Natural Genomes Are a Mess. We Want to Synthesize Better Life.

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July 19 2014 8:01 AM

Tidying Up the Genome

Natural DNA is kind of a mess. Can artificial DNA do more?

Hamilton Smith is scientific director of synthetic biology and bioenergy at the J. Craig Venter Institute in La Jolla, California. He shared the 1978 Nobel Prize in physiology or medicine for his discovery of an enzyme that cuts DNA, an advance vital to genetic engineering. He told Kat Austen he wants to find the smallest genome that will keep a bacterium alive—and tidy up evolution's sloppy work.

You helped make the first synthetic cell, using an artificial version of the genome of the bacterium Mycoplasma mycoides. What are you doing with it?
Our goal is to throw away everything except the core genes that keep the cell alive, to make a reduced cell. Our best estimate is that we will end up with about 400 to 450 genes. To that end, we divided the synthetic genome into eight pieces and from each section removed all the genes we think are non-essential. Each of those eight pieces is viable when combined with the rest of the naturally occurring genome. The question was could we combine the eight pieces, have our reduced cell and be done?

And what was the answer?
It didn't work. But we found a number of combinations that did work. So right now we have a half-reduced genome. That grows pretty well. We're closing in on the full answer though.

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What might a reduced cell enable?
Once we have it we can build on it. The interesting part is to add genetic sequences to enable the cell to grow in different environments, make different compounds, or use photosynthesis, for example.

What else could you do with it?
There's no question we're going to end up with a reduced cell with several hundred genes. We don't know the function of about 100 of those genes, so right there we're probably going to make discoveries about what's truly essential. The other thing we want to know is: How plastic is the cell? In other words, how much can we rearrange the genes? Evolution has sloppily put them together. A lot of the cell's processes are scattered around. We're putting them together into one neat form.

So you're tidying up the genome?
We want to see how much we can make it a more understandable genome. Genes to do with translation of DNA into proteins over here, cell replication over here, transport over here.

Synthetic biology is in its infancy. What else might help usher it into the mainstream?
The automation of the chemical synthesis of DNA. That's the next big aim. What's going to drive synthetic biology is cheap, accurate DNA synthesis. And not just short stretches of DNA known as oligonucleotides, but possibly entire genes. If you can do that with a machine, where you just enter your DNA sequence and the next day you have a piece of DNA 10,000 bases long that you can experiment with, then that will drive the field. We have a big operation aiming to automate DNA synthesis.

How might that transform the field?
I'm sure right now many young people could think of interesting genetic material to design but it's too expensive. If it's cheap and easy you can just keep churning out stuff. It would become trivial to design whole genomes after a while.

This article originally appeared in New Scientist.

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