GENETIC ENGINEERING AND HUMAN HEALTH

Genetic engineering, recombinant deoxyribonucleic acid (DNA) technology, and biotechnology constitute a set of techniques used to achieve one or more of three goals: to reveal the complex processes of how genes are inherited and expressed, to provide better understanding and effective treatment for various diseases (particularly genetic disorders), and to generate economic benefits, which include improved plants and animals for agriculture and the efficient production of valuable biopharmaceuticals. The characteristics of genetic engineering possess both vast promise and potential threats to humankind. It is an understatement to say that genetic engineering has revolutionized medicine and agriculture in the twenty-first century. As this technology unleashes its power to have an impact on daily life, it has also brought challenges to ethical systems and religious beliefs.

Soon after the publication of the short essay by Francis Crick and James Watson on DNA structure in 1953, research began to uncover the way by which DNA molecules can be cut and spliced back together. With the discovery of the first restriction endonuclease by Hamilton Smith and colleagues in 1970, the real story of genetic engineering began to unfold. The creation of the first engineered DNA molecule through the splicing together of DNA fragments from two unrelated species was made public in 1972. What soon followed was an array of recombinant DNA molecules and genetically modified bacteria, viruses, fungi, plants, and animals. The debate over the issues of “tinkering with God” heated up, and public outcry over genetic engineering was widespread. In 1996, the birth of Dolly, a ewe that was the first mammal cloned from an adult body cell, elevated the debate over the impact of biological research to a new level. Furthermore, a number of genetically modified organisms (GMOs) have been released commercially since 1996. In 2006, it was estimated that more than 75 percent of food products in the United States contained some ingredients from GMOs.

Genetic engineering holds tremendous promise for medicine and human well-being. Medical applications of genetic engineering include the diagnosis of genetic and other diseases, treatment for genetic disorders, regenerative medicine using pluripotent (stem) cells, the production of safer and more effective vaccines and pharmaceuticals, and the prospect of curing genetic disorders through gene therapy. Many human diseases such as cystic fibrosis, Down syndrome, fragile X syndrome, Huntington’s disease, muscular dystrophy, sickle cell anemia, and Tay-Sachs disease are inherited. There are usually no conventional treatments for these disorders because they do not respond to antibiotics or other conventional drugs. Genetic engineering is currently used successfully in the treatment of chronic lymphocytic leukemia (CLL), Parkinson’s disease, and X-linked severe combined immunodeficiency (SCID). Another area in which genetic engineering is commonly used is the commercial production of vaccines and pharmaceuticals through genetic engineering, which has emerged as a rapidly developing field. The potential of embryonic stem cells to become any cell, tissue, or organ under adequate conditions holds enormous promise for regenerative medicine. Particularly large studies have focused on animal models, mostly mice, to serve as human models for genetic modifications. Also, pig to human organ transplantation is a field that is rapidly growing due to the inadequate human organ availability.

Prevention of genetic disorders. Although prevention may be achieved by avoiding any environmental factors that cause an abnormality, the most effective prevention, when possible, is to reduce the frequency of or eliminate entirely the harmful genes (mutations) from the general population. As more precise tools and procedures for manipulating individual genes are optimized, this will eventually become more commonly used. As of 2013, take-home kits for under $100 that assess individual DNA are available to the public, allowing people to gain an understanding of the genetic diseases they may have or carry. However, the prevention of genetic disorders at present is usually achieved by ascertaining those individuals in the population who are at risk for passing a serious genetic disorder to their offspring and then offering them genetic counseling and prenatal screening, followed (in some serious cases) by the option of selective abortion of affected fetuses.

Genetic counseling is the process of communicating information gained through classic genetic studies and contemporary research to those individuals who are themselves at risk or have a high likelihood of passing defects to their offspring. During counseling, information about the disease itself-its severity and prognosis, whether effective therapies exist, and the risk of recurrence-is generally presented. For those couples who find the risks unacceptably high, counseling may also include discussions of contraceptive methods, adoption, prenatal diagnosis, possible abortion, and artificial insemination by a donor. The final decision must still rest with the couple themselves, but the significant increase in the accuracy of risk assessment through genetic technology has made it easier for parents to make well-informed decisions.

For those couples who find the burden of having an affected child unbearable, prenatal diagnosis may solve their dilemma. Prenatal screening could be performed for a variety of genetic disorders. It requires samples, acquired through either amniocentesis or chorionic villus sampling, of fetal cells or chemicals produced by the fetus. After sampling, several analyses can be performed. First, biochemical analysis is used to determine the concentration of chemicals in the sample and therefore to diagnose whether a particular fetus is deficient or low in enzymes that facilitate specific biological reactions. Next, analysis of the chromosomes of the fetal cells can show if all the chromosomes are present and whether there are structural abnormalities in any of them. Finally, the most effective means of detecting the defective genes is through recombinant DNA techniques. This has become possible with the rapid increase of DNA copies through a technique called “polymerase chain reaction” (PCR), which can produce virtually unlimited copies of a specific gene or DNA fragment, starting with as little as a single copy. Routine prenatal diagnosis can be performed to screen a fetus for Down syndrome, Hunting-ton’s disease, sickle cell anemia, and Tay-Sachs disease.

TREATMENT OF DISEASES AND GENETIC DISORDERS

Genetic engineering may be used for direct treatments of diseases or genetic disorders through various means, including the production of possible vaccines for acquired immunodeficiency syndrome (AIDS), the treatment of various cancers, and the synthesis of biopharmaceuticals for a variety of metabolic, growth, and development diseases. In general, biosynthesis is a process in which the gene coding for a particular product is isolated, cloned into another organism (mostly bacteria), and later expressed in that organism (the host). By cultivating the host organism, large quantities of the gene products can be harvested and purified. A few examples can illustrate the useful features of biosynthesis.

Genetic engineering, the manipulation of genetic material, can be used to synthesize large quantities of drugs or hormones, such as insulin.

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Insulin is essential for the treatment of insulin-dependent diabetes mellitus, the most severe form of diabetes. Historically, insulin was obtained from a cow or pig pancreas. Two problems exist for this traditional supply of insulin. First, large quantities of the pancreas are needed to extract enough insulin for continuous treatment of one patient. Second, insulin so obtained is not chemically identical to human insulin; hence some patients may produce antibodies that can seriously interfere with treatment. Human insulin produced through genetic engineering is quite effective yet without any side effects. It has been produced commercially and made available to patients since 1982.

Another successful story in biosynthesis is the production of human growth hormone (HGH), which is used in the treatment of children with growth retardation called “pituitary dwarfism.” The successful biosynthesis of HGH is important for several reasons. The conventional source of HGH was human pituitary glands removed at autopsy. Each child afflicted with pituitary dwarfism needs twice-a-week injections until the age of twenty. Such a treatment regime requires more than a thousand pituitary glands. The autopsy supply could hardly keep up with the demand. Furthermore, as a result of a small amount of virus contamination in the extracted HGH, many children receiving this treatment developed virus-related diseases.

Another gene therapy treatment that has recently been approved in Europe is alipogene tiparvovec, used for people with a lipoprotein lipase deficiency (LPLD). LPLD is a condition that results in high fat concentration in the bloodstream and increase the risk of pancreatitis. Alipogene tiparvovec has been shown to greatly reduce the incidence of pancreatitis and decrease fat concentrations in the blood in a few weeks. Other biopharmaceuticals under development or in preclinical or clinical trials through genetic engineering include anticancer drugs, antiaging agents and possible vaccines for AIDS and malaria.

Genetic engineering can include the concept of modifying or using portions of the genetic system, like messenger ribonucleic acid (mRNA), to obtain a desired therapeutic result. mRNA gene therapies use a component of the genetic system, mRNA, to cause cellular production of specific proteins impacting illness and disease, including (severe acute respiratory syndrome) SARS-CoV-2 viral infections. Messenger RNA vaccines induce cells to produce protein molecules prompting an immune response. These vaccines are currently widely used as a vaccine against Covid infections. This same technology has potential for treating or preventing influenza, autoimmune diseases, and cancer. mRNA therapies are currently researched or in clinical trials for infectious diseases including herpes simplex 2, malaria, rabies, influenza, human immunodeficiency virus (HIV), and hepatitis C. Some allergies, cancers, and autoimmune diseases are in research for mRNA induced production of therapeutic proteins.

Researchers at Tel Aviv University have genetically engineered human spinal cord tissue and implanted the engineered tissue in a laboratory setting involving muscle tissue with chronic paralysis. Walking ability was reportedly restored at an 80 percent success rate. Clinical trials in human patients are anticipated. Genetically engineered fat cells were reprogrammed to resemble embryonic stem cells. The stem cells were then processed in a manner mimicking the embryonic spinal cord development of the spinal cord. These cells became implants of neuronal networks containing motor neurons. Broadly speaking, three types of gene therapy exist: germ line therapy, enhancement gene therapy, and somatic gene therapy. All gene therapy trials currently underway or in the pipeline are restricted to the somatic cells as targets for gene transfer. Germ line therapy involves the introduction of novel genes into germ cells, such as eggs or in early embryos. Although it has the potential for correcting defective genes completely, germ line therapy is highly controversial. Enhancement gene therapy, through which human potential might be enhanced for some desired traits, raises an even greater ethical dilemma. Both germ line and enhancement gene therapies have been banned based on the unresolved ethical issues surrounding them.

Somatic gene therapy is designed to introduce functional genes into body cells, thus enabling the body to perform normal functions and providing temporary correction for genetic abnormalities. The cloned human gene is first transferred into a viral vector, which is used to infect white blood cells removed from the patient. The transferred normal gene is then inserted into a chromosome and becomes active. After growth to enhance their numbers under sterile conditions, the cells are reimplanted into the patient, where they produce a gene product that is missing in the untreated patient, allowing the individual to function normally. Several disorders are currently being treated with this technique, including SCID. Individuals with SCID have no functional immune system and usually die from infections that would be minor in normal people. While several young boys with SCID remarkably showed almost complete recovery following gene therapy, a high percentage of them have subsequently developed leukemia following the introduction of genetically engineered bone marrow stem cells. Gene therapy is also being used or tested as a treatment for cystic fibrosis, skin cancer, breast cancer, brain cancer, and AIDS.

Most of these treatments are only partially successful, and they are prohibitively expensive. Over a ten-year period, from 1990 to 2000, more than four thousand people were treated through gene therapy. Unfortunately, most of these trials were failures that led to some loss of confidence in gene therapy. These failures have been attributed to inefficient vectors and the inability in many cases to specifically target the required host tissues. In the future, as more efficient vectors are engineered, gene therapy is expected to be a common method for treating many genetic disorders.

GENETIC ENGINEERING IN AGRICULTURE, FORENSICS, AND ENVIRONMENTAL SCIENCE

As the use of genetic engineering expands rapidly, it is difficult to generate an exhaustive list of all possible applications, but three other areas are worth noting: forensic, environmental, and agricultural applications. Although these areas are not directly related to medicine, they certainly have profound impacts on human well-being. There are numerous ways that genetic engineering may be used to benefit agriculture and food production. First, the production of vaccines and the application of methods for transferring genes are likely to benefit animal husbandry, as scientists can alter commercially important traits such as milk yield, butterfat, and proportion of lean meat. For example, the bovine growth hormone produced through genetic engineering has been used since the late 1980s to boost milk production by cows. A mutant form of the myostatin gene has been identified and found to cause heavy muscling after this gene was introduced first into a mouse and later into the Belgian Blue bull. This technique marks the first step toward breeding cows and meat animals with lower fat and a higher proportion of lean meat. Other examples of using genetic engineering in animal husbandry include hormones for a faster growth rate in poultry and the production of recombinant human proteins in the milk of livestock.

Second, genetic engineering is expected to alter dramatically the conventional approaches of developing new strains of crops through breeding. The technology allows the transferring of genes for nitrogen fixation; the improvement of photosynthesis (and therefore yield); the promotion of resistance to pests, pathogens, and herbicides and tolerance to frost, drought, and increased salinity; and the improvement of nutritional value and consumer acceptability. Genetically engineered tobacco plants have been grown to produce the protein phaseolin, which is naturally synthesized by soybeans and other legume crops. The first genetically engineered potato was approved for human consumption by the US government in 1995 and by Canada in 1996. This NewLeaf potato, developed by corporate giant Monsanto, carries a gene from the bacterium Bacillus thuringiensis. This gene produces a protein toxic to the Colorado potato beetle, an insect that causes substantial loss of the crop if left uncontrolled. The production of this protein by potato plants equips them with resistance to beetles, hence alleviating crop loss, saving on the cost on pesticides, and reducing the risk of environment contamination.

Antiviral genes have been successfully transferred and expressed into cotton, and the release of new cotton strains with resistance to multiple viruses is a matter of time. At least five transgenic corn strains with resistance to herbicides or pathogens had been developed and commercially produced by US farmers by 2002. Some genes coding tolerance to drought and to subfreezing temperatures have been cloned and transferred into or among crop plants, some of which have already made a great impact on agriculture in developing countries. Initial effort has been made to replace chemical fertilizers with more environment-friendly biofertilizers. Secondary metabolites produced naturally by plants have also been purified and used as biopesticides. Genetically enhanced vitamin enriched food is on the rise as well. A prime example is “golden rice,” rice that has been engineered to have a higher content of vitamin A. Currently, many grain, produce, milk, and meat produced by animals or plants have been genetically engineered in some manner.

Genetic engineering is also useful in forensics. DNA fingerprints from samples collected at crime scenes provide strong evidence in trials, thus helping to solve many violent crimes. DNA can be isolated easily from tissue left at a crime scene, a splattering of blood, a hair sample, or even skin left under a victim’s fingernails. A variety of techniques can be used routinely to determine the probability of matching between sample DNA and that of a suspect. DNA fingerprints are also useful in paternity and property disputes and in the study of the genealogy of various species.

The metabolism of micro-organisms can be altered through genetic engineering, which enables them to absorb and degrade waste and hazardous material from the environment. The growth rate and metabolic capabilities of micro-organisms offer great potential for coping with some environmental problems. Sewage plants can use engineered bacteria to degrade many organic compounds into nontoxic substances. Microbes may be engineered to detoxify specific substances in waste dumps or oil spills. Many bacteria can extract heavy metals (such as lead and copper) from their surroundings and incorporate them into compounds that are recoverable, thus cleaning them from the environment. Many more such applications have yet to be tested or discovered.

PERSPECTIVE AND PROSPECTS

Since the discovery of the double-helical structure of DNA by Francis Crick and James Watson in 1953, human curiosity regarding this amazing molecule has propelled the advancement of biological sciences in an unprecedented fashion. The first successful experiment in genetic engineering was described in 1972 when DNA fragments from two different organisms were joined together to produce a biologically functional hybrid DNA molecule. The next milestone came in 1975, when Edward Southern introduced Southern blotting, a technique that has many applications and has proved invaluable for the subsequent development of genetic engineering. This technique is used to identify a particular gene or DNA fragment from a mixture of thousands of different genes or DNA fragments. Later, the automated DNA sequencers, which can rapidly churn out letter sequences from DNA fragments, and the discovery of reverse transcriptase and PCR further improved the capabilities of scientists in studying and manipulating DNA molecules and the genes that they carry.

Using these techniques, the first prenatal diagnosis of a genetic disease was made in 1976 for alpha-thalassemia, a genetic disorder caused by the absence of globin genes. This represented a monumental step forward in the use of genetic tools in the medical field. It paved the way for the later development in which mutations in many genes could be detected in early pregnancy. Three years later, insulin was first synthesized through genetic engineering. In 1982, the commercial production of genetically engineered human insulin became a reality.

Gene therapy trials began in 1990, first with SCID. The first complete human genetic map was published in 1993, and various new techniques in DNA fingerprinting and the isolation of specific genes were developed. Also, an increasing number of pharmaceuticals have been produced through genetic engineering. Two versions of the draft copy of the human genome were published in 2001, launching the genomic revolution, and by 2006 complete DNA sequences of the genomes of over two hundred model research organisms, from bacteria to mice, were publicly available for researchers. In the twenty-first century, genetic engineering will continue to offer more benefits in medicine and in agriculture in undreamed of ways.

In retrospect, genetic engineering presents a mixed blessing of invaluable benefits and dilemmas that science and technology have always offered humankind. There are those who would like to restrict the uses of genetic engineering and who might prefer that such technology had never been developed. Others believe that the benefits far outweigh the possible risks and that any potential threat can be overcome easily through government regulation or legislation. Others do not take sides on the debate in general but are greatly concerned with some specific applications.

Obviously, the power of genetic engineering demands a new set of decisions, both ethical and economical, by individuals, government, and society. Considerable concern has been expressed by both scientists and the general public regarding possible biohazards from genetic engineering. What if engineered organisms prove resistant to all known antibiotics or carry cancer genes that might spread throughout the community? What if a genetically engineered plant becomes an uncontrollable super weed? Would these kinds of risks outweigh the potential benefits? Others argue that the risk has been exaggerated and therefore do not want to impose limits on research. Genetic engineering has also generated legal issues concerning intellectual properties and patents for different aspects of the technology.

Even more controversial are the many ethical issues. Perhaps the most obvious ethical issue surrounding genetic engineering is the objection to some applications that are considered socially undesirable and morally wrong. One example is bovine growth hormone. Some vigorously opposed its use in boosting milk production for two main reasons. First, the recombinant hormone could change the composition of the milk. However, this view was dismissed by experts from the National Institutes of Health (NIH) and the Food and Drug Administration (FDA) after a thorough study. Second, many dairy farmers feared that greater milk production per cow would drive prices down even farther and put some small farmers out of business.

Numerous aspects of the application of genetic engineering to humans also present ethical challenges. In some couples, both people carry a defective gene and have an appreciable chance of having an affected child. Should they refrain entirely from having children of their own? For genetic disorders caused by chromosomal abnormalities, such as Tay-Sachs disease, prenatal diagnosis can detect the defect in a fetus with great precision. Should the fetus be aborted if the screening result is positive? Should screening tests of infants for genetic disorders be required? If so, would such a requirement infringe the rights of the individual by the government? Perhaps the greatest concern of all is the possibility of designing or cloning a human being through genetic engineering. The debate over the ethical, legal, and social implications of genetic engineering should help in the formulation and optimization of public policy and laws regarding this technology, and genetic engineering research and its applications should proceed with caution.

See also: Bacteriology; Bionics and biotechnology; Cancer; Cells; Chemotherapy; Cloning; Cytology; Diabetes mellitus; DNA and RNA; Enzyme therapy; Enzymes; Ethics; Fetal tissue transplantation; Gene therapy; Genetic counseling; Genetics and inheritance; Genomics; Hormones; Immunization and vaccination; Mutation; Pharmacology; Screening; Stem cells.