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The Third Component: Part II, Chapter 20

Alison Christy 8 March 2009

www.lablit.com/article/477

Photo Credit: Tim Christy

John had a strong moral code, but it was his own moral code. Dishonesty and infidelity were immoral, but divorce was fine, and so was dating your own graduate student

Editor's note: We are pleased to continue the weekly serialization of The Third Component, a novel by Alison Christy: a scientist at loose ends after earning her PhD sets off to Russia in search of a missing piece of her family's past.

Chapter 20

Epigenetic Regulation in Saccharomyces cerevisiae

"Thank you for your introduction, Yelena. I am very happy to be here."

Anna clears her throat and looks out at her audience: mostly young, solemn, bored.

"So, um, I don’t know how much you know about – well. I’ll just start from the beginning."

She smiles. Her hands are shaking. She hates how her hands shake, even when she knows she shouldn’t be nervous, even when the only thing making her nervous is how much her hands are shaking.

"Over the last few decades we’ve become increasingly aware that phenotype – meaning the appearance and constitution of any organism – please stop me if you have any questions – we’ve become increasingly aware that phenotype cannot be entirely determined by a combination of genotype and environment. The classic experiments of Gartner in the Seventies and Eighties demonstrated that animals, living in controlled environments and inbred to the point where their genes were identical, still can show variation in their phenotypes."

If there was one thing Anna had learned from her years as a Ph.D. student, it was how to present this very talk about her work. She has presented it to John a hundred times, to her labmates, to her thesis committee, at genetics conferences. She knows every word of it and could do it blindfolded, standing on her head; she just doesn’t know if the people here understand any of it. Yelena stands in the corner of the room, nodding vigorously at everything she says; the rest of the room watches her without reaction.

"Even earlier, in the Sixties, Storrs and Williams saw individual differences in genetically identical newborn quadruplet armadillos. You yourself may know a set of human monozygotic twins – genetically identical and raised in the same family – and you may have seen that even these virtually identical humans can have differences in height and eye color, and can get different diseases, like diabetes and schizophrenia. Um, schizophrenia – that’s a mental illness. In the brain.

Surely they would interrupt her if there was something they didn’t understand. She just couldn’t worry about it. She just had to get through this and if they didn’t understand, they just didn’t understand.

"So, it appears that there are three factors at work here. There’s genetics, there’s environment, and then there’s something else. And maybe you already know, Gartner called this something else the ‘third component.’ "

Anna explained how it is believed that this 'third component' is a pattern of DNA modification known as epigenetics. Broadly, the phenomenon of epigenetics includes everything that can make multiple phenotypes from a single genotype. The label epigenetics refers more specifically to DNA modifications that turn genes on and off, altering how they interact with the machinery of a cell and thus determining whether or not a protein is produced.

Epigenetic changes can occur randomly, Anna told her audience, as in the case of the quadruplet armadillos and the human identical twins. It can happen in normal development, as in the case of imprinting, where either the paternal or maternal allele of a gene is turned off epigenetically. But epigenetics can also happen due to events that occur during the lifetime of an organism.

When Anna started her research, she thought the field of epigenetics was going to change the world. Cancer? Epigenetics. Obesity? Epigenetics. It was the thing no one had thought of yet: there was Nature, there was Nurture, and then there was this revolutionary new phenomenon that changed everything. Genetic modifications, which could be hereditary, could be environmental, or could be completely random, or probabilistic – how could this new answer not fit with every unsolved problem?

John believed in hereditary epigenetics like other people believed in religion. It would be, he told Anna, their Nobel prize-winning work. They were going to revolutionize the world, they were going to change everything: McLoughlin and Forsch were going to be the next Watson and Crick.

"For instance, some plants, when exposed to cold, undergo a process called vernalization that allows the plant to flower, and this has been shown to be an epigenetic phenomenon. This vernalization is not passed down from generation to generation, as the Soviet scientist Lysenko found when he attempted to “educate” plants through repeated cold exposure."

Somehow she had actually forgotten that she mentioned a Soviet scientist in this part of her talk. She hopes that she doesn’t get a lot of questions about Lysenko after the talk: all she knows about him is that he thought plants could inherit vernalization, which seemed completely crazy to Darwinian scientists at the time, but which sounds now like something John would have tried, if he were interested in plants.

He even thought that the female body might use the nine months of gestation to change the epigenetics of the fetus, turning off certain paternal genes and turning on certain maternal ones. “We’re all more like our mothers, aren’t we?” he said, though they both acknowledged that there could be a hundred reasons for increased mother-offspring similarities.

"The best characterized example of heritable epigenetics is paramutation in plants, a phenomenon in which expression of one allele is heritably altered by the presence of another allele. This has been studied in maize."

John had a strong moral code, but it was his own moral code. Capitalism was immoral; dishonesty and infidelity were immoral, but divorce was fine, and so was dating your own graduate student, although no one could know. (“Yes, you’re a student, but you’re a consenting adult,” he had said. “You’re intelligent and you understand what you are getting into.”) Allowing his daughters to be raised almost exclusively by his ex-wife and her new husband, that was fine – and in fact had biological precedent, he told Anna.

"So we know that the environment can change our epigenetics; and we know that some kinds of epigenetics can be heritable. Our lab thinks, however, that there are times when the epigenetic changes that occur in response to an environmental stimulus actually can be passed down to offspring."

But Anna had to understand that he didn’t want to go through all of that again with her: marriage, children, divorce. He wanted just the two of them: uncomplicated, working toward a common, noble goal.

"We study this hypothesis in a yeast model. Saccharomyces cerevisiae, the same yeast you use in making beer or bread, makes an ideal model for the study of genetics and epigenetics. It grows rapidly, but unlike E. coli it doesn’t cause disease so you don’t have to take special precautions in the laboratory; it exists in either a haploid or diploid state, which means that it can mate with other yeast cells but it doesn’t have to; and it has a very active machinery for homologous recombination."

Which was what he had said from the beginning. She was the one, he said, who had been dishonest about what she wanted: dishonest with him, or possibly with herself.

Anna goes on to describe the specifics of her work on epigenetic changes in yeast; specifics which are barely interesting to her anymore, let alone to the audience. After all, she is not the one who published this work. The exact same experiments were described in an article by someone named Shabir Chaudry, a post-doctoral student in the Boden lab at Stanford, in Molecular Genetics, January 2000.

Because the other thing they don’t tell you about science when they are pouring liquids together that turn pink is that the actual practice of science is always a competition. There are always other scientists trying to figure out the same problem, and whoever figures it out first gets the publication and the accolades. This was true for Watson and Crick, it was true for Einstein, it was probably true for Newton. This means that other scientists will steal your work if they can. Or rush work to publication. Because if you take your time, if you get caught up in slight details that your advisor wants to iron out before you publish to make a complete, dramatic story – if you’re caught with six years of research and someone else publishes first, you might as well not bother.

When Anna complained about the long hours and the small pay in graduate school, her mother would say, “At least you’re doing something good for humanity.” But it’s hard to feel that you’re contributing to the greater good of science when you know that your work is always redundant, and it’s just about getting there first.

Anna’s final slide acknowledges the work of Professor John McLoughlin and the others in her lab. The audience claps politely. Then come the questions:

“Are you married?”

“Why not?”

“Do you think a scientist that is woman, have a difficult time to becoming successful in America? I mean with money?”

“What I asking, are the sexisms in America?”

“Have you tried exposing your yeast cells to other environmental mutagens, for instance diethylstilbestrol or gamma radiation?”

“Do you carry gun? Do most Americans carry gun?”

The audience claps again, and as they begin to leave the auditorium Anna turns to Yelena to ask her how she thought it went and whether she might be interested in going out for coffee to discuss Michael Perch and his recent disappearance. And then she should try to figure out how to get to Kolpashevo; or maybe she should just get a ride to the Tomsk Airport and catch a plane back to America. No one could say she didn’t try; no one would blame her if it just didn’t work out.

But then she hears a voice behind her, saying her name, and she turns, thinking once again that there are so many Annas in Russia and wishing she could stop responding to her name like an automaton.

And the person calling her name is Frank.

{Continued next week}