Genetically modified mammal

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Genetically modified mammals are mammals that have been genetically engineered. They are an important category of genetically modified organisms. The majority of research involving genetically modified mammals involves mice with attempts to produce knockout animals in other mammalian species limited by the inability to derive and stably culture embryonic stem cells. [1]

Contents

Usage

The majority of genetically modified mammals are used in research to investigate changes in phenotype when specific genes are altered. This can be used to discover the function of an unknown gene, any genetic interactions that occur or where the gene is expressed. Genetic modification can also produce mammals that are susceptible to certain compounds or stresses for testing in biomedical research. [2] Some genetically modified mammals are used as models of human diseases and potential treatments and cures can first be tested on them. Other mammals have been engineered with the aim of potentially increasing their use to medicine and industry. These possibilities include pigs expressing human antigens aiming to increasing the success of xenotransplantation [3] to lactating mammals expressing useful proteins in their milk. [4]

Mice

Genetically modified mice are often used to study cellular and tissue-specific responses to disease (cf knockout mouse). This is possible since mice can be created with the same mutations that occur in human genetic disorders, the production of the human disease in these mice then allows treatments to be tested. [5]

The oncomouse is a type of laboratory mouse that has been genetically modified developed by Philip Leder and Timothy A. Stewart of Harvard University to carry a specific gene called an activated oncogene. [6]

Metabolic supermice are the creation of a team of American scientists led by Richard Hanson, professor of biochemistry at Case Western Reserve University at Cleveland, Ohio. [7] [8] The aim of the research was to gain a greater understanding of the PEPCK-C enzyme, which is present mainly in the liver and kidneys.

Rats

A knockout rat is a rat with a single gene disruption used for academic and pharmaceutical research. [9] [10] [11] [12]

Goats

BioSteel is a trademark name for a high-strength based fiber material made of the recombinant spider silk-like protein extracted from the milk of transgenic goats, made by Nexia Biotechnologies. Prior to its bankruptcy, the company successfully generated distinct lines of goats that produced recombinant versions of either the MaSpI or MaSpII dragline silk proteins, respectively, in their milk. [13]

Pigs

The enviropig is the trademark for a genetically modified line of Yorkshire pigs with the capability to digest plant phosphorus more efficiently than ordinary unmodified pigs that was developed at the University of Guelph. [14] Enviropigs produce the enzyme phytase in the salivary glands that is secreted in the saliva.

In 2006 the scientists from National Taiwan University's Department of Animal Science and Technology managed to breed three green-glowing pigs using green fluorescent protein. [15] Fluorescent pigs can be used to study human organ transplants, [16] regenerating ocular photoreceptor cells, [17] neuronal cells in the brain, [17] regenerative medicine via stem cells, [18] tissue engineering, [19] and other diseases.

In 2015, researchers at the Beijing Genomics Institute used transcription activator-like effector nucleases to create a miniature version of the Bama breed of pigs, and offered them for sale to consumers. [20]

In 2017 scientists at the Roslin Institute of the University of Edinburgh, in collaboration with Genus, reported they had bred pigs with a modified CD163 gene. These pigs were completely resistant to Porcine Reproductive and Respiratory Syndrome, a disease that causes major losses in the world-wide pig industry. [21]

Cattle

In 1991, Herman the Bull was the first genetically modified or transgenic bovine in the world. [22] [23] The announcement of Herman's creation generated considerable controversy. [24]

In 2016 Jayne Raper and her team announced the first trypanotolerant transgenic cow in the world. This team, spanning the International Livestock Research Institute, Scotland's Rural College, the Roslin Institute's Centre for Tropical Livestock Genetics and Health, and the City University of New York, announced that a Kenyan Boran bull had been born and had already successfully had two children. Tumaini – named for the Swahili word for "hope" – had been given a trypanolytic factor from a baboon via CRISPR/Cas9. [25] [26]

Dogs

Ruppy (short for Ruby Puppy) was in 2009 the world's first genetically modified dog. [27] A cloned beagle, Ruppy and four other beagles produced a fluorescent protein that glowed red upon excitation with ultraviolet light. [28] It was hoped to use this procedure to investigate the effect of the hormone oestrogen on fertility. [28]

A team in China reported in 2015 that they had genetically engineered beagles to have twice the normal muscle mass, inserting a natural myostatin gene mutation taken from whippets. [29] [30]

Primates

In 2009 scientists in Japan announced that they had successfully transferred a gene into a primate species (marmosets) and produced a stable line of breeding transgenic primates for the first time. It was hoped that this would aid research into human diseases that cannot be studied in mice, for example Huntington's disease, strokes, [31] [32] Alzheimer's disease and schizophrenia. [33]

Cats

In 2011 a Japanese-American Team created genetically modified green-fluorescent cats in order to study HIV/AIDS and other diseases [34] as Feline immunodeficiency virus (FIV) is related to HIV. [35]

Related Research Articles

<span class="mw-page-title-main">Genetically modified organism</span> Organisms whose genetic material has been altered using genetic engineering methods

A genetically modified organism (GMO) is any organism whose genetic material has been altered using genetic engineering techniques. The exact definition of a genetically modified organism and what constitutes genetic engineering varies, with the most common being an organism altered in a way that "does not occur naturally by mating and/or natural recombination". A wide variety of organisms have been genetically modified (GM), from animals to plants and microorganisms. Genes have been transferred within the same species, across species, and even across kingdoms. New genes can be introduced, or endogenous genes can be enhanced, altered, or knocked out.

<span class="mw-page-title-main">Genetic engineering</span> Manipulation of an organisms genome

Genetic engineering, also called genetic modification or genetic manipulation, is the modification and manipulation of an organism's genes using technology. It is a set of technologies used to change the genetic makeup of cells, including the transfer of genes within and across species boundaries to produce improved or novel organisms. New DNA is obtained by either isolating and copying the genetic material of interest using recombinant DNA methods or by artificially synthesising the DNA. A construct is usually created and used to insert this DNA into the host organism. The first recombinant DNA molecule was made by Paul Berg in 1972 by combining DNA from the monkey virus SV40 with the lambda virus. As well as inserting genes, the process can be used to remove, or "knock out", genes. The new DNA can be inserted randomly, or targeted to a specific part of the genome.

<span class="mw-page-title-main">Green fluorescent protein</span> Protein that exhibits bright green fluorescence when exposed to ultraviolet light

The green fluorescent protein (GFP) is a protein that exhibits bright green fluorescence when exposed to light in the blue to ultraviolet range. The label GFP traditionally refers to the protein first isolated from the jellyfish Aequorea victoria and is sometimes called avGFP. However, GFPs have been found in other organisms including corals, sea anemones, zoanithids, copepods and lancelets.

<span class="mw-page-title-main">Human genetic enhancement</span> Human enhancement by means of a genetic modification

Human genetic enhancement or human genetic engineering refers to human enhancement by means of a genetic modification. This could be done in order to cure diseases, prevent the possibility of getting a particular disease, to improve athlete performance in sporting events, or to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. These genetic enhancements may or may not be done in such a way that the change is heritable.

Polly and Molly, two ewes, were the first mammals to have been successfully cloned from an adult somatic cell and to be transgenic animals at the same time. This is not to be confused with Dolly the Sheep, the first animal to be successfully cloned from an adult somatic cell where there wasn’t modification carried out on the adult donor nucleus. Polly and Molly, like Dolly the Sheep, were cloned at the Roslin Institute in Edinburgh, Scotland.

<i>Plasmodium berghei</i> Single celled parasite, rodent malaria

Plasmodium berghei is a single-celled parasite causing rodent malaria. It is in the Plasmodium subgenus Vinckeia.

A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the phenotype of an organism. Transgene describes a segment of DNA containing a gene sequence that has been isolated from one organism and is introduced into a different organism. This non-native segment of DNA may either retain the ability to produce RNA or protein in the transgenic organism or alter the normal function of the transgenic organism's genetic code. In general, the DNA is incorporated into the organism's germ line. For example, in higher vertebrates this can be accomplished by injecting the foreign DNA into the nucleus of a fertilized ovum. This technique is routinely used to introduce human disease genes or other genes of interest into strains of laboratory mice to study the function or pathology involved with that particular gene.

Cre-Lox recombination is a site-specific recombinase technology, used to carry out deletions, insertions, translocations and inversions at specific sites in the DNA of cells. It allows the DNA modification to be targeted to a specific cell type or be triggered by a specific external stimulus. It is implemented both in eukaryotic and prokaryotic systems. The Cre-lox recombination system has been particularly useful to help neuroscientists to study the brain in which complex cell types and neural circuits come together to generate cognition and behaviors. NIH Blueprint for Neuroscience Research has created several hundreds of Cre driver mouse lines which are currently used by the worldwide neuroscience community.

Conditional gene knockout is a technique used to eliminate a specific gene in a certain tissue, such as the liver. This technique is useful to study the role of individual genes in living organisms. It differs from traditional gene knockout because it targets specific genes at specific times rather than being deleted from beginning of life. Using the conditional gene knockout technique eliminates many of the side effects from traditional gene knockout. In traditional gene knockout, embryonic death from a gene mutation can occur, and this prevents scientists from studying the gene in adults. Some tissues cannot be studied properly in isolation, so the gene must be inactive in a certain tissue while remaining active in others. With this technology, scientists are able to knockout genes at a specific stage in development and study how the knockout of a gene in one tissue affects the same gene in other tissues.

<span class="mw-page-title-main">Animal testing on rodents</span> Overview article

Rodents are commonly used in animal testing, particularly mice and rats, but also guinea pigs, hamsters, gerbils and others. Mice are the most commonly used vertebrate species, due to their availability, size, low cost, ease of handling, and fast reproduction rate.

<span class="mw-page-title-main">Brainbow</span> Neuroimaging technique to differentiate neurons

Brainbow is a process by which individual neurons in the brain can be distinguished from neighboring neurons using fluorescent proteins. By randomly expressing different ratios of red, green, and blue derivatives of green fluorescent protein in individual neurons, it is possible to flag each neuron with a distinctive color. This process has been a major contribution to the field of neural connectomics.

In molecular cloning and biology, a gene knock-in refers to a genetic engineering method that involves the one-for-one substitution of DNA sequence information in a genetic locus or the insertion of sequence information not found within the locus. Typically, this is done in mice since the technology for this process is more refined and there is a high degree of shared sequence complexity between mice and humans. The difference between knock-in technology and traditional transgenic techniques is that a knock-in involves a gene inserted into a specific locus, and is thus a "targeted" insertion. It is the opposite of gene knockout.

<span class="mw-page-title-main">Genetically modified mouse</span>

A genetically modified mouse or genetically engineered mouse model (GEMM) is a mouse that has had its genome altered through the use of genetic engineering techniques. Genetically modified mice are commonly used for research or as animal models of human diseases, and are also used for research on genes. Together with patient-derived xenografts (PDXs), GEMMs are the most common in vivo models in cancer research. Both approaches are considered complementary and may be used to recapitulate different aspects of disease. GEMMs are also of great interest for drug development, as they facilitate target validation and the study of response, resistance, toxicity and pharmacodynamics.

<span class="mw-page-title-main">Genetically modified animal</span> Animal that has been genetically modified

Genetically modified animals are animals that have been genetically modified for a variety of purposes including producing drugs, enhancing yields, increasing resistance to disease, etc. The vast majority of genetically modified animals are at the research stage while the number close to entering the market remains small.

<span class="mw-page-title-main">Intravital microscopy</span> Imaging of cells in living animals

Intravital microscopy is a form of microscopy that allows observing biological processes in live animals at a high resolution that makes distinguishing between individual cells of a tissue possible.

Genetically modified sperm (GM sperm) is sperm that has undergone genetic modification for biomedical purposes, including the elimination of genetic diseases or infertility. Although the procedure has been tested on animals such as fish, pigs, and rabbits, it remains relatively untested on humans. In the case of pigs, the goal of research is to inexpensively produce organs and supplement the shortage of donated human organs. Although GM sperm has the potential to detect and treat genetic diseases, it will likely take many years for successful use in patients.

<span class="mw-page-title-main">GCaMP</span> Genetically encoded calcium indicator

GCaMP is a genetically encoded calcium indicator (GECI) initially developed in 2001 by Junichi Nakai. It is a synthetic fusion of green fluorescent protein (GFP), calmodulin (CaM), and M13, a peptide sequence from myosin light-chain kinase. When bound to Ca2+, GCaMP fluoresces green with a peak excitation wavelength of 480 nm and a peak emission wavelength of 510 nm. It is used in biological research to measure intracellular Ca2+ levels both in vitro and in vivo using virally transfected or transgenic cell and animal lines. The genetic sequence encoding GCaMP can be inserted under the control of promoters exclusive to certain cell types, allowing for cell-type specific expression of GCaMP. Since Ca2+ is a second messenger that contributes to many cellular mechanisms and signaling pathways, GCaMP allows researchers to quantify the activity of Ca2+-based mechanisms and study the role of Ca2+ ions in biological processes of interest.

A knockout mouse, or knock-out mouse, is a genetically modified mouse in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are important animal models for studying the role of genes which have been sequenced but whose functions have not been determined. By causing a specific gene to be inactive in the mouse, and observing any differences from normal behaviour or physiology, researchers can infer its probable function.

<span class="mw-page-title-main">History of genetic engineering</span>

Genetic engineering is the science of manipulating genetic material of an organism. The first artificial genetic modification accomplished using biotechnology was transgenesis, the process of transferring genes from one organism to another, first accomplished by Herbert Boyer and Stanley Cohen in 1973. It was the result of a series of advancements in techniques that allowed the direct modification of the genome. Important advances included the discovery of restriction enzymes and DNA ligases, the ability to design plasmids and technologies like polymerase chain reaction and sequencing. Transformation of the DNA into a host organism was accomplished with the invention of biolistics, Agrobacterium-mediated recombination and microinjection. The first genetically modified animal was a mouse created in 1974 by Rudolf Jaenisch. In 1976 the technology was commercialised, with the advent of genetically modified bacteria that produced somatostatin, followed by insulin in 1978. In 1983 an antibiotic resistant gene was inserted into tobacco, leading to the first genetically engineered plant. Advances followed that allowed scientists to manipulate and add genes to a variety of different organisms and induce a range of different effects. Plants were first commercialized with virus resistant tobacco released in China in 1992. The first genetically modified food was the Flavr Savr tomato marketed in 1994. By 2010, 29 countries had planted commercialized biotech crops. In 2000 a paper published in Science introduced golden rice, the first food developed with increased nutrient value.

Breast cancer metastatic mouse models are experimental approaches in which mice are genetically manipulated to develop a mammary tumor leading to distant focal lesions of mammary epithelium created by metastasis. Mammary cancers in mice can be caused by genetic mutations that have been identified in human cancer. This means models can be generated based upon molecular lesions consistent with the human disease.

References

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