By Tim Friend, USA TODAY

　　
　　Cracking the human genetic code - a 10-year effort involving thousands of scientists worldwide - is essentially complete, and the door to the future of medicine has been thrown wide open.

On Monday, scientists involved in two separate projects - at the publicly funded Human Genome Project in the USA and Britain and at the private company Celera Genomics in Rockville, Md. - will announce the historic achievement, which is similar in scale to man walking on the moon. Their announcements will launch an unprecedented era of scientific discovery.

The genetic code, a compilation of 3.5 billion letters that scientists call the Book of Life, has been wrested from the nucleus of our cells, deconstructed to its minimal essence like the individual notes of a grand symphony, and reassembled from beginning to end. If the entire code, or this genetic symphony, were printed in this newspaper, it would fill 151,910 pages and create a 42-foot-high stack of folded newspapers at the newsstand.

Generations of scientists will spend most of the next century interpreting the code's meaning and learning to play it on computers in increasingly complex ways that they believe will lead to treatments for most, if not all, human diseases. The genetic code also will launch a mammoth growth industry and marry the new darlings of Wall Street: computer technology and biotechnology.

Scientists from the public and private projects predict that the information contained in the genetic code will allow them for the first time to study the interactions of many different genes involved in complex diseases such as cancer and heart disease and to develop drugs that target these diseases at their most fundamental root levels.

Researchers also will be able to compare the human genetic code with those of other organisms, including the fruit fly, the mouse and yeast. Looking for similarities will reveal genes that are key to life's basic process as well as to disease. Comparisons also will provide volumes of information about how humans differ from other creatures and how we evolved.

"The completion of these projects is the beginning of the next phase of human biology," says Mike Pallazzola, senior director of biosystems at Amgen Inc. in Thousand Oaks, Calif. In the late 1980s, Amgen became one of the first biotechnology companies to create a drug based on a gene discovery. Today it is one of the most voracious consumers in the world of gene sequence data. "Now scientists everywhere can do a lot of things they couldn't do before," he says.
　　
　　J. Craig Venter, who spearheaded the Celera program, and Francis Collins, the U.S. leader of the international Human Genome Project, are expected to announce the completion of their projects at press conferences Monday in Washington, D.C.

"Achieving this milestone is an exhilarating moment in history, and a credit to the ingenuity and dedication of some of the brightest scientists of the current generation," Collins told USA TODAY. "Even more importantly, it brings us a major step closer to understanding and better treating a host of diseases for which genomics offers the best hope of prevention and cure."

Announcements also will be made in London by John Sulston, director of the Sanger Centre, Cambridge, and co-leader of the Human Genome Project; Michael Dexter, director of the Wellcome Trust; and Michael Morgan, chief executive of the Wellcome Trust Genome Campus. The U.S. public project is funded by taxpayers through the National Institutes of Health. The British effort is funded by the Wellcome Trust, a private philanthropy.

The public sequencing effort has been conducted by the Sanger Centre; the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts; Washington University School of Medicine in St. Louis; Baylor College of Medicine in Houston; and the Joint Genome Institute in Walnut Creek, Calif.

What Celera intends to announce Monday is that it has assembled the 3.5 billion letters of genetic code into their natural order. According to Venter, who formed Celera with PE Corp. in 1998, company scientists have placed the letters in the same order as they are found on the 24 human chromosomes in the DNA of every cell. While some letters are missing and others may be out of order, Harold Varmus, former director of the National Institutes of Health, said publicly this week that he believes Celera's data are accurate and essentially complete.

Celera announced in March that it had completed a similar sequencing effort on the fruit fly with government-sponsored Drosophila Genome Project scientists. The fruit fly is an important model for understanding human disease. At the time, Human Genome Project scientists attacked Celera's fruit fly data. But the data are now regarded as highly accurate and foreshadowed Celera's successful sequencing of the human genome.

Spelling out instructions

The genetic sequence at the focus of Monday's announcements is represented by the first letters of the four components of DNA - guanine, adenine, thymine and cytosine, or G,A,T,C. The sequence, which varies in its order depending on its function, spells out every instruction of every gene in the human body.

About 3% of the sequences represent the instructions for all of the proteins made in the body, such as insulin or hemoglobin. The remainder make up mysterious regions of DNA that stretch for relatively vast distances between genes. These regions are certain to hold important genes, such as those that act as master switches that turn other genes on and off. Having the full genetic sequence of the entire genome will allow scientists to view the whole human genetic landscape and begin to understand how genes interact with one other and their environments.

"This is the first time in history that the human genetic code has been assembled in a linear fashion," Venter says. To assemble the 3.5 billion letters of genetic sequence in their correct order, Celera's scientists - actually its supercomputers - performed 480,000,000,000,000,000,000 calculations, he says.

The Human Genome Project, which was launched in 1990, will report that it has completed a "working draft" of the human genome, which contains the genetic sequence of an estimated 90% of human DNA with more than 20% of the sequence arranged in near perfect order on a genetic map.

Human Genome Project scientists have used a different strategy, which makes direct comparisons between their achievement and Celera's difficult.

Varmus said Celera technically finished the sequence first but that the two groups are very close. He also emphasized that Human Genome Project data, unlike Celera's, are freely available to scientists worldwide in academia and at drug and biotechnology companies.

"We're engaged right now in an intense effort involving quite a large number of people to dig out what the interesting features are, determine how many genes there are, see what they look like, how they are organized along chromosomes, how they fit together and how the sequences snuggle up next to each other," says Collins, who in 1993 took over the U.S. project from James Watson, one of the founding fathers of the Human Genome Project. "These are all answerable questions with the working draft."

Now what?

"What does all this mean? From a pure science point of view, we now have coverage of the human genome," says Richard Gibbs, director of the sequencing center at Baylor. "If it is the instruction book of life, then we've looked at every page, and 90% of the pages have been analyzed in sufficient detail to see most of the sentences. We have a pretty good idea of the content and the composistion of this instruction book. To break away from the analogy, we have the raw material in the database from which to extract the human gene list. That's the importance of next week's announcement."

Although the two sides have been bitter rivals in a race and war of words, a behind-the-scenes agreement by Venter and Collins is expected to yield something akin to a shared victory, or at least a truce. Sources say the two sides believe a public showing of goodwill will polish their images for the history books.

"Everyone can have a happy ending," Collins says.

Scientists agree that the achievements by Celera and the Human Genome Project have dramatic and positive implications for human society. Some predict the expected health benefits will begin to appear with regularity in about 10 years.

"We will see an increasing proportion of gene-based medicines coming to the market that are targeted to the disease process," says Paul Herrling, director of global research at Novartis Pharmaceutiucal Corp. in Basel, Switzerland. "Many traditional therapies address the end stages of disease. These new therapies will address the disease process, so if a person has Alzheimer's disease or diabetes, we will develop medicines that stop or slow down the disease process. Having the human sequence is just the beginning."

The first fruits of the projects - profits and power - will fall to companies and scientists who commercialize the data. Certainly the investors in the most successful companies will benefit.

Celera's human sequence data are being mined by key drug companies, including Pfizer, Novartis and Amgen, for targets for drug development. The companies pay Celera $5 million to $15 million per year for access to the data. Celera says it charges academic scientists a reduced amount - $2,000 to $10,000 per lab - for the data. Vanderbilt University currently pays for an academic subscription. Celera may announce Monday how it plans to make its data freely available for academic research.

There's a glimpse of the future in the relationships being built between Celera and other institutions and at the companies springing up as direct result of the Human Genome Project's free accessible data. City of Hope, a comprehensive cancer treatment and research center at Duarte, Calif., announced a partnership March 20 with Celera to hunt through the gene sequence data for gene variations involved in breast cancer.

"For the first time we can actually sit and find out which of the variations are causing disease," says Larry Couture, vice president of technology transfer and development at City of Hope. "This is a huge milestone. Is it curing disease? No. Is it directly leading to the discovery of new therapeutics for disease? No. But it gives us a tool for the first time to find out which genes are associated with which diseases, to know which pathways and genes to go after."

A San Francisco firm, Double Twist Inc., is the first to base a company on the public data from the Human Genome Project and begin repackaging it for customers, primarily drug companies. Double Twist is involved in the complex process known as annotation, which means identifying individual genes from the sequence data and learning their function, locations and relationships with other genes.

Discoveries also are being made by academic laboratories using the public data. Eric Green, chief of the Genome Technology Branch at the National Human Genome Research Institute at the National Institutes of Health, has traced the discovery of more than a dozen genes by outside laboratories directly to the public sequence data.

　　 "The real advance," Green says, "is being able to identify more efficiently genes associated with human diseases. Perhaps the most important point is to contrast how we are today compared to two years ago. Imagine exploring the continent without a map and only a collection of random photographs and a satellite photo showing the outline. Now we have the Rand McNally for the human body."