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The Language of Genetics
An Introduction
By Denis R. Alexander Templeton Press
Copyright © 2011 Denis R. Alexander
All rights reserved.
ISBN: 978-1-59947-343-7
CHAPTER 1
The Birth of Genetics
The birth of scientific ideas is never straightforward. Theories twist and turn. Blind alleys are pursued. The different results that seem so obviously connected with the benefit of hindsight are at first kept in splendid isolation, or even in opposition.
The birth of genetics—the word itself derived from the Greek "to give birth"—illustrates all these complexities. This is no heroic tale of one triumphant discovery after another, but a story about a dark maze full of groping investigators whose insights gradually enabled us to understand the language of genetics, a research field that now continues to expand its range of discoveries at a breathless pace.
Our own curiosity about what we now call "heredity" and "genetics" is not as modern as it may at first seem. Four thousand years ago the Assyrians and Babylonians were manipulating genes when they pollinated date palms, not knowing a thing about genetics. An Assyrian bas-relief sculpture shows the artificial pollination of date palms at the time of King Ashurnasirpal II of Assyria, who reigned from 884 to 859 BCE. The foundation we stand on today is built on a rich history, which began with questions about inheritance of traits in humans, animals, and plants. In time, the search was on for the pattern of this inheritance, and finally—in the twentieth century—the mechanism that eventually provided the basis for genetics. The birth of genetics is a story that takes us from ancient Greek speculation about twins, through the key discoveries of Gregor Mendel in the nineteenth century, and on to the 1953 discovery by James Watson and Francis Crick of the structure of DNA, the double-helix, which has become the biological icon of our age.
Early Ideas about Heredity
The early Greek philosophers speculated extensively about the mysteries of human heredity. Hippocrates (c. 460–370 BCE), considered the father of modern medicine, expounded an idea that much later came to be known as pangenesis, in which the material of inheritance is collected from throughout the body, delivered to the reproductive organs, and passed to the embryo at the moment of conception. As Hippocrates wrote, "The offspring resembles its parent because the particles of the semen come from every part of the body."
Aristotle (384–322 BCE) opposed this idea of inheritance by reassembled particles, objecting, not unreasonably, "How could there be such particles for abstract characters as voice or temperament, or from such nongenerating sources as nails or hair?" Instead Aristotle saw inheritance in more qualitative terms in which sperm provided the "active element," bringing the offspring to life, whereas the female contributed the nutrition that would help the offspring to grow. Aristotle considered two types of explanation for development. In the preformationist idea, a miniature individual exists in the egg or sperm, and then begins to grow into the offspring upon stimulation. In the theory of epigenesis, which Aristotle himself favored, the new organism develops from an undifferentiated mass by the addition of parts. As happens so often in the history of ideas, the Greek philosophers thus set the general agenda for the discussion about inheritance for the next two thousand years. Was it a question of physical particulate inheritance; or the passing on of preformed miniature individuals, like preformed Russian dolls, one inside the other; or the development of new organisms out of an undifferentiated mass? All these suggestions played important roles in the discussions that followed over the centuries.
Accurate observations of familial inheritance were more common than satisfying explanations of how the pattern of inheritance worked. Rules to prevent the consequences of what we now call hemophilia, in which blood fails to clot properly, can be found in the Jewish Talmud, and in 200 CE Rabbi Judah the Patriarch exempted a third son from circumcision if two elder brothers had bled to death. Even more striking is the Talmudic exemption that was also provided to the boy's male cousins, providing that they were sons of his mother's sisters, but not sons of his mother's brothers or his father's siblings. This exemption recognizes what we now call an X-linked pattern of inheritance, which is explained below.
Identical twins also drew much early attention and speculation. St. Augustine (354–430) argued against astrology on the grounds that twins born at virtually the same time, under the same planets, could have very different personalities. Much later Martin Luther (1483–1546) echoed the same argument, ridiculing astrology by pointing out that Esau and Jacob in the Old Testament were twins, yet had very different characters.
As the experimental method gained broader application with the scientific revolution of the sixteenth and seventeenth centuries, so some key findings were made that helped to lay the groundwork for the later science of genetics. James I's personal physician, William Harvey (1578–1657), who described the heart as a pump and explained its role in the circulation of the blood, also published On the Generation of Animals in 1651, arguing that all living organisms arose from eggs. Such was the fascination with the very small, aroused by new discoveries with the microscope, that preformationist ideas gained more attention, with either eggs or sperm being touted as the location of the "homunculus," the preformed miniature individual destined to become the new offspring. But as critics pointed out, the theory did not explain why offspring were such a mingling of the features of both parents.
The Swedish botanist Carl Linnaeus (1707–1778) first published his famous system of classification of all known living things in 1735, a classification that provides the basis for all further classifications right up to the present day. At the time Linnaeus believed that the number of species had been fixed at the time of the creation. But as Vítezslav Orel comments, "Subsequent experimental crossing of plants convinced him that hybridization gave rise to combinations of parental traits. He thought the genus rather than the species to be the basic unit of creation, and now admitted the possibility of new species appearing in nature and disappearing from it. He formed an open system, interpreting it in harmony with the Creator's design."
The introduction of the microscope opened up a fascinating new world of detailed biological structure that readily lent itself to mechanical types of description. Using the microscope, the polymath Robert Hooke (1635–1703) described for the first time in his famous work Micrographia (1665) the existence in plants of what he called "cells," the name suggested to him by their resemblance to monks' cells. Over a century later, Robert Brown (1773–1858), an extraordinarily gifted microscopist, was the first to identify the existence of the cell nucleus, where we now know the genetic material resides—at least in those cells that contain a nucleus, known as eukaryotes (in prokaryotes, such as bacteria, the genetic material is not separated from the rest of the cell).
By the mid-nineteenth century, botanists had carried out systematic breeding experiments, and the microscope had opened up the world of the cell and its nucleus. But the puzzling complexity of different patterns of inheritance eluded any clear explanation. Charles Darwin (1809–1882), brilliant naturalist that he was, whose theory of natural selection was destined to change the face of biology, nevertheless failed to uncover the laws of inheritance. Had he done so, evolution would have been a more complete theory much earlier.
Darwin set out his own views on inheritance in the second volume of his 1868 work, the Variation of Plants and Animals under Domestication. There Darwin presented his theory of pangenesis, apparently unaware how similar his account sounded when compared to that of Hippocrates more than two thousand years earlier:
I venture to advance the hypothesis of Pangenesis, which implies that every separate part of the whole organisation reproduces itself. So that ovules, spermatozoa, and pollen-grains,—the fertilised egg or seed, as well as buds,—include and consist of a multitude of germs thrown off from each separate part or unit.
Darwin gave the name "gemmules" to these hypothetical physical units that were gathered up from all parts of an organism and "packaged" in some way in the eggs and sperm, from there to be passed on to the offspring. Darwin believed, like his forerunner Jean-Baptiste Lamarck (1744–1829), in the inheritance of acquired characteristics: the external environment could modify the inheritable gemmules. He also maintained that inheritance resulted in a "blending" of the characteristics of both parents, with the "gemmules" playing a key role in the blending process.
But Darwin, always self-critical to a fault, was only too aware that his theory of inheritance was incomplete and certainly did not explain all the data; it was a "provisional hypothesis or speculation," as he modestly concluded. This became apparent through his own plant breeding experiments carried out in the back garden of his home in Kent, Down House, and also by his study of the inheritance of deafness in various families. The varying patterns of inheritance puzzled Darwin. He could find no obvious consistency that lent itself to a clear explanation.
Genes—the Birth of an Idea
Ironically, at the very time that Darwin was puzzling over the inheritance of deafness and proposing his theory of pangenesis, which was in fact wrong, an Augustinian Moravian monk named Gregor Mendel (1822–1884) had not only carried out the key experiments that would lay the foundation of modern genetics, but also published his results in 1866.
Moravia at the time was, in the words of the historian Edward Larson, "a region of the Austro-Hungarian Empire, then a protomodern police state with quasi-medieval remnants of ecclesiastical privilege." Mendel was the only son of a peasant farmer. In 1843 he gained admission to the wealthy and scholarly St. Thomas Monastery of the Augustinian Order near the Moravian capital of Brünn (now Brno in the Czech Republic), where he remained for the rest of his life, eventually becoming its abbot. Following ordination as priest in 1847, Mendel was assigned to teach in a secondary school in the city of Znaim (now Znojmo), but he failed the exam necessary to obtain a teaching certificate. He then went to study mathematics and biology in the University of Vienna in 1851, and there he gained the analytical expertise that would be so useful in his later breeding experiments.
Following graduation, Mendel returned to teaching in Brünn, where again he attempted the teachers' certificate exam. This time he withdrew at the last moment due to illness, some think brought on by his own anxiety about taking the exam again. Mendel did continue to teach science part-time in the technical school close to the monastery, and by all accounts was an inspiring teacher. Clearly, passing exams successfully may not necessarily be life's most important hurdle. Indeed, during the following period—1856 to 1863—Mendel carried out the key plant breeding experiments in the monastery gardens that were destined to change the face of modern biology.
As Mendel was careful to point out in the publication of his results, a long history of plant breeding experiments preceded his own. The brilliance of his approach was to link careful experimental observations with the mathematical analysis that revealed what much later came to be known as "Mendel's Laws of Inheritance." His experiments essentially consisted of "growing, crossbreeding, observing, sorting and counting nearly thirty thousand pea plants of various carefully selected varieties." Like much successful work in science, the experiments involved a judicious choice of materials to work with, a lot of patience, a sharp eye for detail, and smart analytical skills. Mendel also had a great love of fine food and good cigars, both reportedly consumed in prodigious quantities, which no doubt helped with the analysis.
Mendel's experiments revealed several key findings. His starting varieties of pea plants had bred true for many generations. Today we would say that they were genetically pure lines, displaying reproducible traits over many generations. This was an important factor in his success. When Mendel cross-hybridized these different varieties, the traits inherited by the next generation of peas (the "hybrids") were "particulate"—their seeds were either wrinkled or smooth, or the plants were either tall or short. The hybrids showed only one of the two possible character traits present in the parents, inconsistent with the idea of "blending inheritance" in which different traits merged with each other. Mendel also noticed that some traits were "dominant" and some were "recessive." When he crossed the tall pea plants with the short pea plants, then the first generation was all tall, but the ratio of tall to short plants in the second generation came to approximately three to one—tall was a dominant trait, and short was a recessive trait. If he crossed tall with tall, then he got only tall, and likewise short with short yielded only short plants. Experiments with peas having multiple different characteristics suggested that each trait—for example, height, color, texture—was inherited independently through subsequent generations.
Mendel read the paper summarizing his results at two meetings of the Brünn Natural History Society in 1865, but for the next thirty-five years his paper, buried away in the little-known Proceedings of the Natural History Society of Brünn, was cited only a few times and its importance went unrecognized. There is no evidence, for example, that Darwin knew about Mendel's work. This provides a good illustration of the way science works. New findings not only have to be widely disseminated to gain attention, preferably in a high-profile journal, but they also have to fall on ready soil. Some results can be so well ahead of the research field as a whole that they are simply ignored, and Mendel's key results seem to have suffered such a fate for the rest of the century.
Soon after Mendel's publication, in 1869, Friedrich Miescher discovered a weak acid in the nuclei of white blood cells (isolated from the pus on bandages collected from the local hospital in Tübingen, Germany). It would be nearly a century until that substance, deoxyribonucleic acid (DNA), was identified as the molecule responsible for Mendel's results. In the meantime, the mystery of inheritance continued to pique the curiosity of many.
August Weismann (1834–1914) made the important observation, published in 1893, that the body had two different types of cells, the "somatic cells" that made up the bulk of the body and did not pass on their information to succeeding generations, and the "germ cells" (the egg and sperm cells) that did pass on information. Moreover, he noted that the two types of cell replicated in different ways. Somatic cells came from germ cells, but not vice versa, rendering the inheritance of acquired characteristics impossible. As such, Weismann's finding contradicted the theory of pangenesis. To make quite sure, he chopped the tails off fifteen hundred rats, repeatedly over twenty generations, and reported that no rat was ever born in consequence without a tail. It really did seem that the property of being a tailless rat was not inherited, though to be fair on Darwin's theory of pangenesis, he had always insisted that major changes in an organism, like a mutilation, could not be inherited. Ironically Weismann's own theory of "germinal selection" suggested that some changes in the germ line could be brought about by beneficial changes imposed by the environment that could then be inherited. The Lamarckian idea that acquired characteristics could be inherited turned out to be very persistent.
Finally, at the turn of the century, Mendel's seminal work was rediscovered and extended by three fellow plant breeders: Hugo de Vries (1848–1935) in Amsterdam, son of a Mennonite deacon who later became prime minister of the Netherlands; Carl Correns (1864–1933) in Tübingen, who was encouraged to study botany by a correspondent of Mendel; and Erik von Tschermak (1871–1962) in Ghent, whose grandfather had taught Mendel during his time in Vienna. All three had been using different plant breeding systems to investigate inheritance, and each confirmed a three-to-one ratio between dominant and recessive traits in his own system. With varying degrees of alacrity, they recognized that Mendel's work had foreshadowed their own, and together they helped to launch Mendel to the central place that he still enjoys in the history of genetics.
(Continues...)
Excerpted from The Language of Genetics by Denis R. Alexander. Copyright © 2011 Denis R. Alexander. Excerpted by permission of Templeton Press.
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