What are the medical applications of genetic engineering?

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Genetic engineering has produced a wide range of medical applications, including recombinant DNA drugs, transgenic animals that produce pharmaceutically useful proteins, methods for the diagnosis of disease, and gene therapy to introduce a functional gene to replace a defective one.
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Multiple Applications: Drug Production

Genetic engineering, the manipulation of DNA to obtain a large amount of a specific gene, has produced numerous medical applications. As a result of the completion in 2003 of the Human Genome Project—the determination of the DNA sequences of all the chromosomes in humans—genetic engineering will continue at an accelerated pace and result in even more important medical applications.

Recombinant DNA technology can be used to mass-produce protein-based drugs. The gene for the protein of interest is cloned and expressed in bacteria. For example, insulin needed for people with Type I diabetes mellitus was isolated from the pancreases of cattle or pigs in slaughterhouses, an expensive and far from ideal process. There are some small chemical differences between human and cow and pig insulin. About 5 percent of those receiving cow insulin have an allergic reaction to it and therefore need insulin from other animals or human cadavers. In 1982, the human gene for insulin was isolated, and a transgenic form called Humulin was successfully produced using Escherichia coli bacteria grown in a controlled environment by pharmaceutical companies.

Many other protein-based drugs are produced in bacteria using recombinant DNA technology. Among these are human growth hormone, to treat those deficient in the hormone; factor VIII, to promote blood clotting in hemophiliacs; tissue plasminogen activator, to dissolve blood clots in heart attack and stroke victims; renin inhibitor, to lower blood pressure; fertility hormones, to treat infertility; epidermal growth factor, to increase the rate of healing in burn victims; interleukin-2, to treat kidney cancer; and interferons, to treat certain leukemias and hepatitis.

Transgenic Pharming

Sometimes a protein from a higher organism that is expressed in bacteria does not function properly because bacteria cannot perform certain protein modifications. In such cases, the protein can be produced in a higher organism. In transgenic pharming, a gene that codes for a pharmaceutically useful protein is introduced into an animal such as a cow, pig, or sheep. For example, a transcriptional promoter from a sheep gene that is expressed in sheep’s milk is spliced to the gene of interest, such as for alpha-1-antitrypsin, ATT, a glycoprotein (a protein modified with sugar groups) in blood serum that helps the microscopic air sacs of the lungs function properly. People who lack ATT are at risk for developing emphysema. This sheep promoter and ATT gene are injected into the nuclei of fertilized sheep ova that are implanted in surrogate mother sheep. The offspring are examined, and if the procedure is successful, a few of the female lambs will produce the ATT protein in their milk. Once a transgenic animal is created that expresses the ATT gene, transgenic animals expressing the gene can be bred to each other to produce a whole flock of sheep making ATT—an easier way to obtain ATT than isolating it from donated human blood.

Vaccines

Recombinant DNA methods can be used to produce DNA vaccines that are safer than vaccines made from live viruses. Edible vaccines have also been created by introducing into plants genes that will cause a specific immune response. For example, a vaccine for hepatitis has been made in bananas. The idea is that by eating the fruit, individuals will be vaccinated.

Diagnosis

Recombinant DNA methods are used in the diagnosis, as well as treatment, of diseases. Oligonucleotide DNA sequences specific for, and which will only bind to, a particular mutation are used to show if that particular mutation is present. Also, DNA microarrays are important for gene expression profiling, to aid in cancer diagnosis. For example, oligonucleotides representing portions of many different human genes can be fixed to special “chips” in an array. Messenger RNAs from a cancer patient are bound to the array to show which genes are expressed in that cancer. A certain subtype of cancers expresses a certain group of genes. This knowledge can be used to design specific treatment regimens for each subtype of cancer.

Mice and other animals are used as models for human diseases. Through recombinant DNA technology, a specific gene is “knocked out” (inactivated) to study the effect of the loss of that gene. Mice models are particularly useful in the study of diseases such as diabetes, Parkinson disease, and severe combined immunodeficiency disorder (SCID).

Gene Therapy

In gene therapy, a cloned functional copy of a gene is introduced into a person to compensate for the person’s defective copy. Due to ethical concerns, germ-line gene therapy is not being conducted. Many geneticists and bioethicists oppose germ-line therapy because any negative consequences of the therapy would be passed on to future generations. Therefore, germ-line therapy must wait until scientists, policymakers, and legislators are more confident of consistently positive outcomes. In general, there is support for somatic gene therapy, where the somatic tissue of an individual is modified to produce the correct gene product.

Gene therapy has been attempted for a number of diseases, including SCID and hemophilia. Gene therapy trials have been under close scrutiny, however. During clinical trials for gene therapy, one young man died in 1999 and two cases of leukemia in children were detected. These trials used inactivated viruses as vectors, which may have played a role in the death and leukemia cases. Efforts are therefore focusing on the development of DNA delivery systems that do not use viruses.

Future Prospects

In the future, stem cells may be used to generate tissues to replace defective tissues. Catalytic RNAs (ribozymes) may be used to repair genetically defective messenger RNAs. RNA-mediated interference may be used to inactivate partially, rather than knock out, genes to determine the genes’ functions in the cell. With the completion of the DNA sequence of the human genome, more genes will inevitably be identified and their functions determined, leading to many more applications to medical diagnosis and therapy.

Variable number tandem repeat (VNTR) typing is used in DNA fingerprinting. This technology has also been used to study how diseases are transmitted. A 2008 study published in Tuberculosis mapped out the genes of forty-one Mycobacterium tuberculosis pathogens from the Warao people, a native population in a geographically isolated area of Venezuela with a high tuberculosis (TB) incidence. This genetic study demonstrated that 78 percent of the TB strains clustered together, suggesting a very high transmission rate. VNTR typing has been shown to be useful in studying the epidemiology of tuberculosis. More information valuable in the treatment and prevention of disease may be acquired with this type of genetic analysis in the future.

Numerous genetic tests have been developed, including genetic testing for breast cancer. Half of an individual’s genes are inherited from the mother and half from the father. A mutated BRCA1 or BRCA2 gene can be inherited from either the father or mother. Although genetic susceptibility for breast cancer is increased if one inherits a mutated BRCA1 or BRCA2 gene, environmental factors play large roles in determining whether a person develops breast cancer. More mutations in other cancer protection genes need to occur before cancer develops. Causes of these mutations acquired during a lifetime are largely unknown and are important parts of scientific research. Current genetic research involves not only studying the DNA genetic code but also looking at how RNA, another important genetic entity, may be contributing to cancers.

A study in 2009 showed that corneal stem cells can repair cloudy corneas in mice. The outermost portion of the eye, the cornea, protects structures underlying it and provides 70 percent of the eye’s focusing power. A scar can result from deep corneal scratches and may impair vision. Mice treated with corneal stem cells cleared their cloudy corneas. Further study and investigation of this type of stem cell therapy could develop potential stem cell corneal scarring therapies for humans.

Key Terms clone : in recombinant DNA technology, a piece of DNA into which a gene of interest has been inserted to obtain large amounts of that gene gene targeting : the process of introducing a gene that replaces a resident gene in the genome gene therapy : any procedure to alleviate or treat the symptoms of a disease or condition by genetically altering the cells of the patient germ-line gene therapy : a genetic change in gametes or fertilized ova so all cells in the organism will have the change and the change will be passed on to offspring knockout : the inactivation of a specific gene within a cell (or whole organism, as in the case of knockout mice), to determine the effects of loss of function of that gene somatic gene therapy : a genetic change in a specific somatic tissue of an organism, which will not be passed on to offspring stem cell : a an undifferentiated cell that retains the ability to give rise to other, more specialized cells transgenic animal : an animal in which introduced foreign DNA is stably incorporated into the germ line Bibliography

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