They Dream of Genes

Science is like a hungry furnace that must be fed logs from the forest of ignorance ... in the process, the clearing we call knowledge expands, but the more it expands ... the more ignorance comes into view.

-- Matt Ridley, "Genome" (1999)

With his green felt hat tugged down over wispy black hair, and his thick black beard, Jim Kent looks like a woodcutter who has just hacked a path through a forest a whisker ahead of a band of treasure-seeking dwarves. In a way he has. Only Kent's forest consisted of 400,000 pieces of data and those "dwarves" were employees of biotech giant Celera Genomics. As for the treasure that both Kent and Celera sought, it was a document of unparalleled worth -- the first rough draft of the complete human genome.

The human genome is best compared to a very long yet very compressed book -- a biological Zip drive, if you will -- tucked inside the nucleus of each of the 100 trillion cells of our bodies. Organized into 23 chapters, one for each chromosome, each genome contains encoded instructions that help shape appearance, intelligence, health and behavior. No single human genome is the definitive edition of our book of life. Yet each version contains a how-to-manual for putting together a human being.

Little wonder, then, that the public and private sectors ended up competing to be the first to put together this priceless document. It was a high-stakes race with access to -- and control of -- the knowledge contained in our genetic blueprint at stake. More surprising was that Kent, a graduate student at University of California at Santa Cruz, became the unlikely hero of this sprint.

Trying to access the secret of life has always been a diabolical business -- it cost Adam and Eve their paradise, Dracula and Faust their souls and Dr. Frankenstein his sanity. But in 1953, scientists Francis Crick and James Watson seemed to have found the secret without striking any satanic deals.

They discovered that DNA contained a code written along a spiraling double helical staircase. This code could copy itself, potentially into infinity, using only four chemical letters (A, T, G and C). But unraveling this code proved to be a riddle of Tolkienesque proportions, one that biologists are still working on.

As Kent puts it, "It's like we've painstakingly laid out the Dead Sea scrolls and photocopied them, but we still only have a vague understanding of what language they're written in."

To complicate matters, the information in these "scrolls" is so vast it could fill 800 Bibles, but so compressed it could fit on the head of a pin. Yet by 1995, an academic consortium of scientists had already been chipping away for five years at the massive task of mapping all this data under the publicly funded umbrella of the Human Genome Project.

Research Wars

The Human Genome Project had first been envisioned 10 years earlier by former UCSC chancellor Robert S. Sinsheimer. At first, biologists had resisted the idea. Mapping the human genome was the biological equivalent of putting a man on the moon, and some feared that its cost -- an estimated $3 billion -- would suck dry the well of microbiological research funds. But the vision prevailed, and by 1990, the Human Genome Project was up and plodding, financed by the U.S. National Institute of Health and England's philanthropic Wellcome Trust.

More than a thousand scientists in the United States and England, as well as in France, Germany, China and Japan, toiled away using slow but methodical research techniques, and by 1998 they had mapped 90 percent of our genetic blueprint for life.

And that's when a privately launched bombshell hit.

In May 1998, Dr. Craig Venter, a brilliant and controversial scientist, announced he was forming a company (which would later become Celera) with the objective of sequencing the human genome first -- and patenting the results.

While working at the National Institute of Health, Venter had been part of the first mass patenting of genes (which had, scandalously enough, been undertaken by the U.S. government itself). And now here he was, heading a commercial operation with massive sequencing capabilities, and threatening to snatch the treasure and lock it up in patents. If he succeeded, the fruits of years of research could be inaccessible for years, except to those willing and able to pay a hefty price.

In response to this threat, more money was pumped into the Human Genome Project, and a new deadline was set. Then in the winter of 1999, Eric Lander, director of the Genome Center at MIT's Whitehead Institute, asked Dr. David Haussler, a professor of computer science at UCSC and a leader in the field of bioinformatics, for help analyzing the project's data. Haussler took a look and said he'd need to assemble the data first, though he wasn't sure how. By spring 2000, he was still looking for the solution. Enter Kent.

Hero's Journey

A former computer animation programmer, Kent, 41, had returned to UCSC -- where he had earned two degrees in mathematics more than a decade earlier -- this time to study biology. As part of his graduate research, he analyzed the DNA of the lab worm C. elegans. And now it was May 2000, and he had just passed his Ph.D. qualifying exam.

Seeing that Haussler, a senior colleague with whom Kent had already collaborated, was still working on sequencing the Human Genome Project data, Kent made Haussler an offer neither of them would ever forget: Maybe he could modify his worm-analysis program for human DNA?

The offer pitched Kent into the forefront of the race with Celera. Nine months later, sitting in Haussler's office in front of a white board scrawled full of probability algorithms, Kent confesses that he was surprised at the significance his role in that race assumed.

"I thought I'd be one of thousands of researchers figuring out how you go from a genome to a human," Kent recalls, "but it turned out we needed this basic assembly first. I was at the right place at the right time with the right abilities and a little bit of luck."

What Kent calls luck, the rest of us would call genius. Working 80-hour weeks in a converted garage behind his bungalow, Kent (aided and abetted by 100 Pentium 111 processors) designed and wrote in one month flat a computer program called GigAssembler. which organized the project's data into a coherent sequence using what Kent terms "a greedy algorithm." GigAssembler enabled Haussler, Kent and a team of UCSC researchers to analyze the Human Genome Project's data and put together a working draft of the genome's sequence.

On June 22, 2000, they made history as they witnessed the human genome's first assembly -- an event Kent likens to the Wright brothers' first flight.

"People were working on that project, too, all over the world, and it was never 100 percent clear who actually flew first," he says, referring to the fact that their version of the genome, while less complete, was assembled a few days earlier than Celera's.

Recalling that moment, the ever-youthful-looking Haussler (who is in his late 40s) leans his lanky frame back in his chair and smiles. "Watching all those As, Ts, Gs and Cs came flying across the screen at the first assembly was the personal thrill of my career," he says. "To see it all come together here in Santa Cruz was amazing. That's the day we flew."

That first flight signaled an end to the assembly race, which was declared an official draw just four days later. On June 26, 2000, Dr. Francis Collins, director of the publicly funded Human Genome Research Institute, appeared at a White House press conference alongside Celera founder Venter.

It was a cordial event. Each announced that his group had successfully assembled the human genome and would publish the results, simultaneously (an event that occurred in February 2001, but in separate journals -- the public consortium publishing in Nature, the private sector in Science).

But Kent and Haussler weren't done. On July 7, 2000 -- two weeks after their breakthrough -- they placed their version squarely in the public domain by posting it on the web.

"The data wasn't yet perfect, although it's going to be mighty fine come 2003," Kent says, flashing a smile. "But it's very powerful knowledge. The genie's out of the bottle, and I think it's better for everybody to have a crack at it, than have it hidden away somewhere."

Haussler nods his agreement. "We didn't want the genome to be controlled by a few," he says. "It has to belong to all of humanity." And humanity was waiting. On July 7, UCSC servers put out half a terabyte of information, as 20,000 people downloaded the genome.

And by Christmas, a compressed copy of it, which Kent jokingly refers to as "Hillary's stocking stuffer," was on CD and en route to the White House to be put in a time capsule.

Nine months later, interest is still growing, with the UCSC browser at receiving an average of 40,000 hits daily.

"People are looking for genes that have been predicted, and for critical evidence they are disease related," Haussler says. "We get letters from people commenting on the fact that there are no restrictions, no patents, no protections -- that it's going out to humanity, no strings attached, and the realization that it's irreversible, that it's out in the public, that it's free. You can't go back once that happens and lock it away."

Our Genes in Their Hands

Or can you? Despite Kent and Haussler's efforts and their decision to put their version of the genome in the public domain, all our genes do not belong to us. Celera has already applied for patents on between 500 and 1,000 human genes, and other biotech companies are standing in line.

As Kent explains, "Celera had access to the public consortium's data, while not sharing their own, thereby ending up with a 10-percent data edge. But without our intervention, Celera might have ended up patenting a lot more choice genes to maximize shareholder value. And their customers would have patented even more, while smaller and academic labs in particular would have had less access. So, we've had some impact."

In the past, researchers were allowed to patent genes in bulk on the basis of a few hours' work -- "and several weeks with their patent lawyers," Kent adds. But this January, the United States Patent and Trademark Office tightened the law.

"Now people will have to do a substantial amount of research to demonstrate they've gone beyond the published state of the art," Kent explains. "They'll have to demonstrate more knowledge of the function of the gene as well as a path toward a drug, before they can patent and monopolize a gene for 17 years. But some people feel the law still isn't strong enough."

Despite all this, Kent and Haussler aren't hostile toward their peers at Celera. "The rift between Craig Venter and the academic consortium predated UCSC's involvement," Kent says, "so we don't really share it. Venter has always marched to a different drummer, and I kinda like the drummer he marches to. It's partly because of him the public project's adopting new technologies and going more quickly."

As for Haussler, he says the people he knows at Celera understand the nobility, excitement and value of the project. "Their feeling was that the only way this project was going to happen was through a substantial investment and the kind of growth directiveness that typifies Celera. So, I respect their choice. And I don't think of it as an evil enterprise. When you look at the broader scale, we're not going to get to new medicine without substantial private investment."

Double-Edged Helix

Written in a linear, one-dimensional form, the human genome uses a very small alphabet (A, T, G and C) to form 1 billion exclusively three-letter words with a multiplicity of meanings. These words generate stories, or genes, which act much like pieces of software: they can run on any system and have the same function whether they are on the genome of catfish, caterpillars or Catherine Zeta-Jones.

A genome is clever -- it can reproduce and read itself. But it also makes mistakes, like any photocopying machine -- mistakes that eventually add up to old age or disease. And over 50 percent of our genome consists of repetitious and scrambled phrases -- the so-called "junk" DNA. If our genome were a continent, it would be a vast repetitive landscape with only the occasional city, a gene, twinkling in the darkness between. But in its entirety it's a very powerful tool.

With the assembled genome in hand, biotechnicians hope to develop tailor-made drug treatments. They also hope to cure, or even eliminate, genetic diseases like schizophrenia, Alzheimer's and Parkinson's, but the genome has a darker side, too. It's the key to a Pandora's box of designer babies, postnatally modified people, and clones.

So what kind of changes is the assembly of the human genome likely to bring in the short term? Kent predicts that we'll see a new generation of drugs better tailored to individuals -- a change that will happen soon, "because pharmaceutical companies have the scent of money on this one. I wouldn't be surprised if within a year or two the drop of blood taken in the emergency room goes toward finding out what your genetic code is to help determine how much of a drug they should give you and whether you would have an adverse reaction to a particular drug."

Genetic testing, for instance, may also help people sensitive to formaldehyde, which is emitted by new carpets and other components in new buildings. Says Kent, "A lot of people go around moaning, saying, 'I can't work in the new building, it's making me sick,' to which their boss says, 'You slacker!' But in the future, you'll be able to see if there's a genetic reason for all those headaches."

On the other hand, employers could use tests to try to weed out prospective employees with predispositions not only for headaches but also for developing a series of fatal diseases. And without adequate protective legislation, such tests could lead to increased insurance rates for people with high-risk genes.

So far, neither state governments nor the federal government have passed laws specific to genetic testing. "As technology develops," Haussler says, "we'll be able to ascertain a lot about people from their genetic code. Certainly, you shouldn't be able to do this surreptitiously and use that information against them."

Laws, such as the 1992 Americans with Disabilities Act, already exist to protect people from having their medical information used against them. Kent hopes that legislators will realize that genetic information should be treated with the same sort of confidentiality.

"Besides," he adds, "we all have about 100 pre-existing genetic conditions," a reality that could make it impossible to develop comprehensive tests. But selective tests for the top 50 diseases will soon be possible, thereby providing people who have genes for incurable conditions with the bleakest form of self-knowledge possible, although also giving them a chance to decrease their risks.

Within five years, Kent expects we'll begin benefiting from gene-targeted therapies and that parents will have the possibility of patching embryos for genetic disease. He worries, though, about the potential loss of genes that are currently deemed negative.

"Eighty percent of people in America want to be thinner than they are, right?" he says. "But it doesn't take much of a change in their environment for having an accumulation of a little bit of fat to be a very good thing indeed."

Twenty years down the line? By then we'll likely have better therapies based on greater genetic understanding, as well as the possibility that we'll be able to avoid giving our offspring a "bad" gene. But Kent also anticipates an explosion of fashionable genes and greater disparities between the rich and the poor, based on access to such "benefits."

"At age 12, most Americans no longer wear clothes their mom buys them," Kent muses. "What makes you think that in 50 years, they're gonna be content with genes their mom and dad put into them? What happens when people want to have modifications to be stronger, smarter, faster, for instance? The Olympic committee will have a lot of fun trying to figure it all out."

Yours, Umbilically

Kent believes that eventually postnatal genetic modifications of children will be a common scenario. He recommends that people arrange for their children's umbilical cords to be frozen, not in the family icebox, but at liquid nitrogen temperature.

"Very flexible cells are present in this region that are likely to have medical uses," he explains. That way, if a certain type of your cells breaks down -- as happens with diabetes or Parkinson's disease -- these cells could relatively easily be induced to grow into replacements. And they may end up useful for gene therapy if you turn out to have a genetic disorder."

The tailoring of children, however, strikes him as riskier and therefore less likely.

"Maybe a somewhat selective guiding of things from the parents is not too dangerous," he says. "But you can go further and say, 'Why don't we patch in just a little bit of Keanu Reeves here.' That makes me worried. Diversity is very important for the evolution of the species."

Even scarier is the prospect of newer, modified genes.

"About a year ago, scientists found a way to modify a particular gene inside a mouse that made it learn its mazes faster -- the smart mouse," says Kent, who speculates that such modifications might work well in humans at first. "But all of a sudden at age 20, you might start having uncontrollable brain seizures. And that's the problem. How many children are you going to want to test these things out on?"

Just because a procedure isn't ethical, doesn't mean it isn't possible. Human modifying, tailoring and cloning are all on the cards, not because the public approves, but because a relative few are desperate or rich enough to take action. But to what end?

It likely won't be easy to improve on the genome, a thing we've been working on for 3 billion years. Besides, the genome is not the complete story of life. Having the blueprint for Michelangelo, Shakespeare or Einstein does not a genius make. We are bigger than the sum of our genes. Nurture and flat-out luck still play their parts.

Does Kent ever worry about the power of the tool he helped unleash?

"Did Robert Oppenheimer stop [the] fighting among the superpowers, or did he set us up to destroy ourselves? What we're doing isn't as drastic as destroying the species, but ultimately it'll come down to modifying the species. And that scares me," Kent admits.

Whether we have the wisdom to handle the knowledge revealed to us in assembling the human genome is the next big question. But it would be unfair to blame scientists like Kent, who has taken his leave and is disappearing into the redwoods that dwarf UCSC campus, if we can't see the forest for the trees.

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