Thinking Like Engineers

Weight, density, tensile strength, gauge, purity. Mechanical engineers are keen to know how different parts and materials compare using combinations of values like these. It's often joked that if only airplanes were made of the same thing as their black boxes, we would never have to worry about fatal crashes. But, of course, such a plane would never be able to get off the ground in the first place! Engineers have had to strike a balance in the tradeoff between strength and weight. Biology, too, has tradeoffs inherent to its materials, but the details are a bit more subtle.

All organisms in nature are full of tradeoffs analogous to engineers designing planes. Natural selection has had to find the balance between tradeoffs such as "How much energy should be spent on reproduction vs. foraging?" and, at the molecular genetic level, "How much of protein X should be produced in relation to protein Y?" Biological engineers are faced with their own set of tradeoffs, often in conflict with what natural selection would "prefer." For example, researchers trying to engineer bacteria to produce a drug have to find an optimal rate of drug production by the cells. If they force the cells to produce too much of the drug, the cells could die from toxic effects or diversion of energy from their basic metabolic needs. But if they tune the dial too low then they are wasting resources and under producing a potentially vital drug. Natural selection, on the other hand, favors those cells that do away with producing the drug altogether, because then they can spend more energy on growing and reproducing.

In most cases we don't have solid measurements of what might be called biological equivalents of tensile strength or weight. The numbers either don't exist or they are so context dependent that they have to be measured from scratch for each application. As I hinted at above, one problem is how long a synthetic device will remain functional in cells. Just as mechanical parts break, biological ones mutate. However there is a broad array of parameters that synthetic biologists are interested in knowing. One good example is promoter strength.

Promoters recruit the enzyme RNA polymerase to begin transcribing a gene. A promoter is said to be strong if RNA polymerase binds frequently. If we had a list of promoters, each with a matching promoter strength, then we could make an informed decision about which to choose. In the drug manufacturing application, we might want to choose moderately strong promoters that churn out lots of product without over-taxing the cells. But there's no way to count how many RNA polymerases bind to a given promoter. Instead we have to rely on indirect methods such as the clever approach reported by Cox, Dunlop, and Elowitz (2010).

They built a DNA device where you can insert three promoters of your choice to regulate the production of fluorescent proteins that glow red, yellow, and cyan within living cells (see image). Since there is little or no overlap between these colors, they can be distinguished from one another with proper instrumentation. Machines called fluorimeters shine light on a culture containing fluorescent proteins and quantify the fluorescence that is given off. The intensity tells you how strong the promoter corresponding to that color of fluorescent protein is. By studying three promoters within the same cell you can understand how they interact within the context of each other's presence.

There is still a lot of work to be done on measuring and characterizing biological parts. Promoter strength is an easily understandable example, but there are many other parameters that should be studied. Most part pages on the Registry of Standard Biological Parts report little, if any, specifications. However, there is a growing list of measurement parts, and some iGEM teams are devoting part of their time to characterizing registry parts. The availability of measurements allows informed engineering, which in turn allows for more rapid and extensive innovation.

Image Credit: Danny Masson (via Wikimedia); Cox, Dunlop, & Elowitz (2010). Figure 3A.

References:

Cox, R. S., Dunlop, M. J., & Elowitz, M. B. A Synthetic Three-Color Scaffold for Monitoring Genetic Regulation and Noise. Journal of Biological Engineering 4, 10 (2010).