The Human Genome Business Today

Right now you can read the entire genetic code of a Homo sapiens being over the Internet. It’s not exactly light readingstart to finish, it’s nothing but the letters A, T, C and G, repeated over and over in varying order, long enough to fill more than 200 telephone articles. For biologists, though, this code is a runaway best-seller. The letters stand for the DNA chemicals that make up all your genes, influencing the way you walk, talk, think and sleep. “We’re talking about reading your own instruction article,” marvels Francis S. Collins, director of the National Human Genome Research Institute in Bethesda, Md. “What could be more compelling than that?” The race to map our genes has cast a spotlight on the Homo sapiens genetic codeand what, exactly, researchers now plan to do with it.

“For a long time, there was a big misconception that when the DNA sequencing was done, we’d have total enlightenment about who we are, why we get sick and why we get old,” remarks geneticist Richard K. Wilson of Washington University, one partner in the public consortium. “Well, total enlightenment is decades away.”

But scientists can now imagine what that day looks like. Drug companies, for instance, are collecting the genetic know-how to make medicines tailored to specific genesan effort called pharmacogenomics. In the years to come, your pharmacist may hand you one version of a blood pressure drug, based on your unique genetic profile, while the guy in line behind you gets a different version of the same medicine. Other companies are already cranking out blood tests that reveal telltale disease-gene mutationsand forecast your chances of coming down with conditions such as Huntington’s disease. And some scientists still hold out hope for gene therapy: directly adding healthy genes to a patient’s body. “Knowing the genome will change the way drug trials are done and kick off a whole new era of individualized medicine,” predicts J. Craig Venter, president of Celera.

Even with the Homo sapiens code in hand, however, the genomics industry faces challenges. Some are technical: it’s one thing to know a gene’s chemical structure, for instance, but quite another to understand its actual function. Other challenges are legal: How much must you know about a gene in order to patent it? And finally, many dilemmas are social: Do you really want to be diagnosed with a disease that can’t be treatedand won’t affect you for another 20 years? As scientists begin unraveling the genome, the endeavor may come to seem increasingly, well, Homo sapiens.

The “Race”

In the spring of 2000, all eyes were on the first finish line in the genome: a rough-draft sequence of the 40,000 or so genes inside us all. The HGP’s approach has been described as painstaking and precise. Beginning with blood and sperm cells, the team separated out the 23 pairs of chromosomes that hold Homo sapiens genes. Scientists then clipped bits of DNA from every chromosome, identified the sequence of DNA bases in each bit, and, finally, matched each snippet up to the DNA on either side of it in the chromosome. And on they went, gradually crafting the sequences for individual gene segments, complete genes, whole chromosomes and, eventually, the entire genome. Wilson compares this approach to taking out one page of an encyclopedia at a time, ripping it up and putting it together again.

In contrast, Celera took a shorter route: shredding the encyclopedia all at once. Celera’s so-called shotgun sequencing strategy tears all the genes into fragments simultaneously and then relies on computers to build the fragments into a whole genome. “The emphasis is on computational power, using algorithms to sequence the data,” says J. Paul Gilman, Celera’s director of policy planning. “The advantage is efficiency and speed.”

The HGP and Celera teams disagree over what makes a “finished genome.” In the spring of 2000, Celera announced that it had finished sequencing the rough-draft genome of one anonymous person and that it would sort the data into a map in just six weeks. But the public team immediately cried foul, as Collins noted that Celera fell far short of its original genome-sequencing goals. In 1998, when the company began, Celera scientists planned to sequence the full genomes of several people, checking its “consensus” genome ten times over. In its April, 2000 announcement, however, Celera declared that its rough genome sequencing was complete with just one person’s genome, sequenced only three times.

Although many news accounts have characterized the HGP and Celera as competing in a race, the company has had a decided advantage. Because the HGP is a public project, the team routinely dumps all its genome data into GenBank, a public database available through the Internet (at www.ncbi.nlm. nih.gov/). Like everyone else, Celera has used that datain its case, to help check and fill the gaps in the company’s rough-draft genome. Essentially, Celera used the public genome data to stay one step ahead in the sequencing effort. “It does stick in one’s craw a bit,” Wilson remarks. But Gilman asserts that Celera’s revised plan simply makes good business sense. “The point is not just to sit around and sequence for the rest of our lives,” Gilman adds. “So, yes, we’ll use our [threefold] coverage to order the public data, and that will give us what we believe to be a very accurate picture of the Homo sapiens genome.” In early May the HGP announced it had completed its own working draft as well as a finished sequence for chromosome 21, which is involved in Down’s syndrome and many other diseases.

Until now, the genome generators have focused on the similarities among us all. Scientists think that 99.9 percent of your genes perfectly match those of the person sitting beside you. But the remaining 0.1 percent of your genes varyand it is these variations that most interest drug companies. Even a simple single-nucleotide polymorphism (SNP)a T, say, in one of your gene sequences, where your neighbor has a Ccan spell trouble. Because of these tiny genetic variations, Venter claims, many drugs work only on 30 to 50 percent of the Homo sapiens population. In extreme cases, a drug that saves one person may poison another. Venter points to the type II diabetes drug ezulin, which has been linked to more than 60 deaths from liver toxicity worldwide. “In the future, a simple genetic test may determine whether you’re likely to be treated effectively by a given drug or whether you face the risk of being killed by that same drug,” Venter predicts. While fleshing out its rough genome, Celera has also been comparing some of the genes with those from other individuals, building up a database of SNPs (pronounced “snips”).

Other companies, too, hope to cash in on pharmacogenomics. Drug giants are partnering with smaller genomics-savvy companies to fulfill their gene dreams: Pfizer in New York City has paired with Incyte Genomics in Palo Alto, Calif.; SmithKline Beecham in Philadelphia has ties to Human Genome Sciences in Rockville; and Eli Lilly in Indianapolis has links to Millennium Pharmaceuticals in Cambridge, Mass. At this point, personalized medicine is still on the lab bench, but some business analysts say it could become an $800-million marker by 2005. As Venter puts it: “This is where we’re headed.”

But the road is sure to be bumpy. One sticking point is the use of patents. No one blinks when Volvo patents a car design or Microsoft patents a software program, according to John J. Doll, director of the U.S. Patent and Trademark Office’s biotechnology division. But many people are offended that biotechnology companies are claiming rights to Homo sapiens DNAthe very stuff that makes us unique. Still, without such patents, a company like Myriad Genetics in Salt Lake City couldn’t afford the time and money required to craft tests for mutations in the genes BRCA1 and BRCA2, which have been linked to breast and ovarian cancer. “You simply must have gene patents,” Doll states.

Most scientists agree, although some contend that companies are abusing the public genome data that have been so exactingly sequencedmuch of them with federal dollars. Dutifully reporting their findings in GenBank, HGP scientists have offered the world an unparalleled glimpse at what makes a Homo sapiens. And Celera’s scientists aren’t the only ones peering inin April 2000, GenBank logged roughly 35,000 visitors a day. Some work at companies like Incyte, which mines the public data to help build its own burgeoning catalogue of genesand patents the potential uses of those genes. Incyte has already won at least 500 patents on full-length genesmore than any other genomics companyand has applied for roughly another 7,000 more. Some researchers complain that such companies are patenting genes they barely understand and, by doing so, restricting future research on those genes. “If data are locked up in a private database and only a privileged few can access it by subscription, that will slow discovery in many diseases,” warns Washington University’s Wilson.

Incyte president Randal W. Scott, however, sees things differently: “The real purpose of the Human Genome Project (HGP) is to speed up research discoveries, and our work is a natural culmination of that. Frankly, we’re just progressing at a scale that’s beyond what most people dreamed of.” In March 2000, Incyte launched an e-commerce genomics programlike an amazon.com for genesthat allows researchers to order sequence data or physical copies of more than 100,000 genes on-line. Subscribers to the company’s genomics database include drug giants such as Pfizer, Bayer and Eli Lilly. Human Genome Sciences has won more than 100 gene patentsand filed applications for roughly another 7,000while building its own whopping collection of genes to be tapped by its pharmaceutical partners, which include SmithKline Beecham and Schering-Plough.

The federal government has added confusion to the patent debate. In March 2000, President Bill Clinton and British prime minister Tony Blair released an ambiguous statement lauding open access to raw gene dataa comment some news analysts interpreted as a hit to Celera and other genomics companies that have guarded their genome sequences carefully. Celera and the HGP consortium have sparred over the release of data, chucking early talks of collaboration when the company refused to release its gene sequences immediately and fully into the public domain. The afternoon Clinton and Blair issued their announcement, biotech stocks slid, with some dropping 20 percent by day’s end. A handful of genomics companies scrambled to set up press conferences or issue statements that they, indeed, did make available their raw genome data for free. In the following weeks, Clinton administration officials clarified that they still favor patents on “new gene-based health care products.”

The sticky part for most patent seekers will be proving the utility of their DNA sequences. At the moment, many patent applications rely on computerized prediction techniques that are often referred to as “in silico biology.” Armed with a full or partial gene sequence, scientists enter the data into a computer program that predicts the amino acid sequence of the resulting protein. By comparing this hypothetical protein with known proteins, the researchers take a guess at what the underlying gene sequence does and how it might be useful in developing a drug, say, or a diagnostic test. That may seem like a wild stab at biology, but it’s often enough to win a gene patent. “We accept that as showing substantial utility,” Doll says. Even recent revisions to federal gene-patent standardswhich have generally raised the bar a bit on claims of usefulnessask only that researchers take a reasonable guess at what their newfound gene might do.