Next-Next Generation Sequencing

A psychiatrist and a molecular biologist plopped their butts down on the diner’s red glitter-vinyl cushioned booths. The brisk afternoon called for coffee, though not at the lukewarm temperature at which the robo-waiter served.

Heeey Claudia, thanks again for getting back to me so quickly. And really, it was great of you to even help out in the first place. This patient of mine is hopeless. He still can’t seem to move past his ‘alien abduction’,” Allen said while making air quotes with his fingers (on one hand only, the other hand was wrapped around the coffee mug, a desperate attempt at insulation).

“And here I was just telling my husband how it almost feels like there’s no use for biologists anymore, since the singularity ban and all,” Claudia said with clear enunciation. She hid her annoyance at the air quotes well enough.

“Well, if your biotech company hadn’t revealed the plan for the ‘perfect’ human, it wouldn’t’ve been so bad. The economy needs sick people to buy fixes.” He knew he had to walk back his accusatory tone. “At least we both still have jobs, though.”

The unintentional slight reminded her that the past, after all this time, still had the power to take small bites out of her composure at any moment. It was unnerving. Sensing this, Allen grabbed the shared coffee pot and refilled her mug.

“And I wouldn’t normally ask anybody to investigate a crazy claim like this, but if this guy, this patient of mine, is able to get some closure, it means I can get him permanently off my to-do list. So, what’s the deal? Were you able find out if there’s a secret message in his DNA, like they, the aliens, told him was the case? If so, all he has to do is recite it and they’ll stop coming after him.”

““It wasn’t any bother at all, really. The gene analysis app on my phone let me analyze his spit sample with ease. Sorry I didn’t reply to your e-mails sooner — grants and stuff.”

“Got to pay that outrageous Austin rent, am I right?” Allen thought about his New New Braunfels mortgage while he said this.

“Don’t remind me. If aliens were actually abducting people at least the housing market would take a hit. But anyway, maybe with this gene scan result he can rest easy knowing there aren’t any little green people messing with his DNA anywhere,” she said.

“Finally, an expert opinion he might listen to. I’m tired of hearing this guy go on and on about getting probed. What’s even more nuts is the thought that anybody’d want to. So, everything checked out?”

“Well, yes… and no. Predictably, his DNA profile shows he has a strong probability of suffering from — no surprise here, paranoid schizophrenia. And there is no ‘special DNA’ sequence with any kind of encoded information. But there is something else.” She let a smile steal the corner of her mouth.

“Go on…”

“Well see, there’s this old idea about a hidden biosphere — the shadow biosphere.”

“Sounds dark? I’m all ears, buddy. As long as we’re not talking about shadow aliens probing my patient. Then I’m going to have to take this cold coffee to go,” he said. Subconsciously, his anti-robot prejudice grew.

“Not aliens, not quite. It’s an ecosystem of organisms which, some argue, we have yet to discover here on Earth. Creatures which happen to not use DNA. No evidence for this, so far, of course. Unless you count the odd behaviors of certain clays. Anyway — ”

“When you guys catalog any animal or bug in biology it’s based on DNA sequencing, reading the DNA. How would you find a shadow species — using your instruments — that doesn’t have any DNA?” Allen imagined Claudia hunched over a lab bench, and then visualized himself, in his comfortable leather chair, notepad and pen in hand. Both thoughts tired him. This also put the caffeination of the coffee under suspicion.

“That right there is precisely the question of relevance. I’m sure you can see how it’s related to what the aliens call ‘special DNA’. Well, after we saw that his genome was typical as ever, I wondered — maybe the aliens weren’t talking about a special sequence of DNA but actually some chemical alternative to DNA. A pseudo-DNA, not the DeoxyriboNucleic Acid we’re used to,” she stressed the first letters for emphasis like a true professor. “We’d never detect something like that because we always rely on enzymes that very specifically can only detect and read DNA.”

“I see. So you’d need a special enzyme that could read this pseudo-DNA? And maybe this would support some kind of shadowy biological monster? One that’s also microscopic and deadly?” Allen asked, pleased that he was following along on the Bio 101 discussion without coaching.

“Yes, I guess. The enzyme would work with any other kind of pseudo-DNA that might base pair with DNA. Get this, though, this wacky enzyme that could do something like that, interconvert between a pseudoDNA and DNA — it exists. It’s called the XNA polymerase. Some completely unmodified humans engineered it from scratch over a century ago.”

“XNA… ‘X’ like in ‘X-Files’?” He was still trying to catch up on the fiftieth season.

“It can read DNA, RNA, any-NAs based on totally wild chemistries. That’s what the X is for. X can be almost anything. The important thing is that it lets us sequence whatever the XNA is.”

“Like the ‘X-Files’.”

“No…yeah, ok, whatever ‘like the X-Files’. In any case, we used this XNA enzyme on your guyses’ cells instead of the regular DNA sequencing enzyme.”

“Wait, why hasn’t anyone done this before? Pseudo-DNAs littered across the planet and in our bodies would be a big deal,” Allen said.

“I know, right? But remember, back then the funding was pitiful. And before people were able to get too ambitious with heavy synthetic biology, of course, there was the singularity ban,” she pointed out.

“Right. My parents lived through that era and still have no clue what was going on. I guess they still think I’m a medical doctor. Whatever. Anyway, what’d you get from my patient?”

“A whole lot of pseudo-DNA T’s. T’s, as in one of the four DNA bases, A, T, C, or G. Only the T’s. No way to write a message from the stars with just one letter, which is unfortunate for your patient’s deeply held belief about extraterrestrials, I’m afraid.” She caught herself wanting to make air quotes around “extraterrestrials”.

“But…”

“But, we’re getting a huge grant to characterize it further. My guess is the pseudo-DNA is meant to bind to DNA or RNA strands. Maybe since T’s bind with A’s, it hangs onto sequences that contain a lot of A’s. The clear target would be messenger RNAs, which have long tails made up only of A’s. If these got passed down through cells’ lineages by some new mechanism, we’re basically re-writing what inheritance can mean.” She leaned back, letting the smile overcome her face.

“Just how big of a grant are we talking about, Claud?”

“Millions. Of pennies. But it’ll do.”

“Coffee’s on you, then, I suppose.” He buzzed the robotic waiter. “I’ll have some blueberry pie, too. And some pancakes. With lab links, not the old-fashioned sausage. And everything should be warm, not hot or cold.”

The android paused at the table.

He murmured, “Please.”

“Right away, sir,” it buzzed. Had the robo-waiter mimicked Allen’s voice?

Claudia met Allen’s eyes and whispered, “The truth is out there.”