Scientific Method / Science & Exploration

Ten years on: why a complete human genome mattered


Open a recent edition of Science or Nature, and you're likely to be bombarded with articles about a significant anniversary: ten years have passed since the announced completion of the human genome.

These articles tend to focus on how the genome is (or isn't) transforming medicine, science, or society. Sure, it sounds like a terrific milestone, but did it change anything about life in the lab?

I started graduate school back when the debate about whether to sequence the human genome began, and my research career ultimately benefitted from the technology that came out of the program. Most of what you'll read about the anniversary will involve grand perspectives and talk of "breakthroughs," and those are important, but I'd like to offer a grunt-level view of just how much the human genome project changed biology. This is a personal perspective, and any mis-rememberances or erroneous interpretations are my own.

One of my clearest memories, however, is that back when the project was first proposed, there were real questions about whether it would ever get off the ground.

Why bother?

My graduate career began at the same time that biologists and policymakers had kicked off a public debate about whether to sequence the entire human genome. The project would be an enormous undertaking in terms of funding, resources, and personnel, one that might pull federal funding from individual labs.

It was also a bit of a departure for biology, which hadn't known the big-budget science projects that were common in fields like astronomy and physics. Needless to say, allocating this much money to one idea made many researchers uneasy.

And it wasn't clear that such a project was even necessary. Over time, bits of the human genome were being filled in piecemeal without any grand, overarching project. Researchers studying human genes had walked slowly and painfully along chromosomes, filling in sequences as they went. Others cloned the human versions of genes found in other organisms. Some groups just randomly sequenced every piece of DNA that was made into messenger RNA.

Bit by bit, the most important parts of the human genome were being uncovered—I was certainly among those wondering if we really needed a huge and expensive project to sequence the whole thing.

Faith in the piecemeal approach turned out to be naive. Most of the human genome doesn't seem "important" by the criteria we normally use to judge these things, but there are key pieces of regulatory DNA, including some that's distinct to humans, scattered amidst all the noise. Without getting the whole genome, we would not have identified many of the sequences that help make us uniquely human. And we'd certainly have missed many things we didn't even know about back then, like the micro-RNAs that regulate genes.

Those worried about the cost were mostly brought on board with what seemed like a political compromise: we'd use all the major research organisms—flies, mice, worms—as test cases for the human genome, to better understand the challenges and improve technology. That way, most biologists would see some benefits from the grand project, even if they never looked at the human sequence.

It was a good sales pitch, though the human genome would end up being completed before the mouse.

The author as a grad student at Cal.

An expensive gamble

Deciding to fund the project was one thing; actually figuring out how to do it was another. At the time, I was at the University of California-Berkeley, and the school was interested in getting in on the genome work (it never fully panned out for them, as many other genome centers eclipsed the school). As part of that interest, Berkeley looked to hire a faculty member who could do pioneering work in the genome.

Interview talks from potential hires were depressing. At the time, DNA sequencing was done by setting up reactions by hand and running the results on a gel. This process was followed by a couple of days in which the gel was used to expose a film, and the film was later read by hand.

Biologists could run a few gels per day, but it was pretty difficult for all but the most efficient to get more than a thousand bases of sequence per day. The human genome contained three billion bases. The math was ugly.

Some of that work would obviously lend itself to automation, but many researchers had the sense that we needed a completely new technology for DNA sequencing. Lots of people had ideas, a few of which still resurface today, but it wasn't unreasonable at the time to think that we had launched a project without knowing if or how we could even complete the thing

Eventually, these problems were solved through a combination of automation and miniaturization, along with a few clever twists on the existing sequencing method. Still, none of that was known when money was first committed to the project, making the whole thing something of a gamble.

Silence descends

Once the project was approved, it seemed to vanish. It's not that nothing was being done, it's just that the things that were being done—technology development, building the infrastructure to process and store the data, preparing everything needed to obtain the sequence—had little to no impact on most biologists. I was working in a fly lab at the time, and absolutely none of these developments changed the way things worked there.

But by the end of graduate school, changes did arrive—especially after the competition between the publicly-funded sequencing effort and the private project of Craig Venter really kicked off. Venter felt he had a better way of sequencing genomes, and he used the fly as his demonstration project. His method worked, and the fly genome was done (although it took fly researchers a few years to figure out what to do with it).

Venter's triumph ended up highlighting a significant difference in approach. The public project was creating an ordered array of DNA that matched the physical arrangement in the chromosomes, but snipped into small pieces that were easy to manipulate and sequence. That's what was taking up all those years where nothing was apparently getting done.

Venter thought he had found a way around that step, just sequencing at random and then lining the sequenced bits up afterwards with computers; hey, it worked for the fly genome.

As it turns out, Venter's approach worked reasonably well for making a rough draft of a vertebrate genome, at least with the current software we have for lining things up (Venter's wasn't as good as what we have now). But it doesn't appear to be good enough to push a project past the draft stage, at least for vertebrate genomes, which have a lot of repetitive DNA that lines up to thousands of locations scattered around the genome.

So, while the public project was criticized for its slow progress, it seems to have been necessary to reach the goals it set for itself. But Venter's aggressive approach and public sniping led to bad feelings, which were only partly smoothed over by the two parties getting together for a joint announcement.

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