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Subject: ISB News Report - October
Date: Tue, 1 Oct 1996 14:23:33 -0400 (EDT)

                    ISB News Report - October 1996


  What's in the Pipeline?
  A Reader Responds
  A Word from USDA's Biotechnology Information Center
  Virus Resistant Papayas Deregulated
  A Review of Transgenic Aquatic Organisms
  Antifreeze Transgenes Increase Cold Tolerance and Freeze Protection
  Will EASDAQ Help Growth of European Agbiotech Firms?


As this summer's field tests are winding down to harvest and
termination, planning is well underway for the next round. As of
September 13, dozens of notification letters and permit requests for
off-season trials have been received at USDA/APHIS's Biotechnology
Permits unit, and no doubt more are on the way.=20

A quick survey of submissions reveals a lot of overlap in the
development of herbicide tolerant and insect resistant corn lines. Male
sterility, which may be suitable for biological confinement to prevent
gene flow through pollen transmission, will be evaluated in rapeseed,
Brassica oleracea, and corn. Antibiotic-producing soybeans and rapeseed
that produces a pharmaceutical protein are also scheduled for field

Under the notification procedure, crops having the following traits
will be tested in warm, sunny fields in Puerto Rico and/or Hawaii,
except where noted (acknowledgment of some notifications may still be
awaiting state response):

- - Lepidopteran resistance, Coleopteran resistance, or glyphosate
      tolerance (Monsanto)
- - altered fiber strength (Agracetus)
- - Lepidopteran resistance and Bromoxynil tolerance (Calgene, in
- - resistance to Lepidopteran pests (Limagrain, Monsanto, Great Lakes
      Hybrids, WyFFels Hybrids, Pioneer)
- - glyphosate tolerance (Pioneer, Limagrain, DeKalb, WyFFels Hybrids,
      Monsanto, Great Lakes Hybrids, and Northrup King)
- - phosphinothricin tolerance and Lepidopteran resistance (WyFFels
- - resistance to Coleopteran and Lepidopteran pests (Monsanto)
- - altered fertility or seed composition (Pioneer)
- - resistance to Northern corn leaf blight and Lepidopterans (Northrup
- - glyphosate and phosphinothricin tolerance (DeKalb)
- - resistance to fungal pathogens and phosphinothricin tolerance
- - resistance to European corn borer (DeKalb, in Florida)

- - resistance to Lepidopteran insects (Calgene)
- - increased solids (BHN Research, in Florida)

- - phosphinothricin tolerance (University of Illinois, in Illinois)
- - antibiotic production (Agracetus)
- - phosphinothricin tolerance and increased lysine level (DeKalb)
- - pollen visual marker (University of Illinois, in Illinois)

Under current APHIS rules, engineered crops other than corn, cotton,
tobacco, tomatoes, potatoes, and soybeans are field tested under the
permit procedure. Permits have been issued for field tests of:
- - rapeseed with altered fatty acid metabolism (Cargill, in Arizona)
- - Brassica oleracea that is male sterile and phosphinothricin tolerant
      (American Takii, in California)
- - rapeseed that is male sterile and phosphinothricin tolerant (Tilak
      Raj Sawheny, in Arizona)
- - wheat resistant to barley yellow dwarf virus and wheat streak mosaic
      virus (University of Idaho, in Idaho)
- - phosphinothricin tolerant beets (Betaseed, in Oregon)
- - wheat resistant to fungus infection (Monsanto, in Arizona)
- - peppers resistant to cucumber mosaic virus (Seminis Vegetable Seeds,
      in Florida)

Permits are pending for field tests of:
- - rapeseed producing pharmaceutical protein (Pioneer, in California)
- - glyphosate tolerant rapeseed (Monsanto, in California)
- - rapeseed with an altered oil profile (Calgene, in California and
- - glyphosate tolerant wheat (Monsanto, in Arizona)

Connect to the USDA/APHIS/BBEP Biotechnology Permits homepage
( for updated information on field tests
and product deregulations.

*    *    *    *    *    *    *    *    *    *    *    *   *
Editor's Note:  The News Report published in August an article by Neal
Stewart, University of North Carolina at Greensboro, entitled Risk
Assessment of Transgenic Plants: Going Beyond the Crossroads. In it, he
argues that widespread release of certain crop/transgene combinations
may have potential long-term ecological effects that cannot be
predicted from short-term small scale research. The most obvious
examples are fitness-enhanced crops which can freely cross with related
wild or weedy species, such as insect resistant sunflowers. If we, the
agricultural biotechnology community, acknowledge that gene flow will
occur in some instances, do we avoid a potential problem by not
allowing the commercial release of certain products, or do we pursue
the benefits of the technology and respond with management and
mitigation should a problem arise? In the article, Stewart asserts that
we are already at the crossroads and must now make conscious, informed
decisions. The article prompted several thoughtful responses, one of
which is reprinted below.

Pat Traynor, Editor

I was most interested and pleased to see Dr. Stewart's comment, as I
believe a national discussion of how our regulatory agencies should do
risk assessment of biotechnology is long overdue. I'm a toxicologist
working for a regional office of the Environmental Protection Agency.
My specialty is human health risk assessment, and I've become very
interested in the methodologies being used to assess the risks of this
novel technology.

Several observations:
1. Dr. Stewart rightly suggested that regulatory agencies should
critically analyze risk assessment data and take to heart
recommendations from independent scientists. But there is a much more
fundamental need. For biotechnology there are no commonly accepted risk
assessment protocols, guidance, methodologies, testing guidelines or
science policies, as we have with human health risk assessment.

There is in place today a systematic approach to human health risk
assessment because in 1983 the National Academy of Science conducted a
study of the institutional means for risk assessment (published as
"Risk Assessment in the Federal Government; Managing the Process"). It
became the basis of a common framework for human health risk assessment
now used by all federal agencies.

A similar framework is now needed - indeed, is overdue - for assessment
of products of biotechnology. Assessments are done on an ad hoc basis
by different agencies (EPA, FDA, USDA) and within at least EPA, by
different programs. Obviously, this creates assessments which are not
comparable, and are of variable quality. Assessors working
independently and using different protocols are not sharing insights,
raising common issues or learning from one another how to address the
unique challenges raised by this new technology.

General principles, such as: "Avoid the commercialization and
large-scale release of any crop engineered with fitness-altering genes
and capable of interbreeding with wild relatives" (Dr. Stewart's
excellent wording) are needed not only to protect the environment, but
to guide manufacturers in their applications, and to protect the
industry from the stigma of ill-conceived products.

2. Dr. Stewart touched on the costs and benefits of taking the
avoidance vs management/ mitigation paths. The question of who bears
the costs and who reaps the benefits is interesting and not always
simple. True, the manufacturer must pay substantial research and
development costs, but the likely far larger costs of any environmental
or human health disasters will be borne by society. The manufacturer
may reap a substantial economic benefit if its product succeeds, but of
course this is an economic risk. On the other hand, economic success
for an individual company does not necessarily assure societal
benefits. Under the Toxic Substances Control Act (TSCA) for example,
efficacy of a product is not required for approval of an application;
in fact if a company could successfully market an ineffective product,
their projected profits would be counted as the benefit to be weighed
against potential environmental risks. EPA is facing this situation
right now as it ponders approval of a genetically engineered
nitrogen-fixing soil bacterium with questionable efficacy.

3. As Dr. Stewart pointed out, there is tremendous economic pressure to
develop new products for short-term gain, without thought about the
long-term consequences. There is also tremendous political pressure: to
help small businesses, to make the U.S. a technological leader, to keep
government out of the private sector, to reduce regulations. The
management of our regulatory agencies feels that pressure. I hope that
scientists such as Dr. Stewart will take advantage of the respect
accorded them, and offer their views to a larger audience, so that
political pressure can be balanced with reasoned concerns. =20

Suzanne Wuerthele=20
EPA Regional Office, Denver, CO

How do I learn about research related to genetically engineered algae?
What biotech-related databases are available online? What organizations
are involved in biotechnology education? These are just a few of the
thousands of questions handled each year by the Biotechnology
Information Center (BIC) in Beltsville, MD. The BIC is one of 10
information centers located at the National Agricultural Library, which
is part of USDA's Agricultural Research Service. Now in its 11th year
of operation, the BIC is regarded as one of the foremost sources of
information about agricultural biotechnology around the world.

The BIC staff is familiar with concepts and techniques used in
biotechnology and will perform complimentary searches of the AGRICOLA
database on specific topics or conduct an exhaustive search of major
databases on a cost recovery basis. In addition to developing aids to
assist consumers, educators, researchers, and policy makers, the
Center's Internet website ( provides access
to an extensive collection of biotechnology documents and links to
other sites. In any given month, users from more than 30 countries
connect to the site, accessing up to 19,000 documents. One of the most
popular areas of the BIC site provides access to full-text
biotechnology patents.=20

Much of BIC's strength lays in its commitment to continually updating
all of its resources, guides, bibliographies, and databases. The "Quick
Bibliographies", commonly called QB's, provide customers with a list of
all the latest articles, papers, books, and monographs pertaining to a
particular subject area, thus saving the patron hours of time spent in
library research. Most recently, BIC added the following QB's to its
list: Risk Assessment/Biosafety; Public Perception; Gene Gun/Biolistic
Technology; Bioethics, Legislation and Regulation; Patenting Issues;
Commercialization and Economic Aspects; Herbicide Tolerance/Resistance
in Plants; Viral Resistance in Plants/Viral Coat Proteins; and
Education and Training. These titles are now or will be soon available
via BIC's webpage. =20

Another BIC specialty is its extensive collection of
biotechnology-related audio-visuals and audio-tapes. All are available
for loan to any individual within the United States through a standard
interlibrary loan request. Some of the latest additions to this
collection include, "Licensing Veterinary Biologics: Traditional and
Recombinant Vaccines", "Whither Biogenetics?", "Designer Plants", and
"Superanimals, Superhumans?".=20

To learn more about the Biotechnology Information Center resources and
services, call 301-504-5947 or email:


The first genetically engineered perennial crop was cleared for
commercial production September 5, when USDA/APHIS biotechnology staff
concluded that two lines of papaya trees modified with the coat protein
gene from papaya ringspot virus (PRV) are just as safe to grow as
papaya cultivars developed through traditional breeding practices. The
trees were developed by researchers at Cornell University and the
University of Hawaii.=20

Papaya ringspot virus is the most important pathogen of payaya on a
worldwide basis; all major production areas are affected and the virus
continues to spread into new areas where papayas are grown. PRV, a
member of the potyvirus group transmitted by aphids, is a tenacious
pathogen that has never been successfully eradicated once introduced.
A 1992 outbreak of PRV in Hawaii's Puna district, where 95% of the
state's papayas are grown, has become so widespread it is unlikely that
it can be contained by control measures.

Genetic resistance has been identified in papaya germplasm but the
trait is polygenic, only moderately effective, and not found in
cultivars suited to Hawaii. Cross-protection by deliberate inoculation
with a mild mutant strain of PRV (HA 5-1) to prevent subsequent
infection by more virulent strains offers some protection against
Hawaiian strains of PRV. However, while cross-protected trees have only
relatively mild disease symptoms, yield is reduced 10-20% and the
approach requires inoculation of every seedling generation.=20

These limitations were circumvented by transforming the cultivar
'Sunset' with the coat protein gene of mild PRV strain HA 5-1. After
initial tests in the greenhouse, a two-year field test of transformed
line 55-1 showed that R0 plants and their progenies are highly
resistant to Hawaiian isolates of PRV; the line is susceptible to virus
isolates from other parts of the world, including Thailand. Greenhouse
tests of transformed line 63-1 indicate resistance to Hawaiian PRV
isolates and better resistance to Thai isolates than line 55-1.=20

The APHIS determination that transgenic 'Sunset' papaya lines 55-1 and
63-1 shall no longer be regulated is based on their conclusions that
the transgenic lines:
- - do not exhibit plant pathogenic properties
- - will not lead to the emergence of new plant viruses
- - are no more likely to become weeds than other types of papaya
- - will not increase the weediness potential of any other cultivated or
      wild species
- - will not harm threatened or endangered species or beneficial
- - will not cause damage to processed agricultural commodities

According to Dennis Gonsalves, principal investigator from Cornell
University, growers in Hawaii are anxious to get the new papaya lines

Pat Traynor
Information Systems for Biotechnology


Gene transfer techniques have been applied to a large number of aquatic
organisms, both vertebrates and invertebrates. Gene transfer
experiments have targeted a wide variety of applications, including the
study of gene structure and function, aquaculture production, and use
in fisheries management programs. This article briefly reviews the
status of development of transgenic aquatic organisms.=20

Because fish have high fecundity, large eggs, and do not require
reimplantation of embryos, transgenic fish prove attractive model
systems in which to study gene expression. Transgenic zebrafish have
found utility in studies of embryogenesis, with expression of
transgenes marking cell lineages or providing the basis for study of
promoter or structural gene function. Although not as widely used as
zebrafish, transgenic medaka and goldfish have been used for studies of
promoter function. This body of research indicates that  transgenic
fish provide useful models of gene expression, reliably modeling that
in "higher" vertebrates.=20

Perhaps the largest number of gene transfer experiments address the
goal of genetic improvement for aquaculture production purposes. Most
experiments entail transfer of genes for growth hormone (GH) or other
growth factors. Devlin and coworkers reported the most dramatic results
to date, with transgenic coho salmon families exhibiting growth rates
11 times those of non-transgenic controls (1). However most studies,
such as those involving transgenic Atlantic salmon and channel catfish,
report growth rate enhancement on the order of 30-60%. In addition to
the species mentioned, GH genes also have been transferred into striped
bass, tilapia, rainbow trout, gilthead sea bream, common carp,
bluntnose bream, loach, and other fishes.=20

Shellfish also are subject to gene transfer toward the goal of
intensifying aquaculture production. Growth of abalone expressing an
introduced GH gene is being evaluated; accelerated growth would prove
a boon for culture of the slow-growing mollusk. A marker gene was
introduced successfully into giant prawn, demonstrating feasibility of
gene transfer in crustaceans, and opening the possibility of work
involving genes affecting economically important traits. In the
ornamental fish sector of aquaculture, ongoing work addresses the
development of fish with unique coloring or patterning. A number of
companies have been founded to pursue commercialization of transgenics
for aquaculture. As most aquaculture species mature at 2-3 years of
age, most transgenic lines are still in development and have yet to be
tested for performance under culture conditions.=20

A number of experiments utilize gene transfer to develop genetic lines
of potential utility in fisheries management. Transfer of GH genes into
northern pike, walleye, and largemouth bass are aimed at improving the
growth rate of sport fishes. Gene transfer has been posed as an option
for reducing losses of rainbow trout to whirling disease, although
suitable candidate genes have yet to be identified. Richard Winn of the
University of Georgia is developing transgenic killifish and medaka as
biomonitors for environmental mutagens, which carry the bacteriophage
phi X 174 as a target for mutation detection. Development of transgenic
lines for fisheries management applications generally is at an early
stage, often at the founder or F1 generation.=20

Broad application of transgenic aquatic organisms in aquaculture and
fisheries management will depend on showing that particular GMOs can be
used in the environment both effectively and safely. Although our base
of knowledge for assessing ecological and genetic safety of aquatic
GMOs currently is limited, some early studies supported by the USDA
biotechnology risk assessment program have yielded results. Data from
outdoor pond-based studies on transgenic catfish reported by Rex Dunham
of Auburn University show that transgenic and non-transgenic
individuals interbreed freely, that survival and growth of transgenics
in unfed ponds was equal to or less than that of non-transgenics, and
that predator avoidance is not affected by expression of the transgene.=20

Laboratory studies of transgenic medaka by Bill Muir and colleagues at
Purdue University indicated that large males gain a higher frequency of
matings, but that transgenic offspring exhibit decreased viability;
computer modeling suggests that the demographic viability of medaka
populations could be threatened by introduction of transgenics.
Possible impacts of monosex or triploid grass carp stocks will be
assessed by Bill Shelton of the University of Oklahoma; although these
carp will not be transgenic, the results will have bearing on use of
transgenic stocks as insights will be gained on the efficacy and
environmental safety of these means of reproductive confinement.=20

Given the desire to pursue research and development with genetically
modified aquatic organisms in the face of incomplete knowledge
regarding environmental risks, a decision support tool for assessing
and managing risks was developed. The Performance Standards for Safely
Conducting Research with Genetically Modified Fish and Shellfish was
produced by a working group under USDA's Agricultural Biotechnology
Research Advisory Committee with input from a wide range of aquatics
professionals (2). The Performance Standards serve as a guide for a
researcher to assess potential risks associated with a proposed
experiment with an aquatic GMO, and to adopt appropriate confinement
should any risk be identified. Documented completion of the performance
standards should help the researcher gain approval for the experiment
from an institutional biosafety committee. The Performance Standards
have been converted into a computer software package, which can be
obtained without cost by downloading it from the NBIAP website at, by e-mail request at, or by
calling 540/231-3747. Print copies are available from the Biotechnology
Information Center of the National Agricultural Library (see article
elsewhere in this issue).

1.  Devlin, R.H., T.Y. Yesaki, E.M. Donaldson, and C.-L. Hew. 1995.
Aquaculture 137:161-169.=20

2. Agricultural Biotechnology Research Advisory Committee. 1995.
Performance Standards for safely conducting research with genetically=20
modified   fish  and   shellfish. Part I. Supporting text. Document no.
95-04. Part II. Flowcharts and accompanying worksheets. Document no.
95-05. National Agricultural Library, Beltsville, MD.=20

Eric Hallerman
Virginia Tech

Marine fish that live in icy waters, such as wolf fish and sea raven,
often synthesize antifreeze proteins (AFPs) to protect against
freezing. Transfer of AFP genes into economically important fish
species has been proposed as a method for conferring freeze protection.
Production of AFP-expressing strains of salmon and other fish, for
example, would promote the development of sea-pen aquaculture in colder
regions of the world.=20

Experiments to introduce AFP genes suggest that genetically stable
germ-line transformed fish can be produced (1). Integration of a winter
flounder AFP gene into the genome of the Atlantic salmon following
microinjection of eggs was accompanied by low level expression in a
small number of fry. Inheritance of the AFP gene was stable, and about
50% of the offspring resulting from transgenic F1:wildtype crosses
contained the gene. When goldfish oocytes were microinjected with ocean
trout AFP genes, nearly a quarter of the resulting 2-month old fish
contained one to several copies of the transgene. More than 50% of the
offspring of separate crosses between two transgenic males and a
control female inherited the gene, and AFP was detected in both F1 and
F2 progeny. Transgenic goldfish experimentally challenged with low
temperatures also had significantly greater tolerance for cold
conditions than controls, implying that the AFP gene product may
provide cold tolerance as well as freeze protection.

Transgenic expression of fish AFP genes may also be a means of
increasing the frost resistance and freeze tolerance of plants (2).
Tobacco plants transformed with the winter flounder AFP gene produced
mRNA, demonstrating that the gene was transcribed, but no detectable
AFP protein was produced. However, protein was detected after cold
exposure (4 C for 24 h), suggesting that this may be a suitable
strategy for producing frost resistant plants.

1.  Molecular Marine Biology and Biotechnology, vol. 1, 1992,
      p.309-317; vol. 4, 1995, p. 20-26.
2.  Plant Molecular Biology, 1993, p.377-385.

J. Glenn Songer
University of Arizona


It is well known that one of the more onerous tasks facing the
biotechnology industry is the relentless pursuit of capital to fund
research and development. This has been particularly difficult for
European firms due to the lack of a European stock exchange which
catered to high-risk technology firms in industries like biotech. This
month a new option has arisen in the form of the European Association
of Securities Dealers Automated Quotation (EASDAQ) stock exchange.

The pan-European EASDAQ is an initiative of the European Association of
Securities Dealers (EASD) and the European Venture Capital Association.
One of the major incentives behind the development of the EASDAQ was
the need to fill a void that has left most of Europe's smaller growth
companies without access to liquid public markets. It is estimated that
only 2.2% of European companies with less than 500 employees have
raised capital on a stock exchange. This lack of public equity markets
has also had an impact on the venture capital community's ability to
raise funds. All of this is in contrast to the situation in the United
States, where the National Association of Securities Dealers Automated
Quotation market (NASDAQ) boasts listings of over 4,900 companies. The
NASDAQ has been a significant source of capital for biotechnology firms
in the U.S. and abroad, and the hope of many is that the EASDAQ will
ultimately play the same role for European biotechnology. One study
conducted by Coopers & Lybrand indicated that as many as 500 stocks
(including biotechnology stocks) could be traded on the EASDAQ within
5 years, representing firms from most of the major European countries

Not everyone is so enthusiastic about the prospects for the new
European exchange. A recent article in Nature Biotechnology questions
whether or not the need for such an exchange still exists in Europe, as
was the case when the initiative was first put forth several years ago.
For one thing, since the time that the EASDAQ concept was proposed in
1994, the London Stock Exchange (LSE) has revised its listing rules,
making it easier for high-tech companies such as biotechnology firms to
enter the market. In addition, other small-cap markets have reemerged
including the Alternative Investment Market (AIM) in London and the
Nouveau March=82 in Paris. Finally, a number of European firms have
accessed capital through the NASDAQ, which the EASDAQ ultimately hopes
to leverage through a relationship with NASDAQ offering a dual listing
to firms listed on either exchange.=20

Those concerned about the value of the EASDAQ fear that there simply
may not be enough buying and selling of stock to provide adequate
commissions to brokers who provide access for large institutional
investors. One possible=0Coutcome that has been mentioned is that the EASDA=
Q will be used more by
non-UK firms who have less access to domestic markets, while UK-based
firms will tend to list on the LSE or AIM. Time will tell how many
other biotechnology firms will follow in the footsteps of the European
biomedical diagnostics firm Innogenetics, the first European bioscience
firm to be quoted on the new exchange (2). =20

1.  EASD home page on the Internet World Wide Web @ http://ourworld.

2.  Ward, M. EASDAQ opens, with some unease.  Nature Biotechnology,
Vol. 14, No. 9, September 1996, pp. 1075-1076.

William O. Bullock
Institute for Biotechnology Information, LLC
Research Triangle Park, NC

*  *  *  *  *  *  *  *    END    *  *  *  *  *  *  *  *  *  *  * =20
The material in this News Report is compiled by NBIAP's Information
Systems for Biotechnology, a joint project of USDA/CSREES and the
Virginia Polytechnic Institute and State University. It does not
necessarily reflect the views of the U.S. Department of Agriculture or
of Virginia Tech. The News Report may be freely photocopied or
otherwise distributed without charge. P.L. Traynor, Editor.

Information Systems for Biotechnology, 120 Engel Hall, Virginia
Polytechnic Institute and State University, Blacksburg, VA 24061-0308,
tel: 540-231-2620, fax: 540-231-2614, email:

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