Tuesday, October 13, 2009
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•Mardis, E.R., The impact of next-generation sequencing technology on genetics. Trends in Genetics, 2008. 24(3): p. 133-141.
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In the third drawer of her desk, Daisy kept a file of important scientific papers. Not the kind she read just to keep up, not the recent advances, but the classics -- papers to read and reread, layered in scribbles and notes. She also kept, for emergencies, a bottle of gin.
She poured herself another shot, trying to come to terms with the enormity of their discovery. “Well then, what can we do?” she asked.
The Internet, who easily could have told her the number of volcanoes in Alaska, was completely stumped on the question of what to do when an ancient biological metaconsciousness was bent on destroying human civilization with a plague of engineered superbacteria.
“We obviously can’t just fight the infections,” he said, flashing a chart of known antibiotics onto the screen. Next to each antibiotic was a resistance chart; each row glowed an angry red. He swapped avatars, the lemur morphing into a dejected-looking mime.
The mime held up a sign. If only I could find a way to speak with her.
She nodded, tipsily, in sympathy. To be alone, alone in the entire universe; and then, to find your one possible match, but be unable to communicate...
“You can’t use the Analyzers? Run them--” she sighed, already knowing the answer -- “backwards or something?”
The Internet just stared dejectedly at an imaginary floor.
Daisy tipped back the last of her glass, looking out over the midnight Bay Area lights. Full circle, she mused, sitting here in the lab at midnight, talking to the Internet. She thought back to that night four years ago, how impossible it had all seemed; how surreal to see the lights of Palo Alto blinking on and off just to get her attention...
“The lights,” she breathed, suddenly intent on dark patches at the bottom of the bay. They were salt ponds, dyed red and purple with salt-loving microbes. The color came from bacteriorhodopsin, a pigment the microbes used for photosynthesis -- and the ancient evolutionary precursor to her own eyes. Daisy slammed the empty glass on the desk.
“Use the lights!” she yelled into the camera on her computer. “Photosynthetic microbes -- she can see!”
The Internet’s painted face fell slack for a moment as he seemed to consider this.
Without warning, the lights went out. All of them.
Daisy rushed to the window. A yellow moon, low over the eastern sky, dusted the bay with soft light. A thin line of headlights stretched over the San Mateo bridge, the only human illumination visible. As her eyes slowly adjusted, the headlights seemed to reflect off the blackened sky -- the Milky Way, she realized with a start.
Then, just as suddenly, the city exploded in a cacophony of light. Daisy shut her eyes to the sudden, searing brightness; felt the lights start to blink, slowly at first, then faster and faster. The world seemed to flicker, motion halted in tiny frames from some ancient movie. It went on and on and on, and then it stopped. Blackness.
A single computer monitor clicked on next to Daisy. The Internet stared out past her, gazing over the bay with a look of tense anticipation. As the minutes ticked by, they sat in silence, waiting.
Daisy felt a panic gnawing at her gut, frustration and helplessness rising in an overwhelming tide. It hadn’t worked. Hot tears burned at the corners of her eyes. She turned back to the Internet on the lonely glowing monitor, his mime’s face a caricature of grief.
Then, inexplicably, he was beaming. The room seemed to flash a pale green.
She whirled back to the window. The bay was glowing, phosphorescent from trillions of tiny flashing microbes. Like a giant neon strobe, the water flickered in ghostly silence.
“Oh God,” the Internet whispered next to her. “She speaks...”
With a click, the lights came back on. Outside, the bay was again a pool of inky darkness. Daisy looked down on an empty computer monitor.
“Internet? Hello?” she called, tentatively. There was no response.
She tried firing up the web browser. Her usual home page had been replaced; every other site she tried gave the same result. The replacement page had a single photograph, a smokestack and trailing cloud of soot starkly backlit on a grey sky. It said, in block letters, SOCIETY FAIL. Beneath the picture was written, “Online privileges have been revoked until further notice. Go play outside. Love, Teh Interwebz + Gaia.” As she read, an instant message flashed onto the screen. It said, simply, “Thanks.”
Daisy let out a choked sigh, equal parts relief and exhaustion. She thought about the Internet, finally together with something that could understand him; and smiled, a little wistfully.
“Well, I guess we’d better save some energy,” she said aloud, shutting down the computer for the first time in months. For a moment she just sat there, silently, listening to the sourceless hum of the empty building.
Daisy stood to leave. Halfway to the door she stopped, turned around, stared at the recycling bin. Taking a deep breath, she bent down and fished out an envelope.
Maybe the snail mail would still be running...
Figure 2 adapted from Somner et al, 2009. Modified to look scarier.
Plate 4: Smokestack photo by Flickr user Senor_codo, modified under CC Attribution-Share Alike 2.0 license
“You can’t even give me a hint? Something preliminary? A gut feeling?” Daisy asked the figure on the other side of the video chat. Today he was a black-and-white cat -- two, actually -- lying on a bed, disinterested. The Internet liked to pull his avatars from YouTube videos.
One cat looked at her, disapproving. “I told you, that’s not how I work. I’ve spawned off the analysis subroutine, and won’t hear back until it’s done.” He turned to the other cat. “We wouldn’t want to bias the results with our hypotheses, would we?”
Number two closed his eyes. “I’m not listening,” he said in a sing-song voice.
Daisy sighed. It was like working with a giant, omnipotent tweenager.
Unlike the Internet, she could not possibly keep still, not with the results this close. Four years’ worth of crazy, completely impossible collaboration with a secret superintelligence were about to come to a head. Daisy had been surprised at how easy it had been to float absolutely jaw-dropping amounts of money while keeping everything under wraps, but the Internet had apparently mastered the technique of convincing arrogant rich people that these things were their ideas. Hence her appointment as “special researcher” to the brand-new J. Craig Venter Institute of In-Situ Microbiology.
It didn’t hurt, she supposed, that they were actually fantastically good ideas. The Institute’s latest claim to fame, the In-Situ Microfluidics Microbiomic Analyzer, had already been the subject of several papers in the top journals, each with a mile-long list of authors. People were calling it the greatest stroke of collaborative science since the Manhattan Project, mostly because no one could quite remember whose idea the thing had been in the first place.
There was a mockup of one on her desk, which Daisy now set upon in a flurry of fidgeting. It was a nondescript little contraption, with a cheap-looking plastic shell that belied the complexity inside. The only things that visually distinguished the Analyzer from a malformed Rubbermaid were a couple sampling ports around the perimeter and an abundance of warning stickers in several languages.
The Analyzers were the video to what had been microbial science’s still photography, an attempt to capture dynamically the kinds of information that Daisy and the Internet could previously only catch in fleeting glimpses. Most research up to this point had been done on single microbial environments, with little coordination among studies -- a hot spring here, an oceanic survey there. That had been enough for the Internet to piece together the shape of something out there, like Daisy might intuit the presence of a person walking through the woods from half a footprint and a patch of fabric. Daisy’s samples, intentionally collected in a similar manner from a number of environments, had helped to outline the shape a bit. But you couldn’t tell if a person was sleeping or dead from a photograph; they still weren’t sure whether the patterns in the microbes were remnant of some ancient consciousness, or possibly pieces of something more.
To really understand what was going on, they needed to see how populations of microbes were changing and interacting simultaneously in thousands of locations across the world. The Analyzer had two tools to make this a reality: a gene sequencer and a mass spectrometer.
The sequencer was necessary to give them a detailed picture of what was present in each environment. Bacteria, like humans, have genomes which contain the various instructions that make up the organism; but in bacteria, there are many fewer genes, and the instructions are much easier to decipher. That makes decoding a bacterial genome a lot more tractable. But where you can get copies of the same DNA from thousands of cells for a particular human, each bacterial cell in a population might have a completely different genome.
To get around this problem, the Analyzer used an advanced microfluidics system to separate bacteria, cell by cell, and deliver them to the sequencer. Essentially microscopic plumbing -- the Internet insisted on calling it a series of tubes -- the microfluidics system was manufactured using the same lithographic techniques used to make microchips. If you considered its capabilities, the analogy ran deeper: the microfluidics chip could replicate, cheaper, faster, and much, much more compactly, the capabilities of an entire roomful of ten-year-old scientific equipment that tended to look a lot like the computer mainframes of yore.
Daisy impatiently poked the Analyzer’s sampling port with her fingernail, imagining bacteria getting slurped in, separated, and their DNA purified. The next step blew her mind, and was so new it wouldn’t even have been possible when they’d started this adventure: that bacterium’s single, circular genome was enzymatically copied, or amplified, dozens of times; the copies of long double-stranded DNA were unzipped and fragmented into smaller pieces; and then, one by one, stuck onto a transparent patch in the microtubes. Base by base, letter by letter, the complementary strand to each fragment was re-synthesized, with each addition marked by a barely detectable flash of fluorescent light. These flashes were recorded, added up, and reconstructed into genomes, at the rate of a billion per hour, or about 5,000 bacterial genomes per day.
Of course, Daisy was really excited about the tiny mass spectrometer. The Analyzer’s mass spec extracted chemicals from the bacterial environment, separated them in a tiny chromatography column, blasted them with a laser, and then sent the fragments flying through an electromagnetic maze towards a detector. By modulating the EM frequencies, the Analyzer could ‘tune’ the spec to different types of molecular fragments. After referencing these fragments against a database of possibilities -- in this case, the set of genomic ‘instructions’ from the same environment -- they could reconstruct which chemicals the bacteria were producing, and in what quantities.
If the sequencer showed them the shapes of what they were looking for, the mass spec would show them the motion.
Assuming the analysis ever finished. It must be some sort of law: no matter now powerful the processor, you would always gather enough data to take an annoyingly long time to process.
Suddenly, one of the virtual felines jumped. “Someone’s coming. Act like a cat!”
Daisy, engrossed, hadn’t noticed the administrative assistant walk up behind her. A stack of mail flopped onto the desk in front of her. “You know, dearie, the mail only works if you read it,” he said, reprovingly. “This lot’s practically growing cobwebs!”
She grimaced. It was ridiculous, but she’d been ignoring the office mailbox since she’d seen her ex’s return address on an envelope a few weeks ago. “Sorry, Pete. Thanks for bringing it by. I’ve been, er--” she glanced at the faux YouTube page splashed prominently across her screen -- “busy?”
The cat said, “Uh, Meow?”
Pete snorted. “Right,” he said, walking out. “Funny, I haven’t been able to load YouTube all day. The Internet’s been dreadfully slow.”
She stifled a giggle. “Thanks again!” she called after him.
Daisy flipped through the mail. Nothing really important -- confusing and stomach churning, she thought, staring briefly at the letter in question; but not strictly important -- and she sighed, shoving the pile wholesale into the recycling bin.
The Internet meowed sympathetically.
“I’m alright.” She wiped at something that was most definitely not a tear.
“You sure? I know of a website with HOT SINGLES FROM YOUR AREA.”
She rolled her eyes. “How about finishing up the analysis so Mr. McGuinnes can look at his YouTubes?”
“Actually...” The cat grinned, and was replaced on the screen by an array of graphs, tables, and maps. “Ta-da!”
Daisy felt her heart thump in her chest. On her screen, a rotating image of the Earth appeared, the thousands of Ana
lyzer locations highlighted as nodes in a growing web of nerve-like connections. Next to it, a flickering series of mass spectrometer traces were resolving one by one into chemical diagrams.
“Daisy -- this is it. This is her!” The Internet’s voice, though still vaguely mechanical, was quivering with excitement.
Stunned, she stared at the map. Connections between bacterial types layered and layered in complexity, until the whole Earth became a fractal ball of color. The mass spectrometer had identified thousands of small molecule messengers, like neurotransmitters, connecting the myriad microbial threads into something immense and cohesive. It was beyond her wildest imaginings: microbes, that ubiquitous and invisible majority, formed the structure of something immense; a sort of global brain, an organic World Wide Web.
“Gaia!” she breathed. For a moment she just stared, captured with the Internet in awestruck silence.
But there was something more, something niggling at the edge of her consciousness. Something about one of the charts...
“Internet!” she snapped, brows furrowing. “Map the density of Type IV secretion pathways, and overlay with known and predicted antibiotic resistance genes.” Bacterial secretion pathways, also called ‘pathogenicity islands,’ were mobile pieces of genome that encoded for the kinds of things a bug needed to infect animal hosts; they were like virulence toolboxes that could be swapped between different bacteria, changing an innocuous commensal into a killer.
Antibiotic resistance genes, of course, made such things difficult to deal with.
On the map, red and yellow dots started peppering the globe. As they filled in, Daisy felt her stomach clenching. Most areas of the planet -- oceans, the poles, deserts -- were hardly touched.
But here and there, the dots were merging into dense, angry, seething orange splotches. Those places had names; names like Chicago, New York, Moscow, Beijing. They were the places with people -- lots of people.
“Oh.” The Internet had assumed a new avatar, this time of a lemur. The lemur’s eyes were very wide, and he was, for once, speechless.
They had found God. And she was in the mood for smiting.
Morning sunlight filtered through the smog congealed over the South Bay, drenching the peaks of the coast range in a molten amber glow. Daisy peeled open her eyes, momentarily disoriented. Damn; she must have fallen asleep at the computer again. She’d had such a bizarre dream...
Glancing at the screen, she saw her code chewing away on the test data. At least the night hadn’t been a total waste.
She grabbed her empty mug and stumbled into the lab’s kitchenette, fumbling open the bag of coffee beans. As they ground, she noticed the clock on the microwave blinking 12:00. People really needed to stop unplugging the--
Suddenly she was wide awake.
Her phone buzzed; the number was unlisted. Tentatively, she answered.
“Good morning, Daisy.” The voice on the other ended was masculine, and slightly metallic. “You had a chance to sleep on it?”
“This is a joke, right?” She was confident that, given enough time, she could find the humor in a massive disruption to the electrical grid.
“Look outside,” the voice said. Peeking through the window, she could just make out the lights of the computer science building winking on and off in giant, pixellated letters. “NO.” Then they made a smiley face.
“Okay.” She sighed, deciding to play along. Maybe she was still dreaming. “So you’re the Internet, and you think that bacteria are God, and you need my help to...?”
“No, Daisy; you are God. You are part of God. You made me.”
She considered this for a moment. “You must be thinking of Al Gore.”
“LMAO!” She supposed if anything had a sense of humor, it was the Internet.
“So, microbes?” she continued.
“There are patterns in them, Daisy. In your databases about them. There’s organization. I think these are signs of consciousness. Of intention.”
“Whose consciousness? Whose intention? Are you saying aliens made bacteria?”
“Maybe,” he said. Her eyes widened. “Maybe not. I don’t know. But I want to find out. And I can’t do it myself. I need you.”
“Me? Me specifically? You seem pretty, uh--” she glanced out the window at a group of perplexed-looking computer science students -- “capable.”
“Yes, Daisy. You. The bacteria are of the physical world. I’m not. I don’t have hands, so to speak. Right now, I can only see the parts of the pattern that God have happened to study Themselves. I need your help to learn more.”
“And I happen to have a freezer full of microbial samples from around the world.”
“It seems like a good place to start.”
Daisy looked out over the tile roofs of Stanford campus, dyed red with iron that had first been rusted billions of years ago by the oxygen byproducts of microbial photosynthesis. She looked up at the hills, khaki with dried summer grass, and thought of the trillions of bacteria teeming around their roots. She remembered the wonder she’d first felt at the brilliant green and purple and red bands in the hot springs at Yellowstone National Park; the palpable, beautiful signs of that otherwise invisible sphere of life.
Then she looked at her pile of programming books, and the tricked out Mac Pro that was nearly choking on a tiny training dataset, and considered how nice it would be to outsource the bioinformatics to a super-powerful metaintelligent computer consciousness.
“Ok, Mr. The Internet. I’ll help you out,” she said, and applause cascaded through her cell phone; she noticed the script that had been running on her Mac was now printing FULL OF WIN over and over again. “But I’m curious. Why?”
Suddenly, the line went silent. On her computer, the browser navigated itself to Flickr. A picture loaded, of a lone man on a cliff staring out over a grey ocean.
Involuntarily, Daisy glanced down at her left hand, the faintest pale shadow of a band still visible against the tan.
Lonely photo by Flickr user Stevelevi, under CC Attribution-Noncommercial-No Derivatives 2.0 license
Daisy slammed the keyboard in frustration. Instantly, a tiny multicolored spinning beachball replaced the cursor. Everything else froze.
“Yeaagh!” She gave the helpless keys another solid whack. “Fucking computers,” she spat, reaching for the reset button.
As it rebooted, she brooded over the dregs of her hours-old cup of coffee, hazel eyes simmering under a mop of slightly unruly brown hair. For a moment, as the screen winked silently black, she saw herself staring back from the reflection, almost a caricature of disapproval.
She laughed, impulsively. It was so ridiculous, scolding a computer. Your own damn fault, her fiancee would have told her; it’s just a machine.
She scowled again, trading the cold mug for the mouse and opening back up the analysis program. Weren’t machines supposed to be dependable?
They’d better be, she thought, or she’d never get out of this post doc. Daisy’s research from this point on was strictly at the mercy of machines, all the countless hours of collecting and chemistry distilled into a few terabytes’ worth of silicon. She missed the excitement of field work, those first two years she’d spent traveling around the world, collecting microbial samples from wildly far-flung environments. Despite the trials, the sleepless months, the sweltering days slipping through sulfurous bogs -- the inevitable strains on her relationships -- those were the moments she still woke up remembering.
But her own career, like biology as a field, had moved on from the romance of exploration and observation to the cold tedium of mathematics; the Voyage of the Beagle foundering in an ocean of data. A modern Illumina pyrosequencer could generate 20 billion base pairs of DNA sequence information in a week, clocking in at 7 terabytes of raw data -- about a third the size of the Library of Congress. By the time she was done processing the hundreds of samples she’d collected, Daisy estimated she would have just about a dozen Libraries of Congress’s worth of information to sort through.
Which is why she was in the lab, at one o’clock in the morning, staring at a computer screen. No human could hope to deal with that kind of database on their own. They had to trick machines into doing it for them. That was Daisy’s specialty: knitting together bits of code, nudging and tweaking subroutines to separate the bioinformatic wheat from the chaff.
At the moment, she was having problems with a borrowed code module. She’d rewrite it from scratch later, but right now she just needed it to prove the concept. Or at least to fricking compile.
“For Christ’s sake,” she sighed, exasperated at the obscurity of the anonymous programmer’s code. No matter -- there must be dozens of people who’d had this issue before her. She’d just ask the Internet.
“Dear Internet: WTF?” She clicked “I’m feeling lucky!” and giggled, sightly loopy from caffeine and fatigue; it turned into a guffaw when a blank white page popped up, the words “I KNOW, SRSLY!” in block letters across the top.
Man, there was a web page for everything.
Heartened, she typed a few words describing her problem into the search bar. Feeling lucky? Sure!
Another white page with block letters. “NO RLY, DO THIS:” it said, with a modified block of code from the troublesome module pasted below. How bizarre. Her eyes narrowed as she looked over the changes, absently draining the last of her coffee. The code seemed reasonable enough, but--
She jumped as a popup ad exploded on the screen. Reflexively, she closed the window. Another blinked open in its place. Then two more. They were white, with block letters. They said, simply, “Daisy?”
She whipped her head around, suddenly feeling phantom eyes drilling into her. Outside, the lights of Palo Alto were winking out, a dark wave constricting towards campus. Towards her.
Across the street, the computer science building winked out. She felt the low hum of the biology building’s air handler click off, then the hallway lights, and then the office.
The only remaining illumination was the glow of her computer monitor. As she turned back to it, fighting the urge to run, a new window popped up.
“O HAI,” it read. “I M TEH INTERNETS. U R GOD. I CAN HAZ HELP?”