commentary

Building outside of the box: iGEM and the BioBricks Foundation

Christina D Smolke

Innovative community efforts in academia and non-profits to engage student researchers, encourage open sharing of DNA constructs and new methodology as well as build a Registry of Standardized Biological Parts have been central to the emergence of .

ne aspect of synthetic biology is to high school levels are incredibly excited about Because of time and technology limita- Odevelop tools that make the engineering biotech; by participating in iGEM, teams of tions, combined with the complexity of of biology easier. Such engineering research students work together with the goal of iden- the systems designed by the students, the can benefit from communities and venues tifying and prototyping an engineered genetic projects designed in these courses were not that collectively engage and support work to program that addresses a real-world problem or successfully constructed, much less charac- develop, test and support open technology opportunity. Second, young would-be genetic terized and debugged. Even so, by working platforms. Two community-based efforts, engineers are capable of getting new ideas to directly with students in these early courses, the International Genetically Engineered work; just some examples of successful projects the instructors learned about and developed Machines (iGEM) competition and the include Escherichia coli that smell like bananas, solutions to three basic challenges limit- BioBricks Foundation (BBF), have enabled that are newly responsive to light, that produce ing work. First, given such communities and venues to form a full rainbow of pigments, that float or sink a limited budget for de novo DNA synthe- through unconventional approaches. With in response to transcription signals or that sis, the instructors discovered the utility of the field of biological engineering poised detect environmental pollutants. Third, an having students share and reuse parts; this to achieve hitherto unprecedented levels open technology platform based on standard led directly to the world’s first Registry of of precision, efficiency and scale, I provide biological parts—even if the parts collection Standard Biological Parts. Second, given the here a perspective on the role of these two itself remains incredibly immature—can be relative immaturity of the gene synthesis

© All rights reserved. 2009 Inc. Nature America, organizations in shaping the ideology, values a powerful enabling tool. The iGEM students industry at the time, many of the students’ and culture of the synthetic biology commu- receive a kit of the best available genetic parts desired DNA parts could not be synthesized nity. at the beginning of each competition, and then because of problems in cloning or expres- contribute their favorite new parts to the collec- sion; this led the instructors to help obtain, The genesis of iGEM tion at the end, so that future students can build optimize and freely provide variable copy Last month marked the completion of the upon their work—thousands of parts are now number vectors with enhanced transcrip- fifth annual iGEM competition. Over 1,100 available to iGEM students. tional insulation for use in the commercial people from 100 teams participated in the The iGEM competition grew out of gene synthesis process. And third, given the three-day event, the iGEM Jamboree held at month-long courses that were taught at MIT complexity of system function desired by the Massachusetts Institute of Technology by Drew Endy, Tom Knight, Randy Rettberg, the students, too much time was being spent (MIT; Cambridge, MA, USA), at which stu- Pamela Silver and Gerry Sussman during simply trying to understand how each system dents presented their research projects to peers MIT’s extended January intersessions in 2003 might work; this led to the formalization of a and policy experts and a mixed audience from and 2004. The objective of these courses was first functional abstraction hierarchy based academia, industry and social sciences. to learn from students how to become better on a common transcription signal carrier, The iGEM Jamboree is now the largest syn- engineers of biology. On the basis of conver- now called polymerase per second, or PoPS. thetic biology event in the world and, beyond sations with Lynn Conway, a pioneer of early Inspired in part by the success of other its intrinsic value for participants, highlights VLSI (very large-scale integrated) electronics student-oriented engineering competitions, for observers several amazing aspects of the during her time in the 1970s at the Xerox such as the FIRST Robotics Competition (an field. First, students at the undergraduate and Palo Alto Research Center in California, the annual competition organized by the For MIT instructors decided to initially focus Inspiration and Recognition of Science and Christina D. Smolke is in the Department of on the idea of decoupling the design and Technology, FIRST, organization), the group Bioengineering, , Stanford, construction of genetic circuits, and later to made a decision to extend their early efforts California, USA. explore the use of abstraction as a tool for into a multischool biological design compe- e-mail: [email protected] managing biological complexity. tition with funding from the US National

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would find it easier to adopt any proposed standards. Second, the first proposed stan- dard was not broadly accepted. As researchers worked with the initial physical assembly standard, they found that it was problematic for coupling certain types of parts together. This led to a feeling from some participants that standards were being imposed that were not applicable for many of the systems they would like to build. And third, the quality of the parts in the registry was not generally good, which presented a huge challenge to the major goal of the registry—the reuse of parts to support efficiency in design and construc- tion. A glance through the registry will show that many parts have not been confirmed

A ppleyard. as working and do not have any, much less thorough, associated characterization data. Complaints and frustrations grew as teams attempted to use parts from previous years’ iGEM and David and iGEM projects and found that they did not work as designed or in some cases were not even The most recent iGEM in October at MIT Killian Court. Teams attended from over 100 universities and from 26 different countries. the correct sequence. Although iGEM head- quarters (currently at MIT) has more recently implemented a quality control check at the Science Foundation. Related decisions were dard specified an idempotent assembly level of sequencing, the sheer number of parts made to extend the event from a one-month method (assembly reactions that leave the received makes it impractical for iGEM staff design challenge, to a summer-long design, key elements unchanged) for physically to have a direct role in parts characterization build and test experience. linking parts together and associated and functional validation. sequence requirements. These ideas were In response, the leadership began putting A competition matures disruptive to prevailing practice in molecular in place a value system within iGEM that The first 2004 synthetic biology competi- biology at the time, and as a result met with would enable the community to address tion had participation from five invited US significant resistance from many in the basic these challenges over time. In particular, universities—Boston University, Caltech, and applied biological research communities. mechanisms were put in place that rewarded MIT, Princeton and the University of Texas, As resources and broader support for such team participation in the areas of contrib- Austin. The name iGEM was decided upon work were not available at the time within uting and documenting biological parts soon thereafter and the competition has the biotech community—whether from fed- that were compatible with approved stan-

© All rights reserved. 2009 Inc. Nature America, been held each summer since 2005, growing eral agencies, foundations or industry—to dards, contributing characterization data dramatically to its current size of over 100 help develop a registry at a professional scale, for these parts, and even for developing and universities and extending its geographical the leadership of iGEM asked the teams to documenting new and improved technical reach to 26 different countries. build the registry over time through their standards (see the BBF request for comment As iGEM has grown, it has expanded its accrued contributions. process below). Although prizes recognize goals, refined its approach, and responded This participant-based ‘get’ and ‘give’ specific achievements of a select number of to the needs of a young and rapidly growing approach to developing a collection of teams (best in class), medals are also awarded community. Early on the leadership within standard biological parts led to the first set to those who meet specified requirements; iGEM made a decision to focus the experi- of challenges faced by iGEM. First, getting any iGEM team can earn a gold medal. In ence on standardized parts and open shar- people to adopt standards in a field that addition, the teams are provided with the ing, where teams were tasked with examining has been operating without them is diffi- medal requirements up-front, so that they whether integrated biological systems could cult. Many laboratories build up their own know what the judging will be based on, be efficiently built from standard biological assembly methods and constructs and will and are asked to evaluate their own projects parts. The Registry of Standard Biological have a laboratory-specific catalog of parts in terms of meeting these requirements. In Parts, envisioned as an online catalog that that are incompatible with any proposed addition to addressing the issues outlined would organize and document parts encod- standard, such that transferring over those above, the medal system rewards teams for ing biological functions, thereby became a parts and knowledge base to a new standard helping another iGEM team, character- central resource for making available samples will require a significant amount of effort, izing or improving existing registry parts, of DNA encoding parts to all participants. time and resources. Although the purpose of and developing advances in human practice The requirements associated with defin- standardization is to streamline a process and issues as they relate to synthetic biology. This ing a ‘standard’ biological part were related ultimately make the integration of parts more reward structure has worked extremely well to the first technical standard intro- reliable and efficient, any such payoff would in building the value system within the com- duced by Tom Knight for a physical parts be on a longer time scale. Therefore, younger munity. The iGEM competition has also used assembly method1. This technical stan- laboratories with less of a historical backlog the rewards structure to explicitly celebrate

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foundational and applied advances by setting students and teachers, community build- and educational materials. up tracks (food/energy, environment, health/ ing and growing a standard biological parts There is also an ongoing question about medicine, manufacturing, new application, collection. Many schools have developed the competition aspect of iGEM. Specifically, foundational, information processing and courses in synthetic biology based on their many of the students take the competition software), where the best project in each experiences with iGEM and some have very seriously. Although this results in high- track is awarded a prize. In addition, special started or are starting entire research cen- quality and impressive research projects— prizes are awarded for specific contributions ters focused on the topic. Even the number and has importantly not hindered the open such as best part, standard, human practice of successful projects is increasing over time. and supportive culture—it also may have advance, wiki and experimental measure- Although several projects have resulted in undesired personal consequences. Many ment. The most valued prize for the teams peer-reviewed publications with signifi- students are so disappointed when their is the Grand Prize, for which the team is cant follow-up work from the researchers team does not make it to the list of finalists awarded the BioBrick Trophy (a gigantic after iGEM2–5, many more are succeeding in that they can be seen crying after the finalist Lego-like machined aluminum brick with the pushing the limits of biological systems that announcements. There are also stories that names of winning teams etched on it, similar can be engineered under time, financial and the amount of time some teams dedicate to to trophies used in professional sports) that expertise constraints. their projects is so intense it can be detrimen- the winning team holds for a year and then And this gets to the real test of iGEM: can tal to other parts of their lives, often leading passes off to the Grand Prize Winner at the the process of engineering biological systems to the break up of personal relationships. following year’s competition. be made so efficient and reliable that a team Is this something that iGEM can or should of undergraduates (or high school students) try to change? Or, is this part of the human Community building with little experience can successfully build experience around competitions, especially By engaging student researchers directly, an an interesting and exciting system in sev- of this scale? Without the competition part interesting thing has happened over time. eral months? And, will these systems ever of iGEM, would the community invest as The iGEM participants are forming a com- approach the complexity and scale of projects heavily? Finally, there are questions around munity and are invested in building out the conducted through traditional genetic engi- the post-iGEM experience. After the students necessary technologies supporting the engi- neering tools that currently take on the order finish iGEM and return to their schools and neering of biology. They are actively engaged of 150 skilled researcher years to complete6? plan for their future career goals, what com- in tackling the challenges and proposing munity do the students find, if any, support- solutions, as opposed to just complaining Ongoing challenges ing synthetic biology beyond iGEM? about the problems. Through the iGEM By most measures iGEM is a fantastic suc- experience, they learn the importance of cess; however, it is facing new challenges as a The BioBricks Foundation having high-quality, well-characterized parts result of this success. iGEM headquarters and The BBF is a not-for-profit organization that and standards that support the sharing of individual teams face challenges in continued was started in 2004 by many of the people these parts. And you can see it working in the financial support. Teams are responsible for involved in iGEM to represent the public community; the parts that work, the parts their own fundraising, which includes fees interest in the foundational technologies that are easy for others to take and build into associated with participating in iGEM and that help define the field of synthetic biol- their systems—these get picked up by other running the team and its research project. ogy. The original goal of the BBF was to teams and used in new projects and new The international nature of iGEM, and the invent and bring to life a legal framework

© All rights reserved. 2009 Inc. Nature America, applications (in technology-driven work, this differences in fundraising models between that accelerates and enables the accrual of represents success). When teams waste pre- countries make this particularly challenging. an open collection of functional genetic ele- cious time trying to work with poor-quality Funds supporting research through traditional ments encoding standard biological parts. parts, they can share and document their federal agencies or foundations in many coun- However, as highlighted through experiences experiences through iGEM, thus giving back tries are scarce, and many of the more suc- with iGEM, the successful development of important information to the community. cessful teams have significant buy-in from an open technology platform requires several This type of reuse, validation and feedback is their universities or are turning to industrial components to be in place, the first being, often not available through traditional scien- sponsorship when they can. This is highlighted in particular, a community of people that tific reporting mechanisms, which generally in the cramming of sponsor names and logos supports the platform’s development and celebrate novelty versus distilling processes onto the backs of team T-shirts, giving iGEM benefits from its existence. In addition, an to practice. When teams identify problems a feel of NASCAR or professional sports. The open technology platform based on standard with existing standards, they can go through differences in funding levels between teams biological parts requires that the technical the process of identifying new standards that and the intense competitive spirit associated standards that define the parts exist and are might address existing issues and then put with iGEM bring up questions as to whether open. Therefore, the BBF has also directed them out to the community for use and com- something should be done to level the resource its efforts to standards development for the ment. These collective experiences have over playing field (e.g., setting upper limits to bud- field (legal and technical) and community time helped build a sense of responsibility in gets), such that huge disparities in resources engagement and development. The subse- many of the teams and have led to improve- do not lead many teams to feeling like hopeless quent text explores each of these activities ments in the quality and documentation of participants in the competition. iGEM as an in more detail. parts in the registry. organization has run on lean resources, and To encourage the development and use of iGEM’s initial goal of inventing and at the organizational level additional resources technical standards in synthetic biology, the improving the underlying technologies of could make a significant difference in the abil- BBF has run several workshops on the topic. synthetic biology has expanded and evolved ity to improve the student experience through These workshops were organized to discuss to become much more about education of improvements to the registry, parts collection the importance of technical standards in bio-

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tech and prioritize areas most critically in systems comprising dozens of genetic com- developing educational materials regarding need of standards. From these discussions, ponents, never mind anticipated genome- policy issues related to synthetic biology, in the BBF developed and launched a process by scale engineering projects. Although the BBF particular ownership, sharing and innova- which people can define and propose techni- has advocated for the need to consider new tion frameworks underlying biotech. cal standards for biotech through the BBF property rights law in support of the future Because of the diversity of backgrounds request for comment (RFC) process, which of biotech, they developed the BPA to sup- represented in the synthetic biology com- was inspired by the Internet Engineering Task port the immediate maturation of an open munity, the BBF plays a key role in providing Force (Fremont, CA, USA) RFC process. An technology platform supporting genetic leadership and a focal point for this growing RFC can propose a standard, describe best engineering. field. The BBF has focused its early efforts on practices/protocols, provide information, or Mark Fischer was involved in helping to addressing very challenging concepts in the comment, extend, or replace an earlier RFC. draft the legal frameworks for free software in field. Property rights law in biotech through The RFC document is made available online the 1980s. However, the differences in prop- patents is well established and entrenched, through the BBF website (http://biobricks. erty rights between biotech (patents) and such that work to change this system to one org/) and feedback and comments are col- software (copyright) presented several chal- that might be more appropriate for a future lected for each RFC. lenges to a direct translation of the licenses biotech meets significant resistance. The In its first year, 51 RFCs have already been used to support open and free software. As a BPA is a step toward building a community published. Many of these have been submit- result, the BPA represents a bilateral agree- that supports an open technology platform ted by iGEM teams, as one of the optional ment (or contract) between the contributor in biotech. However, for this vision to truly tasks for teams to earn a gold medal is to and user. The language within the BPA allows succeed, high-quality open parts are needed. develop and define a new technical standard the contributor to acknowledge invention In addition, most people (including founda- through the RFC process. Glancing through over the uses of a part, disclose informa- tions and companies) look to biotech as a set the list of RFCs, they cover concepts as broad tion on whether there is a patent on it or of applications. The BBF is working below the as standard definitions, assembly strategies, not, and promise not to assert any property level of applications. Although their work in part characterization and reporting meth- rights against others under certain condi- community building and legal and technical ods, visual description languages, model- tions of use, so that the part can be freely standards supports all biotechnological appli- ing languages and design tools. Over time, used. The BPA also allows the user to state cations, raising funds for such foundational as more knowledge is gained regarding best acceptance of use of the part and promise work is typically much more challenging. technical standards, the BBF will likely need to use it according to the conditions put to play a role in filtering through the RFCs in place by the agreement. However, the Conclusions and determining the smaller set of standards agreement does not put any encumbrance The systematic application of engineered to be used by the field. on downstream uses, such as a give-back or biological systems to the problems posed share-alike clause. In doing so, the BBF hopes by hunger, disease, environmental quality A legal framework that the BPA will support the development of and finite resources remains both extremely The BBF and a team comprising Lee Crews a shared open platform that both academics compelling, yet challenging, given the current and Mark Fischer of the law firm Fish & and industry can use, while still allowing pro- state of tools supporting biotech. Both iGEM Richardson (Boston), Drew Endy of Stanford prietary systems to be built upon this open and the BBF are leading different, but syner- University (Stanford, CA, USA), David platform. The aim of the BPA is to reduce the gistic, efforts focused on developing commu-

© All rights reserved. 2009 Inc. Nature America, Grewal of Harvard University (Cambridge, legal ambiguity around the use and reuse of nity, sharing and open technology platforms MA, USA) and Jennifer Lynch and Jason standard biological parts, and the BBF hopes supporting biotech. Importantly, although Schultz of the University of California, that the BPA will encourage both industry advanced technologies can be used for good Berkeley (Berkeley, CA, USA) have also been and academia to support and play a role in or harmful purposes, the activities of iGEM developing a legal framework that supports the development of a next-generation open and the BBF, including education, outreach an open collection of biological parts. The technology platform in biotech. and community building, are directed toward final draft of this framework—the BioBricks biasing systems heavily in favor of construc- Public Agreement (BPA)—is now available Community engagement tive outcomes. The ideology, values, tools online through the BBF website for com- The BBF has also worked to support the and culture realized by iGEM and the BBF ments (http://hdl.handle.net/1721.1/49434). broader synthetic biology community. In seem likely to continue to make important The BBF felt that an ownership, sharing and particular, the BBF has recently taken on the contributions to the foundations of synthetic innovation framework based on patents (the role of lead organizer of the synthetic biol- biology going forward. property rights mechanisms most commonly ogy conference series (most recently SB4.0 used in biotech) had substantial limitations in Hong Kong; http://sb4.biobricks.org/). ACKNOWLEDGMENTS I would like to thank D. Endy, M. Fischer, D. Grewal, in the context of an engineering process BBF’s leadership of this conference series has R. Rettberg and P. Silver for discussions on iGEM based on the reuse of thousands of different allowed many diverse communities to learn and the BBF. components across many different systems. about and engage with issues of safety, secu- Specifically, the cost and time to define and rity, equity and ethics relating to the field 1. Knight, T. Draft Standard for Biobrick Biological Parts (OpenWetWare, MIT, Cambridge, MA, USA, 2007). obtain patent-based protection is too great to of synthetic biology. In addition, the activi- http://hdl.handle.net/1721.1/45138 support the engineering of many-component, ties of the BBF in iGEM, technical standards 2. Levskaya, A. et al. Nature 438, 441–442 (2005). integrated, genetic operating systems. In and technical standards workshops play an 3. Haynes, K.A. et al. J. Biol. Eng. 2, 8 (2008). 4. Baumgardner, J. et al. J. Biol. Eng. 3, 11 (2009). addition, the costs associated with freedom- important role in building and engaging the 5. Ciglič, M. et al. IET Syn. Biol. 1, 13–16 (2007). to-operate searches become prohibitive for community. The BBF also directs efforts to 6. Ro, D.K. et al. Nature 440, 940–943 (2006).

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