The Once and Future Genome

Week in Review / by Lee Billings /

On the tenth anniversary of the sequencing of the human genome, what is that remarkable feat’s legacy, and what does it mean for the future?

Credit: Flickr user Matthew Fang

Things seemed so simple then. It was ten years ago—June 26, 2000—that US President Bill Clinton and UK Prime Minister Tony Blair announced the successful completion of a “draft sequence” of the human genome. The project itself had begun a decade earlier, through $3 billion in government funding from the US Department of Energy and the National Institutes of Health, and a sturdy framework of international collaboration. In 1998, a private initiative led by Dr. J. Craig Venter had entered the human-genome race, using $300 million in funding and a faster, cheaper sequencing method to catch up to the government program. In the end, fueled by a bubble of exuberance, the public and private approaches finished neck-and-neck, producing suitable draft sequences more or less simultaneously.

Expectation and hyperbole ran high: Soon, the raw power of molecular biology would be bent to human will; at a fundamental level, organisms would be as pliable as Silly Putty. Genomics would revolutionize the diagnosis and treatment of disease. Custom-tailored “personalized medicine” would become standard practice. The Book of Life was finally opened, and humanity would grasp its deepest origins and perhaps its ultimate potential.

Pessimists also weighed in, mustering dark visions of societies segregated solely according to genetic predisposition, and a world horrendously damaged by genetically modified organisms run amok.

Though not necessarily overblown, the celebratory and cautionary brouhaha was certainly premature: A “complete” sequence of the human genome would not actually be obtained until 2003. Genetically engineered utopias and dystopias have yet to manifest—the world muddles along as usual between the extremes. Even today, portions of the genome remain terra incognita, though the significance of these unsequenced regions is uncertain. That trace of uncertainty encapsulates the status of genomics today: One of the indisputable scientific contributions of the sequencing and subsequent study of genomes was to reveal just how ill-informed we were ten years ago. (For a more detailed explanation and excellent perspective on the tenth anniversary of the sequencing of the human genome, I must refer you to The Economist’s special coverage, unparalleled in sophistication and breadth within the rest of the popular press.)

The picture that has emerged since 2000 is that the classical understanding of how life’s core cellular machinery functions is rather shallow. Information is indeed encoded in DNA, transmitted by RNA, and transcribed into proteins; a stretch of DNA carrying information that will be expressed as a protein is in fact a “gene.” But this isn’t nearly the whole story.

Sequencing revealed that genes only constituted a diminutive, fractional percentage of the human genome. These genes coded for the creation of two-dimensional strands of amino acids that then folded into three-dimensional proteins. But a deep understanding of how that transformation progresses, and how a protein’s specific conformal configuration will influence cellular function, is still nascent. The other 98 percent or so of the genome that didn’t code for proteins acquired the misguided label of “junk DNA,” though it’s now clear that much of that “junk” actually serves the purpose of coding for RNA. RNA in turn regulates other genetic and cellular behaviors and functions, to an extent not yet fully known. And the scope and importance of genetic variation between individuals remains hazy. Such subtleties have spawned additional investigations—into things like the “epigenome” and the “proteome”—that will surely uncover additional layers of intricacy.

Grappling with this unexpected complexity has stalled progress on developing new drugs, on practicing better preventive and predictive medicine, on creating designer organisms, on charting life’s history, and on unraveling the function and significance of any particular snippet of the genome. But consensus holds that these promised revolutions are still coming, just slightly delayed. Already treatments discovered or administered through genomic analysis are making their way to market as the vanguard of a new era of personalized and preventive care. Already the first man-made life forms have been created, proofs-of-principle demonstrating the vast potential for bioengineering to enhance agriculture, energy production, and manufacturing. Already the field of “paleogenomics” has yielded a sequence for the Neanderthal genome, revealing a new chapter in human prehistory and shedding light on what precisely made us human in the first place.

And the pace of progress is now accelerating, notably due to the increased use of high-performance computing to distill knowledge via comparative analysis of exponentially increasing amounts of genomic data. For example, just this week an ambitious international consortium called “The 1,000 Genomes Project” released its initial data sets, beginning a drive to define the extent of genetic variation that exists between people. Not to be outdone, the Wellcome Trust announced yesterday its plans to sequence 10,000 human genomes in the next three years, also in pursuit of variations, particularly those that cause disease. In China, the BGI (formerly known as the Beijing Genomics Institute) is installing 128 cutting-edge sequencing machines, which may concentrate enough sequencing power within a single building to overshadow the entire DNA-sequencing capacity of the US. It’s probably no coincidence that China is also ramping up its supercomputing capabilities to deal with the resulting data deluge: In a first, as of last month two of the top ten most powerful supercomputers in the world were Chinese.

An even more potent accelerant for genomic progress is the freefalling cost of genetic sequencing, and thus a rise in available data: The price of a complete genomic sequence is presently too expensive for most individuals to afford, but seems set to fall in coming years to $1,000, perhaps even $100. Costs for genetic synthesis (the on-demand creation of strands of DNA from scratch) are falling as well.

Last week, news came that the aging rocker Ozzy Osbourne planned to have his genome sequenced, ostensibly to show how he’s managed to live so long despite a lifetime of drug-fueled debauchery. Given the diminishing costs and expanding toolset for biotechnological hacking, it’s not inconceivable that in the not-too-distant future someone like Ozzy might also be able to easily create his own custom-designed organisms, for purposes just or depraved. As the ease of sequencing and synthesis grows, so too does the possibility that our genomic reach will exceed our grasp, perhaps through inappropriate or immoral social practices based on specious scientific conclusions, or perhaps through the accumulated unintended consequences of unregulated individual genetic tinkerers. One can only hope that such dire speculations will be as unfounded years hence as last decade’s predictions of imminent genomic utopia and dystopia now seem.

Lee Billings is a staff editor for Seed. He likes space.

Originally published June 25, 2010

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