If I Was an Enzyme, I’d Be Helicase So I Could Unzip Your Genes

When I was five, I encountered the concept of DNA for the first time.

Yes, I’m talking about Mr. DNA and the dino resurrection description in Jurassic Park.

This is was the first time a Michael Crichton story (scientifically shaky though they may be) influenced my interest in a scientific concept (the second being Timeline and quantum mechanics). Genetics is a fascinating branch of scientific study, one that has seen great achievements in my lifetime, such as the mapping of most of the human genome and the first cloned animals.

Anyway, I was thinking about genetics this morning while playing BioShock. If you’ve played the game, you know that one of the primary types of character enhancements are plasmids that alter your genetics.

As an aside, if you haven’t played BioShock yet, crawl out from under that rock you’re calling a home and play it. A horror FPS set in an underwater dystopia with a swing/big band soundtrack- it’s basically a wet dream in video game form. And you’ll understand why most gamers now fear the phrase “Would you kindly…”

Anyway, as I was gathering ADAM from the Little Sisters and upgrading my genes like a madwoman, I recalled an article I was reading on DNA the other day.

And decided we should have a genetics/DNA day, dear galleons.

***

Researchers at the University College of Dublin recently sequenced the first Irish genome.

What’s so special about the Irish?

Let’s backtrack for a second here and pay a visit to Charles Darwin’s expedition aboard the HMS Beagle. Darwin landed at the Galápagos Islands and started exploring the native wildlife. Do you remember what he found?

The Galápagos Islands are home to many endemic species (species are are unique to a particular geographic location, such as an island). The very fact that these species had genetic differences from island to island (such as differing shapes of tortoise shells and differences in mockingbirds) helped solidify Darwin’s theory of natural selection, proving animals evolutionarily adapted to their specific environments.

In a closed environment (such as an island), natural selection can lead to striking differences between a mainland species and its island counterpart. The restricted nature of the island’s ecosystem causes genetic variations not seen in other parts of the world.

Enter the Irish.

Ireland is an outlying European island, so it has the geographic potential to be a semi-closed ecosystem, allowing for genetic variations among its inhabitants. Including the Irish people.

It was this possibility that lead Brendan Loftus, head of the Dublin researchers on this project, to sequence the Irish genome in hopes of finding some of these genetic differences.

In this goal, they were successful. The unnamed Irishman (determined to be genotypically repre sentative of Ireland) was found to possess 400,000 novel mutations of single DNA bases. Of these, about 8000 appear to be inherited along with genes known to influence disorders such as inflammatory bowel disease and liver disease.

The Irish have genetic variations dealing with liver disease?

Say it isn’t so.

In all seriousness, these finds are pretty exciting. The newly discovered mutations may help shed light on the genetic basis of these conditions.

***

And now we’ll hop back across the pond to New York City, where Ned Seeman (worst. surname. ever.) of NYU and his team have designed a four-legged, three-armed DNA nanobot spider.

Now, don’t get too excited. As with most scientific advances, these nanobots are far less sophisticated than those you’ve seen on your favorite science fiction program:

Scientists have been creating rudimentary molecular robots for over a decade. Their current aim is to get DNA molecules to organize themselves and move around. No batteries, no information stored in their little bodies. Just movement generated by the power of DNA-DNA interactions.

This is easier said than done.

The latest DNA nanobots can take up to 50 steps all by themselves (a marked achievement in this field) or pick up and transport nanoparticles. But they aren’t going to be doing anything miraculous for quite some time. Right now, these little bots are like drunken toddlers, stumbling and feeling their ways around the manufactured DNA landscape.

That’s right- in order to get these little buggers to move, scientists have to manipulate DNA. Ordinarily, DNA exists as that famous double-stranded helix, stable and unreactive, untwisting only to replicate itself.

But scientists have found ways to work with DNA.

“We’re pushing the envelope of what’s possible with DNA as a working material because we can understand, control and direct DNA more than any other material,” said chemist Lloyd Smith.

One way of manipulating DNA was invented in 2006 by a Caltech biologist named Paul Rothemund. He folded single strands of DNA to make complex two-dimensional shapes (triangles and stars, for example), then designed smaller staple strands that matched up with adjacent DNA folds. These staple strands latched onto the DNA folds and held the little shapes in place. And when you mix these single-stranded pieces together in a solution, the shapes began to assemble themselves.

This is the birth of the DNA origami surface, a key ingredient in the movement equation for our bots. This origami surface becomes a large, two-dimensional “walking track” for the nanobots, a surface scientists can actually program instructions for the spider’s movement into.

Within the origami surface, scientists can elongate key staple strands to form a crawling trail for the bot. These strands stick up from the 2-D origami floor like seaweed. The staple strands’ DNA letter sequences match up with the sequences on the DNA legs of the bot (A with T, C with G), allowing the spider’s legs to “stick” to the staple strands.

That’s not the tricky part, actually. The hardest part of this is getting the bots to pick up their little legs and step to the next strand.

One way to do this is to use the DNA enzymes in the spider’s legs to slice through the staple strand after connecting. This uproots the leg, allowing it to move to a nearby, intact strand.

The obvious problem with this method is that the origami track is used up after only one run.

“If your motors are forever destroying the tracks, you’ve got to rebuild the tracks, which would cost you a huge amount of energy,” said British physicist Andrew Turberfield. “An automobile that chewed up the road behind it would be a bit unpopular.”

So Turberfield is working on a non-destructive method of moving the bots along the origami track. He and his team have come up with a bot that walks along by flipping over itself, essentially somersaulting along the origami track. This method is based on kinesin, a natural molecular motor that carries cargo around the cell.

But, back to Seeman’s bots. See, these little spiders can do more than walk- they can actually pick up and transport cargo with DNA arms. The cargo is gold nanoparticles wrapped in a single strand of DNA. Just like the staple strands are compatible to the spider’s legs, the gold particle’s DNA wrapper is compatible to the spider’s arms. The bot can now either keep its cargo or drop it off at another station along the origami track. By picking up and dropping off various combinations of particles, the spiders can build molecules.

In the future, Seeman hopes to make longer “assembly lines” for the bots. He also hopes to tweak his bots so that they can pick up and transport more than three building blocks. Because the bots bring together molecules one at a time, the bots could piece together molecular puzzles that don’t react well together in nature, which would be a huge boon to chemists.

On the whole, many scientists are excited about the possibilities these nanobots present for the future. As the technology surrounding these molecular bots evolves, scientists hope to see the bots become sophisticated vehicles that can sense their environment and target diseased tissue without harming healthy cells. This would be dizzyingly useful in the field of medicine, not the least of which would be the incredible power these bots would have for fighting diseases such as cancer.

The bots also have the potential to eventually build nanosized computer chips. But this is all far in the future. As Caltech’s Niles Pierce said, “…to take that [nanobot] locomotion and put it to productive use for fabrication of nanoscale components, that’s still a futuristic goal.”

So, while we won’t be seeing any of the good Doctor’s nanogenes any time soon, we are taking a step along the path. Which is pretty much the norm for scientific endeavors. Which is why so many people are disappointed in the reality of scientific research.

But you and I know better than that, galleons. Scientific progress is about taking baby steps along the path toward a greater goal. It’s not all explosions and collisions and bubbling beakers. This is real science. It’s delicate, complex, and much more subtle than in the movies. But in the end, it’s still important.

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