Christoph Revermann März 2000

Leonhard Hennen

Cloning animals

Summary

TAB

TAB Working report no. 65 Office of Technology Assessment

at the German Bundestag
SUMMARY

The TA project »Potential and risks of the development and use of cloning and
of genetic engineering and reproduction technology in breeding animals for re-
search, in breeding laboratory animals and breeding productive livestock« is
based on an application by the Bündnis 90/Die Grünen parliamentary group in
the German Parliament (Bundestag pub. 13/7160). With the aim of improving
the information basis TAB was to be commissioned to make an inventory of this
complex and ethically-charged issue. The TA project »Cloning animals« was
adopted in summer 1997 by the Committee for Education, Science, Research,
Technology and Technology Assessment of the German Parliament, and started
at the beginning of 1998. The goal of the project was to study

> what influences the use of nucleus transfer cloning may have on biological fun-
damental research,
> what contributions can be expected for the various application-oriented areas
of medicine,
> what impacts are evident for animal breeding and agriculture,
> and finally, which problem areas can be identified and what conclusions can be
drawn.

Even during concept elaboration it became clear that restricting consideration to

purely technical, medical and economic aspects of the use of cloning in animals
would be unsatisfactory. Consideration of the legal and ethical aspects of clon-
ing is also required. The report accordingly addresses the question what regula-
tions (if any) animal cloning is subject to in Germany under current legislation
and whether cloning may be subject to statutory restrictions or even prohibi-
tions. In view of the possibilities the further development of cloning techniques
may have in terms of possible human areas of application (drugs, transplants,
tissue culture etc), it also seemed necessary to consider the actions of doctors,
biotechnologists and animal breeders in the context of scientific and techno-
logical advances and ethical demands. The ethical question posed was whether
conventional ethical principles, classic arguments and relevant models of ethical
evaluation are adequate for the moral evaluation of cloning.

The following sections review the most important results of the study for the
individual issues and conclusions.

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 SUMMARY

THE FUNDAMENTALS: CLONING PROCEDURES

A clone is an individual which is genetically identical with another individual.

Cloning is a form of asexual reproduction which is widespread in nature. In the
case of single-cell organisms and plants, it is an entirely normal process (divi-
sion, vegetative reproduction), in the case of the higher vertebrates genetical-
ly identical individuals can arise naturally through the spontaneous division of
embryos in the early stages of division, with the parts evolving separately into
independent individuals (twins, multiple births).

There are in principle two procedures for artificial cloning of higher organisms:
embryo splitting, and cloning through nucleus transplantation to egg cells or
embryo cells whose genetic material has been removed (nucleus transfer). Clon-
ing techniques come under biotechnology, specifically the (biotechnology) pro-
cedures which do not modify the genetic material in the cell nucleus. Cloning
techniques are, however, generally applied not in isolation but in combination
with other biotechnology and genetic engineering techniques (transgenic, which
modify genetic material). Here, many biotechnological procedures are an essen-
tial element of cloning, while others are optional.

Embryo splitting and nucleus transfer differ fundamentally in terms of the tech-
nique and the degree of genetic identity achieved in the resulting embryos. Em-
bryo splitting changes neither the age nor the (toti-)potency of the cells used.
The (two) embryos from the splitting are in the same stage of development,
exactly the same age as the undivided embryo would have been and genetically
completely identical. The nucleus transfer technique of cloning takes a differ-
ent approach by transferring the genetic program (the cell nucleus with the de-
sired genetic material) from a totipotent blastomer or no longer totipotent cell
(embryonic, foetal or even a differentiated body cell) to an unfertilised egg cell
whose nucleus has previously been removed. This technique basically offers the
possibility of replicating an adult individual and their genetic program. The re-
sult is a new individual whose existence does not derive from the fertilisation of
an egg cell by a sperm cell.

The surprising thing of the cloning technique that resulted in Dolly in 1997 is
that a mammal egg cell to which a nucleus from a differentiated body cell is
transferred can develop into a complete organism. The genetic material in the
cell nucleus of a differentiated body cell is functionally differentiated and mod-
ified in many ways compared to the genetic material in the cell nucleus of a fer-
tilised egg. Previously it had been assumed that cell nuclei from differentiated or
specialised body cells could not in principle be reprogrammed to develop again

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 SUMMARY

into an individual. The Dolly experiment has accordingly raised the problem
of the need to redefine the totipotency of a cell (the developmental potential to
differentiate into any type of cell and tissue).

In principle there are highly promising prospects in the application of cloning,

both for biomedical fundamental research and for agriculture, particularly in
combination with transgenic techniques. However, before we reach the point
where applications are relevant – and, above all, efficient – a series of important
questions have to be resolved. Cloning based on nucleus transfer has not always
succeeded or been successful in the long term. Many of the embryos created in
this way die, not infrequently shortly before or after birth. However, the surviv-
ing animals also frequently have »deficits« which hamper their development and
have a deleterious effect on their health. Today, we do not know yet in detail
what the sources are for the errors which currently prevent cloning based on nu-
cleus transfer from being efficient. The mechanisms for differential gene activa-
tion in normal reproductive and developmental processes are certainly still too
little understood. The question remains what the differences are between natural
development processes and those occurring after artificial nucleus transfer.

BIOMEDICAL RESEARCH AND APPLICATION

Clones of higher organisms are of great interest for biomedical fundamental

research and applied medical research. Currently, four possible areas of appli-
cation of cloning based on nucleus transfer are basically under discussion for
medical purposes.

Animals as drug producers

The first area is so-called »gene pharming«, i.e. the use of transgenic animals to
manufacture (human) proteins with therapeutic use, e. g. in their milk. This is
one of the possible main areas of application in the foreseeable future for cloning
based on nucleus transfer, as this makes creating the transgenic animals more ef-
fective and specific compared with conventional techniques. The advantages of
the active ingredients from biogenetic manufacturing processes (such as insulin,
blood factors or other human bodily substances) are that they can be obtained
in much purer form than with conventional techniques involving animal and
human intermediate products. Given the availability of such animals, produc-
tion of active ingredients can be on a large scale and relatively cheap. However,
there are also risks to the animals due to the genetic (transgenic) manipulation,
the biological activity of the produced protein and the cloning procedure itself.

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 SUMMARY

Hazards to people can arise from changes in the products and possible transmis-
sion of disease (pathogens), and these have to be avoided as far as possible by
careful testing of drugs.

Animal models

Another area where cloning could be used is producing transgenic animals as an-
imal models for human diseases. Animal models are used to study the biochem-
ical and physiological fundamental processes, and provide valuable information
for understanding these in humans, and naturally also on human diseases and
possible therapies. Further, new drugs can be tested in animal models for their
toxicity and pharmacological effect on humans. A major obstacle in developing
animal models has been that so far we have only succeeded in the case of the
mouse in integrating genetically manipulated cells into the germ track of a recip-
ient animal so that the genetic changes can be passed on. However, the physio-
logical and anatomical differences between mice and humans are so great that
symptoms of the genetic changes induced in the mouse often do not match the
symptoms observed in humans.

Cloning using nucleus transfer and somatic cells creates the possibility of induc-
ing specific genetic changes in various species (gene targeting and gene knock-
out). This would also make it possible for the first time to induce disease in
transgenic large animals which could be superior to the former mouse models
in terms of anatomical, physiological or genetic characteristics (depending on
the disease to be studied). It is generally expected that this will contribute in
the medium term to an improved understanding of the clinical picture of genet-
ically-caused human diseases, and developing effective therapies based on this.
Possibilities for research and implementation in this area should accordingly be
specifically encouraged and promoted.

Breeding endogenic body tissue

Cloning could also make a technical contribution to the transplantation of en-

dogenic (autologous) tissue and in so-called cell therapy. The ideal transplant
tissue is easy to identify. Its cells should be as genetically identical as possible
with those of the recipient. The patient’s immune system then no longer rec-
ognises them as alien, eliminating problems of rejection. One optimal solution
would accordingly be creating genetically identical replacement tissue. Research
findings indicate that this could be done through cloning using nucleus transfer.

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 SUMMARY

There is another approach to breeding human replacement tissue which is con-

ceivable in principle. This involves using the nucleus transfer technique to create
an early embryo from which pluripotent embryonal stem cells can be obtained
in vitro. In humans, however, it has not yet been possible to obtain such cells
even from embryos in vitro. Such a technique would also require the ethically
and legally highly questionable creation and utilisation of a human embryo, un-
less egg cells from animals are used as recipients for the nucleus. However, this
development is still in its infancy and involves its own problems, and specifically
difficult ethical questions.

Xenotransplantation

A fourth area in which the use of (transgenic) cloned animals is conceivable is

xenotransplantation (transplanting animal organs into humans). However, to
create »donor animals«, up to a dozen genes would have to be modified in the
pig, for example. This is effectively impossible using conventional techniques of
genetic modification. Cloning could now make it possible to make the desired
genetic modifications to cells in vitro before cloning them using nucleus transfer
to make an animal with multiple genetic modifications. Even if the »ideal« do-
nor animal could be made in this way, however, the basic problems of rejection
would probably remain. It is also not certain that the alien animal organ will
actually perform its function in the human recipient. This also leaves the prob-
lem of animal viruses adapting to humans, with the possible consequence of
epidemics (cf. TAB 1999).

LIVESTOCK BREEDING AND AGRICULTURE

Biotechnological techniques have been in use for some time in animal breeding
and animal production. This development dates back over 50 years to the in-
troduction of artificial insemination. The breeding possibilities of artificial in-
semination quickly took on great significance (in Bavaria, for example, c. 90%
of cows and 60% of sows are artificially inseminated). Progress in breeding is,
however, limited (especially in cattle) by the fact that a cow can only bear one
calf a year. Embryo transfer offers the opportunity here of obtaining ten and
more offspring from valuable cows in a single year. Embryo transfer is now used
extensively for cattle. Other biotechnological methods, e. g. in vitro fertilisation,
gender diagnosis or selection, gene diagnostics and gene transfer, are expected
to lead to great advances in animal breeding if they can be applied without side
effects, cost-effectively and ready for practice.

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 SUMMARY

Cloning itself is not a breeding technique, but one which makes possible genet-
ically-identical replication of individuals. Cloning alone does not involve any
breeding or genetic advance in the resulting clones, compared to the original
individual. The decisive factors in the economic efficiency and expediency of
cloning for animal breeding in agriculture are the effectiveness of the cloning
technique and the (breeding) value of the genetic material available for clon-
ing. If techniques for cloning adult animals can be developed into a routine
procedure, this would also have implications for animal production, whose ex-
tent would largely be decided by the cost of cloning. As long as the procedure
is still very expensive, only isolated and extremely valuable, top-performance
animals will be cloned, e. g. in the event of the loss (from age or disease) of the
services of a very valuable breeding animal, it could be replaced by a clone of
itself.

Transgenic clones

The expected increase in genetic knowledge of productive animals as well as the

associated possibilities for creating transgenic animals combined with cloning
using nucleus transfer make possible the use of new strategies in animal breeding
and production. It is expected that these technologies will also make the »pro-
duction« of transgenic animals with modified (agricultural) characteristics more
efficient than currently possible. The most important goals for gene transfer in
livestock breeding in combination with cloning are: quality enhancement, gene
pharming, boosting resistance to disease, and cost reduction.

Enhanced performance through gene transfer is no longer as important now-

adays in agricultural livestock, as the characteristics responsible for meat and
milk production are complex and multigene, difficult to modify and also ade-
quately handled by conventional breeding. In part, gene transfer is used in an
effort to improve feed conversion or reduce fat formation, particularly in pigs.
This, for example, is one aspect of the primary targets for quality improvement
in animal products, as is the desired change in the composition of milk. Work is
underway on increasing the protein content (specifically casein) and reducing or
entirely removing lactose. This type of milk would also be tolerable for people
who are lactose intolerant. Extending this approach leads to the gene pharming
described above. Due to the high disease-related costs of animal factory farm-
ing, genetic modification of disease resistance in animals has great importance
in animal breeding. Transferring specific disease resistance genes or deactivating
sites on genes which determine specific diseases could improve animal health
and hence (theoretically) the quality of animal products.

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 SUMMARY

Changes to agricultural structures

In agricultural breeding practice the introduction of (practicable) cloning (par-

ticularly in cattle breeding) could result in a restructuring of breeding organi-
sation. Cost considerations together with the requirements for employee quali-
fications would probably lead to the emergence of specialist, capital-intensive,
commercially-oriented breeding companies. It is doubtful whether existing
breeder associations will be able to perform the biotechnological work efficient-
ly. Further, extensive use of cloning can be expected to lead to changes at the lev-
el of stages of production, with differing impact depending on the type and size
of farm. This could reinforce the structural change in this sector and generally
lead to a reduction in the number of farms and jobs in agriculture.

The possibility cannot be ruled out that the impact of cloning on the use pattern
in agricultural land will reinforce the trends in the agricultural sector which
have been evident since the 60s. The complete exploitation of all possible im-
provements in productivity by highly intensive and industrial-style operations
leads to declining prices and – besides the reduction in area needed per animal –
to further reduction in agricultural land while at the same time the number of
livestock production farms and regions is increasing. Even in the highly compe-
tition-oriented livestock production regions, an increase in regional environmen-
tal pollution can accordingly be expected.

LEGAL ASPECTS

Among the legal aspects a particularly significant question to answer is which

regulations govern animal cloning in Germany (and abroad) and under what
conditions cloning is legally permitted or not permitted.

Animal testing – breeding for unhealthy traits

There is no explicit consideration of cloning technologies in the Animal Protec-

tion Act. However, cloning animals could be covered by the provisions of section
7 (1) of the Act (TierSchG), as this includes regulations on animal testing and
cloning procedures are still overwhelmingly in the testing stage. The application
and implications of this section are, however, debated in widely differing terms.
If the removal of the nucleus from the egg is not regarded as modification of ge-
netic material in the legal sense, the transfer of the egg to the brood animal does
not constitute animal testing either. However, if one hold’s the view (like e. g. the
Federal Ministry of Agriculture and others) that cloning using nucleus transfer is

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 SUMMARY

covered by section 7 (1) sentence 2 TierSchG because this involves manipulation

of genetic material and cloning tests for genetically modified animals (or brood
animals) may involve pain or injury, this would make cloning tests using nucleus
transfer clearly subject to approval. Cloning animals could also and specifically
be restricted by section 11b TierSchG (breeding for unhealthy traits) at the point
where the techniques are ready for practical application and are, for example,
used in producing and breeding farm animals. This would, however, only apply
where cloning was used to induce unhealthy changes in the animals which were
retained in subsequent breeding.

The current legal consensus seems to be that sections 7 and 11b of the Animal
Protection Act constitute statutory regulation of cloning to the extent that this
could involve suffering, pain or injury for the animals. A ban on cloning would,
however, only come into question if significant suffering on the part of the ani-
mals is actually demonstrable.

Violation of constitutional rights

Constitutionally speaking, a ban on cloning would violate the constitutional

rights of researchers and professionals under Article 5 (3) (Freedom of research)
and Article 12 (1) (Freedom of occupation) of the German Constitution. A ban
or other limitation on cloning would also constitute interference with the con-
stitutionally-guaranteed academic/scientific freedom. There is no evident barrier
within the constitution which could justify such an intervention. Under Art. 12
(1) of the German Constitution a ban on cloning would accordingly be uncon-
stitutional as it is irreconcilable with the public welfare and not covered by the
statutory reservation of Art. 12 (1) sentence 2.

Under current conditions, cloning animals is according permissible in principle

and subject only conditionally to restrictions under prevailing law.

Inclusion of animal protection in the Constitution

A new situation could arise if animal protection was adopted as a state goal
in the Constitution. A comparison with other countries shows that constitu-
tionally-guaranteed animal protection currently only exists in Switzerland. An-
imal protection acquires constitutional status there at federal level through the
concept of the »dignity of creatures« (Art. 24 amendment para. 3) and sets for
example a barrier to the constitutional right of freedom of research. In Germa-
ny a draft constitutional article on these lines is currently being debated. The
Bundesrat (Upper House) approved on 28.11.1997 draft legislation in the 13th

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 SUMMARY

Bundestag (Lower House) amending the constitution by introducing animal pro-

tection as a state goal.

The Bundesrat motion aimed at adding an Article 20b to the German Consti-
tution with the object of »respecting animals as fellow creatures and protecting
them within the statutory framework against avoidable suffering and injury«.
Animal protection here is mostly understood as limiting animal testing, but also
with respect to factory farming, animal transport and animal slaughter. The Bun-
destag debated this motion without reaching a decision. A final decision is now a
matter for the current (14th) legislature. If such an Article is incorporated in the
Constitution, cloning animals could possibly violate a constitutionally-protected
object, animal protection, as there could be an inherent constitutional barrier to
Article 5 (3). It can at least be said, however, that under a constitutional guar-
antee of animal protection the necessary consideration of other constitutionally
protected objects (such as freedom of research, academic/scientific freedom –
but also freedom of occupation and guarantee of the right of property) could be
achieved in an individual case of application of the law and a court ruling. An-
imal protection as a state goal does not rule out the use of animals by humans,
but raises the requirements for the necessary justification of this use.

ETHICAL ASPECTS

The legal and legal-ethical considerations are associated with ethical consider-
ations of fellow-creature status and an ethical judgement on animal cloning.
Different positions in the social debate and assessment of animal cloning can
be traced back to some extent to different fundamental values. These also de-
termine whether animal cloning is seen as having a new quality compared with
conventional animal breeding or with other new techniques in animal breeding
as well. For some theologically-based positions, cloning is e. g. an interference
with creation which humans have no right to undertake. Anyone who feels that
animals have »intrinsic value« or »creature dignity« will generally regard cloning
as morally dubious, at least. From an anthropocentric position there is above all
the question of the safety of products made with the help of cloning techniques
and the potential risks and hazards – ecological (reducing genetic diversity) and
social (industrial mass production, concentration of capital, new dependencies).
Other positions see animal cloning more as a catalyst which could further re-
inforce other undesired trends which are currently apparent and which result
from the use of other biotechnological and genetic engineering reproductive
techniques, rather than as a qualitatively new step in reproductive technology.

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 SUMMARY

The different social positions represent an effort to attract support for a specif-
ic moral or ethical ideal and so possibly influence the political climate as well.
Given the difficulty of reaching a moral consensus, it is necessary to consider
which ethical principles a possible use of animal cloning needs to orient itself by.
This means not only that a possible use of animal cloning needs to be ethically
justified, but also abandoning the use of the (therapeutic) possibilities offered
by this technique. In this context the focus in ethical assessment of cloning is
the question whether goals of animal cloning and the means or techniques used
imply interference with the sphere of interests of the animals involved, and if in
this case the interference can be ethically justified in terms of the considerations
described above.

Specialists in ethics generally regard the goals of biomedical research and appli-
cation as paramount, with special urgency or even literally vital importance for
human health, and attainable only with the help of cloning of higher animals.
Goals in fundamental research can also be regarded as paramount and justifying
cloning higher animals where no alternative techniques are available. However,
if cloning involves considerable suffering for the animal involved, it is necessary
to consider whether mere human thirst for knowledge is adequate justification,
or whether justification requires specific goals, i.e. the need to avoid considera-
ble human suffering. Goals which are regarded as subordinate in importance to
the above objectives are mostly goals in livestock breeding, where these do not
explicitly involve ensuring the basic human food supply.

CONCLUSION

In applied research, cloning using nucleus transfer opens up new approaches to

creating transgenic animals. Some proteins with therapeutic effect can be cheap-
ly produced in this way. Obtaining autologous replacement tissue seems particu-
larly promising in both medical and ethical terms, and the associated research
is accordingly particularly deserving of promotion. It is not clear whether it will
be possible to create better test models for human diseases in livestock, but the
considerable medical importance justifies increased effort and support in this
area as well. Overall there appear to be a relatively high potential benefits for
research and medicine from cloning using nucleus transfer.

In agriculture the (practicable) production of clones of breeding stock promises

to improve animal performance and quality while simultaneously reducing pro-
duction costs. It is likely that cloning techniques will add further weight to ex-
isting trends in optimising the performance potential of livestock, i.e. high-per-

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 SUMMARY

formance animals. With regard to the questions of genetic improvement and

diversity in animal breeding, selection for specific performance characteristics
can have the goal of standardising (breeding) livestock with the help of cloning,
and hence inevitably standardising livestock generally. The resulting (desired)
genetic status quo is accordingly very probably tied to a reduction in genetic di-
versity. Although there is in principle still great need for research on more exact
documentation of the status quo, appropriate measures should be taken now
to limit »artificial« production of increasing numbers of offspring of individual
animals. This relates to techniques ranging from current routine artificial insem-
ination through to cloning.

It is also likely that the introduction of cloning in combination with other re-
productive and genetic breeding techniques will lead to or intensify extensive
relocation of breeding products (breeding animals) from farms to commercial
companies. This would result in a situation in animal breeding which is similar
to that in plant breeding, where there is an inverted pyramid based on a few
breeding companies, with a large number of propagating firms and numerous
production firms. The pressure on the responsible EU organs and national gov-
ernments to create a favourable environment for the commercial use of genetic
and cloning technologies will probably increase. This includes for example de-
mands to abolish so-called »competition-distorting regulations« such as quotas
and ceilings on promotional measures or stocks. The consequences of possible
further encouragement to this trend, which has been apparent in agriculture
since the 70s, are not only quantitative but also qualitative. It would be im-
portant for policy-makers to ensure that a situation does not arise where the
possible adverse effects of specialisation in animal breeding at the various levels
of breeding, the labour market and farm structure are exacerbated or may even
become irreversible. Overall, the application of cloning using nucleus transfer in
agriculture requires careful consideration of the advantages and disadvantages.
As far as the quantity and quality of human food is concerned, there is no direct
need to clone animals for agricultural use. In addition, the currently foreseeable
effects on the individual farm animal – and also on populations (breeding stock),
breeds and possibly even species – are perhaps at least as serious as the impact
on agricultural structures and the socio-economic conditions for people working
in agriculture.

In ethical terms, an assessment of animal cloning must in principle be based on

the same criteria which are (or should be) used in traditional animal breeding. In
this respect there are various calls for the creation of a national ethics commis-
sion to deal with the moral and ethical issues of advances in biological and bio-
medical technology generally and with the consequences of advances in non-hu-

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 SUMMARY

man biology and medicine. Its task would be to advise policy decision-makers
and inform and educate the public. Possibly, intensive cooperation in the human
area may be desirable with a national ethics commission which is also under
discussion, and under certain circumstances a single ethics commission dealing
with the entire human and non-human area of scientific and technological de-
velopments in biology and biomedicine may be meaningful. As broad groups of
the public are also concerned about the use of cloning techniques with humans,
the implementation of participative processes is important in opinion forming
and policy advice (such as consensus conferences or citzens’ fora). The need for
forward looking and timely consideration and possibly legislation on cloning in
humans cannot be lightly dismissed. Analysis of the legal aspects of animal clon-
ing showed that this is currently legally permissible and subject to only limited
restrictions under present legislation. In principle the question of animal protec-
tion is partly in contradiction to the actual goals of the Animal Protection Act in
Germany at the present time, and in principle animal protection is secondary to
the constitutionally-guaranteed freedom of research.

A different point of view and resulting implications could arise if the Constitu-
tion is amended to incorporate animal protection as a state goal. Constitution-
ally-based animal protection would presumably have relatively great practical
effects. Such a provision would force the courts to strike a balance continuously
between opposing constitutional rights and state goals. Developments in the
field of cloning could in principle demonstrate the need to give animal protec-
tion constitutional status, or even the need for a fundamental debate in politics
and society generally on the (current) treatment of animals in research and ag-
riculture.

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The Office of Technology Assessment at the German Bundestag is an independent scientific
institution created with the objective of advising the German Bundestag and its committees on
matters relating to research and technology. Since 1990 TAB has been operated by the Institute
for Technology Assessment and Systems Analysis (ITAS) of the Karlsruhe Institute for Technol-
ogy (KIT), based on a contract with the German Bundestag
TAB
Office of Technology Assessment
at the German Bundestag