Novartis Foundation Bulletin
Issue 14, February 2003
Welcome to the 14th edition of the Novartis Foundation's e-mail Bulletin.
This issue features reports on:
(Based on presentations given at Novartis Foundation Symposium 252 'Generation and effector functions of regulatory lymphocytes' held in London on 9-11 July 2002)
Back with a vengeance
For decades, scientists have tried to manipulate the immune system to fight disease, but finding the right tools to crank up or slow down immune cells hasn't been easy. Now immunologists may have finally struck gold, and it comes in the shape of a white blood cell known as a regulatory, or suppressor, T cell. Such Regulatory cells are the levers that quieten the immune system, and they are opening up a whole new era in immunotherapy. Keep them subdued, say the scientists, and it soon will be possible to wipe out intractable pathogens that cause hepatitis C, HIV/AIDS and tuberculosis, and even annihilate cancer cells. You may not have heard of these cells already, but you'll be hearing a lot more about them in the years to come as they promise therapeutic solutions where none existed before.
Numerous lab studies in the 1970s proved that 'suppression' existed but there was nothing to distinguish these cells from other, similar T cells in the body. And because the experiments were hard to reproduce eventually immunologists concluded that suppression doesn't exist.
Until 1996, that is, when Shimon Sakaguchi (Kyoto University, Japan) showed that regulatory cells are present normally in the body as a type of CD4+ T lymphocyte (also known as a 'helper' T cell). Crucially, Sakaguchi also found a common identification tag: the CD25 molecule. Nobody yet understands exactly how suppressor cells work, but scientists do know that they protect us from autoimmune diseases by stifling harmful, self-reactive cells that exist even in healthy people.
When it comes to fighting off tumours or chronic infections, however, their influence is detrimental. "In immunology it's always a question of balance. These regulatory cells are both good and bad, and in certain situations it might be better to get rid of them," maintains immunologist Ethan Shevach
(National Institutes of Health, NIAID Laboratory of Immunology, Bethesda,
MD).
In chronic infections, for example, "microorganisms may be using T suppressor cells as a window of escape," says Kim Hasenkrug
(National Institute of Allergy and Infectious Diseases, NIH Rocky Mountain Laboratory,
Hamilton, MT). Indeed, in many viral and bacterial infections such as hepatitis C, HIV/AIDS and tuberculosis, the numbers of suppressor T cells rocket-evidently, they are taking the bite out of killer T cells designed to destroy invaders. The trick is to silence regulatory cells and thereby tip the balance to killer T cells.
To test different tactics, Hasenkrug infected an animal model of mice infected with the Friend leukemia virus, where the numbers of suppressor cells are high. Using antibodies that block TGF-ß and IL-10
receptors—molecules that regulatory cells need to do their job—has proved a winning strategy. The number of CD25+ cells plummeted, and mice regained their ability to reject tumours. In skin infections with the parasite
Leishmania major, Shevach has had similar results using an antibody that depletes CD25+ cells. "You get rid of suppressor cells, and you clear the infection," he confirms.
Vaccines would also benefit from having fewer regulatory cells kicking about. "When you have a suboptimal vaccine, it would be great to get rid of CD25+ cells, at least temporarily," Shevach points out. There are many vaccines out there, especially for HIV, malaria and
Mycobacterium tuberculosis, that have not made it to the clinic because they are not protective enough. Keeping the CD25+ cells out of the picture would allow the immune system to build up a vigorous response. In the clinic, however, the ideal is to silence suppressor cells without eliminating them. But is it possible to stop suppressor cells without eliminating them?
Sakaguchi has developed a monoclonal antibody that can manage just that. Rather than deplete the cells, the antibody blocks their function by locking onto a molecule on their surface called glucocorticoid-induced TNF receptor (GITR). With this anti-GITR, Sakaguchi has already obtained some remarkable results. At a July Novartis Foundation meeting in London
(9-11 July, 2002), he reported that when mice bearing tumours were injected with this antibody, the invigorated immune response shrunk the tumours. "The animal data are very promising, and pharmaceutical companies are pursuing this molecule intensively," he admits.
So would cancer patients also benefit from silencing suppressor cells? "It is an attractive hypothesis, but we don't know yet," insists Jacques Banchereau
(Baylor Institute for Immunology Research, Dallas, TX). In a small clinical trial, Banchereau found that patients with advanced melanoma who were vaccinated with their own dendritic cells taken from blood, loaded with four different synthetic bits of tumour
antigen, cells could trigger an immune response to the tumours. The results are dramatic: of the 10 patients injected, nine remained free of disease for 10 weeks and four were still alive three and a half years
later. "We have seen skin, liver, brain and lung tumours disappear. It's something amazing to do with regulatory cells," Banchereau acknowledges although, for the moment, he is unwilling to give away the details.
"What would happen if you could enhance the effectiveness of these kinds of therapies by removing CD25+ cells?" asks Sakaguchi. "It may be more efficient. And that's possible in the near future as an immunotherapy for cancer."
The hope is that the fruits of such intensive research may soon hit the clinic. "In immunology, we understand a great deal but, unfortunately, the number of drugs that have emerged from that understanding is rather small," Shevach acknowledges. But if the 30 years of ignominy are taken into account, then the time may be ripe for regulatory T cells to take center stage.
Dr Lisa Melton—Science writer, Novartis Foundation, London
This article was published in Scientific
American in December 2002, p 12-13
'Generation and effector functions of regulatory lymphocytes' is due to
be published by John Wiley & Sons, Chichester, UK in July 2003
The Foundation is now selling out-of-print titles ranging from 1998 right back to 1950 at the bargain price of £10 (UK), £12 (Rest of Europe) and £14 elsewhere including postage and packaging. There are some truly fascinating topics including:
Evolution
of hydrothermal ecosystems on earth (and Mars?) (1996)
Genetics of criminal and antisocial behaviour (1995)
Experimental and theoretical studies of conciousness (1993)
Cocaine: scientific and social dimensions (1992)
Human genetic information: science, law and ethics (1990)
The family and its future (1970)
Health and disease in tribal societies (1977)
Conflict in society (1966)
The nature of sleep (1961)
Books are subject to demand, and will be sold on a first come,
first served basis.
Other available titles may be viewed at http://www.novartisfound.org.uk/booksale-03.htm
Based on Ciba Foundation Symposium Volume 73, 'Man and his future' which was published after the symposium held in London on 26-30 November 1962
Back to the future
When Sydney Brenner last chaired a meeting at the Novartis Foundation, on
'Telomeres and telomerase' in 1997, he remarked that "in 20 years time this book will document how people were thinking at the time, which may be more valuable than the papers themselves". The
Novartis (Ciba) Foundation has, for over half a century, recorded and published live debate reflecting various controversies across a wide range of scientific disciplines. Given the rate at which scientific literature becomes outdated, what is quite remarkable is how relevant much of what was discussed is to science today. There is much to glean from the wisdom of those who have graced the conference room here at 41 Portland Place.
Such great scientific thinkers include Sir Julian Huxley who said in 1963 that "During the past three centuries the most powerful agency for providing knowledge has been science", at a symposium on
'Man and his future', which addressed the biological and sociological aspects of man's present and future existence.
Revisiting the pages of this superb out-of-print title, I chanced upon much foresight. J. Bronowski commented that "The population is doubling every 35 years or so. Science and technology, in terms of manpower and publications, are doubling every ten years." And yet, despite the myriad of scientific publications currently available, many questions remain unanswered.
During this symposium a paper on 'The promise of medical science' was presented by A. Szent Györgyi, who was awarded the Nobel prize for Medicine in 1937. He spoke thus: "There is still a wide gulf somewhere which separates us from a deeper understanding of the real meaning of the word
life, and a gulf which also separates molecules from higher structures...I expect the next forward thrust...from the penetration of wave mechanics and solid-state physics into biology and medicine...I find it difficult to believe that such an enormously complicated system could have been built by blind, random mutation...living matter carries itself in a hitherto undefined principle, a tendency for perfecting itself. Whether this principle can be expressed in terms of quantum mechanics, I do not know..."
"Until we start thinking in terms of quantal organization, rather than forces, I agree with Szent Györgyi that we shan't get very far". The great J. B. S. Haldane supported him.
This view did not engender unanimous agreement, as is evidenced by the words of F. H. C. Crick. "I think you are a neo-vitalist, Dr. Szent-Györgyi...I think I disagree with almost everything you said, although I enjoyed your paper very much...the importance of quantum mechanics: I don't believe that large new field relevant to Chemistry remains to be discovered..."
Since this meeting was held, the field of quantum mechanics has grown prolifically, although its impact on biology and medicine remains to be clarified. Szent-Györgyi pointed out that had he asked a physicist to calculate how long it takes an electron to jump from one level to another, that it would have taken months and many computers. But what is more, the effect that any observer has on that electron will alter its position.
This phenomenon is paralleled in D. M. Mackay's insight. During his talk on
'Machines and societies' he said "...the publication of an opinion poll before an election can affect people's voting behaviour, so strongly as to invalidate predictions based on it, even though the same poll, kept secret, would have given
an accurate forecast. The very process of sampling public opinion can often change it significantly..."
Any attempt to resolve phenomena on a quantal scale must be relevant to larger scale and indeed biological (if not sociological) phenomena. In fact, theoretical physicists have in the latter regions of the 20th century reached some resolution between quantum mechanics and gravity, in string theory. The question of the impact of such discoveries on biological theory would, no doubt, provide terrific fodder for an interdisciplinary symposium.
Brona McVittie—Assistant Editor, Novartis Foundation, London
(top)
Although we have sold our last copy of 'Man and his
future', reprints are available from
Books on Demand: http://wwwlib.umi.com
or write to UMI, ProQuest Information and Learning, 300 North Zeeb Road,
PO Box 1346, Ann Arbor, M! 48106-1346, USA
Based on presentations given at Novartis Foundation Symposium 255, 'Retinal dystrophies: functional genomics to gene therapy' which was held in Baltimore on 21-23, October 2002 in collaboration with the Foundation Fighting Blindness)
Bursar's Report
The Novartis Foundation funded an 8-week stay for me at Professor Robert Molday's lab, Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada. In addition, I was invited to attend the Novartis Foundation Symposium 246: Genetics to gene therapy of retinal dystrophies, chaired by Shomi Bhattacharya, in
Baltimore.
Professor Molday's group are working on the identification and functional analysis of vertebrate retinal photoreceptor genes and proteins, using a great variety of biochemical, biophysical, immunochemical, molecular and cell biology approaches
(http://www.biochem.ubc.ca/Faculty/Molday.html). They have extensively studied a protein named ABCR, underlying autosomal recessive macular degeneration in Stargardt's disease (STGD2), as well as cone-rod dystrophy and a form of retinitis pigmentosa. These studies have revealed new insights about the localization and function of the protein. They have recently identified another gene, ELOVL4, encoding an autosomal dominant form of the protein implicated in the disease (STGD3). The putative function of the protein within the membrane-bound ELOngation of Very Long chain fatty acids system suggests the possibility that it interacts-at least functionally-with ABCR, which strongly depends on its lipid environment. When I arrived in Vancouver, I joined the part of the team already working on ELOVL4.
One ELOVL4 mutation leading to STGD3 was known at that time. During my stay, I amplified the coding DNA comprising the ELOVL4 gene plus a short stretch encoding an immunogenic peptide and introduced the insert into a bacterial vector. By in vitro mutagenesis, the STGD3-mutation was generated. Additionally, one amino acid residue was changed, possibly responsible for directing ELOVL4 to the membranes of the cell organelles where it is needed. The resulting constructs were amplified in bacteria. Afterwards, the mutated insert was expressed in mammalian cells by using a suitable vector. The 'tagging' of each construct allowed its detection within the cell, giving clues as to whether its localization inside the cell is impaired by the mutant, compared to the wild-type protein.
Further research about ELOVL4 will be done in Professor Molday's lab in the future, as not all studies based on the constructs mentioned above could be completed during my stay. By investigating differentially tagged wild-type proteins one will address the question whether ELOVL4 interacts with itself or if it functions as a monomer. In case of a complex of several ELOVL4 proteins, it would be possible to investigate the influence of a mutated ELOVL4 allele on complex formation.
I profited a lot from working in Professor Molday's lab, as I learned new techniques that will further my projects in human functional genetics in the future. I highly appreciated the friendly atmosphere in the lab. Everybody was always ready to help. Besides scientific issues, I learned how beautiful Vancouver and the surrounding environment is, taking the opportunity for a trip to the gulf islands and to the Whistler skiing resort as well as enjoying several hiking tours with colleagues from the lab. Since returning to Germany, I have remained in contact with Professor Molday's team and we have started several collaborative projects.
A special highlight was the opportunity to attend the ARVO meeting in Fort Lauderdale, Florida, together with Professor Molday's team. Participating in the Novartis Foundation Symposium with experts in the field of retinal dystrophies from all over the world was a very exciting experience for me.
I am indebted to the Novartis Foundation for enabling me to participate in an exciting symposium and to work in a lab that is scientifically outstanding and which is home to such friendly researchers. I would particularly like to thank Bob Molday for being much more than just a host for 8 weeks, and Ms Allyson Brown from the Novartis Foundation, who enthusiastically supported me from the very start.
Hanno Bolz—Institute of Human Genetics, University of Hamburg
(top)
'Retinal dystrophies: functional genomics to gene therapy' is due to be
published by John Wiley & Sons, Chichester, UK in October 2003
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 'Anaphylaxis' will take place on
28 February 2003 at 1 Wimpole Street in collaboration with the Royal
Society of Medicine
To book your place at the meeting please contact Sharan Gallagher at 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:
-
Reversible acetylation of chromatin and non-histone proteins: biology and relevance to human disease
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 25-27
February 2003 entitled 'Anaphylaxis'. Chaired by
Stephen Galli, Stanford University, USA
Discussion meetings:
The next discussion meetings to take place at the Foundation are:
-
21 Feb 2003: Epigenesis versus preformation in mammalian development
(in collaboration with the Royal Society) -
21 Mar 2003: Autoantibodies as predictors of autoimmune disease
For further details on discussion meetings see http://www.novartisfound.org.uk/disc.htm
Publications
We are pleased to announce the imminent publication of:
Tissue engineering of cartilage and bone
(Novartis Foundation Symposium 249)
For details of this, and other recently published books and how to order see:
http://www.novartisfound.org.uk/nbook.htm
Book Sale 2003
Many more Novartis/Ciba Foundation Symposium Volume titles have
recently been declared out-of-print by the publisher, so we are offering
incredible discount prices on titles dating from 1998 back to 1950.
See http://www.novartisfound.org.uk/booksale-03.htm
for details of the titles and how to order them or e-mail bulletin@novartisfound.org.uk
for more details.
Publicity
Recent publications by our resident science writer include
'Subduing supressors; silencing certain immune cells could defeat
disease'
by Dr Lisa Melton which was published in Scientific
American, December 2002, p 12-13
Hospitality
Details of all conference facilities and accommodation available at the Foundation can be found at
http://www.novartisfound.org.uk/hosp.htm
Personalia
Three members of our international Scientific Advisory Panel retired
during 2002, Professor H R Brunner (one of two members for
Switzerland), Professor M Brunori (Italy) and Professor V T Ivanov
(Russia). We are grateful to these scientists for their help and support
and are very pleased to welcome Professor E Boncinelli, Director, International School for Advanced Studies,
Trieste (Italy), Professor D Duboule from the Department of Zoology & Animal Biology,
University of Geneva (Switzerland) and Professor J Requena (Venezuela).
Full details of personalia and activities at the Novartis Foundation can also be found in the Foundation's 2002 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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