The details make you dizzy. The terminology turns you numb. But when the average person looks at the big picture, the Human Genome Project meets an important rule of thumb for good science, says Maynard Olson, director of the University of Washington Human Genome Center.
“If you can’t explain the research you’re doing to your next door neighbor, it should give you pause,” he says. “The Human Genome Project was never that difficult to explain.”
After more than a decade of data collection and number crunching, the Human Genome Project has produced the molecular blueprint of a human being. By identifying 30,000 to 35,000 distinct genes embedded within the long chemical sequence that forms human DNA, an international army of scientists—including Olson and others from the UW—have captured the code of life.
Their report—published last February in Nature magazine—launched skyrockets. And why not? “The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution,” reads the report’s introduction.
Some compare the genome to a window on the essence of what it means to be human. Through it people hope to see fantastic advances unfold—a cure for cancer, an antidote for aging, a test for the risk of heart disease and other ills—all made possible by understanding the molecular machinery that drives our bodies.
“The stakes are pretty high here because people think there is a Nobel Prize involved.”
Philip Green, UW professor
“It caught the public’s imagination,” says Olson (at left in photo at top), “because they can grasp what it’s all about.”
Or can they?
While the basic biology and the potential payoffs behind compiling a complete tally of human genes—otherwise known as a genome—may have penetrated the Zeitgeist of the new millennium, many of the subplots surrounding this scientific milestone probably have not.
Chief is a rivalry between public and private scientists chasing the same prize: the honor, satisfaction and opportunities—altruistic as well as economic—dangled by cataloging the human genome.
At stake, according to some, is the future of science. Will it be increasingly controlled—and perhaps manipulated—by private corporations that hoard their data to maximize profits? Or will it remain essentially a public endeavor in which research is shared, scrutinized and built upon by all?
The Human Genome Project refers to the work of the International Human Genome Sequencing Consortium. Formed in 1990, the coalition consists of 20 groups—including the UW Genome Center—from the U.S., the United Kingdom, France, Germany, Japan and China.
Funded mostly by the U.S. National Institutes of Health (NIH) and the Wellcome Trust of London, the consortium set its own pace and planned to finish assembling the human genome in 2003.
But that was before the commercial potential of possessing the human genome—and selling research data and patenting genes—drew private enterprise into the quest. In 1998, Celera Genomics Group announced it would launch a competing project—and finish three years sooner.
Craig Venter, a former NIH researcher, is the founder of Celera. The Maryland company’s motto is “Discovery Can’t Wait.”
Venter pioneered a radical alternative to the consortium’s “clone-by-clone” sequencing technique known as “whole genome shotgun cloning.” Combined with massive technology and reliance on existing consortium data, Venter employed the shotgun technique to counter the consortium’s head start—and trigger a war of words over whose method was faster, cheaper and more accurate, whose work was more derivative and whose publication policies best served science.
Numerous pot shots later—and after the consortium hit the gas to match Celera—the two sides agreed to jointly announce completion of separate draft versions of the human genome in June 2000. Likewise, they jointly published articles describing their findings last February—with the consortium’s version appearing in Nature and Celera’s in Science.
Each party claimed superior, if not totally dissimilar, results. In neither case, however, is their version of the genome complete. Both parties still must plug significant gaps—stretches of DNA where the chemical sequence that comprises the genome remains uncharted.
For UW Professor Philip Green (at right in photo at top), those patches of Swiss cheese in the consortium’s sequence are one of several troubling consequences of Celera’s entry into the genome derby.
Had it been up to Green, the Human Genome Project would have skipped publishing a draft sequence and stuck by its original plan of waiting until it could publish a “clean final sequence”—a much more efficient approach, he says.
“Unfortunately, the reason they didn’t do that was the competition with Celera,” says Green.
“We have the code now, but fully understanding the code is the work of a whole other generation and beyond.”
Debbie Nickerson, associate professor of molecular biotechnology
Recently elected to the National Academy of Sciences, Green is a professor of molecular biotechnology and adjunct professor of computer science, disciplines that intersect at precisely the point where exploration of the human genome begins.
At its core, genetics is all about biology. But without computers, scientists couldn’t begin to juggle the billions of variables that must be sifted and sorted in search of the minute chemical clues that disclose distinct genes.
That’s where hybrid scientists such as Green shine. Two software programs he created called Phred and Phrap played a critical role in analyzing raw DNA samples at Human Genome Project labs around the world.
Over the years, the University has been creating curriculum and programs designed to produce more scientists like Green—people who are as comfortable at a microscope as they are at a computer screen.
The fact that the UW Genome Center is one of a relative handful of university-based participants in the Human Genome Project testifies to its status as a hub of computational biology and genetic research.
“The University has a very good collection of faculty who work in the general area of applying computational methods to biology,” says Green, whose position is funded by the Howard Hughes Medical Institute. “It might well be the best in the country.
“Other places may be farther ahead in terms of setting up graduate programs in those areas, but the University of Washington is one of the leaders in that respect as well.”
As consortium scientists gear up to fill the holes they left in the draft sequence—a process that will take three years—Green worries about a possible loss of momentum due to release of a draft.
Moving methodically, consortium scientists had been meticulously exploring specific regions of the genome, with priority placed on those regions linked to particular diseases. The strategy was akin to creating a map of the United States by creating maps of all the terrain within each state, one state at a time.
Then along came Celera, and instead of waiting until 2003 to publish a complete and thorough map, the consortium began jumping from one state to the next without accounting for every bit of terrain. That way it could publish a complete—if not perfectly thorough—draft sequence in time to match Celera.
Olson says it was unfortunate that consortium leaders got caught in the “breathlessness that crept into the system” after Celera’s arrival. On the other hand, “the draft provided lots of data that people are using today sooner than they would have.”
Green believes changing strategies wasted money and produced little benefit—other than boosting the bottom line of Celera’s sister company, Applied Biosystems.
That company produces the powerful machines scientists use to extract strands of DNA from cells. Celera deployed an armada of the devices right from the start, forcing the consortium to do the same if it wanted to keep up, says Green.
“Applied Biosystems is like an arms merchant that supplies both sides in a war,” says Green.
Green believes publishing the draft poses an ongoing risk for the Human Genome Project. By creating the perception that the remaining work is a “mop-up operation,” the draft may discourage some scientists from seeing the project through, he says.
“That is not the way we want science to develop generally and certainly not in an area as sensitive as the human genome.”
Maynard Olson, director of the University of Washington Human Genome Center
If that’s the case, why did consortium leaders dump their original strategy? “They were disturbed about the possibility that Celera would patent the whole genome,” says Green.
And that’s not all. “The stakes are pretty high here because people think there is a Nobel Prize involved,” he says.
If so, it would slap Nobel book ends on a chapter of science that began when James Watson and Francis Crick won the 1962 prize for discovering the double-helix structure of DNA.
Like shelves in a library, DNA molecules contain all of the books—or more precisely genes—necessary to create and sustain a particular organism. And every nucleus of every cell of every organism contains this library.
DNA molecules—a.k.a. chromosomes—resemble ladders with long spiral legs. The rungs consist of two interlocking chemical units called nucleotides. Together, the nucleotides form what are known as base pairs. Base pairs are combinations of either cytosine and guanine or adenine and thymine—referred to collectively as ACTGs.
Genes are sets of base pairs buried in the long and continuous sequence of ACTGs that comprise a DNA molecule. Each gene tells the cell how to make a specific protein—proteins being the catalyst for how cells ultimately develop and function.
Identify the sequence of all the ACTGs present within all of an organism’s DNA and you’ve identified its genome. Identify its genome and you can begin identifying the genes responsible for health and disease—and developing gene-based tests and treatments.
Thanks to the foundation laid by Watson and Crick, all of those facts already were fodder for high school textbooks long before the Human Genome Project began. So why did it take scientists so long to assemble the human genome?
With 3 billion base pairs, the human genome is a mind-boggling procession of ACTGs—enough letters to fill more than 75,000 pages of a newspaper. Split between 24 chromosomes, the sets of base pairs range from a few hundred pairs to several thousand and the genes embedded in them often repeat or overlap.
What’s more, the 30,000 to 35,000 genes hailed as “the human genome” represent only those sets of ACTGs that produce proteins. Like islands in a vast ocean, they are surrounded by a hundred times more “junk” DNA.
Given such complexity, scientists had to develop potent new techniques and technologies before they could bite off the entire human genome instead of nibbling at small pieces as they had done before the Human Genome Project.
The UW’s Olson pioneered some of those techniques. In fact, last year Olson received a City of Medicine award recognizing that work. The award states that without Olson’s development of a yeast artificial cloning system and introduction of certain mapping markers in the 1980s, sequencing the human genome “would not have been possible.”
Olson came to the UW from Washington University in St. Louis—another Human Genome Project site—in 1992 as a founding member of Leroy Hood’s molecular biotechnology department. The UW Human Genome Center took shape in 1994 when the University applied for and received federal funding to host a Human Genome Project sequencing center. Not only did that place the UW in an elite group, it helped the University pursue one of its own priorities.
“The UW has focused on the technology development aspects of human genome sequencing (such as Green’s software programs), which required that we had a center that did enough sequencing that our technology would be taken seriously,” explains Olson.
Olson has long championed the quest for the human genome. When other scientists argued that the Human Genome Project would divert too many resources from other important work, “I argued it would energize other research,” he says.
And it has—with the ripples spreading wider every day. “I get asked to talk to different departments at the UW all the time that before never had much interest in genetics,” he says.
While Olson is passionate about pursuit of the human genome—”I think history will look back on the Human Genome Project as a fundamental transformation of human knowledge”—the UW professor of medicine is conservative about how long it will take for mainstream medical benefits to flow from the project. His estimate: 10 to 20 years.
One remaining hurdle is completing the genomes of other organisms with DNA similar to humans, which will give scientists a way to compare and experiment when they find common genes.
“There’ve been many times when the leadership would have preferred I was more unequivocally enthusiastic about the immediate … impact of what was being done,” says Olson. “It is very exciting. I’m just cautious about claims that it’s going to lead rapidly to greatly improved health care.”
On the other hand, there’s nothing cautious about Olson’s comments concerning the approach and motives of Celera. “I’ve been known as a critic of the private project,” he says.
Debates over techniques and results aside, Olson accuses Celera of “science by press release.” As a private company, it closely controls information about its research. Furthermore, it “misrepresents” the significance of some results—a product of pressure to justify investment in the company, he says.
According to Olson, it’s a poor precedent for the future of science, which traditionally has relied on open publishing and vigorous peer reviews—formal and informal—to ensure accuracy and spur progress. “That is not the way we want science to develop generally and certainly not in an area as sensitive as the human genome,” he says.
Celera did not respond to requests to comment for this story, but Venter told PBS that the consortium would have dragged its feet for several more years if not for competition from Celera. “We made things go faster,” he said. In an Associated Press interview, he called Celera’s data “substantially superior” and criticism of his work “one of the sadder parts of science.”
“There’s two ways to get ahead in science,” Venter continued, “one is to do something that is significant, and the other way is to criticize someone who has done something significant. We’ve chosen the former; some of our critics have chosen the latter.”
Nevertheless, Green and others fret about private companies “locking up” fundamental scientific information. While Celera did eventually publish its draft human genome sequence, it has never made its research freely available on an ongoing basis and continues to curb broad access to its data. What’s more, the company’s recently finished version of a mouse genome—considered critical to understanding the human genome—will not be fully published to guard the data’s commercial value.
By contrast, the consortium places its data in the public domain daily for unfettered use by the world’s scientists—even those at Celera. That is the way fundamental science should be practiced, says Green. “You make discoveries and other people build on those discoveries.”
In that sense, the Human Genome Project is a mighty foundation upon which researchers at the UW and elsewhere can base a lifetime of work. Among them is Debbie Nickerson.
Nickerson, associate professor of molecular biotechnology at the UW, is using Human Genome Project data to search for single nucleotide polymorphisms—variations from the consensus DNA sequence that make each individual unique.
It’s exciting work. This is where scientists will discover genes that may promote or discourage various health problems. They may even find genes that explain why some people live longer than others, says Nickerson.
Just don’t expect blockbuster results anytime soon. Not only must scientists identify particular polymorphisms, they must consider the way they interact with other genes and with the environment, says Nickerson.
“We have the code now,” says Nickerson, “but fully understanding the code is the work of a whole other generation and beyond.”
***
When it comes to the Human Genome Project, Phil Bereano is the kid in the back of the class who keeps asking impertinent—but important—questions.
His biggest question: why undertake the project at all?
“We need to free ourselves from a false ideology that we need this particular knowledge,” says Bereano, a professor of technical communication at the UW.
Bereano contends that Human Genome Project supporters overstated the project’s potential medical benefits when lobbying Congress for funding. Bereano believes more people would reap more immediate benefit by expanding existing health care initiatives than by prospecting for cures in the human genome.
“The questions don’t go away just because the genie is out of the bottle.”
Phil Bereano, professor of technical communication
“It used to be that cancer was considered an environmental disease, but now it’s being treated like a genetic disease,” he says. “It’s a tremendous social change that has been brought by the promises and all the hoopla surrounding the Human Genome Project.”
Maynard Olson, director of the UW Human Genome Center, agrees that genome-based improvements to mainstream medicine will take time. Nevertheless, he says the Human Genome Project is worth the cost because it provides a platform for “revolutionizing basic biological sciences in a whole variety of ways.”
What’s more, “increasing knowledge of the natural world is a powerful social force,” says Olson. For example, objective information from the Human Genome Project about what makes human beings similar and different may promote better racial understanding, he says. After all, “our subjective ideas of race have not served us well,” he notes.
While completion of the draft human genome sequence may have neutered Bereano’s cost argument, “the questions don’t go away just because the genie is out of the bottle.”
For one thing, Bereano has concerns about granting patents for the discovery of medically significant genes—something both Celera and the National Institutes of Health support as a way of stimulating development of new therapies. However, Bereano argues that taxpayers paid for most of the underlying research, that genes are an object of nature and that the level of intellectual innovation involved in their discovery does not constitute an invention.
Olson agrees that patents pose a problem—but only because the patent office has not set a high enough standard of proof that a particular gene or genes truly have medical significance.
Bereano also worries about the priorities of those seeking to develop tests and treatments based on the human genome. Will they look first at products that best serve the public—which funded most of the underlying research—or at those that will turn the biggest profit?
“We’re told our cut will come through better medical care,” he says. “My point is, it will be a long time coming, it won’t be as much as promised and will be available only to a small number of people.”