Novartis Foundation Bulletin
Issue 20, May 2004
Welcome to the 20th
edition of the Novartis Foundation's electronic Bulletin.
This issue features reports on:
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Cardiac stem cells (NF265)
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Bursar's report (NF262)
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Posture and pain (NF260)
(Based on presentations given at Novartis Foundation Symposium 265 "Stem cells: nuclear reprogramming and therapeutic applications" held in London on 2-4 March 2004)
Could we renew our own
heart?
Heart cells are for life - or so the dogma dictated. For years it was
thought that we die with the same myocardiocytes we sported as
one-month-old babies. But researchers at New York Medical College
have discovered that in fact there are self renewing stem cells dotted all
over the heart, constantly rejuvenating this vital organ. "Most
people see the myocardial mass as neither dying nor dividing. If that were
true, none of us would be sitting in this room," pointed out team
leader Bernardo Nadal-Ginard (New York Medical College, Valhalla, USA)
at a recent Novartis Foundation symposium.
Over a person's lifetime, the heart renews itself entirely at least three
or four times courtesy of cardiac stem cells. "So if your doctor
tells you 'your heart is as good as new' it may well be true," jokes
Nadal-Ginard who is finding that with some prodding, these cardiac stem
cells (CSCs) could repair a damaged heart.
CSCs can be spotted in the adult myocardium of mice, rats, dogs, pigs and
humans - both young and old. Nadal-Ginard has found these cells to conform
to the basic identity tests for stem cells: they are clonogenic,
self-renewing and multipotent. A single CSC can generate the heart's three
major cell types: myocytes, smooth muscle and endothelial vascular cells.
What's more, the team has found that when directly injected into the post-ischaemic
myocardium, CSCs are able to reconstitute a functional ventricular wall.
It's true, however, that in the adult heart, most cardiac myocytes are
permanently withdrawn from the cell cycle. But when a normal heart is
forced to work harder, the number of cardiac stem cells is racked up. So
why do these cells fail to prevent scar formation in chronic ischaemia?
Researchers believe that because the damage is so great, CSCs are
overwhelmed and die by apoptosis. Future treatments, Nadal-Ginard
believes, will focus on preventing their demise.
The NY researchers are now looking for strategies that boost the
myocardium's own rejuvenating capacity. There is one molecule - IGF-1 that
promises to do that.
IGF-1 (growth hormone), in transgenic mice, stops cardiac stem cells from
dying, allowing them to finish their job. The outcome is striking. In a
rat model of ischaemia, 60% of the ventricle - myocytes and vessels - is
regenerated in merely 10 days. "I think it is practical to move these
cells around," says Nadal-Ginard. The dramatic improvements in his
animal models suggest that myocardial regeneration may soon become a
reality.
Dr Lisa Melton—Science Writer, Novartis Foundation, London
(top)
NF265 Stem cells: nuclear reprogramming and therapeutic
applications will be published by Wiley, Chichester in November 2004
(Based on presentations given at Novartis Foundation Symposium 262 "Biology of IGF-1: its interaction with insulin in health and malignant states" held in London on 14-16 October 2003)
Bursar's report on the Biology of IGF-1
I was fortunate enough to be awarded the Novartis Foundation Bursary for the symposium "Biology of IGF-I: its interaction with insulin in health and disease states". This symposium was suggested by Professor Zvi Laron and chaired by Professor Derek LeRoith. From the opening remarks of Derek LeRoith to the closing comments by Zvi Laron the science discussed was at the cutting edge. After each seminar given, there were extensive discussions that usually threatened to require more than the allocated time. I have gained several things from attending the symposium;
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a renewed appreciation for the critical role the IGF system plays in normal and pathophysiological states
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the motivation and passion all who attended the symposium had for their work and
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confirmation of my initial intention on further studying the insulin/IGF field.
After attending the symposium I conducted my bursary period in the laboratory of Dr Charles T Roberts Jr (Department of Pediatrics, Oregon Health and Science University, Portland, USA). Several years ago, the insulin receptor isoform lacking the sequence encoded by exon 11(IR-A) was identified as a high-affinity receptor for insulin-like growth factor II, but not for IGF-I. I have shown previously that the C and D domains of IGF-II allow high affinity binding to and activation of the IR-A, whereas the same domains in IGF-I do not. I was keen to determine whether the IR-A signalling specificity of the IGFs was also regulated by these domains. In addition, little is known about the intracellular signalling pathways emanating from the IR-A when activated by IGF-II or by IGF-I;.
Therefore, during my bursary,
I studied IGF signalling through the IR-A and the IR-B (insulin receptor
containing exon 11). I can conclude from my studies that the C domain of
IGF-II is the sole region required to determine IGF signalling specificity
through the IR-A and IR-B. I also showed that IGF-I could potently
activate both IRS-1 and IRS-2, despite its low receptor binding and
activation ability. While in Portland, I still found time to ski on Mount
Hood, see the Portland Trailblazers defeat the Chicago Bulls in overtime
and visit many of the historic landmarks around the beautiful Rose City.
My bursary period was one of the most productive times in my short
research career and the work I completed will be written up for
publication shortly. As a result of my bursary period, a strong
collaboration has been forged between my laboratory in Adelaide, headed by
Professor John Wallace, and Dr Roberts' laboratory.
I would like to thanks the Novartis Foundation for funding the bursary
scheme. Specifically, I would like to thank Miss Allyson Brown for her
tireless work in arranging my bursary and Dr Roberts for his generosity
and academic guidance.
Adam Denley—University of Adelaide, South Australia
'Biology of IGF-1: its interaction with insulin in health and malignant states' will be published by Wiley, Chichester in September 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
Posture and pain
"Arthritis is not going
to decrease in prevalence in western societies. Because of the
demographics, it is only going to increase. We are getting older, but we
are also getting more overweight, which is a major risk factor for OA in
weight-bearing joints. Add to this the increasing number of sports
injuries. The estimate is that the current level of 20 million affected in
the USA will rise to 40 million by 2020." cautions David Felson (Boston
University School of Medicine, USA), the chair of a recently published
Novartis Foundation Symposium on Osteoarthritic joint pain.
Osteoarthritis is the most common form of arthritis. In elderly subjects
the prevalence of each of hand and hip OA is around 2-3% with knee OA
ocurring in 11% of the population aged 65 and over. Osteoarthritis is the
reason why most people have knee and hip replacements. But it's not just
older people, Felson explained; the second most common daily health
symptom in women aged 45-64 is knee trouble. He adds that of people aged
55 and over, about 25% have radiographic osteoarthritis, but many of these
do not have knee pain. Thus, interesting and pertinent questions arise
regarding the discordance between symptoms and pathology.
Ken Brandt (Indiana University School of Medicine, USA) presented
data on the neuromuscular aspects of osteoarthritis, and made the general
observation that individuals vary with respect to how they load their
joints, perhaps because of genetic differences in central programme
generators. Brandt believes that quadriceps weakness may precede
development of knee OA in some people, insofar as it may diminish the
effectiveness of protective muscular reflexes and thereby increase
deleterious joint loading.
Click here
for an excerpt from the ensuing discussion:
In addition to being either a
'digger' or a 'glider', cultural differences can result in
variations in OA distribution. David Felson has looked at populations in
Beijing and compared the prevalence of different kinds of OA to subjects of
the Framingham studies. He has noted a higher prevalance of tibiofemoral
knee OA among elderly Chinese subjects, and this he attributes to the
habit of squatting. Squatting is very common among the Chinese:
approximately 40% of men and approximately 68% of women reported squatting
for at least an hour per day and the length of time spent squatting is
closely correlated to the prevalence of tibiofemoral OA. Curiously hip OA
is 80-90% less frequent in Chinese subjects than in white persons in the
US.
One of the central reasons for this symposium is the discordance between
pain and structural change in OA. Some people may have symptomatic knee
pain, but only half of these have radiographic OA, and a large proportion
of people with radiographic OA have no symptoms at all. Inflammation has
been linked to states of hyperexcitability
which result in altered perception of pain, but what relevance does this
have to non-inflammatory mechanical joint disorders such as OA? The
recently published symposium proceedings on 'Osteoarthritic
joint pain' address this and many other pertinent questions in the
field of OA joint pain.
Brona McVittie—Assistant Editor, Novartis Foundation, London
(top)
'Osteoarthritic joint pain' was published by Wiley, Chichester, in
May 2004 and is available for purchase here
News from
the Foundation
Meetings
Open Meetings:
The next Novartis Foundation Open meeting on 'Genetics
of autoimmunity' will take place on 25 June 2004 at the
Geological Society, Burlington House, London in collaboration with the
Royal Society of Medicine and the Physiological Society.
To book your place at the meeting please contact Sharan Gallagher at the
Royal Society of Medicine
tel: +44 (0) 20 7290 3946
fax: +44 (0) 20 7290 2977
Email: events@rsm.ac.uk
Other forthcoming open meetings include:
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Molecular mechanisms influencing aggressive behaviour 23 July 2004
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Signalling networks in cell shape and motility 2 Sep 2004
to be held in Singapore
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 4-6 May 2004
entitled 'The hERG cardiac potassium channel: structure, function and
long QT syndrome'. Chaired by Michael Sanguinnetti, University of
Utah, USA.
Discussion meetings:
The next discussion meeting to take place is:
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The activities of intermediates during catalysis 6 June 2004
Publications
We are pleased to announce the publication over the last few months of:
Osteoarthritic
joint pain
(Novartis Foundation Symposium 260)
For details of this, and other recently published books and how to order
see: http://www.novartisfound.org.uk/nbook.htm
Book Sale 2004
Many of our out-of-print symposium volumes are available at vastly reduced
prices in this year's book sale.
See the booksale
page for details of the titles and how to order them or e-mail bulletin@novartisfound.org.uk
for more details.
Publicity
Recent publications of Dr Lisa Melton, the Foundation's Science Writer,
include:
Cracking the cancer code
Chemistry world, April 2004, p 24-28
A glimpse into the latest research on Parkinson's Disease
The Parkinson's Disease Society (PDS) and its research special interest
group, SPRING, has collaborated with the British Library for a series of
specially commissioned articles on areas of Parkinson's research. January
23,
2004.
www.parkinsons.org.uk
Proteomics in multiplex
Nature, 6 May 2004, vol 429, p 101-107
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 2004 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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