Genetics, History of
Genetics, History of
Genetics is the study of the biological process of heredity. Although human beings have been interested in heredity—of both themselves and domesticated animals and plants—for thousands of years, genetics as a science was only formally born at the beginning of the twentieth century. At this time, the breeding experiments of Gregor Mendel, an Augustinian monk in Brünn, Austria, originally published in 1866, were rediscovered. The term genetics was introduced in 1906 by the British biologist William Bateson and was meant to distinguish Mendel’s experimental approach from older, speculative theories.
The history of genetics from 1900 onward can be divided conveniently into two periods. During the first, or “classical,” period (1900–1950), the focus was on the extension and modification of Mendel’s original hypotheses to a wide variety of animals and plants (including humans), and to establishing the physical basis for heredity in cell structures known as chromosomes. The second period, that of “molecular” genetics (1950–present), has been dominated by the search for the molecular and biochemical basis of gene structure and function. This period began with experiments showing that the molecule that carried information from parent to offspring is deoxyribonucleic acid (DNA). The working out of DNA’s detailed molecular structure as a double helix was accomplished by James D. Watson and Francis Crick in 1953.
A major assumption throughout both periods has been that the hereditary process is basically the same in all organisms, and genetics thus served as a major unifying principle for biology in the twentieth century. By the end of the century, with completion of the Human Genome Project (which sequenced the DNA of all the functional regions of the human chromosomes, and that of five other species for comparison) and the rise of the computer-based field of genomics (which studies DNA sequences among different individuals and groups of organisms) genetics came to dominate biology both conceptually and commercially. In both periods, genetics has also been used in attempts to elucidate human “races” and the biological basis of racial differences.
Mendel’s hybridization experiments between 1856 and 1865 with the common garden pea, Pisa sativum, laid the groundwork for the development of classical genetics. Mendel had crossed pea plants that differed by one or two observable traits, such as height (either tall or dwarf), or pod color (yellow or green), which led him to put forward several hypotheses, particularly those of dominance and recessiveness. Mendel noted that when he crossed a pure-bred tall plant with a pure-bred short (dwarf) plant, all the offspring of the first generation (called the F1) were tall; thus he proposed that tallness was “dominant” over shortness, and, conversely, that shortness was “recessive” to tallness. However, when he crossed members of the F 1 generation he found that the offspring showed a ratio of roughly three tall plants to one short, and that the one short plant was on average as short as the original short parent.
To explain these results, Mendel hypothesized that each parent contained two “factors” (the term gene was introduced in 1909 by the Danish plant breeder Wilhelm Johannsen) for any trait (in this case height), and that these factors segregated in the formation of the egg or pollen cells (the gametes, or egg and sperm in animals). Using capital letters for dominant traits, and small-case letters for recessives, Mendel represented his original, pure-bred parental plants as T (in the early twenty-first century TT is used, representing a pure or homozygous tall) and t (currently tt is used, representing a pure or homozygous dwarf). During segregation, the two TTs would be separated from each other and would end up in a separate egg or pollen cell; the same would be true of the two tts. The offspring of the F1 would thus all be Tt and would appear tall. When these were crossed with each other, the second generation (F2) could have one of three possible gene combinations: TT, Tt, and tt. Since T was dominant over t, both TT and Tt types would appear tall, and only tt would appear short. This would explain the 3:1 ratio in the F2 (one TT, two Tts, and one tt). Furthermore, when he went on to observe two traits at a time, such as height and pod color, he got all possible combinations—tall-yellow, tall, green, short yellow and short green, and in predictable ratios (9:3:3:1, respectively). These observations suggested to Mendel that various traits in an organism were inherited independently of each other (what became known as the principle of independent assortment).
Mendel’s work also showed that there was a clear-cut theoretical basis for the distinction between what came to be known as an organism’s phenotype (its appearance, as in tall or short) and its genotype (what genes it can pass on to its offspring, as in T or t). Thus Mendel’s F2 tall plants all had the same phenotype, but they did not all have the same genotype. Mendel’s experimental and mathematical approach provided the basis for a new research program that included the search for the physical and chemical nature of the gene itself.
Finding a generally applicable theory of heredity was of great importance in the late nineteenth and early twentieth centuries. For centuries, agricultural breeders had been trying to develop some understanding of how to improve their stocks in an efficient and systematic way. Mendel provided some hope that the process could be made more scientific, and thus more predictable. In addition, one of the major problems Darwin had left unsolved in The Origin of Species and other evolutionary writings was the nature of heredity: Were the variations on which natural selection acted large and discontinuous, or small and continuous? Which variations were inherited and which were not? How could the reappearance of traits that had skipped one or more generations be explained? And finally, because Mendel’s work appeared to apply to humans as well as other organisms (by 1910 a number of human traits, such as eye color, color blindness, hemophilia, the ABO blood groups, and Huntington’s disease had been shown to follow basic Mendelian rules), it was hoped that knowledge of the inheritance patterns, especially of pathological traits, would provide an important way to control human reproduction and eliminate inherited diseases.
The Chromosome Theory of Heredity. The hypothetical nature of Mendel’s “factors” were a major stumbling block in the general acceptance of Mendelian theory. It was Thomas Hunt Morgan and his group, working with fruit flies (Drosophila melanogaster) at Columbia University from 1910 onward, that established the physical basis for Mendelian genetics. Using a combination of breeding experiments and cytological study (microscopical examination of the chromosomes found in the cell nucleus), Morgan and his group were able to establish that genes were discrete units arranged linearly on the chromosomes. Starting from the observation that some traits do not appear to segregate randomly, but are rather inherited together (they are said to be “linked”), Morgan and his group established that in Drosophilia there were four linkage groups, corresponding to the four sets of paired chromosomes characteristic for the species. Moreover, Morgan and his group devised a method, using the process of breakage and recombination that occasionally occurs between members of a chromosome pair, to map the position of genes on the chromosomes. It was the combination of Mendelian breeding experiments with cytological observations that led to what became known as the Mendelian chromosome theory of heredity (MCTH). For this work, Morgan received the Nobel Prize for Physiology or Medicine in 1933, the first such award to be given in genetics.
Almost as soon as biologists and breeders adopted the MCTH they began to encounter exceptions to Mendel’s original formulation. One was linkage, but it was accounted for by the chromosome theory. Another was incomplete dominance, in which the offspring showed a form of the trait intermediate between that of the two parents (as in pink flowers from a cross between white-and red-flowered parents). Another was epistasis, in which genes interact with each other to produce an effect that neither produced on its own. The converse of epistasis was pleiotropy, in which it came to be recognized that every gene has multiple effects, meaning each one influences more than one trait. Still another exception was what became known as quantitative inheritance, in which genes for a trait could exist in different doses, so that a continuous series of phenotypes (from light red to dark red, for example) could be generated simply by breeding for different dosages of a pigment gene. Last of all, it was observed that changes in environmental conditions during development of the organism could alter the expression of genes. Drosophila larvae of one genotype, when raised at a slightly higher-than-normal temperature, produced adult flies that looked like another genotype (these were called phenocopies). Ironically, most geneticists were so focused on the gene itself that they failed to understand the importance of phenocopies for investigating how genes might function during embryonic development. The few who tried to emphasize the plasticity of the gene, such as Richard Goldschmidt of Germany, were strongly attacked.
During the classical period, genetics was used as scientific backing for the eugenics movement in many countries of North and South America, Europe, and Asia. The term eugenics was coined in 1883 by Darwin’s cousin, the geographer and statistician Francis Galton, to refer to the right to be “purely, or truly born” (in a biological sense). In Inquiries into Human Faculty and Its Development, Galton wrote that “Eugenics takes cognisance of all the influences that tend in however remote a degree to give the more suitable races or strains of blood a better chance of prevailing over the less suitable than they otherwise would have had” (pp. 24–25). Galton, along with eugenicists in the United States and Europe, thought that a large number of social and mental traits (e.g., alcoholism, feeblemindedness, schizophrenia, criminality, “nomadism,” pauperism, even a sense of fair play), were all determined by a few Mendelian genes. Especially in the United States (and later in Germany and Scandinavia), eugenicists wanted to apply genetic theories to the guidance of social policy. Prevention of the “unfit” from reproducing was one of the major goals of the eugenics movement. Eugenicists were convinced that “defectives” had a much higher birth rate than normal or “high-grade” people, and that if various methods to reduce this rate were not undertaken, high quality human lines would be “swamped” by those of low quality, causing the population as a whole to degenerate. By appealing to these fears, eugenicists were able to influence more than thirty states to pass compulsory sterilization laws that could be applied to institutionalized individuals, such as those in prisons or state mental hospitals. The U.S. sterilization laws formed the basis for similar laws passed in the late 1920s in the Scandinavian countries, Canada, and, after the Nazis came to power, in Germany in 1933. Sweden and the United States, for example, each forcibly sterilized more than 65,000 people, while Germany, under the Nazis, sterilized 400,000.
Eugenicists were also concerned about what they considered to be the deleterious effects of race-crossing (which at the time also meant crossing between ethnic groups). It was thought that, in such mixtures, whatever good qualities existed in either group would tend to get lost. One writer, the mammalian geneticist William E. Castle at Harvard argued that crosses between a Negro and a white person could produce individuals that were out of proportion. Another, Madison Grant, a wealthy New York lawyer and self-styled anthropologist, wrote in The Passing of the Great Race that race-crossing always produces offspring that revert to the lower type: “Whether we like to admit it or not, the result of the mixture of the two races, in the long run, gives us a race reverting to the more ancient, generalized and lower type… . The cross between a white man and a negro is a negro, and a cross between any of the three European races and a Jew is a Jew” (pp. 15–16). Thus, eugenicists supported strengthening existing antimiscegenation laws.
A further area of social concern for eugenicists was immigration, particularly in the United States, where the influx from eastern and southern Europe, the Balkans, and Russia had exploded in the 1880s. Claiming that these non-Aryan groups were genetically inferior to northern and western Europeans, eugenicists lobbied successfully for immigration restriction. The Reed-Johnson Act (Immigration Restriction Act), passed in 1924, limited immigration from the regions eugenicists claimed harbored inferior genes.
Biochemical genetics deals with the way in which genes act to influence biochemical processes leading to one or another form of a trait, without trying to determine the chemical structure of the gene itself. Molecular genetics, explicitly aims at elucidating the three-dimensional structure of the gene and showing how that structure relates to its function. During much of the classical phase of genetics, it was not even clear what the molecular components of the gene were. The two most likely candidates were proteins and nucleic acids, because chemical analysis of chromosomes had shown they contained both substances.
Proteins versus Nucleic Acid as the Molecule of Heredity. Several lines of evidence initially suggested that proteins might be the genetic material. Proteins are composed of subunits known as amino acids, of which there are some twenty known types. These can be strung together in any sequence, giving an infinite number of different possible protein “words.” Nucleic acids, on the other hand, are made up of only four kinds of subunits (known as nucleotides), and so they appeared to have less potential for carrying the large amount of genetic information thought to be required to “code” for all the traits in an organism. It was the work of Oswald T. Avery, Maclyn McCarty and Colin MacLeod in 1944, and of A.D. Hershey and Martha Chase in 1952, that showed decisively that nucleic acid, most notably the form known as deoxyribonucleic acid (DNA) was the “stuff” of which genes were made.
In a separate line of work, the newly introduced technology of X-ray crystallography was applied to determining the three-dimensional structure of molecules such as proteins and nucleic acids. Much of this work was carried out in England by John Desmond Bernal, Max Perutz, John Kendrew, Maurice Wilkins, and Rosalind Franklin. When a beam of electrons is passed through a crystal made up of a pure sample of a given molecule, the scattered rays can be recorded on a photographic plate; the position and intensity of the dots provides the means for inferring molecular structure. Perutz and Kendrew had already used X-ray crystallography to devise models of the oxygen-carrying molecules myoglobin and hemoglobin, while Wilkins and Franklin were using it in the early 1950s to study DNA. In 1951 a young postdoctoral student, James D. Watson, from the United States, came to work in the Cambridge Laboratory where another young investigator, Francis Crick, a former physicist, was also working. They teamed up to work out a model for the structure of DNA that would account for its ability to replicate itself and to direct the development of adult phenotypes.
X-ray data suggested the DNA molecule was helical in shape (like a spiral staircase), but it was not clear
whether it was one helix (as in parts of some proteins) or multiple intertwined helices. It was only after visiting Rosalind Franklin’s laboratory and seeing her outstanding x-ray diffraction photographs that Watson and Crick were able to decide on the correctness of a double-helix model. Their model showed that DNA consisted of two intertwined helices, each composed of a linear sequence of the nucleotide bases, adenine (A), thymine (T), gua-nine (G) and cytosine (C). Each base on one of the helices was paired by weak chemical bonds (hydrogen bonds) to a base on the other helix, such that A always paired with T, and C always paired with G (these were known as “base pairs”).
Watson and Crick recognized that this model had implications for how DNA replicated, and for how it controlled cell reactions to eventually produce the adult phenotype. To replicate, the two helices separate, each one serving as a template to make its partner. It was also clear that DNA could carry genetic information in the sequence of its nucleotides along each helix. What was less clear at first was how that information was translated into phenotypes. However, one line of evidence going back to the early decades of the twentieth century had shown that the direct product of gene action was the production of a specific protein. In 1941, George Beadle and E. L. Tatum had shown that genes produce enzymes (virtually all enzymes are proteins), which in turn catalyze steps in metabolic reactions, such as those leading to a particular eye color. Mutations in the gene resulted in imperfect proteins, and thus altered phenotype. The Watson-Crick model suggested that the helical strands of DNA were read as a linear sequence in such a way as to determine the amino acid sequence of a specific protein. Mutations were alterations in the sequence of bases on DNA, and they could lead to altered amino acid sequences in the protein product. How all this worked was not clear at first, but it quickly became the focus of the molecular genetics research program of the 1960s and 1970s.
The Genetic Code and Protein Synthesis. A major problem for molecular geneticists was how the sequence of bases in DNA was organized to contain information, as well as how that information was “read.” The first question was that of the “genetic code,” and the second that of translation of that code into specific protein molecules. It was first hypothesized that the minimum number of base sequences on DNA that could code for the twenty-one known amino acids was three (with only four bases, combined into threes there could be sixty-four possible combinations, more than enough for each of the twenty amino acids to have its own code. By a variety of both genetic and biochemical experiments, Crick and his colleagues in England, and Marshall Nirenberg and Severo Ochoa in the United States, determined that the genetic code was indeed composed of three nucleotides (the code was a triplet one, such that TTT coded for the amino acid phenylalanine and AGC for serine). Thus, wherever a specific triplet appeared in the DNA molecule, the amino acid for which it coded would appear at that point in the protein chain. There was thus colinearity between the sequence of triplets in DNA and the amino acids in the corresponding protein for which it coded. Further work showed that the first step in protein synthesis involved transcription of the DNA sequence onto another kind of nucleic acid molecule, called messenger ribonucleic acid (mRNA), which was single-stranded and complementary to the DNA strand that gave rise to it. Further, mRNA met up with other kinds of RNA molecules, known as transfer RNA (tRNA) with each type specific for a given amino acid. The site of this interaction was a small cell structure, the ribosome, and the amino acids brought to the ribosome were joined up in the sequence specified by the mRNA to form the protein.
The new technology associated with molecular genetics had many applications regarding issues of human evolution and the nature of race. One of the earliest applications of the new knowledge of DNA was its use in reconstructing and verifying existing phylogenies of all sorts of organisms, including humans. In the 1980s, DNA from cell organelles known as mitochondria (which have their own DNA inherited strictly from the mother) was used to trace human migrations. Mitochondrial DNA does not undergo a crossing-over and exchange of segments between maternal and paternal genomes (as does nuclear DNA), and it mutates slowly, making it extremely useful for reconstructing lineages and following migration patterns. Applied to human evolution, mitochondrial DNA evidence showed that the human species evolved from ancestors of the twenty-first century’s great apes somewhere between 5 and 6 million years ago in Africa, migrated to other major continents such as Europe and Asia, about 100 to 150 thousand years ago, and differentiated in these regions into separate populations.
DNA and Racial Differences. Biologically, the term race has come to be synonymous with what taxonomists call subspecies, that is, somewhat separate and distinct populations within a species that are capable of interbreeding. When applied to the human species (Homo sapiens), the term has a much less precise biological meaning, because human populations have been so mobile for so long a period of time, and have thus always experienced gene mixing, or gene flow. Most geneticists and anthropologists in the early twenty-first century argue that human racial groups are socially constructed, that racial divisions have been made in particular historical contexts and are based on social, rather than significant biological, distinctions. Thus, when Europeans first came into contact with the people in Africa, Asia, and the Americas, racial classifications arose to support social and political agendas (e.g., the expropriation of land or wealth, or the slave trade). By the later eighteenth and nineteenth centuries, most biologists and anthropologists agreed that the indigenous people of Africa or the New World were the same species as Europeans, but they divided humans into three common subspecies, or “races,” arranged in a hierarchical order: Caucasians were at the top, Asians in the middle, and Negroids (Africans) were at the bottom. These divisions, and the exploitation they justified, were based on a few superficial traits, such as skin color, hair form, shape of the nose, and body proportions. To varying degrees, these divisions have persisted in the social sphere down to the present day. Modern genetic evidence, however, does not support any such divisions as having a significant biological reality. For example, one could group fruits by color (green cucumbers and limes; yellow lemons and bananas; and red cherries and peppers), but biologically these groups would share few other common properties. Applied to the human racial groupings the few traits used to make the distinction do not necessarily predict what other genes an individual will have. This does not mean, of course, that skin color and hair form are not genetic traits. For the classification of humans into the three traditional racial groups to be biologically significant, correlations between skin color, hair form, and a wide variety of other traits would be necessary.
There are several reasons why the concept of race in human beings is not biologically meaningful. One of the problems is that the boundaries between the various racial groupings is far more difficult to draw in humans than in many other animal species. In the twentieth century alone, the number of supposed “racial groups” has been as few as three (Caucasian, Negroid, and Asian) or as great as seventeen or eighteen, including such separate “races” as Irish, Mediterranean, Alpine, Nordic, Anglo-Saxon, and Slavic. For such classifications to be meaningful in a genetic sense, it would be necessary to assume that each group maintained a relatively closed inbreeding system, and that it had done so for hundreds or even thousands of generations. But because of extensive gene flow, few populations of humans have remained isolated for very long. This means that mixing of genes from populations of humans has occurred to such a degree over long historical periods, that there has come to be a greater range of variability within any one geographic group (e.g., Africans and Europeans) than there is between them. While some relatively isolated groups (the Australian Aborigines, for example) have maintained more of a common gene pool than others, such inbreeding is quite rare in humans. For “race,” in its usual social sense, to have any biological meaning would require that the presence of gene A in the group would also correlate with the presence of gene B, C, D, and a host of others. But such correlations do not in fact exist. For example, people often speak of “Africans” (or “African-Americans”) as if all people so identified shared one common genetic background. But North Africans are very different from sub-Saharan or southern Africans, while East Africans are very different from West Africans. For instance, the claim that an African American is more likely to have the gene for sickle-cell anemia (a severe blood disorder in the homozygous mutant state) is an overstatement. It would depend on what part of Africa the individual’s ancestry came from (the sickle-cell gene is rare in Ethiopia or southern Africa, but much more common in central and West Africa).
From a biological and genetic point of view, the only meaningful groupings of human beings are geographic populations. Thus, people who come from a given geographic locality are indeed likely to share more genes in common than those who come from more distant localities, but these differences do not make races in the common social use of the term. Genetically differentiated populations, with a profile of certain gene frequencies, can be identified and described, but they do not map onto the conventional notions of race. It has thus been argued that, biologically speaking, humans comprise one large, global species whose local differentiations are minor compared to those found in many other animal species.
It is clear that modern genetics, especially molecular genetics, has seriously undermined the sociological notion of race as it persisted throughout the nineteenth and twentieth centuries. Human “races,” as any kind of clearly differentiated, taxonomically significant groups, simply do not exist. This does not mean that the social concept of race has therefore lost its significance. Concepts of racial differences and hierarchies do not disappear simply because biology says they have no meaning, but because people struggle in the social arena to combat the racism and ethnocentrism that has for too long been accepted because of its purported (but nonexistent) biological basis.
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Garland E. Allen