Term Paper: Cell Biology for Knockout Mice Experiments With Diabetes

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Cell Biology for Knockout Mice Experiments With Diabetes

Genetic engineering holds some real promise for curing the diseases that afflict mankind and for extending human lives. To further these genetic investigations, scientists use knockout mice in an effort to determine what a gene normally does by observing the effects of its functional elimination. These knockout mice experiments have already provided scientists with some new insights into the etiologies of many diseases and these Genetic engineering techniques hold true promise for the future. This paper provides a review of the relevant peer-reviewed and scholarly literature to determine the mechanisms and techniques of the knockout mice experiments, including how they are performed and how they affect the mice at the cellular level in terms of cell structure and/or function. A discussion of some of the experiments in which knockout mice have been used in the study of diabetes is followed by a summary of the research in the conclusion.

Review and Discussion

Background and Overview.

One of the unfortunate consequences of living in the 21st century is the fact that people today stand a better chance of contracting diabetes than ever before. In fact, over the past few decades, the incidence of diabetes has approached epidemic levels and there are currently 177 million persons with diabetes in the world (World Health Organization 2005). The basis for this increased incidence of diabetes has been directly correlated with many aspects of modern lifestyles, particularly a paucity of exercise combine wit an unhealthy diet characterized by fast food and vending machine snacks (Alonso-Magdalena et al. 106). According to the World Health Organization:

Diabetes causes about 5% of all deaths globally each year;

80% of people with diabetes live in low and middle income countries;

Most people with diabetes in low and middle income countries are middle-aged (45-64), not elderly (65-plus); and,

Diabetes deaths are likely to increase by more than 50% in the next 10 years without urgent action.

There has been a dramatically increased incidence for other pathologies after World War II as well, including cancer, reproductive impairment, and neurodegenerative diseases; all of these conditions have been attributed to the increase of endocrine-disrupting chemicals in the environment (Barondes).

Other environmental factors are also being studied to determine if there is a relationship between environment factors and the incidence of diabetes in the 21st century. In this regard, Lindberg and her colleagues (2007) report that, "Arsenic is a worldwide water contaminant, and chronic exposure has been associated with a large number of health effects, such as different forms of cancer, skin lesions, vascular diseases, liver -- and neurotoxicity, and diabetes mellitus. Studies with GSTO1 knockout mice showed that they still reduced arsenic (V) species, but to a lesser extent (~ 20% of that found in wild-type mice)" (1081). Likewise, according to Stevens and his colleagues (2007), "One of the defining characteristics of life in the modern world is the altered patterns of light and dark in the built environment made possible by use of electric power" (1357). The growing of evidence has determined the underlying mechanisms responsible for photo-transduction in the retina that provide environmental control of circadian and other neurobehavioral responses and the composition and functioning of the clock physiology that exert genetic control of the endogenous rhythms (Stevens et al. 1357). These authors adds that, "There is limited but thus far generally consistent evidence in support of the hypothesis that altered lighting can play a role in breast cancer causation, and there is growing interest in a lighting and/or sleep connection to other conditions such as prostate cancer, obesity, diabetes and depression" (Stevens et al. 1358). While the light detection for the regulatory function performed by the circadian, neuroendocrine, and neurobehavioral systems appear to be mediated principally by intrinsically photoreceptive retinal ganglion cells, experiments using melanopsin knockout mice have demonstrated that the classic rod and cone visual photoreceptors nevertheless appear to have some role in modulating these responses, findings that may ultimately help researchers develop more effective clinical interventions, vaccines and cures (Stevens et al. 1358).

Taken together, the foregoing suggests that environmental factors are responsible for the near-epidemic levels of diabetes around the world and scientists are using such genetically engineered knockout mice to help further their research into the etiology of diabetes and other diseases through a process known as gene targeting, in which an existing gene variant (variant 1) is replaced by an alternative variant (variant 2) of the same gene (Barondes, 2003). Gene targeting is accomplished by taking the variant 1 and "cutting it out" its normal position on a chromosome and substituting variant 2 in the same precise location; what results from this genetically engineering is a line of mice with variant 2 instead of variant 1 (Barondes). In the majority of cases, variant 2 is a man-made gene variant that has been prepared in a test tube by chemical manipulation of isolated copies of variant 1, with the chemical manipulation being intended to effect a specific change in the function of variant 1 by substituting or removing some of its nucleotides (Barondes).

In some cases, variant 2 is designed with a major flaw that causes it be nonfunctional, and variant 2 is then inserted into the DNA of embryos by a technique that exchanges it for variant 1; the descendants of embryos whose variant 1 was replaced by the nonfunctional variant 2 are known as "knockout" mice because the function of the gene has been "knocked out" (Barondes). As Leshner (1999) advises, "In the past few years, we have been able to create genetically altered knockout mice, which lack one or more of these receptors. Studies of the drug-responsiveness and behavior of these mice have illuminated the complexity and the interconnectedness of brain mechanisms. For example, experiments with these knockout mice have demonstrated that the pleasurable effects of cocaine remain despite the absence of the dopamine transporter, a molecule previously thought to be the primary mediator of these effects" (22).

In 2001, Mario Capecchi, Martin Evans, and Oliver Smithies received the Albert Lasker Basic Medical Research Award for their work that led to the development of knockout mice (Lauerman 2002). This author adds that, "Knockout mice, developed in 1989, are now commonly used by medical researchers to replace mice genes with faulty human genes and thereby give human diseases to mice. The development of knockout mice has provided researchers with a powerful tool for testing drugs and with insight into how diseases develop. Although Capecchi, Evans, and Smithies did not actually develop the first knockout mice, their research made such an achievement possible" (Lauerman 312).

While the use of knockout mice is commonplace today, their development was an extremely complicated process that required the better part of the 1980s because of the state of technology of the day: "Snipping out a mouse gene was simple enough by the early 1980s, but replacing that gene with another one was considered an impossible task. Whenever DNA was introduced into a mammalian cell, the new DNA would insert itself at a random site rather than in the place where the gene had been snipped out" (Lauerman 313). At the time, a number of researchers believed that these challenges were insurmountable; however, Capecchi and Smithies independently developed a process called homologous recombination, in which new DNA lines up with a specific site on a chromosome and either replaces the existing gene or is added as a second copy (Lauerman 313). According to this author, "In 1982, Capecchi proved that mammalian cells already had a mechanism for incorporating introduced DNA into specific locations on existing chromosomes, which raised the possibility that scientists could do the same" (Lauerman 313).

The possibility of doing the same and actually doing it were, of course, dramatically different issues and Capecchi and Smithies found it difficult to determine which techniques worked because successes were so rare; nevertheless, these researchers, again working separately, developed methods whereby it was possible to determine if the cells had reached their appropriate destination on the DNA strand. Smithies is credited with first discovering that a cell that had been engineered successfully, and his publication of the discovery in 1985 established the groundwork for future experiments that targeted DNA segments into a mammalian chromosome (Lauerman 313). While this was an innovation, the method developed by Smithies was exceedingly time consuming and Capecchi is credited with developing more efficient techniques to identify cells that had had their DNA altered correctly, research that eventually resulted in methods of incorporating the DNA that were more likely to be successful (Lauerman 313).

In 1988, Capecchi developed a general technique to facilitate the growth of cells that have properly incorporated introduced DNA and to eliminate those that have not incorporated the desired DNA; during the period when Capecchi and Smithies were working separately on the genetic component of the problem, Evans was working on how best to use the mice needed for such experiments (Lauerman 313). According to this author, "In the early 1980s, Evans isolated embryonic stem… [END OF PREVIEW]

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