CHE.496/2009/Responses/a3

Engineering Principles

 * Discussion leader: Patrick

Thaddeus Webb's Response

 * Synthetic Biology -Putting Engineering into Biology

The article by Heinemann and Panke was written to give an overview of the emerging field of synthetic biology. The authors wanted to comment on the various possibilities of the field and the tools that it will need to develop to efficiently design biological machines. The article brought forth many of the arguments made by Drew Endy's article concerning the need for abstraction, standardization and decoupling. It expanded on his ideas by giving concrete tools and goals that the will allow the cheap construction of biological machines. The most important milestone cited by this paper was the knowledge based necessary for the creation of accurate mathematical and computer models with the ability to predict the structure and function of synthesized biological systems. Another tool the article recognized to be of great importance was the ability to quickly and cheaply fabricate DNA sequences. Current cloning procedures are costly and cannot be compiled easily because of the lack of standardization. Cheap De novo synthesis and a standardized cloning vector system such as that used by the iGEM registry of parts will remove the costs associated with fabrication from the process of machine design. Another interesting tool the article mentioned was the creation of simpler organisms with large parts of their genome removed. An organism with a minimal genome would allow the testing and application of machines in the absence of interference from non-vital pathways. The field has already achieved some remarkable applications. Designers can assemble the active sites of proteins in new combinations. Gene networks based on corollaries in other engineering fields are also being designed. For example, several elements have been designed which are comparable to the components of an electrical circuit. This article will be useful for the VGEM team in several ways. The beginning of the article will be useful because it should keep us mindful that the much of the purpose of what we are doing is laying groundwork for others to expound upon. Everything we do should be set to standards so that it will be useful to others in the future. The rest of the article gives us a feeling for the state of the field and where the challenges currently lie. It seems that the most pressing need in the field right now is characterization of basic systems to provide data for modeling.


 * Synthetic biology: new engineering rules for an emerging discipline

The article about synthetic design focused on the realities of designing novel devices in cells and integrating them into ever increasing levels of complexity. It recognized that the inability to accurately predict the interaction of devices was a serious problem and considered this problem in design considerations. The article began by describing the design of devices. Devices work on the level of on interaction or level of biochemical reaction. The authors compared the effectiveness of using devices which operated at the slow transcription and translation levels to the effectiveness of inserting novel allosteric switches into finished proteins. It was interesting to see that computer models were accurate enough to highlight portions of the proteins which could be altered and have a significant impact on the activity of the molecule. The article then described the interfacing of devices into modules. Modules are essentially a biochemical pathway with a specific input and output. Optimizing the interactions of devices has proven to a challenge in designing artificial systems. Devices interact differently with each other than they do with their natural components. Several tools for developing optimization modules include parameter estimation, sensitivity analysis, and in less characterized systems directed evolution. The greatest challenge of inserting modules into cells is the control of modules in the cellular context. Modules interact differently in different contexts and are capable of affecting cells significantly enough to alter the context. This can be controlled by modularity in which interactions between the module and the cell are minimized and designed in a predictable fashion. The article points out that it would be unfortunate to view the parts in complete isolation because we would cease to gain insight from the natural systems and possibilities of alternative systems might be missed. Aside from this point one way to deal with the cellular context would be the recreation of a novel genome. This would create a simple genome which would be easier to work with than natural genomes. The article also discussed the possiblity of expanding the synthetic pathway to multicellular systems. This would be useful because if these systems can be put into communication with each other they can become more reliable as well as more complex. This article will be useful for the VGEM team because it will highlight our considerations when we decide how to design and optimize our devices. We will want to choose parts that will have few interactions with the cell line that we choose. If the pathway does not work initially the tools outlined in this article will be useful for the debugging process. For example, the sensitivity analysis could direct us to what parts of the pathway are most critical to the formation of the output.

Thaddeus Webb 23:30, 15 February 2009 (EST)

Rohini's Response
The “Synthetic biology-putting engineering into biology” article mainly focused on the standardization and separation of design and fabrication with biological systems. The author emphasized the use of decoupling and abstraction strategies by explaining the importance of breaking down complex systems to manageable parts. The example used to illustrate standardization was the new and improved cloning process. Now days, scientists are using a standardized vector format that has made the insertion of DNA much easier and accurately recreates the same restriction sites. I think that the DNA de novo synthesis is a brilliant technology that can be very efficient and cost-effective in fabricating complex biological systems. The article also discussed the constant dilemma researchers within the field of synthetic biology face that is-- trying to engineer biological systems that are constantly evolving. It is difficult to create an efficient design of biological systems. But, with the availability and usage of software tools found in various engineering disciplines, synthetic biologists can try to model the behavior of biological systems.

The “Synthetic biology: new engineering rules for an emerging discipline” article discussed the need for synthetic biologists to be able to modify the behavior of organisms and engineer them to perform new tasks. Biologists manipulate the material properties of cells in order to build biological systems. In order to achieve this, they use various biological devices to build synthetic modules that can perform complex tasks. One of the interesting examples discussed was the insertion of a metabolic pathway into the E. coli bacteria to produce the precursor to the anti-malarial drug. Overall, synthetic biologists are continuously working on reprogramming biological systems by adding, removing and changing existing components.

These two articles provide us with some background knowledge of synthetic biology as well as the direction the field has decided to take in terms of making advancements. The articles clearly define specific challenges that the field presently faces as well as suggests methods that can be taken to overcome these obstacles.

Rohini Manaktala 2/16/09 12:48 a.m.

Joe's response

 * Synthetic Biology -Putting Engineering into Biology

This article begins with the familiar review of the engineering approach- abstraction, decoupling, standardization, system boundaries, and quantitative analysis, and the argument is clearly made that the design of biology engineering is a realistic goal. An interesting point is also brought up that because biological systems have the capacity to replicate and evolve, this will affect many of the systems unlike in chemistry or physics. Fabrication examples such as de novo DNA synthesis and standardized cloning are given, with optimization suggestions for the DNA synthesis. It is also clear that if the current prices can be lowered, the DNA de novo synthesis will be an invaluable force for systems fabrication. Protein and gene network engineering are also exemplified, and a particularly interesting area lies in using the transcription factors to upregulate gene expression. The engineering of networks is heavily emphasized, but many parameters are still unknown, so trial and error still makes up a considerable part of the design process. In the design of systems, it is clear that computer models are needed to help predict system behavior and that parameters and other constants must be collected. It appears that synthetic biology is largely in the data collection stage and that quantitative analysis is needed for forward-engineering design. Synthetic biology is taking into account the whole system, rather than just analyzing single aspects of the system, making the integration of engineering principles necessary for full-scale system design.


 * Synthetic biology: new engineering rules for an emerging discipline

This article focuses on the recent advances in synthetic biology with regard to engineering systems through assemblies of biological molecules. The goal of synthetic biology is stated as "to extend or modify the behavior of organisms and engineer them to perform new tasks." This one sentence is especially powerful, since it shows the necessity of understanding and being able to characterize the system as well as being able to modify it to perform a desired function. Predictability and reliability is stressed, with multicellular systems being the ideal route for achieving overall reliability in performing the functions, based on the power of intercellular communication. Devices that control transcription and translation and devices derived from protein-ligand and protein-protein interactions are exemplified, but the emphasis remains that they must be well characterized. A particularly interesting point is made about the noise that is inherent in biological systems, where careful design can attenuate noise but amplification can result in some systems. Electrical systems are characterized by similar principles, but do not have the unique replicating ability that biological systems possess. The design of the biological systems consists of modeling, construction, and experimental testing but the lack of complete information about the parts of the system often fails to yield fully successful implementation. The importance of models and the integration of standardization, decoupling, and abstraction for dealing with complex systems then becomes apparent. However, biological components can often not exist on their own, so this process has its own problems. Alone, biological components may have no "meaning" and must find their identity as a whole. If the features of the natural biological systems can be integrated with artificial design to perform specified functions, the synthetic biology field will have great success.

Joe Bozzay 04:00, 16 February 2009 (EST)

Maria's Response
Matthais Heinemann’s article seems to give an simple overview of some existing methods of synthetic biology and its relation to engineering. The review delineates the hurtles that must be tackled for the field of synthetic biology to reach the design efficiency that other engineering fields have. These include: (1)An in-depth and reliable knowledge of the governing scientific principles. This can ba a difficult challenge because biology includes many other fields, requiring knowledge about physics, reaction kinetics, chemistry and other fields. One manner to reduce the complexity would be to reduce the bacterium to their ‘minimal genome’ of course this limits work to a few species of bacteria, but can eliminate interference with gene expression and simplify a process. (2) The use of abstraction, such that one can divide a system into individual components which are easier to focus on. (3) Standardizing methods and tools is critical for developing efficient engineering. The article sites vectors as an example technology which can be standardized. Standardization is definitely a realistic and achievable goal, MIT has already paved the way by starting the ‘Registry of Standardized Biological Parts’ and the article states that zinc-finger information can now be found in tables. This is critically important for the VGEM team, with a limited schedule and budget, access to standardized pieces and process will facilitate success. The final criterion Heinemann discusses is the matter of designer verses constructor. He points out that in other engineering disciplines, the design and construction processes are separate. He declares that biology should borrow this organization because in-depth knowledge is required for both processes. Therefore one individual should not try to do them both as is often done in synthetic biology. For our project this seperation will be hard to achieve, but it is possible that different members of the team could focus research differently. The Weiss article was similar in intension, giving an introduction to some synthetic biology technology and processes and discussing their relation to engineering. I found the technical examples more interesting and thorough. The article discussing using abstraction to analyze biochemical reactions and model chemical behavior. Like Heinemann, though, that article states that quantifying reaction constants is still a difficult hurdle to accurate quantitative modeling. It discusses several reactions and the use of transcriptional and translation control to regulate enzyme expression. I thought the article was helpful in that it did more than the first to discuss current methods in the field, which is helping me get up to speed with the information.
 * Maria Fini 19:27, 16 February 2009 (EST):Maria Fini