Doug in lab

SBI Synopsis  

From the Directors:


Welcome to the SBI Synopsis newsletter! In this, our second issue, we feature two of our dynamic young faculty members, Chris Anderson and Michelle Chang, who hold positions both at UC Berkeley and the Physical Biosciences Division at Lawrence Berkeley National Laboratory. Anderson talks about his work with Clotho, which has the potential to become the all-purpose software platform for synthetic biology. Chang, the 2010 recipient of Agilent Technologies' Early Career Professional Award, describes her work with Agilent on the measurement of complex cellular chemistry. In future issues we will be looking at the groundbreaking work of other SBI researchers. To give a taste of what's in store, in this issue we've listed synthetic biology-related publications -- 18 in all -- by SBI authors from just the past three months. We hope you will enjoy this and future issues as we keep you up to date on the latest synthetic biology developments.

Clotho: Weaving the Thread of Artificial Life
Q&A with Michelle Chang
Recent Publications
About Us

Clotho: Weaving the Thread of Artificial Life


The first thing to know about the Berkeley-born software program Clotho, as its website points out, is that "it doesn't do anything." It automates nothing and performs no useful tasks. It is simply a platform. But for that very reason, it may be just what synthetic biology needs right now.


You can describe it as a universal toolbox or a common thread (it is named after the fate in Greek mythology who weaves the thread of life). The point of Clotho is to address what UC Berkeley bioengineer J. Christopher Anderson sees as two fundamental needs of synthetic biology: "Shared data under a standardized data model' and "tools that give you functionality." It's well timed for a young field that is long on ideas and invention but short, up to now, on infrastructure.



The heart of Clotho is an application programming interface (API) that enables users to share a common store of standardized data. 

Anderson, an assistant professor of bioengineering and a Synthetic Biology Institute researcher, runs the Clotho project along with Douglas Densmore, an assistant professor of electrical engineering at Boston University. The program dates back to 2008 when they were both at UC Berkeley - Anderson on the bioengineering faculty and Densmore as a post-doctoral fellow. Densmore wrote the software, which was used and further developed by student teams advised by Anderson in the International Genetically Engineered Machines (iGEM) competition. The teams won iGEM's "Best Software Tool" award in 2008 and 2009, first for the Clotho platform itself and then for Clotho-based applications. Anderson and Densmore further developed and refined the program. In 2010, they issued a version 2.0.


Clotho functions as an environment in which data drawn from any number of sources can be read and used by software running on its application programming interface (API). "It is totally agnostic about the details of how something looks and what you do with it," Anderson says. "All it guarantees is that, under the surface, everything is working with the same underlying information." It can be compared to the iPhone platform, which has tens of thousands of apps written for its API. Clotho currently hosts a few dozen apps, written by Anderson and Densmore. But many more may soon be on the way. There is a contest specifically for Clotho apps at the upcoming iGEM. And the synthetic biology open language (SBOL) standard language adopted by DARPA for its new synthetic biology initiatives is designed to work with Clotho.




The platform is coming along at a good time for synthetic biology, which has a huge amount of genetic data at its disposal but no way to pull all the relevant information together. "It's like the Internet with a list of URLs and that's all you have," says Anderson. On the Internet, this problem was solved by search engines. In synthetic biology, that problem now can be solved by Clotho-based tools that standardize data and link related items. Searching a particular biological part, such as a DNA sequence, also pulls up all the part's features, such as the useful functions it might perform in an engineered biological system.


Clotho apps have the potential to become powerful design tools, matching parts to functions without time-consuming literature searches. Clotho also makes it easier to do the heavy lifting needed to measure biological processes. Anderson says it can be used in determining the relationship between the levels of transcription and translation, a task that requires "modeling reams and reams of data." 


As an open-source platform, Clotho's potential is limited only by the creativity of the researchers using it and developing new Clotho tools. Anderson and Densmore continue to enhance it. Densmore focuses on automated design tools, while Anderson is developing standardized data on biological parts. The rest is up to the synthetic biology community, says Densmore: "We fully expect someone smarter than the both of us to use the Clotho core and to build the best apps for it."



Meeting the Measurement Challenge:

Q&A with Michelle Chang


"Cells do chemistry in a very different way from humans," says Michelle Chang, assistant professor of chemistry at UC Berkeley and a faculty member of the Synthetic Biology Institute. Instead of a flask performing one reaction at a time, a typical cell carries out thousands of reactions simultaneously, and somehow makes them all work together to perform a useful function. 



Measuring the cell's enormously complex chemistry is a key challenge in Chang's research, which seeks to re-program cellular metabolism in order to make new molecules for use in areas such as biofuels, and medicine. The task includes not only tracking the many related reactions but also determining how they act on each other in an organized, quantifiable way. "Until we understand that organization, it is difficult to understand or predict how to make a certain target molecule," Chang says.


In this effort, Chang has an industry collaborator that many would call a perfect match. She is working with Agilent Technologies Inc., the global leader in developing technologies for metabolomics, the measuring and quantifying of every metabolite or small molecule in the cell. As the 2010 recipient of the Agilent Early Career Professor Award, Chang is receiving a two-year unrestricted research grant of $50,000 annually from the company. 


Here's more from Chang about her work with Agilent and how it moves the field of synthetic biology forward: 


Tell us a little about your current research and the role it plays in the development of biofuels and pharmaceuticals. 


Our lab is interested in studying and understanding how enzymes and enzyme networks function inside living cells. This information is essential for elucidating the molecular-level detail of how complex cellular functions are coordinated in vivo but can also be used for developing new methods for chemical synthesis. By using cells to do chemistry, we can sometimes reduce costs compared to more traditional methods used in the chemical industry and make molecules such as pharmaceuticals and fuels more accessible or more environmentally friendly. We are particularly interested in the chemistry involved in second-generation biofuel synthesis. 


How does your collaboration with Agilent fit into that research agenda? 


Living systems run thousands of simultaneous reactions at the same time, and they are somehow organized into a network or system that allows the cell to carry out functions.The fact that Agilent is focusing on developing tools for metabolomics is perfect for our needs because it has the potential to describe changes in all of these reactions in one go. By measuring and modeling how the host cell reacts to and pushes back against genetic modification, we can start to uncover some general principles of how different pathways talk to each other inside cells. 


Where does your research stand on the continuum between foundations and applications? 


I have to admit that our primary interest is in basic science. A lot of what is known about enzyme function has been learned in the test tube and synthetic biology or metabolic engineering approaches allow us a unique opportunity to put them back inside a living cell and ask about its in vivo function and regulation. At the same time, the real test of our knowledge is to ask if we can actually use any of these principles to build synthetic pathways that are robust enough to be used for real world applications. 


You've used the term "second-generation biofuel synthesis" to describe one of your key focus areas. How does that "second generation" differ from the synthesis practiced now? 


The term second-generation biofuels really just refers to any fuel molecule other than ethanol. Although ethanol can be made at extremely high yield, based on our long-term experience with its production, it doesn't have the ideal molecular properties that you would want to see in a gasoline replacement. In the next generation, we hope to make molecules that are both better fuels and that can be made with less energy input.  


Calendar of SBI Events 


July 29, 2011: Third Joint Informational Agilent-UCB Workshop.

Location: UC Berkeley, Blum Hall, Room B100.   

The workshop brings SBI faculty members and Agilent senior managers together for presentations on the latest synthetic biology research.     

Click here for more information. Registrations after July 21 will be accepted as space permits.


Aug. 29-31, 2011:  "Bio-Based Future" Workshop

Location: UC Berkeley, Center for Information Technology Research in the Interest of Society (CITRIS).

SBI, the Joint BioEnergy Institute (JBEI) and the University of Copenhagen, are co-sponsoring this three-day event that will examine the future of biology-based technologies. It will feature more than two dozen leading scientists presenting their pioneering work in the emerging field of synthetic biology. Read more  


Recent Publications


The work of SBI researchers has been widely published in leading scientific journals. Here is a list of synthetic biology articles -- appearing in the past three months -- of which one or more members of the SBI faculty were authors. The citations are listed by Institute member with links to abstracts or open-access full articles, when available:


J. Christopher Anderson:  


Leguia M, Brophy J, Densmore D, Anderson JC. Automated assembly of standard biological parts.

Methods Enzymol. 2011;498:363-97 (abstract).


Xia B, Bhatia S, Bubenheim B, Dadgar M, Densmore D, Anderson JC. Developer's and user's guide to Clotho v2.0 A software platform for the creation of synthetic biological systems.

Methods Enzymol. 2011;498:97-135 (abstract).


Adam Arkin:


Bates JT, Chivian D, Arkin AP. GLAMM: Genome-Linked Application for Metabolic Maps.

Nucleic Acids Res. 2011 Jul;39 Suppl 2:W400-5. Epub 2011 May 29 (full article).


Lucks JB, Qi L, Mutalik VK, Wang D, Arkin AP. Versatile RNA-sensing transcriptional regulators for engineering genetic networks.Proc Natl Acad Sci U S A. 2011 May 24;108(21):8617-22. Epub 2011 May 9 (full article).


Adam Arkin and Jennifer A. Doudna:


Aviran S, Trapnell C, Lucks JB, Mortimer SA, Luo S, Schroth GP, Doudna JA, Arkin AP, Pachter L. Modeling and automation of sequencing-based characterization of RNA structure.

Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11069-74. Epub 2011 Jun 3 (full article).  


Lucks JB, Mortimer SA, Trapnell C, Luo S, Aviran S, Schroth GP, Pachter L, Doudna JA, Arkin AP. Multiplexed RNA structure characterization with selective 2'-hydroxyl acylation analyzed by primer extension sequencing (SHAPE-Seq).Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):11063-8. Epub 2011 Jun 3 (full article).


Harvey Blanch and Douglas Clark:


Graham JE, Clark ME, Nadler DC, Huffer S, Chokhawala HA, Rowland SE, Blanch HW, Clark DS, Robb FT. Identification and characterization of a multidomain hyperthermophilic cellulase from an archaeal enrichment.Nat Commun. 2011 Jul 5;2:375 (abstract).


Levine SE, Fox JM, Clark DS, Blanch HW. A mechanistic model for rational design of optimal cellulase mixtures.Biotechnol Bioeng. 2011 Jun 23 (Epub ahead of print) (abstract). 


Trinh CT, Li J, Blanch HW, Clark DS. Redesigning Escherichia coli Metabolism for Anaerobic Production of Isobutanol. Appl Environ Microbiol. 2011 Jul;77(14):4894-904. Epub 2011 Jun 3 (abstract).   

Jamie Cate:   


Galazka JM, Cate JH. A new diet for yeast to improve biofuel production. Bioeng Bugs. 2011 Jul 1;2(4). (Epub ahead of print) (abstract)


Michelle Chang:


Brown ME, Walker MC, Nakashige TG, Iavarone AT, Chang MC. Discovery and Characterization of Heme Enzymes from Unsequenced Bacteria: Application to Microbial Lignin Degradation. J Am Chem Soc. 2011 Jun 14. (Epub ahead of print) (abstract


Weeks AM, Chang MC. Constructing de Novo Biosynthetic Pathways for Chemical Synthesis inside Living Cells. Biochemistry. 2011 Jun 21;50(24):5404-18. Epub 2011 May 26 (abstract).


Jennifer A. Doudna:


Sashital DG, Jinek M, Doudna JA. An RNA-induced conformational change required for CRISPR RNA cleavage by the endoribonuclease Cse3. Nat Struct Mol Biol. 2011 Jun;18(6):680-7. Epub 2011 May 15 (abstract)  


John Dueber:


Whitaker WR, Dueber JE. Metabolic pathway flux enhancement by synthetic protein scaffolding. Methods Enzymol. 2011;497:447-68 (abstract). 


Dan Fletcher:


Richmond DL, Schmid EM, Martens S, Stachowiak JC, Liska N, Fletcher DA. Forming giant vesicles with controlled membrane composition, asymmetry, and contents. Proc Natl Acad Sci U S A. 2011 Jun 7;108(23):9431-6. Epub 2011 May 18 (abstract).


Jay Keasling:


Beller HR, Goh EB, Keasling JD. Definitive alkene identification needed for in vitro studies with ole (olefin biosynthesis) proteins. (Letter to the editor) J Biol Chem. 2011 Jul 1;286(26):le11.


Zhang F, Keasling J. Biosensors and their applications in microbial metabolic engineering. Trends Microbiol. 2011 Jul;19(7):323-9. Epub 2011 Jun 12 (abstract). 


Zhang F, Rodriguez S, Keasling JD. Metabolic engineering of microbial pathways for advanced biofuels production. Curr Opin Biotechnol. 2011 May 25. (Epub ahead of print) (abstract). 





The Synthetic Biology Institute at UC Berkeley is an interdisciplinary research organization dedicated to enabling the widespread production of new biological systems to benefit humanity.  It develops the standards and technologies needed for transformative applications in energy, pharmaceuticals, chemistry, materials, food and other industries that affect our daily lives.


Its affiliated researchers represent eight departments in four colleges at UC Berkeley and three divisions at Lawrence Berkeley National Laboratory. The Berkeley scientific community has already established a leading global role in synthetic biology research. SBI builds on this base of advanced science by providing new opportunities for collaboration and education as well as a common technology infrastructure.