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Synthetic
How Life Got Made
By Sophia Roosth The University of Chicago Press
Copyright © 2017 The University of Chicago
All rights reserved.
ISBN: 978-0-226-44063-7
CHAPTER 1
Life by Design: Evolution and Creation Tales in Synthetic Biology
"Them?"
"Nature and God."
"I thought you didn't believe in God," said Jimmy.
"I don't believe in Nature either," said Crake. "Or not with a capital N."
— Margaret Atwood, Oryx and Crake, 206
The perfect match, you and me
I adapt, contagious
You open up, say welcome
...................
The perfect match, you and I
You fail to resist
My crystalline charm
...................
My sweet adversary, ooh
My sweet adversary, oh
My sweet adversary
— Björk, "Virus," Biophilia
I had a virus I couldn't kick. Feverish and congested, I hurried from the MIT walk-in clinic to listen to Drew Endy lecture to the Department of Biological Engineering. On this overcast day in November 2005, Endy was one year into a tenure-track professorship at MIT (he had first arrived at MIT in 2002 as a research scientist). He looked young — about ten years younger than I knew he could possibly be, given his academic trajectory. The only aspect of his appearance that betrayed his age was his hair color, which had, in just the few months since the summer we had met, begun to fade from light brown to gray. He wore wire-rimmed glasses and kept his hair close-cropped, but photographs reveal that as a graduate student at Dartmouth in the mid-1990s, he had sported an abundant beard that suggested a previous incarnation as an outdoorsman. When not busy with teaching, researching, and preaching the gospel of synthetic biology, Endy blew off steam by whitewater rafting, hiking, and kiteboarding and would organize semiannual lab field trips to get his students off campus and outdoors.
Despite the intervening decade between earning his PhD and arriving at MIT, Endy continued to dress like a graduate student, a quirk that was tolerated, if not embraced, by the laid-back sartorial culture of MIT. On any given day, Endy would wear a T-shirt advertising some aspect of his work in synthetic biology: shirts emblazoned with logos of the BioBricks Foundation, MIT, or Creative Commons, and one that merely promoted "DNA." Today was no different. Perhaps some of Endy's persona was self-consciously constructed to incarnate a social type, even a caricature: the enthusiastic inventor, the youthful and magnetic leader of a new movement in scientific research. By 2005 he had become such a high-profile spokesperson for the field that his persona had already triggered backlash, with an editorial in Science noting obliquely: "Some of his peers privately complain that Endy is a larger-than-life self-promoter." No wonder the room that day was packed, with students sitting cross-legged on the floor and overflowing into the hallway on the first floor of MIT's building 68, running along Ames Street.
After a superlative introduction by fellow professor Penny Chisolm, Endy launched into a lecture that was equal parts autobiography and research report: "So, to get started, this is how I got into molecular genetics and biology ..." Over the next hour, Endy revealed that he too had a virus he couldn't kick. Indeed, he had been living with it for over a decade. This one, a bacteriophage named T7, didn't infect him (it feeds only on bacteria). It had, however, infected his thinking, spurring him to understand biology differently.
In this, as in many of Endy's talks, his style betrayed a tension between the logical and rigorous approach of an engineer, in which discipline he had trained, and the starry-eyed naïveté sometimes projected by scientists when presenting their work to a wider audience. Endy reported to the assembled faculty and students the origins of his current research: how, as a graduate student in the 1990s, he had developed a software model that, using data from sixty years of molecular biology research on bacteriophage T7, computed the complete intracellular developmental cycle of the bacteriophage, focusing on the infection of a single E. coli bacterium by a lonephage. But his model, he told us, was lousy — it didn't work; it couldn't predict the behavior of T7.
Reflecting on his thwarted doctoral and postdoctoral work, Endy told his audience that those years were "pretty depressing to me, because now I'm coming back to this problem, where I want to understand how this thing works, and I want to understand how this thing works when I shuffle up all the [genetic] elements, right? And if I've got 72 elements, then I've got 72 factorial permutations, right? More than the number of protons in the universe, probably. And so it's not clear if I can build out a computer model that's going to let me explore this space, that I'm ever going to be able to get traction on this problem." Simmering down his question to a bullet point, he snapped, "What's wrong with the T7 genome?" I had been observing in Endy's lab for three months when I attended this lunchtime lecture, but his question shocked me nonetheless. I had never before heard a life scientist ask what was wrong with a living system. What sort of question was this — ontological? Normative? Ethical? Wrong to whom? Wrong by what metric? It was "wrong," I would learn, because it was disorganized and cluttered with genetic junk. It resisted Endy's best efforts to simulate, model, or understand it. The virus was wrong, in short, because it was a bad design. So he set about redesigning it.
Making Life Better
The MIT Synthetic Biology Working Group's self-described mission was to "mak[e] life better, one part at a time." The two labs constituting the group, led by Endy and Tom Knight, posted this slogan on their website when they founded the working group in fall 2002. If this book queries what synthetic biologists mean by "life," then this chapter draws upon ethnographic fieldwork among MIT synthetic biologists to ask what they mean by "better." Synthetic biology was — and remains — a diverse assemblage of interests, agendas, and research programs. Yet despite vast differences in academic background and wide variation in research agendas, these researchers are united by the philosophy that biology is a substrate amenable to the same engineering strategies employed by mechanical, electrical, and computer engineers to build the nonliving world, and they approach their engineering projects accordingly. Further, they are confident that building new living systems will advance their understanding of how biology works at a more fundamental and profound level than discovery-based experimental science can uncover: that manufacture will heighten understanding.
In this chapter I narrate the T7.1 project, one research agenda that dominated MIT's Synthetic Biology Working Group during my first years there. This was an effort to synthesize a "better" version of the genome of the T7 virus. In telling this story, I trace two lineages mirroring one another. First, I track how Drew Endy moved from a background in structural engineering into life sciences research, how he became the Principal Investigator of the lab in which I conducted much of my fieldwork, and how he reached the conviction that life can and must be understood by simplifying it. Second, I follow the career of a simple biological agent that drew Endy away from structural engineering and pushed him to think about questions of evolution and biological complexity. This humble bacteriophage (a virus that infects bacteria; literally, "bacteria-eater") both piqued Endy's curiosity and frustrated him. T7 is a bacteriophage that either replicates within or bursts bacteria (cycles scientists respectively call lysogenesis and lysis). Endy's encounter with T7 — his "sweet adversary," to borrow a verse from Björk — encapsulates a constellation of concepts and terms that are central to MIT synthetic biologists' thinking about life and that will recur throughout this book: simplicity, minimalism, simulation, design and evolution, nature and artifice.
When these synthetic biologists set about to manufacture simpler forms of life, their thinking is animated by two altogether different understandings of "design." One construes their efforts as improving upon natural selection by "rationally" engineering living things in a goal-oriented manner. Such thinking, I show, is animated by a belief that evolution renders genomes that are cluttered, "junky," and poorly organized. The other takes design to be synonymous with "creation." As such, they imagine themselves to be both objects and agents of evolution.
In the early 2000s MIT synthetic biologists cast themselves in three very different roles. They simultaneously saw themselves as unnatural, building artificial organisms that are "fit" to thrive only in the artificial environment of the laboratory; as natural, doing the work that comes to them "naturally"; and as supernatural, effecting feats of biological engineering that render them divine. I arrive at the conclusion that these stories are animated by a religious discourse, which I evaluate using ethnographic examples culled from lab meetings, private conversations with graduate students, and published material. In invoking this language, MIT synthetic biologists slip between ideas about biological design, anxieties and hopesabout "intelligent design," and Judeo-Christian accounts of creating life. Such stories cast MIT synthetic biologists as both godlike agents of biological evolution and unwitting participants in or targets of an evolutionary impulse.
Slouching Away from Bethlehem
How did Endy come to be delivering this lecture before MIT's Department of Biological Engineering? And what were the origins of his idée fixe with T7? Raised in Valley Forge, a small town in southeastern Pennsylvania, Endy, like many of the engineers with whom I spoke, remembered fondly youthful inclinations toward engineering, fueled by playing with Legos, Erector Sets, and Lincoln Logs. Endy studied civil engineering at Lehigh University, a small college in Bethlehem, Pennsylvania, a postindustrial steel town less than two hours by car from his parents' home. The blast furnaces of the Bethlehem Steel Plant, now shuttered, still roared when Endy lived there, a symbol of American industrial manufacture. "The Steel," as it was called, forged iron for railroads, skyscrapers, and guns used during World War II. Endy spent the summer of 1991 working for Amtrak, fixing bridges servicing the railroad between Washington, DC, and New York City. The shadow cast by Bethlehem Steel on Endy's early education struck me as especially formative when he explicitly compared — even denied any difference between — structural and biological engineering. As he rhetorically asked in his lecture, "What's the difference between building a bridge and designing a genome?" Such thinking denies any meaningful difference between the living and nonliving worlds, at least when it comes to their use as engineering substrates.
Bethlehem Steel is also the plant where Frederick Winslow Taylor first formulated his principles of scientific management, a manufacturing philosophy some synthetic biologists also hope to build into biological engineering, making it faster, more streamlined, and less error prone by "standardizing" parts and protocols and setting up "assembly lines" for manufacturing engineered microbes. After receiving his undergraduate degree, Endy remained in Bethlehem for two years to earn a master's degree in environmental engineering.
He next headed to Dartmouth, where he embarked upon a PhD in biochemical engineering and biotechnology. It is here that he first encountered T7. As he recalled for his audience, as a graduate student at Dartmouth, his doctoral research involved building a software model that would simulate and predict the behavior of T7. Could biologists, he hypothesized, use fifty years' worth of experimental data to predict growth rates of viral plaques (infected bacterial cells grown in culture)?
To understand the stakes of this question, we must pause Endy's trajectory into the synthetic biology lab to trace the history of bacteriophage T7, asking how it too became an object of synthetic biology. Bacteriophages are some of the best-understood and well-characterized infectious agents in biology laboratories. Milislav Demerec and Ugo Fano, working at Cold Spring Harbor in 1944, are widely credited for isolating bacteriophage T7 from a standard anticoliphage mixture prepared by bacteriologist Ward J. MacNeal. T7 was the last virus isolated from a series of seven phages that were numbered in the order in which they were discovered (T for "type"). Experiments with T7 demonstrated in 1952, just one year before Watson and Crick elucidated the structure of the double helix, that bacteriophages were near-perfect parasites — they assimilated and converted all host DNA into viral DNA. A few years later, researchers reflected on the role of RNA by studying the behavior of T7, concluding that it was "possible that the specific kind of RNA synthesized by the host under the influence of the infective phage may serve as the proper functional unit for the synthesis of phage specific protein." This observation helped midcentury biologists to lay down the "Central Dogma," the tenet that "DNA makes RNA makes protein."
A slim genome, T7 was in 1983 one of the first living things to be sequenced, as it comprised fewer than forty thousand base pairs. It was simple enough and short enough for its sequencing to be tractable by 1983's standards. Although T7 first snuck its way into molecular biology labs, smuggled within the bacterial Trojan horse it had infected and whose DNA it slowly converted into its own, by the time Endy began studying it as a graduate student fifty years later, it had become a workhorse of molecular biology and genetics, arguably one of the most comprehensively understood objects of biological experimentation. Hence, Endy was curious as to whether T7 could be modeled computationally — as he put it in his lecture, "whether or not our understanding of this relatively well studied natural biological system is good enough to support analysis."
In his 1997 doctoral thesis, Endy writes that his work was "motivated by the desire to develop the coupling between the information database and reductionist tools of the biologist and the synthetic tools of the engineer. ... To improve our understanding of biological systems and through such understanding better apply them." He used his programmed model to try to predict what would happen in mutant versions of the same virus. If you moved around chunks of viral genetic material called coding regions (the "seventy-two elements" Endy would mention in his lecture) to make viruses that, for example, expressed RNA polymerase in a different order than they had before, would the computer model still be predictive? Building a model, on his reasoning, should effectively verify the sum total of the data molecular biologists had gathered about bacteriophage T7 during its long tenure in research laboratories.
But this was not as simple a doctoral research project as Endy had hoped. It would stretch beyond his graduate work to animate his postdoctoral work (and later would be taken up by his graduate students at MIT). Splitting his postdoctoral work between the University of Wisconsin at Madison and the University of Texas at Austin, Endy began studying genetics and microbiology, thinking that because he had trained outside the life sciences, perhaps he had missed some crucial information about the virus in programming his model.
During these years, Endy compared the predicted growth rates of his computer-modeled mutant bacteriophages with the actual growth rates of the mutant viruses, which as a postdoc he modified and cultured in the lab. But the results, he found, did not square: the computational model was an awful predictor of actual viral growth. What, he asked us, does it mean when the sum total of molecular biology's published data on bacteriophage T7 fails to predict how the virus reacts to perturbations and modifications of its genetic material? Endy took it as a failure of experimental "discovery-based" biology: all the knowledge painstakingly gathered from classical genetics, molecular biology, and virology, everything life scientists had learned about T7 from 1944 to now, was not enough to predict the behavior of an infectious agent so simple it is arguably only marginally alive.
(Continues...)
Excerpted from Synthetic by Sophia Roosth. Copyright © 2017 The University of Chicago. Excerpted by permission of The University of Chicago Press.
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