Living Machines: Some Assembly Required Kit-based competitions challenge teams of students to learn microbiology and design principles in the context of

Natalie Kuldell

f you were a new student arriving at teams a common task, challenging them, for Massachusetts Institute of Technology example, to “design a machine that puts a round (MIT) in Cambridge during the early peg into a square hole” or to “build a mechani- I 1970s with an expressed interest in me- cal device that can roll down a 30° incline plane chanical engineering, you would have in 3 minutes.” With an explicit design challenge been advised to enroll in a class called “Intro- to meet, students no longer spent so much time duction to Design.” Students in this class were wondering what to build and, instead, could provided components such as wooden spools concentrate on designing and engineering spe- and metal rods, and were told to build a useful cific types of machines. The second change was device from these parts. to make each of these engineering assignments A teaching assistant from that era noted that competitive. Student teams engaged in sports- students taking that class spent little time engi- like battles to determine which team’s machine neering their machines because it took them so could perform with the greatest accuracy, con- long to decide what to build. When that teach- sistency, and precision. Not surprisingly, MIT ing assistant, Woodie Flowers, became an MIT students enjoyed measuring their success against professor and took over teaching that class, he others. made two big changes that had a major impact A generation later, other disciplines are em- on the students. The first was to assign all the bracing the notion of teaching through kit-based design competitions. A prime example is the annual FIRST Robotics Competition, Summary which was founded by Flowers of MIT and inventor Dean Kamen, president of DEKA • The impetus for a popular annual contest for Research & Development Corporation in students learning synthetic biology traces to an Manchester, N.H. Last year, for example, introductory course in engineering and design at more than 350 high school teams from five MIT. countries worked with kits having the same • The first chapter of iGEM involved a group of parts, each group striving to build the 16 undergraduate students at MIT in 2003 try- ing to make bacterial cells into a “living light- “best” robots within six weeks. Their ef- house” using standardized DNA “parts.” forts are judged regionally, with the local winners advancing to the finals, where the • The annual iGEM contest now includes stu- dents from four continents who compete re- teams match their robots against one an- gionally, with those winners gathering in No- other in a competitive atmosphere that ri- vember for a Jamboree. vals what happens at the Super Bowl or Natalie Kuldell is an • Formal educational modules at BioBuilder har- World Cup. This design competition engen- Instructor of Biolog- ness the iGEM approach for teaching engineer- ders not only palpable enthusiasm but last- ical Engineering at ing in the context of high school and college ing learning among the students who partic- the Massachusetts biology, an approach that may be adapted for ipate. Moreover, the event continues to Institute of Technol- teaching other scientific disciplines. grow, attracting more teams and younger ogy, Cambridge, students. Mass.

Volume 7, Number 1, 2012 / Microbe Y 13 Tapping into Competitive tion. The project judged most impressive that Spirits to Teach Biology year was from the University of Texas (UT) at Biology is the new frontier where kit-based de- Austin. The UT team designed and built a strain sign competitions are generating keen enthusi- of E. coli that could serve as the pixels in a asm. Specifically, those contests are playing out photograph. in the field of biological engineering called syn- To reach this goal, the UT students fused a thetic biology. light-responsive sensor protein from cyanobac- Here, too, the impetus traces to MIT. In 2003, teria to the transmembrane protein from a two- several faculty members and researchers there, component signaling pathway (EnvZ/OmpR) including Drew Endy, now at Stanford Univer- that is native to E. coli. They transformed the sity, Tom Knight, now at Ginkgo BioWorks, gene for this fusion protein into a strain harbor- Gerald Sussman, and Randy Rettburg chal- ing an OmpR-regulated promoter that directed lenged a group of 16 students to build “a living transcription of a reporter gene, ␤-galactosi- lighthouse” from Escherichia coli bacteria, stip- dase, thereby assembling what they called their ulating that their goal was to make bacteria that “coliroid” strain. When grown in the dark, the emit light predictably and reliably. coliroid cells transcribe more of the lacZ gene, During January at MIT, classes are suspended turning an indicator in the media black. In the for several weeks for a session called IAP, Inde- light, LacZ transcription drops, allowing the pendent Activities Period. During the 2003 in- yellow media to show. The students displayed a dependent session, that group of 16 students photograph in which the cells spell out “hello struggled to complete the living lighthouse proj- world” at the 2004 Jamboree. A report describ- ect, working with a limited budget against a ing their experiments appeared the next year in tight deadline. Seeking shortcuts or other ploys Nature. that would accelerate their progress, they fig- The iGEM program continues to grow each ured out a scheme to make the sharing of useful year. In 2010, 130 teams from 26 countries snippets of DNA more efficient. They found participated. In 2011, iGEM grew further, hold- that, by standardizing DNA segments into ing three preliminary competitions to determine “parts,” it became easier to assemble them into which teams from the Americas, Europe, and increasingly more complex genetic programs. Asia would progress to the final Jamboree, held That winter session project from 2003 later in November. Other plans call for extending this was turned into an annual contest, called the competition to teams from high schools. Thus, International Genetically Engineered Machines iGEM increasingly resembles FIRST Robotics, (iGEM) competition. Held each summer, the with both programs encouraging teams from main goal of iGEM is to build “biological sys- colleges and high schools to design machines tems from standardized (DNA) parts.” from kits and for those teams to compete against Unlike the MIT Introduction to Design class one another. or the FIRST Robotics Competition, however, no single design challenge unifies the work of the iGEM teams, and they do not pit their biological Kits for Making Robots Differ from machines against one another. Instead, students Those for Engineering Cells from the participating schools work on their Although the outlines of the iGEM and FIRST own campuses during the summer months, and Robotics competition are alike, there are critical then come to MIT in the fall to celebrate their differences between the kits used for building engineered cells at a “Jamboree.” Projects are robots and those used to engineer living cells. compared based on their ability to “impress the For instance, a student in mechanical engineer- judges”—a subjective measure, but one that spurs ing has no trouble distinguishing wooden spools the teams to work diligently on their projects. from metal rods, even if those parts are mixed together in a single package. By contrast, iGEM The iGEM Synthetic Biology students typically work with identical-looking Competitions Keep Growing flecks of freeze-dried DNA, making it trivially By 2004, five U.S. teams were invited to partic- easy to begin a summer-long project with the ipate in the iGEM synthetic biology competi- wrong stock of DNA.

14 Y Microbe / Volume 7, Number 1, 2012 Kuldell: Hands-on Teaching of Synthetic Biology, and a Stint as a Professional Dancer Natalie Kuldell worked summers sachusetts Institute of Technology cell and developmental biology at at the National Institutes of (MIT) in Cambridge and a visit- Harvard University in 1994. She Health (NIH) while in high ing scientist at nearby Harvard was a postdoctoral fellow at Har- school, and it proved transforma- Medical School. Her research fo- vard Medical School from 1994 tive. “It seemed so great to be able cuses on understanding the con- to 1997. to head into the lab every day,” trol of gene expression in eukary- Kuldell spent a year between she says, crediting her mentors, otic cells. Working with Fred college and graduate school as a NIH biochemists Alan Peterkof- Winston at Harvard, she exam- professional dancer in Boston, sky and Marshall Nirenberg, for ines artificial gene expression sys- performing with several compa- inspiring her. “I was hooked, and tems in cells of Saccharomyces nies, including the Performing I knew at age 16 that their job was cerevisiae. Arts Ensemble and the Kelly Don- the one I wanted. Since they stud- Kuldell also serves as associate ovan Dancers. “I continued to ied chemistry in college, rather director of education and training dance, but in a diminished role in than biology, that’s what I did, at SynBERC, a multi-university the company, through graduate knowing full well that I’d go to program in synthetic biology, and school, through becoming a mom, graduate school in the life sci- directs BioBuilder.org, an inter- and through my academic transi- ences, as they did.” active website that features syn- tions,” she says. “I still dance ev- The experience also helped her thetic biology learning materials, ery week. I continue to feel con- to realize the importance of some of them animated narra- nected to the wonderful dance hands-on learning, an approach tives. She also set up an educa- community here in Boston, even she now takes when teaching. “I tional foundation whose goal is to though I no longer perform.” De- learned early on that part of what make current topics in research spite this history as a performer, makes science exciting is when available as synthetic biology cur- she keeps a low profile. “I’ve often you can puzzle through some con- ricula for college and high school said that my goal is to be the per- fusing or surprising data,” she teachers. son who does the most good that says. “But when I got to my sci- As a youngster in Manhattan, no one ever heard of,” she says. ence classes at school, very few of Kuldell attended a bilingual Kuldell began dating her hus- the experiments we ever ran in French/English school, but soon band Scott Kuldell when they class captured this investigative moved with her family to Mary- both were in high school. “We part of science. So I’ve tried to land, where she attended middle bring that excitement of doing and high school. Her father, a went to different colleges—me to real science to my students. I take physician, worked for the Food Cornell, him to Dartmouth—but what’s current in research, and and Drug Administration, while we managed to work things out, transform those questions into her mother worked as a nurse. and landed in Boston,” she says. teachable modules. The labora- Both are retired. “Neither was “We’ve been here ever since.” tory classes I teach at MIT defi- disappointed that I didn’t choose They have two children, 15 and nitely benefit from this philoso- medicine since they know I get 12. “They are, no doubt, the phy, and lately I’ve been trying to faint when I see blood,” she says. greatest contributions I’ve made expand the approach to other After high school, she attended to this world,” she says. schools through the BioBuilder Cornell University, where she .org web site.” earned her B.A. in chemistry in Marlene Cimons Kuldell, 46, is an instructor in 1987, then moved to the Boston Marlene Cimons lives and writes in biological engineering at the Mas- area to complete her doctorate in Bethesda, Md.

For iGEM contestants, the confusion in re- iGEM teams contribute materials that make up trieving parts can be compounded by uncer- the latest kit. This “give-and-get” approach tainties over how to use them. Each summer, keeps the iGEM kit growing. However, it also

Volume 7, Number 1, 2012 / Microbe Y 15 means that each successive team deals with laboratory scientist, “Izzy,” a veteran of the many parts that are incompletely documented iGEM program, and “Device Dude,” a curious and poorly understood. For example, standard- young student who is new to the program. izing junctions between DNA parts should al- These three imaginary characters work low the same cloning scheme to be useful for any through ongoing challenges in biological engi- assembly. However, because not all parts in the neering while they hang out in the lab or walk kit conform to the original standard, students across the bridge linking Boston and Cam- find themselves frustrated when parts cannot be bridge. In their conversations, these three char- cloned, when cloned parts do not transform acters explore foundational ideas about engi- well, and when transformed parts do not gener- neering like abstraction and biological processes ate expected behaviors once in cells. such as bacterial gene expression. The animated The complexity of systems that students cartoons and the comic strips are freely accessi- design can exceed the capacity of the cells to ble on the BioBuilder website. Although they support those systems. Although a mechanical may be viewed in any order, they are organized engineer can drop a souped-up engine into a in a way that makes them useful for guiding humble car chassis and know what to expect, a student activities in classrooms and laborato- biological engineer taking on the equivalent task ries. may find that inserting a highly demanding—or One recent BioBuilder activity included a souped-up—genetic program into cells instead project that started with the bacterial photogra- leads them to die or mutate. phy system that the UT Austin student team These limitations, however, can provide edu- developed in 2004. Other laboratory activities cational opportunities. Although they are not a explore both engineering and biology chal- formal part of the iGEM mission, failure analy- lenges. For example, students are asked to com- sis could be one of the most important ways pare two different genetic approaches for mak- iGEM educates its student participants. This ing bacteria smell like bananas during log-phase approach, if taken up more broadly by academic growth. One approach depends on a constitu- and industrial partners, could advance the tech- tively active sigma-70 promoter to express the nical standards of the whole field of genetic ATF1 gene of the yeast S. cerevisiae during log engineering. It also provides a valuable investi- phase. The other program connects a stationary- gative framework for teaching engineering in phase promoter to a transcriptional inverter de- the context of biology. The teaching materials available at BioBuilder.org are part of an early vice that directs transcription of ATF1. This effort along these lines (http://www.biobuilder BioBuilder activity extended an engaging proj- .org/). ect that was developed by the MIT iGEM team in 2006. Moreover, it encourages students to delve into system design questions while learn- ing a variety of microbiological and measure- BioBuilder Content Includes Failure ment techniques as they track the scent intensity Analysis and Cartoons, and and growth curves of the strains that they engi- Appeals to the Senses neer. BioBuilder content begins with the unreliable After completing each BioBuilder activity, behavior and unexpected results from iGEM students are asked to share their findings team efforts and other academic research proj- through an online forum. This feature is in ects. It converts “glitches” from those projects keeping with the “give and get” philosophy of into teachable modules suitable for advanced iGEM. It also instills in students the notion that, high school and early college settings. in this developing field, their contributions Leveraging the success of the publication matter. “Adventures in Synthetic Biology,” which is BioBuilder began as a collaboration between presented in comic book style by Drew Endy of the MIT Department of Biological Engineering , each BioBuilder module be- and several nearby secondary school teachers, gins with open-access animations and comic- especially Jim Dixon from Sharon High School. strip narratives. Regular characters in these il- Hence, the activities address the needs of high lustrated episodes include “Systems Sally,” a school teachers and take into consideration for-

16 Y Microbe / Volume 7, Number 1, 2012 mal standards for engineering curricula. Indeed, Teachers Comment on Current some activities offer an alternative approach BioBuilder Outlook to current lessons—enabling teachers to substi- In the summer of 2011, a group of 27 U.S. high tute BioBuilder activities for some of the stan- school and college teachers visited MIT to learn dard classroom exercises. For example, the about BioBuilder and to immerse themselves in winning iGEM project from the University of Cambridge team in 2009 included genetic pro- the vocabulary that engineers use for designing grams that turned E. coli a rainbow of colors. and building systems. Midway through the In documenting their project, members of that week, the teachers were asked to describe their team noted how the intensity of the colors var- own visions of perfect teaching days. Their col- ied in cells with different genetic backgrounds. lective focus was on their students, whom they This observation has been recast into a Bio- said they want to “engage” to keep “classrooms Builder laboratory activity in which students buzzing with excitement.” The teachers also can transform two color-generating plasmids envision their students “doing things” and into two cell types, namely E. coli B and K12 “making connections and contributions.” strains, to learn how those two cell types affect Kit-based design competitions have a strong system performance. This project provides track record eliciting just these kinds of sought- the same technical training as a standard lab after student behaviors. The materials available project now available for advanced placement at BioBuilder.org are one additional part of this biology students. Additionally, the BioBuilder effort to move this experimental design frame- project provides students with stronger incen- work into the formal teaching of biology and tives for carrying out the procedures, and it . There is no reason to think that also forces them to ask more questions. More- other subjects such as chemistry, physics, and over, it provides an online forum to support mathematics would not also benefit from having teachers who would like to adopt these activities similar curricula. The central idea is demand- in their classrooms, connecting them to other ing—and empowering—students of biology to teachers who already are following the Bio- think as engineers, defining problems and then Builder approach. designing and implementing solutions.

SUGGESTED READING Campbell, A. M. 2005. Meeting report: synthetic biology jamboree for undergraduates. Cell Biol. Edu. 4:19–23. Dixon, J., and N. Kuldell. 2011. BioBuilding: using banana-scented bacteria to teach synthetic biology, p. 255–271. Methods Enzymol. 497:255–271. Kuldell, N. 2007. Authentic teaching and learning through synthetic biology. J. Biol. Eng. 1:8. (doi:10.1186/1754-1611-1-8) Levskaya, A., A. A. Chevalier, J. J. Tabor, Z. B. Simpson, L. A. Lavery, M. Levy, E. A. Davidson, A. Scouras, A. D. Ellington, E. M. Marcotte, and C. A. Voigt. 2005. Synthetic biology: engineering Escherichia coli to see light. Nature 438:441–442 (doi:10.1038/nature04405).

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