BioBuilder: Synthetic Biology in the Lab (2015)

Biological Engineering with Synthetic Biology’s Toolkit

The engineer’s process of “design-build-test” is similar to the scientific method of “hypothesize-test-analyze.” And though these processes are most often presented as linear endeavors that start with “design” for engineers and “hypothesis” for scientists, in reality they are iterative efforts that can begin at any point in the cycle. Consequently, the hands-on BioBuilder activities have several points of entry into the design-build-test paradigm and are intended to generate more scientific hypotheses, tests, and analyses. With any of the BioBuilder activities, you can explore the connection between the scientific and engineering approaches as you evaluate rationally designed living systems. Maybe you’ll want to pursue scientific exploratory options that launch from the starting material we provide, or maybe you’ll want to design new systems that work more reliably than the ones we provide or that meet new needs. Either way, this short preview of the scientific and engineering approaches in the BioBuilder labs is intended to frame these efforts within the practices of each field.

Traditional explanations approach engineering by describing the design stage and approach science by describing hypotheses, so let’s consider for a minute how these points of departure work. Design-first engineering becomes possible when there is sufficient foundational knowledge to tackle a problem from the ground up. This forward engineering approach is what comes to mind for most people when they envision the engineering process. In many ways, it is the most logical and satisfying way to begin, because it means there’s already a lot known about the system, thus it’s possible to model and simulate how a newly engineered system will behave. Computer-aided design has been game-changing in this regard. For example, the Boeing 777 was the first airplane to have been completely and successfully designed on a computer. It took 238 teams of engineers to design the plane, with each team covering its own areas of expertise and responsibility. Through division of labor and abstraction of the complex challenge into manageable tasks, the plane was successfully designed. When the prototype was finally built and tested, it not only met all the initial system requirements but it performed even better than expected. This design-first success could not have been accomplished without a deep scientific understanding of physics, building materials, and atmospheric conditions.

Unfortunately, we are a long way from understanding how biology works at this level of detail. It is not yet possible to tell a computer, “Make me a cell that detects arsenic and turns red when levels are unsafe” and have it spit out the string of ACTG’s needed to execute this behavior in a living system. Nonetheless, just because we don’t know how everything works doesn’t mean synthetic biologists shouldn’t attempt to forward-engineer. We do know a lot about how DNA is organized into functional units, for instance. In practice, it just means synthetic biologists often build many versions of a particular design when they forward-engineer biological systems.

Reverse engineering is an example of entering the design-build-test cycle at the test phase. A pre-existing object can be disassembled into components for the purposes of replicating or modifying the design. We can thank reverse engineering for everything from knock-off designer handbags to the iconic Jerrycans first used to carry fuel during World War I. Jerrycans were invented in Germany and considered a huge improvement over previous designs. The British later “reinvented” the containers for their own use after finding discarded cans on the battlefield and reverse engineering them. Currently, synthetic biology depends heavily upon reverse engineering. Many designs are inspired, if not outright taken, from complex systems found in nature. To use and modify parts or devices taken from an organism, synthetic biologists must first identify the minimal components needed to reconstruct it in another cell type, which then requires extensive testing to confirm that it behaves as anticipated.

The least intuitive entry point in the design-build-test cycle is build. Imagine rolling some dice to determine where to place the next brick in a house you’re building, and then hoping you end up with a structure that not only works but that you can rebuild and redesign in the next round of the cycle. It doesn’t seem like a very smart way to engineer anything. Interestingly, though, this is precisely the way life is built by evolution. New species emerge from random shuffling of DNA sequences, and successful versions move on to the next round of reproduction. Nature has found a way to combine the “build-test” steps into one.

In synthetic biology, the building process itself can be relatively straightforward, akin to assembling IKEA furniture, or more unpredictable, as when trying an unfamiliar recipe—or cooking without one! Just how efficiently you can build a design and reproduce it depends a lot on how detailed the instructions are and on the quality of the starting materials. When there is variability in the starting materials or when there is less known about a particular system, the more unreliable or unpredictable the building phase tends to be.

Like good scientific experiments, engineering successes often lead to more questions and challenges. Engineers might want to know how robust their new system is. Does the prototype continue to function after repeated use? Can it function under a variety of conditions? When a prototype doesn’t work, the analysis can be even more complex. Which components of the original design do work? Are failures occurring at the level of parts, devices, or systems? Thoughtful data analysis underlies good science and good engineering. Initial findings inform the next round of design-build-test or hypothesize-test-analyze. The cycles begin again with better information and they repeat until the work gets done. The BioBuilder investigations were designed to introduce the complexities and possibilities of engineering biology.