Picturing DNA
Chapter 1:
What Is the Human Genome Project & Why Is It Important to Us?

A group of bonobos, a subspecies of chimpanzee, attracts a crowd of human visitors to their cage at the San Diego Zoo. The bonobos stand upright much of the time, spin and dance, occasionally have spats, but much more often make love-face to face. Their behavior is uncannily familiar, almost human. They share almost all of our genes, and we undoubtedly shared a common ancestor. But that is not enough to make them human. For all our similarities, bonobos and humans cannot breed-we are separate species.

We humans can have children with any and all human groups. Those living on isolated islands in the South Pacific, in remote villages in the Andean highlands or in the Arctic north can mate with people raised in Central Asia, sub-Saharan Africa, Scandinavia or the Great Plains of North America. We are a single species. In fact, we all seem to be descended from one man and one woman, a genetic Adam and Eve, who lived in Africa some 150,000 years ago. Our external features-what scientists call our phenotypes-are different. We have a wide array of skin color, eye shape and color, hair texture. However our interior profile, or genotype - the organization of our genes on our chromosomes-identifies us all as Homo sapiens.

As a species, we are born completely dependent on our parents. We must learn to raise our infant heads, turn over, crawl, walk and speak. What language we speak, and what we eventually say, depends on where we live and what kind of family we have joined. But our eagerness to learn to turn over, walk and talk is what makes us human. We inherit instructions for these crucial developments, and these instructions, along with a great deal more information, are coded in our genes, in our DNA.

Introduction

Chapter 2

Chapter 3

Chapter 4

Chapter 5

Chapter 6

Chapter 7

Epilogue

The resemblances and the subtle differences between species fascinated many nineteenth century biologists, but none was more obsessed with the puzzle than Charles Darwin. Upon returning from a three-year, around-the-world voyage in 1839, Darwin examined the finches his shipmates had gathered in the Galapagos Islands off the coast of Ecuador. When he compared the now-stuffed specimens with the notes he had taken in the islands, he realized that he had evidence of the way animals evolve into separate species. Isolation and environmental differences seemed to encourage the survival of individuals with traits that made them likely to thrive in a given environment. Over time, the incremental changes in the finches added up until the finches on one island were obviously different from the birds that had bred on another. Darwin realized that somehow each generation is born different, even though nothing that happens to an animal during its lifetime affects the next generation. For the rest of his life, he pondered the problem, trying to understand exactly how one species evolves into another. He knew there must be a mechanism to account for the change, but he never identified it.

Darwin never knew, nor did most people in the English-speaking world at the time, that three years before he explained the theory of evolution through natural selection in his 1859 book The Origin Of Species, an Austrian monk named Gregor Mendel had published, in German, a paper describing experiments he carried out by breeding pea plants. Mendel meticulously noted the probability with which visible characteristics-height and color-were transmitted from one generation to the next. He demonstrated that hereditary traits are transmitted by what he called "factors." But Mendel's revolutionary insight was ignored for decades; he was writing about plants, not animals, and he was a monk living apart from the mainstream of scientific discussion. It was only in 1900, after both Mendel and Darwin were gone, that Mendel's laws describing the operation of what he called dominant and recessive characteristics were rediscovered. In the early years of the twentieth century, a new generation of biologists armed with microscopes was developing a new science called cell biology. They identified Mendel's "factors"-the mechanism that carries information from one generation to another-as "genes." And they located these genes on chromosomes, threadlike structures in the nucleus of each living cell.

Both scientists and the general public had had as a model the intense breeding of animals that had begun in the late eighteenth century to produce bigger bulls and faster race horses. Why not selectively breed people, suggested the distinguished English mathematician Sir Francis Galton, who happened to be Darwin's cousin and who enthusiastically coined the term "eugenics" in 1883. The idea caught on, and people all over the world were swept up with the idea of improving the quality of the human race by manipulating human reproduction. The enthusiasts in the United States tended to be members of the upper classes concerned with population growth, particularly that of eastern and southern European immigrants. They wanted to encourage "good" families to produce lots of children and discourage the growth of undesirable families-by which they meant the poor and the unhealthy. They attributed shiftlessness, poverty and criminality to bad genes. Some eugenicists also believed that breeding between white people and members of what they considered inferior "races" (which they identified by skin color and ethnic origin) was especially deleterious.

The Nazis' eventual-and grotesque-adoption of the ideology and practice of eugenics
was mirrored on what had already been done on a smaller scale in the United States.
For example, a 1927 ruling of the U.S. Supreme Court had permitted states to sterilize thousands of inmates of public asylums and hospitals who had been deemed unfit to reproduce by panels of doctors and bureaucrats. The eugenicists efforts were doomed by unexamined racial prejudice, a failure to credit social and cultural factors in human development and a lack of scientific sophistication. For all these reasons-even if Hitler
had never come to power-eugenics was doomed to be a marginal movement. By the end
of World War II, eugenics had been discredited, both within the scientific community and without. Biologists interested in the problems of inherited characteristics limited their research to plants like corn and insects like the fruit fly, where social questions would not enter the inquiry.

Marching to the beat of their own drum, some early human geneticists continued to study hereditary patterns in people; they focused on conditions like colorblindness and diseases such as hemophilia. As early as the 1930s, human geneticists were fascinated by the study of human blood groups, which displayed patterns of inheritance that conformed to Mendel's laws.

After World War II, new discoveries in cell biology and genetics followed. The most important breakthrough, and one that caught the public eye, was the 1953 discovery by James Watson and Francis Crick that genes are ribbon-like strands of deoxyribonucleic acid (DNA) arranged in the now-celebrated double helix. Watson and Crick revealed once and for all the mechanism by which genes preserve a record of human evolution-a mechanism that also creates the template by which cells reproduce themselves.

DNA is made up of four nucleotides, usually referred to by the abbreviations A, T, C and G, which stand for the nucleotides adenine, thymine, cytosine and guanine. Adenine and thymine are always paired together, as are cytosine and guanine. The two strands of DNA in the double helix, Watson and Crick showed, join periodically in rungs formed by one or the other of the base pairs. Approximately 3 billion base pairs make up the human genome. The order in which they occur influences, among other things, what we look like, how we fight off infection or succumb to serious medical afflictions, and how we behave. Studies of the human genome reveal that while more than 99 percent of human DNA sequences are the same in every person who has ever lived, the human genome is so vast that tiny variations make us each unique.

Gene mapping is based on a technique called linkage analysis, which had been developed from work with fruit flies early in the 1900s. Biologists had noticed that if one form of two separate traits-eye color and wing type, for example-occur in an individual fruit fly, they were probably inherited together, and their respective genes, which are said to be linked, probably lie close together on the same chromosome. Genes that lie close to each other are jointly inherited with higher frequency than those that lie far apart.

By the 1930s, linkage maps had been drawn for fruit flies. A distant goal began to take shape; perhaps someday scientists would be able to create a "map" that could identify the chromosomal address of each of the approximately 100,000 genes that make us who and what we are.

Creating such a map began to seem feasible to molecular biologists in 1973 after the invention of a technique in which a fragment of DNA is snipped out of one gene from a member of one species and spliced into another. When material from a human being was grafted into mouse DNA, scientists found it easier to manipulate and study. Another innovation was the technique of chemically staining material so that the unique pattern of each of the twenty-two human chromosomes could be identified. Throughout the 1980s, the ever-increasing power of computers made it easier to automate and speed up the sequencing process. Visionaries began to believe it might be possible to map and sequence the entire human genome, but they did not have a time frame.

Among these visionary thinkers was a physicist working at the Department of Energy (DOE) in Washington. The Department had a long history of support for biomedical research, including the biological effects of radiation on genetic mutation. In 1983, the DOE began to maintain a database for DNA sequence information. The accumulating data led to speculations about the possibility of identifying the base-pair sequences for the entire human genome. This would give scientists a complete picture of which DNA fragments lay where on each chromosome. With this information, biologists could establish genetic markers that would prove unique to each individual. The idea took hold. By the mid-1980s groups of scientists were discussing the technical details that lay behind the launching of the project.

Momentum grew as scientists released dramatic data to the public about new genetic discoveries. As early as 1959, researchers in France and England had shown that individuals born with Down's syndrome had three copies of chromosome 21 instead of the normal two. In 1983, researchers announced that they had located the marker for the gene for Huntington's disease, a devastating, inevitably fatal neurological disease caused by a single gene. In the following years, biologists identified a number of genes that they called oncogenes because they were implicated in the onset of cancer. By the end of the twentieth century, some four thousand rare medical conditions, including cystic fibrosis, sickle-cell anemia, Tay-Sachs disease and phenylketonuria (PKU) were shown to be the result of a single mutation in a single gene; more such cases will surely emerge. However, the majority of medical problems, including cancers, heart disease, hypertension, and diseases of the brain, appear to be caused by a complex interplay among a variety of genetic combinations (mostly alterations or mutations in DNA which occur after birth) interacting with environmental factors. More voices were added to the chorus of those demanding that the United States government support the effort to sequence the human genome. One supporter likened the effort to the program that led to the conquest of space.

Q&A with Dr. David Baltimore

Q. Do certain genes make you susceptible to a disease?

Baltimore: I would say that in general there are many diseases, not all of them, there are many diseases for which there is a genetic component. There are only a few diseases where genes totally penetrate them. That is, if you have the gene, then you have the disease.

Q: Like Huntington's?

Baltimore: Like Huntington's in its extreme form. But there are gradations of Huntington's. There are people who get very mild Huntington's and there are people who don't get anything at all. And then there are people who get very sick.

Q: You actually can tell from the genes what kind of Huntington's it is?

Baltimore: Yes, because there are clearly people who were never diagnosed with Huntington's who had the proto-Huntington's gene. So at the margins, most genes that cause disease can be counteracted by either other genes or by environmental influences.

Q: When you talk about other genes, do you mean by some kind of gene therapy?

Baltimore: Through other genes in your own DNA. All of us have a background variation in our genes which is enormous. That's why we're different from one another. And sometimes those genes can counteract a bad gene-compensate for it. So a given gene on one genetic background can be very severe in its effects. The same gene on a different genetic background may be very mild in its effects.

Q: So it's the package that counts.

Baltimore: That's right. So you can modify genes in two ways. One is by environment. If you're sensitive to a given microorganism and you're not exposed to it, you'll never know that you have a genetic sensitivity to it. That's a simple example. As I said, there are genetic modifiers-even though you have a bad gene, you don't see it.

After much negotiation, the details of the project were worked out, and Congress granted funds to both the National Institutes of Health (NIH) and the DOE to begin systematic research into the human genome. In 1990, the Human Genome Project was inaugurated as a formal federal program under the leadership of James Watson, the co-discoverer of the double helix. Almost simultaneously, Japan and a consortium of European countries announced similar projects. The Japanese would discover that they had neither the money nor the expertise to play a major part in the work that followed, but Europeans, particularly French and British scientists, remained in the competition. A leading French scientist noted that it would probably have been easier and cheaper to begin by exploring the genome of a mouse or a rabbit, but, he pointed out, "man is the sole species that will pay to have its genome sequenced," and he believed that the return on that investment in technology, medicine and biology would be unprecedented. Said a German biologist: "The 'Book of Man,' some 3,500 million base pairs long, may well be available on compact discs by the year 2000; it should have some European authors."

There were dissenters. Some scientists and politicians complained about the diversion of funds from

other research in molecular biology and biomedicine. Other people, laymen as well as specialists, worried about the risks of returning to a kind of politics that might raise the ghosts of the eugenics movement and Nazism. A thoughtful report preparedby a member of the environmental party in Germany, which actually supported the Genome Project, nonetheless warned against what it called "test-tube eugenics" and reminded its audience that the application of human genetic information would almost surely involve fateful decisions about what are "normal and abnormal, acceptable and unacceptable, viable and non-viable forms of the genetic make-up of individual human beings before and after birth."

James Watson had already thought a great deal about these and related questions. He had been arguing since the early 1970s that scientists and society in general must generate a broad debate about the social implications on the horizon. And indeed, as the Human Genome Project was launched under his leadership, Watson recognized the cultural implications of the project and announced that roughly 3 percent of the total budget would be allocated for the study of the ethical issues raised by the scientific discoveries.

By October 1990, even before the United States government's massive effort was officially underway, almost two thousand human genes had already been mapped and logged into a common database at Johns Hopkins University. The data was also logged into the GenBank at Los Alamos as well as a laboratory in Europe. The National Institutes of Health confidently predicted that the first complete composite human sequence based on DNA taken from an anonymous group of ten to twenty men and women of various nationalities would be available by 2003.

The Genome Project has moved so rapidly that the first "working draft" covering the sequence of an estimated 90 percent of the human genome was completed well ahead of schedule in the spring of 2000, and by some definitions, a complete draft was completed that summer. It probably will take another three years to fill in the gaps and increase its accuracy. It is no longer possible to postpone discussing its ethical and political implications.

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Picturing DNA by Bettyann Holtzmann Kevles & Marilyn Nissenson
Copyright © 2000 Bettyann Holtzmann Kevles & Marilyn Nissenson
All Rights Reserved