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Breaking the Code to the Genome

June 15, 2000 at 12:00 AM EDT
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SUSAN DENTZER: Scientists are on the verge of something many never expected to see, a virtual parts list of the genetic makeup of human beings.

DAVID BOTSTEIN, Stanford University: When I went into science, the idea that I would live to see not just a sequence of anything, but the sequence of the human genome, I would have thought you were all nuts.

SUSAN DENTZER: It is an achievement that some liken to having a window into the very essence of being human.

FRANCIS COLLINS, National Human Genome Research Institute: I think of getting the human sequence as rather analogous to figuring out what the score looks like for this incredible piece of music called “The Song of Human Life.”

SUSAN DENTZER: It’s also a saga of stunning advances in science and technology – paid for with billions of public and private dollars. The likely outcome is a revolution in medicine.

STELIOS PAPADAPOULOS: It is without limits because the ultimate limit of this activity is the cure of all ills for all humankind.

SUSAN DENTZER: All these experts are talking about the completion of the so-called “working draft” of the human genome. That’s the catalog of more than 3 billion chemical units that make up our entire DNA. The event closes a chapter in a modern epic more than 15 years in the making. Among other things, it’s been a tale of rivalry among researchers locked in a race to decode the genome.

One contender is Francis Collins of the National Human Genome Research Institute, who spearheaded America’s government-funded gene- sequencing effort.

Another rival is J. Craig Venter of Celera Genomics, a private company that announced at a congressional hearing in April that it, too, had sequenced a human genome.

J. CRAIG VENTER, Celera Genomics: This is a very exciting milestone in Celera’s history and in science. We’re going to have now the complete repertoire of human genes, which is the beginning of the next phase of science.

SUSAN DENTZER: Just what does it mean to have sequenced the genome? Most of us know that humans have 80,000 or more genes distributed along 23 pairs of chromosomes like these. We probably learned in school that these genes determine many of our features, such as whether our eyes are blue or brown. But what we may not have mastered is how genes produce these attributes or determine the body’s other functions. Here’s how that works.

Our genes, copies of which are in most of our cells, are made up of DNA. As diagrammed by scientists, in its chemical structure DNA looks like a twisted ladder, or a double helix. The rungs of the DNA ladder are made up of four chemicals, whose names begin with the initials “a,” “t,” “g,” and “c.” These chemicals, or letters, pair up, and a total of 3.2 billion pairs make up our DNA. We don’t know, at least yet, what the vast percentage of the DNA does. But we do know that a small portion of our genes function like tiny factories. In a complicated way, the “a,” “t,” g,” and “c” chemicals in the DNA copy themselves many times over to produce the proteins that carry out most of the body’s vital work. So when we talk about sequencing the entire human genome, we mean figuring out exactly how all three billion pairs of these letters are arrayed, in large part to make this protein- manufacturing process possible. Francis Collins says a whole new world of genetic research began to open up in the 1980′s.

FRANCIS COLLINS, National Human Genome Research Institute: Some visionary folks– some people called them dreamers, some people called them nuts– began to contemplate the idea that we might, in an organized fashion, actually try to map and sequence all of the human DNA, not fifty or a hundred years from now, but in an organized effort maybe over the course of fifteen or twenty years. That was very hotly debated.

SUSAN DENTZER: For one thing, these were the days before much of the labor- saving technology used to sequence the genome was even available, such as robots or very high-speed supercomputers. Stanford geneticist David Botstein says the costs seemed likely to reach billions of dollars before the job was done.

DAVID BOTSTEIN, Stanford University: Many scientists, including me, had real doubts. But at the same time, even the most dedicated opponents understood that actually knowing the whole genome was going to be in itself a very valuable, potentially revolutionary thing in biology.

SUSAN DENTZER: Botstein was among those eventually appointed to a scientific panel that drew up a plan to tackle the project. First, to gain more knowledge and skill, scientists would decode the genomes of simpler organisms, like the fruit fly, that still had plenty in common with humans’ genetic makeup. Botstein headed a project to sequence the genome of one organism, the yeast.

DAVID BOTSTEIN: The idea was to take advantage of the fact that evolution has been very slow, relatively, and to sequence a few simple organisms with very small genomes where the genes are much better understood.

SUSAN DENTZER: In the meantime, the hope was that the technology to carry out gene sequencing would improve and costs would drop. After the plan was hammered out, the Human Genome Project was officially launched. That’s an international consortium of academic and other researchers led by the United States and Britain. Collins says the group’s first task was to draw up a so-called map of the human genome.

FRANCIS COLLINS: If the genome is sort of like the United States, and each chromosome is a different state, it was to try to lay out where in fact are the major landmarks, the mountain ranges, the major cities, a few of the small towns.

SUSAN DENTZER: Literally that meant breaking all of human DNA up into sections that were roughly 35,000 letters long, then trying to figure out how these chunks were distributed along our chromosomes. With that job accomplished, Collins says the group turned to the tougher task of gene sequencing, or figuring out how each of the more-than three billion pairs of letters was arranged.

FRANCIS COLLINS: That is in many ways, you might imagine, a mind-numbing experience, and it is done primarily by automated instruments.

SUSAN DENTZER: In fact, by this point technology was advancing fast enough to make this sequencing possible. And it was about to take an even greater leap forward.

J. CRAIG VENTER, Celera Genomics: So we basically, per day here, sequence 100,000 to 200,000 samples, each one giving us about 600 letters of genetic code, twenty-four hours a day, seven days a week.

SUSAN DENTZER: Craig Venter, formerly a biochemist at the National Institutes of Health, was running a private genomics research institute in the mid-1990′s. One day he got a call out of the blue from a private company.

J. CRAIG VENTER: They had an exciting new technology, and they wanted me to see it, and they were also thinking of putting up all the money to sequence the genome, the human genome, and was I interested.

SUSAN DENTZER: With a combination of lasers and other high-tech tools, the machines could actually distinguish samples of DNA letter by letter, producing a sequence as long as several thousand letters in a three-hour run.

J. CRAIG VENTER: We spent a day looking at the prototype machines they had. By the end of that day, we had a plan to sequence the human genome within a two-year period.

SUSAN DENTZER: In effect, Venter and his backers had dreamed up a shortcut to sequencing the genome with the aid of automat sequencers, supercomputers, and mathematical tools. The company they founded to do that was Celera Genomics.

J. CRAIG VENTER: We reasoned that we could take the chromosome, break it up into small pieces, sequence the 500 to 600 letters at a time, and then use the computer to basically solve a jigsaw puzzle.

SUSAN DENTZER: In 1998, Venter’s group approached Francis Collins and offered to bring the new technology and tactics to work on the Human Genome Project. At the time, the consortium’s own sequencing efforts seemed likely to take another ten years. But in the end, Venter and his colleagues were rebuffed. So Venter and his new company, Celera Genomics, went their own way. That culminated in Celera’s announcement last April. The company had met its own two- year deadline and arguably stood to win the sequencing race.

J. CRAIG VENTER: I think you’ll find most people in this field will honestly tell you that would have been ten years away if it wasn’t for Celera. Whether Celera is the first to sequence it or not, we made things go faster.

SUSAN DENTZER: Celera’s achievement hasn’t come without bitterness and sniping on both sides. Critics like William Haseltine, a former Harvard biologist who now has a private genomics company, point fingers at the Human Genome Project for having wasted time and money.

WILLIAM HASELTINE: We can now see how faulty it was by the virtue of the fact that a startup company could virtually complete the whole thing for one-twentieth the price, in one-tenth the time.

SUSAN DENTZER: Collins rejects the charge.

FRANCIS COLLINS: Every single milestone set by the Genome Project from its beginning has been achieved on or ahead of schedule, and for the most part at a price substantially less than the original projections.

SUSAN DENTZER: Meanwhile, the human genome own working draft version of the genome. How much it differs from Celera’s will only be clear once the two are published scientific journals later this year and scientists have a chance to study them. Both sequences will also be available on Web sites– the Human Genome Project’s on its Wweb site, Genbank, and Celera’s on celera.com.

Still, Collins admits that much will remain to be done even after the working draft is released.

FRANCIS COLINS: It will still have lots of gaps, places where we just didn’t have that part of the sequence, lots of places where we’re not absolutely sure that that letter was a “t” and not a “c.” So over the next couple of years we will be closing those gaps, dealing with the ambiguities, trying to resolve any of the areas that we weren’t quite sure of.

SUSAN DENTZER: Researchers around the world are losing no time putting the new genomics knowledge to work. An especially fruitful area of research is looking for misspellings in genetic letters that can help cause disease. Stelios Papadapoulos is a New York investment banker specializing in biotechnology. He says roughly 25 of perhaps 100 or more genomics companies are trying to turn genetic discoveries into viable drugs and other therapies.

STELIOS PAPADAPOULOS: Each one of these companies is really going after a slice of infinity, and a slice of infinity is also infinite. It is the beginning of a very long walk toward identifying every gene, every important gene, every gene relevant to disease, and then finding ways to treat those diseases based on the genetic information, the genomic information.

SUSAN DENTZER: In fact, according to some estimates, 10,000 or more new drugs derived from genetic discoveries could be on the market in coming years. That’s up from the several hundred new drug targets now being pursued by pharmaceutical companies. Dennis Henner directs research at the biotechnology company Genentech.

DENNIS HENNER: At Genentech in five to ten years, and probably most of the pharmaceutical companies, every project moving forward will have been touched in some way by this new information.

SUSAN DENTZER: Another company aiming to be at the forefront of genetically based drug development is Human Genome Sciences, headed by William Haseltine. He says his company identified the lion’s share of human genes five years ago.

WILLIAM HASELTINE: We have over 120,000 human genes. Now, whether that’s a complete collection or not, it’s certainly a very large collection. And the way I look at what genomics has done, is it’s given us a splendid new collection of the body’s own substances that we can use for medicine.

SUSAN DENTZER: Haseltine says Human Genome Sciences is now working with major pharmaceutical companies to turn its gene discoveries into new ways to fight conditions like obesity and osteoporosis. Stanford geneticist Botstein says both the human genome project and Celera can take credit for helping to move the technology this far, this fast.

DAVID BOTSTEIN: What I’m most impressed with is the speed with which it all happened; that, you know, when humans put their minds to some problem, we can accomplish a great deal of good.

SUSAN DENTZER: Scientists are now awaiting publication of the full results of both sequencing efforts in scientific journals later this year.