Transgenic Animals: An Overview

This article provides an overview on transgenic animals.

The dependence of man on animals such as cattle, sheep, poultry, pig and fish for various purposes (milk, meat, eggs, wool etc.) is well known.

Improvement in the genetic characteristics of livestock and other domestic animals (e.g., high milk yield, weight gain, etc.), in the early days, was carried out by selective breeding methods.

This technique primarily involves a combination of mating and selection of animals with improved genetic traits. Although selective breeding is very time consuming and costly, it was the only method available, till some years ago, to enhance the genetic characteristics of animals.

For larger animals with long gestation period, it might take several decades to create a desired character by conventional breeding. With the advent of modern biotechnology, it is now possible to carry out manipulations at the genetic level to get the desired characteristics in animals.

Trans-genesis refers to the phenomenon of introduction of exogeneous DNA into the genome to create and maintain a stable heritable character. The foreign DNA that is introduced is called transgene. And the animal whose genome is altered by adding one or more transgenes is said to be transgenic.

The transgenes behave like other genes present in the animals’ genome and are passed on to the offspring’s. Thus, transgenic animals are genetically engineered or genetically modified organisms (GMOs) with a new heritable character. It was in 1980s, the genetic manipulation of animals by introducing genes into fertilized eggs became a reality.

Importance of Transgenic Animals-General:

Trans-genesis has now become a powerful tool for studying the gene expression and developmental processes in higher organisms, besides the improvement in their genetic characteristics. Transgenic animals serve as good models for understanding the human diseases.

Further, several proteins produced by transgenic animals are important for medical and pharmaceutical applications. Thus, the transgenic farm animals are a part of the lucrative world-wide biotechnology industry, with great benefits to mankind. Trans-genesis is important for improving the quality and quantity of milk, meat, eggs and wool production, besides creating drug resistant animals.

Milk as the Medium of Protein Production:

Milk is the secretion of mammary glands that can be collected frequently without causing any harm to the animal. Thus, milk from the transgenic animals can serve as a good and authenticated source of human proteins for a wide range of applications. Another advantage with milk is that it contains only a few proteins (casein, lactalbumin, immunoglobulin etc.) in the native state, therefore isolation and purification of a new protein from milk is easy.

Commonly used Animals for Trans-genesis:

The first animals used for trans-genesis was a mouse. The ‘Super Mouse’, was created by inserting a rat gene for growth hormone into the mouse genome. The offspring was much larger than the parents. Super Mouse attracted a lot of public attention, since it was a product of genetic manipulation rather than the normal route of sexual reproduction. Mouse continues to be an animal of choice for most transgenic experiments. The other animals used for trans-genesis include rat, rabbit, pig, cow, goat, sheep and fish.

Position Effects:

Position effect is the phenomenon of different levels of gene expression that is observed after insertion of a new gene at different position in the eukaryotic genome. This is commonly observed in transgenic animals as well as plants. These transgenic organisms show variable levels and patterns of transgene expression. In a majority of cases, position effects are dependent on the site of transgene integration. In general, the defective expression is due to the insertion of transgene into a region of highly packed chromatin. The transgene will be more active if inserted into an area of open chromatin.

The positional effects are overcome by a group of DNA sequences called insulators. The sequences referred to as specialized chromatin structure (SCS) are known to perform the functions of insulators. It has been demonstrated that the expression of the gene is appropriate if the transgene is flanked by insulators.

Animal Bioreactors:

Trans-genesis is wonderfully utilized for production proteins of pharmaceutical and medical use. In fact, any protein synthesized in the human body can be made in the transgenic animals, provided that the genes are correctly programmed. The advantage with transgenic animals is to produce scarce human proteins in huge quantities. Thus, the animals serving as factories for production of biologically important products are referred to as animal bioreactors or sometimes pharm animals. Frankly speaking, transgenic animals as bioreactors can be commercially exploited for the benefit of mankind.

Once developed, animal bioreactors are cost- effective for the production of large quantities of human proteins. Routine breeding and healthful living conditions are enough to maintain transgenic animals. A list of the therapeutically important proteins produced by animal bioreactors is given Table 41.2.

Transgenic Animals in Xenotransplantation:

Organ transplantation (kidney, liver, heart etc.) in humans has now become one of the advanced surgical practices to replace the defective, non­functional or severally damaged organs. The major limitation of transplantation is the shortage of organ donors. This often results in long waiting times and many unnecessary deaths of organ failure patients.

Xenotransplantation refers to the replacement of failed human organs by the functional animal organs. The major limitation of xenotransplantation is the phenomenon of hyper acute organ rejection due to host immune system.

The organ rejections is mainly due to the following two causes:

i. The antibodies raised against the foreign organ.

ii. Activation of host’s complement system.

Pigs in Xenotransplantation?

Some workers are actively conducting research to utilize organs of pigs in xenotransplantation. It is now identified that the major reason for rejection of pig organs by primates is due to the presence of a special group of disaccharides (Gal-α 1, 3-Gal) in pigs, and not in primates.

The enzyme responsible for the synthesis of specific disaccharides in pigs has been identified. It is α 1, 3-galactosyltransferase, present in pigs and not in primates. Scientists are optimistic that knockout pigs lacking the gene encoding the enzyme α 1, 3-galactosyltransferase can be developed in the next few years. Another approach is to introduce genes in primates that can degrade or modify Gal-α 1, 3-Gal disaccharide groups (of pigs). This will reduce immunogenicity.

Besides the above, there are other strategies to avoid hyperactive organ rejection by the hosts in xenotransplantation.

i. Expression of antibodies against the pig disaccharides.

ii. Expression of complement— inactivating protein on the cell surfaces.

By the above approaches, it may be possible to overcome immediate hyperactive rejection of organs. The next problem is the delayed rejection which involves the macrophages and natural killer cells of the host.

Another concern of xenotransplantation is that the endogenous pig retroviruses could get activated after organ transplantation. This may lead to new genetic changes with unknown consequences.

The use of transgenic animals in xenotransplantation is only at the laboratory experimental stages, involving animals. It is doubtful whether this will become a reality in the near future.

There is a vigorous debate concerning the ethics of xenotransplantation and the majority of general public are against it.