Biomedicine

Rewriting the Genome

Sequencing and synthesizing DNA keeps getting faster and cheaper. George Church explains the impacts of these advances.

The genomic revolution is being driven by advances in analytical and computational techniques, and George Church has been behind many of them. Starting in the late 1970s, Church helped create the tools, including early software and protocols for DNA sequencing, that eventually made possible the Human Genome Project.

George Church, professor of genetics at the Harvard Medical School and a pioneer of genomics. (Credit: Mark Ostow.)

These days, Church, a professor of genetics at the Harvard Medical School, and his 50-person lab are still finding ways to synthesize and sequence DNA faster and more cheaply. One of his latest interests is synthetic biology, in which researchers design and synthesize biological “parts” that they then incorporate into microbes or cells.

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Some anticipated products of synthetic biology: engineered cells that produce novel types of pharmaceuticals, redesigned biological therapeutics that are more effective and safer, and biosensors that can be built directly into cells.

Technology Review: What is synthetic biology?

George Church: Genetics turned into genomics when you dealt with the whole genome. Biology turns into systems biology when you deal either with the whole of the cell or some fairly large part of it. Genetic engineering turns into synthetic biology when you use what you learn from parts and theory to engineer real systems.

TR: How could synthetic biology help you design more-effective drugs?

GC: Some groups are making cells that sense tumors and respond by producing a toxin. Synthetic biology will help you engineer the cell to home in on the tumor, to recognize the tumor, and, once it is confirmed, to start making a tumor-specific drug.

TR: You and your colleagues recently developed a new way to synthesize DNA. What are the benefits?

GC: It’s about reducing cost at a reasonable accuracy. Right now the cost of synthesizing a base [using conventional technology] is about 10 cents. That’s the current street price for raw oligonucleotides. For synthesizing simple genes, it’s more like $1.30 a base. [Our method] can manufacture oligonucleotides at .01 cent per base.

TR: How will getting the cost down aid synthetic biology?

GC: It means you’re willing to make many more [genetic] constructs. Making more constructs means you’re much more likely to make something that works or something useful.

TR: The new method also allows you to make longer stretches of DNA, right?

GC: Longer stretches are certainly enabled. The implications are that we are getting closer to being able to arbitrarily “program” the millions of base pairs in microbes or billions of base pairs in plants and animal genomes similar to the way that we program computers.

TR: There has been a lot of buzz about a $1,000 personal genome.

GC: That’s sequencing. So we’re off synthesis now.

TR: Right. Now we’re talking about sequencing an individual’s genome.

GC: We might never get a perfect $1,000 diploid genome [the six billion base pairs in a human’s two sets of chromosomes]. The question is, what can we afford and what do we get for it? Think back to the beginning of the computer industry. They didn’t say, “Oh, we’re going to get you a $1,000 supercomputer.” No, they said, “What can people afford? And what can we give them for it?” And what they gave us was the likes of the Apple II computer, and people started writing software for it. Current personal computers cost about the same but deliver more. The same thing may happen with personal genomes.

TR: So what are people likely to spend to know their own genome?

GC: I think what is affordable – and remember, this is a lifetime expense; your personal genome will hopefully last you 80 years or more – is $10,000. If I can save $100 on average a year, it is a no-brainer. That’s the cost of a couple days of missed work, or one diagnostic test that can be put off due to low risk, or avoiding bad choices on a year’s worth of drugs. Then the question is, how much of a person’s genome can we sequence for $10,000? Seven thousand dollars will buy you a million base pairs of DNA [using conventional technology], which is one-6,000th of your diploid genome. Not very much.

Polony sequencing [a method developed by Church and colleagues] is about a hundred times less expensive. So you can sequence about 1 percent of the genome [for $10,000]. That’s not bad. You could focus on likely places you’re going to have problems.We got a factor-of-ten improvement in the last six months, so if we could get another 10 percent improvement in the next year, that would give us 10 percent of the genome. If we could pick 10 percent of the genome for which we have lifestyle, nutritional, or synthetic solutions, that would be a good deliverable for a $10,000 investment. And it will just get better from there.

TR: We jumped from synthesis to sequencing.

GC: I do that all the time. It may sound like a wordplay, but it is actually a very fundamental concept. There is almost no synthesis that doesn’t involve sequencing, and vice versa. And that is why I have really emphasized this connection in my lab. They are very synergistic.

Home page photo credit: Mark Ostow

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