in brain development. This gene was first identified in 2002 as being responsible for a form of lissencephaly, the XLAG (X-linked lissencephaly associated with abnormal genitalia). In parallel, this gene was also found by J. Chelly’s group to be involved in non-specific X-linked mental retardation.
A year ago I returned to France to set up my own project at Brest within the U613 INSERM unit. My aim is to identify the genes upstream and downstream ARX in order to gain greater insight into its role in brain development, I have decided to inactivate or overexpress ARX in mouse embryonic brains using ex vivo electroporation. After the Novartis Foundation meeting, I spent 10 days in Dr François Guillemot’s lab (National Institute for Medical Research, Mill Hill, London) learning this technique. Despite the shortness of this bursary period, I found it to be a very interesting, challenging and enjoyable experience. Indeed, Dr Guillemot’s lab members were all very friendly and helpful.
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Gaëlle Friocourt (bursar) and François Guillemot (host). |
I am very grateful to the Novartis Foundation for the opportunity to attend the symposium and to Dr Guillemot and his group for welcoming me in to their laboratory.
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.
No bursaries are currently being advertised.
News from the Foundation
Symposia:
Two symposia have taken place since the last bulletin. The most recent, Defining
optimal immunotherapies for type 1 diabetes (symposium 292), was held at the
Novartis Foundation in London on 11–12 July. The chair was Matthias von
Herrath of the Department of Immune Regulation
at the La Jolla Institute for Allergy and Immunology, San Diego, USA.
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Symposiasts at 'Defining optimal immunotherapies for type 1 diabetes' (292). |
The biology of extracellular molecular chaperones (symposium 290) was held at the Novartis Foundation in London on 5–7 June. The chair was Péter Csermely from the Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.
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Symposiasts at ''The biology of extracellular molecular chaperones' (291) |
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From left to right:
Brian Henderson (co-proposer of symposium 291), Péter Csermely
(chair), |
Discussion
meetings:
The
next discussion meetings to take place are:
15 September 2007
Origin and differentiation of the Earth: past to present
Novartis Foundation / European Science Foundation Discussion Meeting
Organizer: Professor Andrew Jephcoat
1-2 October 2007
Auditory object
Novartis Foundation Discussion Meeting
Organizer: Professor Tim Griffiths
5
October 2007
Virus triggers in type 1 diabetes in children
Novartis Foundation Discussion Meeting
Professor Keith Taylor
8-9 October 2007
Multilingualism from an interdisciplinary perspective
Novartis Foundation / European Science Foundation Discussion Meeting
Organizer: Professor Gabriella Vigliocco
14 November 2007
Photosynthetic and atmospheric evolution
Novartis Foundation / Royal Society Discussion Meeting
Organizer: Professor Euan Nisbet
22-23 November 2007 Physiology of movement in the child
Novartis Foundation / Castang Foundation Discussion Meeting
Organizer: Dr Martin Bax
Publications
We
are pleased to announce the publication over the last few months of:
Tinkering:
the microevolution of development
(Novartis
Foundation Symposium 284)
Published June 2007
Vascular
development
(Novartis
Foundation Symposium 283)
Published July 2007
Dietary
Supplements and health
(Novartis
Foundation Symposium 282)
Published July 2007
For
details of these, 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
‘Chinese medicine in western packaging: The past decade has seen a global awakening to the truly curative powers of many ancient medicines, from black bear bile to the Asian plant Epimedium. Lisa Melton delves deeper’, Chemistry World, May 2007, pps 46-49.
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.
The Director's Report for 2006 can be found at http://www.novartisfound.org.uk/DirRep2006.htm.
If you would like to receive a copy of the 2007 handbook, please send an email including postal details to: bulletin@novartisfound.org.uk.