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DNA: The Secret of Life


DNA: The Secret of Life










































































































































































































































































































































































































































































































































































































































  

Chapter One: Beginnings of Genetics: From Mendel to Hitler

M y mother, Bonnie Jean, believed in genes. She was proud of her father's Scottish origins, and saw in him the traditional Scottish virtues of honesty, hard work, and thriftiness. She, too, possessed these qualities and felt that they must have been passed down to her from him. His tragic early death meant that her only nongenetic legacy was a set of tiny little girl's kilts he had ordered for her from Glasgow. Perhaps therefore it is not surprising that she valued her father's biological legacy over his material one.

Growing up, I had endless arguments with Mother about the relative roles played by nature and nurture in shaping us. By choosing nurture over nature, I was effectively subscribing to the belief that I could make myself into whatever I wanted to be. I did not want to accept that my genes mattered that much, preferring to attribute my Watson grandmother's extreme fatness to her having overeaten. If her shape was the product of her genes, then I too might have a hefty future. However, even as a teenager, I would not have disputed the evident basics of inheritance, that like begets like. My arguments with my mother concerned complex characteristics like aspects of personality, not the simple attributes that, even as an obstinate adolescent, I could see were passed down over the generations, resulting in "family likeness." My nose is my mother's and now belongs to my son Duncan.

Sometimes characteristics come and go within a few generations, but sometimes they persist over many. One of the most famous examples of a long-lived trait is known as the "Hapsburg Lip." This distinctive elongation of the jaw and droopiness to the lower lip--which made the Hapsburg rulers of Europe such a nightmare assignment for generations of court portrait painters--was passed down intact over at least twenty-three generations.

The Hapsburgs added to their genetic woes by intermarrying. Arranging marriages between different branches of the Hapsburg clan and often among close relatives may have made political sense as a way of building alliances and ensuring dynastic succession, but it was anything but astute in genetic terms. Inbreeding of this kind can result in genetic disease, as the Hapsburgs found out to their cost. Charles II, the last of the Hapsburg monarchs in Spain, not only boasted a prize-worthy example of the family lip--he could not even chew his own food--but was also a complete invalid, and incapable, despite two marriages, of producing children.

Genetic disease has long stalked humanity. In some cases, such as Charles II's, it has had a direct impact on history. Retrospective diagnosis has suggested that George III, the English king whose principal claim to fame is to have lost the American colonies in the Revolutionary War, suffered from an inherited disease, porphyria, which causes periodic bouts of madness. Some historians--mainly British ones--have argued that it was the distraction caused by George's illness that permitted the Americans' against-the-odds military success. While most hereditary diseases have no such geopolitical impact, they nevertheless have brutal and often tragic consequences for the afflicted families, sometimes for many generations. Understanding genetics is not just about understanding why we look like our parents. It is also about coming to grips with some of humankind's oldest enemies: the flaws in our genes that cause genetic disease.



Our ancestors must have wondered about the workings of heredity as soon as evolution endowed them with brains capable of formulating the right kind of question. And the readily observable principle that close relatives tend to be similar can carry you a long way if, like our ancestors, your concern with the application of genetics is limited to practical matters like improving domesticated animals (for, say, milk yield in cattle) and plants (for, say, the size of fruit). Generations of careful selection--breeding initially to domesticate appropriate species, and then breeding only from the most productive cows and from the trees with the largest fruit--resulted in animals and plants tailor-made for human purposes. Underlying this enormous unrecorded effort is that simple rule of thumb: that the most productive cows will produce highly productive offspring and from the seeds of trees with large fruit large-fruited trees will grow. Thus, despite the extraordinary advances of the past hundred years or so, the twentieth and twenty-first centuries by no means have a monopoly on genetic insight. Although it wasn't until 1909 that the British biologist William Bateson gave the science of inheritance a name, genetics, and although the DNA revolution has opened up new and extraordinary vistas of potential progress, in fact the single greatest application of genetics to human well-being was carried out eons ago by anonymous ancient farmers. Almost everything we eat--cereals, fruit, meat, dairy products--is the legacy of that earliest and most far-reaching application of genetic manipulations to human problems.

An understanding of the actual mechanics of genetics proved a tougher nut to crack. Gregor Mendel (1822-1884) published his famous paper on the subject in 1866 (and it was ignored by the scientific community for another thirty-four years). Why did it take so long? After all, heredity is a major aspect of the natural world, and, more important, it is readily, and universally, observable: a dog owner sees how a cross between a brown and black dog turns out, and all parents consciously or subconsciously track the appearance of their own characteristics in their children. One simple reason is that genetic mechanisms turn out to be complicated. Mendel's solution to the problem is not intuitively obvious: children are not, after all, simply a blend of their parents' characteristics. Perhaps most important was the failure by early biologists to distinguish between two fundamentally different processes, heredity and development. Today we understand that a fertilized egg contains the genetic information, contributed by both parents, that determines whether someone will be afflicted with, say, porphyria. That is heredity. The subsequent process, the development of a new individual from that humble starting point of a single cell, the fertilized egg, involves implementing that information. Broken down in terms of academic disciplines, genetics focuses on the information and developmental biology focuses on the use of that information. Lumping heredity and development together into a single phenomenon, early scientists never asked the questions that might have steered them toward the secret of heredity. Nevertheless, the effort had been under way in some form since the dawn of Western history.

The Greeks, including Hippocrates, pondered heredity. They devised a theory of "pangenesis," which claimed that sex involved the transfer of miniaturized body parts: "Hairs, nails, veins, arteries, tendons and their bones, albeit invisible as their particles are so small. While growing, they gradually separate from each other." This idea enjoyed a brief renaissance when Charles Darwin, desperate to support his theory of evolution by natural selection with a viable hypothesis of inheritance, put forward a modified version of pangenesis in the second half of the nineteenth century. In Darwin's scheme, each organ--eyes, kidneys, bones--contributed circulating "gemmules" that accumulated in the sex organs, and were ultimately exchanged in the course of sexual reproduction. Because these gemmules were produced throughout an organism's lifetime, Darwin argued any change that occurred in the individual after birth, like the stretch of a giraffe's neck imparted by craning for the highest foliage, could be passed on to the next generation. Ironically, then, to buttress his theory of natural selection Darwin came to champion aspects of Lamarck's theory of inheritance of acquired characteristics--the very theory that his evolutionary ideas did so much to discredit. Darwin was invoking only Lamarck's theory of inheritance; he continued to believe that natural selection was the driving force behind evolution, but supposed that natural selection operated on the variation produced by pangenesis. Had Darwin known about Mendel's work (although Mendel published his results shortly after The Origin of Species appeared, Darwin was never aware of them), he might have been spared the embarrassment of this late-career endorsement of some of Lamarck's ideas.

Whereas pangenesis supposed that embryos were assembled from a set of minuscule components, another approach, "preformationism," avoided the assembly step altogether: either the egg or the sperm (exactly which was a contentious issue) contained a complete preformed individual called a homunculus. Development was therefore merely a matter of enlarging this into a fully formed being. In the days of preformationism, what we now recognize as genetic disease was variously interpreted: sometimes as a manifestation of the wrath of God or the mischief of demons and devils; sometimes as evidence of either an excess of or a deficit of the father's "seed"; sometimes as the result of "wicked thoughts" on the part of the mother during pregnancy. On the premise that fetal malformation can result when a pregnant mother's desires are thwarted, leaving her feeling stressed and frustrated, Napoleon passed a law permitting expectant mothers to shoplift. None of these notions, needless to say, did much to advance our understanding of genetic disease.

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 scientific revolution. 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.



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.

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 l2 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:

The elephant is reckoned to be the slowest breeder of all known animals, and I have taken some pains to estimate its probable minimum rate of natural increase: it will be under the mark to assume that it breeds when thirty years old, and goes on breeding till ninety years old, bringing forth three pairs of young in this interval; if this be so, at the end of the fifth century there would be alive fifteen million elephants, descended from the first pair.

All these calculations assume that all the baby fruit flies and all the baby elephants make it successfully to adulthood. In theory, therefore, there must be an infinitely large supply of food and water to sustain this kind of reproductive overdrive. In reality, of course, those resources are limited, and not all baby fruit flies or baby elephants make it. There is competition among individuals within a species for those resources. What determines who wins the struggle for access to the resources? Darwin pointed out genetic variation means that some individuals have advantages in what he called "the struggle for existence." To take the famous example of Darwin's finches from the Galápagos Islands, those individuals with genetic advantages--like the right size of beak for eating the most abundant seeds--are more likely to survive and reproduce. So the advantageous genetic variant--having a bill the right size--tends to be passed on to the next generation. The result is that natural selection enriches the next generation with the beneficial mutation so that eventually, over enough generations, every member of the species ends up with that characteristic.

The Victorians applied the same logic to humans. They looked around and were alarmed by what they saw. The decent, moral, hardworking middle classes were being massively outreproduced by the dirty, immoral, lazy lower classes. The Victorians assumed that the virtues of decency, morality, and hard work ran in families just as the vices of filth, wantonness, and indolence did. Such characteristics must then be hereditary; thus, to the Victorians, morality and immorality were merely two of Darwin's genetic variants. And if the great unwashed were outreproducing the respectable classes, then the "bad'' genes would be increasing in the human population. The species was doomed! Humans would gradually become more and more depraved as the "immorality" gene became more and more common.

Francis Galton had good reason to pay special attention to Darwin's book, as the author was his cousin and friend. Darwin, some thirteen years older, had provided guidance during Galton's rather rocky college experience. But it was The Origin of Species that would inspire Galton to start a social and genetic crusade that would ultimately have disastrous consequences. In 1883, a year after his cousin's death, Galton gave the movement a name: eugenics.



Eugenics was only one of Galton's many interests; Galton enthusiasts refer to him as a polymath, detractors as a dilettante. In fact, he made significant contributions to geography, anthropology, psychology, genetics, meteorology, statistics, and, by setting fingerprint analysis on a sound scientific footing, to criminology. Born in 1822 into a prosperous family, his education--partly in medicine and partly in mathematics--was mostly a chronicle of defeated expectations. The death of his father when he was twenty-one simultaneously freed him from paternal restraint and yielded a handsome inheritance; the young man duly took advantage of both. After a full six years of being what might be described today as a trust-fund dropout, however, Galton settled down to become a productive member of the Victorian establishment. He made his name leading an expedition to a then little known region of southwest Africa in 1850-52. In his account of his explorations, we encounter the first instance of the one strand that connects his many varied interests: he counted and measured everything. Galton was only happy when he could reduce a phenomenon to a set of numbers.

At a missionary station he encountered a striking specimen of steatopygia--a condition of particularly protuberant buttocks common among the indigenous Nama women of the region and realized that this woman was naturally endowed with the figure that was then fashionable in Europe. The only difference was that it required enormous (and costly) ingenuity on the part of European dressmakers to create the desired "look," for their clients.

I profess to be a scientific man, and was exceedingly anxious to obtain accurate measurements of her shape; but there was a difficulty in doing this. I did not know a word of Hottentot [the Dutch name for the Nama], and could never therefore have explained to the lady what the object of my footrule could be and I really dared not ask my worthy missionary host to interpret for me. I therefore felt in a dilemma as I gazed at her form, that gift of bounteous nature to this favoured race, which no mantua-maker, with all her crinoline and stuffing, can do otherwise than humbly imitate. The object of my admiration stood under a tree, and was turning herself about to all points of the compass, as ladies who wish to be admired usually do. Of a sudden my eye fell upon my sextant; the bright thought struck me, and I took a series of observations upon her figure in every direction, up and down, crossways, diagonally, and so forth, and I registered them carefully upon an outline drawing for fear of any mistake; this being done, I boldly pulled out my measuring tape, and measured the distance from where I was to the place she stood, and having thus obtained both base and angles, I worked out the results by trigonometry and logarithms.

Galton's passion for quantification resulted in his developing many of the fundamental principles of modern statistics. It also yielded some clever observations. For example, he tested thc efficacy of prayer. He figured that if prayer worked, those most prayed for should be at an advantage; to test the hypothesis he studied the longevity of British monarchs. Every Sunday, congregations in thc Church of England following the Book of Common Prayer beseeched God to "Endue the king/queen plenteously with heavenly gifts; Grant him/her in health and wealth long to live." Surely, Galton reasoned, the cumulative effect of all those prayers should be beneficial. In fact, prayer seemed ineffectual: he found that on average the monarchs died somewhat younger than other members of the British aristocracy.

Because of the Darwin connection--their common grandfather, Erasmus Darwin, too was one of the intellectual giants of his day--Galton was especially sensitive to the way in which certain lineages seemed to spawn disproportionately large numbers of prominent and successful people. In 1869 he published what would become the underpinning of all his ideas on eugenics, a treatise called Hereditary Genius: An Inquiry into Its Laws and Consequences. In it he purported to show that talent, like simple genetic traits such as the Hapsburg Lip, does indeed run in families; he recounted, for example, how some families had produced generation after generation of judges. His analysis largely neglected to take into account the effect of the environment the son of a prominent judge is, after all, rather more likely to become a judge--by virtue of his father's connections, if nothing else--than the son of a peasant farmer. Galton did not, however, completely overlook the effect of the environment, and it was he who first referred to the "nature/nurture" dichotomy, possibly in reference to Shakespeare's irredeemable villain, Caliban, "a devil, a born devil, on whose nature/Nurture can never stick."

The results of his analysis, however, left no doubt in Galton's mind.

I have no patience with the hypothesis occasionally expressed, and often implied, especially in tales written to teach children to be good, that babies are born pretty much alike, and that the sole agencies in creating differences between boy and boy, and man and man, are steady application and moral effort. It is in the most unqualified manner that I object to pretensions of natural equality.

A corollary of his conviction that these traits are genetically determined, he argued, was that it would be possible to "improve" the human stock by preferentially breeding gifted individuals, and preventing the less gifted from reproducing.

It is easy...to obtain by careful selection a permanent breed of dogs or horses gifted with peculiar powers of running, or of doing anything else, so it would be quite practicable to produce a highly-gifted race of men by judicious marriages during several consecutive generations.

Galton introduced the terms eugenics (literally "good in birth") to describe this application of the basic principle of agricultural breeding to humans. In time, eugenics came to refer to "self-directed human evolution" by making conscious choices about who should have children, eugenicists believed that they could head off the "eugenic crisis" precipitated in the Victorian imagination by the high rates of reproduction of inferior stock coupled with the typically small families of the superior middle classes.



Eugenics these days is a dirty word, associated with racists and Nazis--a dark, best-forgotten phase of the history of genetics. It is important to appreciate, however, that in the closing years of the nineteenth and early years of the twentieth centuries, eugenics was not tainted in this way, and was seen by many as offering genuine potential for improving not just society as a whole but the lot of individuals within society as well. Eugenics was embraced with particular enthusiasm by those who today would be termed the "liberal left." Fabian socialists--some the era's most progressive thinkers--flocked to the cause, including George Bernard Shaw, who wrote that "there is now no reasonable excuse for refusing to face the fact that nothing but a eugenic religion can save our civilization." Eugenics seemed to offer a solution to one of society's most persistent woes: that segment of the population that is incapable of existing outside an institution.

Whereas Galton had preached what came to be known as "positive eugenics," encouraging genetically superior people to have children, the American eugenics movement preferred to focus on "negative eugenics," preventing genetically inferior people from doing so. The goals of each program were basically the same--the improvement of the human genetic stock--but these two approaches were very different.

The American focus on getting rid of bad genes, as opposed to increasing frequencies of good ones, stemmed from a few influential family studies of "degeneration" and "feeblemindedness"--two peculiar terms characteristic of the American obsession with genetic decline. In 1875 Richard Dugdale published his account of the Juke clan of upstate New York. Here, according to Dugdale, were several generations of seriously bad apples--murderers, alcoholics, and rapists. Apparently in the area near their home in New York State the very name "Juke" was a term of reproach.

Another highly influential study was published in 1912 by Henry Goddard, the psychologist who gave us the word "moron," on what he called "The Kallikak Family." This is the story of two family lines originating from a single male ancestor who had a child out of wedlock (with a "feebleminded" wench he met in a tavern while serving in the military during the American Revolutionary War), as well as siring a legitimate family. The illegitimate side of the Kallikak line, according to Goddard, was bad news indeed, "a race of defective degenerates," while the legitimate side comprised respectable, upstanding members of the community. To Goddard, this "natural experiment in heredity" was an exemplary tale of good genes versus bad. This view was reflected in the fictitious name he chose for the family. "Kallikak" is a hybrid of two Greek words, kalos (beautiful, of good repute) and kakos (bad).

"Rigorous" new methods for testing mental performance--the first IQ tests, which were introduced to the United States from Europe by the same Henry Goddard--seemed to confirm the general impression that the human species was gaining downward momentum on a genetic slippery slope. In those early days of IQ testing, it was thought that high intelligence and an alert mind inevitably implied a capacity to absorb large quantities of information. Thus how much you knew was considered a sort or index of your IQ. Following this line of reasoning, early IQ tests included lots of general knowledge questions. Here are a few from a standard test administered to U.S. Army recruits during World War I:

Pick one of four

The Wyandotte is a kind of: 1) horse 2) fowl 3) cattle 4) granite

The ampere is used in measuring: 1) wind power 2) electricity 3) water power 4) rainfall

The number of a Zulu's legs is: 1) two 2) four 3) six 4) eight

[Answers are 2, 2, 1 ]

Some half of the nation's army recruits flunked the test and were deemed "feebleminded." These results galvanized the eugenics movement in the United States: it seemed to concerned Americans that the gene pool really was becoming more and more awash in low-intelligence genes.



Scientists realized that eugenic policies required some understanding of the genetics underlying characteristics like feeblemindedness. With the rediscovery of Mendel's work, it seemed that this might actually be possible. The lead in this endeavor was taken on Long Island by one of my predecessors as director of Cold Spring Harbor Laboratory. His name was Charles Davenport.

In 1910, with funding from a railroad heiress, Davenport established the Eugenics Record Office at Cold Spring Harbor. Its mission was to collect basic information--pedigrees--on the genetics of traits ranging from epilepsy to criminality. It became the nerve center of the American eugenics movement. Cold Spring Harbor's mission was much the same then as it is now: today we strive to be at the forefront of genetic research, and Davenport had no less lofty aspirations--but in those days the forefront was eugenics. However, there is no doubt that the research program initiated by Davenport was deeply flawed from the outset and had horrendous, albeit unintended, consequences.

Eugenic thinking permeated everything Davenport did. He went out of his way, for instance, to hire women as field researchers because he believed them to have better observational and social skills than men. But, in keeping with the central goal of eugenics to reduce the number of bad genes, and increase the number of good ones, these women were hired for a maximum of three years. They were smart and educated, and therefore, by definition, the possessors of good genes. It would hardly be fitting for the Eugenics Record Office to hold them back too long from their rightful destiny of producing families and passing on their genetic treasure.

Davenport applied Mendelian analysis to pedigrees he constructed of human characteristics. Initially, he confined his attentions to a number of simple traits--like albinism (recessive) and Huntington disease (dominant)--whose mode of inheritance he identified correctly. After these early successes he plunged into a study of the genetics of human behavior. Everything was fair game: all he needed was a pedigree and some information about the family history (i.e., who in the line manifested the particular characteristic in question), and he would derive conclusions about the underlying genetics. The most cursory perusal of his 1911 book, Heredity in Relation to Eugenics, reveals just how wide-ranging Davenport's project was. He shows pedigrees of families with musical and literary ability and of a "family with mechanical and inventive ability, particularly with respect to boat-building." (Apparently Davenport thought that he was tracking the transmission of the boat-building gene.) Davenport even claimed that he could identify distinct family types associated with different surnames. Thus people with the surname Twinings have these characteristics: "broad-shouldered, dark hair, prominent nose, nervous temperament, temper usually quick, not revengeful. Heavy eyebrows, humorous vein, and sense of ludicrous; lovers of music and horses."

The entire exercise was worthless. Today we know all the characteristics in question are readily affected by environmental factors. Davenport, like Galton, assumed unreasonably that nature unfailingly triumphed over nurture. In addition, whereas the traits he had studied earlier, albinism and Huntington disease, have a simple genetic basis--they are caused by a particular mutation in a particular gene--for most behavioral characteristics, the genetic basis, if any, is complex. They may be determined by a large number of different genes, each one contributing just a little to the final outcome. This situation makes the interpretation of pedigree data like Davenport's virtually impossible. Moreover, the genetic causes of poorly defined characteristics like "feeblemindedness" in one individual may be very different from those in another, so that any search for underlying genetic generalities is futile.



Regardless of the successor failure of Davenport's scientific program, the eugenics movement had already developed a momentum of its own. Local chapters of the Eugenics Society organized competitions at state fairs, giving awards to families apparently free from the taint of bad genes. Fairs that had previously displayed only prize cattle and sheep now added "Better Babies" and "Fitter Families" contests to their programs. Effectively these were efforts to encourage positive eugenics--inducing the right kind of people to have children. Eugenics was even de rigueur in the nascent feminist movement. The feminist champions of birth control, Marie Stopes in Britain and, in the United States, Margaret Sanger, founder of Planned Parenthood, both viewed birth control as a form of eugenics. Sanger put it succinctly in 1919: "More children from the fit, less from the unfit--that is the chief issue of birth control."

Altogether more sinister was the growth of negative eugenics--preventing the wrong kind of people from having children. In this development, a watershed event occurred in 1899 when a young man called Clawson approached a prison doctor in Indiana called Harry Sharp (appropriately named in light of his enthusiasm for the surgeon's knife). Clawson's problem--or so it was diagnosed by the medical establishment of the day--was compulsive masturbation. He reported that he had been hard at it ever since the age of twelve. Masturbation was seen as part of the general syndrome of degeneracy, and Sharp accepted the conventional wisdom (however bizarre it may seem to us today) that Clawson's mental shortcomings--he had made no progress in school--were caused by his compulsion. The solution? Sharp performed a vasectomy, then a recently invented procedure, and subsequently claimed that he had "cured" Clawson. As a result, Sharp developed his own compulsion: to perform vasectomies.

Sharp promoted his success in treating Clawson (for which, incidentally, we have only Sharp's own report as confirmation) as evidence of the procedure's efficacy for treating all those identified as being of Clawson's kind--all "degenerates." Sterilization had two things going for it. First, it might prevent degenerate behavior, as Sharp claimed it had in Clawson. This, if nothing else, would save society a lot of money because those who had required incarceration, whether in prisons or insane asylums, would be rendered "safe" for release. Second, it would prevent the likes of Clawson from passing their inferior (degenerate) genes on to subsequent generations. Sterilization, Sharp believed, offered the perfect solution to the eugenic crisis.

Sharp was an effective lobbyist, and in 1907 Indiana passed the first compulsory sterilization law, authorizing the sterilization of confirmed "criminals, idiots, rapists, and imbeciles." Indiana's was the first of many: eventually thirty American states had enacted similar statutes, and by 1941 some sixty thousand individuals in the United States had duly been sterilized, half of them in California alone. The laws, which effectively resulted in state governments deciding who could and who could not have children, were challenged in court, but in 1927 the Supreme Court upheld the Virginia statute in the landmark case of Carrie Buck. Oliver Wendell Holmes wrote the decision:

It is better for all the world if, instead of waiting to execute degenerate offspring for crime, or to let them starve for their imbecility, society can prevent those who are manifestly unfit from continuing their kind... Three generations of imbeciles is enough.

Sterilization caught on outside the United States as well--and not only in Nazi Germany. Switzerland and the Scandinavian countries enacted similar legislation.



Racism is not implicit to eugenics--good genes, the ones eugenics seeks to promote, can in principle belong to people of any race. Starting with Galton, however, whose account of his African expedition had confirmed prejudices about "inferior races," the prominent practitioners of eugenics tended to be racists who used eugenics to provide a "scientific" justification for racist views. Henry Goddard, of Kallikak family fame, conducted IQ tests on immigrants at Ellis Island in 1913 and found as many as 80 percent of potential new Americans to be certifiably feebleminded. The IQ tests he carried out during World War I for thc U.S. Army reached a similar conclusion: 45 percent of foreign-born draftees had a mental age of less than eight (only 1 percent of native-born draftees fell into this category). That the tests were biased--they were, after all, carried out in English--was not taken to be relevant: racists had the ammunition they required, and eugenics would be pressed into the service of the cause.

Although the term "white supremacist" had yet to be coined, America had plenty of them early in the twentieth century. White Anglo-Saxon Protestants, Theodore Roosevelt prominent among them, were concerned that immigration was corrupting the WASP paradise that America, in their view, was supposed to be. In 1916 Madison Grant, a wealthy New Yorker and friend of both Davenport and Roosevelt, published The Passing of the Great Race, in which he argued that the Nordic peoples are superior to all others, including other Europeans. To preserve the United States' fine Nordic genetic heritage, Grant campaigned for immigration restrictions on all non-Nordics. He championed racist eugenic policies, too:

Under existing conditions the most practical and hopeful method of race improvement is through the elimination of the least desirable elements in the nation by depriving them of the power to contribute to future generations. It is well known to stock breeders that the color of a herd of cattle can be modified by continuous destruction of worthless shades and of course this is true of other characters. Black sheep, for instance, have been practically obliterated by cutting out generation after generation all animals that show this color phase.

Despite appearances, Grant's book was hardly a minor publication by a marginalized crackpot; it was an influential best-seller. Later translated into German, it appealed--not surprisingly--to the Nazis. Grant gleefully recalled having received a personal letter from Hitler, who wrote to say that the book was his Bible.

Although not as prominent as Grant, arguably the most influential of the era's exponents of "scientific" racism was Davenport's right-hand man, Harry Laughlin. Son of an Iowa preacher, Laughlin's expertise was in racehorse pedigrees and chicken breeding. He oversaw the operations of the Eugenics Record Office, but was at his most effective as a lobbyist. In the name of eugenics, he fanatically promoted forced sterilization measures and restrictions on the influx of genetically dubious foreigners (i.e., non-northern Europeans). Particularly important historically was his role as an expert witness at congressional hearings on immigration: Laughlin gave full rein to his prejudices, all of them of course dressed up as "science." When the data were problematic, he fudged them. When he unexpectedly found, for instance, that immigrant Jewish children did better than the native-born in public schools, Laughlin changed the categories he presented, lumping Jews in with whatever nation they had come from, thereby diluting away their superior performance. The passage in 1924 of the Johnson-Reed Immigration Act, which severely restricted immigration from southern Europe and elsewhere, was greeted as a triumph by the likes of Madison Grant; it was Harry Laughlin's finest hour. As vice president some years earlier, Calvin Coolidge had chosen to overlook both Native Americans and the nation's immigration history when he declared that "America must remain American." Now, as president, he signed his wish into law.

Like Grant, Laughlin had his fans among the Nazis, who modeled some of their own legislation on the American laws he had developed. In 1936 he enthusiastically accepted an honorary degree from Heidelberg University, which chose to honor him as "the farseeing representative of racial policy in America. In time, however, a form of late-onset epilepsy ensured that Laughlin's later years were especially pathetic. All his professional life he had campaigned for the sterilization of epileptics on the grounds that they were genetically degenerate.



Hitler's Mein Kampf is saturated with pseudoscientific racist ranting derived from long-standing German claims of racial superiority and from some of the uglier aspects of the American eugenics movement. Hitler wrote that the state "must declare unfit for propagation all who are in any way visibly sick or who have inherited a disease and can therefore pass it on, and put this into actual practice," and elsewhere, "Those who are physically and mentally unhealthy and unworthy must not perpetuate their suffering in the body of their children." Shortly after coming to power in 1933, the Nazis had passed a comprehensive sterilization law--the "law for the prevention of progeny with hereditary defects"--that was explicitly based on the American model. (Laughlin proudly published a translation of the law.) Within three years, 225,000 people had been sterilized.

Positive eugenics, encouraging the "right" people to have children, also thrived in Nazi Germany, where "right" meant properly Aryan. Heinrich Himmler, head of the SS (the Nazi elite corps), saw his mission in eugenic terms: SS officers should ensure Germany's genetic future by having as many children as possible. In 1936, he established special maternity homes for SS wives to guarantee that they got the best possible care during pregnancy. The proclamations at the 1935 Nuremberg Rally included a "law for the protection of German good and German honor," which prohibited marriage between Germans and Jews and even "extra-marital sexual intercourse between Jews and citizens of German or related blood." The Nazis were unfailingly thorough in closing up any reproductive loopholes.

Neither, tragically, were there any loopholes in thc U.S. Johnson-Reed Immigration Act that Harry Laughlin had worked so hard to engineer. For many Jews fleeing Nazi persecution, the United States was the logical first choice of destination, but the country's restrictive--and racist--immigration policies resulted in many being turned away. Not only had Laughlin's sterilization law provided Hitler with the model for his ghastly program, but his impact on immigration legislation meant that the United States would in effect abandon German Jewry to its fate at the hands of the Nazis.

In 1939, with the war under way, the Nazis introduced euthanasia. Sterilization proved too much trouble. And why waste the food? The inmates of asylums were categorized as "useless eaters." Questionnaires were distributed among the mental hospitals where panels of experts were instructed to mark them with a cross in the cases of patients whose lives they deemed "not worth living." Seventy-five thousand came back so marked, and the technology of mass murder--the gas chamber--was duly developed. Subsequently, the Nazis expanded the definition of "not worth living" to include whole ethnic groups, among them the Gypsies and, in particular, the Jews. What came to be called the Holocaust was the culmination of Nazi eugenics.



Eugenics ultimately proved a tragedy for humankind. It also proved a disaster for the emerging science of genetics, which could not escape the taint. In fact, despite the prominence of eugenicists like Davenport, many scientists had criticized the movement and dissociated themselves from it. Alfred Russel Wallace, the co-discoverer with Darwin of natural selection, condemned eugenics in 19l2 as "simply the meddlesome interference of an arrogant, scientific priestcraft." Thomas Hunt Morgan, of fruit fly fame, resigned on "scientific grounds" from the board of scientific directors of the Eugenics Record Office. Raymond Pearl, at Johns Hopkins, wrote in 1928 that "orthodox eugenicists are going contrary to the best established facts of genetical science."

Eugenics had lost its credibility in the scientific community long before the Nazis appropriated it for their own horrific purposes. The science underpinning it was bogus, and the social programs constructed upon it utterly reprehensible. Nevertheless, by midcentury the valid science of genetics, human genetics in particular, had a major public relations problem on its hands. When in 1948 I first came to Cold Spring Harbor, former home of the by-then-defunct Eugenics Record Office, nobody would even mention the "E word"; nobody was willing to talk about our sciences past even though past issues of the German Journal of Racial Hygiene still lingered on the shelves of the library.

Realizing that such goals were not scientifically feasible, geneticists had long since forsaken the grand search for patterns of inheritance of human behavioral characteristics--whether Davenport's feeblemindedness or Galton's genius--and were now focusing instead on the gene and how it functioned in the cell. With the development during the 1930s and 1940s of new and more effective technologies for studying biological molecules in ever greater detail, the time had finally arrived for an assault on the greatest biological mystery of all: what is the chemical nature of the gene?

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Excerpted from DNA: The Secret of Life by James D. Watson. Copyright © 2003 by James D. Watson. Excerpted by permission of Knopf, a division of Random House. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.