By the early nineteenth century, better microscopes had defeated preformationism. Look as hard as you like, you will never see a tiny homunculus curled up inside a sperm or egg cell. Pangenesis, though an earlier misconception, lasted rather longer – the argument would persist that the gemmules were simply too small to visualize – but was eventually laid to rest by August Weismann, who argued that inheritance depended on the continuity of germ plasm between generations and thus changes to the body over an individual's lifetime could not be transmitted to subsequent generations. His simple experiment involved cutting the tails off several generations of mice. According to Darwin's pangenesis, tailless mice would produce gemmules signifying "no tail" and so their offspring should develop a severely stunted hind appendage or none at all. When Weismann showed that the tail kept appearing after many generations of amputees, pangenesis bit the dust.
Gregor Mendel was the one who got it right. By any standards, however, he was an unlikely candidate for scientific superstardom. Born to a farming family in what is now the Czech Republic, he excelled at the village school and, at twenty-one, entered the Augustinian monastery at Brünn. After proving a disaster as a parish priest – his response to the ministry was a nervous breakdown – he tried his hand at teaching. By all accounts he was a good teacher, but in order to qualify to teach a full range of subjects, he had to take an exam. He failed it. Mendel's father superior, Abbot Napp, then dispatched him to the University of Vienna, where he was to bone up full-time for the retesting. Despite apparently doing well in physics at Vienna, Mendel again failed the exam, and so never rose above the rank of substitute teacher.
Around 1856, at Abbot Napp's suggestion, Mendel undertook some scientific experiments on heredity. He chose to study a number of characteristics of the pea plants he grew in his own patch of the monastery garden. In 1865 he presented his results to the local natural history society in two lectures, and, a year later, published them in the society's journal. The work was a tour de force: the experiments were brilliantly designed and painstakingly executed, and his analysis of the results was insightful and deft. It seems that his training in physics contributed to his breakthrough because, unlike other biologists of that time, he approached the problem quantitatively. Rather than simply noting that crossbreeding of red and white flowers resulted in some red and some white offspring, Mendel actually counted them, realizing that the ratios of red to white progeny might be significant – as indeed they are. Despite sending copies of his article to various prominent scientists, Mendel found himself completely ignored by the scientific community. His attempt to draw attention to his results merely backfired. He wrote to his one contact among the ranking scientists of the day, botanist Karl Nägeli in Munich, asking him to replicate the experiments, and he duly sent off 140 carefully labeled packets of seeds. He should not have bothered. Nägeli believed that the obscure monk should be of service to him, rather than the other way around, so he sent Mendel seeds of his own favorite plant, hawkweed, challenging the monk to re-create his results with a different species. Sad to say, for various reasons, hawkweed is not well-suited to breeding experiments such as those Mendel had performed on the peas. The entire exercise was a waste of his time.
Mendel's low-profile existence as monk-teacher-researcher ended abruptly in 1868 when, on Napp's death, he was elected abbot of the monastery. Although he continued his research – increasingly on bees and the weather – administrative duties were a burden, especially as the monastery became embroiled in a messy dispute over back taxes. Other factors, too, hampered him as a scientist. Portliness eventually curtailed his fieldwork: as he wrote, hill climbing had become "very difficult for me in a world where universal gravitation prevails." His doctors prescribed tobacco to keep his weight in check, and he obliged them by smoking twenty cigars a day, as many as Winston Churchill. It was not his lungs, however, that let him down: in 1884, at the age of sixty-one, Mendel succumbed to a combination of heart and kidney disease.
Not only were Mendel's results buried in an obscure journal, but they would have been unintelligible to most scientists of the era. He was far ahead of his time with his combination of careful experiment and sophisticated quantitative analysis. Little wonder, perhaps, that it was not until 1900 that the scientific community caught up with him. The rediscovery of Mendel's work, by three plant geneticists interested in similar problems, provoked a revolution in biology. At last the scientific world was ready for the monk's peas.
Mendel realized that there are specific factors – later to be called "genes" – that are passed from parent to offspring. He worked out that these factors come in pairs and that the offspring receives one from each parent.
Noticing that peas came in two distinct colors, green and yellow, he deduced that there were two versions of the pea-color gene. A pea has to have two copies of the G version if it is to become green, in which case we say that it is GG for the pea-color gene. It must therefore have received a G pea-color gene from both of its parents. However, yellow peas can result both from YY and YG combinations. Having only one copy of the Y version is sufficient to produce yellow peas. Y trumps G. Because in the YG case the Y signal dominates the G signal, we call Y "dominant." The subordinate G version of the pea-color gene is called "recessive."
Each parent pea plant has two copies of the pea-color gene, yet it contributes only one copy to each offspring; the other copy is furnished by the other parent. In plants, pollen grains contain sperm cells – the male contribution to the next generation – and each sperm cell contains just one copy of the pea-color gene. A parent pea plant with a YG combination will produce sperm that contain either a Y version or a G one. Mendel discovered that the process is random: 50 percent of the sperm produced by that plant will have a Y and 50 percent will have a G.
Suddenly many of the mysteries of heredity made sense. Characteristics, like the Hapsburg Lip, that are transmitted with a high probability (actually 50 percent) from generation to generation are dominant. Other characteristics that appear in family trees much more sporadically, often skipping generations, may be recessive. When a gene is recessive an individual has to have two copies of it for the corresponding trait to be expressed. Those with one copy of the gene are carriers: they don't themselves exhibit the characteristic, but they can pass the gene on. Albinism, in which the body fails to produce pigment so the skin and hair are strikingly white, is an example of a recessive characteristic that is transmitted in this way. Therefore, to be albino you have to have two copies of the gene, one from each parent. (This was the case with the Reverend Dr. William Archibald Spooner, who was also – perhaps only by coincidence – prone to a peculiar form of linguistic confusion whereby, for example, "a well-oiled bicycle" might become "a well-boiled icicle." Such reversals would come to be termed "spoonerisms" in his honor.) Your parents, meanwhile, may have shown no sign of the gene at all. If, as is often the case, each has only one copy, then they are both carriers. The trait has skipped at least one generation.
Mendel's results implied that things – material objects – were transmitted from generation to generation. But what was the nature of these things?
At about the time of Mendel's death in 1884, scientists using ever-improving optics to study the minute architecture of cells coined the term "chromosome" to describe the long stringy bodies in the cell nucleus. But it was not until 1902 that Mendel and chromosomes came together.
A medical student at Columbia University, Walter Sutton, realized that chromosomes had a lot in common with Mendel's mysterious factors. Studying grasshopper chromosomes, Sutton noticed that most of the time they are doubled up – just like Mendel's paired factors. But Sutton also identified one type of cell in which chromosomes were not paired: the sex cells. Grasshopper sperm have only a single set of chromosomes, not a double set. This was exactly what Mendel had described: his pea plant sperm cells also only carried a single copy of each of his factors. It was clear that Mendel's factors, now called genes, must be on
the chromosomes.
In Germany Theodor Boveri independently came to the same conclusions as Sutton, and so the biological revolution their work had precipitated came to be called the Sutton-Boveri chromosome theory of inheritance. Suddenly genes were real. They were on chromosomes, and you could actually see chromosomes through the microscope (see Plate 2).
Not everyone bought the Sutton-Boveri theory. One skeptic was Thomas Hunt Morgan, also at Columbia. Looking down the microscope at those stringy chromosomes, he could not see how they could account for all the changes that occur from one generation to the next. If all the genes were arranged along chromosomes, and all chromosomes were transmitted intact from one generation to the next, then surely many characteristics would be inherited together. But since empirical evidence showed this not to be the case, the chromosomal theory seemed insufficient to explain the variation observed in nature. Being an astute experimentalist, however, Morgan had an idea how he might resolve such discrepancies. He turned to the fruit fly, Drosophila melanogaster, the drab little beast that, ever since Morgan, has been so beloved by geneticists.
In fact, Morgan was not the first to use the fruit fly in breeding experiments – that distinction belonged to a lab at Harvard that first put the critter to work in 1901 – but it was Morgan's work that put the fly on the scientific map. Drosophila is a good choice for genetic experiments. It is easy to find (as anyone who has left out a bunch of overripe bananas during the summer well knows); it is easy to raise (bananas will do as feed); and you can accommodate hundreds of flies in a single milk bottle (Morgan's students had no difficulty acquiring milk bottles, pinching them at dawn from doorsteps in their Manhattan neighborhood); and it breeds and breeds and breeds (a whole generation takes about ten days, and each female lays several hundred eggs). Starting in 1907 in a famously squalid, cockroach-infested, banana-stinking lab that came to be known affectionately as the "fly room," Morgan and his students ("Morgan's boys" as they were called) set to work on fruit flies (see Plate 3).
Unlike Mendel, who could rely on the variant strains isolated over the years by farmers and gardeners – yellow peas as opposed to green ones, wrinkled skin as opposed to smooth – Morgan had no menu of established genetic differences in the fruit fly to draw upon. And you cannot do genetics until you have isolated some distinct characteristics to track through the generations. Morgan's first goal therefore was to find "mutants," the fruit fly equivalents of yellow or wrinkled peas. He was looking for genetic novelties, random variations that somehow simply appeared in the population.
One of the first mutants Morgan observed turned out to be one of the most instructive. While normal fruit flies have red eyes, these had white ones. And he noticed that the white-eyed flies were typically male. It was known that the sex of a fruit fly – or, for that matter, the sex of a human – is determined chromosomally: females have two copies of the X chromosome, whereas males have one copy of the X and one copy of the much smaller Y. In light of this information, the white-eye result suddenly made sense: the eye-color gene is located on the X chromosome and the white-eye mutation, W, is recessive. Because males have only a single X chromosome, even recessive genes, in the absence of a dominant counterpart to suppress them, are automatically expressed. White-eyed females were relatively rare because they typically had only one copy of W so they expressed the dominant red eye color. By correlating a gene – the one for eye color – with a chromosome, the X, Morgan, despite his initial reservations, had effectively proved the Sutton-Boveri theory. He had also found an example of "sex-linkage," in which a particular characteristic is disproportionately represented in one sex.
Like Morgan's fruit flies, Queen Victoria provides a famous example of sex-linkage. On one of her X chromosomes, she had a mutated gene for hemophilia, the "bleeding disease" in whose victims proper blood clotting fails to occur. Because her other copy was normal, and the hemophilia gene is recessive, she herself did not have the disease. But she was a carrier. Her daughters did not have the disease either; evidently each possessed at least one copy of the normal version. But Victoria's sons were not all so lucky. Like all males (fruit fly males included), each had only one X chromosome; this was necessarily derived from Victoria (a Y chromosome could have come only from Prince Albert, Victoria's husband). Because Victoria had one mutated copy and one normal copy, each of her sons had a 50-50 chance of having the disease. Prince Leopold drew the short straw: he developed hemophilia, and died at thirty-one, bleeding to death after a minor fall. Two of Victoria's daughters, Princesses Alice and Beatrice, were carriers, having inherited the mutated gene from their mother. They each produced carrier daughters and sons with hemophilia. Alice's grandson Alexis, heir to the Russian throne, had hemophilia, and would doubtless have died young had the Bolsheviks not gotten to him first.
Morgan's fruit flies had other secrets to reveal. In the course of studying genes located on the same chromosome, Morgan and his students found that chromosomes actually break apart and re-form during the production of sperm and egg cells. This meant that Morgan's original objections to the Sutton-Boveri theory were unwarranted: the breaking and re-forming – "recombination," in modern genetic parlance – shuffles gene copies between members of a chromosome pair. This means that, say, the copy of chromosome 12 I got from my mother (the other, of course, comes from my father) is in fact a mix of my mother's two copies of chromosome 12, one of which came from her mother and one from her father. Her two 12s recombined – exchanged material – during the production of the egg cell that eventually turned into me. Thus my maternally derived chromosome 12 can be viewed as a mosaic of my grandparents' 12s. Of course, my mother's maternally derived 12 was itself a mosaic of her grandparents' 12s, and so on.
Recombination permitted Morgan and his students to map out the positions of particular genes along a given chromosome. Recombination involves breaking (and re-forming) chromosomes. Because genes are arranged like beads along a chromosome string, a break is statistically much more likely to occur between two genes that are far apart (with more potential break points intervening) on the chromosome than between two genes that are close together. If, therefore, we see a lot of reshuffling for any two genes on a single chromosome, we can conclude that they are a long way apart; the rarer the reshuffling, the closer the genes likely are. This basic and immensely powerful principle underlies all of genetic mapping. One of the primary tools of scientists involved in the Human Genome Project and of researchers at the forefront of the battle against genetic disease was thus developed all those years ago in the filthy, cluttered Columbia fly room. Each new headline in the science section of the newspaper these days along the lines of "Gene for Something Located" is a tribute to the pioneering work of Morgan and his boys.
The rediscovery of Mendel's work, and the breakthroughs that followed it, sparked a surge of interest in the social significance of genetics. While scientists had been grappling with the precise mechanisms of heredity through the eighteenth and nineteenth centuries, public concern had been mounting about the burden placed on society by what came to be called the "degenerate classes" – the inhabitants of poorhouses, workhouses, and insane asylums. What could be done with these people? It remained a matter of controversy whether they should be treated charitably – which, the less charitably inclined claimed, ensured such folk would never exert themselves and would therefore remain forever dependent on the largesse of the state or of private institutions – or whether they should be simply ignored, which, according to the charitably inclined, would result only in perpetuating the inability of the unfortunate to extricate themselves from their blighted circumstances.
The publication of Darwin's Origin of Species in 1859 brought these issues into sharp focus. Although Darwin carefully omitted to mention human evolution, fearing that to do so would only further inflame an already raging controversy, it required no great leap of imagination to apply his idea of natural selection to humans. Natural selection is the force that determines the fate of
all genetic variations in nature – mutations like the one Morgan found in the fruit fly eye-color gene, but also perhaps differences in the abilities of human individuals to fend for themselves.
Natural populations have an enormous reproductive potential. Take fruit flies, with their generation time of just ten days, and females that produce some three hundred eggs apiece (half of which will be female): starting with a single fruit fly couple, after a month (i.e., three generations later), you will have 150 X 150 X 150 fruit flies on your hands – that's more than 3 million flies, all of them derived from just one pair in just one month. Darwin made the point by choosing a species from the other end of the reproductive spectrum:
Dna: The Secret of Life Page 3
