T I B T E C H - A P R I L 1986

Competition and pressure to speed

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
Biotechnology and regulation: the need to plan competitive future
research and marketing strategies. In

different perspectives in the the US especially, regulation is

perceived as a significant factor in
determining whether the US bio-
United States and the technology industry can remain
ahead of international competition.
European Community According to one of the papers
prepared for the Brookings Confer-
ence, the competitiveness of the US
biotechnology industry should be
Is existing legislation adequate to contrast to the other activities, measured both against 'conven-
regulate biotechnology? agricultural applications involve tional' technology producing similar
The theme of a recent conference * deliberate, potentially large-scale products and against the biotech-
was the legal and regulatory issues releases of organisms that have been nology industries in other coun-
surrounding biotechnology. One of engineered specifically to survive in tries 1.
the central issues of the current the environment. Agricultural aims Some representatives of US indus-
debate in the US and Europe is include reducing plant vulnerability try fear that other industrialized
whether biotechnology, and particu- to environmental stresses, discover- countries will set up regulatory
larly the deliberate release of gen- ing and controlling infectious agents schemes before agreement is reached
etically manipulated microorgan- in animals and in fields post-harvest, among the US authorities, and that
isms into the environment, can be reducing dependence on chemical this could lead to competitive ad-
adequately regulated by existing pesticides, chemical fertilizers and vantages for foreign companies,
law. Whereas the Administration in irrigation, and increasing the nutri- particularly if regulation in those
the US has taken the position that tional qualities of seeds, fruits, countries is less severe than in the
existing legislation is adequate, the grains and vegetables. US. Approval and testing procedures
Biotechnology Regulation Inter- The development of agricultural in the US are lengthy: in the
service Committee (BRIC) of the applications has proceeded much pharmaceutical industry, according
European Commission is still assess- faster than expected. In the US many to the US Pharmaceutical Manufac-
ing the adequacy of the existing companies have already applied for turer's Association, the average time
regimes. The outcome will probably field tests for genetically manipu- needed to obtain approval of a new
be that in some areas (for example lated plants and microbial pesti- drug is seven to ten years at a cost of
for some pharmaceutical applica- cides, and several tests have been $74 million 1. Although foreign regu-
tions) the existing European regula- approved by the US Administration. latory proceSSes may be less severe,
tory framework is sufficient, but in The US Department of Agriculture US legislation currently prohibits the
other areas, especially in the field of (USDA) is currently funding many export by US firms of products for
deliberate release and waste treat- biotechnology research projects of which US approval has not been
ment, new legislation will be neces- which 87 projects involve the release obtained. Important discussions are
sary. of genetically engineered micro- now taking place to find a remedy for
organisms within the next five years. this perceived barrier to US com-
The need for regulation of deliberate Many US universities are also ex- pet~ivity abroad.
releases pected to apply for field test ap- Another issue concerning inter-
The new discoveries in biotech- proval soon. Large scale deliberate national competition is the pressure
nology are currently having their release of recombinant DNA organ- from industry on US regulatory
greatest impact in four commercial isms and exotic organisms will also be authorities to accept foreign testing
spheres: agriculture, pharmaceuti- an integral part of biotechnological data in US approval submissions.
cals, medical therapies and speci- techniques in industry for controlling Relaxation of this requirement might
ality chemicals. Of these, the agricul- environmental pollution, cleaning up be acceptable if data were collected
tural applications are of the most toxic pollutants and extracting miner- from other industrialized countries
important potential concern from an als from ores. The same developments where proper testing procedures are
environmental point of view. In can be expected in Europe within the enforced: however, the validity of the
next few years. data might be in doubt if they were
*Second Annual Broota'ngs Conference Regulating all these applications collected from (for example) Third
on Biotechnology held 18-19 February requires evaluation of the existing World countries where testing facili-
in Washington DC. legislation. ties were less adequate, or where
(~ 1986, Elsevier Science Publishers B.V., Amsterdam 0166-9430/86/$02.00
 T I B T E C H - A P R I L 1986

procedures might not be as accur- v i r o n n l e n t 3. Many of the applied • Will they have a deleterious
ately followed. Obviously caution release experiments will to be per- effect?
and selectivity in accepting foreign formed with bacteria in agricultural Very little information is available to
data is required to maintain safety settings and, in assessing the risks of answer these questions.
standards in the US and to prevent release, it will be necessary to know Predictive ecology is also neces-
Third World countries from being not only about the source of the sary to provide techniques for
used as testing grounds. genes but also about the potential measuring environmental impacts of
microbial recipients in soil. How- genetically engineered organisms.
Assessing the risks involved in ever, only 10% of the organisms in There are almost no accepted
deliberate release soil can be cultured in the laboratory methodologies for evaluating the
The root of the concern about new and very little is known about safety of genetically-engineered pro-
techniques of biotechnology is its genetic exchange in bacteria other ducts and processes: the risk assess-
power to generate new forms of life: than E. coli outside the laboratory, ment tools and data used for chemi-
genetic engineering can provide especially in soil. In any case, cal substances cannot be used for
combinations of traits in an organ- because conditions in the laboratory organisms 5.
ism that are very unlikely ever to be are very restrictive, oversimplified Most scientists agree that intro-
produced by selection in nature and artificial, extrapolating from ducing large numbers of new organ-
while mass culture can produce bulk laboratory situations can lead to isms will affect the environment,
quantities of these organisms, or of unreliable predictions. altering, for example, the level of
naturally-occurring, but rare, organ- Given that answering questions' existing species, food chains, or the
isms. With conventional techniques about horizontal transfer is regarded species composition in a particular
like selective breeding, genes are as relatively simple compared with habitat 1. The science of ecology is
also recombined to produce new, forecasting whether any harm will not well enough developed to pro-
genetically stable varieties of organ- result from such horizontal transfer, vide a sufficiently detailed model to
isms. However, what distinguishes it is obviously going to be very determine whether the release of a
recombinant-DNA techniques is that difficult to estimate the potential genetically-engineered organism has
they bypass the natural reproductive hazards from release experiments. affected the environment above the
systems of organisms and allow More research is obviously required normal background of natural eco-
direct transfers of genes between on the interaction between genetic- logical change 1. Same scientists
unrelated organisms. The new tech- ally modified microorganisms, the even argue that without the funda-
niques vastly increase the pool from soil and the environment. mental understanding of how the
which traits can be drawn to alter ecosystem ('the machine') works it is
any organism. New organisms can be The importance of ecology as a hardly possible to assess the impact
produced at a more rapid rate than in predictive science of the release of particular organisms
the past. Knowledge of the genetic reper- and to predict the secondary rami-
The regulatory authorities are, toire of released organisms is impor- fications.
therefore, confronted with having to tant in assessing probable hazards,
assess the risks to health, welfare but alone it will not provide enough Case-by-case and step-by-step: US
and the environment of releasing information to make adequate pre- and European approaches
living organisms and plants. Since dictions of environmental risks of Notwithstanding the obviously in-
the existing legislation was not deliberate release. There seems to be adequate scientific basis of risk
designed to anticipate, evaluate and a pressing need for developing an assessment for the release (acci-
control risks from genetically modi- interdisciplinary approach to pre- dental or deliberate) of genetically-
fied organisms, the assessment is dictive ecology in order to fill the engineered microorganisms, regula-
difficult. In assessing risk, one ad- information gaps. According to tory authorities in the US and
vantage of biotechnology (and, in Martin Alexander, a microbial eco- Europe have started approval pro-
particular, genetic engineering) is logist from Cornell University and cedures: in the US some field tests
that it is more directed and control- former member of the Recombinant have already been approved.
led than conventional techniques. DNA Advisory Committee of the US
This could reduce the likelihood of a Environmental Policy Agency (EPA), Case-by-case
new genotype containing undetected five key questions need to be In the US, regulatory agencies
problems 1,2. answered in some detail before we follow a case-by-case licensing pro-
However, as was pointed out in an can predict the fate of genetically- cedure to regulate biotechnology
Office of Technology Assessment altered organisms in the environ- products. Each agency with biotech-
(OTA} draft staff paper presented at ment 4. nology products within its jurisdic-
the Brookings Biotechnology Confer- tion decides whether the product fits
ence, despite the control over pro- • Will they survive? within the agency's competence. By
duction processes, laboratory experi- • Will they multiply? combining past experience and gen-
mental data are inadequate to accur- • Will they transfer their inserted erating new information on genetic-
ately assess the probability of hori- genetic changes to other species? ally modified organisms, the agency
zontal transfer when altered organ- • Will they be transported or dis- secures a progressively larger data
isms are introduced into the en- seminated to new sites? 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
 TIBTECH - APRIL 1986

public at large is kept uninformed, mistake, born of concern for share Assessment, Congress of the United
no basis for understanding and trust prices or scientific prestige, to try to States, Draft Staff Paper
can be established. Over the next few sell the public the wonders of 4 Alexander, M. (1985) Issues Sci.
months it will become extremely biotechnology without properly Techno]. Spring, 61-64
5 Doyle, J. (1985) in EPI Perspectives,
important for governments and regu- addressing, the risks. Public sus- Special Annual Edition 1984/1985,
latory authorities to initiate open picion delays development as the Environmental Policy Institute
public debates on deliberate release 'ice-minus' case has clearly demon- 6 Commission of the European Com-
in order to provide balanced inform- strated. munities (1985) Biotechnology and
ation. Without open debate a polar- Rules Governing Pharmaceuticals in
ized, unworkable entrenchment will References the European Community, revised
develop between the biotechnology 1 Biotechnology: A Legal~Regulatory text, IIIA 3, Brussels
industry and its opponents. In Analysis (1986) Paper prepared in 7 Magagnini, St. (1985) The Sacramento
Europe the BioTa2000 multi-media conjunction with the Second Annual Bee Magazine, December, 7-12
programme, partly financed by the Brookings Conference oil Biotech- 8 Maykuth, A. (1986) Philadelphia In-
nology quirer, January 10, 1
European Commission, has started
to provide the public with informa- 2 Dixon, B. (1985) Engineered Organ-
tion. isms in the Environment: Scientific
Issues, Lay Summary, American ANNEMIEKE J. M.ROOBEEK
Many of the positive contributions Society for Microbiology
that the new genetic technologies 3 Genetic Issues in Environmental
could make, like crops with disease Applications of Genetically Altered Department of Economics, University
and insect resistance or with higher Organisms (1986) Biological Applica- o f Amsterdam, ]odenbreestraat 23,
nutritional value, are at stake. It is a tions Program, Office of Technology 1011 N H Amsterdam, The Netherlands.
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ant antihistamines which were

Interferons: what future? thought to reduce nasal clearance of
interferon), but these techniques did
not detract from the need for almost
It is hard for us to imagine how volunteers to prevent vaccinia. This unlimited supplies of interferon if a
revolutionary were the discovery was an expensive business and even market were to be found and needed
and first description of the substance though the trial was very successful to be filled. Using buffy coat leuco-
that Alec Isaacs called 'interferon' in (vaccinia appearing to be highly cyte interferon, many other virus
the late 1950s 1. To many it was a susceptible in rive), it was consid- infections were successfully pur-
figment of a vivid scientific imagina- ered of very dubious commercial sued during the 1970s including
tion, yet the original observations merit. herpes simplex eye infections,
were carefully repeated in many In the mid-1960s Kari Cantell herpes zoster in immunosuppressed
laboratories and the production by started to make leucocyte interferon patients, hepatitis B virus-associated
cells of a soluble substance to from buffy coats from blood destined chronic active hepatitis, cytomegalo-
explain viral interference was more for transfusion, and managed to virus infection in renal transplant
or less accepted by the 1970s. When make sufficient to supply nearly all recipients, herpes simplex labialis
interferon was discovered, it was the important trials reported through and papillomavirus infections of
realized that it was possible to the 1970s. The successful trial re- various types.
interfere with viral replication with- ported in 1973 (Ref. 2) of repeated It was partly because of the excit-
out necessarily endangering cellular intransal sprays of interferon against ing results in viral studies, but
metabolism and many thought that experimental common colds in perhaps more because of the un-
interferon might prove to be a useful volunteers given rhinovirus type 2, reasonable prediction that interferon
antiviral agent. used about one year's manufacturing would have powerful effects against
However, a major problem was in supply from this process. Thus al- h u m a n tumours, that DNA chemists
material supply and this remained though it was a success, there was addressed the problems of cloning
so until the cloning of interferon insufficient interferon to pursue fur- and expressing h u m a n interferon
genes inE. coliin the late 1970s, and ther studies, let alone sell interferon genes. This was done remarkably
the concomitant successful develop- for common colds. successfully and several pharma-
ment of large-scale lymphoblastoid Greenberg and coworkers 3 estab- ceutical companies have collabor-
interferon production. To give ex- lished the m i n i m u m dose of inter- ated with gene technology firms to
amples of the early supply problems, feron which could protect volun- develop the products of this work. It
a two-year collaboration between teers against rhinovirus and devised should be understood that even
Glaxo and Wellcome laboratories ways of enhancing the effects (for though successful trials had been
produced sufficient monkey kidney example, by putting a cotton wool done with buffy coat interferon, each
cell interferon for a single small dose pledget saturated with interferon product of gene cloning needed to be
to be inoculated intradermally in 36 into the nose or by using concomit- thoroughly evaluated for quality
(~ 1986, Elsevier Science Publishers B.V., Amsterdam 0166-9430186/$02.00