Life Script

How the Human Genome Discoveries Will Transform Medicine and Enhance Your Health

Nicholas Wade

• Publisher: Simon & Schuster
• Year: 2002
• Print ISBN: 9780743223188
• eBook ISBN: 9780743217392
• Topic: Biological Sciences
• Subtopic: Genetics & Genomics
• Index: Biological Sciences

With the decoding of the human genome, researchers can now read the script in which evolution has written the program for the design and operation of the human body. A new generation of medical treatments is at hand. Researchers are developing therapies so powerful that there is now no evident obstacle to the ancient goal of conquering most major diseases.
Nicholas Wade has covered the sequencing of the genome, as well as other health and science stories, for The New York Times, in the course of which he has interviewed many of the principal researchers in the field. In this book he describes what the genome means for the health of present and future generations.
Someday soon physicians will have access to DNA chips that, from a drop of blood, will screen a person's genes for all the diseases to which he or she may be genetically vulnerable. From full knowledge of the instruction manual of the human body, provided by the genome, pharmaceutical companies hope to develop a new generation of sophisticated drugs; one of the first genome-derived drugs is already undergoing clinical trials. Another vital tool will be regenerative medicine, a new kind of therapy in which new organs and tissues will be grown from a patient's own cells to replace those that are old or diseased.
With the help of DNA chips, medical researchers will soon be able to diagnose diseases such as cancer much more precisely and to tailor specific treatments for each patient. Individualized medicine will also become an important part of the pharmaceutical world. Many drugs will be prescribed based on information from DNA chips that identify which of a range of drugs is best for each patient, as well as which drugs are likely to cause side effects. The medicine of the post-genomic era will be customized for a patient's genetic make-up, providing treatments based on a precise understanding of the mechanism of disease.
Life Script describes a future in which good health, even perfect health, may become the standard for everyone -- at every age.

1

The Most Wondrous Map

“Nearly two centuries ago, in this room, on this floor, Thomas Jefferson and a trusted aide spread out a magnificent map—a map Jefferson had long prayed he would get to see in his lifetime. The aide was Meriwether Lewis, and the map was the product of his courageous expedition across the American frontier, all the way to the Pacific.”

So said President Bill Clinton, speaking in the East Room of the White House to an audience of scientists and government officials and, by teleconference, with Prime Minister Tony Blair in London. The occasion, on the morning of Monday, June 26, 2000, marked the completion of the Human Genome Project or rather, since in truth the genome was almost but not entirely finished, “the completion of the first survey of the entire human genome.”¹

In the audience were the members of the two rival teams who had battled each other to the finish line. The race for scientific distinction is often fierce, and there are few greater scientific prizes than the human genome. This race was fueled by political differences as well as hope for glory. A consortium of academic biologists in the United States and Britain had embarked on decoding the human genome with the intent of making it a communal good, freely available to the scientific and medical communities. Though they were not oblivious to the personal rewards of success, their goal was the disinterested creation of publicwealth, in the belief that medical advance would be speediest if all biologists had full and free access to the human genome sequence.

But in May 1998, almost eight years after the public consortium had begun to lay the technical groundwork and was within sight of success, a commercial enterprise headed by J. Craig Venter jumped into the fray with the goal of decoding the human genome as a profit-making venture. Venter, formerly an academic biologist like his rivals, believed that speed too was a public good and that with centralized management and a different strategy he could sequence the human genome much faster than the consortium seemed likely to do.

With such different motives and such high stakes, the race for the genome was especially intense. Each team confidently predicted that the other’s strategy would fail, while working round the clock to ensure its own success. As the finishing post neared, it became clear that each had achieved enough of its own goals to assert a plausible claim of victory. Venter’s company, Celera, had the edge on the scientific front, since his genome sequence was more complete than the public consortium’s. But the consortium had achieved its political goal: its version of the human genome, containing almost all human genes, was publicly available for the free use of scientists around the world.

In June 2000, the two sides were persuaded at the last moment that each stood to gain more from a decorous declaration of joint victory than from rival assertions of victory, spiced with mutual derogation of the other’s achievement.

And so it was that Clinton, in his speechwriter’s metaphor, came to compare the decoding of the human genome with Lewis’s historic map of an America bounded by the Pacific and Atlantic oceans.

“Today,” the president said, “the world is joining us here in the East Room to behold a map of even greater significance. We are here to celebrate the completion of the first survey of the entire human genome. Without a doubt, this is the most important, most wondrous map ever produced by humankind.”

Shifting analogies, the president went on to compare the sequencing of the genomic script to “learning the language in which God created life. . . . With this profound new knowledge, humankind is on the vergeof gaining immense, new power to heal. Genome science will have a real impact on all our lives—and even more, on the lives of our children. It will revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases. . . . In fact, it is now conceivable that our children’s children will know the term ‘cancer’ only as a constellation of stars.”

The scene then shifted to a large television monitor, where from London Prime Minister Tony Blair praised the “huge role” the United States had played in bringing the Human Genome Project to fruition. “Huge role” does not mean “leading role” or “central role” or even “ essential role.” The backhanded compliment was Blair’s way of signaling that the project was British in its roots, though implemented with American money. To underscore the point, Blair had seated with him Fred Sanger, the biologist after whom Britain’s DNA sequencing center was named. Sanger, a genial, unassuming fellow who has made few public utterances, invented a highly ingenious method of decoding the sequence of chemical units in DNA. Almost every problem the two teams of sequencers had grappled with as they completed the human genome, Sanger had wrestled with twenty years before. The only biologist to win two Nobel Prizes—one for a method of sequencing proteins, one for his DNA method—Sanger launched the field of genomics in 1977 by sequencing the genome of a small virus 5,375 units in length. But without advanced computers, automation, and a method of amplifying DNA not invented until 1985, Sanger had been unable to take his tour de force further.

The two teams that decoded the human genome had depended on Sanger’s method, though with its chemistry altered so that it could be performed by machine instead of manually. The Human Genome Project started in earnest when John Sulston at the Sanger Centre, with his American partner Robert Waterston, began to test the new sequencing machines on a pilot project, the genome of the roundworm, a microscopic animal much studied in laboratories. The center’s work was supported by the Wellcome Trust of London, the world’s largest medical philanthropy.

“For let us be in no doubt about what we are witnessing today,” Blaircontinued, “a revolution in medical science whose implications far surpass even the discovery of antibiotics, the first great technological triumph of the twenty-first century.” Today’s announcement, the prime minister said, “opens the way for massive advances in the treatment of cancer and hereditary diseases, and that is only the beginning.”

Clinton then turned to Francis Collins, director of the National Human Genome Research Institute and the leader of the academic consortium. Collins, a born again Christian, said, “It is humbling for me and awe-inspiring to realize that we have caught the first glimpse of our own instruction book, previously known only to God.”

Though Clinton and Blair had already praised Venter, Collins in introducing him heaped further laurels on his head, twice calling his strategy innovative and referring to his “landmark achievement” in assembling his own genome sequence.

With a build-up of such authority, Venter saw no particular need to minimize the significance of his achievement. “Today, June 26 in the year 2000,” he began, “marks a historic point in the 100,000-year record of humanity. We’re announcing today for the first time our species can read the chemical letters of its genetic code.”

The human genome sequence, Venter said, “represents a new starting point for science and medicine, with potential impact on every disease.” He suggested that the genome might even generate quick treatments for cancer, saying, “There’s at least the potential to reduce the number of cancer deaths to zero during our lifetimes.”

Could anything, even the human genome sequence, live up to such intense billing? A turning point in history, a divine revelation, a cure for cancer, all rolled into one?

Some critics were quick to suggest that disease-causing gene variants might be very hard to find, despite having the genome sequence in hand, and that even if they were, few people would want to be tested unless treatments were available too. “The new genetics will not revolutionize the way in which common diseases are identified or prevented,” two skeptics wrote inThe New England Journal of Medicine.²

The harshest verdict came from William Haseltine, Venter’s formerpartner and chief executive of Human Genome Sciences. “Most of us in the pharmaceutical industry would agree that the draft sequence basically is a non-event in our world,” he said of the genome sequence toThe Wall Street Journala month after the White House announcement.³Elsewhere he described the announcement as “a symbolic moment, like sending men to the moon symbolized our intent to use space, like Admiral Peary’s journey to the North Pole symbolized the intent to explore the Arctic.”⁴

Haseltine’s point was not that the genome sequence was as dubious as Peary’s claim to have reached the pole but that he himself had chosen a much faster method of exploiting its information, by extracting readymade transcripts of genes from the cell instead of ferreting for the genes themselves in the genome sequence. Many biologists, however, would agree in principle with the optimistic assessments offered at the White House, although probably few would offer any kind of timetable for curing cancer. For several reasons, the sequencing of the human genome does indeed mark a milestone in the history of science and medicine, perhaps in human history too.

Just as Meriwether Lewis’s map showed the finiteness of America, vast as it was, the genome for the first time places limits on human biology. The working of the human body is no longer a boundless mystery. There’s still enigma enough, but the genome sequence defines the extent of the problems to be solved and bolsters biologists’confidence that they will eventually be soluble. That means that the genetic roots of disease will at least be understood in exquisite detail.And the usual long interval between laboratory understanding and practical treatments may shrink as the genome quickens the pace of every aspect of biology.

The promise of the genome is almost unimaginably broad. Every disease is caused or in some measure influenced by a person’s genes. This is true even of infectious diseases: their prime cause may be a bacterium or virus but people vary widely in their susceptibility, depending on their genetic make-up. The major degenerative diseases of old age, such as cancer, heart disease, diabetes and Alzheimer’s, are strongly influenced by genes that predispose a person toward them.

Possession of the human genome sequence means that the genes that contribute to these diseases—they are variant versions of normal genes, not special genes whose only role is to wreak havoc—can be tracked down and studied. In the pre-genome era biologists had some limited successes in identifying variant genes, but the genome sequence is expected to make gene hunting much faster and more systematic.

Discovery of a variant gene by itself does nothing for a patient. But it makes an excellent start to understanding the exact mechanism of a disease. Researchers can examine the protein product that is specified by the variant gene, identify the protein’s usual role in the cell and how it differs because of the variation in the gene, and figure out how the aberrant protein causes or contributes to the symptoms of the disease.

The present proposals for developing medical treatments from genomic knowledge may or may not be successful, as is always the case with research, but there is a widespread view among biologists that a new era has begun, one that incorporates all the single gene biology of the past and enables living cells to be studied for the first time in their totality, on a genome-wide basis.

The genome is the infrastructure that unites all the branches of biology; in doing so, it promises to accelerate dramatically the pace of advance in medicine. Most basic biology, such as study of how genes and cells work, is done in laboratory organisms such as the mouse, the fruit fly, and the roundworm, and then confirmed in human cells. The knowledge gained from these animals can be related much more quickly to humans now that the genomes of these species have been sequenced and can be compared directly. With a few keystrokes, a researcher can now ascertain whether a new gene found in the mouse or fruit fly or roundworm has counterparts in people. The mouse in particular, a fellow mammal, has turned out to be surprisingly similar to people on a genomic level and all the more helpful for that reason in interpreting the human genome.

The human genome sequence will prove invaluable in another way: it provides the basis for explaining and integrating all knowledge about the human body. For example, biologists are already beginning to understandthe anatomy and physiology of the cochlea—the organ of hearing—in terms of the genes that that make each of its components.⁵This anatomical dissection at the genetic level has been possible through studying the genetic causes of deafness. The ear is a delicate mechanism, with such fine tolerances that a mutation in almost any of the genes involved in building it causes loss of hearing. Through these mutations, the genes themselves have been discovered. It is easy to envisage the time when all the body’s other organs will be described in terms of the genes that specify their development in the embryo and their function and maintenance throughout life. The genome will become a unifying explanation for all of human biology and medicine.

The genome, in other words, is more than just a sequence. It is a means of reorienting biology and medicine and of accelerating the pace of discovery in all the biomedical sciences.

Beyond its practical importance, the genome bears on the nature of human life. It does not say what life is nor determine the life of any individual. It may not reach to the deepest mysteries of human existence. But it defines with great precision every component of every human cell, and these components specify with great exactness the steps from an egg to a newborn. The rules for the architecture of the brain are surely implicit in the genome, even though the genome defines only genes. The infinite varieties of human thought and behavior are too complex to be determined by the finite information embodied in the genome. But behavioral information can be inscribed in the genome, as is already known from the discovery of genes that determine feeding behavior in the roundworm and courtship rituals in the fruit fly. It is certainly possible, even likely, that many general rules of human behavior are implicit in the genes.

Humans have far fewer genes than was generally expected to be the case. The fruit fly has almost 14,000 genes, the roundworm 19,000, and people only 30,000 or so. The enormous increase in complexity between a worm and a person is obviously not reflected in the only slightly greater number of genes and must lie in other factors, such asthe more complex nature of human proteins, which allows more interactions between them.

Biologists, as they consider the genome’s impact on their work, are also moved by the prospect of doing science in new ways. Analysis of the genome has to be done on computer, a circumstance that is forcing the digitization of other aspects of biology. There used to be two kinds of biological experiment: in vitro and in vivo (in glassware and in live animals). There is now a third: in silico, meaning biology that is done by querying genome data in distant data banks. “The instructions for assembling every organism on the planet—slugs and sequoias, peacocks and parasites, whales and wasps—are all specified in DNA sequences that can be translated into digital information and stored in a computer for analysis,” two biologists wrote recently. “As a consequence of this revolution, biology in the twenty-first century is rapidly becoming an information science. Hypotheses will arise as often in silico as in vitro.”⁶

Some observers expect the pace of biological research to accelerate because so many of the world’s biologists are becoming networked by the need to consult genomic databases. “Networking biology started in the 1990s and we think will accelerate to the point where genomic and protein information will become available to all scientists; that will be a vast change coming over the research community in the next decade,” says Randal Scott, chairman of Incyte.⁷

The genome is important for another reason: it may reflect the beginning of an intellectual turning point in biological research.Molecular biology’s successes have come from a rigorous reductionism—the approach of ignoring the whole organism, however interesting, in favor of red...

Table of contents

• Cover
• Colophon
• Also By
• Title Page
• Copyright
• Contents
• Preface
• 1:The Most Wondrous Map
• 2:The Race For The Human Genome
• 3:The Meaning Of The Life Script
• 4:To Close Pandora's Box
• 5:Regenerative Medicine
• 6:The Quest For Immortality
• 7:Bravo, New World
• Notes
• Bibliography
• Index
• About The Author