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Modern Genetic Analysis Chapter 1. Genetics and the Organism
Genetics and Human Affairs

Genetics seems to hold a special place in human affairs. Not only is it relevant in the same sense that other scientific disciplines are, but it also has much to tell us about the nature of our humanity, and in this sense it is unique among the biological sciences.

Modern Society Depends on Genetics

Take a look at the clothes you are wearing. The cotton of your shirt and jeans came from cotton plants that differ from their wild ancestors in having been through intensive breeding programs involving the methodical application of standard genetic principles. The same could be said for the sheep that produced the wool for your sweater and coat. Think also about your most recent meal. You can be sure that the rice, the wheat, the chicken, the beef, the pork, and all the other major organisms that feed the humans on this planet have been specially bred and selected through the application of standard genetic procedures by plant and animal breeders (Figure 1-3). The so-called Green Revolution, which dramatically increased crop productivity on a global scale, is a genetic success story about the breeding of highly productive strains of certain major crop species (Figure 1-4).

To maximize crop production, a farmer may plant a vast area with seeds of a single genetic constitution, a practice called monoculture. Because pathogenic and predatory organisms attack plant crops, special resistance genes are bred into crop lines to protect them. In some cases resistance genes are effective for decades, but in others pathogens overcome the resistance genes in a few years. Random genetic changes occur constantly in populations of pathogens (disease-causing organisms), and such changes sometimes confer new pathogenic ability. This leaves the entire monoculture at risk. For this reason, plant geneticists always have to be one step ahead of the pathogens to prevent widespread epidemics of plant disease or destruction that might have devastating effects on the food supply (Table 1-1 and Figure 1-5).

Fungi and bacteria have also been specially bred for human needs. Yeast is an obvious example; it forms the basis of multibillion-dollar industries producing baked goods, alcoholic beverages, and fuel alcohol. Fungi provide the antibiotic penicillin; the immunosuppressant drug cyclosporin, which prevents rejection of organ transplants; and a whole range of important industrial compounds such as citric acid and amylase. Bacteria provide medical science with such antibiotic chemicals as streptomycin. Most of the industries using fungi and bacteria have benefited from the application of the genetic principles of breeding, but now we are in a new age in which DNA can be manipulated directly to synthesize entirely novel strains of microbes in a test tube, tailored exclusively to human needs. This technology is called molecular genetic engineering. For example, we now have bacterial strains producing mammalian substances such as insulin for diabetes treatment and growth hormone for treatment of pituitary dwarfism. The insulin made by such strains is the genuine human type, in contrast to earlier products, which were extracts of cattle or pig insulin. Some of the substances produced by these "designer" microbial strains are extremely difficult to obtain from other sources. For example, some children need treatment with growth hormone to grow at normal rates: one year's treatment of human growth hormone for one child previously had to be extracted from the pituitary glands of approximately 75 human cadavers. Likewise, special derivatives of fungal and bacterial strains are being genetically engineered to produce larger amounts of their natural beneficial products. Molecular genetic engineering was first applied to microbes, but now the same techniques are being applied to plants and animals, resulting in engineered types that could never have been produced by selective breeding.

In molecular genetic engineering the genetic makeup is changed by exposing cells to fragments of "foreign" DNA carrying genes coding for desirable proteins, often from another species. Such DNA is taken up by the cells and then inserts itself into one or more of the recipient's chromosomes; it is then inherited like any other gene. Cells modified in this way are called transgenic. From a transgenic cell a multicellular transgenic organism can be produced, all of whose cells contain the additional foreign DNA. Using this technique, a wide range of commercially profitable designer organisms can be generated. The application of genetic engineering to commerce is broadly called biotechnology. It is estimated that the biotechnology industry, with genetics as its basis, will become one of the most profitable industries of the coming decades. Whether this is true or not, biotechnology joins the other elements of the genetic cornucopia in supporting mankind at its present high population size and living standard.

Another important area of human affairs that is using genetics is forensic science. All members of the human species carry more or less the same set of DNA. But minor variation in the DNA contributes to human variation. If a large DNA sample from an individual is available for analysis, special techniques permit scanning large numbers of DNA segments to generate a DNA "fingerprint." Except in the case of identical twins, such fingerprints are specific to individuals. DNA fingerprints are widely used in police investigations. Even plant DNA fingerprints can be useful. In one reported case, the DNA from two tiny seeds obtained from the back of a suspect's truck clearly established that the truck had been parked under one specific tree, near which a murder victim's body had been found. Often only very small DNA samples are available from samples of blood, semen, or even hair follicles, so segments of the fingerprint have to be studied one at a time. Many individuals in the population share specific small segment types, so this type of evidence must be interpreted more cautiously. These partial fingerprints can eliminate or narrow down the number of possible suspects in a criminal case but do not identify a specific individual.

Genetics Is a Crucial Component of Medicine

A large portion of human ill health has a genetic basis. For example, it has been estimated that at least 30 percent of pediatric hospital admissions have a direct genetic component. However, current research is revealing more and more genetic predispositions to serious conditions, as well as to milder ailments, so this figure is almost certainly an underestimate.

Genetic ill health has many facets. Many inherited genetic diseases (such as cystic fibrosis, phenylketonuria, and muscular dystrophy) are caused by abnormal forms, mutations, of single genes inherited through the gametes (sperm and egg). The positions of the single genes that cause some of the better-known hereditary disorders are shown on the human chromosome maps in Figure 1-6 on the next page. Many of the genes shown have been isolated and analyzed at the molecular level. Some recent isolations are the genes responsible for inherited types of Alzheimer's disease and breast cancer. Abnormal forms of gene S182 located on chromosome 14 are responsible for 80 percent of early-onset familial Alzheimer's disease, accounting for 10 percent of all cases of this disease. Gene S182 normally codes for a membrane protein. Familial (inherited) breast cancer accounts for 5 percent of all breast cancers in our population. Abnormal forms of genes BRCA1 and BRCA2 together account for two-thirds of the cases of familial breast cancer. BRCA1 is also associated with predisposition to ovarian cancer. BRCA1 codes for a protein that likely functions to regulate the activity of other genes. In both these cases, understanding how genes cause the rarer familial forms of the disease will also undoubtedly lead to an understanding of and effective therapy for the more common "sporadic" forms of the diseases.

The determination of some human disorders is complex because the conditions are caused by the interaction of several genes, all of which also interact with the environment. Examples of disorders showing such complex inheritance are heart disease and diabetes. Molecular genetic technology has opened up new avenues for finding and isolating these multiply interacting genes.

Gene isolations in experimental animals can also provide insights that have potential impact on human health. For example, single genes have been isolated that have a major effect on obesity in mice. One gene ob codes for a signaling protein that is part of the system for telling the mouse that it has eaten enough food. Another gene CPE causes the mouse to slowly become obese and develop susceptibility to diabetes.

The more common "sporadic" type of cancer is caused by the sudden appearance of a mutant form of a gene in a somatic cell, a body cell that does not produce egg or sperm. Because such cancers are in somatic tissue, by definition they are not passed on to the next generation. However, as we saw earlier, predisposition to certain cancers is inherited. It is little appreciated that cancer, which touches all our lives in some way, is a genetic disease.

Another type of genetic illness is caused by chromosomal anomalies, abnormalities of chromosomal structure or number. A familiar example is Down syndrome, caused by possession of an extra copy of one specific chromosome. Most cases of Down syndrome arise de novo in each generation from cellular "accidents" in the gonads of parents with otherwise normal chromosome sets. Such accidents result in an abnormal sperm or egg, and these in turn lead to a child with Down syndrome.

Genetics has shown that genes are at the root of a large number of diseases, but genetics can also provide relief from suffering in many cases. Already molecular genetic probes are being used to detect defective genes in prospective parents. Furthermore, the defective genes themselves are being isolated and characterized by molecular genetic techniques. For example, the DNA of the gene that causes cystic fibrosis has been isolated and analyzed. By discovering the nucleotide sequence of a disease-causing gene, it is possible to deduce the structure and function of the protein it encodes and hence understand the physiological defect caused by the mutation. Once the disease is understood, better therapeutic treatments can be designed. Ultimately, there is the hope that direct gene therapy will relieve many genetic diseases. In gene therapy a copy of a normal gene is inserted transgenically into cells carrying the defective counterpart. The first reported cases of attempted human gene therapy were two children suffering from severe combined immunodeficiency disease (a hereditary illness of the white blood cells). Cells of the patients were removed, a correctly functioning gene was inserted into them, and the cells were then reinserted back into the children to become part of the blood cell population in their bodies. Since this first case, several more attempts at gene therapy have been reported, and undoubtedly many more will follow in the years ahead. However, gene therapy is still in its infancy. The action of a single gene depends on many factors, all of which have to be in the correct alignment to result in relief of symptoms.

Geneticists are also at work studying the human immunodeficiency virus (HIV) that causes acquired immune deficiency syndrome (AIDS). As a natural part of their reproduction, viruses in the group containing HIV insert copies of their genetic material into the chromosomes of the individuals they infect. Therefore, in a sense AIDS, too, is a genetic disease, and an understanding of how such viral genes integrate and function is an important step in overcoming the disease.

There is currently under way a massive research project that is sequencing all 3 billion nucleotides in the human genome, and medicine will be a primary beneficiary. This human genome project is an international collaborative effort by many laboratories, each working on specific chromosomal regions. Already high-resolution physical maps have been obtained for the DNA of several complete chromosomes (including the Y chromosome and chromosome 21). Such maps are a necessary prelude to completely sequencing chromosomes. Although the potential benefits for medicine are immense; perhaps most exciting is the opportunity finally to study the blueprints for building what is arguably the most complex structure in the known universe, Homo sapiens (Figure 1-7).

Genetics Affects One's World View

We each acquire our individual view of the universe and of our own position in that universe gradually, from the beginning of our consciousness. This viewpoint represents our identity as individuals. It drives our attitudes and our actions, and as such determines the kind of people we are and, ultimately, the kind of society we live in. Any new knowledge has to be accommodated into this world view, or the world view has to be changed to make it fit. Genetics has provided some powerful new concepts that have radically changed humanity's view of itself and its relation to the rest of the universe.

Probably the best example of how genetics changes personal world view comes from genetic, chromosomal, DNA, and protein studies that show we are related not only to apes and other mammals, but also, more surprisingly, to all the other living things on the planet, including plants, fungi, and bacteria. Living things share a common system for storing and expressing genetic information and show homology (similarity based on evolutionary relatedness) in many structures, even down to the genes themselves. That there is a continuous spectrum of relatedness within the living world is a powerful intellectual notion that unifies us with other living organisms. This notion radically affects one's world view. It suggests a view of humanity not as the pinnacle or the center of creation, but as one form equal to other life-forms. Admittedly, this brings us into the domain of philosophy and religion, but that is the point: genetics forces us to consider issues that question how we see ourselves.

Some of the world's biggest and most pressing social issues have an indirect genetic component. For example, some major problems of prejudice and social suffering center on behavioral differences between races and between the sexes. Is IQ correlated with race? Do men and women have different genetic predispositions to aggressive behavior? Genetics provides a way of analyzing and thinking about these complex and unresolved issues.

One of the biggest global concerns of biologists is the alarming rate at which we are destroying natural habitats, especially in the tropics, which hold vast reservoirs of plant and animal life. Here again the problem has a crucial genetic component because the issue is one of conserving genetic diversity; it is necessary to know the minimum levels of diversity required by healthy populations and what population sizes can maintain these levels. Hence a deep understanding of the impact of destroying natural habitats requires an understanding of genetics.

Another genetic issue with potential global impact is the genetic health of our populations. Many geneticists are concerned because our human genomes are under assault by an ever-increasing array of environmental agents, especially radiation and chemicals, that are capable of causing random mutations in genes. The vast majority of such mutations would inevitably be deleterious. In the short run they might not significantly increase the frequency of inherited disease, but over the long run, as the mutations accumulate, they would combine and interact to produce disease, an effect that has been called a "genetic time bomb."

Of course, genetic technology, like any other technological advance, brings with it its own share of ethical dilemmas. The Green Revolution, for example, is a success in terms of productivity, but the high levels of fertilizer and pesticide application required for the new plant varieties has raised concerns about water pollution and the ability of farmers in poor countries to buy the expensive fertilizers. The ability to experimentally create genetically identical sheep (to "clone" sheepsee Genetics in Process 1-1) has sparked a heated debate about the ethics of applying the same technique to humans. Indeed the synthesis of new transgenic life-forms by genetic engineering has led to a rash of concerns about the morality and legality of such designer plants and animals. Access to information about individuals' genetic makeup is also a problem in such areas as health insurance and forensics. Already there are credible published claims about specific genes that predispose people to such behavioral patterns as aggressiveness and homosexuality. What would be the impact of knowledge about these genes on the rights of the individuals who carry them? It would be too glib to say that these are not the problems of scientists but of society; scientists must share the responsibility for the societal impact of their discoveries, and the possible outcomes of new information should be thought through as thoroughly as possible before results are released into the public domain.

The examples cited here show that many of the issues that confront us daily as individuals and as societies intimately involve genetics. Only by understanding the genetic component of these issues can we as global citizens hope to make wise decisions for the future of an ever more crowded and complex world.

© 1999 by W. H. Freeman and Company. All rights reserved.