Transgenic Animals Are Valuable In The Study Of Human Diseases For Which Of The Following Reasons?

Transgenic Animals

Marie Buy, Editorial Banana, Canadian Quango on Animal Intendance (CCAC)

(From CCAC Resource Supplement, Spring/Summer 1997. Used with permission of CCAC)

The term transgenic animal refers to an animal in which there has been a deliberate modification of the genome - the material responsible for inherited characteristics - in contrast to spontaneous mutation (FELASA September 1992, revised February 1995). Foreign DNA is introduced into the creature, using recombinant DNA engineering, and then must be transmitted through the germ line so that every prison cell, including germ cells, of the beast contain the same modified genetic textile.

one. Historical background

Prior to the evolution of molecular genetics, the merely way of studying the regulation and function of mammalian genes was through the observation of inherited characteristics or spontaneous mutations. Long before Mendel and whatever molecular genetic knowledge, selective breeding was a common practice amongst farmers for the enhancement of chosen traits, e.g., increased milk production.

During the 1970s, the commencement chimeric mice were produced (Brinster, 1974). The cells of two different embryos of dissimilar strains were combined together at an early stage of development (eight cells) to form a single embryo that subsequently developed into a chimeric developed, exhibiting characteristics of each strain.

The mutual contributions of developmental biology and genetic technology permitted rapid development of the techniques for the creation of transgenic animals. DNA microinjection, the first technique to testify successful in mammals, was outset applied to mice (Gordon and Ruddle, 1981) and then to various other species such as rats, rabbits, sheep, pigs, birds, and fish. Two other main techniques were and so developed: those of retrovirus-mediated transgenesis (Jaenisch, 1976) and embryonic stem (ES) cell-mediated factor transfer (Gossler et al., 1986).

Since 1981, when the term transgenic was first used by J.W. Gordon and F.H. Ruddle (1981), there has been rapid development in the utilise of genetically engineered animals as investigators have institute an increasing number of applications for the technology.

2. Methods of creation of transgenic animals

For applied reasons, i.e., their small size and low price of housing in comparison to that for larger vertebrates, their short generation time, and their adequately well defined genetics, mice have become the master species used in the field of transgenics.

The iii principal methods used for the creation of transgenic animals are DNA microinjection, embryonic stalk cell-mediated gene transfer and retrovirus-mediated gene transfer.

a) Dna microinjection.

This method involves the directly microinjection of a called gene construct (a single gene or a combination of genes) from another member of the same species or from a different species, into the pronucleus of a fertilized ovum. It is one of the showtime methods that proved to be constructive in mammals (Gordon and Ruddle, 1981). The introduced DNA may lead to the over- or under-expression of certain genes or to the expression of genes entirely new to the fauna species. The insertion of DNA is, however, a random procedure, and there is a loftier probability that the introduced gene will not insert itself into a site on the host DNA that will let its expression. The manipulated fertilized ovum is transferred into the oviduct of a recipient female, or foster mother that has been induced to human activity as a recipient by mating with a vasectomized male.

A major advantage of this method is its applicability to a broad variety of species.

b) Embryonic stem cell-mediated gene transfer.

This method involves prior insertion of the desired Dna sequence by homologous recombination into an in vitro culture of embryonic stalk (ES) cells. Stem cells are undifferentiated cells that have the potential to differentiate into any type of cell (somatic and germ cells) and therefore to requite ascension to a complete organism. These cells are and then incorporated into an embryo at the blastocyst stage of development. The result is a chimeric animate being. ES jail cell-mediated gene transfer is the method of pick for factor inactivation, the and so-called knock-out method.

This technique is of particular importance for the study of the genetic control of developmental processes. This technique works particularly well in mice. It has the advantage of allowing precise targeting of defined mutations in the factor via homologous recombination.

c) Retrovirus-mediated factor transfer.

To increase the probability of expression, gene transfer is mediated by means of a carrier or vector, by and large a virus or a plasmid. Retroviruses are normally used as vectors to transfer genetic material into the jail cell, taking advantage of their ability to infect host cells in this fashion. Offspring derived from this method are chimeric, i.due east., not all cells conduct the retrovirus. Transmission of the transgene is possible only if the retrovirus integrates into some of the germ cells.

For any of these techniques the success rate in terms of live nascency of animals containing the transgene is extremely low. Providing that the genetic manipulation does not lead to ballgame, the result is a offset generation (F1) of animals that need to exist tested for the expression of the transgene. Depending on the technique used, the F1 generation may result in chimeras. When the transgene has integrated into the germ cells, the so-chosen germ line chimeras are then inbred for x to 20 generations until homozygous transgenic animals are obtained and the transgene is nowadays in every prison cell. At this stage embryos conveying the transgene tin can be frozen and stored for subsequent implantation.

Transgenic Animals equally Biotechnology

Transgenic animals are just one in a series of developments in the expanse of biotechnology. Biotechnology has transformed the style in which we sympathise processes such as engineering and manufacturing. These terms now include the use of living organisms or their parts to make or change products, to change the characteristics of plants or animals, or to develop micro-organisms for specific uses. The novel uses of biological techniques such as recombinant Dna techniques, cell fusion techniques, mono and polyclonal antibiotic engineering and biological processes for commercial production have altered traditional distinctions and methods (Us Congress, Office of Applied science Assessment, 1989). Genetic manipulations at the level of Dna take also changed long held views as to what is considered to be animal, establish and human. In turn, these changes have fabricated it more than difficult to evaluate the ways in which animals are used and accept obscured distinctions betwixt pure and applied research.

Consideration of the acceptability of creating specific transgenic animate being strains or genetic manipulation involving interchanging DNA between species and kingdoms could exist a simple animal care issue or a societal decision. The following is an effort to show what the power to create transgenic animals or engage in other forms of DNA manipulation ways in terms of traditional ACC functions, not forgetting that this impacts on wider considerations of human responsibility for the welfare of other life forms.

The cosmos of transgenic animals is resulting in a shift from the use of higher society species to lower order species, and is also affecting the numbers of animals used. This shift in the patterns of animal use is being monitored by the CCAC through the utilise of the Animal Use Data Form.

An example of the replacement of higher species past lower species is the possibility to develop disease models in mice rather than using dogs or non-human primates.

In the long term, a reduction in the number of animals used, for example to report human diseases, is possible due to a greater specificity of the transgenic models adult. On the other mitt, the success of the method has led to using its potential for investigating a wider range of diseases and atmospheric condition. The actual use of some species may be increased, in improver to the numbers of animals which are sacrificed equally donors during the creation process. The potential of the technology has also fabricated information technology possible to consider employing cattle, swine, sheep and goats every bit processing units to manufacture proteins or as organ donors.

The complex interactive processes of living mammals are not reproducible in vitro. However, transgenic animals provide a means of evaluating genetic modifications in terms of anatomical and physiological changes in a complex system. Transgenic models are more than precise in comparing to traditional animal models, for case the oncomouse with its increased susceptibility to tumor development enables results for carcinogenicity studies to exist obtained within a shorter time-frame, thus reducing the course of tumor evolution in experimentally afflicted animals. However, models are not strict equivalents, then as with any other system care must exist taken in cartoon conclusions from the information.

A representative, simply non-inclusive, list of purposes for which transgenic animals have been used indicates the wide ranging application of this biotechnology:

in medical enquiry, transgenic animals are used to identify the functions of specific factors in complex homeostatic systems through over- or under-expression of a modified cistron (the inserted transgene);
in toxicology: equally responsive exam animals (detection of toxicants);
in mammalian developmental genetics;
in molecular biology, the analysis of the regulation of gene expression makes use of the evaluation of a specific genetic change at the level of the whole animal;
in the pharmaceutical industry, targeted product of pharmaceutical proteins, drug product and product efficacy testing;
in biotechnology: as producers of specific proteins;
genetically engineered hormones to increase milk yield, meat production; genetic engineering of livestock and in aquaculture affecting modification of animal physiology and/or anatomy; cloning procedures to reproduce specific blood lines; and
developing animals specially created for use in xenografting.

Important general considerations include the extent to which experience acquired in the laboratory with regard to husbandry should influence manufacture standards for keeping animals created specifically as living machines for the production of proteins, antibodies, etc. What words are advisable to draw and evaluate the condition of animals at present used equally production units? The successful cloning of Dolly underlines the fact that innovative developments in fauna science are role of the mainstream of biotechnology. In addition, the utilise of xenografts, at least at the public health level makes animate being and human welfare inseparable.

For fauna welfare concerns regarding the employ of transgenic animals, see Transgenic Animals, Animal Welfare and Ethics (optional).

For a practical application of transgenics, run across Transgenic Goats (optional).

Medical applications of transgenics (optional)

Gametogenesis
From Sperm and Egg to Embryo

Genetic Regulation of Development

Organizing the Multicellular Embryo

Generating Prison cell Variety

The Foundations of Developmental Biological science
Learning Resources

Research Resources

Developmental Biological science Tutorial
The Developmental Biology Journal Order

Bibliography

Brinster, R. (1974). The effect of cells transferred into mouse blastocyst on subsequent evolution. J. Exp. Med.:1049-1056.

Donnelly, Southward., McCarthy, C.R. and Singleton, R. Jr. (1994). The Brave new World of Animal Biotechnology, Special Supplement, Hastings Centre Written report.

Federation of European Laboratory Animal Science Associations (FELASA) September 1992, revised Feb 1995. Transgenic Animals - Derivation, Welfare, Use and Protection.

Gordon, J.West. and Ruddle, F.H. (1981). Integration and stable germ line transformation of genes injected into mouse pronuclei. Science 214:1244-1246

Gossler, A. et al. (1986). Transgenesis by means of blastocyst-derived embryonic stalk prison cell line. Proc. Natl. Acad. Sci. 83:9065-9069.

Jaenisch, R. (1976). Germ line integration and Mendelian transmission of the exogenous Moloney leukemia virus. Proc. Natl. Acad. Sci. 73:1260-1264.

Moore, C.J. and Mepham, T.B. (1995). Transgenesis and creature welfare. ATLA 23:380-397.

US Congress, Function of Technology Assessment (1989). New Developments in Biotechnology: Patenting Life. Special Report OTA-BA-370. 3pp. Washington DC: US Printing Office.

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