How did the field of genetics develop historically?
The prevailing public attitude of the mid-nineteenth century was that all species were the result of a special creation and were immutable; that is, they remained unchanged over time. The work of Charles Darwin challenged that attitude. As a young man, Darwin served as a naturalist on the HMS Beagle , a British ship that mapped the coastline of South America from 1831 to 1836. Darwin’s observations of life-forms and their adaptations, especially those he encountered on the Galápagos Islands, led him to postulate that living species shared common ancestors with extinct species and that the pressures of nature—the availability of food and water, the ratio of predators to prey, and competition—exerted a strong influence over which species were best able to exploit a given habitat. Those best able to take advantage of an environment would survive, reproduce, and, by reproducing, pass their traits on to the next generation. He called this response to the pressures of nature “natural selection”: nature selected which species would be capable of surviving in any given environment and, by so doing, directed the development of species over time.
When Darwin returned to England, he shared his ideas with other eminent scientists but had no intention of publishing his notebooks, since he knew that his ideas would bring him into direct conflict with the society in which he lived. However, in 1858, he received a letter from a young naturalist named Alfred Russel Wallace. Wallace had done the same type of collecting in Malaysia that Darwin had done in South America, had observed the same phenomena, and had drawn the same conclusions. Wallace’s letter forced Darwin to publish his findings, and in 1858, a joint paper by both men on the topic of evolution was presented at the London meeting of the Linnean Society. In 1859, Darwin reluctantly published On the Origin of Species by Means of Natural Selection . The response was immediate and largely negative. While the book became a best seller, Darwin found himself under attack from religious leaders and other prominent scientists. In his subsequent works, he further delineated his proposals on the emergence of species, including man, but was never able to answer the pivotal question that dogged him until his death in 1882: If species are in fact mutable (capable of change over long periods of time), by what mechanism is this change possible?
Ironically, it was only six years later that this question was answered, and nobody noticed. Gregor Mendel is now considered the “father” of genetics, but, in 1865, he was an Augustinian monk in a monastery in Brunn, Austria (now Brno, Czech Republic). From 1856 to 1863, he conducted a series of experiments using the sweet pea (Pisum sativum), in which he cultivated more than twenty-eight thousand plants and analyzed seven different physical traits. These traits included the height of the plant, the color of the seed pods and flowers, and the physical appearance of the seeds. He cross-pollinated tall plants with short plants, expecting the next generation of plants to be of medium height. Instead, all the plants produced from this cross, which he called the F1 (first filial) generation, were tall. When he crossed plants of the F1 generation, the next generation of plants (F2) were both tall and short at a 3:1 ratio; that is, 75 percent of the F2 generation of plants were tall, while 25 percent were short. This ratio held true whether he looked at one trait or multiple traits at the same time. He coined two phrases still used in genetics to describe this phenomenon: He called the trait that appeared in the F1 generation “dominant” and the trait that vanished in the F1 generation “recessive.” While he knew absolutely nothing about chromosomes or genes, he postulated that each visible physical trait, or phenotype, was the result of two “factors” and that each parent contributed one factor for a given trait to its offspring. His research led him to formulate several statements that are now called the Mendelian principles of genetics.
Mendel’s first principle is called the principle of segregation. While all body cells contain two copies of a factor (what are now called genes), gametes contain only one copy. The factors are segregated into gametes by meiosis, a specialized type of cell division that produces gametes. The principle of independent assortment states that this segregation is a random event. One factor will segregate into a gamete independently of other factors contained within the dividing cell. (It is now known that there are exceptions to this rule: two genes carried on the same chromosome will not assort independently.)
To make sense of the data he collected from twenty-eight thousand plants, Mendel kept detailed numerical records and subjected his numbers to statistical analysis. In 1865, he presented his work before the Natural Sciences Society. He received polite but indifferent applause. Until Mendel, scientists rarely quantified their findings; as a result, the scientists either did not understand Mendel’s math or were bored by it. In either case, the scientists completely overlooked the significance of his findings. Mendel published his work in 1866. Unlike Darwin’s work, it was not a best seller. Darwin himself died unaware of Mendel’s work, in spite of the fact that he had an unopened copy of Mendel’s paper in his possession. Mendel died in 1884, two years after Darwin, with no way of knowing the eventual impact his work was to have on the scientific community. That impact began in 1900, when three botanists, working in different countries with different plants, discovered the same principles as had Mendel. Hugo De Vries, Carl Correns, and Erich Tschermak von Seysenegg rediscovered Mendel’s paper, and all three cited it in their work. Some sixteen years after his death, Mendel’s research was given the respect it deserved, and the science of genetics was born.
In 1877 Walter Fleming identified structures in the nuclei of cells that he called chromosomes; he later described the material of which chromosomes are composed as “chromatin.” In 1900, William Bateson introduced the term “genetics” to the scientific vocabulary. Wilhelm Johannsen expanded the terminology the following year with the introduction of the terms “gene,” “genotype,” and “phenotype.” In fact, 1901 was an exciting year in the history of genetics: the ABO blood group system was discovered by Karl Landsteiner; the role of the X chromosome in determining gender was described by Clarence McClung; Reginald Punnett and William Bateson discovered genetic linkage; and De Vries introduced the term “mutation” to describe spontaneous changes in the genetic material. Walter Sutton suggested a relationship between genes and chromosomes in 1903. Five years later, Archibald Garrod, studying a strange clinical condition in some of his patients, determined that their disorder, called alkaptonuria, was caused by an enzyme deficiency. He introduced the concept of “inborn errors of metabolism” as a cause of certain diseases. That same year, two researchers named Godfrey Hardy and Wilhelm Weinberg published their extrapolations on the principles of population genetics.
From 1910 to 1920, Thomas Hunt Morgan, with his graduate students Alfred Sturtevant, Calvin Bridges, and Hermann Müller, conducted a series of experiments with the fruit fly Drosophila melanogaster that confirmed Mendel’s principles of heredity and also confirmed the link between genes and chromosomes. The mapping of genes to the fruit fly chromosomes was complete by 1920. The use of research organisms such as the fruit fly became standard practice. For an organism to be suitable for this type of research, it must be small and easy to keep alive in a laboratory and must produce a great number of offspring. For this reason, bacteria (such as Escherichia coli ), viruses (particularly those that infect bacteria, called bacteriophages), certain fungi (such as Neurospora ), and the fruit fly have been used extensively in genetic research.
During the 1920s, Müller found that the rate at which mutations occur is increased by exposure to x-ray radiation. Frederick Griffith described “transformation,” a process by which genetic alterations occur in pneumococci bacteria. In the 1940s, Oswald Avery, Maclyn McCarty, and Colin MacLeod conducted a series of experiments that showed that the transforming agent Griffith had not been able to identify was, in fact, DNA. George Beadle and Edward Tatum proposed the concept of “one gene, one enzyme”; that is, a gene or a region of DNA that carries the information for a gene product codes for a particular enzyme. This concept was further refined to the “one gene, one protein” hypothesis and then to “one gene, one polypeptide.” (A polypeptide is a string of amino acids, which is the primary structure of all proteins.)
During the 1940s, it was thought that proteins were the genetic material. Chromosomes are made of chromatin; chromatin is 65 percent protein, 30 percent DNA, and 5 percent RNA. It was a logical conclusion that if the chromosomes were the carriers of genetic material, that material would make up the bulk of the chromosome structure. By the 1950s, however, it was fairly clear that DNA was the genetic material. Alfred Hershey and Martha Chase were able to prove in 1952 that DNA is the hereditary material in bacteriophages. From that point, the race was on to discover the structure of DNA.
For DNA or any other substance to be able to carry genetic information, it must be a stable molecule capable of self-replication. It was known that along with a five-carbon sugar and a phosphate group, DNA contains four different nitrogenous bases (adenine, thymine, cytosine, and guanine). Erwin Chargaff described the ratios of the four nitrogenous bases in what is now called Chargaff’s rule: adenine in equal concentrations to thymine, and cytosine in equal concentrations to guanine. What was not known was the manner in which these constituents bonded to each other and the three-dimensional shape of the molecule. Groups of scientists all over the world were working on the DNA puzzle. A group in Cambridge, England, was the first to solve it. James Watson and Francis Crick, supported by the work of Maurice Wilkins and Rosalind Franklin, described the structure of DNA in a landmark paper in Nature in 1953. They described the molecule as a double helix, a kind of spiral ladder in which alternating sugars and phosphate groups make up the backbone and paired nitrogenous bases make up the rungs. Arthur Kornberg created the first synthetic DNA in 1956. The structure of the molecule suggested ways in which it could self-replicate. In 1958, Matthew Meselson and Franklin Stahl proved that DNA replication is semiconservative; that is, each new DNA molecule consists of one template strand and one newly synthesized strand.
Throughout the 1950s and 1960s, genetic information grew exponentially. This period saw the description of the role of the Y chromosome in sex determination; the description of birth defects caused by chromosomal aberrations such as trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome); the description of operon and gene regulation by François Jacob and Jacques Monod in 1961; and the deciphering of the genetic code by Har Gobind Khorana, Marshall Nirenberg, and Severo Ochoa in 1966.
The discovery of restriction endonucleases (enzymes capable of splicing DNA at certain sites) led to an entirely new field within genetics called biotechnology. Mutations, such as the sickle-cell mutation, could be identified using restriction endonucleases. Use of these enzymes and DNA banding techniques led to the development of DNA fingerprinting. In 1979 human insulin and human growth hormone were synthesized in Escherichia coli. In 1981, the first cloning experiments were successful when the nucleus from one mouse cell was transplanted into an enucleated mouse cell. By 1990, cancer-causing genes called oncogenes had been identified, and the first attempts at human gene therapy had taken place. In 1997, researchers in England successfully cloned a living sheep. As the result of a series of conferences between 1985 and 1987, an international collaboration to map the entire human genome began in 1990. A comprehensive, high-density genetic map was published in 1994. In 2003 the human genome was completed and the finished human genome sequence was published in 2004.
In the decade or so since the end of the Human Genome Project, genome sequences for several species have been completed. These include sequences for the rat and chicken (2004), dog and chimpanzee (2005), honey bee (2006), rhesus macaque (2007), platypus (2008), and bovine (2009). The first personal genome was sequenced in 2007. Human genome sequences for different geographic and cultural groups, such as the Han Chinese (2007), Yoruba (2008), Korean (2009), and Southern African (2010) have also been completed; the Neanderthal genome sequence was finished in 2010. In 2011 Eric D. Green, Mark S. Guyer, and the National Human Genome Research Institute reported that specific genes for about three thousand Mendelian (monogenic) diseases had been discovered, along with genetic associations between more than nine hundred genomic loci and multigenic traits. Such discoveries have been made possible by the collection of comprehensive catalogs of genetic variation in the human genome.
The impact of genetics is immeasurable. In less than one hundred years, humans went from complete ignorance about the existence of genes to the development of gene therapies for certain diseases. Genes have been manipulated in certain organisms for the production of drugs, pesticides, and fungicides. Genetic analysis has identified the causes of many hereditary disorders, and genetic counseling has aided innumerable couples in making difficult decisions about their reproductive lives. DNA analysis has led to clearer understanding of the manner in which all species are linked. Techniques such as DNA fingerprinting have had a tremendous impact on law enforcement.
Advances in genetics have also given rise to a wide range of ethical questions with which humans will be struggling for some time to come. Termination of pregnancies, in vitro fertilization, and cloning are just some of the technologies that carry with them serious philosophical and ethical problems. There are fears that biotechnology will make it possible for humans to “play God” and that the use of biotechnology to manipulate human genes may have unforeseen consequences for humankind. For all the hope that biotechnology offers, it carries with it possible societal changes that are unpredictable and potentially limitless. Humans may be able to direct their own evolution; no other species has ever had that capability. How genetic technology is used and the motives behind its use will be some of the critical issues of the future.
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