T I B T E C H - A P R I L 1986
Competition and pressure to speed
Biotechnology and regulation:
different perspectives in the
United States and the
European Community
Is existing legislation adequate to
regulate biotechnology?
The theme of a recent conference *
was the legal and regulatory issues
surrounding biotechnology. One of
the central issues of the current
debate in the US and Europe is
whether biotechnology, and particu-
larly the deliberate release of gen-
etically manipulated microorgan-
isms into the environment, can be
adequately regulated by existing
law. Whereas the Administration in
the US has taken the position that
existing legislation is adequate, the
Biotechnology Regulation Inter-
service Committee (BRIC) of the
European Commission is still assess-
ing the adequacy of the existing
regimes. The outcome will probably
be that in some areas (for example
for some pharmaceutical applica-
tions) the existing European regula-
tory framework is sufficient, but in
other areas, especially in the field of
deliberate release and waste treat-
ment, new legislation will be neces-
sary.
The need for regulation of deliberate
releases
The new discoveries in biotech-
nology are currently having their
greatest impact in four commercial
spheres: agriculture, pharmaceuti-
cals, medical therapies and speci-
ality chemicals. Of these, the agricul-
tural applications are of the most
important potential concern from an
environmental point of view. In
*Second Annual Broota'ngs Conference
on Biotechnology held 18-19 February
in Washington DC.
contrast to the other activities,
agricultural applications involve
deliberate, potentially large-scale
releases of organisms that have been
engineered specifically to survive in
the environment. Agricultural aims
include reducing plant vulnerability
to environmental stresses, discover-
ing and controlling infectious agents
in animals and in fields post-harvest,
reducing dependence on chemical
pesticides, chemical fertilizers and
irrigation, and increasing the nutri-
tional qualities of seeds, fruits,
grains and vegetables.
The development of agricultural
applications has proceeded much
faster than expected. In the US many
companies have already applied for
field tests for genetically manipu-
lated plants and microbial pesti-
cides, and several tests have been
approved by the US Administration.
The US Department of Agriculture
(USDA) is currently funding many
biotechnology research projects of
which 87 projects involve the release
of genetically engineered micro-
organisms within the next five years.
Many US universities are also ex-
pected to apply for field test ap-
proval soon. Large scale deliberate
release of recombinant DNA organ-
isms and exotic organisms will also be
an integral part of biotechnological
techniques in industry for controlling
environmental pollution, cleaning up
toxic pollutants and extracting miner-
als from ores. The same developments
can be expected in Europe within the
next few years.
Regulating all these applications
requires evaluation of the existing
legislation.
(~ 1986, Elsevier Science Publishers B.V., Amsterdam 0166-9430/86/$02.00
up regulation in the United States
The pressure from industry to
define clearly which agency is
responsible for particular aspects of
the regulatory problem stems from
the need to plan competitive future
research and marketing strategies. In
the US especially, regulation is
perceived as a significant factor in
determining whether the US bio-
technology industry can remain
ahead of international competition.
According to one of the papers
prepared for the Brookings Confer-
ence, the competitiveness of the US
biotechnology industry should be
measured both against 'conven-
tional' technology producing similar
products and against the biotech-
nology industries in other coun-
tries 1.
Some representatives of US indus-
try fear that other industrialized
countries will set up regulatory
schemes before agreement is reached
among the US authorities, and that
this could lead to competitive ad-
vantages for foreign companies,
particularly if regulation in those
countries is less severe than in the
US. Approval and testing procedures
in the US are lengthy: in the
pharmaceutical industry, according
to the US Pharmaceutical Manufac-
turer's Association, the average time
needed to obtain approval of a new
drug is seven to ten years at a cost of
$74 million 1. Although foreign regu-
latory proceSSes may be less severe,
US legislation currently prohibits the
export by US firms of products for
which US approval has not been
obtained. Important discussions are
now taking place to find a remedy for
this perceived barrier to US com-
pet~ivity abroad.
Another issue concerning inter-
national competition is the pressure
from industry on US regulatory
authorities to accept foreign testing
data in US approval submissions.
Relaxation of this requirement might
be acceptable if data were collected
from other industrialized countries
where proper testing procedures are
enforced: however, the validity of the
data might be in doubt if they were
collected from (for example) Third
World countries where testing facili-
ties were less adequate, or where

procedures might not be as accur-
ately followed. Obviously caution
and selectivity in accepting foreign
data is required to maintain safety
standards in the US and to prevent
Third World countries from being
used as testing grounds.
Assessing the risks involved in
deliberate release
The root of the concern about new
techniques of biotechnology is its
power to generate new forms of life:
genetic engineering can provide
combinations of traits in an organ-
ism that are very unlikely ever to be
produced by selection in nature
while mass culture can produce bulk
quantities of these organisms, or of
naturally-occurring, but rare, organ-
isms. With conventional techniques
like selective breeding, genes are
also recombined to produce new,
genetically stable varieties of organ-
isms. However, what distinguishes
recombinant-DNA techniques is that
they bypass the natural reproductive
systems of organisms and allow
direct transfers of genes between
unrelated organisms. The new tech-
niques vastly increase the pool from
which traits can be drawn to alter
any organism. New organisms can be
produced at a more rapid rate than in
the past.
The regulatory authorities are,
therefore, confronted with having to
assess the risks to health, welfare
and the environment of releasing
living organisms and plants. Since
the existing legislation was not
designed to anticipate, evaluate and
control risks from genetically modi-
fied organisms, the assessment is
difficult. In assessing risk, one ad-
vantage of biotechnology (and, in
particular, genetic engineering) is
that it is more directed and control-
led than conventional techniques.
This could reduce the likelihood of a
new genotype containing undetected
problems 1,2.
However, as was pointed out in an
Office of Technology Assessment
(OTA} draft staff paper presented at
the Brookings Biotechnology Confer-
ence, despite the control over pro-
duction processes, laboratory experi-
mental data are inadequate to accur-
ately assess the probability of hori-
zontal transfer when altered organ-
isms are introduced into the en-
v i r o n n l e n t 3. Many of the applied
release experiments will to be per-
formed with bacteria in agricultural
settings and, in assessing the risks of
release, it will be necessary to know
not only about the source of the
genes but also about the potential
microbial recipients in soil. How-
ever, only 10% of the organisms in
soil can be cultured in the laboratory
and very little is known about
genetic exchange in bacteria other
than E. coli outside the laboratory,
especially in soil. In any case,
because conditions in the laboratory
are very restrictive, oversimplified
and artificial, extrapolating from
laboratory situations can lead to
unreliable predictions.
Given that answering questions'
about horizontal transfer is regarded
as relatively simple compared with
forecasting whether any harm will
result from such horizontal transfer,
it is obviously going to be very
difficult to estimate the potential
hazards from release experiments.
More research is obviously required
on the interaction between genetic-
ally modified microorganisms, the
soil and the environment.
The importance of ecology as a
predictive science
Knowledge of the genetic reper-
toire of released organisms is impor-
tant in assessing probable hazards,
but alone it will not provide enough
information to make adequate pre-
dictions of environmental risks of
deliberate release. There seems to be
a pressing need for developing an
interdisciplinary approach to pre-
dictive ecology in order to fill the
information gaps. According to
Martin Alexander, a microbial eco-
logist from Cornell University and
former member of the Recombinant
DNA Advisory Committee of the US
Environmental Policy Agency (EPA),
five key questions need to be
answered in some detail before we
can predict the fate of genetically-
altered organisms in the environ-
ment 4.
• Will they survive?
• Will they multiply?
• Will they transfer their inserted
genetic changes to other species?
• Will they be transported or dis-
seminated to new sites?
T I B T E C H - A P R I L 1986
• Will they have a deleterious
effect?
Very little information is available to
answer these questions.
Predictive ecology is also neces-
sary to provide techniques for
measuring environmental impacts of
genetically engineered organisms.
There are almost no accepted
methodologies for evaluating the
safety of genetically-engineered pro-
ducts and processes: the risk assess-
ment tools and data used for chemi-
cal substances cannot be used for
organisms 5.
Most scientists agree that intro-
ducing large numbers of new organ-
isms will affect the environment,
altering, for example, the level of
existing species, food chains, or the
species composition in a particular
habitat 1. The science of ecology is
not well enough developed to pro-
vide a sufficiently detailed model to
determine whether the release of a
genetically-engineered organism has
affected the environment above the
normal background of natural eco-
logical change 1. Same scientists
even argue that without the funda-
mental understanding of how the
ecosystem ('the machine') works it is
hardly possible to assess the impact
of the release of particular organisms
and to predict the secondary rami-
fications.
Case-by-case and step-by-step: US
and European approaches
Notwithstanding the obviously in-
adequate scientific basis of risk
assessment for the release (acci-
dental or deliberate) of genetically-
engineered microorganisms, regula-
tory authorities in the US and
Europe have started approval pro-
cedures: in the US some field tests
have already been approved.
Case-by-case
In the US, regulatory agencies
follow a case-by-case licensing pro-
cedure to regulate biotechnology
products. Each agency with biotech-
nology products within its jurisdic-
tion decides whether the product fits
within the agency's competence. By
combining past experience and gen-
erating new information on genetic-
ally modified organisms, the agency
secures a progressively larger data
base enabling it to make quicker and
TIBTECH - APRIL 1986

more accurate decisions. The experi- likely that, for a single product, Public perception as the decisive
ence gained by the review of pre- assessment and regulation by differ- factor in regulation
vious applications and the data base ent agencies will be needed (e.g., for In November 1985, the EPA
should eventually lead it to issue health risks, specific agricultural approved the first deliberate release
'generic' regulations. It is estimated risks or environmental risks). The into the environment of a genetic-
that at least three years of case-by- step-by-step approach can lead to a ally-engineered living organism, a
case regulations will be necessary better overall understanding of the strain of P s e u d o m o n a s syringae
before general regulation schemes complexity of ecosystems than can a which lacks the ice-nucleating pro-
can be installed. fragmented case-by-case assessment. tein of the natural species. The
A disadvantage of the case-by-case The extensive juridical framework presence of these 'ice-minus' bac-
approach is that it shelters the in the European Community could teria on crops, to the exclusion of
agencies from the full complexity of enable this more comprehensive their natural counterparts, is ex-
possible risks, because information approach. Two EC directives are pected to reduce frost damage which,
is only gained from the specific cases relevant here; firstly, the Council worldwide, is estimated to cost $14
that fall under the authority of the directive on the major accident × 109 annually.
agency. Another objection is that it hazards of certain industrial activi- The EPA approval of the ice-
probably will not generate enough ties (82/501/EEC, the 'Seveso' Direc- minus experiment by Advanced
information to establish generic tive) and secondly, the Directive on Genetic Sciences (AGS) of Oakland,
regulations. One can also question the laws, regulations and adminis- California (which allows AGS to
the extent to which case-by-case trative provisions relating to the spray about 8 x 1012 bacteria on the
reviewing can give the necessary classification, packaging and label- blossoms of 2 400 strawberry plants
information in the absence of proper ling of dangerous substances (67/548/ in Monterey county) is regarded as a
ecological testing. Furthermore, it is EEC, the 'Sixth Amendment' on the significant breakthrough in the regu-
doubtful, because of industrial testing and notification of new lation process 7'8. According to EPA,
secrecy, whether the limited inform- chemical substances). an extensive peer review process
ation and experience gained in test- It has been said that because more involving experts both inside and
ing product A can be used to test information of the different phases outside the federal government had
product B. can be collected this approach could taken place before approval was
All in all, it would seem to make be turned out to be more flexible given.
more sense to set up uniform de- than the US case-by-case approach. However, on the same day that the
tailed test protocols (or as uniform However, the step-by-step approach approval was announced, the Foun-
and detailed as possible). These will only be applied for European dation on Economic Trends, led by
should include new ecological test- legislation and even then further Jeremy Rifkin, filed suit against EPA,
ing procedures. For example, testing specific elaboration of regulations is challenging the procedure by which
in microcosm, or in greenhouses needed. In the European Member authorization was made. Rifkin
should be a prerequisite of approval States existing national legislation stated that EPA is not equipped to
for field tests. will remain as the backbone of assess the risks. According to him no
biotechnology regulation. Here, as in tests have been done on insect
Step-by-step the US, pressure from industry to transmission and the ice-minus bac-
The OECD-Ad H o c Group on consider biotechnotogy products teria have been tested at 70°F rather
Safety and Regulations in Biotech- just like any other (chemical) pro- than at 32 and 24°F. Lately, Rifkin
nology proposed an assessment duct and to refrain from new legis- has been joined by microbiologists
method that comes closely to the lation will be strong. Although a and ecologists who have said that
above mentioned test protocols. This European agreement for regulating the widespread use of the ice-minus
'incremental step-by-step' assess- biotechnology and pharmaceuticals bacteria could cause adverse cli-
ment provides an opportunity to get has recently been reached *, and matic effects like drought. The costs
more detailed information on a obvious arguments can be given for and damages of drought could event-
broad range of biotechnological pro- new European, rather than national, ually be much higher than the costs
ducts and processes and it has found regulation of the deliberate release of of frost.
a response in the European Com- modified and exotic microorganisms, The approval of the ice-minus
munity: the BRIC-group of the Euro- competition will make it difficult for bacteria experiments could have
pean Commission is currently elab- Member States to agree on a common opened the door in the US for many
orating this approach for the Euro- framework for European biotech- more field tests. Now, however, local
pean context. Processes are seen as a nology regulation. government authorities have re-
flow or chain of activities, rather than jected the planned field tests .for ice-
one activity and assessment on this minus bacteria. One important
basis is particularly useful for ana- *On 16 January 1986 the European reason for this local refusal is that
lysing risks in deliberate release. Parliament approved the five Commission insufficient information was given to
Every step of the chain (laboratory, proposals 6 to promote high technology the public in Monterey. Scientists
greenhouse, small field test, field and biotechnology medicines; a decision may dispute among themselves
test, waste streams, etc.) requires a by the Council of Ministers may he about safety, procedures and other
different form of regulation. It is expected later in 1986. important issues, but as long as the

public at large is kept uninformed,
no basis for understanding and trust
can be established. Over the next few
months it will become extremely
important for governments and regu-
latory authorities to initiate open
public debates on deliberate release
in order to provide balanced inform-
ation. Without open debate a polar-
ized, unworkable entrenchment will
develop between the biotechnology
industry and its opponents. In
Europe the BioTa2000 multi-media
programme, partly financed by the
European Commission, has started
to provide the public with informa-
tion.
Many of the positive contributions
that the new genetic technologies
could make, like crops with disease
and insect resistance or with higher
nutritional value, are at stake. It is a
[] [] [] []
Interferons: what future?
It is hard for us to imagine how
revolutionary were the discovery
and first description of the substance
that Alec Isaacs called 'interferon' in
the late 1950s 1. To many it was a
figment of a vivid scientific imagina-
tion, yet the original observations
were carefully repeated in many
laboratories and the production by
cells of a soluble substance to
explain viral interference was more
or less accepted by the 1970s. When
interferon was discovered, it was
realized that it was possible to
interfere with viral replication with-
out necessarily endangering cellular
metabolism and many thought that
interferon might prove to be a useful
antiviral agent.
However, a major problem was in
material supply and this remained
so until the cloning of interferon
genes inE. coliin the late 1970s, and
the concomitant successful develop-
ment of large-scale lymphoblastoid
interferon production. To give ex-
amples of the early supply problems,
a two-year collaboration between
Glaxo and Wellcome laboratories
produced sufficient monkey kidney
cell interferon for a single small dose
to be inoculated intradermally in 36
(~ 1986, Elsevier Science Publishers B.V., Amsterdam
mistake, born of concern for share
prices or scientific prestige, to try to
sell the public the wonders of
biotechnology without properly
addressing, the risks. Public sus-
picion delays development as the
'ice-minus' case has clearly demon-
strated.
References
1 Biotechnology: A Legal~Regulatory
Analysis (1986) Paper prepared in
conjunction with the Second Annual
Brookings Conference oil Biotech-
nology
2 Dixon, B. (1985) Engineered Organ-
isms in the Environment: Scientific
Issues, Lay Summary, American
Society for Microbiology
3 Genetic Issues in Environmental
Applications of Genetically Altered
Organisms (1986) Biological Applica-
tions Program, Office of Technology
[] [] [] [] [] []
volunteers to prevent vaccinia. This
was an expensive business and even
though the trial was very successful
(vaccinia appearing to be highly
susceptible in rive), it was consid-
ered of very dubious commercial
merit.
In the mid-1960s Kari Cantell
started to make leucocyte interferon
from buffy coats from blood destined
for transfusion, and managed to
make sufficient to supply nearly all
the important trials reported through
the 1970s. The successful trial re-
ported in 1973 (Ref. 2) of repeated
intransal sprays of interferon against
experimental common colds in
volunteers given rhinovirus type 2,
used about one year's manufacturing
supply from this process. Thus al-
though it was a success, there was
insufficient interferon to pursue fur-
ther studies, let alone sell interferon
for common colds.
Greenberg and coworkers 3 estab-
lished the m i n i m u m dose of inter-
feron which could protect volun-
teers against rhinovirus and devised
ways of enhancing the effects (for
example, by putting a cotton wool
pledget saturated with interferon
into the nose or by using concomit-
0166-9430186/$02.00
TIBTECH - APRIL 1986
Assessment, Congress of the United
States, Draft Staff Paper
4 Alexander, M. (1985) Issues Sci.
Techno]. Spring, 61-64
5 Doyle, J. (1985) in EPI Perspectives,
Special Annual Edition 1984/1985,
Environmental Policy Institute
6 Commission of the European Com-
munities (1985) Biotechnology and
Rules Governing Pharmaceuticals in
the European Community, revised
text, IIIA 3, Brussels
7 Magagnini, St. (1985) The Sacramento
Bee Magazine, December, 7-12
8 Maykuth, A. (1986) Philadelphia In-
quirer, January 10, 1
ANNEMIEKE J. M.ROOBEEK
Department of Economics, University
o f Amsterdam, ]odenbreestraat 23,
1011 N H Amsterdam, The Netherlands.
[] [] [] [] []
ant antihistamines which were
thought to reduce nasal clearance of
interferon), but these techniques did
not detract from the need for almost
unlimited supplies of interferon if a
market were to be found and needed
to be filled. Using buffy coat leuco-
cyte interferon, many other virus
infections were successfully pur-
sued during the 1970s including
herpes simplex eye infections,
herpes zoster in immunosuppressed
patients, hepatitis B virus-associated
chronic active hepatitis, cytomegalo-
virus infection in renal transplant
recipients, herpes simplex labialis
and papillomavirus infections of
various types.
It was partly because of the excit-
ing results in viral studies, but
perhaps more because of the un-
reasonable prediction that interferon
would have powerful effects against
h u m a n tumours, that DNA chemists
addressed the problems of cloning
and expressing h u m a n interferon
genes. This was done remarkably
successfully and several pharma-
ceutical companies have collabor-
ated with gene technology firms to
develop the products of this work. It
should be understood that even
though successful trials had been
done with buffy coat interferon, each
product of gene cloning needed to be
thoroughly evaluated for quality