cross-disciplinary research
project at NTNU:
Prediction and modification
in functional genomics: combining bioinformatical, bioethical, biomedical and
biotechnological research
Summary:
We propose a cross-disciplinary
research project covering bioethics, bioinformatics, biotechnology and
biomedicine. The project will focus on prediction
and modification, linked to important
basic research areas including medical diagnosis, gene regulation and
metabolism, to the development of bioinformatics tools for these research
areas, and to research on bioethical implications of such investigations.
What is the benefit of
creating a cross-disciplinary research project where researchers in
bioinformatics, bioethics, biomedicine and biotechnology collaborate to
investigate questions related to prediction and modification in functional
genomics? Firstly, the biomedical and biotechnological questions investigated
are interesting in their own right, and research into these questions will not
only gain the separate fields of biomedicine and biotechnology, but will
introduce important questions to be answered by bioethics and bioinformatics.
Secondly, the bioethical issues will be investigated and will lead to important
information on the perception of risk for individuals and for society. In a
knowledge based society created on the basis of the progress in biotechnology,
biomedicine and bioinformatics, we are confronted with the important task to
design a new system of technology governance. Incorporation of a public input
in decision making in this regard will provide for a democratic legitimacy of
the new system, as well as prevent the block in further development of these
fields. Thirdly, the models and methods developed within bioinformatics will
gain bioinformatics as a research field in its own right, and will lead to
improved understanding of the biomedical, biotechnological and bioethical
questions. Finally, the sum of achievements from each discipline in this cross-disciplinary
research project will be greater than what would have been achieved in four
separate research projects.
This cross-disciplinary
research project is concentrated around the scientific research and
achievements of seven collaborating research fellows and their respective
research groups. We apply for funding of four research fellows, and ask that in
addition two research
fellows are funded through the supplementary budget given to NTNU in connection
with the revised state budget.
Contents:
1)
Cross-disciplinary
research problem.
2)
Project aims and
cross-disciplinary gains.
3)
future project
development.
4)
Project
organization and relation to Program for bioinformatikk and Bioetisk
forskergruppe.
5)
statement of
collaboration and conduct.
A)
Project
participants and
candidate research fellows
B)
short
description of the planned research connected to the research fellows
1)
Cross-disciplinary research
problem
The last few years promising
new fields of research have been introduced. The progress of functional
genomics, has given researchers a better possibility to predict future diseases
and to genetically modify natural organisms. Prediction and modification
are the keywords for this interdisciplinary genomic research project, which
integrates biomedicine, biotechnology, bioinformatics and bioethics.
Functional genomics is a new
discipline where knowledge gained from whole genome sequencing is exploited in
order to give insight into molecular mechanisms underlying biology. The main
challenges are to describe the functions of all genes and their products and to
understand the roles of these genes and gene products in normal biology and
disease- or in modified biology. Central to functional genomics is genome-wide
scans of gene expression and proteins, and the development of bioinformatical
tools.
Diagnosis is the determination
of the nature of a case of disease. A diagnosis is set on the basis of the
information collected from the patient, by the findings in a clinical
examination and specific investigations based on e.g. blood samples, ultrasound
examinations and biopsies. Through these examinations the cause and seriousness
of the disease can be found. When a diagnosis is reached, plans for treatment
can be decided. Diagnosis is sought at the earliest possible stage of the
development of a given disease, so that treatment can be started immediately to
thereby improve the prognosis for the patients. Some diseases, for example
gastric carcinomas, are often not detected until the disease is at an advanced
stage. Consequently, the 5-year survival rates are low and most often in the
order of 10-20%. There is therefore a need for improved diagnostic tools for
early detection of disease.
An area more than 40 times
the size of Denmark was last year cultivated with genetically modified plants
(GMPs). The area used for GMP has sustainable increased more than 10% annually
the last 5 year period (EPSO March 2003). This first generation of commercially
used GMPs has mainly been modified to increase the resistance against pests or
to be resistant against herbicides. Both technologies have largely been adapted
by the farmers in the countries where these plants are cultivated. Genetically,
these modifications of the plants represents only simple additative traits.
In future generations of
genetically modified plants attempts will be done to modify and control
metabolic processes both by genetically taking control of ongoing processes and
by adding/changing biosynthesis and degradation in such a way that new products
are formed. Two such example will be production of long chain fatty acids
(functional food/feed) and manipulation of the nitrogen assimilation of crop
plants. This represents a much more complex biological manipulation and
traditional tools to monitor effects and changes will only be of limited help.
There are tens of thousands of products of primary and secondary metabolism of
plants. High throughput methods and analysis are needed where large samples can
be monitored rapidly although with a high precision. Being more complex to
analyse, the next generations of GMPs will also be harder to evaluate with
respect to consumer risks. It is therefore of outmost interest to establish a
scientific sound system that provide data and methods for analysis of such
data.
In bioethics prediction and modification both draw attention to the ethical problem of
risk-perception.
Better predictive diagnostic tools leads to the possibility of
presymptomatic testing and screening. Individuals without symptoms can benefit
from early diagnosis. The prize to pay is that individuals without symptoms
have to cope with different kinds of risk labels. They are not sick, nor
completely healthy - they are at risk. From an ethical point of view they are
at risk not only for a future disease, but also at risk of losing their open
future and be identified as sick patients. This kind of risk poses an ethical
challenge to the biomedical progress on early detection of possible diseases,
as well as to bioinformatics as a generator of risk information.
There is also a need for
risk information associated with the concept of modification of biological systems, in particular genetically
modified plants. In many countries, including Norway, the public is sceptical
to the use of genetically modified
plants in agriculture and food production, thus the public feel at risk. One
way or another, this poses an ethical problem; either the public is justified
in their suspiciousness to genetically modified organisms, and the research is
ethically problematic. Or the public is wrong and their suspiciousness is
ethically problematic. As with genetic prediction of future diseases, genetic
modification of natural organisms raises questions about how the risk should be
perceived, what is the relation between expert knowledge and the average
understanding by the lay people and ultimately whether the introduction of even
more risks to our risk society can do more good than harm. Thus, a case-based
analysis of ethically relevant uncertainty in the dispute on genetically
modified food would be highly relevant.
We have witnessed recently a
public controversy about genetically modified food, which among other things
has caused a profound political split between Europe and the US. These events
have underlined that both: successful development of science and of the
biotechnological industry depends on consumers, their risk perception of
biotechnology and attitudes to it. International surveys show that people have
two main sources of concerns: ethical issues based on fundamental values and beliefs and the issue of risk. This underlines the importance of
mapping these values and of risk perception, and balancing them against values
and perception of scientists, industry and other stakeholders. Afterwards this
information can be used in the deliberation process when the new generations of
genetically modified food will be developed. Investigation of the genetically
and biologically effects of controlled manipulations of metabolic processes
must be based on biotechnological and bioinformatical modelling and analysis of
plant data.
With the common task of prediction and modification in
functional genomics we will in this research project focus on two specific
research themes in biomedicine and biotechnology. Important ethical questions
have been raised concerning both genetical prediction and modification. We will
finally stress the need for bioinformatical tools to improve biological and
medical understanding of the mechanisms underlying genetic prediction and
modification. Bioinformatics is the field of science in which biology, computer
science, and information technology merge into a single discipline. The
ultimate goal of the field is to enable the discovery of new biological
insights as well as to create a global perspective from which unifying
principles in biology can be discerned. There are important sub-disciplines
within bioinformatics: (1) the development of new algorithms and statistics
with which to assess relationships among members of large data sets, (2) the
analysis and interpretation of various types of data including nucleotide and
amino acid sequences, protein domains, and protein structures; and (3) the
development and implementation of tools that enable efficient access and
management of different types of information.
Thus, bioinformatics is both
a research area in its own right, as well as a service towards other research
areas like biotechnology and biomedicine.
There has to be an active multidisciplinary research activity focusing
on making techniques from informatics, mathematics and statistics available for
solving important problems in biology (biotechnology and biomedicine). This
interaction between biomedicine, biotechnology, bioinformatics and bioethics is
the fundament upon which this cross-disciplinary research project is
based.
2) Project aims and cross-disciplinary gains
The common focus of this
project is prediction and modification in
functional genomics. The project can be decomposed into four axes. These
axes are the,
·
biomedical
axis: prediction based on gene
expression - the study of gastrin regulated genes and gastric carcinomas, and
identification of predictive markers for cancer diagnosis
·
biotechnological
axis: genetic prediction and modification
– the study of genetically controlled changes of plant metabolism,
·
bioinformatical
axis: genetic prediction and modification
- development of statistical, mathematical, chemometrical and informatical
models and methods, for generation of predictive models for medicine and
biotechnology
·
bioethical
axis: risk and genetic prediction -
presymptomatic screening, risk-perception and public health, public
perception, identifying stakeholders
and mapping their values with the aim to incorporate them into policy process
and consensus building.
The four axes provide
balance and symmetry in the project necessary to be able to achieve
cross-disciplinary gains. The biomedical questions guide the development of
bioinformatical methods and the findings from applying the bioinformatical
methods give raise to new interpretations and new questions to the biomedical
and biotechnological studies. Specifically, the biomedical and biotechnological
researchers need information from the bioinformatical researchers on design of
experiments, analysis and interpretation of data. The bioinformatical
researchers need precise biomedical and biotechnological hypotheses and
background knowledge to use biotechnological and biomedical data optimally when
developing new statistical methods for data analysis. The bioethical-medical
work is based on studying and discussing both the biomedical, biotechnological
and bioinformatical work. The analyses and interpretations of
the results necessitate close contact with the bioethical-political dimension
of this collaboration in order to better understand the processes and premises
that influence the authorities and decisions when new technologies is
introduced on a larger scale.
Specific project aims
Ø
The
principal biomedical objective is to
achieve a better understanding of molecular mechanisms involved in
gastrin-mediated regulation of cellular, physiological and pathophysiological
processes in the gastrointestinal tract; and to exploit this knowledge in
development of improved diagnostic tools for gastric cancer. Component
objectives:
o
Identify
molecular mechanisms involved in gastrin responses
o
Discover
informative molecular markers for gastric cancer
o
Evaluate
the use of these markers for presymptomatic diagnosis of gastric cancer
o
Identify
molecular mechanisms involved in gastric cancer with the aim to assist in the
search for improved treatment
Ø
The
principal biotechnological objective
is to produce plants with specific genetically controlled modifications in
primary and secondary metabolism and regulatory components and to acquire
metabolic and transcript profiles for modelling and metabolic and regulatory
networks.
o
Production
of plants with gene specific knock-outs and genetically controlled
modifications.
o
Trancriptional
profiling using high density DNA microarrays and validation of these data by
small scale methods of molecular genetics.
o
Metabolic
profiling of samples from knock-out plants and transgenic plants with specific
metabolic or regulatory modifications.
o
Evaluation
of the environmental impact on transcriptional and metabolic profiles and the
value of slow and rapid profiling methods.
o
Evaluate
the global effects of genetically modifying plants in the context of potential
consequence and risk assessments (health & environment).
Ø
The
principal bioinformatical objective
is to solve the problems raised by the biomedical and biotechnological
objectives. That is,
o
Develop
new statistical tools for analysis of microarray data. Focus will be on
development of methods for selecting optimal designs for microarray
experiments, finding differentially expressed genes between modified and
non-modified plants and methods for using measured gene expressions for
discrimination between different subclasses of tumours and prediction of prognosis
and choice of treatment.
o
Develop
new tools for modeling gene-protein networks with the aim to identify central
regulators and effectors of gastrin-mediated biological responses.
o
Develop
tools for prediction of gene function from gene expression and biological
background data.
Ø
The
principal bioinformatical (metabolic
networks) objective is directed against the integration of data to predict
and model metabolic networks.
o
Develop
new tools for integrated analysis of data for transcriptional and metabolic
profiling.
o
Analyse
and predict the role(s) of molecular switches controlling signal transduction
pathways and cascades.
o
Develop
tools and algorithms for analyses of data from rapid sampling experiments.
o
Develop
tools for prediction of gene function from gene expression and biological
background data.
o
Evaluate
the global effect/responses at transcript and metabolite level of single
component metabolic engineering/genetically controlled modifications.
Ø
The
principal bioethical-medical
objective is to explore the expectations and ethical considerations of
researchers and clinicians concerning the application of the new diagnostic
tools compared to expectations and possible ethical dilemmas expressed during
the development of methods currently in use for presymptomatic diagnostics.
This knowledge is important in studying the processes behind the implementation
of new medical technology on a larger scale. Focus is also on discussing
ethical questions related to presymptomatic cancer diagnosis in a general setting
of risk assessment and quality of life. That is:
o
Study
expectations to the clinical application during the development of a new
diagnostic method in order to establish documentation in a prospective
perspective of the process behind the implementation of new diagnostic
technologies.
o
Study
considerations and ideas prevalent at the time of development of diagnostic
application of technologies in current use for presymptomatic diagnostics and
tracing of risk factors for disease (example: Mammography, cervical smears).
o
Study
the course of diagnostic tools once estimated as indispensable in clinical use
and the considerations and processes behind their decay (example: Pelvimetry in
assessing risk for obstetrical complications).
o
Study
previous scientific breakthroughs and expectations in the scientific and lay
community for public health improvement (Examples: DNA discovery, establishing
smoking as a major disease risk, cloning of sheep Dolly)
Ø
The
principal bioethical-political objective
is to study and develop the contribution to the bioethics discourse that will
help to build consensus between civil society, science, industry and other
stakeholders. To achieve this aim the following sub-goals will be pursued:
o
to
identify and include all relevant stakeholders
o
to
map the values and ethical basis of the stakeholders
o
to
promote the dialogue among stakeholders;
o
to
analyze what mechanisms can be used to facilitate the incorporation of the
public views in policy making.
project
interactions
The project is based on
funding for seven research fellows. Three research fellows are based within the
biomedical and biotechnological axes (one in molecular biology, one in medicine
and one in biotechnology). Further, two research fellows are based within the
bioinformatical axes (one on statistical methods applied to microarray data and
one on modelling of metabolic networks) and two within the bioethical axis (one
towards the biomedical question related to presymptomatic screening,
risk-perception and public health and one towards public perception,
genetically modified organisms and consensus building). Short research plans
for the research fellows are presented in Appendix B.
The research fellows will
work with basis in their respective research groups. Supervision will primarily
be conducted within the research group, but collaboration is expected to take
place at several levels
o
daily
contact between collaborating participants across all disciplines, and
o
quarterly
meetings for the whole group.
To electronically unite the
project participants, a web-page for the project will be developed at http://www.bioemit.math.ntnu.no (bioemit is short
for BIO-Ethical-Medical-Informatical-Technological). The web-page will make our
project accessible to colleagues and others interested in our research, and
will be used to announce meetings, lectures and publications. Invited guest
lectures are an important part of the background research for the bioethical
research in this project, and these lectures will be open to all, and announced
at NTNU.
3) future project development
This
cross-disciplinary research project is built on four axes, where each axis is a
field of research in its own right.
The project has its focus on prediction
and modification in functional genomics. With this focus many medical and
biotechnological questions are candidates for investigation. In order to arrive
at the most fruitful cross-disciplinary results, we have found it necessary to
concentrate on two concrete questions, here related to medical diagnosis
(prediction) and genetically modified plants (modification). However, we will
have an open attitude towards including other related biomedical and
biotechnological questions into this cross-disciplinary project – if it will
gain the project.
We will conclude by focusing on future
development of bioethical questions and bioinformatics as a research field at
NTNU.
One of our main goals for the future
development of the bioethical dimension of the project is in understanding how
we as a society can acquire an optimal level of knowledge in functional
genomics (gene technology) and at the same time avoid unnecessary risk. And,
which possible uses of functional genomics can help us in arriving at the
Norwegian goal of sustainable development.
Food, its ways of production
and our eating habits are standing before a future revolution. A lot of ethical
values are involved in our attitudes and perception of food; this among other
has determined why use of genetic manipulation in this field was met with such
an opposition. New applications are to come: Crops engineered with the purpose
not to contain allergens, plants with changed metabolic pathways, plants
working as vaccines, milk with increased quantity of casein. If we do not wish
to lose the beneficial potential of gene technology we should agree on
acceptable criteria by which to establish ground rules for new applications in
the agrifood sector. The platform for these criteria will serve us as a useful
tool to govern many future developments with social consensus.
Bioinformatics
is an important multidisciplinary research field internationally, nationally
and within NTNU. The bioinformatics research in this project will be linked to
the biomedical and biotechnological focus on genomic prediction and
modification, and initially one research fellow will focus on statistical
methods applied to microarray data, and one research fellow will focus on
modelling of metabolic networks. There are strong links between these two
areas, and they are highly relevant to biomedical prediction and
biotechnological modification in general.
However,
the two bioinformatics positions do not cover the more general needs for
bioinformatics positions at NTNU, in particular with respect to the service
aspect of bioinformatics. This has to be strengthened by new positions in the
near future. Some support can be secured through a new bioinformatics support
position at the IT/AV-section of the Faculty of Medicine, which recently has
been financed through funding for strategy and adaptation (S&O). However,
currently this will mainly be support for hardware and software installation,
we also have to find good solutions for giving support on actually using the
software in a professional way. This has to be a future priority with respect
to funding.
As
bioinformatics is a relatively new multidisciplinary research area, it is
important to actively bring the various disciplines together, in order to become
familiar with each others research areas, and see where the really exciting
possibility for collaboration actually are. Here Programme for Bioinformatics
will have an important role, in creating meeting places for information and
discussion (seminars, working groups etc), disseminate information (web,
mailing lists) and coordinate the activity in general.
4) Organization of the project:
The project will be lead by
associate professor Mette Langaas,
Institutt for matematiske fag, IME. This department will also have the
administrative responsibility for the project.
The project leader will
perform the daily project responsibilities.
The leader will be part of a
project management group consisting of one representative from the group of
supervisors for each of the seven research fellows around which the research in
this project is concentrated. At present the project management group is:
- Postdoc Siri
Forsmo. Institutt for samfunnsmedisin, DMF (bioethics-medical)
- Professor Knut
Erik Solem, Inst. for sosiologi og statsvitenskap, SVT
(bioethics-political/biotechnological)
- Professor Atle
Bones, Institutt for biologi, NT (biotechnology
- Professor
Astrid Lægreid, Institutt for kreftforskning og molekylær medisin, DMF
(biomedicine)
- Professor Arne
K. Sandvik, Institutt for kreftforskning og molekylær medisin, DMF
(biomedicine)
- Associate
professor Mette Langaas, Institutt for matematiske fag, IME
(bioinformatics/statistics)
- Associate
professor Finn Drabløs, Inst. for kreftforskning og molekylær medisin, DMF
(bioinformatikk).
In addition two observers
will participate in the project management group:
- One
representative for Program for Bioinformatikk ved NTNU: Associate
professor. Finn Drabløs, Inst. for kreftforskning og molekylær medisin,
DMF (bioinformatikk)
- One
representative for Bioetisk Forskningsgruppe: Postdoc Berge Solberg, Filosofisk institutt, HF
(bioetikk)
Responsibilities of the project management group:
The project management group
will be responsible that the project aims and objectives are fulfilled and that
the project budget is followed. The project management group can adjust aims
and objectives and research plans, and make necessary changes in the budget in
accordance with changes in the project plan. The project management group is
responsible for future growth and development of the project, in particular
through coordination of future applications and initiatives based on this
cross-disciplinary collaboration.
Relation to Program for bioinformatikk and Bioetisk forskergruppe
Program for bioinformatics
at NTNU and Bioetisk forskergruppe ved NTNU are independent projects/programs
at NTNU. They have a research interest in this
project, but as a group they will keep their independent relationship to all
projects at NTNU. This conclusion has been reached in both
programs after discussion in the program committees.
The present
cross-disciplinary project will develop methods of general interest and will
contribute in discussions of bioinformatical and bioethical problems at NTNU.
However, Program for bioinformatikk and Bioetisk forskergruppe should be funded
as independent projects at NTNU, and this current cross-disciplinary research
program will therefore support the effort of both Programmes to seek separate
funding at NTNU.
However, both Program for
bioinformatikk and Bioetisk forskergruppe have a strong interest in this
research project. Program for bioinformatikk will receive funding from the
project for organising a joint annual seminar on bioinformatics aspects that
are relevant to researchers at NTNU, and Bioetisk forskergruppe will need
funding for coordination the multi-disciplinary research on presymptomatic
testing and risk perception on a national and international level. One primary
task will be to organise a workshop with other researchers within the Nordic
countries.
6) statement of collaboration and conduct
This project proposal has been developed and written in close
collaboration by Atle Bones, Finn Drabløs, Siri Forsmo, Galina Gaivoronskaia,
Mette Langaas, Astrid Lægreid, Berge Solberg and Knut Erik Solem (in
alphabetical order).
We hereby confirm that the described work will be carried out in
collaboration and with the aim of the best possible scientific outcome of this
cross-disciplinary project. We will encourage discussion in the science
community on normative issues and follow relevant guidelines.
Trondheim, March 14, 2003
Atle Bones Finn
Drabløs Siri Forsmo
Galina Gaivoronskaia Mette
Langaas Astrid Lægreid
Berge Solberg Knut
Erik Solem
