Transgenic Animals - ppt (SONU)

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Transgenic animal models in the development of new drugs, and also as disease models; techniques for their development; and their applications

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Transgenic Animals: :

Transgenic Animals: Presented by: Sonu M.Pharma (P’Cology) Ist year Rayat Bahra Institute of Pharmacy Mohali, Punjab

Transgenic Animals::

Transgenic Animals:

Transgenic Animals::

Transgenic Animals: Definition:   An organism (typically a mouse) that is engineered to carry a foreign gene, or transgene of choicem as part of its own genetic material. Transgenics are genetically modified organisms with DNA from another source inserted into their genome. A large number of transgenic animals have been created such as Mice, Cows, Pigs, Sheep, Goats, Fish, and Frogs. Currently, no transgenic animal or animal product is approved by the FDA or USFDA for human consumption.

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Purpose:   These animals are very useful for delineating the function of newly discovered genes as well as for producing useful proteins in large animals. Animals that have their DNA manipulated in this way are known as transgenic animals. Transgenic animals are useful as disease models and producers of substances for human welfare .

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Animal biotechnology is the field to engineer transgenic animals, i.e., animals that carry genes from other species. Other transgenic animals are produced as disease models (animals genetically manipulated to exhibit disease symptoms so that effective treatment can be studied ). e.g. - the OncoMouse® (Harvard mouse) , carrying a gene that promotes the development of various human cancers .

What is a Transgenic animal?:

What is a Transgenic animal? A transgenic animal is one whose genome has been changed to carry genes from other species . For example, an embryo can have an extra, functioning gene from another source artificially introduced into it, or a gene introduced which can knock out the functioning of another particular gene in the embryo .

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The first transgenic animals were Rudolf Jaenisch’s mice . Jaenisch is a professor of biology at MIT. In the 1970s he successfully introduced an outside gene into the mice embryos.  The mice and their offspring developed leukemia. E.g. , transgenic cattle were created to produce milk containing particular human proteins, which may help in the treatment of human emphysema .

Some of the goals of transgenic animal creation are: :

Research into animal and human disease Improve livestock animals Use of animals as bioreactors Some of the goals of transgenic animal creation are:

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Benefits of Transgenic Animal Research Regulation of gene expression 2) Immune system function 3) Genetic diseases 4) Viral diseases 5) Cancer research 6) Toxicological studies 7) Development of new entity (drug) 8) Beneficial for Pharmaceutical research 9) Transgenic animals as disease models

Negatives of Transgenic Animals:

Many animals die or are born horribly disfigured as research is conducted. One theory is that transgenic animals can radically change the direction of evolution, which can result in drastic consequences for nature and humans alike. Negatives of Transgenic Animals

Methods for Transforming Genes::

Injection of DNA into the nucleus of a fertilized egg cell and implanting it into the uterus (in vitro) of an organism. (DNA microinjection or Pronuclear inj n ) Injection of DNA into embryonic stem cells. Using viruses to transfer genes into cells using recombinant DNA. Sperm- mediated gene transfer, or introducing genetic material into sperm that fertilize eggs. Methods for Transforming Genes:

1. DNA microinjection:

1 . DNA microinjection In the past 20 years, DNA microinjection has become the most widely applied method for gene transfer in animals. Introducing the transgene DNA directly into the zygote at an early stage of development. (No vector required) This method involves: 1) transfer of a desired gene construct (of a single gene or a combination of genes that are recombined and then cloned) from another member of the same species or from a different species into the pronucleus of a reproductive cell; 2) in vitro culture of the manipulated cells to develop to a specific embryonic phase; and 3) then transfer of the embryonic cells to the recipient female.

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Microinjection into the germ line > transgenic animal Gene injected into the male pronuclei (i.e Pronuclei inj n )

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2. Retrovirus-mediated gene transfer (RMGT): The word “retro” means, when the virus vectors infect a host cell, the viral RNA is reverse transcribed in the cytoplasm making linear double-stranded DNA. A retrovirus is a virus that carries its genetic material in the form of RNA rather than DNA. In this method, retroviruses are used as vectors to transfer genetic material into the host cell, resulting in a chimera, an organism consisting of tissues or parts of diverse genetic constitution. Infecting mouse embryo with a retrovirus which carry the new gene.

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When cells are infected by retroviruses, the resultant viral DNA, after reverse transcription and integration, becomes a part of the host cell genome to be maintained for the life of the host cell. 3. Sperm-mediated gene transfer (SMGT) In 1989 Lavitrano et al. described a simple and efficient technique, sperm-mediated gene transfer to produce transgenic mice. Use of “Linker protein" to attach DNA to sperm which transfer the new DNA during fertilization. In this technique, DNA was mixed with sperm cells before in vitro . 30% of offspring mouse were integrated foreign DNA. The basic principle of sperm-mediated gene transfer is: seminal plasma-free sperm cells are suspended in the appropriate medium, and then incubated with DNA.

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The resultant DNA-carrying sperms are then used to fertilize eggs, via in vitro fertilization or artificial insemination or, in the case of aquatic animals, via waterborne (natural) fertilization.

4. Embryonic stem cell-mediated gene transfer:

4. Embryonic stem cell-mediated gene transfer The blastocyst (inner layer of a fertilized egg) is harvested and mixed with recombinant DNA and inserted back in the blastocyst . This method involves: I solation of totipotent stem cells (stem cells that can develop into any type of specialized cell) from embryos . T he desired gene is inserted into these cells . Cells containing the desired DNA are incorporated into the host's embryo.

Embryonic stem (ES) cells:

Embryonic stem (ES) cells Pluripotent stem cells derived from the inner cell mass of the blastocyst Can be cultured, manipulated and then reinjected into blastocysts, where they can go on to contribute to all parts of embryo. In principle, ES cells also might be able to generate large quantities of any desired cell for transplantation into patients.

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isolated directly from the inner cell mass of embryos at the blastocyst stage .

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Mouse Knock-outs require embryonic stem (ES) cells These are derived from the inner cell mass (ICM) of a blastocyst (the ICM is what will become the fetus) ES cells are pluripotent meaning they can become all the different cell types found in an adult

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Totipotent and Pluripotent cells Totipotent cells = meaning that its potential is total. P luripotent cells =   (capable of developing into any type of cell or tissue ) they can give rise to many types of cells but not all types of cells (no fetus developed).

Applications of Transgenic Animals:

Applications of Transgenic Animals Transgenic technology holds a great potential in different-different groups on the basis of benefits of these animals to human welfare can be grouped into areas: Agricultural, Medicinal, and Industrial field.

1. Agricultural Applications:

1. Agricultural Applications Breeding Traditional cross breeding have been used for ages to create chickens, cows, pigs etc. Farmers have always used selective breeding to produce animals that exhibit desired traits (e.g., increased milk production, high growth rate). Traditional breeding is a time-consuming, difficult task. Researchers have now used gene transfer to improve the productivity of livestock.

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It also offers farmers an easy way to increase yields. Scientists can improve the size of livestock genetically. Transgenic cows exist that produce more milk or milk with less lactose or cholesterol. Transgenic cows have been used to produce milk which are richer in proteins and lower in fat.

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(B) Quality Herman, a transgenic bull carries a human gene for Lactoferrin (gene responsible for higher iron content) Pigs and cattle that have more meat on them. Sheep that grow more wool. Eggs can be made healthier with high quality protein. (C) Disease resistance Disease-resistant livestock is not a reality just yet. But there has been improvement in disease reduction in animals.

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The Foot- and- Mouth disease in England in 2000 led to destruction of herds of cattle, sheep and goat. Scientists are attempting to produce disease-resistant animals, such as influenza-resistant pigs, but a very limited number of genes are currently known to be responsible for resistance to diseases in farm animals. Transgenic disease protection promises a long term cost effective method of battling animal diseases.

2. Medical Applications:

2. Medical Applications A).Xenotransplantation Transplant organs may soon come from transgenic animals. e.g. Transgenic pigs may provide the transplant organs needed to alleviate the shortfall. Currently, xenotransplantation is hampered by a pig protein that can cause donor rejection but research is underway to remove the pig protein and replace it with a human protein. For organ and tissue transplantation, which is known as a "species of daughter cells “

B) Nutritional supplements and pharmaceuticals::

B) Nutritional supplements and pharmaceuticals: Milk-producing transgenic animals are especially useful for medicines. Products such as insulin, growth hormone, and blood anti-clotting factors may soon be or have already been obtained from the milk of transgenic cows, sheep, or goats . This transgenic milk is a more nutritionally balanced product than natural milk and could be given to babies or the elderly with special nutritional or digestive needs.

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C) Human gene therapy Human gene therapy involves adding a normal copy of a gene (transgene) to the genome of a person carrying defective copies of the gene. Finland produced a calf with a gene that makes the substance that promotes the growth of red cells in humans .

Uses of Animal Models::

Uses of Animal Models: Transgenic mice can be used both as model systems for human diseases and as test cases to determine if the production of a potential therapeutic agent is feasible. However, a mouse or rodent is not a human being, even though it is a mammal, and thus the information gathered from transgenic rodent is not always medical relevant. But, on the other hand, clinical insight about the etiology of a complex diseases can be discovered. With this aim, Alzheimer disease, arthritis, muscular dystrophy, tumorigenesis, hypertension, neurodegenerative disorders, endocrinological dysfunction, coronary disease, obesity and many others have been developed.

3. Industrial Applications:

3. Industrial Applications By extracting polymer strands from the milk and weaving them into thread, the scientists can create a light, tough, flexible material that could be used in such applications as military uniforms, medical microsutures , and tennis racket strings . Biosteel is an extraordinary new product that may be soon used in bullet proof vests and in suture silk for stitching wounds . Animals have been used as “Bioreactors” to produce proteins . Genes for desired proteins are introduced via transgenics to the target cells .

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The target cells are cloned and several such cells are raised into adults. These adults may produce milk or eggs (due to the presence of introduced gene rich in desired protein). Toxicity-sensitive transgenic animals have been produced for chemical safety testing. Microorganisms have been engineered to produce a wide variety of proteins, which in turn can produce enzymes that can speed up industrial chemical reactions .

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Historical development of Transgenic Animals

Transgenic Models in Drug Development::

Transgenic Models in Drug Development: Search for new drug targets. Validation of drug targets. Safety testing. Protein production.

SOME IMPORTANT ADVANCES:

SOME IMPORTANT ADVANCES Though the field of transgenic animals has advanced considerably but few advancements are considered to be most important. Introduction of the transgene Transgene integration Transgene expression Transgene transmission Use of embryonic stem cells Pharmaceutical products from transgenic animals

Problems and prospects:

Problems and prospects Transgenic animals have potentially broad application for the improvement of animal production quality, the enhancement of productivity, the studies of human disease models and the production of pharmaceuticals. Dietary and food safety concerns: Foreign gene inserted in the chromosome locus may also result in different genetic changes in different degrees, causing unintended effects. Environmental impacts: It may also lead to the loss of the wild allele, resulting in a decline in genetic diversity Respect for life and “unnaturalness” of genetic engineering: it might devalue nature and commercialize life.

Conclusion::

Conclusion: Transgenic animal techniques have developed rapidly and provided more and improved platforms for the preparation of transgenic animals since their emergence. All of these developments will provide new ideas and bring forth important changes in fields like medicine, health and livestock improvement. In particular, the economic and social benefits from the production of bioreactors, drug production, and organ culture for human transplantation will be great.

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