CELEX: 51988PC0424
Language: pt
Date: 1988-07-20
Title: Proposta de DECISÃO DO CONSELHO que adopta um programa especifico de investigação no domínio da saúde : Medicina Predictiva - análise do genoma humano (1989-1991) (apresentada pela Comissão)

ARCHIVES HISTORIQUES
DE LA COMMISSION
COLLECTION RELIEE DES
DOCUMENTS "COM"
COM (88) 424
Vol. 1988/0156
 ---pagebreak--- Disclaimer
Conformément au règlement (CEE, Euratom) n° 354/83 du Conseil du 1er février 1983 concernant
l'ouverture au public des archives historiques de la Communauté économique européenne et de
la Communauté européenne de l'énergie atomique (JO L 43 du 15.2.1983, p. 1) modifié en dernier
lieu par le règlement (UE) 2015/496 du Conseil du 17 mars 2015 (JO L79 du 25. 3.2015, p. 1), ce
dossier est ouvert au public. Le cas échéant, les documents classifiés présents dans ce dossier
ont été déclassifiés conformément à l'article 5 dudit règlement ou sont considérés déclassifiés
conformément aux articles 26(3) et 59(2) de la décision (UE, Euratom) 2015/444 de la
Commission du 13 mars 2015 concernant les règles de sécurité aux fins de la protection des
informations classifiées de l'Union européenne.
In accordance with Council Regulation (EEC, Euratom) No 354/83 of 1 February 1983 concerning
the opening to the public of the historical archives of the European Economic Community and the
European Atomic Energy Community (OJ L 43, 15.2.1983, p. 1), as last amended by Council
Regulation (EU) 2015/496 of 17 March 2015 (OJ L 79, 27.3.2015, p. 1), this file is open to the
public. Where necessary, classified documents in this file have been declassified in conformity
with Article 5 of the aforementioned regulation or are considered declassified in conformity with
Articles (26.3) and 59(2) of the Commission Decision (EU, Euratom) 2015/444 of 13 March 2015
on the security rules for protecting EU classified information.
In Übereinstimmung mit der Verordnung (EWG, Euratom) Nr. 354/83 des Rates vom 1. Februar
1983 über die Freigabe der historischen Archive der Europäischen Wirtschaftsgemeinschaft und
der Europäischen Atomgemeinschaft (ABI. L 43 vom 15.2.1983, S. 1), zuletzt geändert durch die
Verordnung (EU) Nr. 2015/496 vom 17. März 2015 (ABI. L 79 vom 25.3.2015, S. 1), ist dieser Akt
der Öffentlichkeit zugänglich. Soweit erforderlich, wurden die Verschlusssachen in diesem Akt in
Übereinstimmung mit Artikel 5 der genannten Verordnung freigegeben; beziehungsweise werden
sie auf Grundlage von Artikel 26(3) und 59(2) der Entscheidung der Kommission (EU, Euratom)
2015/444 vom      13.   März 2015     über die   Sicherheitsvorschriften für den Schutz von  EU-
Verschlusssachen als herabgestuft angesehen.
 ---pagebreak---        COMISSÃO DAS COMUNIDADES EUROPEIAS
                                                COM ( 88 ) 424   final - SYN 146
                                                Bruxelas , 21 de Outubro de 1988
                                  Proposta de
                             DECISÃO DO CONSELHO
            que adopta um programa especifico de investigação
no domínio da saúde : Medicina Predictiva - análise do genoma humano
                                  ( 1989-1991 )
                         ( apresentada pela Comissão )
 ---pagebreak---                                                                V
    PROPOSAL FOR A COUNCIL DECISION ADOPTING A SPECIFIC RESEARCH
                 . PROGRAMME ,IN T*i& FIELD OF HEALTH i
              PREDICTIVE 'MEDICINE . V HUMAN GENOME ANALYSIS
                         't .    CONTENTS
0.      SUMMARY                        -                         ... 1
1.      REASONS FOR PROPOSAL t
1 .     What is Predictive Medicine ?
1 .     The scientific basis for Predictive Medicine
1 .   L      The organization of genetic information :
             Mapping human genes
1 .  22      The occurrence of genetic disease
1 .  33      Technologies for mapping genes
1 .   3.1
     3.1     Genetic linkage maps
1 .   3.2
     3.2     Physical maps
1 .   3.3
     3.3     Ordered clone libraries
1 .   3.4
     3.4     Sequencing
1 .   3.5
     3.5     Management of information and materials
1 .  4i      Applications of gene mapping in Predictive Medicine
1 .   1.1
     4.1     Diagnostic applications
1 .   1.2
     4.2     Identification of genes associated with disease
1 .   1.3
     4.3     Gene therapy
1.      Social and ethical considérations
2.      THE PREDICTIVE MEDICINE PROGRAMME : HUMAN GENOME ANALYSIS 10
3 . ' JUSTIFICATION OF THE CONFORMITY OF THE PROGRAMME WITH
        THE OBJECTIVES AND METHODS OF THE EUROPEAN COMMUNITY
3.1 . Conformity with the objectives of the framework
        programme of research and technological development         12
3.2 Justification of the scientific content of the programme :
        the international challenge and European scientific
        cohesion                                                    13
3.3     Relation to other Community research programmes             13
3.4     Precompetitive nature of the research                       14
3.5     Management and évaluation                                   14
4.      IMPLEMENTATION AND FINANCIAL MEANS                          15
4.1 . Networks of facilities
4.2     Research contracta                                          16
4.3     Training                                                    16
4.4     Scientific Management                                       17
4.5     Commission Staff                                            17
4.6     Summary of Financial Means                                  17
                                                                    l/
             PROPOSAL FOR COUNCIL DECISION AND ANNEX                18
             FINANCIAL RECORD                                       26
            IMPACT ON SMALL AND MEDIUM-SIZED ENTERPRISES            30
                              A
 ---pagebreak---                                     SUMMARY
Infectious disease is no longer the major cause of illness or
death in the Western world . Instead , much disease has a genetic
component s it may be the result of inheritance of a single
defective gene ( monofactorial ) or of the interaction of multiple
ge.ie defects ( multifactorial ) with environmental factors .        Many
common and debilitating diseases such as coronary artery disease ,
diabetes and the major psychoses*, fall into tha latter category ,
i.e. the disease results from the exposure of genetically
susceptible people to environmental factors . Predictive Medicine
seeks to predict susceptibility to diseases with a view to their
prevention and early diagnosis , as well as to improved prognosis
and , eventually , treatment .
The human genome is the complete set of genetic material
( deoxyribonucleic acid , or DNA ) which embodies the instructions
describing each human being .         It is now possible to analyse , or
map , the genome in such a way that one can " read " these
instructions and , in so doing , locate the genes which , when
altered , give rise to particular diseases . Along the way it will
be possible to make fundamental new discoveries in biology and
acquire new technology for medicine .
The      Predictive Medicine     Programme  will  contain the  following
strands       :
     .1 improvement of the resolution of the human genetic map , i.e.
    crea tion of a map of the human genome , consisting of DNA
    7i' = i-Vers , which would enable researchers to locate genes easily
    and quickly ;
    the setting up of ordered clone libraries ,                 i.e.   of
    collections of ordered sets of DNA fragments which fully
    r-' - ^esent the DNA present in the entire genome , selected
    chromosomes or chromosomal fragments ;
    the improvement of advanced genetic technologies and , through
    a       training programme ,    the spreading of these advanced
    technologies throughout the Member States .
The programme is a European response to the international
challenges presented by the large-scale biological research
projects in the United States ( Mapping and Sequencing the Human
Genome ) and Japan ( Human Frontier Science Programme ). Although
it is a programme of basic precompetitive research , both new
information and new materials of potential commercial value will
result ? new technological processes will also be developed .
These , will all contribute to the development of Europe 's
biotechnology industry - often based in small and medium-sized
enterprises .
                                       1 tà_n.
 ---pagebreak--- As the title implies , the content of the programme will have the
ultimate aim of identifying genes involved in disease , with a
view to their isolation and structural analysis .
The enormous increase in genetic information - or rather the uses
to which it may be put - does raise ethical questions . Aspects
such as personal privacy must be weighed against general health
care considerations ; the ability to diagnose disease will outrun
the possibilities of treating it .    These and many other issues
must be given serious consideration .
                                 2
 ---pagebreak--- RESEARCH PROGRAMME IN THE FIELD OF HEALTH      s PREDICTIVE MEDICINE-
                         HUMAN GENOME ANALYSIS
 1 .         REASONS FOR PROPOSAL
 1.1         WHAT IS PREDICTIVE MEDICINE ?
Fifty years ago the principal cause of morbidity and mortality
was infectious disease but with the discovery of antibiotics , and
improvements in hygiene and pest control , it is now a minor one
in industrialized countries .        Apart from the consequences of
accident or war , much disease today has a genetic component which
may be of greater or lesser importance . Over the past few years
a great deal has been learned about those diseases which are due
to the inheritance of a single defective gene , though in most
cases we are still very far from a remedy .
However , when it comes to the common diseases such as coronary
artery disease , diabetes , cancer , autoimmune diseases , the major
psychoses and other important diseases of Western society , the
position is far less clear .         These conditions have a strong
environmental     component and although genetic         factors  are
undoubtedly involved , they do not follow any clear-cut pattern of
inheritance .    Put another way , the disease results from the
exposure of genetically susceptible individuals or populations to
environmental causes ; prevention will depend on reducing the
levels of exposure either in populations or , more probably , in
susceptible individuals . As it is most unlikely that we will be
able to remove completely the environmental risk factors , it is
important that we learn as much as possible about the genetically
determined predisposing f'cfcrs and hence identify high-risk
individuals . In summary , Predictive Medicine seeks to protect
individuals from the kinds of illnesses to which they are
genetically most vulnerable and , where appropriate , to prevent
the transmission of the genetic susceptibilities to the next
generation .
1.2   SCIENTIFIC BASIS FOR PREDICTIVE MEDICINE
1.2.1   THE ORGANIZATION OF GENETIC INFORMATION :
        MAPPING HUMAN GENES
The human genome is the complete set of genetic material -
deoxyribonucleic acid ( DNA ) - which embodies the instructions
describing each human being . It is now within the realms of
possibility to " read " these instructions in their entirety and ,
in doing so , to make fundamental new discoveries in
biology , to learn to predict and ultimately treat genetic
diseases , and to acquire new technology for medicine .
Each human being has two sets of 23 chromosomes along which are
arranged an unknown number of genes (a seguence of bases in DNA
which codes for one protein ), the best total estimate of which is
50,000 to 100,000 . Each gone is composed of DNA , which is a
                                   3
 ---pagebreak--- thread - like substance made up of nucleotides (a purine or
pyrimidine base attached to a sugar and phosphate group ), and
generally found as two strands wrapped around each other in the
form of a double helix . The two strands are held together by
bonds between base pairs of nucleotides . The linear pattern of
nucleotides in the genome is known as the DNA sequence and its
length is measured in base pairs of DNA . The human genome
contains about 3,000 million base pairs .
A variation in this hereditary set of instructions occurs when
there is a mutation , or change in the sequence or number of
nucleotides in one or more genes . The challenge is to find the
genes which , having mutated , give rise to a particular disease .
Logically , this must be achieved by first locating the position
of the genes along the chromosomes and then defining the
sequence     of    nucleotides      that   determine  normal    genetic
characteristics ;     only by defining the normal genetic structure
can the abnormal then be recognized . Such a genetic map is the
equivalent of a dictionary since it provides a unique ordering of
the genes . We need only think of the problem of looking up a
word without a dictionary or of finding a book in a library
without a       catalogue .  Having access to this        " human gene
dictionary " is thus absolutely fundamental to the speed with
which we can analyse human genetic variation and to our
understanding of the complex ways in which genes interrelate to
determine human development .
1.2.2     THE OCCURRENCE OF GENETIC DISEASE
Genetic variation giving rise to disease can be present in all
body cells , including the germ ( egg and sperm ) cells , and can be
transmitted from one generation to the next . Other variation is
present only in somatic ( non-sexual ) cells and has consequences
only for that person . Many types of cancer arise as a result of
mutations of the latter type .
In broad terms , disease involving inherited genetic factors can
be divided into three categories :
   single gene defects          ( monofactorial ) which show simple
   Mendelian inheritance patterns . Most of these conditions are
   rare in themselves but since there are many of them , they
   represent in total a substantial burden of disease . Currently
   some 4,200 single gene defects are recognized and manifest in
   2.5% of all liveborn in Western European populations ;
   multiple gene defects ( multifactorial ), in which multiple
   genetic and environmental factors are involved . Many common
   debilitating diseases fall into this category ;
   abnormalities of chromosome number and structure , as in Down 's
   syndrome .
                                      4
 ---pagebreak--- The incidence of some diseases which are due to single gene
defects is given in Table 1 ; that of some common diseases of
multifactorial origin is in Table 2 .
Table 1 : Occurrence of some single gene defect diseases in
               Europe
Disease                     Occurrence related to        Prognosis
                            number of births
Cystic fibrosis                 1 / 2,500               Life rarely
                                                        exceeds 20 years
Sickle cell disease             1 / 6,000 *             Variable serious ¬
                                                        ness , often lethal
Phenylketonuria                 1 / 15,000              Favourable if early
                                                        diagnosis
Lesch-Nyhan Syndrome             1 / 16,000              Kidney and brain
                                                        disturbance ,
                                                        generally lethal
Beta-thalassemia                    **                  Life rarely exceeds
                                                        20 years
Duchenne muscular               1 / 7,000 ***           Myopathy after the
dystrophy                                               the age of four ,
                                                        fatal outcome
                                                        around 20 years
Immunodef iciencies                    *Ar              High death rate
* Infrequent in Europeans , sickle cell disease (a haemolytic
anaemia ) may have a frequency exceeding 1 / 100 in some African
populations , 1 / 400 in Caribbean islanders and 1 / 2,500 in black
Americans .
** Infrequent in Northern Europe , beta-thals.ssaemia ( another
haemolytic anaemia ) is widespread in the Mediterranean basin ,
with a maximal occurrence in Cyprus (1 to 2 / 100 ).
*** Linked to the X chromosome , this disease occurs only in boys ,
with a frequency of 1 / 3,500 ( 1 / 7,000 for all births ).
**** The occurrence of genetic immunodeficiencies is low .
Table 2 : Common chronic diseases with a multifactorial
              genetic component
Disease                              Frequency         Frequency in 1st
                                     in general        degree relatives
                                     population        of affected persons
Peptic ulcer                                 1 / 25          1 / 10
Rheumatoid arthritis                         1 / 50          1 / 20
Diabetes mellitus :
 insu lin - dependent                        1 / 500         1 / 33
 in s ul in - independent                    1 / 50          1 / 10
Ischaemic heart disease < 65 yrs             1 / 50          1 / 10
Severe manic-depressive psychosis 1 / 100                    1/6
Epilepsy ( grand mal )                         1 / 200         1 / 25
                                           5
 ---pagebreak--- 1.2.3      TECHNOLOGIES FOR MAPPING GENES
There are different ways of constructing maps of the human
genome . In its most simple form gene mapping means assigning a
gene to a specific chromosome . The first such assignment , made
in 1911 , was of the gene for colour-blindness to the X chromosome
and this depended on the observation that males and not females
were affected .      In the same way . several other X-linked genes
were discovered but some fifty years passed before the
development of new techniques allowed the assignment of genes tc
the other 22 pairs of chromosomes . Even then there was no way of
locating genes whose product was unknown until , in the 1970s ,
recombinant DNA technology         provided a new approach .    This
approach , called reverse genetics , depends on first localizing a
disease gene to a particular chromosome by its association with
genetic markers ( identifiable regions on a chromosome ) within
families exhibiting the disease .       This process is expedited by
the availability of genetic linkage maps for each chromosome .
1 . 2.3.1    GENETIC LINKAGE MAPS
A genetic linkage map shows the distance between genes , and
other genetic markers , on the basis of the frequency with which
they are inherited together . Genes that are close together on a
chromosome usually stay together , or linked , during the division
of egg and sperm cells , a process during which some parts of the
chromosomes recombine .        The distance along      genetic maps ,
represented by recombination frequency , is measured by how often
a particular gene is inherited separately from some marker and is
expressed in centimorgans . If a gene and a marker on the same
chromosome are separated only 1% of the time , the distance
between them is 1 centimorgan and this distance is on average 1
million base pairs of DNA , although there will be major
differences from this depending upon which chromosome region is
under consideration .     Such observations are made by studying the
cosegregation of genetic markers within families , and very
large pedigrees are required to establish linkage relationships
between genetic markers with sufficient reliability .            For
example ,    currently about 600 individuals in 40 large families
have been used to establish a linkage map to the 9 centimorgan
level .     An improvement to between 1 and 5 centimorgans will
necessitate an expansion of the total number of large families by
a further 20 .
Recombinant DNA technology introduced a new dimension to genetic
linkage mapping . Scientists discovered that restriction enzymes
- the tools used to recognise a particular , short DNA sequence
and cut it at that site - sometimes failed to cut the DNA of some
people in the expected places .        As a result , fragments of a
different length were produced and these variations were
inherited .     Known as restriction fragment length polymorphisms
( RFLPs ) , they are used as reference points along the genome
                                    6
 ---pagebreak--- To identify RFLPs generated from very large pieces of DNA , it is
necessary       to    use   radioactively    labelled ,  single-stranded
sequences of DNA called DNA probes , which form base pairs
 ( hybridize ) with complementary sequences in the RFLP markers .
Some useful probes for RFLP mapping are fragments of genes ,
others are complementary to a new generation of markers ,
 "v triable number tandem repeats ", which make use of the clusters
of repetitive DNA sequences found , in varying numbers , throughout
the human genome .
1.2 . 3 . 2 PHYSICAL MAPS
A physical map of the human genome shows the actual distance ,
measured in base pairs of DNA , between genes or markers . Various
low resolution methods of physical mapping are known which are
dependant upon dividing single human chromosomes into several
fragments .      However , they locate only very large pieces of DNA ,
into which either a few or thousands of genes might fit .
Mechanisms for finding a gene of interest in long stretches of
DNA remain primitive .
New methods of separation of very large DNA fragments produced by
restriction enzymes which cut at very rare sites allow the
construction of long-range restriction fragment maps , which have
a considerably higher resolution and bridge the gap between the
single gene and the entire chromosome .
1.2 . 3 . 3 ORDERED CLONE LIBRARIES
Development of higher resolution physical maps is extremely
valuable in helping to locate genes of medical importance . Also ,
for physical mapping projects , it is necessary to have access to
large stocks of DNA and clone libraries can provide such a
source .
Cloning is making multiple copies of a DNA fragment by
incorporating it into a self-replicating molecule which can then
be   introduced     into  a  host cell .  Libraries  are  collections of
cloned DNA fragments from a common source . To construct a
physical map , the order of the cloned DNA fragments relative to
one another along the chromosomes must be known . The goal is to
create a complete set of overlapping clones , whose order is
known , to cover the entire human genome . Once the physical
relationship between cloned fragments has been established , their
nucleotide sequence can be determined .
1.2 . 3 . 4 SEQUENCING
The ultimate physical map will be the total DNA sequence of the
human genome . Although it is feasible to consider sequencing the
genome , to determine the total sequence of 3,000 million base
pairs in a reasonable time would require a very considerable
improvement in existing techniques .
                                     7
 ---pagebreak--- However , there is a case for first sequencing those regions of
the genome which are believed to be clinically or scientifically
important . These would include chromosome regions xn which
clinically important genes are either expressed - i.e.
transcribed into messenger ribonucleic acids ( mRNAs ) which are in
turn translated into proteins - or serve some regulatory
function . One method which has been proposed is first to sequence
DNA copies ( cDNA ) of cellular messenger RNA transcripts , with a
view to using that information to identify which genes are
expressed in the genome .
1.2.3.5    MANAGEMENT OF INFORMATION AND MATERIALS
The production of higher resolution genetic and physical maps
will each generate an enormous amount of data ; establishing the
correlations between them will generate even more . In both cases
there will also be a considerable requirement for the
distribution and collection of materials , e.g. probes , DNA
clones . The efficient management ( and integration ) of the
information and of the handling of materials will be of prime
importance , and argues for the identification of a number of
central    facilities  each  to become  the  centre   of a research
network .
1.2.4     APPLICATIONS OF GENE MAPPING IN PREDICTIVE MEDICINE .
1 t2.4.1 DIAGNOSTIC APPLICATIONS
Tests for genetic disorders are generally used in prenatal
diagnosis of abnormalities such as Down 's syndrome or in
screening the newborn for conditions amenable to treatment , such
as phenylketonuria . They are also used in screening         adults
( often from particular ethnic groups ) for increased risks of
transmitting genetic disease to the next generation - for
instance , by identifying carriers of diseases such as sickle cell
anaemia , beta-thalassaemia , Tay-Sachs disease , etc .
Most of the currently available tests are based not on
identifying the abnormal gene(s ) but on detecting the gene
product ; hence they are limited to some 200 disorders where a
gene product or biochemical marker is known , a small number in
comparison to the 4,200 known single gene defects . Other
limitations to this approach lie in the inaccessibility of some
tissues to sampling ( eye , brain ) and the probability that the
disease will have manifested itself - perhaps irreversibly - by
the time that the genetic defect is detected . Tests which
directly detect the genetic lesion in the DNA overcome many of
these limitations .
In the last five years , 400 or more genetic disorders have been
mapped to a particular chromosome ; of these , some 40 have been
defined in depth and include Huntington 's disease ( chorea ),
cystic fibrosis and Duchenne muscular dystrophy . In each of
these cases , a diagnosis can be made by a DNA-based test without
knowing the gene 's product or function . Further , the test can
be used for preclinical diagnosis of a disease of late onset
                                  8
 ---pagebreak---  ( such as Huntington 's ), for prenatal diagnosis and for detecting
carrier status .
1.2 . 4 . 2 IDENTIFICATION OF GENES ASSOCIATED WITH DISEASE
Importantly , detection of the gene by reverse genetics can lead
tc. our understanding its function and its role in the pathology
of the disease concerned . Examples where this has already
occurred        include    Duchenne     muscular  dystrophy ,   chronic
granulomatous       disease    (a white blood     cell disorder )   and
retinoblastoma (a form of eye cancer ). It can be expected that
in the coming years many other disease genes will be isolated ,
including those involved in such disorders as colon carcinoma and
severe mental retardation .          The availability of a higher
resolution genetic linkage map would simplify considerably the
identification of the genes involved in many common diseases
which , as mentioned above , are caused by multiple gene defects .
Computational methods exist which permit the subpartitioning of
genetic       linkage data and       identification of     those genes
contributing to multiple gene detects .
This      information ,   when   combined with     that  derived   from
overlapping clone libraries , will permit the rapid isolation and
structural analysis of the genes concerned . Improved prediction
of disease susceptibility will result . One of the most important
disease categories is that involving heart and vascular disease .
1.2.4.3       GENE THERAPY
It   is    hoped  that  eventually  it   may be possible  to correct a
defective gene by inserting normal DNA directly into a cell - a
process known as gene therapy . This ultimately depends on the
discovery of safe methods of inserting the DNA and of a means of
ensuring that the DNA corrects the target defect without
producing any other adverse effects . Gene mapping will not have
any direct effect on the prospects for gene therapy but the
knowledge gained about the function of genes may have an
indirect benefit .
1.3      SOCIAL AND ETHICAL CONSIDERATIONS
Information about human genetic make-up will increase enormously
in the course of mapping the human genome ; simpler , faster and
less costly methods of screening for genetic susceptibility to
disease will be developed . This will provide the possibility of
therapeutic intervention to prevent the manifestations of
disease . As genes are identified which are associated with an
increased risk of common diseases , such as heart disease ,
diabetes and arthritis , population screening will become a
possibility . In Western Europe , where there is a steadily ageing
population and an associated ever-increasing cost of health care ,
the prospects both of cheaper testing and of earlier intervention
making possible a decrease in morbidity are very attractive ones .
This enormous increase in genetic information does raise ethical
questions . Improvements in diagnosis and risk prediction will
                                      9
 ---pagebreak--- inevitably   precede    the  development  of therape -. tic remedies ,
creating a growing gap between diagnosis and treatment . The
information about an individual 's genetic const ! tut icv will be
more precise , more detailed and more easily obtained ; it will
benefit individuals by informing them about health risks but it
could also be used to their detriment by third parties such as
employers or insurance companies . Further ethical considerations
wiil arise from the increased range of prenatal diagnoses which
will become easily available - parents may seek to choose the
sex of their children , for instance . These questions do not
arise directly from the information which is collected but from
the uses to which it is put . This implies that , independently of
the technical possibilities and benefits offered by human genome
analysis , it is vital that politicians and Society as a whole
consider seriously the dilemmas presented . Aspects such as
personal privacy , including the right of the individual to know
or not to know , must be weighed against general health care
considerations .
Dialogue and information transfer on the social consequences and
ethical aspects of such research will be organised , in a
systematic manner , with the various interested parties .
There is a unanimous opinion that , also for ethical reasons ,
there must be a rejection of any possibility of modifying the
genetic constitution of human germ cells , even for purely
therapeutic reasons ; this topic will be excluded from this
European Community research programme .
2.     THE PREDICTIVE MEDICINE PROGRAMME : HUMAN GENOME ANALYSIS
The framework programmed ) originally stated that the technical
content of the Predictive Medicine Programme would " mainly be
oriented towards better knowledge of the human genome , immunity
techniques     ( applicable    to   cancer , autoimmune     diseases ,
infections ), genetic engineering processes aiming at repairing
DNA defects ( e.g. in congenital diseases of genetic origin ) and
development of diagnostic test kits ( e.g. for AIDS)” . Since a
choice has to be made , it seems appropriate to concentrate
endeavours on definition of the human genome .
The programme will have these aims :
1)      To achieve a high-resolution genetic map ( at 1 to 5
centimorgan level ) of the human genome . This will require an
increase from 40 to 60 in the number of large families currently
under study in Europe ,      the extra 20 , where possible , to be
families known to have a genetic modification of medical
interest ; the setting up of a network of 10 to 15 European
laboratories with both the interest in and the capability of
working with material from these families ; the establishment of
1 Framework Programme for Community Activities in the field of
   Research and Technological Development ( 1987-1991 ).
   OJ N° L 302 , 24.10.1987 , p. 1-23 .
                                   10
 ---pagebreak--- one or two centres which would provide DNA prepared from the
families to the members of the collaborating network , and also
maintain and distribute to them a collection of the necessary
probes ; and consideration of the role of computing facilities
both to enable participants to handle the collection and
reduction of these data and also to carry out the preparation of
ths map .
2)    To set up collections of ordered DNA clones either from the
entire genome or from selected chromosomes . These ordered clone
libraries , which might be produced in several centres , will
require the establishment of facilities for maintaining the
stocks of cloned DNA fragments , and for distributing DNA - free
of charge - to a network of European laboratories interested in
matching genetic material to these cloned fragments . A related
project could be the sequencing of cDNA clones isolated
independently and mapping them with an ordered clone library .
3)     To improve advanced genetic technologies , with the further
aim of spreading them more evenly among European laboratories .
Examples are : production of new biochemical reagents ( restriction
enzymes ), procedures for labelling DNA probes , amplification of
genes , vectors for the transfer of human genes , methods of
cloning long DNA segments , development of software to help
sequencing , development of new strategies for sequencing , and
creation of overlapping clone banks . The best way to support
this kind of work is by research contracts , with priority given
to collaborations between laboratories in different Member States
working on a common subject , and also to those where there is
participation by industrial laboratories . Communication between
the contracting laboratories will be so managed as to achieve a
collaborative research network .
In the process of improving the genetic map and creating the
ordered clone libraries , due attention will be given to those
chromosomes or chromosome regions known to contain the genes
responsible for specific genetic diseases , especially where this
will optimize the use of existing family material . There is also
a  need   to learn more  about  the location and  function   of the
currently unknown groups of genes involved in the multi ¬
factorial disorders which form the major part of the burden of
disease and where risk prediction is particularly important . A
pragmatic approach will be adopted to maintaining a suitable
balance between these objectives , and to avoiding unnecessary
overlaps with other genome analysis programmes .
A European pilot network for the prevention of one particular
disease taken as a model would be a valuable goal for medical
research in the Community , but this kind of project would need
careful preparation ( both in choice of target and of methods ),
and the setting up of a large-scale programme would be premature .
However , the Predictive Medicine Programme could support the
organization of a collaborative action for the preparation of a
more detailed project . The development of an extensive European
network might be an objective for the follow-up to this
                                 11
 ---pagebreak--- programme . Diseases of particular interest in this respect might
be cystic fibrosis and phenylketonuria .
3.     JUSTIFICATION OF THE CONFORMITY OF THE PROGRAMME WITH THE
       OBJECTIVES AND METHODS OF THE EUROPEAN COMMUNITY
3.1    CONFORMITY WITH THE OBJECTIVES OF THE FRAMEWORK PROGRAMME OF
       RESEARCH AND TECHNOLOGICAL DEVELOPMENT
The Predictive Medicine Programme involves both technological
research and training actions which will contribute to the
achievement of many of the aims listed in the framework
programme .
1)      The activity " Quality of life” includes the Predictive
Medicine Programme in its " Health " line . This aspect is obvious ,
because the development of Predictive Medicine will decrease the
prevalence of many diseases which are very distressing for the
patient and his family , ( incapacitating or painful chronic
diseases , often with a fatal outcome ), as well as being socially
very expensive for the Community .
2)    The goal " to promote scientific research and technological
development at Community level in order to strengthen the
scientific and technological basis of its industry " is also
explicitly addressed by the programme , which aims to promote
advanced technologies with a high added value ( e.g. DNA probes
for diagnostic kits ). Informed estimates of the potential
European market for DNA probes in the next decade suggest that it
is worth between 1,000 and 2,000 million ECU /year .
3)       The goal of " participation of small and medium-sized
enterprises " will also be met because most of the high
technology enterprises which are able and willing to collaborate
in the programme are in this category .
4 ) The goal of " harmonious development of the Community with a
view to strengthening its economic and social cohesion " is
especially important in this field , where the state of scientific
development differs widely between Member States . The provision
of a large number of grants for intra-Community exchanges of
scientists ,      together      with     obligatory     trans-national
collaboration , will aim at promoting greater contact between
individual scientists and at technology transfer to the currently
less advanced laboratories in Member States .
For the future , a follow-up to this programme might include the
launching of a large-scale operation concerning one of the main
diseases     of children   ( coordinated  action  including  research ,
forecasting , prevention and treatment ). This would be the best
way to convince Europeans in general that the creation of a
 " Europe of health " is not merely a matter of public relations but
a living reality .
                                    12
 ---pagebreak---  3.2     JUSTIFICATION OF THE SCIENTIFIC CONTENT OF THE PROGRAMME :
         THE INTERNATIONAL CHALLENGE AND EUROPEAN SCIENTIFIC
         COHESION
The justification of the scientific content of the programme was
set out     in the discussion of the scientific basis    for Predictive
Mv.dicine ( cf . 1.2 ). It is argued that the ability to understand
normal genetic function , and hence to recognize the abnormal and
then predict disease susceptibility , rests on having access to a
 " human gene dictionary ", i.e. a detailed map of the position of
the genes on the chromosomes . This involves improvement of the
genetic map and the physical map , and the setting-up of ordered
clone libraries of the human genome - in the short-term perhaps
of either selected chromosome regions or genes . The total
sequencing of the genome , which is the next logical step , is
still a remote goal because existing techniques are too slow to
allow the sequencing of the 3,000 million base pairs in an
acceptable time ; a start could , however , be made on sequencing
the cDNA .
The Predictive Medicine Programme would thus enable Europe to
accept      the challenge of      remaining a vital       international
scientific force in human genetics .
The United States ( US ) report " Mapping and Sequencing the Human
Genome " ( 2 ) is a wide-ranging plan which includes the genetic map ,
the physical map , an ordered DNA clone library and , ultimately ,
sequencing . This impressive and prestigious programme - it has
been compared to the " Apollo " project in the field of space - has
captured the imagination of many scientists and politicians . For
Japan , the " Human Frontier Science Programme " is a proposal for
an international research programme in basic biology and the
development of associated key technologies . At the time of
writing the content of this programme has not been agreed , but it
may well include a commitment to human genome analysis and / or the
development of fast automatic DNA sequencing equipment .
Whatever view one may have of these projects , the European
Community cannot remain indifferent . Furthermore , in the case of
the American programme ,         active European participation is
explicitly sought . The Predictive Medicine Programme provides the
means for Europe to participate in an exciting project in one of
the most advanced sectors of biological research .
3.3    RELATION TO OTHER COMMUNITY PROGRAMMES OF RESEARCH
Within the framework programme , the Predictive Medicine Programme
will be coordinated with the following specific Community
programmes of research and technological development , in order to
avoid overlap and to ensure coherence of research efforts :
2 " Mapping and Sequencing the Human Genome ", Report of the Board
    of Basic Biology Commission on Life Sciences , National Research
    Council . National Academy Press Publisher , Washington D.C. , 1988 .
                                    13
 ---pagebreak---      The " Medical and Health Research " Programme 1987-1991 , and
     especially its area 1.1.4 " Early detection and diagnosis of
     Cancer " which is closely related to the genetic field
     through the topic of oncogenes .             Both programmes f orm an
     important part of the " Europe against Cancer " Programme ,( ^ ) .
     The " Advanced Informatics          in Medicine     in    Europe " ( AIM )
     programme , especially its          Action Line      II    " Strengthening
     Europe 's position in Medical and Bioinformatics                 ( MBI ) and
     health care ", which could give support for the development of
     effective communication and information processing within the
     proposed networks .
     The   biotechnology       programmes ,    especially      the     programme
     BRIDGE ,    being prepared at present , with which it would be
     carefully coordinated in respect of expression vectors , gene
     transfer and , more generally , the           genetic engineering of
     animal and human cells .
     The   " Environmental      Protection "   Programme ,    especially      its
     research areas :      " Environment and Human Health " and " Genetic
     Effects of Environmental Chemicals ".
     The     " Radiation     Protection "    Programme ,     especially       its
     mutagenesis area .
     The         " Stimulation "      Programme ,        especially           its
     " Biocommunication " area .
The programme will also benefit from synergy                        with other
activities of the Community in the field of                         Information
Technology and Telecommunication ( IT&T ).
3.4 PRECOMPETITIVE NATURE OF THE RESEARCH
The programme is one of basic precompetitive research . However ,
both new information and new materials of potential commercial
value will result . It is generally agreed that all the mapping
and sequence information should be freely available but that
associated        technological     developments      -    of      instruments ,
equipment , reagents or software - should be protected in the
usual way by patents , copyright , etc .
3.5 . MANAGEMENT AND EVALUATION
The existing CGC on Medical and Health Research should deal with
the Predictive Medicine Programme and will advise the Commission
in the manner defined in the Council decision creating CGCs . The
programme will be submitted to evaluation procedures                           in
accordance with the " Community plan of action relating to the
3 Decision of the Council and of the representatives of Member
  States of 7 July 1986 , concerning an action programme of the
  European Communities against cancer . O.J. N° C 184 , 23.7.87 , p.19 .
                                       14
 ---pagebreak--- evaluation of Community research and development activities "^).
The CGC may wish to obtain specialized advice and meet in
variable configurations ; it may also wish to set up a Working
Party to advise the Commission on the management of the
Predictive Medicine Programme .
4 .       IMPLEMENTATION AND FINANCIAL MEANS
After the approval of the Medical and Health Research Programme ,
15 million ECU remain on the sub-activity " 1.1 Health " of the
framework programme for the implementation of the Predictive
Medicine Programme . Four main chapters of expenditure are
proposed , for two networks ( human genetic map and ordered clone
library of the human genome ), research contracts for work in
advanced genetic technologies , and training grants . In addition
there would be overheads and staff expenses . The indicative
budget distribution is :
CHAPTER                                    MODE OF ACTION         BUDGET
                                                             ( Million ECU )
Improvement of the human              Support to a network of      4.0
genetic map                           centralized facilities
Ordered clone library                     As above                 4.0
Research on advanced                  Research contracts           3.5
genetic technologies :
e.g. reagents ( restriction
enzymes ), gene detection , gene
vectors , cloning , computer
software , cDNA cloning and
sequencing .
Grants ( particularly post -               Grants                  2.5
doctoral , 100 scientist-years )
Scientific management , including                                  0.45
eva luation
Staf f                                                             0.55
                                           TOTAL                  15.0
4.1 .     NETWORKS OF FACILITIES
Progress with the human genetic map and the creation of ordered
clone libraries of the human genome will be achieved most
effectively by building on existing laboratories through the
creation of networks . Efficient management , both of information
and of biological materials , will be of prime importance for both
4 Communication to the Council concerning a Community plan of
    action relating to the evaluation of Community research and
    development activities for the years 1987 to 1991 .
    0 . J . N " C 14 , 20.1.87 , p. 5 .
                                         15
 ---pagebreak--- actions , and it is proposed therefore to identify a central
laboratory in each case to act as the focus for management , i.e.
to become the centre of a network of laboratories .
Four million ECU will be used for the development of a European
network for the improvement of the human genetic map , and another
four million ECU for setting up a network of laboratories
concerned with an ordered clone library of human DNA . These sums
amount to approximately 10% of the sums suggested in the report
of the US Office of Technology Assessment as appropriate for the
US Human Genome Project . Although modest , at least in the
exploratory phase of these activities , Europe 's contribution to
the international effort will be a significant one .
4 .2   RESEARCH CONTRACTS
The basic research on advanced genetic technologies in the
programme will be funded through cost-shared and marginal cost
contracts with public and private institutions in the Member
States . The contribution to research contract funding from the
Community budget is estimated at 3,500,000 ECU . This figure is
based    on  an   estimate   of  20   research  contracts  on  advanced
technologies , of about 150,000 to 200,000 ECU per contract ( for
three years ) according to the size of the project . It corresponds
to the expected response from European laboratories in the field .
In the selection process , priority will be given to proposals
involving a number of Member States and /or participation by
private enterprises . The management of communication between the
various contracting laboratories will be a first step towards the
establishment of a European network in molecular genetics .
Although the sum involved in each contract may seem small , the
impact will be amplified by the complementarity of the programme
to national research efforts . It should be noted that no single
European country would be able to develop the complete range of
research facilities and networks described above .
4.3 . TRAINING
An average estimate of the requirements for training in the
period under consideration is about 100 scientist-years , i.e.
2,500,000 ECU . Two aspects deserve special consideration :
(i)    Steps must be taken to ensure that those Member States which
       currently lack a capability in the techniques of modern
       molecular genetics are given the opportunity to acquire it ;
( ii ) Only if there are very compelling reasons will scientists be
       permitted to train outside the proposed European networks ;
       in order to smooth the path for the transfer of technology ,
       and   for    the   return  of    the  individual   newly-trained
       scientist , it is expected that 30 to 50% of such a
       scientist 's    time will be spent introducing the new
       techniques into his own laboratory setting .
                                     16
 ---pagebreak--- 4.4 .     SCIENTIFIC MANAGEMENT
Budgetary provision of 450,000 ECU is considered necessary for
the external scientific management of the programme . This
assessment , based upon an analysis of current annual needs in
similar        programmes ,   covers    the     expenses      of    meetings ,
p<-. •. ticipation in symposia , travel and subsistence costs of
experts        and    Commission    staff ,    visits     to     laboratories
participating in the programme ( two visits to each contracting
laboratory , i.e. about 50 visits in the course of the programme ),
and the convening of six workshops during the same period . Funds
are also included for the preparation of a follow-up to the
present programme ( studies and preparatory meetings ) which might
include inter alia the setting up , as mentioned previously , of a
large network of research , forecasting , prevention and treatment
for one of the major genetic diseases of children .
The cost       for scientific management amounts       to  3%   of the total
budget       requested   for  the  programme ,   including      the  cost  of
evaluation .
4.5       COMMISSION STAFF
Expenditure of 550,000 ECU for a staff of two is considered
necessary for the execution of the programme .                 This estimate
includes new staff only , i.e. one official of category A ( 93,000
ECU /year ) and one of category C ( 37,000 ECU /year ), inflation
being estimated at 4% per year ; this estimate includes only the
minimal requirements necessary for the                 management of the
programme .
4.6       SUMMARY OF FINANCIAL MEANS
                                            ( Million ECU )
Networks of facilities                               8.0
Research contracts                                   3.5
Training                                             2.5
Scientific management                                0.45
Staff                                                0.55
                                  TOTAL             15.00
 ---pagebreak---                           PROPOSTA DE DECISÃO DO CONSELHO
                      que adopta um programa de investigação
             e desenvolvimento tecnológico no domínio da saúde :
        Medicina Predictiva    - análise do genoma humano ( 1989-1991 )
0 CONSELHO DAS COMUNIDADES EUROPEIAS ,
Tendo em conta o Tratado que institui a Comunidade Económica Europeia , nomeada¬
mente , o nQ 2 do seu artigo 130Q Q,
Tendo em conta a proposta da Comissão ( 1 ),
Em cooperação com o Parlamento Europeu ( 2 ),
Tendo em conta o parecer do Comité Económico e Social (3 ),
Considerando que o artigo 130Q K do Tratado estabelece que será aplicado um
programa-quadro através de programas especificos , desenvolvidos no âmbito de
cada actividade ;
Considerando que ,     pela     sua Decisão de 28 de Setembro de 1987 (4 ), o
Conselho adoptou um programa-quadro de investigação e desenvolvimento tecnoló¬
gico da Comunidade ( 1987-1991 ), no qual prevê actividades no domínio da saúde ,
Considerando que , para a avaliação de cada programa especifico e para a selec -
ção de acções comunitárias , o programa-quadro estabelece critérios entre os
quais se encontra a contribuição para o reforço da coesão económica e social da
Comunidade , em conjungação com a procura de qualidade cientifica e técnica ;
( 1 ) JO nû
( 2 ) JO nû
( 3 ) JO nQ
( 4 ) JO nû L 302 , de 24.10.87, p. 1 .
                                                                                  Ù
 ---pagebreak---                                            - 2 -
 Considerando que dois programas plurianuais sucessivos de investigação e forma ¬
 ção para a Comunidade Económica Europeia no domínio da biotecnologia ( 5 ), o úl ¬
timo dos quais ainda a decorrer , demonstraram a possibilidade e a utilidade de
uma acçâo comunitária para promover a utilização da biologia moderna para fins
 científicos e industriais ;
Considerando que o programa de biotecnologia actualmente em curso não inclui
alguns domínios de investigação importantes para a saúde do homem e a qualidade
de vida , para o desenvolvimento industrial da biotecnologia para fins médicos e
para o controlo do aumento das despesas sociais e de saúde ;
Considerando que o programa-quadro prevê no ponto 1.1 . " Saúde " da sua acção
"Qualidade de vida " o " Inicio de novas actividades relacionadas com o desenvol ¬
vimento da medicina predictiva ;
Considerando que , em consequência , é unanimemente aceite a necessidade de um
programa especifico de investigação e desenvolvimento tecnológico no domínio
da medicina predictiva e que , em especial , é necessário :
      desenvolver as tecnologias de base respeitantes ao estudo do genoma humano
      como requisito prévio para um grande número de desenvolvimentos em biotecno
      logia para a saúde e para garantir a ampla distribuição dessas tecnologias
      pelos laboratórios europeus , e
      melhorar a resolução do mapa genético humano e aperfeiçoar o mapa fisico
      através da criação de bibliotecas organizadas de clones como base para lo¬
      calizar genes de importância médica e para uma melhor compreensão global
      da função de gene ;
Considerando que , para atingir os objectivos supracitados , é necessário efectuar
acções a nivel comunitário no sentido de :
      prencher algumas lacunas existentes no conhecimento cientifico e tecnológi ¬
      co , as quais constituem um obstáculo ao pleno desenvolvimento dos recursos
      da biotecnologia moderna no dominio da medicina , e
      promover , através de acções concertadas entre laboratórios públicos e pri ¬
      vados , a cooperação europeia transnacional com o objectivo de acelerar a
      aplicação de tecnologias já disponíveis , promovendo simultaneamente áreas
      cientificas europeias que favorecerão novas abordagens a desenvolver ;
Considerando que o Comité de Investigação Cientifica e Técnica ( CREST ) foi con
sultado sobre estas medidas ,
( 5 ) JO nQ L 375 , de 20.12.1981 , p. 1 .
      JO nQ L 83 , de 25.3.1985 , p. 1 .
 ---pagebreak---                                                 - 3 -
- ADOPTOU A PRESENTE DECISÃO :
                                             Artigo 1Q
  É adoptado por um período de três anos , a partir de 1 de Janeiro de 1989, um
programa especifico de investigação e desenvolvimento tecnológico para a Comu¬
nidade Económica Europeia no domínio da Medicina Predictiva - análise do genoma
humana, tal . como definido no Anexo .
                                             Artigo 22
0 montante considerado necessário para a execução do programa é de 15
milhões de ECUs , incluindo despesas com um efectivo de duas pessoas .
                                             Artigo 32
0 Anexo Técnico estabelece as disposições pormenorizadas para a execução do
programa .
                                             Artigo 4Q
1.     No segundo ano de execução do programa, a Comissão efectuará a sua revisão,
        cujos resultados comunicará ao Conselho, e ao Parlamento Europeu , conjunta ¬
        mente , se for caso disso , com quaisquer propostas de alteração ou prolon¬
        gamento .
 2.     Será efectuada uma avaliação dos resultados obtidos por peritos independen¬
        tes , a qual será publicada sob a forma de comunicação ao Conselho e ao Par¬
        lamento Europeu .
 3.     Os relatórios supracitados serão pst^bel^cidps tendo. emt conta os objectiuos e os cri ¬
       térios de avaliação fixados no Anexo II da presente decisão e em conformidade com as disposi ¬
        ções do nQ 2 do artigo 22 do programa-quadro .
                                             Artigo 52
 1.     A Comissão é responsável pela execução do programa e será assistida pelo
        Comité Consultivo de Gestão e Coordenação ( CGC ) no domínio da Investigação
        Médica e de Saúde , instituído pela Decisão 84 /338 / EURATOM / CECA / CEE (6 ).
 2.     Os contratos celebrados pela Comissão regulamentarão os direitos e obriga¬
        ções de cada parte e , em especial , os métodos de divulgação , protecção e
        exploração dos resultados da investigação .
 ( 6 ) JO n2 L 177 de 4.7.1984 , p. 25 .
                                                                                                      20
 ---pagebreak---                                         4
                                    Artigo 6Q
A Comissão está autorizada a negociar , em conformidade com o artigo 130Q N do
Tratado CEE , acordos com países não comunitários e organizações internacional s ,
em especial com os países não comunitários participantes na Cooperação Europeia
 no domínio da Investigação Cientifica e Técnica ( COST ) e com os países que
 concluíram acordos-quadro de cooperação cientifica e técnica com a Comunidade ,
 a fim de os associar plena ou parcialmente ao programa .
                                   Artigo 7Q
Os Estados-membros são destinatários da presente decisão .
Feito em                                1988
                                                      Pelo Conselho
                                                     0 Présidente
                                                                                   2 'Ζ
 ---pagebreak---                                                5
ANEXO
          para um programa espec-ffico de investigação no domínio da saúde :
                     Medicina Predictiva - análise do genoma humano
1.    OBJECTIVOS
      Utilização e aperfeiçoamento de novas biotecnologias para a previsão de riscos
      mIn^Ór    iC° precoce' Prevenção, prognóstico e tratamento de algumas doenças hu¬
      manas e para uma melhor compreensão da hereditariedade .
2.    CONTEÚDO
      Investigação comunitária pré-competitiva , estabelecimento e reforço de redes de
       laboratórios europeus e formação destinada a permitir a utilização da biotecno¬
       logia moderna para aperfeiçoar a previsão de riscos, diagnóstico precoce, pro¬
      gnóstico   e tratamento de algumas doenças humanas (em especial , as doenças here¬
      ditárias e o cancro ).
2.1 .    APERFEIÇOAMENTO DO MAPA GENÉTICO DO HOMEM
      Estabelecimento de uma rede de alcance mundial situada na Europa para a recolha
      de grandes familias de ADN com vista ao fornecimento gratuito a investigadores
      de material genético bem caracteri zado e de um conjunto de sondas para determi ¬
      nar a localização das posições relativas de genes nos cromossomas . Possível
      fornecimento de instalações informáticas para o tratamento dos dados .
2.2 .    ESTABELECIMENTO DE UMA BIBLIOTECA ORGANIZADA DE CLONES DE    ADN  HUMANO
      Estabelecimento de uma rede europeia de laboratórios que efectuem trabalho de
      estabelecimentp de bibliotecas de clones abrangentes e de apoio à sequenciação
      limitada de ADNc .
2.3 .    INVESTIGAÇÃO SOBRE 0 APERFEIÇOAMENTO DE TECNOLOGIAS GENÉTICAS AVANÇADAS
      Novos reagentes bioquímicos ( enzimas de restrição , etc .). Aperfeiçoamento dos
      métodos de detecção e localização de marcadores genéticos ( técnicas de rotula -
      gem de sondas de ADN , amplificação de genes , etc .). Desenvolvimento de novos
      sectores para a clonagem de grandes fragmentos de ADN e de processos de trans-
      dução de cromossomas . Desenvolvimento de sistemas      modelo para a expressão
      reprodutível e estável de genes importantes do ponto de vista médico tanto
      in vivo como in vitro . Desenvolvimento de novo suporte lógico para a recolha e
      tratamento de dados de sequenciação e mapas de genomas .
2.4 .    FORMAÇÃO
      Estabelecimento de um programa de formação para dar apoio , conjuntamente com a
      transferência de tecnologia de métodos de genética molecular , aos Estados-membros
      em que estas técnicas se encontram actualmente pouco desenvolvidas e , em especial ,
      a transf erência de técnicas para a área clínica .
 ---pagebreak---                                            - 6 -
3. EXECUÇÃO
   O programa será executado através de contratos de acções a custos repartidos ou
   de custos marginais , apoio a instalações e redes centralizadas , contratos de for_
   mação , subsídios de formação , cursos , consultas con peritos nacionais , organiza ¬
   ção de reuniqes de grupos de estudo , participação em seminários e simpdsios e
   publicações .
   A participação da Comissão pode variar desde cerca de 50 % para os contratos a
   custos repartidos e pode elevar -se a 100 % noutros casos .
   Os participantes podem ser instituições de investigação , universidades , empresas
   privadas ou combinações das mesmas , localizadas em Estados-membros ou nos países
   terceiros referidos no artigo 6Q .
   Os projectos devem ser executados por participantes provenientes de mais de um
   país e incluir , pelo menos , um participante de um Estado-membro .
 ---pagebreak---                                         - 7-
CRITÉRIOS DE AVALIAÇÃO
O plano de acção comunitária respeitante à avaliação dos programas comunitários
de investigação e desenvolvimento ( 7 ) previ que os marcos e objectivos de cada
programa de investigação sejam          estabelecidos de forma verificável e , se
for caso disso, quantitativa . Esses critérios são os seguintes :
1.   0 objectivo a longo prazo do presente programa consiste em contribuir para
     a luta contra as doenças humanas decorrentes da variação genética ( incluin¬
     do doenças genéticas sensu stricto e muitas doenças comuns com uma componen^
     te genética , tais como doenças cardiacas e o cancro ), através da previsão
     dos riscos , diagnóstico precoce , prevenção , aperfeiçoamento de prognóstico
     e , por último, terapia . A Comissão propõerse atingir este objectivo através
     de :
     - gestão de uma rede de laboratórios estabelecida em torno de instalações
        europeias para : a ) o aperfeiçoamento do mapa genético humano e b ) o es¬
        tabelecimento de bibliotecas ordenadas de clones de ADN humano , quer do
        genoma completo quer de cromossomas" escolhidos , conjuntamente com a se¬
        quência de ADNc ;
     - lançamento de um programa de contratos de investigação pré-competitiva
        sobre tecnologia genética avançada ;
     - estabelecimento de um programa de formação para o aumento da distribuição
        de modernas tecnologias genéticas e para melhorar o conhecimento tecnológico
        nos laboratórios europeus .
2.   0 principal objectivo a curto prazo consiste no estabelecimento, por inter¬
     médio do programa , das redes europeias de laboratórios anteriormente refe¬
     ridas nos seguintes domínios :
     - mapa genético humano
     - bibliotecas organizadas de clones de ADNchumanoi e sequenciação de ADNc
     - tecnologias genéticas avançadas .
Estes objectivos devem ser verificados em 1990-1991 .
3.   Os objectivos específicos a alcançar no espaço de três anos de duração do pro¬
     grama são os seguintes :
3.1 Respeitantes ao mapa genético humano :
     - o total actual de 40 grandes famílias bem estudadas , as quais formam a
        base do mapa genético , deve ser aumentado para 60 famílias ;
(7 ) JO nQ C 14 de 20.1.87 , p. 5 .
                                                                                   24
 ---pagebreak---                                       - 8 -
    - o material genético dessas famílias e as sondas de ADN devem, ser gratui ¬
       tamente postos à disposição dos laboratórios europeus interessados ;
    - deve ser estabelecida uma instalação central para apuramento de resulta ¬
       dos e elaborar um mapa genético aperfeiçoado ao nível de 1 a 5 centimorgan .
3.2 As estratégias para o estabelecimento de bibliotecas organizadas de clones
    de ADN humano devem ser comparadas com uma abordagem definida , devem ser
    estabelecidas instalações para a manutenção de existências de fragmentos
    clonados de ADN e os clones disponíveis elevem ser enviados gratutitamente
    aos laboratórios europeus interessados .
3.3 Devem ser obtidos aperfeiçoamentos significativos nas seguintes tecnologias
    genéticas avançadas :
    - Novos reagentes , tais como enzimas de restrição ,
    - Metodologia para clonagem de grandes fragmentos de ADN e para a transdução
       de cromossomas ,
    - Vectores de genes adaptados a células humanas in vitro ,
    - Metodologia para a detecção de um gene especifico numa célula ( exemplos :
       como tornar mais fácil a utilização de sondas de ADN e a amplificação de
       genes ) ,
    - Localização , clonagem e sequenciação de novos genes , especialmente os re ¬
       lacionados com doenças ,
    - Novo suporte lógico para armazenar , reunir e analisar dados de sequências
       de ADN .
4.  Além disso , o programa deve corresponder aos seguintes critérios :
4.1 Durante a execução do programa , devem ser tidos em devida consideração
    os aspectos éticos complexos da genética humana , evitando quaisquer riscos
    para o ambiente .
4.2 Os desenvolvimentos de carácter médico devem ser     real ou potencialmente
    favorecidos pelos resultados obtidos .
4.3 Devem ser obtidas oportunidades potenciais para desenvolvimentos comerciais .
4.4 0 nivel tecnológico global dos laboratórios europeus participantes deve ter
    aumentado .
4.5 Tendo em conta os resultados de actividades de investigação comunitários
     no    sector público ou privado no dominio da genética humana , o grupo de
    avaliação determinará se o Programa de Medicina f¥edictiva contribuiu
    para a aplicação dos resultados das referidas actividades noutras regiões
    da Comunidade que não aquelas em que a investigação foi realizada .
                                                                                    2 S
 ---pagebreak---                                      1
FINANCIAL RECORD
PREDICTIVE MEDICINE PROGRAMME
1.    RELEVANT BUDGET HEADING
    - Post :   Line 7312
    - Title :     Specific  research   and technological  development
      programme    in the field of health - Predictive Medicine .
2.    LEGAL BASIS
      Article 130 of the Treaty ,
      Council Decision .
3 .   DESCRIPTION OF ACTION AND OBJECTIVES
3 . 1 Description
      Community programme (1 January 1989-31 December 1991 ) for
      research and training in predictive medicine , carried out by
      means of implementation of laboratory networks , research and
      training contracts , consultancies by experts , organization
      of workshops , contribution to symposia , and studies .
3 . 2 Objectives
      The objectives of the programme are the following : Community
      research and technological development in molecular genetics
      to achieve a better understanding of genetic disease and
      hence improve the prospects for diagnosis and therapy .
4 .   JUSTIFICATION OF ACTION
      The choice of predictive medicine as one of the targets for
      Community efforts in health matters takes into account three
      elements :
      - The priority to be given to advanced technologies , and
        particularly to modern biotechnologies , the importance of
        which for European economic development is an indisputable
        fact .
      - The seriousness of     the human and social aspects of some
        diseases - in particular the common diseases which result
        from a combination of genetic factors interacting with the
        environment .
      - The economic importance of health expenditure , which is
        constantly increasing in Europe and is a serious problem
        for the governments involved .
                                    26
 ---pagebreak---                                         2
These     three  elements  come     together      in    the    definition         of   a
research action programme in the field of biotechnologies to be
applied to predictive medicine : this field covers diseases often
of long duration , socially expensive and very distressing in
hu nan terms , where it is now possible to anticipate their early
decoction . This will lead to their prevention and eventual
treatment , through using the resources of modern biotechnology
while stimulating European industry .
5 .   FINANCIAL INCIDENCE OF ACTION ON EXPENDITURES
      ( including costs for staff and expenses for administrative
      and technical management )
                                                                    Million ECU
5.1 .    Total cost over the whole of the expected duration                    30
5.2 .       Participation in funding :
          - From the Community budget                                          15
          - From national budgets and other sectors
            at national level                                                  15
5.3 .       Multiannual Schedule of Commitment Appropriations                        and
            Payments from the Community budget
5.3.1 . Commitment Appropriations
                             1989     1990     1991             TOTAL
Staff                        0.14     0.20     0.21                0.55
Administration               0 . 20   0.12     0.13                0.45
Contracts and
training     grants          1.66     6 . 68   5.66               14 . 00
Total                        2.00     7 . 00   6.00               15 . 00
5.3.2 . Payments
                        1989     1990     1991   1992     1993             TOTAL
Staff                   0.14     0.20     0.21      _        _
                                                                           0.55
Administration          0.20     0.12     0.13      -        -
                                                                           0.45
Contracts and
training grants         0.46     2.98     5.36    4 . 10   1.10           14 . 00
Total                   0.80     3.30     5.70    4 . 10   1 . 10         15 . 00
                                       27
                                                                                         27
 ---pagebreak---                                        3
5.3.3 . Methods of calculation
5 . 3 . 3.1 . Staff expenditure
The staff requirements for the implementation of this programme
are :
1 category A staff , (*)
1 category C staff .       (*)
The above-mentioned calculation of staff expenses is based on the
following annual figures for 1989-1991 : 93,000 ECU for an A post ,
37,000 ECU for a C post , inflation being allowed for at 4% per
year . Expenditure for missions of Commission staff , for national
experts and auxiliary staff are also included under this heading .
5 . 3 . 3 . 2 . Expenditure for administrative and technical operation
This heading covers the expenses of meetings , participation in
symposia , and travel and subsistence costs of experts , as well as
the publication and dissemination of results and information ,
together with the cost of           scientific and technical assistance
whenever it proves necessary              for the implementation of the
programme .
5 . 3 . 3 . 3 . Expenditure in respect of contracts
The budget foreseen for contracts and training grants ( 14 million
ECU ) should permit the conclusion of research and development
contracts         ( for a total   amount   of 11.5 million ECU ) with  an
average length of 2.5 years ( the duration of the programme being
three years , but allowance being made for the period of the call
for proposals and the period of administrative negotiation ), and
for a variable amount according to the subject of the research .
With regard to training contracts and the short-term training
grants , the method of calculation is based upon an average cost
of 29,000 ECU per year per scientist . It is foreseen that
approximately 20-22 training contracts and 10-15 short-term
training grants will be allocated each year . The total amount
devoted to training actions will be 2.5 million ECU .
6.      Financing of expenditure
The appropriations required to cover the Community 's contribution
to this project are to be entered in the Community 's future
budgets .
 (*)    6 months in 1989 .
                                       28
 ---pagebreak---                           4
Type of Control
Administrative control by the Director-General for
Financial     Control      ( DG XX )       as     regards      budget
implementation , and by the Contracts Division of DG XII .
Scientific Control by the            responsible      officials    in
DG XII assisted by the CGC .
Audit by the Court of Auditors in accordance with the
provisions of the Treaty .
Evaluation   in  accordance     with     the   Community     plan  of
action *  See also the Evaluation           Criteria   in  the Annex
to the Council Decision .
Financial Record
Summary
Action : Research and technical development in
          Predictive Medicine .
                                 Expenses            Staff
                          ( Million ECU )            ABC
                                                ( Number of posts )
                 TOTAL :              15 .           1-1 .
                         29
 ---pagebreak---   STATEMENT ON THE IMPACT ON SMALL AND MEDIUM-SIZED ENTERPRISES ,
                    COMPETITIVENESS AND EMPLOYMENT
Although not primarily aimed either at the support of small and
medium-sized enterprises or at the solution of the problems of
industrial     competitiveness and employment ,       the Predictive
Medicine Programme should nevertheless have some positive results
in this respect :
1.        The improvement in advanced genetic technologies should
          lead to worthwhile developments :
             The production of new reagents ( such as restriction
             enzymes ) could provide a good opportunity for the
             commercialization of high added value substances .
             The    obtaining    of     new   DNA  probes ,  and    the
              simplification of their practical use , should permit
              the development of new diagnostic kits . Informal
              estimates of the potential market for DNA probes in
              the next decade in Europe indicate that it is worth
              between 1,000 and 2,000 million ECU/year .
              New techniques for gene amplification might also give
              rise to development of commercial kits .
2.        Most of the high technology enterprises which are both
          able and willing to collaborate belong to the category
          of small and medium-sized enterprises , and should be
          stimulated by the implementation of the programme .
3.        In the longer term , the Predictive Medicine Programme
          can   be  considered  as    a  valuable contribution   to  an
          alternative approach to the problem of steadily
          increasing health expenditure in European society , and
          this should ultimately result in an increase in the
          competitiveness of the Community .
                                    30