AN1: This chapter's musical number is Porcelain by Moby, though I think Cosima and her friends would be blasting Dub Pistols' Countermeasure at the end :)
AN2: This chapter is super science-y because evo devo is super super cool! It also lays the groundwork for Cosima's thought processes in a later chapter. That said, I'm definitely trying to strike a good balance between science and story, so let me know what you think in the reviews and I'll do my best to adjust.
AN3: Hope everyone had a Happy Thanksgiving in the states! And thank you so much for all the positive feedback on and shares of this story - it's very motivating to hear from you all!
Jason Goodwin tapped Cosima's shoulder. Her gaze reluctantly slid from Burggren et al.'s review, Epigenetics in Comparative Biology and to her student's panicked features. They silently exited the lecture room to talk in the hall.
"Ms. Niehaus? Yeah, I have a clarification question about... about..." he flipped through the pages. She forced a smile. She hated answering questions during tests; it turned what was usually a learning opportunity into an awkward negotiation.
He found the page. "Here. Uh, about question #32."
It was one of the questions she had written about mammalian anterior-posterior body plan development. "Sure, shoot."
"So, I get that Hox11aaccdd means all three sets of the gene are knocked out. But it doesn't say whether 11 usually inhibits Hox10 or Hox12?"
"Jason, you should know that."
He looked crestfallen and Cosima coughed to cover up a sigh. So much effort had gone into her section plan on this topic and he was such an earnest student - one who came to all her office hours yet refused to use her first name.
"Okay, um, try to remember the Wellik and Capecchi article. How did the Hox numbers line up with the different types of vertebrae?" She had to hold her hands down Dr. Strangelove style to keep them from giving it away.
Despite all the immensely complex genetics going into development, evolution had set up Hox genes - the literal body blueprint genes - in the simplest way possible: 1) as the numbers increased, they encoded body regions increasingly further from the head; 2) higher numbered Hox genes repressed lower numbered Hox genes in order to differentiate these regions; 3) hell, they even lined up in ascending order on the genome. Teaching, however, revealed that she often took her knowledge for granted. In fact, the more she knew about something, the harder it was to convey. She'd been charged with planning the Hox gene section because of her dissertation topic... and it was a disaster. Too many details and not enough generalizable take-aways. This was the other thing she hated about questions during a test: they revealed teacherly bungles without affording any chance to correct them.
Jason looked at her hopefully, but she shook her head and showed him the lecture room door; she'd already said too much. She sat down again and Maria tipped her an imaginary hat, Jason's latest question put her ahead in their bet. At least she might get a free drink out of fucking up Hox genes. She took respite in her blossoming epigenetics library.
Finally, the exam finished. The shuffle of papers turned into a muttering of students comparing their experiences: some gnashing, some bravado, and a few heartfelt thanks directed towards the TAs. Jason shook Cosima's hand and presented her with a mug emblazoned with "SCIENCE. It works, Bitches." His insight into her taste floored her and as he thanked her, she witnessed his unpreoccupied smile for the first time. When all the students had disappeared out the door, Maria began alphabetizing the exams while Cosima checked for trash and lost items. They didn't speak until stepping outside, noontime heat breaking the intensity of exams and student farewells.
"Hey, did it seem like all the questions were about my PCR section?" Maria asked.
"Nuh-uh, no way. Everyone was still confused about Hox genes."
"What? I thought you did great with that."
"Ha. You're just being nice. Also, your explanation of PCR was flawless - it was that guest lecturer who totally biffed the thing about primers."
Cosima started towards the seminar room where all the other TAs would meet to grade but Maria had other ideas.
"Em, where are you going?"
"Microbio lounge. We have a rendezvous to make." She had that mischievous look Cosima knew well.
"What do you have going on this time?"
"We, my friend, are getting a catered lunch. But that's all I'm saying about it."
"Maria! We have to do scantrons with everyone else-"
"Pssht, we'll do that later."
Cosima sighed and lugged the cart after her friend. Maria cheerfully changed the subject. "So, what did Jason give you?"
"Oh!" Cosima fished in her messenger bag and pulled out the mug. "This."
"'SCIENCE. It works, Bitches.' Wow. That's kind of amazing!"
"I know, right? Also hella unexpected."
"Well, you can drink your free wine from it. Jason: 4; Kim: only 2. Man, she must have studied so hard this time."
Cosima looked at the mug and thought about all her office hours this semester. "Dude, we did alright by them, huh?"
"Teaching?"
"Yeah."
"Oh, definitely." Maria pulled her into a side hug and they continued towards the microbio lounge.
Air conditioning and the unmistakable smell of Burrito Brothers Taco Co. washed over Cosima as she stepped inside. She could hear Davy's favorite iPhone app, a beer pong themed tower defense game.
"Davy! You brought lunch!"
"Hey hey, Cosimbro!" He tossed the phone and brought her into a backslapping hug. "Yo, did you ever untangle yourself from those two Canadians?"
"What?" Then she remembered her last text to him. "Oh, heh. Not 'til this morning."
"She was pretty late." Maria inserted.
"Damn, girl! There's no way you can pack up all that game to Minnesota." He went in for a high five, "Y'know, I could take some o' that off your hands."
"Ha! In your dreams, man. This shit is non-transferable." She bypassed his high five and patted his shoulder patronizingly.
"Oh, snap!"
Cosima laughed and unwrapped the sweet potato burrito he proffered. Davy was probably the smartest biochemistry grad student at UF but he compensated for it by dialing frat-boy up to eleven. Right now he wore a black muscle tank with obscenely low-cut arm holes and a custom slogan, Schrodinger's cat walks into a bar and doesn't. These little details - the ones that revealed his irony and almost unraveled his whole routine - had instantly endeared him to her. On his part, Davy had made a point to bro-friend her right after she managed to seduce Suzanne Prendick, a leggy brunette with an amazing southern drawl; she was easily the hottest women in their cohort and this development with Cosima had surprised everyone, including Suzanne.
Davy slid Maria's chicken burrito across the table, "Hey, Em! Mission accomplished?"
"Shh!" She glanced at Cosima, "She doesn't know yet."
"What don't I know?"
Maria abandoned her lunch with a huff, "Well, I was going to wait until after we finished eating, but..." She got up and rummaged in the cart as Davy returned Cosima's questioning look with a shit-eating grin. He was always giving away their pranks by laughing too early or otherwise dropping character. Maria returned with a small stack of exams and handed them to her face down.
"Turn to the second to last page."
Cosima obeyed and discovered a question that had definitely not come up during proofreading. At the top, in huge Comic Sans: For zero points and the entertainment of your TAs, please illustrate your favorite topic from Genetics and Development. Bonus zero points if you incorporate one of your TAs in the illustration. The rest of the page was filled with one student's crude drawings of fruit flies that appeared to have glasses and dreadlocks.
"Oh wow. This is, like, the nicest, most nerdy thing ever!"
"Does it beat the mug?" Maria asked.
"Haha yes. Barely though."
"Y'know, we're gonna miss you, Cosima."
"Aww..."
The sentimental exchange whooshed over Davy's head as he leaned over and pointed at one of the fruit flies, "Is that a dread coming out of its nose?"
Cosima inspected it closer, "Oh, no that's the Antennapedia mutant. Yeah, a chromosomal inversion causes an abdominal Hox gene, Antp, to be expressed in the head... so it grows legs instead of antenna."
"Oh weird. And why the hell does this fly have glasses on its legs?"
Cosima laughed. "That's so cute! It's another Hox mutation. We talked about how if you ectopically express the gene for eye development, you'll get eye cells in random places - like all over the legs."
"And you would do this because...?"
"Actually, it's super cool." Cosima stood up and started to pace the room, "So the gene that kicks off eye development is called eyeless-"
"Naturally."
"No it makes sense, 'cause the flies without this gene were literally eyeless."
Davy reclined again, posture saying, you're science ranting right now but Imma let you finish. Maria took this chance to dig into her burrito.
"So eyeless. Necessary and sufficient for eye development in flies. Turns out, we humans also have the eyeless gene and if it's knocked out then our eye doesn't develop normally." Cosima took off her glasses to emphasize her point.
"Hmm." Davy seemed mildly impressed and made for the next student cartoon.
"But wait, I haven't even...!" She gesticulated with the first exam still in hand, "The super amazing thing is that you can rescue eyeless-knockout flies by giving them the human version of eyeless protein! Bam!" She replaced her glasses, "They develop eyes no problem."
"You're telling me these flies got human eyes."
"Oh no, no, no. No, don't be ridiculous. Eyeless is just a developmental signal saying, 'Hey, make an eye here.' It turns on other genes which actually construct the species-specific eye. What's so cool is that the signal has stayed virtually the same over 300 million years of evolution! At least! Can you imagine when humans and flies last shared the same common ancestor? That's how long the eyeless gene has been around doing what it does best, makin' eyes."
Davy sliced the air with ninja hands, "Evo-devo, yo!"
"Hell yeah!" Cosima dropped back into her seat and allowed the student cartoon gallery to continue.
"I curated the best ones for ya." Maria said in between mouthfuls.
"And I thought you were just struggling with the alphabet back there." Cosima teased.
They munched on burritos for a while, passing cartoons, laughing occasionally, and doing a moderately successful job of keeping the exams salsa-free. Davy held up one towards the end of the stack, "What's up with the mountain climbing?"
"Huh?" Cosima took it from him. The picture showed her as a stick figure planting a flag on top of a mountain surrounded by smaller hills, everything bracketed by x-, y-, and z-axes. "Oh! It's an adaptive landscape."
Davy quirked an eyebrow and offered her an imaginary microphone, "Adaptive landscape. Go!"
"Okay, okay. It's a way to visualize Darwinian fitness. See, these axes represent lots of different traits - like, uh, body size, brain size, and attractiveness to potential mates, for example. The y-axes is fitness so the higher points mean more adaptive combos of those traits, the valleys mean less."
"So they're saying you've got game!"
"Haha, they kinda are!"
"Accurate, hey-oh!" He finally got his high five.
"Wait, Cosima, when did you teach this?" Maria asked. "That definitely wasn't on the syllabus."
"Oh, um, I sorta got on a tangent talking about Hox genes and body plan evolution."
Maria looked at her sideways, "Musta been one helluva tangent."
"Dude, I was talking about how duplications of Hox genes can, in one generation, create an entirely new kind of animal. Y'know, like going from a fly with 1 set of wings to a wasp-like thing with 2 sets. Totally syllabus."
"Okay. So far."
"And then Janie asked why we aren't seeing crazy evolution of new body plans like we did in the Cambrian Explosion. I mean, c'mon, what an amazing question! So, I started to explain why evolution is more constrained now than it was before, how a random mutation was more likely to jump you up higher on adaptive mountains back when..."
Cosima stopped when she saw her friends exchanging a look. "Um, I've been talking a lot. Davy, you wanna spit about protein folding thermodynamics?"
He smiled and shook a hand. "Nah, I'm on summer break. And we were just, um, thinking... you really love this stuff, huh?
"Yeah, obvs."
"Yeah, we um..." He looked suddenly awkward and Cosima caught a glimpse of what he must have been like in high school.
Maria set her burrito down with an audible plop, "We're staging a scientific intervention."
"You're what?"
"Epigenetics? Cloning? Cosima, you can't be serious." She pressed.
Cosima tried to laugh it off, "You guys don't need to worry about it."
Davy put a hand on her arm, "Dude, you're following your idol across the country and then randomly decide you're gonna change your dissertation to outside her expertise? Outside your expertise? We're worried."
Cosima recoiled her arm, "Hey, it's not that big of a deal! Look, they both deal with development, and," she ran with an idea just starting to form, "evo devo is all about how epigenetic controls change over time, transcription factors and regulatory regions..."
Maria cut in, "Yeah, but they're asking completely different questions and on different time scales. Not to mention you'd need to master different methods and a whole new body of literature!" She shot Davy an exasperated look. He said quietly, "You're a rational human, Cosima, I'm sure you have a good reason. Just tell us what's going on."
Cosima felt trapped by their concern and vulnerable from their attack on her plan to regain some semblance of control over her life. She opened her mouth to speak but the levies built from fond farewells of friends and former students broke, letting the horror of last night flood back in. Doubt spread like mold over the idea of her and Beth taking on the cabal of scientists who had designed them. But worse, the scrutiny of her friends felt more acute than the objective eyes monitoring her from afar. The room shifted and she felt suddenly unseaworthy; water threatened to seep from her eyes. She took off her glasses to wipe at them as though she were merely tired.
When she looked up, her friends were regarding her with a mixture of shock and concern, not daring to say anything lest they break her hold on composure. She let out a shaky laugh, "Uh, is it okay if we postpone this intervention?" She took a breath, "I've had a... a weird 24 hours." After a long pause, Maria whispered, "Yeah, of course. That's completely fine." Davy nodded in agreement. Cosima picked at tortilla scraps and waited until the sensation of drowning subsided. Finally she said, "Maria, we should probably go grade soon."
"Oh shit, what time is it?"
Davy seemed relieved to have a question he could field, "It's almost 2."
"Okay, when you're done with your burrito, Cosima, we'll go."
"I'm done. Let's get this over with."
"Fine by me."
Cosima stood to gather her things but Davy stopped her with a rare, real hug. Enveloped in his height and the smell of Old Spice, she wondered - and not for the first time, what would have happened if Suzanne were out of the picture. She held him for a little longer when he started to pull away. Then she looked up to see pity in his eyes and the moment was gone. She punched his shoulder, "Hey, thanks for lunch, man."
"Anytime, bro. You just let me know when you're hungry and I'll run Taco Co. up to Minneapolis."
"Ha, if only."
"See you tonight?"
"Fo sho, fo sho."
"Good. A'ight, later chicas!" And he shoved out the door, longboard in tow.
Maria and Cosima repacked the exams in silence. Once outside, the humidity seemed to buffer the awkwardness and they found ways to talk about superficial things. The other TAs barely acknowledged their arrival so they, too settled into the monotony of grading.
Later that night, when Davy and Maria picked her up from her apartment, they all acted as if nothing out of the ordinary had happened. Cosima pretended her biggest decision was whether to hook up with Suzanne one last time or to smoke out Davy and Maria with the remainder of her weed. Familiar laughter filled Davy's Jeep but as Gainesville's halogen street lights flashed by, she could already sense a distance from her friends. She felt a strange gratefulness that moving away would clean the slate for this new reality as a self-aware clone.
To: Dr. Aldous Leekie
From: Daniel Rosen
Subject: Leverage for Immunology position
Date: July 17th 2009
Aldous,
Your hunch on D.C. paid off.
See attached email to the IRB Compliance Committee chair written by her advisorbut never sent. He is up for tenure soon and seems he did not want this on his record either. We have removed this file as well as D.C.'s incriminating communications from his computer and back-up drives.
She will defend her PhD in December, suggest sending first offer in February 2010.
Daniel
AN: At least one of the scientific articles I cite for this chapter and many following are going to be from after 2012, because, like, who are we kidding, we want the most cutting edge stuff out there! Also, if we're willing to accept that Susan and Ethan Duncan cloned an ovary-load of people 12 years before real world scientists created Dolly, a single sheep and the first mammal to be cloned... then I'm gonna take a free pass on the timing of article publishing (which can take years even after the results are gathered and analyzed because the peer review process is long, arduous, and - appropriately - has a lot of check-points for quality, ethics, veracity, etc.)
Chapter 3 Sources
Note: you can find the all SciTB sources complete with hyperlinks (how fancy!) on the scienceintheblack tumblr slash sources
## Adaptive Landscapes and why evolution may get more constrained over time
Loewe, Laurence. "A Very Short Introduction to EvoSysBio." Evolutionary Systems Biology - Introduction. Evolutionary Systems Biology, n.d. Web. 28 Nov. 2014. /intro/. As advertised - also has a great picture of an adaptive landscape.
Kauffman, S. A. 1989. Cambrian explosion and Permian quiescence – implications of rugged fitness landscapes. Evolutionary Ecology 3:274-281.
## Epigenetics
Burggren WW, Crews D (2014) Epigenetics in Comparative Biology: Why We Should Pay Attention. Integrative and Comparative Biology 54: 7-20. A really good (and super recent!) review paper synthesizing the importance of epigenetics to evolution research.
## Evo-devo and Hox genes
Brody, Thomas B. "Antennapedia." Interactive Fly, Drosophila. Society for Developmental Biology, 20 Mar. 2001. Web. 28 Nov. 2014. . . Not the most read-able summary ever, but this is the kind of secondary source that geneticists look at all the time to get a summary of information about a gene.
Clements J, Hens K, Merugu S, Dichtl B, de Couet HG, et al. (2009) Mutational analysis of the eyeless gene and phenotypic rescue reveal that an intact Eyeless protein is necessary for normal eye and brain development in Drosophila. Developmental Biology 334: 503-512.
Understanding Evolution Team. "Evo-devo." Understanding Evolution. University of California Museum of Paleontology, n.d. Web. 21 Nov. 2014. .edu/ evolibrary/article/evodevo_01. An introduction to evo-devo by none other than Cosima's alma mater! They do a good job explaining Hox genes succinctly.
Wellik DM, Capecchi MR (2003) Hox10 and Hox11 genes are required to globally pattern the mammalian skeleton. Science 301: 363-367. A classic paper on the role of Hox genes in patterning the mammalian body plan.
Note: it can get confusing to distinguish between genes and the proteins those genes code for. The scientific convention is to use italics when talking about the gene (e.g. the eyeless gene) and roman type for the protein (e.g. the eyeless protein).
As always, I want to acknowledge that I'm writing in the universe of Orphan Black, a copyrighted creative work by Graeme Manson and John Fawcett, produced by BBC America.