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In 2017 scientists in the United Kingdom created more than 1.9 million transgenic organisms. With the rapid increase in the assistance of transgenic animals and their assistance in health research, the claims exists that transgenic organisms offer a viable and effective future for human health. (Callaway, 2018)

Transgenic organisms refer to the process known as “genetic engineering.” Genes of one species can be modified, or genes can be transplanted from one species to another. Genetic engineering is made possible by recombinant DNA technology. Organisms that have altered genomes are known as transgenic.

After selecting the claim ‘Transgenic organisms offer a viable and effective future for human health’, research revealed the conflict between the ethics of the use of transgenic animals and the benefits that can be derived from their use. (PCRM, 2013) Further research revealed significant activities underway with transgenic mice in the research of Muscular Dystrophy. This led to this research question:

How effective are transgenic mice in assisting human health concerning Duchenne

Muscular Dystrophy?

Background

Muscular dystrophy (MD) is a progressive muscle-wasting disorder that is caused by mutations in the dystrophin gene. Duchenne Muscular Dystrophy (the most common form of muscular dystrophy) is caused by a mutation in the DMD gene. The protein Dystrophin is coded by this gene. The primary symptom of non-functional Dystrophin is the progressive weakening of muscles. (MDA, 2018)

The use of animal models, and specifically, transgenic animals such as mice has contributed significantly to the development of a potentially ground breaking treatment of DMD, known as Gene Therapy. Gene therapy is a potential treatment option for those experiencing significant diseases that have derived from a defective or absent protein though a gene mutation. (YG, 2016)

Replacement or repair the defective dystrophin gene by gene therapy is one highly promising therapeutic strategy. Numerous animal models of DMD have been developed though the model, mdx mice is the most commonly employed model in DMD research and has been used to lay the groundwork for DMD gene therapy.

A genetically modified mouse can be created in two ways. With the first, the fertilized egg of a pregnant house is injected with a DNA sequence containing that gene of interest. This process is called pronuclear injection and is commonly used to add to the mouse’s genome with additional genes. The second method uses human DNA to modify mouse embryonic stem cells, prior to injecting them into the pregnant mouse. This second method is used to remove a single gene in the mouse’s genome.

Evidence

The primary goal of DMD gene therapy is to improve muscle pathology and to enhance muscle function. Gene therapy can convert the DMD phenotype to the benign BMD phenotype and can also prevent or slow down the development of muscle disease if affected individuals are treated early enough.

Figure 1: (Tidy, 2016)

The Dystrophin gene is located on the X Chromosome and it codes for the dystrophin protein, which localises to the cell membrane. Dystrophin is a critical muscle protein and acts like a “molecular shock absorber”. (Tidy, 2016)

The DMD mdx mutation is a spontaneous C-to-T transition at position 3185 (exon 23) in the dystrophin muscular dystrophy (DMD) gene, resulting in a termination codon in place of a glutamine codon, and expression of a truncated protein.

Figure 2: (McGreevy, 2015) “The Protein” Structure of Dystrophin

The Schematic outline of dystrophin and the dystrophin-associated glycoprotein complex is represented in figure 2. (McGreevy, 2015)

Genome editing is a way of making specific changes to the DNA of a cell or organism. An enzyme cuts the DNA at a specific sequence, and when this is repaired by the cell a change or 'edit' is made to the sequence. This method restored dystrophin protein expression in cardiac and skeletal muscle to varying degrees, and expression increased from 3 to 12 weeks after injection. Postnatal gene editing also enhanced skeletal muscle function, as measured by grip strength tests 4 weeks after injection. This method provides a potential means of correcting mutations responsible for DMD and other monogenic disorders after birth.  (Long, 2016)

CRISPR/Cas9 is the most common genome editing technology used to mutate the DMD gene. Through this method, Exon 23 of the mdx mouse is disregarded through stimulating double-strand breaks in the introns adjoining the exon. Containing a multiple of three nucleotides and a nonsense mutation, exon 23 removals maintain the normal reading frame and restores dystrophin. (Tremblay, 2016)

With reference to figure 3, Serum creatine Kinase (CK), a diagnostic marker for muscular dystrophy that reflects muscle leakage, was measured in 3 variations of mice- mdx, mdx-C and wild-type (naturally occurring) mice. Consistencies surrounding histological results, serum CK levels of the mdx-C mice noticeably declined compared with mdx mice. The levels were “inversely proportional to the percentage of genomic correction.” (Veltrop, 2018) The three variations of mice also underwent grip-strength testing in order to calculate muscle performance. Ultimately figure 3 depicts that mdx-C mice showed enhanced muscle performance compared with mdx mice. (Veltrop, 2018)

Figure 3: (Veltrop, 2018)

The results of this table highlight the value of using transgenic mice in research. The conclusions drawn would not have been discovered without the use of a significant number of animals.

Research has revealed DMD is more severe in humans than animals such as mice because of differences in human chromosomes. Characteristics of the chromosomes create limitations with the capacity of the stem cells to regenerate. This reduces the ability for humans to recover from the damage caused by the dystrophin mutation. (The Jackson Laboratory, 2018)

Results of DMD gene therapy in mdx Mice is shown:

“Preliminary analysis of muscle at four weeks shows signs of widespread regeneration, including central nucleation, along with some ongoing necrosis and endomysia fibrosis.” (Roberts, 2013)

Figure 4: (Molano, 1998)

As seen in figure 4, after the Mice were treated with genome editing through skipping mutant dystrophin exons in postnatal muscle tissue; the cardiac muscle which is mutated with DMD, is partially restored. (Long, 2016)

Genomic editing within the germ line is not currently feasible in humans. However, genomic editing could, in principle, be envisioned within postnatal cells in vivo if certain technical challenges could be overcome. Making this a reality would create a major improvement to human health – in particularly to those subject to hereditary issues such as DMD.

Evaluation

Human methods of studying disease address; limited overlaps between mouse and human biology, the true contributions genetic defects have to human disease, the cost-intensive nature of using animals as subjects, and serious welfare concerns.

The evidence presented in the paper supporting the value of the use of transgenic mice in advancing the cause of human health is significant. The positive impact of gene therapy on mice and the potential development of human gene therapies for those carrying hereditary issues such as the DMD gene mutation, is well-documented. However, before coming to a conclusion on the question presented we must consider the potential downsides of this research and the potential use of alternatives.

Several alternatives do exist and these include: epidemiological studies, bioinformatics, systems biology, tissue engineering, in vitro (human cell and tissue cultures) research, in silico (computer-based) techniques, stem cell methods, and human-centred studies. While all promising in their own right, none offer the ‘silver bullet’ that might lead to them taking a lead role.

The evidence has showed that numerous welfare concerns surrounding testing of transgenic mice must be gauged. For one, many procedures are painful and invasive. The Canadian council did a survey on animal care and uncovered that a majority of procedures which GM mice partake in cause “moderate to severe physical discomfort” to the animal. Majority of procedures are performed without pain relief. (PCRM, 2013)

In addition to the disease or condition that is induced in GM mice, trans genesis can result in any number of unanticipated side effects, such as lameness, susceptibility to disease, stress, reduced fertility, reduced adult body weight, and immune impairment. A loss of gene function, called an insertional mutation, can also occur. Estimates of insertional mutation frequency in GMM range from 7-20 percent. (PCRM, 2013)

More than 50 percent of mice in laboratories exhibit behaviors that are indicative of distress, which can accumulate over time and result in severe mental trauma which parallels that seen in humans kept in similar conditions. (PCRM, 2013)

Conclusion

This task has sought to understand the effectiveness of the use of transgenic mice in assisting human health, specifically concerning muscular dystrophy. Real welfare based concerns are raised in literature regarding humans playing god and mice being deliberately diseased and the associated pain and suffering. These concerns must be taken seriously and must continue to be covered under animal welfare and related codes of practice

However, the evidence discussed points to significant advances in research through the use of transgenic mice, including the creation of embryonic treatments involving gene therapy. Such developments give real hope to the next generation and beyond – hope which would have either not been possible or significantly delayed, without the use of

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