Cell Biology for Knockout Mice Term Paper

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Stem cells are cells that can develop into other forms of cells; Evans's cells could develop into entire mice. Evans eventually began altering the genetic material in the stem cells, creating mice that had genetic material from other creatures and could pass that material on to their offspring" (313). These findings, together with the research conducted separately by Capecchi and Smithies, enabled several teams of researchers to develop knockout mice (Lauerman 313).

In 2007, Evans received the Nobel Prize for medicine for these discoveries and the development of knockout mice that could be used to help scientists better understand and possibly cure diseases such as cystic fibrosis, heart disease, diabetes and cancer (Briton wins Nobel Prize 4). According to the editors of Environmental Health Perspectives (2005), the Comparative Mouse Genomics Centers Consortium (CMGCC) already has 54 transgenic or knockout mouse models developed at varying stages of construction and characterization (with regard to genotyping and phenoytping) for use as single nucleotide polymorphisms mice (Mouse models to improve understanding of the biological significance of human polymorphisms, 2005). Today, knockout mice are providing an increasing amount of valuable scientific information concerning the potential roles of genes in biological and behavioral processes and in the pathophysiology of many diseases which are discussed further below.

Mechanisms and Techniques of Knockout Mice Experiments.

Knockout mice are generally used to find out what a gene normally does; the mice are using for this purpose by observing the effects of functional elimination of certain genes on its functioning; however, just as the development of the knockout mice themselves was enormously challenging, this process is also not as straightforward as it sounds because the gene may be involved in a number of interacting biological processes (Barondes). As Bowers (2000) also points out, the fundamental requirements for creating such a transgenic or "knockout" mouse include:

Identifying and isolating the candidate gene of interest from its original organism (i.e., from the DNA of the organism's cells); and,

Selecting a suitable promoter that is placed adjacent to the transgene. The choice of promoter by the scientist depends on its location in the brain and the time in which (i.e., prenatal or postnatal) the transgene must be expressed (175).

While scientists are currently able to control the expression of the transgene through the careful selection of the promoter (promoters are stretches of DNA associated with a specific gene that guide the expression of the gene to specific areas in the brain and turn the expression of the gene 'on' either prenatally or postnatally), one limitation of the transgenic technique is its inability to target the integration of the transgene to its natural location on the chromosome (Bowers 175). As this author points out, "The site of integration is unique for each microinjection, and the transgene can be randomly inserted anywhere on any chromosome. This outcome can result in the disruption of a sequence of one of the host animal's own genes (i.e., known as insertional mutagenesis), producing changes in behavior that could mistakenly be attributed to the transgene itself" (Bowers 175).

In addition, scientists are still unable to control the number of integrated copies of the transgene, and the presence of additional copies of a gene does not necessarily indicate an increased overexpression of the gene being studied (Bowers 175). According to Bowers, "To control for this, the existence of more than one founder and consequently more than one line of mice for each transgene is desirable. The site of integration and level of expression will differ in each founder, and transgenic mice that descend from the same founder will share the same chromosomal integration site. If each transgenic line displays the same changes in behavior, it is more likely that it is attributable to the transgene" (175). Furthermore, the human body has also been shown to compensate for the loss of certain genes by increasing or decreasing the activities of related genes (Barones).

Despite these constraints to research, knockout mice have traditionally been used to study developmental processes and as models to study the etiology of human diseases and the environmental factors that may contribute to their incidence (Bowers 175). Some of the information that scientists have derived from their knockout experiments with mice have already yielded some impressive results. For example, a noteworthy discovery was made from the knockout of a gene that encodes a protein that can be divided to produce two different brain peptides (Barondes).

Termed "hypocretins" because they are manufactured in the hypothalamus, these two peptides are also called orexins (from the Greek word for "appetite" -- the same root that is used in "anorexia") in some cases because they are thought to increase appetite (120).

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In an effort to investigate the behavioral functions of the hypocretins, Chemelli, Sinton, Elmquist et al. (1999) knocked out the hypocretin gene, thereby deleting both of these peptides; when the researchers videotaped the knockout mice to monitor their movements, they determined that the mice kept falling asleep for short periods, an abnormal pattern of behavior is characteristic of narcolepsy (cited in Barondes at 121).

While these observations were being made, a role for hypocretins in narcolepsy was identified elsewhere by Lin, Hungs, and Mignot (2001). This team of researchers had been investigating a genetic form of narcolepsy in a line of Doberman pinschers by using the same gene-hunting techniques that resulted in the identification of gene variants that cause Alzheimer's disease and determined that this variant encodes an inactive form of a receptor for one of the hypocretins (hypocretin receptor-2). Based on this discovery, the Chemelli experiment knocked out this hypocretin receptor in mice and confirmed that its absence -- like the absence of the hypocretins themselves-causes narcolepsy (cited in Barondes at 121).

Studies Using Knockout Mice in the Study of Diabetes.

In recent years, knockout mice have been used to identify epitopes on several autoimmune disease-related antigens such as collagen and cartilage glycoprotein, the autoantigens associated with arthritis, glutamic acid decarboxylase and insulin associated with type 1 diabetes, nicotinic acetylcholine receptor involved in myasthenia gravis, RO60 (SS-a) lupus-related antigen, myelin basic protein, myelin olygodendrocyte glycoprotein and proteolipid protein implicated in the development of multiple sclerosis; in addition, the use of certain knockout mice has been shown to be an effective tool for the identification of T-cell epitopes on malarial parasites and mycobacterial antigens that could be used to generate a new type of more effective subunit vaccines (Chapoval and David 2003:245). More recent studies of specific types of knockout mice immune responses to tumor-associated proteins has provided researchers with new insights that have identified epitopes of potential clinical value for design of anticancer vaccines (Chapoval and David 246).

To date, though, an experimental correlation between endocrine-disrupting chemicals and diabetes in humans has not been established; however, a connection at the epidemiologic level in humans has been recently proposed for dioxin, an environmental contaminant that acts through other than estrogen receptors (ERs) as an endocrine disruptor (Bertazzi et al. 2001; Remillard and Bunce 2002). What is currently known is that a large number of endocrine-disrupting chemicals act by using the biological actions as the sex hormone 17?-estradiol; generally, these chemicals bind to the classic estrogen receptors (ERs); however, they can also act through novel estrogen targets (Nadal et al. 2005).

At the physiological level, these mechanisms are believed to be involved in maintaining normal insulin sensitivity and to be beneficial for cell functioning; however, abnormal levels may promote insulin resistance similar to what takes place during normal puberty and pregnancy (Alonso-Magdalena et al. 107). Consequently, exposure to an exogenous chemical acting as the natural hormone, but at an inappropriate concentration and during an improper time window, may exacerbate the risk of developing insulin resistance (Alonso-Magdalena et al. 107).

In spite of the many clinical studies that have identified associates between sex steroids and actions of insulin, there remains a dearth of studies that have specifically investigated the molecular basis of the interaction between [E.sub.2], the pancreatic [beta]-cell function, blood glucose homeostasis, and the development of diabetes (Alonoso-Magdalena et al. 107). According to these authors, "Pancreatic [beta]-cells contain both types of ERs, ER-[alpha] and ER-[beta]" (Alonso-Magdalena et al. 107). Although their functions are still greatly understudied, ER-[alpha] and ER-[beta] are involved in important aspects of the [beta]-cell physiology, including protection against [beta]-cell death caused by cytokines, as well as a beneficial effect on diabetes in mice expressing human islet amyloid peptide following prolonged application (Geisler et al. 2002). In addition, the involvement of ERs in lipid and glucose metabolism has been demonstrated in ER-[alpha] knockout mice that display increased adiposity, insulin resistance, and glucose intolerance (Heine et al. 2000).

Conclusion

The research showed that, taken to either of its potential extremes, genetic engineering either holds enormous promise for curing a wide range of the maladies that have historically affected the human condition, or to bring about a "Brave New World" where evil scientists manipulate humans at the genetic level to effect desirable social change. While only time will tell which….....

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