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A history of the experiments with genetic manipulation and cloning

These issues need to be considered by all stakeholders, including veterinarians, to ensure that all parties are aware of the ethical issues at stake and can make a valid contribution to the current debate regarding the creation and use of genetically engineered animals.

In addition, it is important to try to reflect societal values within scientific practice and a history of the experiments with genetic manipulation and cloning technology, especially publicly funded efforts that aim to provide societal benefits, but that may be deemed ethically contentious.

As a result of the extra challenges that genetically engineered animals bring, governing bodies have started to develop relevant policies, often calling for increased vigilance and monitoring of potential animal welfare impacts 2.

Veterinarians can play an important role in carrying out such monitoring, especially in the research setting when new genetically engineered animal strains are being developed. Several terms are used to describe genetically engineered animals: In the early stages of genetic engineering, the primary technology used was transgenesis, literally meaning the transfer of genetic material from one organism to another. However, with advances in the field, new technology emerged that did not necessarily require transgenesis: For clarity, in the new CCAC guidelines on: There are 3 types of cloning: DNA cloning, therapeutic cloning, and reproductive cloning 3.

Reproductive cloning is used if the intention is to generate an animal that has the same nuclear DNA as another currently, or previously existing animal. The process used to generate this type of cloned animal is called somatic cell nuclear transfer SCNT 4. During the development of the CCAC guidelines on: The different applications of genetically engineered animals are presented first to provide context for the discussion.

Current context of genetically engineered animals Genetic engineering technology has numerous applications involving companion, wild, and farm animals, and animal models used in scientific research. The majority of genetically engineered animals are still in the research phase, rather than actually in use for their intended applications, or commercially available.

In addition to the insertion of foreign genes, gene knock-out techniques are also being used to create designer companion animals. For example, in the creation of hypoallergenic cats some companies use genetic engineering techniques to remove the gene that codes for the major cat allergen Fel d1: Companion species have also been derived by cloning.

With the exception of a couple of isolated cases, the genetically engineered pet industry is yet to move forward. However, it remains feasible that genetically engineered pets could become part of day-to-day life for practicing veterinarians, and there is evidence that clients have started to enquire about genetic engineering services, in particular the cloning of deceased pets 5. Wild animals The primary application of genetic engineering to wild species involves cloning. This technology could be applied to either extinct or endangered species; for example, there have been plans to clone the extinct thylacine and the woolly mammoth 5.

The History of Cloning

Individuals involved in field conservation often harbour suspicions that hi-tech approaches, backed by high profile publicity would divert funding away from their own efforts. Examples include transgenic pigs and sheep that have been genetically altered to express higher levels of growth hormone 9.

Genetic engineering of animals: Ethical issues, including welfare concerns

Genetically engineered farm animals can be created to enhance food quality 9. Such advances may add to the nutritional value of animal-based products. Farm species may be genetically engineered to create disease-resistant animals 9. Specific examples include conferring immunity to offspring via antibody expression in the milk of the mother; disruption of the virus entry mechanism which is applicable to diseases such as pseudorabies ; resistance to prion diseases; parasite control especially in sheep ; and mastitis resistance particularly in cattle.

Genetic engineering has also been applied with the aim of reducing agricultural pollution. The best-known example is the EnviropigTM; a pig that is genetically engineered to produce an enzyme that breaks down dietary phosphorus phytasethus limiting the amount of phosphorus released in its manure 9. Despite resistance to the commercialization of genetically engineered animals for food production, primarily due to lack of support from the public 10a recent debate over genetically engineered AquAdvantageTM Atlantic salmon may result in these animals being introduced into commercial production 11.

Effort has also been made to generate genetically engineered farm species such as cows, goats, and sheep that express medically important proteins in their milk. This product is used as a prophylactic treatment for patients that have hereditary antithrombin deficiency and are undergoing surgical procedures. Research animals Biomedical applications of genetically engineered animals are numerous, and include understanding of gene function, modeling of human disease to either understand disease mechanisms or to aid drug development, and xenotransplantation.

Through the addition, removal, or alteration of genes, scientists can pinpoint what a gene does by observing the biological systems that are affected. While some genetic alterations have no obvious effect, others may produce different phenotypes that can be used by researchers to understand the function of the affected genes. Genetic engineering has enabled the creation of a history of the experiments with genetic manipulation and cloning disease models that were previously unavailable.

Animal models of human disease are valuable resources for understanding how and why a particular disease develops, and what can be done to halt or reverse the process. However, as Wells 13 points out: As discussed by Rudmann and Durham 14: In relation to organ transplants, scientists have developed a genetically engineered pig with the aim of reducing rejection of pig organs by human recipients 15.

This particular application of genetic engineering is currently at the basic research stage, but it shows great promise in alleviating the long waiting lists for organ transplants, as the number of people needing transplants currently far outweighs the number of donated organs.

Ethical issues of genetic engineering Ethical issues, including concerns for animal welfare, can arise at all stages in the generation and life span of an individual genetically engineered animal. The following sections detail some of the issues that have arisen during the peer-driven guidelines development process and associated impact analysis consultations carried out by the CCAC.

The CCAC works to an accepted ethic of animal use in science, which includes the principles of the Three Rs Reduction of animal numbers, Refinement of practices and husbandry to minimize pain and distress, and Replacement of animals with non-animal alternatives wherever possible 17. Together the Three Rs aim to minimize any pain and distress experienced by the animals used, and as such, they are considered the principles of humane experimental technique. However, despite the steps taken to minimize pain and distress, there is evidence of public concerns that go beyond the Three Rs and animal welfare regarding the creation and use of genetically engineered animals 18.

Concerns for animal welfare Invasiveness of procedures The generation of a new genetically engineered line of animals often involves the sacrifice of some animals and surgical procedures for example, vasectomy, surgical embryo transfer on others.

These procedures are not unique to genetically engineered animals, but they are typically required for their production. During the creation of new genetically engineered animals particularly mammalian species oocyte and blastocyst donor females may be induced to superovulate via intraperitoneal or subcutaneous injection of hormones; genetically engineered embryos may be surgically implanted to female recipients; males may be surgically vasectomized under general anesthesia and then used to induce pseudopregnancy in female embryo recipients; and all offspring need to be genotyped, which is typically performed by taking a history of the experiments with genetic manipulation and cloning samples, sometimes using tail biopsies or ear notching 19.

However, progress is being made to refine the genetic engineering techniques that are applied to mammals mice in particular so that less invasive methods are feasible. For example, typical genetic engineering procedures require surgery on the recipient female so that genetically engineered embryos can be implanted and can grow to full term; however, a technique called non-surgical embryo transfer NSET acts in a similar way to artificial insemination, and removes the need for invasive surgery 20.

This means that large numbers of animals are produced to obtain genetically engineered animals that are of scientific value, and this contradicts efforts to minimize animal use. In addition, the advancement of genetic engineering technologies in recent years has lead to a rapid increase in the number and varieties of genetically engineered animals, particularly mice 21.

Although the technology is continually being refined, current genetic engineering techniques remain relatively inefficient, with many surplus animals being exposed to harmful procedures.

1885 - First-ever demonstration of artificial embryo twinning

One key refinement and reduction effort is the preservation of genetically engineered animal lines through the freezing of embryos or sperm cryopreservationwhich is particularly important for those lines with the potential to experience pain and distress 22.

This rise in animal use challenges the Three Rs principle of Reduction a history of the experiments with genetic manipulation and cloning. It has been reasoned that once created, the use of genetically engineered animals will reduce the total number of animals used in any given experiment by providing novel and more accurate animal models, especially in applications a history of the experiments with genetic manipulation and cloning as toxicity testing 25.

However, the greater variety of available applications, and the large numbers of animals required for the creation and maintenance of new genetically engineered strains indicate that there is still progress to be made in implementation of the Three Rs principle of Reduction in relation to the creation and use of genetically engineered animals 21. Unanticipated welfare concerns Little data has been collected on the net welfare impacts to genetically engineered animals or to those animals required for their creation, and genetic engineering techniques have been described as both unpredictable and inefficient 19.

The latter is due, in part, to the limitations in controlling the integration site of foreign DNA, which is inherent in some genetic engineering techniques such as pro-nuclear microinjection.

In such cases, scientists may generate several independent lines of genetically engineered animals that differ only in the integration site 26thereby further increasing the numbers of animals involved.

This conflicts with efforts to adhere to the principles of the Three Rs, specifically Reduction. With other, more refined techniques that allow greater control of DNA integration for example, gene targetingunexpected outcomes are attributed to the unpredictable interaction of the introduced DNA with host genes. These interactions also vary with the genetic background of the animal, as has frequently been observed in genetically engineered mice 27.

For example, many of the early transgenic livestock studies produced animals with a range of unexpected side effects including lameness, susceptibility to stress, and reduced fertility 9.

A significant limitation of current cloning technology is the prospect that cloned offspring may suffer some degree of abnormality. Studies have revealed that cloned mammals may suffer from developmental abnormalities, including extended gestation; large birth weight; inadequate placental formation; and histological effects in organs and tissues for example, kidneys, brain, cardiovascular system, and muscle. One annotated review highlights 11 different original research articles that documented the production of cloned animals with abnormalities occurring in the developing embryo, and suffering for the newborn animal and the surrogate mother 28.

Genetically engineered animals, even those with the same gene manipulation, can exhibit a variety of phenotypes; some causing no welfare issues, and some causing negative welfare impacts. It is often difficult to predict the effects a particular genetic modification can have on an individual animal, so genetically engineered animals must be monitored closely to mitigate any unanticipated welfare concerns as they arise.

For newly created genetically engineered animals, the level of monitoring needs to be greater than that for regular animals due to the lack of predictability. Once a genetically engineered animal line is established and the welfare concerns are known, it may be possible to reduce the levels of monitoring if the animals are not exhibiting a phenotype that has negative welfare impacts. To aid this monitoring process, some authors have called for the implementation of a genetically engineered animal passport that accompanies an individual animal and alerts animal care staff to the particular welfare needs of that animal 29.

This passport document is also important if the intention is to breed from the genetically engineered animal in question, so the appropriate care and husbandry can be in place for the offspring. With progress in genetic engineering techniques, new methods 3031 may substantially reduce the unpredictability of the location of gene insertion. As a result, genetic engineering procedures may become less of a welfare concern over time.

Now scientists are faced with ethical limits as well: Questions regarding whether it is acceptable to make new transgenic animals go beyond consideration of the Three Rs, animal health, and animal welfare, and prompt the discussion of concepts such as intrinsic value, integrity, and naturalness 33.

Philosopher Bernard Rollin applied this concept to animal ethics as follows: Views such as those put forward by Rollin have been argued against on the grounds that health and welfare or animal interests may not be the only things to consider when establishing ethical limits. It is often on these grounds that people will argue that genetic engineering of animals is morally wrong. An alternative view put forward by Schicktanz 36 argues that it is the human-animal relationship that may be damaged by genetic engineering due to the increasingly imbalanced distribution of power between humans and animals.

For some, the genetic engineering of animals may not put their moral principles at risk.

Current context of genetically engineered animals

For example, this could perhaps be because genetic engineering is seen as a logical continuation of selective breeding, a practice that humans have been carrying out for years; or because human life is deemed more important than animal life. So if genetic engineering creates animals that help us to develop new human medicine then, ethically speaking, we may actually have a moral obligation to create and use them; or because of an expectation that genetic engineering of animals can help reduce experimental animal numbers, thus implementing the accepted Three Rs framework.

For others, the genetic engineering of animals may put their moral principles at risk. For example costs may always be seen to outweigh benefits because the ultimate cost is the violation of species integrity and disregard for the inherent value of animals.

Some may view telos as something that cannot or should not be altered, and therefore altering the telos of an animal would be morally wrong. Some may see genetic engineering as exaggerating the imbalance of power between humans and animals, whilst others may fear that the release of genetically engineered animals will upset the natural balance of the ecosystem.

In addition, there may be those who feel strongly opposed to certain applications of genetic engineering, but more accepting of others. For example, recent evidence suggests that people may be more accepting of biomedical applications than those relating to food production 37. Such underlying complexity of views regarding genetic engineering makes the setting of ethical limits difficult to achieve, or indeed, even discuss. However, progress needs to be made on this important issue, especially for those genetically engineered species that are intended for life outside the research laboratory, where there may be less careful oversight of animal welfare.

Consequently, limits to genetic a history of the experiments with genetic manipulation and cloning need to be established using the full breadth of public and expert opinion. This highlights the importance for veterinarians, as animal health experts, to be involved in the discussion.

Preserving intellectual property can breed a culture of confidentiality within the scientific community, which in turn limits data and animal sharing.

Such limits to data and animal sharing may create situations in which there is unnecessary duplication of genetically engineered animal lines, thereby challenging the principle of Reduction.