Over the past twenty years or so, the confluence of embryology and genetic engineering has resulted in the creation of transgenic animals; animals whose genome has been deliberately modified. The use of transgenic animals has become widespread as genetic engineering technologies have permitted intervention at the primary level of life. Transgenic technology has evolved rapidly and has given rise to public concerns about the ethics of transgenic animal development. Recently the Canadian Council on Animal Care (CCAC) issued guidelines on transgenic animals specifically to assist Animal Care Committees (ACCs) to review transgenic protocols, and to provide guidance for animal care facilities which house these animals and for researchers who create and use them. This supplement to RESOURCE is intended to provide additional information to ACCs concerning the ethical issues of transgenic animal production and use. As with other scientific advances, transgenic research has also spawned a new vocabulary. To assist in understanding some of the terminology, ACC members are advised to consult Biotechnology from A to Z (Bains, 1993), or a similar modern science dictionary.
This section outlines animal welfare concerns which are likely to arise in the creation of transgenic animals and their maintenance in the laboratory setting. Consideration will also have to be given to developments which involve species to be held outside the confines of the laboratory.
In addition to the Guide to the Care and Use of Experimental Animals, the CCAC has recently developed guidelines on transgenic animals that will be subject to regular review due to the fast rate of evolution of this field. The intention behind the production of these guidelines is to assist the ACC members and investigators in evaluating the ethics of technological aspects of the proposed creation, care and use of transgenic animals; to ensure that transgenic animals are used in accordance with the CCAC statement Ethics of Animal Investigation; and to ensure that the well-being of Canadians and the environment are protected.
The creation and use of transgenic animals are subject to all of the considerations raised by the CCAC guidelines on animal use protocol review. However, special consideration must be given to the procedures involved and in particular to possible welfare concerns for both the parent generation and the progeny.
Evaluation of proposals for the creation of transgenic animals may be divided into two interrelated parts: first, the justification for creation of the particular transgenic animal; and, secondly the welfare issues underlying the creation process itself. Special attention must be devoted to new protocols that use, for example, previously uncharacterized vectors or new transgenes, and/or are being performed by investigators who are new to the techniques.
As in all animal experimentation, justification for the use of the transgenic animal involves weighing the possible benefits of the experiment (e.g., advances in biomedical knowledge, the understanding and treatment of disease, improvements in production of foodstuffs or pharmaceuticals) versus the consideration of the ethical cost of the experiment in terms of the potential suffering of the animal. This is particularly difficult for novel transgenic animals as it is not possible to predict with absolute certainty what the effect of a novel transgenic manipulation will be on the animals. For this reason, the protocol must include a strategy to address unanticipated suffering and to establish endpoints for the termination of the experiment. For these reasons, the guidelines require a transgenic information sheet to be completed with the protocol submission. In addition, a separate protocol is required for the creation of a novel transgenic animal, and for its subsequent use.
Category D level of invasiveness must be assigned to each creation protocol, until the effects on the progeny are known. Any harmful effects observed must be reported to the ACC.
The review of transgenic animal use protocols must take into consideration the effects of the transgenic modification on the animal itself, in addition to the subsequent effects incurred by the procedures.
As with any other laboratory animals, transgenic animals must be accorded high standards of care and use. Therefore, all standard operating procedures for laboratory management, human health (investigators and technicians involved with transgenic animals), and animal welfare (as part of the creation protocol, during the subsequent development of the progeny and as part of the animal use protocol) have to be evaluated accordingly.
The implications of transgenic techniques for animal welfare have been discussed by Moore and Mepham (1995). Specific welfare aspects have to be taken into consideration with transgenic animals. They include: the extent of discomfort experienced by the parents during the experimental procedures; the effect of the expression of the transgene (the modified gene inserted) on the created transgenic animal; and the effects on their progeny.
Physical and biological containment for transgenic animals should be adequate to assure the biosafety of the animal care staff which work with the animals, to prevent any possibility of the transfer of the gene within the non-transgenic colonies maintained in the same facilities, and to protect potentially immuno-compromised transgenic animals from pathogens.
The purpose of any breeding operation is to preserve the traits of interest and to restrict causes of genetic variability. Some problems associated with the breeding of transgenic mice may arise. For example, during the creation of transgenic mice, contamination of the media used in collecting eggs and blastocysts for microinjection can occur.
Establishing and maintaining lines requires careful management. As part of the general process of transgenic animal creation, each animal used must be carefully identified. Cage cards and good records with details of breeding information are necessary to be able to identify with certainty the genetic characteristics and modifications of the animal. The data recorded should include the identity, breeding, pedigree and any other pertinent data such as any dates, observations or laboratory analysis information. Since transgenic animals are not easily replaceable, the cost of containment is an important factor in transgenic experimental design.
Embryo freezing is used for the preservation of transgenic strains. To protect colonies against disease, contamination or any other cause of loss, a large number of preimplanted embryos are kept, by cryopreservation. This also reduces the cost of maintaining a transgenic mouse line when it is not needed for experimentation.
With the development of transgenic animals, just a small genomic change can induce unpredictable and quite drastic changes at the level of the whole animal. This is the main challenge for transgenic animal management. It is therefore important to have a clear procedure for monitoring the animals and for dealing with unanticipated suffering.
The evaluation of animal and human welfare as it may be affected by biotechnology is a complex issue. One of the elements most notable in this process is the absence of an informed sense of the processes involved. ACCs share the responsibility for educating members on relevant aspects of animal care and use. Education concerning transgenic animal care and use is of particular importance, involving the careful consideration of the reasons for manipulating the genome of any organism as genetic engineering is a sensitive social issue.
The ethical review process is complicated by the fact that many techniques and developments in biotechnology are eligible for patent. The reluctance of biotechnologists to reveal proprietary information is understandable. Nonetheless, current work in fish culture, genetically altered animals for organ replacement, and cloning underlines the fact that transgenic research is wide ranging. To be able to provide a competent review, ACC members need to develop a similar broad understanding of the underlying principles.
A thorough discussion of biotechnology issues, including transgenic animals is needed, particularly to develop some consensus as to the relative value of benefits to be obtained from the use of transgenic animals. One of the more challenging questions is how to account for the interests of the animals involved.
The field of transgenic animal biotechnology is likely to become of increasing importance as the techniques develop further and are applied to many more animal species. Welfare and ethical concerns will also continue to evolve. Consequently, education together with thoughtful ethical decision-making will remain the keystone of the review of transgenic protocols.
The CCAC has made a commitment to review the guidelines on transgenic animals on a regular basis. For any additional information on transgenic animals, a reading list on the subject has been developed and can be obtained from the CCAC Secretariat.
Bains, W. (1993). Biotechnology from A to Z. pp. 358 IRL Press.
Canadian Council on Animal Care (1993). Guide to the Care and Use of Experimental Animals, Vol. 1, 2nd Edn.
Donnelly, S., McCarthy, C.R. and Singleton, R. Jr. (1994). The Brave New World of Animal Biotechnology, Special Supplement, Hastings Center Report.
Moore, C.J. and Mepham, T.B. (1995). Transgenesis and animal welfare. ATLA 23:380-397.