Impact of Genetics on Science and Society (Part A)
Functional Genomics and Proteomics: Impact on Therapeutic Strategies (Part B)
1st-2nd July 2001, Dublin
The meeting was held in University College Dublin, Ireland, over two days. The first day was organised
solely by the MCFA, with the second day carried out in collaboration with the British Pharmacological
Society (BPS). On the 1st July, MC Fellows were given the opportunity to orally present their research
work. For this, 10 abstracts were selected for short talks. On the 2nd July, 6 posters were presented by
MC Fellows. All ran for MCFA Awards for the best talk and poster.
After welcome talks by Dr. Ana M. Cerdeño (MCFA Chair) and Dr. William M. Gallagher (Local
Organiser), the entire morning of the 1st July was dedicated to the short oral presentations from the MC
Fellows. The topics of these presentations were varied in nature, ranging from discussion of image
processing techniques to promotion of flowering in Arabidopsis (abstracts of the talks are included in
Annex I). After lunch, two hours were dedicated for all people present in the meeting to interact with
AVENTIS Pharma, the MCFA and Science’s NextWave representatives.
The afternoon of the 1st July was dedicated to discussion of the impact of genetics on science
and society, with the context provided by 6 lay-oriented seminars. William Gallagher and Prof. Finian
Martin both chaired the session. Prominent experts in the field spoke on the following topics:
(a) Science and Society
Dr. Andrew Moore
(b) Genes and Genomes – The Basics
Dr. James McInerney
(c) Genetics: A Spirally Problem
Dr. Tom Shakespeare
(d) What Does Genetic Testing Mean for You?
Prof. Andrew Green
(e) Genetics, Policies and Ethics
Dr. Marja Sorsa
(f) Gene Therapy – an Overview
Dr. Jane Farrar
Andrew Moore (European Molecular Biology Organisation, Germany) highlighted the various activities
that EMBO are carrying out in order to get science closer to the general public and other scientists. He
provided, as a key model example, the meeting organised last year in Heidelberg, Germany, under the
title “Science and Society; Developing a New Dialogue”. At this conference, scientists, social scientists,
philosophers, journalists and representatives of consumer groups convened. Dr. Moore also discussed
the need to be pro-active with respect to the communication of science to the public. EMBO recently
launched a scheme, “Science in the Pub”, where scientists and interested lay people meet on an
informal basis to chat.
The bioinformatics expert, Dr. James McInerney (National University of Ireland – Maynooth,
Ireland) gave the audience a basic insight into genes and genomics, outlining the main historical
advances in the field, and ending with a resume of possible future developments. Dr. Tom Shakespeare
(International Centre of Life, United Kingdom), constituted the turning point of the afternoon. He focused
on what is happening today, not the future. What if ignorance was bliss? He made his point through the
fact that current applications in human genetics are mainly diagnostic and that the absence of therapies
can raise anxiety without improving the situation at all. He also talked about discrimination against
disabled people, pointing out there are also psychological costs for this outflow of genetic information.
The following speaker, Prof. Andrew Green (Our Lady’s Hospital for Sick Children, Ireland),
discussed the concepts behind genetics testing, with an emphasis on relevance to patient care and
choice. Being tested for having or not having a particular genetic alteration can have far-reaching
consequences. As also indicated by Dr. Shakespeare, someone could be diagnosed as having a
genetic alteration, but there might be no cure for it. Is this information going to be released to insurance
companies or employers? What about genetic discrimination?
Dr. Marja Sorsa (Ministry of Education and Science, Finland) discussed genetics and ethics
policy within the European Union. She explained how all these new developments in science have
raised ethical concerns. In order to face these concerns, various international organisations have been
preparing documents for guidance to researchers and policy makers. Dr. Sorsa discussed how amongst
the recent directives by the European Union, we can find those related to data protection, protection of
biotechnological inventions and in vitro diagnostic medical devices. She said that these directives have
been or are in the process of being implemented in the National legislation by the Member States.
To finish the day, we were presented with an overview of the latest key issues in the
development of gene-oriented therapies by Dr. Jane Farrar (Trinity College Dublin, Ireland). These
issues have derived directly from the information that has emerged from the Human Genome
Sequencing Project, and are related to both the understanding of disease and the quest for novel cures.
After an open reception, the MC fellows and speakers proceeded to dinner in a nearby public house and
a good time was had by all!
On the 2nd July, the MCFA joined with members of the BPS in a symposium entitled
“Functional Genomics and Proteomics: Impact on Therapeutic Strategies”. Ten internationally-renowned
speakers in the field spoke during morning and afternoon sessions (see Programme). During lunchtime,
a series of short careers talks were held. This was an extremely popular event with over 100 young
scientists attending. Discussions between speakers and the audience were quite animated at times! A
trade exhibit was held throughout the day, with over 25 companies displaying their wares.
Upon closure of the meeting, a wine and cheese reception was held during which the MC
Fellow posters were viewed. That night, MC Fellows, BPS members and speakers visited the Old
Jameson’s Distillery in the centre of Dublin city, where after rounds of whiskey tasting and food,
attempts (good and not-so-good) at Irish dancing were evident. MCFA Awards (for best Oral and Poster
presentation) were presented on the nights of 1 st and 2nd July, which comprised of a commissioned
piece of iron artwork from the blacksmith Mr. Michael Halley, along with £100 cash.
1
Table of Contents
Introduction - Genetics: Science and Society
3
Programme - Impact of Genetics on Science and Society
5
MCFA Oral Presentations
6
Plenary Session
7
MCFA Poster Presentations
8
Acknowledgements & Contacts
9
Appendix I –MCFA Oral Presentations
10
Appendix II – Plenary Session
20
Appendix III – MCFA Poster Presentations
28
Genomes, Nanotechnology and Quantum Computation:
The 2001 Human Odyssey
35
Programme - Functional Genomics and Proteomics:
Impact on Therapeutic Strategies
36
Careers Section
40
2
Genetics: Science and Society
We are aware of GENETICS as a term. 'Dolly the Sheep' is now a catch phrase
associated with genetic manipulation. Fears and hopes are abound. The recent
announcement of a draft of the human genome was hailed in certain quarters as the
most important advance of this century, greater perhaps even than the Moon-derived
"small step for man, one giant leap for mankind". But is it clear to all what are the
ramifications of the Human Genome Project?
To provide emphasis, the media and scientists are often prone to exaggeration. The
recent furore surrounding the Human Genome Project is a good example. The current
sequence of the human genome is still essentially only a draft, given that the genetic
material of a limited number of individuals was used to generate it. The issue of what
is the model sequence remains, with the question of what is considered 'perfection'
still looming over the Genetic Horizon.
A number of questions remain downstream from the Human Genome Project, some of
which have significant technical, social and ethical dimensions.
- Should a company, or individual, be allowed to own genes?
- How will genetic information be disseminated, both to scientists and society?
- What level of privacy will be enforced with respect to an individual's genetic
make-up?
- To what extent will society permit genetic determinism?
There are obvious potential benefits to a post-Human Genome Project world. The
genetic basis of complex diseases, such as cancer and mental disorders (e.g.
schizophrenia), will finally become transparent with downstream treatments a reality.
However, genetic enhancement for cosmetic reasons should then also be a possibility.
Again, the concept of extreme examples arises. Comparisons can be found in the
hopes and fears engendered by the Computer Age. Now, computers are tools to be
used by humans. But, we have also become reliant on their use.
Whether we feast contentedly on the fruit of a gene-enriched civilisation, or choke on
the same, is an open question.
3
To tackle some of the issues raised above, an open conference is being held this
Sunday (1st July) at the University Industry Centre, University College Dublin. Six
prominent Irish-based and international speakers from a variety of backgrounds,
including those involved in biomedical research, genetic counselling, education and
government, will present a series of short general talks.
The primary aim of the conference is to encourage interdisciplinary communication,
e.g. between basic and clinical scientists, academics and industrialists, biologists and
mathematicians. In addition, it is hoped that the conference will allow for significant
interactions between the general public and scientist groups, as well as foster
professional relationships between renowned and emerging biomedical scientists.
Consistent with the latter aim, a Careers Section is planned to highlight career
opportunities for young scientists.
The conference is funded by a number of sources, including the Wellcome Trust,
University College Dublin, AVENTIS Pharma and Science magazine.
4
IMPACT OF GENETICS ON SCIENCE AND
SOCIETY
Hosted by the MCFA
09.00 - 20.00 Sunday 1st July 2001
Location: University Industry Centre, UCD
Programme
09.00-12.45
MCFA Member Oral Presentations
09.00-09.30
09.30-10.45
Welcome Talks , Ana Cerdeño, The Sanger Centre, UK,
William Gallagher, University College Dublin, Ireland
5 Research Talks (12min + 3min discussion each)
10.45-11.15
COFFEE BREAK
11.15-12.30
5 Research Talks (12min + 3min discussion each)
12.30-13.30
LUNCH
13.30-15.00
One-to-One Session with AVENTIS Pharma, Science Next Wave
Marie Curie Fellowship Association
15.00-18.00
Plenary Session - "The Impact of Genetics on Science and Society"
15.00-15.10
Introduction by Chairpersons
William Gallagher, University College Dublin, Ireland
Finian Martin, University College Dublin, Ireland
15.10-18.00
A series of 20 min talks & 5 min discussions / seminars



Science and Society - Andrew Moore, European Molecular
Biology Organisation, Germany
Genes and Genomes - The Basics, James McInerney, National
University of Ireland - Maynooth, Ireland
Genetics: A Spiralling Problem, Tom Shakespeare, International
Centre for Life, UK
COFFEE BREAK



What Does Genetic Testing Mean for You? - Andrew Green,
Our Ladies Hospital for Sick Children, Ireland
Genetics, Policies and Ethics - Marja Sorsa, Ministry of
Education and Science, Finland
Gene Therapy - an Overview - Jane Farrar, Trinity College
Dublin, Ireland, Ireland
General Discussion and Summation
18.00-20.00
Reception (MCFA Award - Best Oral Presentation)
5
MCFA Oral Presentations
9.00-12.30pm
The human Y chromosome: population histories and disease
Lluis Quintana-Murci, Institut Pasteur, FRANCE
Image processing techniques with applications in medical biology
Stelios Zimeras, MEDCOM Gmbh, GERMANY
Association mapping using simple sequence repeats (SSRs) and wild barley
germplasm
Victor Ivandic, Scottish Crop Research Institute, UNITED KINGDOM
Genetic algorithms and ant colony optimisation for designing GPS surveying
networks
Hussain Saleh, University of East London, UNITED KINGDOM
Protein interactions with the cytoplasmic region of Axl receptor tyrosine kinase
Sassan Hafizi, Lund University, SWEDEN
Coffee Break
Characterisation of isogenic mutants in N. meningitidis serogroup B identified by
genome analysis
Jeannette Adu-Bobie, Chiron Vaccines, ITALY
Where the rubber meets the road: characterising metabolic fluxes in humans
John Jones, University of Coimbra, PORTUGAL
CONSTANS promotes the transition to flowering in Arabidopsis through a
multiple response
Federico Valverde, John Innes Centre, UNITED KINGDOM
Identification of genes controlled by the CsgD protein of Escherichia coli, a
regulator of initial microbial adhesion to solid surfaces, using a functional
genomic approach
Paolo Landini, Swiss Federal Institute for Environmental Technolgoy,
SWITZERLAND
Molecular genetics of breast cancer
Angelika Burger, University of Freiburg, GERMANY
(Poster and Oral Communication; Competing for poster prize only)
6
Plenary Session
Talks from 3.00-6.00pm
Chairpersons: Dr William Gallagher, Prof. Finian Martin
 Science and Society
Dr. Andrew Moore, European Molecular Biology Organisation, GERMANY
 Genes and Genomes - The Basics
Dr. James McInerney, National University of Ireland - Maynooth, IRELAND
 Genetics: A Spiralling Problem
Dr. Tom Shakespeare, International Centres for Life, UNITED KINGDOM
 What Does Genetic Testing Mean for You?
Prof. Andrew Green, Our Ladies Hospital for Sick Children, IRELAND
 Genetics, Policies and Ethics
Dr. Marja Sorsa, Ministry of Education and Science, FINLAND
 Gene Therapy - an Overview
Dr. Jane Farrar, Trinity College Dublin, IRELAND
Wine and food reception from 6.00-8.00pm
7
MCFA POSTER PRESENTATIONS
Monday 2nd July
Investigation of the role of Ig signalling function at late stages of B cell
development, by conditional gene mutagenesis in the mouse
Nathalie Uyttersport, Institute for Genetics - University of Cologne, GERMANY
Physiology and flavour formation derived from amino acids
Maria Tabernero, Unilever Research Vlaardingen, NETHERLANDS
Fluxgate sensors for medical applications
Pavel Ripka, Power Electronics Research Centre, Galway, IRELAND
Using a distributed genetic algorithm to discover intron/exon boundaries in DNA
strands
Filippo Neri, Unilever Research Port Sunlight Lab, UNITED KINGDOM
Characterisation of drug-DNA interactions using the surface plasmon resonance
technology
Carolina Carrasco, Institut de Recherches sur le Cancer, FRANCE
Pharmacogenomics of Omani population: preliminary data on the occurrence of
mutant alleles at the CYP2D6 gene locus
Musbah Tanira, Department of Pharmacology, Sultan Qaboos University,
SULTANATE OF OMAN
(Not competing for poster prize; BPS participant)
Molecular genetics of breast cancer
Angelika Burger, University of Freiburg, GERMANY
(Poster and Oral Communication; Competing for poster prize only)
8
We wish to gratefully acknowledge
the following:
Cell Media
UCD
Contact Details:
Dr. William Gallagher
Department of Pharmacology
Conway Institute of Biomolecular and Biomedical Research
University College Dublin
Belfield
Dublin 4
Ireland
Tel: +353 1 716 1511
Fax: +353 1 269 2749
E-mail: william.gallagher@ucd.ie
9
Appendix I
MCFA ORAL PRESENTATIONS
The human Y chromosome: population histories and disease.
Lluis Quintana-Murci, Institut Pasteur, FRANCE
The human Y chromosome is strictly paternally inherited and, in most of its length,
does not recombine during male meiosis. These features make the Y a very useful
genetic marker to investigate the evolution, migrations and range expansions of
modern humans. An increasing number of informative Y polymorphic markers,
defining specific Y chromosome lineages (or haplogroups), are available today for
population genetic studies. These haplogroups present a strong geographical
clustering, a feature that makes the Y a powerful tool to infer the history of
populations in terms of human evolution, population affinities and demographic
history. In this context, we have recently identified two Y-chromosome lineages,
which trace diffusion of people, and possibly languages, in south-western Asia. The
geographic distribution, frequency clines and estimated ages of these two Ychromosome lineages supports a model of demic diffusion of early farmers from
south-western Iran -and of pastoral nomads from western and central Asia - into India,
associated with Dravidian and Indo-European-language dispersals, respectively.
Population genetic studies generally assume that the markers used to infer population
histories are selectively neutral. However, current data suggest that the effects of
selection on patterns of Y chromosome distribution are minimal, however as interest
focuses on biological functions of the Y chromosome which have a major impact on
male fitness such as fertility, these assumptions may be challenged.
10
Image processing techniques with applications in Medical Biology
Stelios Zimeras, MEDCOM Gmbh, GERMANY
The Bayesian approach to reconstruction in spatial processes involves the modelling
of prior informations, in addition to the degradation process. It is this prior
component, describing local characteristics of the spatial process, which is often
modelled using a Markov random field (Mrf). Models based on Markov random fields
are widely used to model spatial processes, especially in biology, where
reconstructions of the cells could be presented as a spatial pattern model. A particular
subclass of Mrf is the auto-models, introduced in Besag (1974) and further studied in
Cross and Jain (1983), Besag (1986), Aykroyd et. al. (1996), Zimeras (1997).
However, this prior component usually involves unknown prior parameters, which
control the influence of the prior distribution. Key components of any statistical
analysis using such models are the choice of an appropriate model as a prior
distribution and the estimation of prior model parameters. In many applications,
appropriate values of these parameters will be found be trial- and- error, in other
cases a fully Bayesian approach will be adapted and the prior parameters estimated in
the same way as other model parameters.
In all these cases it is, at least implicitly, expected that the procedures depend
smoothly on the prior parameters and that there is a unique relationship between the
parameters and different types of behaviour of the process. In this work, spatial
behaviour of the auto-models shall be investigated using simulated and real data from
auto-binomial and auto-Poisson models, which could be used to model biological
structures or treatment diseases. A simple deterministic model based on the univariate
iterative scheme which appears to emulate the behaviour of auto-models and allows
us to make predictions regarding the behave of the spatial models would be analysed.
For well-defined regions in the parameter space this iterative scheme is unstable
leading to catastrophic behaviour (Chandler 1978; Zimeras, 1997). This instability
coincides with structural changes in the corresponding spatial model and that the
critical boundaries for the iterative scheme coincide with those for the spatial model.
Finally for the simulated data, the Gibbs sampler was used to produce realisations
illustrating a wide range of possible models.
References
1. Aykroyd R. G., Haigh J. G. B. and Zimeras S. (1996): Unexpected spatial
patterns in exponential familly auto-models, Graphics, Models and Image
processing, Vol 58, No 5, 452-463.
2. Besag J. (1974): Spatial interaction and the statistical analysis of lattice
systems, J. Royal Statistical Society, Series B, 36, 192-236.
3. Besag J. (1986): On the statistical analysis of dirty pictures, J. Royal
Statistical Society, Series B, 48, 259-302.
4. Chandler D. (1978): Introduction to Modern Statistical Mechanics, Oxford
University Press, N. York.
5. Cross G. R. and Jain A. K. (1983): Markov random field texture models,
IEEE Trans. Pattn. Anal. Mach. Intell., 5(1), 25-39.
6. Zimeras S. (1997): Statistical models in medical image analysis, Ph.D. Thesis,
Leeds University, Department of Statistics.
11
Association mapping using simple sequence repeats (SSRs) and wild
barley germplasm
Victor Ivandic, Scottish Crop Research Institute, UNITED KINGDOM
Simple sequence repeats (SSRs) are hypervariable DNA elements consisting of
tandemly repeated motifs such as (AC)n and occur abundantly in most eukaryotic
genomes. In this study, 33 genetically mapped SSRs were analysed in collections of
wild barley, Hordeum spontaneum C. Koch, the progenitor of cultivated barley,
Hordeum vulgare. Wild barley genotypes from Iran, Turkey and Israel (n = 39), and
genotypes from a single site in Israel, Tabigha (n = 52) were examined. Associations
between SSRs and quantitative trait variation were investigated using regression
analyses based on SSR length variation and SSR allele class differences. Data on
flowering time under four different growing regimes (short days, long days,
unvernalised and vernalised), phenotypic responses to experimentally imposed water
stress and powdery mildew susceptibility were used. Most of the associations between
SSRs and flowering time observed could be accounted for by close linkage with
earliness per se genes. However, novel genomic regions controlling flowering time in
wild barley were also detected. A large number of associations between SSRs and
plant performance (development, morphology and yield), water stress tolerance and
powdery mildew susceptibility were identified. Most of the associations detected
correspond well to previously identified QTL for agronomically important traits,
dehydrin genes known to be involved in abiotic stress tolerance, and powdery mildew
resistance genes. In vitro studies have shown that mutations in SSR repeat number can
cause quantitative variation in transcriptional activity and biological function of
mammalian and human genes (reviewed by Kashi et al. (1997) TIG 13: 74-78). The
results presented here indicate that some SSRs are associated with quantitative trait
expression in wild barley and cannot be regarded as being biologically neutral.
12
Genetic algorithms and ant colony optimisation for designing GPS
surveying networks
Hussain Saleh, University of East London, UNITED KINGDOM
Abstract not available
13
Protein interactions with the cytoplasmic region of Axl receptor
tyrosine kinase
Sassan Hafizi, Lund University, Department of Clinical Chemistry, Wallenberg
Lab, University Hospital Malmo, SE-205 02 Malmo, SWEDEN
Background. Axl is a member of a distinct subfamily of receptor tyrosine kinases.
Stimulation of Axl has been observed in response to two homologous vitamin Kdependent proteins, protein S and the product of growth arrest specific gene 6 (Gas6).
However, little is known about the molecular mechanisms of Axl activation at the
receptor level. Therefore, the aim of this study is to identify intracellular proteins that
physically interact with the cytoplasmic portion of Axl and thus may be important in
initiating signal transduction pathways. For this, we have employed the yeast twohybrid system to study positive interactions in vivo in yeast. Methods. The cDNA
sequence encoding the entire intracellular region of human Axl was cloned into a
vector and transformed into Saccharomyces cerevisiae yeast cells. The resulting
protein was expressed as a fusion containing the DNA-binding domain (DNA-BD) of
yeast transcriptional activator GAL4. In the same cells were co-expressed protein
products of a human heart cDNA library fused to the GAL4 activation domain (AD).
A physical interaction of Axl with any of these library proteins would result in
activation of four GAL4-responsive reporter genes. Results. The results of one largescale library screen yielded several positive clones, which still expressed all 4 reporter
genes after testing three times. Subsequently, the DNA sequences of a number of
these have been determined. Experiments are now underway to confirm these
interactions, which have identified new binding partners for Axl and thus will shed
more light on the mechanisms of Axl signalling.
14
Characterisation of isogenic mutants in N. meningitidis serogroup b
identified by genome analysis.
Jeannette Adu-Bobie, Immunobiological Research Institute of Siena, Chiron
Vaccines, Via Fiorentina 1, Siena 53100, ITALY
The genome of N. meningitdis serogroup B has enabled the identification of
previously unknown surface exposed antigens. These genome derived Neisseria
antigens (GNA) are highly conserved in sequence among different serogroup B
strains, other meningitidis serogroups as well as gonococus, and most of them induce
antibodies with bactericidal activity. Some of these antigens show high sequence
homology with proteins of known function expressed by different bacteria. To verify
whether the function of these antigens is conserved also in meningococcus, and to
define their putative role in pathogenesis and virulence, isogenic mutants were
generated in serogroup B strain MC58. The morphology, phenotype and ability of the
mutants to adhere to and invade epithelial and endothelial cells are being studied. The
virulence of the mutants in the infant rat model is under investigation.
15
Where the rubber meets the road: characterising metabolic fluxes in
humans,
John Jones, University of Coimbra, PORTUGAL
A large and growing number of genetic defects are linked to alterations in
intermediary metabolism of fat and glucose. It is likely that a significant portion of
these will involve mutations of hepatic enzymes that are involved in the regulation of
gluconeogenesis and fat synthesis. The liver is a highly accessible organ for genetic
manipulation and therefore will be a probable site for the first generation of genetic
therapy aimed at correcting disorders in systemic fat and glucose metabolism. To this
end, we are developing practical and non-invasive stable isotope tracer methods for
quantifying hepatic intermediary metabolism in humans.
We will present
characterisation of hepatic glucose synthesis from healthy individuals and from two
patients with cirrhosis.
16
CONSTANS promotes the transition to flowering in Arabidopsis
through a multiple response
Federico Valverde, John Innes Centre, Norwich, UNITED KINGDOM
The transition to flowering in Arabidopsis is mediated by CONSTANS (CO) in the
long-day pathway. CO is regulated at the RNA level by the circadian clock and the
photoperiod and the protein may follow the same pattern of expression. GFP-CO
constructs and Western experiments show that CO is nuclear localised and the lack of
any DNA binding activity seems to indicate that it activates transcription through
protein-protein interactions. Microarray experiments have shown that CO activates
genes directly involved in the flowering signal, as well as other of general metabolism
and development. Plants overexpressing CO under a 35S promoter show a pleiotropic
phenotype including dwarfism, reduced fertility and death under continuous blue
light. EMS mutagenised 35S:CO plants showing early flowering phenotype have an
increased vitality which may indicate an altered response to CO in other
developmental pathways
17
Identification of genes controlled by the CsgD protein of Escherichia
coli, a regulator of initial microbial adhesion to solid surfaces, using a
functional genomic approach.
Paolo Landini, Department of Environmental Microbiology, Swiss Federal
Institute for Environmental Technology, 8600 Dubendorf, SWITZERLAND
In nature, bacteria are often found in closely associated communities known as
biofilm, whose formation requires complex cellular processes involving several steps:
initial adhesion to a solid surface, formation of a microcolony, and establishment of a
spatially and functionally organised community. Our research focuses on the
molecular mechanisms of initial adhesion to a surface and establishment of cell-cell
interactions in the bacterium Escherichia coli. We are currently studying the
biosynthesis of curli, protein-made extracellular structures involved in adhesion, and
their regulation at the genetic level, using a combination of classical genetics and
functional genomics. Regulation of the curli-encoding csg genes is extremely
complex and involves several proteins, such as OmpR (part of an osmolarity-sensing
regulatory pathway), RpoS (an alternative sigma factor induced in stationary phase of
growth), the CpxA/CpxR system (which is induced by denaturation of periplasmic
proteins) and CsgD, considered a specific regulatory factor for curli biosynthesis. In
this communication we show that the CsgD regulatory protein directly controls the
expression of at least three more genes in E. coli: pepD, yagS, and yaiC. We propose
that a sequence conserved in all these promoters, as well as in the promoter of the
csgB gene involved in curli formation, is the binding site for CsgD. While the yaiC
gene is homologue to the adrA gene of Salmonella typhimurium, which is also
involved for microbial adhesion and cell-cell communication, pepD and yagS appear
to be involved in cellular processes other than adhesion, suggesting a more “global”
role for the CsgD protein.
18
Molecular genetics of breast cancer
Angelika M. Burger1, Suzanne C. Richter2, Michael J. Wong2, Richard Kitching2,
Barbara G. Beatty3 , Renate Grugel1 and Arun Seth2,. 1Tumor Biology Center at
University of Freiburg, GERMANY, 2Sunnybrook and Women's College Health
Sciences Centre, University of Toronto, Canada, 3Ontario Cancer Institute,
University of Toronto, Canada.
Abstracts not available
19
Appendix II
Plenary Session
3.00-6.00
Science and Society
Andrew Moore, European Molecular Biology Organisation, Germany
When EMBO was founded in 1963, molecular biologists were regarded as pursuing
purely academic questions. Their aim was to acquire knowledge of living systems at
the molecular level; the nuts and bolts of life. As is the case in any area of human
exploration, in the years that followed, discoveries that could be exploited were. They
found fertile soil in the form of medical, industrial and agricultural applications, and
hence brought the fruits of molecular biology into the consumer domain. This was
largely a silent revolution, but the very fact that molecular biology started to solve
important problems with very little fuss or resistance would later backfire. In the years
that followed, a growing resistance developed to what was seen as an undemocratic
imposition of an untested technology. It reached its peak in 1998 with the Swiss
referendum as to whether to ban genetic engineering. Since then it has become
universally recognised that supplying the public with information on science and
technology will not suffice; the public wishes to be involved in a democratic process
of dialogue about scientific applications that could affect them or the environment.
EMBO was established to promote molecular biology in Europe, its responsibilities
did not end with the delivery of scientific results. Its unique position as a highlyrespected international organisation of leading scientists gave it a responsibility to
contribute to discussions on the general impact of molecular biology on society. This
is a topic of great concern among both EMBO members and the fellows, who will
make up the next generation of Europe’s scientists.
The Organisation recognises the value of many national activities at the interface of
science and society, and its international nature gives it the potential to identify the
best practices in individual countries. These can then be brought to the attention of
scientists in other countries, the goal being to generate a unified voice of authority on
developments in molecular biology that affect the public. EMBO is currently devoting
time and resources to investigating ways to increase its impact and involvement in
this area.
EMBO is already active at the interface of science and society in various ways. Its
science and society committee (10 EMBO members geographically widely distributed
in Europe) meets annually to discuss the matters of greatest concern, and plan
accordingly the following year’s activities. The most prominent of these is an
interdisciplinary joint conference co-organised with the EMBL. In 2000, under the
title “Science and Society; Developing a new dialogue” scientists, social scientists,
philosophers, journalists and consumer group representatives convened in Heidelberg
to debate topics as diverse as “genometyping” and the perception of “self” (see
http://www.embo.org/GEOD_day_report.html and
20
http://www.EMBL-Heidelberg.DE/ExternalInfo/stefanss/). In 2000 the conference
received funding from the EC via GEOD (Genetics in Europe Open Days), a project
of the European Genetics Foundation in Sestri Levante, Italy.
This broad-based meeting is followed in 2001 by another joint EMBO/EMBL
meeting entitled “From genomes to cures”, 16 – 18 November 2001. The 2001
conference will specifically involve biology teachers from throughout Europe since
EMBO has a strong belief in improving and maintaining biology education as a vital
part of improving public dialogue and awareness in the life sciences.
In 2000 EMBO also organised and provided the majority of prize money for a
genetics journalism competition in German speaking countries, as part of the GEOD
project. With this valuable experience, EMBO wishes to extend this concept to a panEuropean journalism prize in the life sciences in following years.
Other pilot projects that are intended for European wide expansion are a seminar on
the further education of biology teachers, to take place on July 6 – 8, 2001
(www.embo.org/Lehrertagung.html), and a novel approach to bringing scientists and
the public closer, “Science in the pub” (www.embo.org/Genau.html).
EMBO’s annual associated meeting on science and society, held at the same time as
the new members meeting, continues to address interesting topics of general concern.
In 1999 in Prague the title was “Biotechnology and the environment”; in 2000 near
Nice, it was “Repairing the body”; in 2001 in Crete, the impact of basic research on
the economy will be examined under the title “the economic impact of basic
research”.
Not wishing to forget its fellows, EMBO invites all long term fellows (past and
present) to a media workshop on the communication of science, as part of the fellows
meeting in Heidelberg (24 – 27 June 2001). With this initiative, EMBO wishes to
raise the awareness among the younger generation of researchers of the need for clear
communication with media and public, and provide them with some of the tools they
might need.
EMBO is keen to develop networks of competence and information in science and
society both within its membership, and with other organisations. One aim is to
establish an information service that would provide museums, exhibitions, visitor
centres and the media with accurate information on topics in molecular biology; this
would draw largely, though not exclusively, on the EMBO membership, and would
help to increase the general awareness in other circles of EMBO’s expertise. In
collaboration with other initiatives, for example the European Federation of
Biotechnology’s Task Group on Public Perceptions of Biotechnology, GEOD, and
local projects such as the Heidelberger Life-Science Lab, EMBO is contributing
actively to improving communication between the public and scientists.
Please contact Andrew Moore, PhD (moore@embo.org) for more details.
EMBO fellows network (http://www.embo.org/Fellnet.html)
21
EMBO long term fellows are at an exciting time in their scientific careers, a time
when collaborations blossom, and many establish their own group. To aid this
process, and foster a sense of community among the best of Europe's young molecular
biologists, it was decided to invite long term fellows to a meeting at the end of their
fellowships (up to 2 years spent in a foreign country of their choice). There they
would present their research, and network with their peers, building collaborations
and friendships.
The first fellows meeting took place in Heidelberg in September 1997 and involved
those who started their EMBO Fellowship in 1994. It proved a great success, and has
become an annual event. Fellows are enthusiastic about the meeting, and many attend
in subsequent years. Apart from the scientific presentations, and the opportunity to
talk to peers and establish collaborations, the meeting generates a lively debate on
topics as diverse as science and society, women in science, and academia versus
industry. A popular component of the meeting is "My scientific biography and
science", talks given by the EMBO members who chair each session of the meeting.
(seehttp://www.embo.org/FM00_Abstracts.html and
http://www.embo.org/Fellmeet00_report.html for a flavour of last year’s meeting).
This year's meeting (http://www.embo.org/FM01.html) incorporates a novel concept;
it ends with a media workshop in which professional journalists will discuss the
communication of science to the press and lay public.
From the Fellows Meeting grew the idea of a lasting network supported by Webbased resources. These now include the following:
 Fellows Directory
(http://www.embo.org/Fellowsarea/Fellows_secure_page.html): A searchable
database of fellows past and present, containing contact information, interests,
willingness to give advice on grants, and living abroad.
 Job Market (http://www.embo.org/Positionsvacant.html): A searchable database
of positions worldwide in the life sciences
 Survival Pack (http://www.embo.org/Survivalpack.html): A growing source of
information on living abroad
 Free access to Science Next Wave
(http://www.embo.org/Fellowsarea/Fellows_secure_page.html): EMBO is
working with Science's Next Wave on contents sharing and generation, and
EMBO fellows, past and present, now have free access to Next Wave.
Please contact Andrew Moore, PhD (moore@embo.org) for more details.
22
Genes and Genomes – The Basics.
James O. McInerney, Bioinformatics and Pharmacogenomics Laboratory,
National University of Ireland, Maynooth, Co. Kildare, IRELAND
The year 1995 will be remembered as the year when the Genomic era began in
earnest. The completion of the DNA sequence of the human pathogen Haemophilus
influenzae – a common causative agent of pneumonia – heralded the onset of largescale molecular genetic ventures. In the next few years we were to see the completion
of dozens of prokaryotic genomes and even a small eukaryotic sequence was
completed, that of Saccharomyces cerevisiae, the brewers yeast. Just as the century
was about to close, the rate of progress in genomics really gathered pace. Celera
Genomics Corporation entered the race to sequence the human genome and additional
funding was made available to the public venture so they could release the data into
the public domain before it became possible to have it patented. A joint release of the
preliminary sequence was made in June 2000 with simultaneous publication of two
drafts in February of this year in the journals Nature and Science. This was a
significant landmark and its affect on medicine will be significant. As we move
forward we are beginning to address issues such as how variation in the human
genome affects susceptibility to disease and reaction to drugs. The disciplines of
pharmacogenomics (the integration of genomics and drug development) and
theranostics (the prescription of a drug in combination with a genetic test for
appropriateness) are beginning to develop and the era of personalised medicines is
upon us. This presents both challenges and opportunities, the potential for great
advances but also the dangers of unethical misuse of these technologies.
23
Genetics: A spiralling problem?
Tom Shakespeare, International Centre for Life, UNITED KINGDOM
Increasing genomic knowledge can be seen as a good thing, because knowledge is
power. But sometimes ignorance is bliss. Pharmaco-genetics and gene therapy are
future applications. Current applications are largely diagnostic. Problems here are to
do with efficacy and unintended consequences of genetic interventions, and to do with
funding research and development, and ensuring equal access to new drugs and
therapies.
Post-natally, prediction and diagnosis in the absence of effective therapies or
behavioural changes may raise anxiety without improving health. Problems of
privacy and discrimination are raised by features of genetic information. Defining
health and illness in individual genetic terms may detract from wider social and
economic changes and contribute to a shift in priorities which has detrimental effects.
Pre-natally, genetic diagnosis raises the difficult moral problem of abortion. While
supporting a woman’s right to choose, there are important reservations about the
context in which choice is made, and the values underlying extensions in clinical
genetics. Will people who do not take advantage of diagnostic techniques be blamed?
Will disability be seen as a problem best avoided? Will there be increasing
discrimination against disabled people post-natally because of selective termination
pre-natally? As well as social and ethical problems, there are psychological costs of
this information and new responsibilities which the ability to terminate pregnancy on
grounds of foetal abnormality present.
These perspectives are important to balance the rhetoric and enthusiasm associated
with genomics. Much of the language of advocates is hyperbolic, and sometimes
misleading, and often offensive to people with genetic conditions. Appropriate
interventions and responses are needed in the case of genetic differences. Disclosure
dilemma abound. Increasing diagnostic powers of gene chips, and increasing insights
into behavioural genetics, make it imperative to build a more robust model for dealing
with genetic information.
References
1. Gabe J and Conrad P (2000) Sociological Perspectives on the New Genetics.
Oxford: Blackwells.
2. Kerr A and Shakespeare TW (2001) Genetic Politics: from eugenics to
genome. Cheltenham: New Clarion Press.
3. Marteau, TM and Drake, H. (1995) Attributions for disability: the influence
of genetic screening. Social Science and Medicine 40:1127-32
4. Rapp R (2000) Testing Women, Testing the Fetus: the social impact of
amniocentesis in America, New York: Routledge.
5. Shakespeare T (1999) ‘Losing the plot’?: medical and activist discourses of
contemporary genetics and disability. Sociology of Health and Illness, 21, 5:
669-688
6. Parens E and Asch A (2000) Prenatal Testing and Disability Rights.
Washington: Georgetown University Press.
24
What does genetic testing mean for you?
Andrew J. Green; Prof. of Medical Genetics, UCD; Director, National Centre for
Medical Genetics, Our Lady’s Hospital, Crumlin, Dublin 12
The major advances in human genetics over the last decade, culminating in the
sequencing of the human genome announced 6 months ago, have promised much in
terms of benefit for medicine. One of the perceived benefits is more widespread and
accurate genetic testing for many disorders, which are known to have a genetic
component. Genetic tests have been portrayed as giving certainty, and an absolutist
approach towards the practice of medicine.
Already, for a small number of families, predictive genetic testing for single gene
disorders is being carried out. In these families, a genetic test can give certainty (e.g.
you do not have the genetic alteration known to cause a disease in you family).
However, genetic testing can also move uncertainty to a different level (you do have
the genetic alteration known to cause the disease in you family, but we can’t tell you
how, when, or in what way you may be affected).
Predictive genetic tests raise complex issues about genetic information which may be
released to insurance companies or employers, with the potential to discriminate on
the basis of one’s genome.
In the future, genetic tests may be used to determine one’s relative risk of developing
a complex disorder such as high blood pressure, diabetes, or Alzheimer’s disease. But
these tests will not give the certain yes/no answer many people seek. Instead, these
genetic tests will give a compound likelihood of developing a range of these
disorders, making interpretation and prognosis estimation difficult.
Thus genetic testing raises a new model of interpretation and application of new
technology, which will require a change in the thinking from both doctors and their
clients in how to deal with the new genetics.
25
Genetics, Policies and Ethics
Marja Sorsa, Department for Education and Science Policy, Ministry of
Education, Helsinki, Finland
Genetic technologies are in the forefront of public debates on the prospects, benefits
and risks involved with the development of science and new technologies. Science
has to achieve a new social contract with the society, and such governance may have
its effects on the directions and priorities on research funding. This is a new challenge
also to the scientific community to intensify communication with the public - who
wants to be involved in making decisions, which might be of concern to their future
and well-being.
Bioethics has developed from the public awareness that scientific and technological
progress has important human and social implications, which raise ethical concerns.
The various uses and applications of genetic testing entail a variety of ethical
questions, many of which focus on the ownership and use of this information as part
of human integrity. The controversies between paternalism vs. autonomy of decision,
protection of confidentiality or anonymity, prevention of discrimination and
stigmatisation, prevalence of safety and scientific quality are among the ethical issues
involved. Commercialisation of genetic testing also poses ethical questions, which are
highly relevant with predictive genetic testing, especially with applications designed
to test employees or insurance applicants.
The basic principles of respect for autonomy, non-maleficience, beneficence and
justice must be followed also the research stage of biomedical studies. The individuals
must have the right to withdraw at any time of the study without consequences in
further treatment. There must be the right to be informed or not to be informed about
the study results. It is the responsibility of the researcher to guide for appropriate
treatment or prevention of specific exposure conditions. Confidentiality must prevail
throughout the study and future use and handling of individual data and samples.
Various international, European and national level legal and advisory instruments
have been prepared for the guidance of research, researchers and policy makers. The
Council of Europe Convention on Human Rights and Biomedicine (1997) and the UN
Universal Declaration on Human Genome and Human Rights (1998), prepared by
UNESCO, have clear ethical implications on genetic research. Among the recent
directives by the European Union, the directive on Data Protection (1995) refers to the
principle of respect for privacy, the directive on Protection of Biotechnological
Inventions (1998) refers to morality as a contraindication of patenting, and the
directive on In Vitro Diagnostic Medical Devices (1998) refers to the protection of
integrity of human persons. The directives have been or are in the process of being
implemented in the national legislation of EU Member States and thus pose ethical
implications on genetic research applications.
The Framework Programme of research and technological development of the EU
clearly specifies that all research activities shall be carried out "in compliance with
fundamental ethical principles". Also the new framework programme for 2002-2006,
contributing towards the creation of the European Research Area, will follow the
respect of fundamental ethical principles as they appear in the Charter of Fundamental
Rights of the European Union (2000).
26
Gene Therapy – An Overview
Jane Farrar, Smurfit Institute of Genetics, Genetics Dept., Trinity College
Dublin.
During the presentation a number of key issues relating to the development of gene
therapies will be discussed. Issues that will be touched upon include the powerful
impact of the information emerging from the Human Genome Sequencing Project on
both our understanding of the genetic aetiologies of many disorders and our ability to
design effective drug / gene therapies for such diseases. The broad scope of potential
targets for gene-based therapeutics will be profiled including Mendelian disorders,
polygenic disorders, infectious disorders and the modulation of normal physiological
responses. Prerequisites for developing gene-based therapeutics will be outlined using
inherited eye disorders as an example. Additionally, the failures, successes and future
challenges for the field of gene therapy will be reviewed.
27
Appendix III
MCFA POSTER PRESENTATIONS
Investigation of the role of Ig signalling function at late stages of B
cell development, by conditional gene mutagenesis in the mouse.
Nathalie Uyttersprot, K. Rajewsky, Institute for Genetics, University of Cologne,
GERMANY
The B cell antigen receptor complex (BCR), which consists of a membrane-anchored
immunoglobulin (Ig) in association with a heterodimer of the transmembrane
proteins Ig and Ig, plays an essential role at all stages of B cell development as
well as for B cell activation (1). Ig and Ig contain immunoreceptor tyrosine-based
activation motifs (ITAMs) within their cytoplasmic tail and constitute the signalling
subunits of the BCR. It has been shown that Ig and Ig
within the BCR and cooperate for efficient signalling. In vivo studies have
emphasised the importance of Ig and Ig signalling function during B
lymphopoiesis in the bone marrow (2-4). In contrast, the role of Ig and Ig in mature
or memory B cells is still poorly understood. This work was initiated in order to
investigate the role of BCR signalling subunits at later stages of B cell development.
For this purpose, we designed a strategy, based on the Cre/loxP technology (5-6), to
generate mutant mice that would conditionally express signalling-defective forms of
Ig. These mutant forms of Ig carry either a truncated cytoplasmic domain (Ig C)
or tyrosine-to-phenylalaline mutations within the ITAM (Ig YY-FF).
Homologous recombinant ES cells carrying the IgC conditional allele have been
used to generate chimeric mice, which are currently being crossed to wild type mice
in order to transmit the mutant allele through the germline. These mice will allow us
to address the requirement for an intact BCR signalling function in the survival signal
provided by the cell surface expression of Ig on peripheral mature B cells, as well as
during the generation and maintenance of memory B cells.
References
1, Reth M. & Wienands J. (1997) Annu.Rev.Immunol. 15 453-479.
2. Gong S. & Nussenzweig M.C. (1996) Science 272 411-414.
3. Torres R.M., Flaswinkel H., Reth M., Rajewsky K. (1996) Science 272 1802
1804.
4. Reichlin A., Hu Y., Meffre E., Nagaoka H., Gong S., Kraus M., Rajewsky K.,
Nussenzweig M.C. (2001) J.Exp.Med. 193 13-23.
5. Rajewsky K., Gu H., Kuhn R., Betz U.A., Muller W., Roes J., Schwenk F.
(1996) J.Clin.Invest. 98 600-603.
6. Sauer B. (1998) Methods 14 381-392.
28
Physiology and flavour formation derived from amino acids
Maria Tabernero, Unilever Research Vlaardingen, NETHERLANDS
The research area comprises the physiology of microorganisms in fermented food
products. The contribution of yeast to the flavour formation is a major research
interest. Many fermented foods contain significant to high amounts of amino acids
derived from plant material. The amino acids are formed by hydrolysis of
proteinaceous material. In many fermented food products the flavours derived from
amino acids are important, e.g. cheese, bread, beer and savoury success such as soy
sauces. Various conversion products are of the group of fusel alcohols and a large
variety of low molecular weight organic acids, alcohols and aldehydes. Each of these
compounds in a certain ratio contributes to the flavour impression of foods. Fusel
alcohol formation is studied at URV for its relevance to savoury sauces such as soy
sauce. Soy sauce contains a high level of amino acids that result in a.o. fusel alcohol.
Fusel alcohol formation can follow various pathways with enzymes both the cytosol
and the mitochondria. The exact pathways, their localisation, the role and regulation
of fusel alcohol formation is still not known. These question can be solved the help of
the yeast genome data combined with defined physiological studies in chemostats and
newly developed modelling techniques.
29
Fluxgate sensors for medical applications
Pavel Ripka*, T. O’Donnell+, S.C. O’Mathuna +, W.G.Hurley*, *Power
Electronics Research Centre, National University of Ireland, Galway on Marie
Curie fellowship from Czech Technical University + NMRC, Cork, IRELAND
Despite of their operational principle being known for 70 years, fluxgates are still the
most sensitive room-temperature vectorial magnetic field sensors. Their resolution is
comparable with that of high-temperature SQUIDs and they are much more practical
devices [1]. Classical fluxgate sensors are rather big and expensive and efforts to
make reduce their size have had limited success. Although some progress was
achieved using double-layer magnetic cores, the performance of microfluxgate
sensors based on CMOS technology is limited by the low thickness of the metallic
layer [2]. A new type of microfluxgate sensors on silicon is proposed. It is based on
the technology for high-aspect ratio flat coils and electrodeposited cores, which was
developed at NMRC Cork, Ireland [3]. At present, computer-assisted design and
simulation are in progress, and the first practical devices will be available in 2002.
These sensors are about 10 mm long and they are suitable to be used in arrays and
multi-axis systems. Possible medical applications include: 1. Tracking devices for
monitoring the 3-D position and also orientation of small permanent magnet which
can be attached to body or medical instrument (such as catheter). The sensor field is
stable and corrections can be made for external fields and field gradients from ferrous
objects and electric currents. Another configuration is being used for tracking the
motion of the body at further distances: signals from small magnetometers attached to
the body are collected and processed. An artificial magnetic field is being used,
because the Earth’s field alone is not sufficient to determine all position and
orientation parameters. Such systems are being designed for virtual and augmented
reality systems [4], but may be also useful for orthopaedics and biokinematics. 2.
Sensor field for magnetopneumography: mapping the distribution of ferromagnetic
particles in the lungs after they are magnetised by strong DC field. This technique was
developed using SQUIDs and because of high cost of these magnetometers and
associated shielded chambers, magnetopneumography never became a practical
diagnostic tool, although it was proven to be more sensitive than X-ray screening. A
classical fluxgate gradiometer was already been shown to have sufficient sensitivity
for this application [5]. 3. Monitoring the position of other magnetic markers, for
example “magnetic biscuits”, which may be used for functional tests of digestive
tract. We are interested in collaboration with other laboratories in similar applications
of microfluxgate sensors.
References
1. P.Ripka (ed.): Magnetic sensors and Magnetometers, Artech 2001.
2. P. Ripka, S.O.Choi, S. Kawahito , A. Tipek, M. Ishida: Micro-fluxgate sensor
with closed core, Sensors and Actuators A 91 (2001), pp. 65-69.
3. M. Brunet, T. O’Donnell, J. O’Brien, S.C. O’Mathuna: Design Study and
Fabrication Techniques for High Power Density Micro-Transformers, Proc.
16th Applied Power Electronics Conference, Mar. 4 – 8, 2001, Anaheim,
California.
4. T. Auer and A. Pinz: The integration of optical and magnetic tracking for
multi-user augmented reality, Computers & Graphics 23, Issue 6, December
1999, pp. 805-808
5. P. Ripka, P. Navratil: Fluxgate sensor for magnetopneumometry, Sensors
and Actuators A60 (1997), 76-79
30
Using a distributed genetic algorithm to discover intron/exon
boundaries in DNA strands
Filippo Neri, DSTA, University of Eastern Piedmont, Italy, and Marie Curie Fellow at
Unilever Research Port Sunlight, UNITED KINGDOM
A distributed genetic algorithm-based concept learner, REGAL and its evaluation
onto a benchmark application (“Splice Junction” dataset) are described. The
benchmark requires to recognize Intron/Exon boundaries in DNA strands. Concept
learning (Michalsky, 1983) is the task of finding a description, in some symbolic
language, for a set of instances of the concept itself. Concept learning have been
applied to a variety of tasks spanning from drug design to computer network security
(Neri, 2000). Genetic algorithms (GA) (Goldberg, 1989) are a Darwinian inspired
method of problem solving. In GAs, a population of potential solutions is evolved till
good ones emerge. In REGAL, each individual encodes a partial concept and, at the
end of the evolutionary process, the whole population hopefully contains alternative
solutions. The system’s architecture is a network of Nodal Genetic Algorithms
coordinated by a Supervisor. The Supervisor dynamically assigns different sets of
instances to each NGA trying to promote the appearance of different species and thus
to maximise the genetic richness of the whole population. In other terms, the
Supervisor tries to increase the emergence of good partial concept descriptions from
which a complete solution can be build. To evaluate the system a benchmark task, the
“Splice Junction” dataset, has been selected (Neri & Saitta 1996). The problem can be
stated as follow: given a sequence of basis, corresponding to a gene in a DNA
molecule, recognise the boundaries between Exons (parts of the DNA sequence
codifying for protein synthesis and then retained after splicing) and Introns (parts not
codifying for protein synthesis and hence spliced out). Three concept have then to be
learned: Exon/Intron boundaries, Intron/Exon boundaries and no boundary. The
dataset consists of 3190 DNA sequences, each 60 nucleotides long. REGAL has been
run three times for 300 generations, for each one of the three classes, with a learning
set of 2000 instances randomly selected from the dataset. In each run REGAL learned
a very general set of rules consistent with the learning set. The average error rates on
the test set of 1190 examples have been EI = 4.40%, IE = 4.20%, NB = 5.20%. From
the performed experiments, REGAL's robustness and performance appears clear. The
results obtained on the splice-junctions datasets, considered non trivial test in the
machine learning community, compare favorably with the ones published in the
literature.
References
1. De Jong, K. et al. (1993). “Using Genetic Algorithms for Concept Learning”,
Machine Learning, 13, 161-188.
Goldberg D.E. (1989). Genetic Algorithms, Addison-Wesley.
2. Michalsky R. (1983). “A theory and methodology of inductive learning”. In
Machine Learning, an Artificial Intelligence Approach, volume I, pages 83-134. Morgan Kaufmann.
3. Neri, F. and Saitta, L. (1996). Exploring the power of genetic search in
learning symbolic classifiers. IEEE Trans. on Pattern Analysis and Machine
Intelligence, PAMI-18:1135--1142.
4. Neri F. (2000). “Mining TCP/IP traffic for network intrusion detection by
using a Distributed Genetic Algorithm”. Proc. of European Conference on
Machine Learning 2000. Barcelona (Spain), LNAI 1810, pp.313-322.
31
Characterisation of drug-DNA interactions using the surface
plasmon resonance technology
Carolina Carrasco, David Wilson and Christian Bailly, Institut de Recherches
sur le Cancer, FRANCE
Surface plasmon resonance (SPR) is becoming one of the major techniques for
investigating molecular interactions between small molecules and nucleic acids (1). It
offers a rapid and powerful tool for screening small molecule libraries and the method
can simultaneously provide kinetic and equilibrium characterisation of the interaction.
In biosensor experiments, the interaction between small molecules in solution and
DNA oligonucleotides immobilised on a sensor chip surface is monitored in real-time,
conferring an improved understanding of the mechanisms whereby small molecules
can recognise and bind to specific nucleotide sequences. We have investigated the
molecular interactions between DNA and two intercalating drugs: the glycoslated
indolocarbazole NB-506 and the indeno- quinoline derivative TAS-103. Both drugs
are potent cytotoxic inhibitors of DNA topoisomerases (2,3) and are currently
undergoing clinical trials as anticancer agents. The interactions of these two
compounds with DNA have been analysed on a BIAcore 3000 instrument using a set
of hairpin oligomers containing various combinations of A-T and G-C base pairs,
such as 5'-CATATATATCCCCATATATATG
and 5'- CGCGCGCGTTTTCGCGCGCG. The association of the compounds with
both AT and GC sequences of DNA is rapid and reaches a steady-state interaction in a
few seconds. Fitting of the steady- state SPR data allowed us to determine and
compare DNA binding affinities as well as the stoichiometry of the interaction. In
addition, the use of different oligonucleotide sequences provided useful information
to better understand the sequence selectivity of the interaction. The SPR results
provide important mechanistic insight into the mode of action of these new anticancer
drugs.
References
1. Davis, T.M. and Wilson D. (2000) Determination of the refractive index
increments of small molecules for correction of surface plasmon resonance
data. Anal. Biochem. 284, 348-53.
2. 2. Kluza, J., Lansiaux, A., Wattez, N., Mahieu, C., Osheroff, N., Bailly, C.
(2000). Apoptotic response of HL-60 human leukaemia cells to the antitumor
drug TAS-103. Cancer Res. 60, 4077-4084.
3. Bailly, C., Carrasco, C., Hamy, F., Vezin, H., Prudhomme, M., Saleem, A.,
Rubin, E. (1999). The camptothecin-resistant topoisomerase I mutant F361S
is cross-resistant to antitumor rebeccamycin derivatives. A model for
topoisomerase I inhibition by indolocarbazoles. Biochemistry 38, 8605-8611.
32
Pharmacogenomics of Omani population: preliminary data on the
occurrence of mutant alleles at the cyp2d6 gene locus
Musbah O. M. Tanira1, N. Al-Nazwan2, H. Al-Barwani2, M. A. Al Zaabi1, R.
Bayoumi2, Departments of 1Pharmacology and 2Biochemistry, College of
Medicine, Sultan Qaboos University, SULTANATE OF OMAN
In Oman, a research programme has been initiated to build up a genetics data-base
aiming at optimising drug therapy. The objective of the first phase of the programme
is to determine genotype frequency of drug metabolizing enzymes (DMEs) in normal
subjects and patients. Previously, we published our first report on N-acetyltransferase
2 genotyping in healthy Omanis (Tanira et al; 2000). In this abstract we are reporting
the preliminary data on CYP2D6 genotyping.
The polymorphic cytochrome CYP2D6 is involved in the metabolism of a wide range
of therapeutically important drugs such as antidepressants, neuroleptics, lipopophilic
betablockers and antiarrhythmics. The enzyme is expressed in three different
phenotypes. Poor metabolisers who lack the active enzyme as a result of inactivating
mutations, rapid metabolisers who have the active gene intact and ultrarapid
metabolisers who have more than one copy of the CYP2D6 gene been expressed. It
has been well recognised that this polymorphism changes with interethnic variation
(Evans 1993, Kalow and Bertillson 1994). Different populations show different
distributions of various CYP2D6 genotypes (Bertilsson 1994). Such variability
indicates that drug dosage requirement may differ among various ethnic groups
Sramek and Pi (1996).
In the present study, we are aiming to define polymorphism of the CYP2D6 gene in
the Omani healthy population. Using Long Polymerase Chain Reaction (LXPCR)
amplification, 38 subjects were investigated. No subject showed numerical change in
the CYP2D6. Further inter-exonal mutations within the gene were examined using
allele specific PCR. Only 22 subjects of the defined 38 normal subjects were
examined. All the 22 individuals did not exhibit mutation A2637del (29A) which is a
frame shift mutation. Only 2 individuals were found with the allele CYP2D6*4
(GA1934) which is the most common defective allele among Caucasians, gene
among Omanis.
So far our results agree with an earlier study of the CYP2D6 genotyping among Saudi
Arabian population (McLellan et al; 1997), stressing the existence of ethnic variation
in this field. The current study is continuing to cover 150 subjects to characterise the
most common mutations and alleles of the CYP2D6 gene among Omanis.
References
1. Bertilsson L, Clin Pharmacokinet 1995, 29:192-209.
2. Evans DAP, Genetics Factors in Drug Therapy, Cambridge University Press,
1993, Chapter 7.
3. Kalow W, Bertilsson L, Adv Drug Res, 1994: 25:1-53.
4. McLellan RA,Oscarson M, et al Pharmacogenetics 1997, 7:187-191.
5. Sramek JJ and Pi EH, Mt Siani J Med 1996, 63:320-325.
6. Tanira, MOM., Simsek, M., Al-Baloushi, KA, Lawatia, K, Al-Barawani H,
and Bayoumi, R AL, Clin Chem 2000, 46:1874.
33
Molecular genetics of breast cancer
Angelika M. Burger1, Suzanne C. Richter2, Michael J. Wong2, Richard
Kitching2, Barbara G. Beatty3 , Renate Grugel1 and Arun Seth2,. 1Tumor Biology
Center at University of Freiburg, Germany,2Sunnybrook and Women's College
Health Sciences Centre, University of Toronto, Canada, 3Ontario Cancer
Institute, University of Toronto, Canada.
Abstract not available
34
MARIE CURIE FELLOWSHIP ASSOCATION
ASSOCIACIÓ D’AMICS UAB
Genomes, Nanotechnology and Quantum
Computation:
The 2001 Human Odyssey
Barcelona (Spain) - 24/25 November 2001
Direct any queries about this conference to:
Dr Josep M. Oliva
Institut de Ciencia de Materials de Barcelona
CSIC
Campus de la UAB
E-08193, Bellaterra
Spain
Tel: 00 34-93-580 1853
Fax: 00 34-93-580 5729
Email: oliva@icmab.es
http://www.mariecurie.org/src/meet/barcelona/index.html
35
FUNCTIONAL GENOMICS AND PROTEOMICS: IMPACT ON
THERAPEUTIC STRATEGIES
Co-hosted by the MCFA, BPS and Elan Corporation, Plc
09.00 - 19.00h Monday 2nd July 2001
Programme A: Fundamental Basis and Relevant Technologies
09.00-09.10 Welcome by Chairpersons.
Michael Ryan, University College Dublin
William Gallagher, University College Dublin
Daniel O' Mahoney, Elan Corporation, Plc
09.10-09.45
Overview: Human Genome and Proteome.
Ewan Birney, European Bioinformatics Institute, UK
09.45-10.20
Genome sequencing of bacterial pathogens.
Julian Parkhill, The Sanger Center, UK (abstract included)
10.20-10.55
Tools for functional genomics, standardisation and production of DNA
and protein glass chips
Wilhelm Ansorge, EMBL Heidelberg, Germany (abstract included)
10.55-11.20
Coffee Break - MCFA Poster Presentations
11.20-11.55
Mining protein complexes and mapping proteomes using mass
spectrometry: A primer.
Andrew Emili, Banting and Best Institute, Canada
11.55-12.30
Genomics and proteomics: impact on receptor pharmacology
Stephen Foord, GlaxoSmithKline, UK
12.30-13.30
Lunch
13.00-14.15
10 min talks + 5 min discussion - Careers Section
Chairperson Welcome Marja Sorsa, Ministry of Education, Finland
William Gallagher, University College Dublin, Ireland
The Marie Curie Fellowship Association
Ana Cerdeno, The Sanger Centre, UK
EMBO Programmes and Young Researchers
Andrew Moore, EMBO, Germany
Science Journalism and PR
Kirstie Urquhart, Science Next Wave, UK
Opportunities in Pharmaceutical Industry
Gary Hampton, Aventis Pharma, France
Career Opportunities in Ireland
Niamh O' Dowd, Science Foundation Ireland, Ireland
36
Programme B: Pharmacological Applications - Disease Implications and Novel
Therapies.
14.30-14.40
Introduction by Chairpersons
14.40-15.10
Neurobiology: Genomics
J. Gregor Sutcliffe, Digital Gene Technologies, USA
15.10-15.40
Cardiovascular disease: Genomics
Desmond Fitzgerald, Royal College of Surgeons in Ireland, Ireland
15.40-16.10
Disease-associated patterns of expressed genes: examples from
diabetic nephropathy and rheumatoid arthritis
Finian Martin, University College Dublin, Ireland
16.10-16.30
Coffee Break - MCFA Poster Presentations
16.30-17.00
Benefiting from human genetic diversity: drug discovery and
pharmacogenomics
Jean-Francois Deleuze, AVENTIS Pharma, France
17.00-17.30
Gene therapy
Ralph Paul, Targeted Genetics, USA
17.30-19.00
Reception and Trade Exhibit - MCFA Poster Presentations
19.00
Buses to Old Jameson Distillery
19.30
Dinner (MCFA Award - Best Poster Presentation)
37
GENOME SEQUENCING OF BACTERIAL PATHOGENS
Julian Parkhill, The Sanger Centre, Wellcome Trust Genome Campus, Hinxton,
Cambridge, CB10 1SA, U.K.
To date, more than 42 bacterial genomes have been completely sequenced and
published, and, at a conservative estimate, sequencing projects for a further 150 are
underway. Of these, 60% and 50% respectively are for pathogenic bacteria.
Genome sequencing of pathogenic bacteria provides insight into the fundamental
structure of these organisms, revealing novel drug and vaccine targets, and allowing
the possibility of rational design of these therapeutic molecules. In addition to these
immediate tangible benefits, bacterial genome sequencing is advancing our basic
understanding of these organisms and the way in which they evolve, shedding light on
the interactions between pathogens and their hosts, and the disease processes
themselves.
Bacteria are enormously diverse, and in many cases a single sequence of a
representative of a species or group is not sufficient; comparative sequencing of
related pathogens, and comparisons between pathogenic and non-pathogenic relatives
will, in turn, reveal a great deal more about the mechanisms of pathogenesis.
38
TOOLS FOR FUNCTIONAL GENOMICS, STANDARDISATION AND
PRODUCTION OF DNA AND PROTEIN GLASS CHIPS
A.Richter, E.Wabek, J.Zimmermann, R.Ventzki, J.Stegemann, H.Erfle, C.Schwager,
W. Ansorge
European Molecular Biology Laboratory, Functional Genomics Technology,
Meyerhofstr.1, Heidelberg, Germany
Functional Genomics requires tools for evaluation of gene expression profiling and
for functional assignment of proteins, e.g. DNA arrays, protein arrays, SAGE, large
scale full length cDNA sequencing, mass spectrometry, cell microinjection, FACS
and others.
DNA chip facility and protocols for production of large scale genomic arrays were set
up at EMBL and used in biological and clinical applications, e.g. whole yeast genome
analysis, metabolism analysis, X-chromosome linked mental disorders, alternative
splicing. Key limiting steps and bottlenecks in the technology were solved, e.g. nonreliable surface attachment of DNA fragments and oligonucleotides, efficient
labelling strategies, glass with minimum fluorescence background resulting in
optimum signal to noise ratio. Surface chemistry was developed for reproducible
covalent attachment of oligonucleotides and of cDNA with wide length range,
enabling to re-use the chips several times in hybridisations. Modified nucleotides for
incorporation into the probes were developed, facilitating stripping of the probe and
re-hybridisation of the slides. Quality of chemicals was verified by electrospray mass
spectrometry, RNA quality on micro-electrophoresis chips. Protocols for reliable
preparation (success rate around 97%) of PCR products from genomic DNA were
established. A horizontal automated, high throughput (up to 1536 fragments
simultaneously) modified ARAKIS DNA sequencing system, developed previously
with EU support, has been used for verification of the quality of PCR products and for
direct computer recording of their length. The established techniques result in low
background, strong signals and highest reproducibility (within 2%) in the DNA
amount in the spots. Set of standard clones is added for quantitative and qualitative
control. Software package ChipSkipper was developed and is used for array data
acquisition and analysis.
39
CAREERS SECTION
13.00-14.15h Monday 2nd July 2001
Location: Arts building, UCD
Hosted by the Marie Curie Fellowship Association
Supported by:
AVENTIS Pharma
The Wellcome Trust
University College Dublin
Science’s Next Wave
Cell Media
As part of the following symposium:
FUNCTIONAL GENOMICS AND PROTEOMICS:
IMPACT ON THERAPEUTIC STRATEGIES
Co-hosted by the MCFA, BPS and Elan Corporation Plc
Contact Point:
Dr. William M. Gallagher
Department of Pharmacology
University College Dublin
Belfield
Dublin 4
IRELAND
Tel. +353-1-7061511
Fax. +353-1-2692749
40
Career Talks
The Marie Curie Fellowship Association
Ana Cerdeno, The Sanger Centre, UK
EMBO Programmes and Young Researchers
Andrew Moore, EMBO, Germany
Science Journalism and PR
Kirstie Urquhart, Science Next Wave, UK
Opportunities in Pharmaceutical Industry
Gary Hampton, Aventis Pharma, France
Career Opportunities in Ireland
Niamh O'Dowd, Science Foundation Ireland, Ireland
Patricia Conroy Human Resources ELAN will also be attending.
Chairpersons:
Marja Sorsa, Ministry of Education, Finland
William Gallagher, University College Dublin, Ireland
41
The Marie Curie Fellowship Association: Before and After the Fellowship
Dr. Ana M. Cerdeño Tárraga.
MCFA Chair (http://www.mariecurie.org)
Senior Computer Biologist
Pathogen Sequencing Unit
The Sanger Centre – Wellcome Trust Genome Campus
Hixton – Cambridge CB10 1SA
United Kingdom
The Marie Curie Fellowship Association (MCFA) represents one of the biggest young
European scientists associations (over 2,500 members). The MCFA is involved in
helping Fellows in both the initial and the final stages of their Marie Curie
Fellowship. In the initial stages, the MCFA has developed a set of so-called
“Welcome Packs” (http://www.mairecurie.org/src/assoc/Loc_Grp/loc_grp.htm) in
every EC Country, with the voluntary help of MCFA members. These packs cover
essential issues in daily life, such as taxation and contracts, and other practical issues
such as tips on looking for accommodation or local contacts. We also provide mailing
lists for every country, through which the new Fellows can ask for help in different
matters. For the final stages of the MC Fellowship, we have developed a jobs database
and a career mailing list, and are developing a CV database. The jobs database was
created in 1998 and is updated on a daily basis and at the moment contains over 6,000
entries (http://www.mairecuire.org/career/jobsoverview.html). The career mailing list
depends mainly on its over 400 subscriber’s job openings postings
(http://www.jiscmail.ac.uk/lists/mcfa-career.html). At the moment it is distributing an
average of 20 messages per month. The CV database is still under development. It
will constitute one of the major CV databases of young scientists in Europe. It will be
used to offer, both to the MCFA and its members, opportunities for contacts with both
industry and academic worlds when positions are opened.
42
EMBO Young Investigator Programme
The EMBO Young Investigator Programme is a part of the growing range of activities
of EMBO. The Programme addresses researchers in the Life Sciences that are within
the first three years of establishing their own independent laboratories, a group that
currently does not have very attractive career opportunities in many European
countries. It can be difficult for young scientists at the start of their independent
research careers to obtain funding because they do not have long track records, a
prerequisite to receiving any kind of grant. This lack of funding possibilities in
Europe may be a factor in deterring young scientists from returning to Europe from
the United States. The extra exposure afforded by membership in the EMBO Young
Investigator Programme should help the young investigators to win additional funds
on their own. For the moment this leverage is a key aim of the programme. The
programme offers an award of EUR 15 000 per year for the three year tenure in most
EMBC member countries. The EMBC also provide the funding for the administration
and networking aspects of the programme. The financial rewards to those that will be
selected as Investigators by an elite EMBO Committee will be few and in some
instances the national response to the financial aspect remains to be clarified. EMBO
has created a fund that would allow to provide additional funding for the selected
young investigators where deemed necessary by the EMBO selection committee. This
extra money could go towards paying a post doctoral fellow, a technician, equipment
or anything else which would help the new laboratory to become truly world class.
The EMBO Council has started the fund with a contribution of EURO 1 500 000.
EMBO is currently seeking additional contributors to this fund.
The programme had its first deadline for applications on the 15th of December 2000.
The EMBO Young Investigator Programme has received 415 applications from all
EMBC member countries. This is an overwhelming response to a new programme
that has not been extensively advertised. The large response is a reflection of the large
demand that such an initiative has in Europe and of course the prestige the EMBO
label carries. To date the EMBO Young Investigator Programme is the only
international programme that is directed towards this important group at this critical
stage in their careers.
43
The applications are evaluated by an EMBO member expert in the field of research of
the candidate before their files are sent to the EMBO selection committee. Selection
Committee members are Maurizio Brunori (I), Doreen Cantrell (UK), Marc Chabre
(F), Maria Carmo Fonseca (P), Yoram Groner (IL), Iain Mattaj (EMBL), Christiane
Nüsslein-Volhard (D), Jean-David Rochaix (CH), Gunnar von Heijne (S) and Maciej
Zylicz (Pol). The final decision on the award will be made end of April 2001. The
EMBO Young Investigators will be invited to a meeting on 3rd-6th July 2001 to be
held at the EMBL where they will present their research and meet the EMBL group
leaders. This will open opportunities to establish links and collaborations, as both
groups represent some of the best young researchers in Europe.
EMBO YIP (http://www.embo.org/YIAtoppage.html)
Please contact Gerlind Wallon, PhD
Dr Gerlind Wallon
Project Manager
EMBO
European Molecular Biology Organization
Postfach 1022.40 D-69012 Heidelberg
Meyerhofstrasse 1, D-69117 Heidelberg
Germany
Tel.: +49 6221 8891 112
Fax: +49 6221 8891 200
e-mail: wallon@embo.org
http://www.embo.org
"From Genomes to Cures" Joint EMBO/EMBL Science and Society conference 16 18 November 2001
Science & Society (http://www.embo.org/Science_and_soc_page.html)
Tagung: Lehrerfortbildung im Fachbereich Biologie; eine Bundesweite Initiative
GENAU! "Science in the pub" (http://www.embo.org/Genau.html)
Fellows Network (http://www.embo.org/Fellnet.html)
_____________________________________________________________________
44
EMBO Programmes and Young Researchers
Young scientists in the postdoctoral stage of their career are at the most mobile stage
of their lives. Many go abroad, often to the USA, but most come back to Europe,
despite the seemingly less attractive environment for science here. Fellowships (such
as the EMBO Long Term and Short Term Fellowships) that encourage movement
assist in this respect. In general, choosing to move geographically during a scientific
career is a good idea; choice of institute and supervisor are equally important
considerations. Fewschemes (EMBO YIP is among them) exist, however, to help
scientists become independent researchers with their own labs. Career and life choices
for scientists at this critical stage of their career can be very difficult. Industry versus
academia, family versus dedication to science, partners and their lives all play a role.
Women often have particular difficulty in breaking through a system that is culturally
masculine. These and more topics will be covered in the presentation.
Dr Andrew Moore
Project Manager
EMBO
European Molecular Biology Organization
Postfach 1022.40 D-69012 Heidelberg
Meyerhofstrasse 1, D-69117 Heidelberg
Germany
http://www.embo.org
45
Science PR and Journalism: A job for everyone?
Science communication has become something of a buzz phrase in the last 15 years or
so. Scientists are being forced to wake up to the fact that funding for their work is
related to public acceptance of what they do. At the same time the number of jobs for
professional science communicators has increased, providing new opportunities for
those scientists who feel they are not ideally suited to the lab. But even if you are
dedicated to a life of research, learning about the role of journalists and public
relations people will stand you in good stead. Most researchers are likely to be asked
to talk to the public about their work at some stage, and if you understand what we do,
and why we do it, you’re likely to be better prepared for your encounters with the
media and the public.
Since leaving the lab in 1995 (yikes, is it really that long ago?!) I’ve worked in PR
(for the British Society for Immunology) and journalism (as UK Editor of Science’s
Next Wave, a weekly career development web magazine for early career scientists,
www.nextwave.org). I’ll aim to share some insights into these jobs, and the reasons
why I believe I’m far better suited to being a science communicator than a hands-on
researcher - and it’s not JUST that I talk a lot…
Dr Kirstie Urquhart
UK Editor Science's Next Wave
http://intl-nextwave.sciencemag.org/uk
Career Resources for Scientists
Science International, Bateman House, 82-88 Hills Road, Cambridge CB2 1LQ
Tel: +44 1 223 326 521
Fax: +44 1 223 326 501
46
Research Career Opportunities in Ireland - Science Foundation Ireland
The Government launched the Technology Foresight Fund of €635 in 2000 to
promote excellence in scientific research in strategic areas relevant to future economic
development in Ireland. This fund is managed by Science Foundation Ireland (SFI).
The initial focus of the Foundation is to support basic research in the areas of
Biotechnology and Information & Communications Technology. The current open
calls for proposals are directed at three focus areas of Biotechnology:

Signal Transduction in Cellular Contexts

Immune Process and Molecular Medicine

Functional Genomics.
and two focus areas of Information & Communications Technology (ICT):

Software Reliability in Complex Software-Intensive Systems

Optical
Transmission
and
Switching
Technologies
(including
related
Nanoscience)
Outstanding proposals in other areas of Biotechnology and ICT will also be
considered. The Foundation will support researchers at two levels, those of Principal
Investigator and SFI Fellow.
This presentation will discuss the new calls for
proposals in terms of areas being funded, the awards available and the application
process.
Dr. Niamh O’ Dowd
Science Foundation Ireland
47