Transgenic Res (2016) 25:575–595

DOI 10.1007/s11248-016-9965-1

REVIEW

Strategies to enable the adoption of animal biotechnology

to sustainably improve global food safety and security
Mark Tizard . Eric Hallerman . Scott Fahrenkrug . Martina Newell-McGloughlin .
John Gibson . Frans de Loos . Stefan Wagner . Götz Laible .
Jae Yong Han . Michael D’Occhio . Lisa Kelly . John Lowenthal .
Kari Gobius . Primal Silva . Caitlin Cooper . Tim Doran

Received: 18 May 2016 / Accepted: 21 May 2016 / Published online: 31 May 2016
Ó Springer International Publishing Switzerland 2016

Abstract The ability to generate transgenic animals
has existed for over 30 years, and from those early
days many predicted that the technology would have
beneficial applications in agriculture. Numerous trans-
genic agricultural animals now exist, however to date
only one product from a transgenic animal has been
approved for the food chain, due in part to cumber-
some regulations. Recently, new techniques such as
precision breeding have emerged, which enables the
introduction of desired traits without the use of
transgenes. The rapidly growing human population,
environmental degradation, and concerns related to
zoonotic and pandemic diseases have increased pres-
sure on the animal agriculture sector to provide a safe,
secure and sustainable food supply. There is a clear
need to adopt transgenic technologies as well as new
methods such as gene editing and precision breeding
to meet these challenges and the rising demand for
animal products. To achieve this goal, cooperation,
education, and communication between multiple
stakeholders—including scientists, industry, farmers,
governments, trade organizations, NGOs and the

M. Tizard
J. Lowenthal
C. Cooper
T. Doran (&) S. Wagner
G. Laible

CSIRO Health and Biosecurity, Geelong, Australia AgResearch, Hamilton, New Zealand
e-mail: Timothy.Doran@csiro.au
C. Cooper J. Y. Han
e-mail: caitlin.cooper@csiro.au Seoul National University, Seoul, Korea

E. Hallerman M. D’Occhio
Virginia Polytechic Institute and State University, University of Sydney, Sydney, Australia
Blacksburg, VA, USA
L. Kelly
S. Fahrenkrug Food Standards Australia New Zealand, Canberra,
University of Minnesota, Recombinetics, Minneapolis, Australia
MN, USA
K. Gobius
M. Newell-McGloughlin CSIRO Food and Nutrition, Werribee, Australia
University of California Davis, Davis, CA, USA
P. Silva
J. Gibson Foreign Animal Inspection Agency, Winnipeg, Canada
University of New England, Armidale, Australia

F. de Loos
Flow Biotech, Soest, The Netherlands

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public—is necessary. This report is the culmination of
concepts first discussed at an OECD sponsored
conference and aims to identify the main barriers to
the adoption of animal biotechnology, tactics for
navigating those barriers, strategies to improve public
perception and trust, as well as industry engagement,
and actions for governments and trade organizations
including the OECD to harmonize regulations and
trade agreements. Specifically, the report focuses on
animal biotechnologies that are intended to improve
breeding and genetics and currently are not routinely
used in commercial animal agriculture. We put
forward recommendations on how scientists, regula-
tors, and trade organizations can work together to
ensure that the potential benefits of animal biotech-
nology can be realized to meet the future needs of
agriculture to feed the world.
Keywords Animal biotechnology
Regulation

Food safety
Transgenic
Gene editing
Precision
breeding
Introduction
What are the future drivers for adoption of animal
biotechnology?
There are mounting pressures on our current animal
agricultural systems, pressures that are going to build
as the world population increases. Maintaining a safe,
secure, and sustainable food supply is the number one
challenge faced by global agriculture in the next
50 years. Taking into account the need to reduce the
environmental impact of agriculture, the limited
amount of land and water resources available, and
the ever- looming threat of zoonotic and pandemic
diseases, innovative solutions from multiple disci-
plines will be required to support agriculture to feed
the world in the coming decades. There are many
challenges that face animal agriculture in industrial-
ized nations; however, much of the increase in food
production needs to occur in developing countries
with growing populations. While there are common
world-wide problems confronting animal agriculture,
differences in climate, culture, resources, and histor-
ical access to technology mean that there are many
distinct animal production systems found around the
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Transgenic Res (2016) 25:575–595
globe. This means that each system will need to
grapple with these common problems in different
ways and to varying degrees. The extent of different
issues that need to be addressed is likely to drive the
adoption of animal biotechnology to provide the rapid
solutions required to meet specific needs. Animal
biotechnology encompasses a range of technologies,
however in the context of this review we will use the
term to refer specifically to those procedures involving
molecular techniques which are aimed at genetic
improvement.
One pressing issue is the significant efficiency gap
between production animals in developed and devel-
oping countries. This gap is due to many factors
including differences in animal health, nutrition,
management, and genetics. In terms of management,
in countries with growing populations there is a push
towards sustainable intensification of the local animal
agriculture systems in order to meet the increasing
demand and help improve the overall efficiency of
production. Sustainable intensification encompasses a
suite of farming practices aimed at making changes
which will enable farmers to raise more animals using
the same amount of resources and to continue to do so
well into the future. In many of these countries, there is
growing interest, and in some places actual steps are
being taken, to improve the genetics of local animals
through traditional breeding programs with access to
high-quality males for artificial insemination and by
employing animal genotyping, both technologies
which are used widely throughout developed countries
(FAO 2007). Genetic improvement of livestock
species must go forward at the regional level so that
the resulting animals are simultaneously more pro-
ductive and well adapted to their local environment.
With these changes, the agricultural systems in these
countries will gain the ability to implement current
and emerging technologies. But increasing animal
numbers and stocking densities will also increase the
likelihood of disease outbreaks and impacts of climate
change on production.
Agricultural animals around the world live in a
wide range of climates and face region—specific
endemic diseases. New technologies are currently
being applied to very pressing issues including disease
resistance, heat tolerance, and improved animal wel-
fare traits (Fahrenkrug et al. 2010). The ability to
rapidly improve traits throughout a population for
characteristics like disease resistance in order to
Transgenic Res (2016) 25:575–595
protect against endemic diseases and prevent the
spread of pandemics will be vital to provide a safe and
reliable food system and to establish a more stable life
for farmers. Established transgenic technologies as
well as emerging technologies utilizing a suite of tools
known as ‘‘molecular scissors’’ (Petersen and Nie-
mann 2015) could make a step change from genetic
marker assisted breeding to help farmers generate
lines of animals that are best-suited to thrive in their
given climate as well as to improve traits associated
with production, helping to simultaneously improve
animal welfare and close the productivity gap.
While the transgenic AquAdvantageÒ Atlantic
salmon has finally gained approval from the U.S.
government, the future of emerging techniques in
animal breeding is still unknown. In countries with
existing intensive agricultural systems, there is ample
room for improvement of these systems. However,
there is not currently a pressing need to produce more
food for the domestic population in developed coun-
tries; thus, the public often does not understand the
benefit of such technologies, and in many cases views
them with skepticism, the resulting political pressure
ultimately slowing their introduction into the market
(Blancke et al. 2015). The newer techniques may gain
greater public acceptance if they are applied to issues
that can readily be solved using biotechnology but are
difficult or impossible to address by other more
traditional means. Unfortunately, it seems likely that
the level of public attention on the animal agriculture
sector needed to drive these changes may occur only in
response to a large-scale human health or animal
welfare crisis similar to the foot-and-mouth outbreak
in the 2001 in the UK or the avian influenza outbreak
in the United States in 2015.
In contrast, in many developing countries, increas-
ing food production is seen as an essential objective;
there is significantly more urgency assigned to future
food security in those countries. They are therefore
generally more positively disposed to adopting new
technologies. However, they are often less able to
implement them, and in some cases are hesitant to
approve the use of technologies that have not been
widely embraced by developed countries. While the
future of established and emerging techniques in
animal biotechnology specifically focused on improv-
ing breeding and genetics remains uncertain, ulti-
mately clear and demonstrable benefits for the public
and industry alike will be the key drivers for adoption
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of these technologies. The diverse needs of distinct
animal agriculture systems around the world present
challenges for widespread adoption of any single
technology, but also provide opportunities for inven-
tive application of animal biotechnology to help solve
region specific problems.
What technologies are available?
Established technology: transgenic technology
In the context of animal biotechnology, transgenic
techniques involve moving a novel gene into the
genome of an animal. This novel gene can be a gene
from a different species or a novel engineered gene
construct, and transgenes can be inserted into the
genome of the recipient species at random or into a
targeted site. There are also cisgenic animals, which
harbor additional copies of genes already present in that
species, at either random or targeted sites within the
genome. Transgenic animals were first developed as a
model of gene expression (Gordon et al. 1980), and the
demonstration that growth hormone-transgenic mice
grow to a larger size by Palmiter et al. (1983) stimulated
interest in altering production traits of agricultural
animals. Subsequent demonstration of plant transfor-
mation techniques (Herrera-Estrella et al. 1983) led to
huge investments in and rapid development of plant
biotechnology. On the animal side, transgenic animals
have been produced for multiple agricultural purposes
(Englehard et al. 2009). While there are multiple ways to
produce transgenic animals, the following are the most
commonly used techniques in mammalian agricultural
species.
DNA microinjection In the first applications of
microinjection a transgene would be injected into the
nucleus of a fertilized egg where it would randomly
insert into the host genome. Now microinjection is
typically used to deliver molecular scissors (which
will be discussed in more depth in the next section)
with or without transgenes. In either case, after
injection the fertilised egg is transferred to a
recipient female, and if successful the offspring will
carry the desired alteration.
Somatic cell-mediated transgenesis Somatic cells
are maintained in culture and a transgene is introduced
into these somatic cells through a variety of means
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including transfection with lipid based complexes,
electrical based nucleofection methods, and viral
based delivery systems. Once delivered, the
transgene either randomly integrates into the genome
through non-homologous end joining (NHEJ) or is
inserted in a defined location through homologous
recombination (HR). Both NHEJ and HR are
relatively rare events, thus the somatic cells must be
screened to find cells that have correctly integrated the
transgene, with is typically done by screening for a
marker gene such as green florescent protein (GFP).
Once a population of integrated cells is established,
somatic cell nuclear transfer can be applied to generate
animals from these cells. The nuclei of individual
integrated somatic cells are transferred into the
‘empty’ oocytes, whose own nuclear genome had
been removed, and fused with an electrical pulse to
activate the newly constructed diploid embryo. Once
fused, the cells behave like typical in vitro-fertilized
embryos, and are transferred into recipient animals.
Many transgenic animals have been generated all
over the world using these methods. This includes
animals which possess sophisticated transgenes allow-
ing them to express proteins in a tissue-specific
manner (Brophy et al. 2003), gene knock-out animals
also carrying reporter transgenes (Richt et al. 2007),
and animals that produce novel miRNAs for gene
knock-down (Jabed et al. 2012). Animals have been
produced to help solve a variety of issues in animal
agriculture and display traits which impact disease
resistance (Wall et al. 2005; Richt et al. 2007), animal
welfare (Noble et al. 2002), environmental effects of
agriculture (Forsberg et al. 2013), and growth and feed
efficiency (Levesque et al. 2008; Xu et al. 2013) to
name a few applications. With the technological
advancements that have occurred in the last few
decades, producing a transgenic animal is now a
relatively straightforward endeavor. Additionally,
research done on many of the already-existing lines
of transgenic animals prove that these animals display
the expected phenotype in experimental settings and
could prove very useful to commercial animal agri-
culture around the world, if they were actually utilized.
Emerging technologies: gene editing and precision
breeding using molecular scissors
New tools have emerged in the last decade that allow
scientists to directly modify the genome sequence
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without the need for transgenes. Tools known as
molecular scissors, including zinc finger nucleases
(ZFNs, Kim et al. 1996), transcription activator-like
effector nucleases (TALENs, Boch et al. 2009) and
clustered regularly interspaced short palindromic
repeats (CRISPR/Cas9, Jinek et el. 2012) allow
scientists to direct the cleavage of a specific DNA
sequence within the genome and use endogenous
cellular pathways to direct DNA repair to introduce
specified alterations to the DNA sequence (Carlson
et al. 2013; Whitworth et al. 2014). This approach can
be used to accurately place transgenes in the genome
in a site specific manner (Wu et al. 2015). However,
what makes these tools particularly exciting is that
they can also be used for a completely new technique
known as precision breeding which uses those
endogenous cellular pathways to change the DNA
sequence from an unfavorable or deleterious form to a
beneficial form that already exists in that species
(Fig. 1). Molecular scissors can also be used to make
novel site directed changes to genes, a process known
as gene editing. For example this would include the
introduction of a stop codon that knocks out gene
function, or small, novel nucleotide changes that
modify the structure or activity of a protein or enzyme.
These tools can be used in mammals at the one-cell
embryo stage, while in poultry they are applied to
germ cells. For a more detailed technical explanation
of the TALEN and CRISPR systems in agricultural
animals, please see Laible et al. (2015) and Petersen
and Niemann (2015).
Random nucleotide mutations occur naturally dur-
ing the formation of the haploid male and female
gametes and when the two gametes merge after
fertilization to form the diploid genome. These
mutations impart genetic diversity into a population
and provide the raw material for adaptive evolution. In
humans, the germline mutation rate is estimated at 1.2
random mutations per every one hundred million
bases, which equals approximately 36 random muta-
tions in the genome (Campbell et al. 2012). Multiple
factors, including region of the genome (Hodgkinson
and Eyre-Walker 2011) and age of parents (Francioli
et al. 2015), can affect this mutation rate. Germline
mutations are both natural and necessary for selective
breeding of a species and underlie the development of
both performance-increasing and -decreasing alleles.
Traditional breeding programs for agricultural
animals take advantage of these natural mutations by
Transgenic Res (2016) 25:575–595
Fig. 1 Precision breeding though use of TALENs. TALENs or
other molecular scissors can cause single and double stranded
DNA breaks at very specific locations in the genome.
Introducing a DNA break activates the endogenous DNA repair
pathways. The non-homologous end joining (NHEJ) pathway
will rejoin the cut pieces of DNA and may introduce small
insertions or deletions at the break site. The homology directed
repair (HDR) pathways will use a homologous template to repair
the break. This homologous template can come from a sister
identifying previously uncharacterized performance-
increasing alleles within a population of animals
through extensive phenotyping and genotyping. When
animals with either multiple known performance-
increasing alleles or an overall enhanced phenotype
are found, they are incorporated into breeding plans in
order to disseminate those alleles and their positive
effects throughout the population. This system works
very well for improvement of performance-related
phenotypes, which are often polygenic. However, if a
favorable trait is directly caused by a single mutation
which occurs in only a few members of a population,
or the desired trait is found in animals that have been
bred for a different purpose (for example, if an allelic
variant that would be desirable for dairy cows is found
only in beef animals), there can be issues moving that
desired allele into a population. If the desired trait
occurs in only a few members of a population, using
only those animals with the desired allele to contribute
579
chromatid or can be supplied exogenously and contain single or
multiple nucleotide polymorphisms compared to the sequence
of the targeted DNA and can confer a desired phenotype onto the
animal. Repair of a targeted DNA break with a desired template
containing single or multiple polymorphisms that already exist
in other members of the species is the basis of precision
breeding, while repair of a targeted DNA break with a desired
template containing novel polymorphisms is the basis of gene
editing
significantly to the gene pool of next generation of
animals reduces genetic diversity in the population
and can pass on yet-unidentified deleterious alleles to
many members of the next generation. To prevent
these possible negative outcomes, breeders will slowly
introduce the desired allele into the population, which
can take many generations to be completed. If the
desired allele occurs in animals bred for a different
purpose, say beef production, using classical breeding
to introduce the trait into dairy animals will take many
generations and years of backcrossing to regain the
original phenotypic characteristic of a high-quality
dairy cow. In contrast, precision breeding utilizes
molecular scissors like TALENs and CRISPR/Cas9 to
generate targeted DNA cleavage sites which can be
repaired though homology-directed pathways, which
can seamlessly introduce known performance-increas-
ing alleles into the genome from basically any source.
This new method for allele introduction preserves
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genetic variation and will transmit only the desired
allele, avoiding transmission of any unidentified
deleterious alleles that may be in close proximity on
the chromosome. It also allows desired alleles to be
easily transferred between breeds with different
purposes.
In addition to looking for beneficial alleles already
existing in a population of animals, through in vitro
research, scientists can identify novel gene variants
that are likely to confer a positive phenotype in vivo.
Gene editing allows these novel gene variants, or
polymorphisms, to be replicated in vivo, and has
already been used successfully in pigs (Lillico et al.
2013; Whitworth et al. 2016). The polymorphisms
made through gene editing are polymorphisms that
could also arise through natural mutation, however to
fall under the definition of gene editing those
polymorphisms are, as of yet, not known to occur in
the target species. Importantly, with both precision
breeding and gene editing, once it is confirmed that the
desired phenotype is displayed as expected in an
animal, the genetic polymorphism underlying the
phenotype can be introduced into a wide range of high-
quality breeding stock within one generation, and
disseminated into the general population in the next
generation, allowing fast introduction of the desired
allele into the population.
Emerging technologies: germ cell technology
Germ cells are the unique cells that give rise to
gametes and transmit parental genetic information to
progeny. With the rapid development of biotechnol-
ogy, the application of technologies utilizing germ
cells has increased. In germ cell research, applications
such as long-term cell culture and induction of germ
cells from somatic cells have been successfully
performed using both genetic and epigenetic
approaches (Song et al. 2014; Hayashi et al.
2013a, b). Genetic manipulation of germ cells is
particularly important for the production of transgenic
birds (van de Lavoir et al. 2006). Combined with
conventional genetic engineering techniques, molec-
ular scissors are being utilized to make precise
changes in germ cells in poultry. For example, the
TALEN system has been used successfully for gene
editing in chickens (Park et al. 2014), as has CRISPR/
Cas9 (Dimitrov et al. 2016; Oishi et al. 2016).
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While research on germ cells in mammalian
livestock species is less advanced relative to other
species, such as the rat and mouse, in avian species,
robust techniques have been developed to establish
culture methods for primordial germ cells (Song et al.
2014), the cells from which germ cells originate.
Several groups have used primordial germ cell-
mediated techniques to produce transgenic birds,
including chickens and quail (Macdonald et al. 2012;
Park and Han 2012; Kwon et al. 2010). By incorpo-
rating knowledge about siRNA- and miRNA-based
expression systems, it is possible to induce specific
knock-out/down regulation or knock-in/cause over-
expression of a gene in poultry (Lyall et al. 2011).
Aided by germ-cell technology and new gene target-
ing tools, poultry could be generated which possess
several agricultural, medical, and biotechnological
advantages including disease-resistance, improved
production, allergen-free products, and improved
breeding.
What are the current barriers to the adoption
of established and emerging technology in animal
production systems?
Since its advent, biotechnology, in particular gene
technology or recombinant DNA techniques, has been
recognised as having the potential to have both
positive and negative impacts upon humans and the
environment, leading to scientists and society calling
for regulatory oversight. Starting in the mid-1980s,
countries have adopted a variety of different regula-
tory approaches (LLOC 2014). These different
approaches were a consequence of already-existing
regulatory frameworks and legal enabling authorities
in the respective countries, as well as different
underlying regulatory philosophies. Despite these
differences, a key common factor has been the
adoption of a process-based rather than a product-
based approach to regulatory oversight, especially
regarding the ‘‘trigger’’ for oversight of a product. The
regulatory trigger issue is particularly pertinent in the
context of some of the newer techniques such as
precision breeding and gene editing. For example, in
some cases it may be virtually impossible to distin-
guish between an animal derived from precision
breeding and an animal derived from traditional
selective breeding. Should such an animal be singled
Transgenic Res (2016) 25:575–595
out for regulation when identical animals, produced
using a different process, are not? Similar questions
are arising in plant agriculture and the United States
Department of Agriculture has already moved ahead,
taking a product based stance and deciding on a
number of occasions that crops produced via gene
editing which are indistinguishable from conventional
crops require no further regulation (Ledford 2013;
Waltz 2016). In Europe, regulation is significantly
more process based, and it remains unclear how gene
editing technologies will be regulated, however the
Swedish Board of Agriculture recently ruled that they
do not deem gene edited plants to fall under the
definition of ‘‘GMO’’, and more countries in the region
are expected to make their own determinations in the
near future (Abbott 2015). In light of the interest that
governments have been showing in the regulation of
gene edited crops, several leading scientists within the
plant genetics community have published manuscripts
addressing issues surrounding the regulation of gene
editing in plants and making suggestions for how
governments can move forward (Jones 2015; Huang
et al. 2016; Wolt et al. 2016). Use of these technolo-
gies in animals faces the same regulatory uncertainty
and leaders within the animal genetics research
community need to proactively address these issues
and put forward scientifically based solutions. In
particular, resolution of where the threshold is set to
require regulation will have a significant impact on the
development and degree of adoption of precision
breeding in a particular country. Additionally, the
degree to which OECD member states can harmonize
their regulatory approaches will determine the pene-
tration of the products of new technologies like
precision breeding and gene editing into international
trade. It is within this context that we consider
regulatory oversight of biotechnology in OECD
member states and key non-member states.
Adoption issues for the food production industry
There are several issues that, in the past, have led to
reluctance from the food production industry to invest
in transgenic technology. First, in some countries such
as the United States, the regulatory burdens for
transgenic food animals are the same as that for
pharmaceuticals (CAST 2011). The second issue is
that only one company has successfully navigated the
approval process for a transgenic food animal. Finally,
581
although in the 1980s and 1990s there was substantial
public funding for animal biotechnology research,
there has been very little funding available over the
past decade or so. Looking at the approval process for
transgenic animals to date, three pharmaceutical
products from transgenic agricultural animals have
reached the market: Atryn from transgenic goats
(Kling 2009), Ruconest from transgenic rabbits (van
Veen et al. 2012), and Kanuma from transgenic
chickens (Becker 2015). These three products treat
serious and rare diseases and are administered intra-
venously. From these products, we have learnt that
production of pharmaceutical proteins in milk and
eggs can be safe for the animals in which they are
produced and the proteins can be safe for patients that
are treated with these products. These products
validated a new system for producing complex
proteins and delivering efficient and safe products.
The transgenic aspect did not seem to influence
regulatory approval or market acceptance of these
pharmaceutical products.
These products do not necessarily teach us much
about the use of transgenic animals in food production,
as the pharmaceutical development track is com-
pletely different from the food development track.
They can however, provide insight into some of the
major barriers that face transgenic animals in the food
production industry. The costs of generating the data
necessary for regulatory approval is a major barrier, as
food products tend to be marketed with lower profit
margins; this burden is a significant barrier for food
products. Second is the expected length of time
required for regulatory approval. The food industry
normally works with shorter timelines and lower
budgets than the pharmaceutical industry. Long
development times and lengthy regulatory approval
processes are a much larger barrier in the food
industry. In the pharmaceutical industry, The Interna-
tional Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for
Human Use (ICH http://www.ich.org/home.html),
which was established in 1990, has led to significant
harmonization in regulations worldwide, improving
on efficiency in the registration processes. The lack of
such harmonization for transgenic food regulations is
another significant barrier for the uptake of transgenic
animals into the food chain. A number of guidelines
for the conduct of food safety assessment of foods
derived from transgenic organisms, including animals,
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have been produced by an ad hoc Task Force of the
WHO/FAO Codex Alimentarius Commission includ-
ing the ‘‘Principles for the risk analysis of foods
derived from modern biotechnology’’ which was
issued in 2003, and the more recent ‘‘Foods derived
from modern biotechnology, second edition’’ in 2009
(WHO/FAO 2009). The WHO and FAO represent
multiple countries around the world, and these guid-
ance documents could still provide the basis for har-
monized legislation throughout different countries,
but thus far the United States and Europe have moved
along different lines and have not taken full advantage
of the available Codex guidelines.
Despite the onerous regulatory requirements placed
on transgenic animals destined for the food chain, a
number of companies have put forward products for
approval. The only transgenic animal for food pro-
duction that has gained approval for consumption is
the AquAdvantageÒ Atlantic salmon produced by
AquaBounty. The salmon line was first developed in
1989 and the company began working with the U.S.
Food and Drug Administration (FDA) towards
approval in 2003, the same year that the first WHO/
FAO Codex Alimentarius Commission guidance doc-
ument was released. In the past decade, the AquAd-
vantageÒ salmon has passed all regulatory
assessments, with the draft Environmental Assess-
ment, preliminary Finding of No Significant Impact,
and the public comment period all completed by early
2013. Throughout the assessment process for the
AquAdvantageÒ salmon, there have been multiple
unexpected and unexplained delays by the FDA (Van
Eenennaam et al. 2013); however in November 2015
the salmon finally gained approval. While it is very
encouraging that a transgenic food animal has finally
found its way through the regulatory system, moving
forward, a 12-year approval timeline is unsustainable
and will significantly hinder development of new
products.
Finally, lack of support from some governments for
basic research has also affected industry adoption of
this technology, particularly in the United States. For
almost a decade starting in the mid-2000s, the annual
U.S. Department of Agriculture request for grant
applications included the text ‘applications whose
primary aim is to improve the efficiency in the
production of clones or transgenic animals through
manipulation of the nucleus will no longer be accepted
by the Animal Genome program’. This statement
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showed a clear disinterest from the critical federal
government-based funding organization, and could
even be interpreted as government resistance to the
technology. This perception, coupled with the expen-
sive and unpredictable regulatory environment, has
led to withdrawal of the private sector from most
investment in transgenic food animals.
Global issues around public perception
When we look at public perception of transgenic
animals in the food chain, we need to consider that
major differences exist around the world. Based on
previous research, it appears that in most northern and
central European countries, a common sentiment is
that the benefits of transgenic food will not outweigh
the perceived potential risks. In southern European
countries like Spain and Italy, attitudes differ and it
appears the majority of the public will accept trans-
genic food because they want the benefits and do not
perceive there to be major risks associated with the
food (Costa-Font et al. 2007). Some countries, such as
Argentina and China, have instituted policies to
specifically fund research into transgenic animals
and their potential use in the food chain. In China, the
government and research institutes hold a positive
attitude towards transgenic food. Nonetheless, there
has been fierce public debate on safety concerns over
instances where food derived from transgenic plants
was trialed in the population in China (LLOC 2014).
Hence, the ideological, regulatory, and political bar-
riers that impede transgenic animal technology vary
significantly between countries and regions. Around
the world, discussions about the regulation of new
technologies, like precision breeding and gene editing,
have begun between scientists, regulators, and the
public, and differences in the approach to regulation
between countries are already emerging (Ledford
2013; Abbott 2015).
What has shaped public perception on transgenic
animals up until now? As the first transgenic animal
food product has only very recently gained approval
and has not yet reached the market, public perception
of risks and benefits of these products are not the result
of any direct experience with actual products. The
information that has shaped public perception is based
on the experience that people might have had with
transgenic plant products and more likely on the fierce
debate over these products and over transgenic
Transgenic Res (2016) 25:575–595
technology in the media. The only transgenic animal
that has made it to the market and is known to the
broader public at this moment is the GloFishÒ (www.
glofish.com), which is a companion animal. Hence,
real awareness of the benefits of the technology has not
yet reached the general public. Even if there was broad
scientific understanding of transgenic technology in
the public domain, this may not be enough to achieve a
positive attitude towards the technology. Fostering a
positive attitude towards new and existing technology
from the public is predicated on segments of the
general public actively acknowledging a personal
need for the technology and those people advocating
for the benefits to which they currently do not have
access.
Navigating through the barriers: areas
where animal biotechnology could make
a substantial impact
Animal and human health
One of the biggest impediments to a safe and secure
food supply has always been the impact of pathogens
on food production and safety. Increased world trade,
transport of food and animals, and expanding agricul-
tural intensification, together with climate and habitat
change, have contributed to the rising incidence and
rapid spread of plant, animal and zoonotic diseases
and have increased the number of emerging infectious
diseases being transmitted from livestock to humans
(Jones et al. 2008). Control of livestock diseases is
primarily done through the use of vaccines, antibi-
otics, and chemicals, which in some cases the
pathogens so selected upon have countered through
the emergence of resistant strains. As more resistant
strains emerge, new multifaceted disease management
strategies are needed. Emerging infectious diseases,
like avian influenza and African swine fever, present
even higher risks of causing severe negative health and
economic impacts through pandemics since there are
no approved treatments for many emerging infectious
diseases.
Development of disease resistant or resilient ani-
mals can be engineered using either new precision
breeding and gene editing technologies or transgenic
strategies. Some early examples of transgenic animals
that have been engineered to be resistant to disease
583
include transgenic cattle that produced an antimicro-
bial compound in their mammary gland which
protected them again mastitis infections (Wall et al.
2005) and catfish producing the antimicrobial protein
cecropin which made them more resistant to enteric
septicemia (Dunham et al. 2002). Another more recent
approach is the introduction of transgenes that express
RNAi molecules that target key viral genes. An RNA
based strategy using decoy RNA has already been
done to generate poultry that do not transmit avian
influenza viruses (Lyall et al. 2011). Molecular
scissors have also already impacted the production
of disease resistant transgenic animals, enabling
scientists to insert a transgene that confers increased
resistance to tuberculosis in a site specific manner in
cattle (Wu et al. 2015).
Many pathogens are dependent on host cell factors
for completing their life cycle and causing disease.
Modification of host cellular genes required for
pathogen entry or replication can be mediated via
gene editing that may be as minimal as a single
nucleotide change. An example is the finding that a
single amino acid change in the RELA (v-rel reticu-
loendotheliosis viral oncogene homolog A) gene is
most likely responsible for the resilience of warthogs
compared to commercial breeds of pigs to infection by
African swine fever virus (Palgrave et al. 2011). Soon
after this discovery successful in vivo gene editing of
the porcine RELA locus was reported (Lillico et al.
2013). Another example of utilizing gene editing in
pigs to confer disease resistance involved the deletion
of a small number of nucleotides in the immune cell
receptor CD163 gene, ablating CD163 expression.
This small change rendered the edited pigs immune to
porcine reproductive and respiratory syndrome virus
(Whitworth et al. 2016).
Within a population of animals, a proportion of
individuals often can be identified that display a
greater than average level of resistance to a particular
pathogen (Wang et al. 2014; Usman et al. 2015). In
such cases, the resistance of the whole population can
be improved over time by continued selection of the
most resistant animals for breeding. However, with
conventional breeding this is slow, typically requiring
several generations of selection, and can be imprecise.
With rapidly improving knowledge of genome
sequence and function providing better understanding
of how genetic variants cause disease resistance,
precision breeding could allow alleles which improve
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disease resistance to be introduced into multiple
breeding animals in one generation, allowing substan-
tially more rapid and more targeted improvement of
disease resistance or disease resilience than is possible
using traditional breeding techniques alone. Together
all of these examples demonstrate that transgenic
technology and new methods including gene editing
and precision breeding could form the cornerstone of a
multifaceted disease prevention and anti-pandemic
strategy in animal agriculture.
Food safely and improvement of the health
characteristics of food
Animal-derived food products are key nutritional
sources for humans, but they are not necessarily safe
for all consumers. Food allergies, intolerance to
certain foods and genetic diseases or genetic predis-
positions to certain diseases render an increasing
proportion of the population incapable of safely
consuming particular foods. Traditional breeding is
unlikely to yield foods safe for all consumers, whereas
animal biotechnology is well suited for the generation
of safer food products. There are many examples
where transgenic technology has been applied to
agricultural animals to produce foods with improved
nutritional characteristics. In efforts to change unfa-
vourably high ratios of n-6 and n-3 polyunsaturated
fatty acids (PUFAs) in modern diets, livestock animals
that are unable to convert n-6 in n-3 PUFAs have been
genetically engineered to produce a different desat-
urase enzyme which resulted in health-promoting,
decreased n-6/n-3 ratios in meat and milk of pigs,
sheep, cattle, and fish (Lai et al. 2006; Pan et al. 2010;
Saeki et al. 2004; Wu et al. 2012; Zhang et al. 2013;
Pang et al. 2014). Previous research has shown that the
fatty acid profiles of pork (Zhang et al. 2009) and beef
(Dinh et al. 2010) differ between breeds, providing an
opportunity to identify the beneficial alleles and for
precision breeding to play a part in improving the fatty
acid content of these foods.
Over the years multiple projects have also been
specifically aimed at improving different characteris-
tics of milk using transgenic technology. Some
projects focused on improving the antimicrobial and
immunomodulatory properties of milk such as human
lactoferrin- enriched cow’s milk (van Berkel et al.
2002) and human lysozyme-enriched goat’s (Maga
et al. 2006) milk have been shown to be beneficial
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when fed to piglets, indicating that these milks could
provide health benefits to children (Cooper et al.
2014). Others have attempted to improve the overall
nutrient content of milk, for example in cows, casein
expression from additional copies of b- and j-casein
resulted in an increase in essential amino acids in
cheese that was processed from the altered milk
(Brophy et al. 2003; Laible et al. 2007). Several
projects have concentrated on designing safer milk for
certain segments of the population. In a proof of
principle experiment, mice were generated which
produce low-lactose milk due to mammary-specific
expression of lactase (Jost et al. 1999). A tissue
specific miRNA based knockdown strategy has been
applied to produce hypoallergenic cow milk devoid of
the allergenic whey protein b-lactoglobulin (Jabed
et al. 2012). In another a proof of principle experiment,
the milk of rabbits has been altered using transgenic
casein gene constructs. These gene constructs were
generated through in vitro site-specific oligonu-
cleotide directed mutagenesis of the phenylalanine
codons in the native rabbit casein gene to produce milk
containing low-phenylalanine casein, which could be
used as a dietary supplement for phenylketonuria
patients (Baranyi et al. 2007). Now using newly
developed gene editing technology the goal of
producing low-phenylalanine containing milk could
be achieved with gene editing and without the need for
transgenes.
There are already a number of transgenic animals
that could produce safer and more healthful products
for our food supply and the future possibilities
presented by gene editing and precision breeding are
wide ranging and impactful. However, by continually
discounting animal biotechnology we are missing
significant opportunities to make foods safer for
certain parts of the population and better adapted to
address modern nutritional issues.
Animal welfare
Until domestication a few thousand years ago, the
predecessors of our modern agricultural animals had
evolved to survive in the wild. Through domestication
and development of specialized breeds, we have
altered many characteristics of domestic animals.
Traits remaining from their wild ancestry and traits
that have been modified through domestication, and
intensification in agricultural production systems can
Transgenic Res (2016) 25:575–595
all cause animal health and welfare issues. For
example, domestic pigs have been bred to increase
litter size; however the amount of colostrum a sow
produces does not increase in response to increased
litter size (Devillers et al. 2007). Thus, pre-weaning
malnutrition and mortality represent an important
animal welfare issue in the pig industry (Kirkden et al.
2013). To increase milk production transgenic pigs
expressing bovine alpha-lactalbumin in the mammary
gland were generated. Piglets suckled on the trans-
genic sows had access to more milk which resulted in
better growth through the suckling period and reduced
incidence of piglet malnutrition and mortality (Noble
et al. 2002; Marshall et al. 2006). Not only does this
transgenic solution help solve the immediate animal
welfare issue but the increased nutrition during the
early postnatal period has lasting effects on the
immune system (Hu et al. 2015), which can lead to
improved health and welfare well into the post-
weaning period.
A trait that could improve dairy cattle welfare and
be introduced into the population through precision
breeding is polled. Most cattle naturally grow horns;
however, certain beef cattle breeds have a natural
genetic variant, known as the polled gene, which
prevents the development of horns. Cattle with horns
pose a safety risk to themselves, their herd mates, and
their handlers. In the dairy industry, removal of horn
buds, known as debudding, is a standard practice.
Horn debudding, while necessary, is a stressful and
invasive procedure that represents a major welfare
issue in the livestock industries. Finding an alternative
would improve animal welfare. Precision breeding
could be used to rapidly introduce the hornless polled
gene into dairy breeds (Tan et al. 2013) without
impacting any other genes, thus improving animal
welfare by transferring a well-characterized and
highly desirable genetic mutation from beef cows into
dairy cows.
In hot climates, heat stress is a substantial animal
welfare issue. Most highly productive breeds of
agricultural animals were developed in the temperate
climates of Europe and North America. Introducing
these very productive breeds into regions with much
warmer climates often has been less successful than
planned because those breeds are adapted to more
temperate climates and struggle with thermoregula-
tion in warmer areas, resulting in welfare and produc-
tivity problems. While the biological processes
585
surrounding heat stress and heat tolerance are quite
complex, there are some known genetic adaptations in
tropical breeds that help them thrive in the warmer
climate, for example a mutation in a hair-growth gene,
known as the ‘slick’ gene. This slick mutation is a
prime candidate for trait introduction through preci-
sion breeding in areas with warmer climates where
cattle commonly experience heat stress (Dikmen et al.
2014). This approach could help alleviate heat stress in
European and North American breeds that have been
introduced to warmer climates, leading to superior
welfare for the animals as well as improved overall
health and productivity.
Many improvements could be made to the everyday
wellbeing of animals used in agriculture through the
use of transgenesis, gene editing, and precision
breeding. As consumers become more vocal about
animal welfare issues and states and countries con-
tinue to enact laws relating to animal management,
animal biotechnology is well placed to play a key role
in enabling solutions. However this potential can only
be realized if there are major changes to the way
society as a whole approaches these technologies.
Improving public perception and industry
engagement
Successful introduction of animal biotechnology into
the food chain requires success on three levels: the
scientific domain, the market domain and the public
domain (Vàzquez-Salat 2013; Vàzquez-Salat and
Houdebine 2013). In the scientific domain, many
scientists are of the opinion that there are indeed
societal problems that would be alleviated by using
animal biotechnology and that it is irresponsible not to
use the technology (Murray and Maga 2010). In the
past two decades, several transgenic animals have
been developed to tackle environmental issues—such
as the Enviropig (Golovan et al. 2001)—or to improve
the health properties of food, such as human lysozyme
and human lactoferrin to improve gut health (Cooper
et al. 2015). As discussed in the previous section,
application of new technologies is accelerating the
development of animals that could become available
to the market. Within the market domain, industry
needs to incorporate science into sound products;
however, they will do so only when they perceive a
benefit of applying emerging technologies. Factors
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that industry will take into account include the risk
associated with uncertain or negative regulatory
environments, possible risks associated with public
perception, economic assessments of market size,
costs of development, marketing and sales, and the
value of the product in the market. The public domain
has a high level of heterogeneity that varies across
sectors as well as regions. Stakeholders include
consumers, interest groups, animal welfare groups,
the media and more. Within this domain, a negative
attitude towards ‘‘GMOs’’ began in the 1990s and not
much headway has been made to change the public
perception towards genetically modified crops. Soon
the first transgenic animal approved for human
consumption will reach the market. Multiple groups
that have been historically against genetically modi-
fied crops have unsurprisingly criticized its approval,
however it is yet to be seen what the reaction of the
general public will be.
Strategies for improving public perception
The original and enduring purpose of genetically
engineering livestock animals is to improve the
agricultural system through improving animal health,
reducing environmental impact, enhancing the well-
being of animals, and providing better products to
consumers. However, to reach this goal, scientists
must have the support of the public. A critical step to
achieving public acceptance of genetic engineering
will be the public observing a high level of consensus
among institutions and agreement between the infor-
mation about the technology provided by scientists,
regulators and industry. For those who are fundamen-
tally opposed to agricultural biotechnology, feeding
the perception that no consensus exists between
authorities is often sufficient to achieve their goal of
preventing the application of transgenic technology in
agriculture, and is likely to be their strategy for
preventing the adoption of other newly emerging
technologies such as precision breeding and gene
editing. To arrive at consensus, public education will
need to shift from focusing on the complex details of
the science to straightforward explanations using real-
world examples which simultaneously provide simple
and accurate information while highlighting the pos-
itive outcomes that the science is capable of produc-
ing. In addition, we should publicize the significant
ongoing scientific efforts of institutions across the
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globe to develop, improve, and assess the safety of the
technology. Multiple technical and ethical forums
already have been held between leading scientists and
bioethics experts from around the world to identify
and address issues surrounding emerging technologies
utilizing molecular scissors including CRISPRs and
TALENs (Reardon 2015; Doudna 2015; Parry et al.
2016). We need to make it clear to the public that
experts have and will continue to seriously consider
the concerns surrounding these technologies from
many perspectives. Bolstering public confidence in the
overall scientific process used to develop these
technologies as well as the measured deliberations
that have been held to ascertain the possible effects of
these technologies is very important. Coupling that
with increased public awareness of the multitude of
positive health, welfare, and environmental outcomes
which could improve day-to-day life for people and
animals could help pave the way for general public
acceptance of animal biotechnology.
Starting a dialog between scientists, industry,
and regulators
Encouraging public acceptance of new technologies is
the collective responsibility of governments, science,
and industry. However, the past has clearly shown that
the relationship between scientists, regulators, and the
food production and food retail industries has not
always been productive. A more constructive working
relationship among these three sectors will be required
to achieve the full benefits from both genetic engi-
neering and precision breeding technologies. All
parties must look for the common ground to work
together to both implement safe and beneficial new
technologies and appropriately regulate the use of old
and new technologies alike. To achieve the goal of
improved public acceptance and building positive
working relationships between scientists, regulators,
and industry will take a concerted effort. It will need to
involve a large number of stakeholders including
scientists, policy-makers, politicians, regulators, con-
sumers, producers, processors and retailers, NGOs,
thought leaders, the media, educators, advocacy
groups, and financial backers. Getting all of the
stakeholders to the table will take time, and it remains
unclear who among scientists, industry, or regulators
will take the lead in spearheading stakeholder
engagement.
Transgenic Res (2016) 25:575–595
As these discussions develop, it is very important
that scientists are clearly able to differentiate among
the various technologies that currently exist. There are
traditional transgenic technologies which involve
taking a gene from one species or a novel engineered
gene and inserting it into a different animal. This is a
technology that the public has heard of and which has
been much maligned by anti-GMO activists and
tainted by issues around transgenic plants. However,
new technologies like precision breeding and gene
editing are also emerging. Precision breeding allows
for transfer of single or multiple nucleotide polymor-
phisms that confer improved traits between members
of the same species. Precision breeding is fundamen-
tally different from transgenic technologies in that it is
simply introducing nucleotide polymorphisms into a
breed or population that are already present naturally
in other populations of the same species. One of the
underlying concepts in precision breeding is that
classical selective breeding and precision breeding can
both yield the same genetic outcome, however that
outcome can be achieved much faster with precision
breeding. Gene editing involves making site specific
nucleotide changes to generate polymorphisms that
are not known to be present in that particular species,
and may or may not be present in other related species.
An important point to note is that because of the
mechanisms underlying gene editing the nucleotide
polymorphisms made via gene editing could also arise
in a population through natural mutation. It is essential
to the public policy debate that transgenic technolo-
gies, precision breeding, and gene editing are recog-
nized as being fundamentally different from each
other. Moving forward within the scientific commu-
nity, there needs to be consensus on the terminology
used around emerging technologies. While as scien-
tists we often strive to adhere to commonly accepted
nomenclature conventions when naming a technique,
when considering terms that will be used and seen by a
broader audience we must also consider the public
reaction to the terminology and consider avoiding
terms which are confusing, highly technical, or have a
pre-existing negative connotation in the public sphere.
Additionally, we must be proactive about naming a
technology so that the scientific terminology becomes
the dominant one used by the public, which is
something the scientific community has, at times,
failed to accomplish in the past.
587
Industry engagement and technology adoption
To increase industry engagement and eventually
facilitate industry adoption, multiple issues will need
to be addressed. The first is overcoming the lack of
communication between regulators, industry, and
scientists. Scientists need access to regulators to
encourage dialog about emerging technologies. The
development of regulations should be a collaborative
process between scientists, industry, and regulators,
not a closed process where science and industry wait
for years for guidance from regulators on how to
progress with a technology.
When thinking about the future of regulation in the
animal biotechnology sector, we must consider the
regulation of plant biotechnology and whether the
regulatory landscape is different for plants and
animals (Fig. 2). While there are some regulatory
issues that are unique to either plants or animals, the
evaluation of food safety should be very similar. For
both plants and animals, a level playing field must be
created for all technologies, both the old and the new.
People have been developing and employing novel
technologies for plant and animal breeding and food
processing for thousands of years. Safety requirements
for new technologies should be in line with the risk
they present in comparison with existing and accepted
technologies (National Research Council 2002). Sim-
ply because a technology is new should not automat-
ically mean that additional barriers must be imposed if
that technology delivers a demonstrably equivalent
product. In fact, all technologies should be measured
to the same standard. Many practices have been in
place since before centralized safety monitoring of the
food system, and some of these existing practices may
not meet the current standards set forth for safety.
Equal and unbiased evaluation of all practices and
technologies would truly give us a safer and more
sustainable agricultural system and not place unduly
high bars against new technologies, while letting
accepted practices that may not actually meet our
current standards continue. A recent opinion paper in
PNAS by Murray and Maga (2016) goes into more
depth on this topic, delving into the unique food safety
considerations associated with transgenic animals. As
examples, the paper presents the possible risks arising
from food products derived from two existing lines of
transgenic animals, one food product which does not
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Fig. 2 Public perception issues posed by plant and animal biotechnology
contain any transgenic protein in the final product, and
another that contains a human protein which has
received ‘‘generally recognized as safe’’ status and is
commonly used a food additive. The paper goes on to
argue that governments should adopt a scientifically
founded, product-based approach and lays out basic
regulatory principles which while triggered by the
presence of transgenic DNA, would only involve
extensive regulation in cases where the transgene
product is either found at levels significantly greater
than normally found in food or if the transgene product
is an orally active compound. We agree that the
application of the principles presented in this paper
would reduce unnecessary regulation by specifically
focusing on the ultimate safety of the product.
To address such discrepancies in the food-safety
evaluation system, industry support is required to
provide the rationale and arguments for changes to
policy positions. If industry is convinced of the
benefits of new technologies and is willing to advocate
for a changed regulatory approach, it can play a
significant role in influencing government policy.
When working with industry, early engagement is
vital so that industry has sufficient time to become
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informed about the issues and science and develop
policy positions. Different food industries may vary
significantly in their attitudes and how much risk they
are willing to accept. If certain sectors are opposed to
particular technologies or are likely to adopt conser-
vative positions, it will be important to identify this
early. Engagement with the food industry needs to
occur at the local, national, and international level
through key industry groups from both food produc-
tion and food retail sectors if unified positions are to be
developed. Overall, both industry participation and
public perception will need to be formed by experi-
ence with the new technology and objective and
correct information. Open and transparent communi-
cation from all parties involved will be the best way
forward, and will take time.
Towards international harmonization
of regulatory oversight
Due to differing regulatory philosophies, legal
enabling authorities, and regulatory institutions,
OECD countries have adopted different approaches
Transgenic Res (2016) 25:575–595
to regulatory oversight of agricultural biotechnology
(LLOC 2014). Some countries have adopted new gene
technology laws, while others have established regu-
latory frameworks by extending the scope of existing
laws. Oversight was vested in different institutions,
including ministries of agriculture, health, environ-
ment, science, or multiple ministries. Some countries
are signatories to the Convention on Biological
Diversity and the subsequent Cartagena Protocol,
while others are not. The respective regulatory
systems matter because, depending on the approach
used, they can either encourage or inhibit the devel-
opment and commercial application of animal
biotechnology within particular countries. At a prac-
tical level, what matters is that the regulatory process
is effective. There are many attributes that would be
critical for an effective process including being
science-based and defensible; proportionate to the
potential risk, transparent to both proponents of
biotechnology products and the public; expeditious;
and credible to the public, which may be more
concerned about non-scientific, values-based issues.
If progress in adoption of animal biotechnology is to
be achieved, it is important, particularly from an
industry perspective, that there is harmonization
among trading partners; lack of harmonization could
result in restricted or reduced market access to some
countries. Noting differences in the regulatory systems
among OECD countries, what can be done to foster
international harmonization of regulatory oversight of
animal biotechnology?
Regulatory philosophy
We call for a knowledge-based approach to policy
regarding regulation of animal biotechnology. Coun-
tries might adopt a product-based (as opposed to a
process-based) approach to biotechnology oversight,
especially as regards the ‘‘trigger’’ for oversight of a
particular product. In particular, as noted above, if an
animal derived from precision breeding cannot be
distinguished from an animal derived from classical
selective breeding, should it be subject to regulation?
The goal of shifting completely to product-based
regulation is an ambitious one, particularly in the short
term; however, it could ultimately be realized by
taking small steps, perhaps by confining the goal in the
first instance to particular techniques that are impor-
tant to the industry; for example precision breeding
589
and RNAi technology. The goal may be more
aspirational than practical from a policy-making
viewpoint, but taking small incremental steps towards
addressing the issue may also be palatable from a
political perspective. Further, regulatory authorities
should assess risks—pertaining to animal well-being,
food safety or environmental safety—not in some
vague, absolute sense, but rather relative to those of
conventional animal production (National Research
Council 2002).
Procedural aspects
As a general principle, there should be clear
pathways to regulatory approval which include set
time-limits, application of ‘‘best practice’’ principles
to regulatory assessment, and accountability for
regulatory decisions. Through the regulatory process,
authorities should ask the proponent only for infor-
mation that will inform the risk assessment, risk
management, or regulatory decision-making; gener-
ation of unneeded information costs time and money
and constitutes a barrier to commercialization. Reg-
ulatory processes must be transparent for the com-
munity as a whole, particularly for those that must
navigate the regulatory system to get products
approved. Adoption of a post-marketing monitoring
system, similar to the systems in place for pharma-
ceuticals, might make it easier for regulatory author-
ities to approve commercialization of a product.
Periodic review of national regulations is appropriate
to ensure that regulatory practice remains consistent
with current scientific thinking.
Of particular interest to industry would be greater
harmonization between countries in terms of the data
and information requirements for regulatory approval.
Significant costs are involved in developing country-
specific data packages, and it would prove beneficial if
agreement could be reached on a common basic data
package or a core set of information that would form
the basis for regulatory approval in different countries.
For example, all countries ask for descriptions of the
genetic transformation, the phenotype of the trans-
genic animal, the stability of the line over generations,
and the claims associated with the animal line.
Agreement on the format of documentation for such
issues would save redundant restatement of these
issues to all countries in which a proponent would like
to commercialize a product.
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With the permission of the proponent for a partic-
ular product, sharing of technical information among
the regulators of different countries would promote
knowledge and harmonization. Regulators might
share case-studies (including descriptions of both
methods and outcomes) of their oversight activities.
Exchange of ‘‘best’’ practices and experience among
regulators would build capacity and help establish
regulatory norms, providing insight into the process of
regulatory actions needed to reach approval for
commercial production of a transgenic animal or an
animal produced via precision breeding. These inter-
actions could be promoted by in-person meetings,
sharing of materials on websites, and participation in
internet-based meetings. Some countries have quite
consciously worked together to coordinate biotech-
nology oversight. For example, foods derived from
gene technology are subject to premarket and safety
assessment by the bi-national Food Standards Aus-
tralia New Zealand (FSANZ), and FSANZ and Health
Canada have recently commenced discussions around
a work sharing arrangement for food safety assess-
ments of genetically modified crops and animals.
Involvement of the OECD
The OECD can play a leading role in promoting
harmonisation of regulatory oversight of animal
biotechnology, especially by promoting interactions
among regulators of member countries with one
another and with leading scientists. It can promote
trade by developing materials promoting regulatory
capacity-building for members and for developing
countries. OECD (2014) has a consensus document for
harmonizing regulatory oversight of biotechnology
concerning plants, fungi, and microbes, but no such
document exists for animals.
Development of points-to-consider frameworks can
guide regulatory oversight and decision-making. It is
noteworthy that criteria published in the Codex
Alimentarius have proven an effective guide for
assessing the safety of products of transgenic crop
plants. The Codex Alimentarius Commission, an
intergovernmental body with over 180 members, aims
to protect the health of consumers, ensure fair trade
practices, and promote coordination of food standards.
In our context, Foods Derived from Modern Biotech-
nology (WHO and UNFAO 2009) contains guidelines
for assessing the safety of foods derived from
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recombinant-DNA animals. The guidelines recom-
mend an approach to food safety assessment where a
conventional counterpart exists and identifies the data
applicable to making such assessments. i.e., the nature
of the recombinant DNA construct and its expression
product, the health status of the recombinant DNA-
containing animal, and the composition of food
products produced, including key nutrients. The
Guidelines do not address issues such as animal
welfare; ethical, moral and socioeconomic aspects;
environmental risks; safety of recombinant DNA-
containing animals used as feed; or safety of animals
fed with recombinant DNA-containing feedstuffs,
issues that influence public attitudes and affect regu-
latory decision-making regarding transgenic animals.
There is currently no Codex Biotechnology Task
Force which could discuss and resolve some of these
issues, particularly in relation to new technologies
such as precision breeding. A re-established Codex
Biotechnology Task Force could address and build
consensus around precision breeding and other new
highly predictable gene targeting technologies.
Recommendations
There are many hurdles to overcome to achieve
worldwide regulatory and commercial acceptance of
transgenic animals in agriculture, as well as many
unanswered questions surrounding the regulation of
emerging technologies such as precision breeding and
gene editing. So far, progress has been slow, and the
path has at times been labyrinthine. While developed
countries stall on implementation of transgenic tech-
nology in agricultural species, pressure mounts on
animal agriculture systems around the world, and the
need for these technologies continues to rise. There are
steps that scientists, regulators, industry, and trade
bodies could take to help accelerate the integration of
transgenic technologies and precision breeding and
gene editing methods into commercial animal agri-
culture production systems across the globe. For
industrial adoption harmonization of regulations and
trade agreements between countries must be estab-
lished; for public acceptance a focus on practical
projects that invoke small genetic alterations deliver-
ing large positive impacts to farmers and the public is
desirable.
Transgenic Res (2016) 25:575–595
1. A concerted effort from governments and trade
bodies is needed to harmonize the regulatory
approach taken towards these technologies. Cur-
rently, different countries have either ‘‘product’’
or ‘‘process’’ based systems with different triggers
that set the regulatory process into motion. As
previously mentioned, both governments and the
pharmaceutical industry have benefited from The
International Conference on Harmonisation of
Technical Requirements for Registration of Phar-
maceuticals for Human Use (http://www.ich.org/
home.html), which led to significant harmoniza-
tion in the regulations worldwide. This harmo-
nized approach allows industry to submit a single
data package for multiple countries, and the
approving agencies can work together to navigate
any issues or concerns that may arise. In food and
agriculture regulation, steps in this direction have
been made by certain countries. Australia and
New Zealand have a joint food safety authority
(FSANZ), and have held talks with the Canadian
food safety authority about establishing a work
sharing arrangement for food safety assessments
of transgenic crops and animals. However, further
harmonization is needed, and the OECD could
take a proactive leadership role by establishing
guidelines for regulation as they have in the past
for pesticides (OECD 2015). In addition to regu-
latory harmonization, the OECD also can work to
prevent possible non-tariff trade barriers blocking
the import and export of animals or products that
result from genome engineering, precision
breeding, or gene editing. Such trade barriers
could block growth of the industry by making
export markets inaccessible. Trade barriers could
also give the false impression of safety concerns
by preventing importation of animals or food
products because they are produced using animal
biotechnology, further fuelling public fear and
misunderstanding about the technology.
2. Scientists and industry leaders must have a major
role in helping the technology move into the
agricultural system. Scientists should aim to produce
animals that provide a clear and demonstrable benefit
to the public at large. Industry also must be open to
developing applications that have clear benefits to
the public even if they do not reduce the time or
resources needed to raise the animals. This paper has
outlined various areas of research and ongoing
591
projects that have clear positive impacts for the
public, including improved animal health, reduced
spread of zoonotic diseases, elimination of food
allergens, and improved animal welfare. Scientists
should be proactive and partner with other public
organizations and NGOs specifically concerned with
issues of public concern, including spread of infec-
tious diseases, food allergens, and animal welfare in
order to successfully relay the potential positive
impacts of this technology to the public.
3. Gaining public acceptance of new technologies by
demonstrating positive benefits of the products of
the technology. The public will need to understand
in clear terms the tangible benefits of a food
product resulting from application of new tech-
nologies like precision breeding or gene editing in
order for industry to achieve acceptance of that
product. In part due to pre-existing attitudes
towards transgenic crops, it is likely that the public
is more prone to accept projects utilizing precision
breeding, to introduce single or multiple nucleo-
tide changes, that already exist in other members
of the same species to produce an animal that is by
definition not transgenic and could have arisen
through traditional breeding. Another set of
viable candidate projects would be those utilizing
gene editing to introduce single or multiple
nucleotide changes between highly related spe-
cies. In terms of traditional transgenic animals, one
transgenic animal has reached regulatory
approval; however that took many years and a
significant financial investment. Looking towards
the future, transgenic animals that harbor transge-
nes that produce non-coding RNAs, such as the
chickens that do not transmit avian influenza
(Lyall et al. 2011) are good candidates since there
is no transgenic protein present in the animal,
which may alleviate some public acceptance
issues.
4. Develop a clear delineation and understanding of
the differences between traditional transgenic
methods and techniques like precision breeding
and other emerging technologies. This starts with
scientific consensus on the terminology of these
emerging technologies and proactive use of that
terminology in all spheres including scientific
publications, media coverage and public education.
Finding the best terminology will involve cooper-
ation between scientists and communications
123
592
experts so that the technology is accurately repre-
sented, and not bogged down by highly technical or
inaccessible language. We propose that technolo-
gies often referred to as precision genome engineer-
ing, utilizing tools such as (but not restricted to)
TALEN and CRISPR, when being used to move
already existing alleles between members of the
same species, be referred to, in our scientific
community, as precision breeding when applied in
agricultural animals. Additionally, we propose that
technologies often referred to as precision genome
engineering, utilizing tools such as (but not
restricted to) TALEN and CRISPR, when being
used to introduce novel polymorphisms into a
species, be referred to, in our scientific community,
as gene editing when applied in agricultural animals.
Future outlook
Biotechnology could play an important role in the
future of agriculture, including ensuring food safety
and security, improving animal health and welfare,
and enhancing the nutritional benefits of various
foods. These benefits can be realized only through
appropriate investment, which will occur only when
the animal agriculture industries have confidence in a
reliable, predictable and clear-cut regulatory process
for new animals and food products. With many nations
poised to take steps forward in deployment of animal
biotechnology, harmonization of regulations will be
critical in a global trade environment.
To date, many OECD nations have made signif-
icant investments in developing biotechnology to
help address areas such as medicine, agriculture and
energy production. The impact of biotechnology is
beginning to deliver tangible gains on many fronts,
for example in advanced biological therapeutics
(Kling 2009; van Veen et al. 2012) and in crop
production (ISAAA 2015). However, in animal
agriculture, even though there are production animals
in existence with beneficial modified traits, only one
transgenic animal has yet been approved for use in
food production, which occurred after a lengthy and
expensive process. In the face of an increasingly
pressing need for secure and sustainable food
production, the benefits of animal biotechnologies
must be moved from the laboratory and into animal
123
Transgenic Res (2016) 25:575–595
agriculture systems. This transition will require
industry demand. However, industry backing will
come in earnest only when there are signals from the
public that they will accept these technologies. Public
acceptance relies on both a desire for the outcomes of
the technology and the belief that the technology is
safe. Engendering public confidence in these tech-
nologies will require a regulatory system that is
trusted, transparent, and proactive and that leads to
approval of safe products in a timely manner.
Achieving harmonised changes to the various exist-
ing international regulatory frameworks will require
coordinated inputs across many developed and
developing economies. Multinational organisations,
such as the OECD, have the opportunity to initiate
and direct the actions needed to ensure that animal
biotechnology can realise its potential to contribute
to a safe and stable food supply for years to come.
Acknowledgments The workshop sponsored by the OECD’s
Co-operative Research Programme on Biological Resource
Management for Sustainable Agricultural Systems.
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