Synthetic biology future applications and technology needs

This page collects together some ideas about potential future applications for synthetic biology, broken down by technology readiness levels, and a list of some of the technologies that need to be developed to realize those applications.

The ideas listed here are based on conversations with many people in the synthetic biology community, most especially members of the Engineering Biology Research Consortium as part of the EBRC roadmap discussions.

Applications

TRL	Application	Comments
0	Synthetic cells	Ability to design and implement cell-like systems containing multiple subsystems to enable energy generation/transfer, sensing, actuation (export of chemicals, movement), decision-making, memory and other functions. Individual functions have been demonstrated in isolation, but limited demonstration of integrated synthetic cells are available. The Build-A-Cell consortium is organized around this problem.
1	Engineered multi-functional (living) materials	Biology is able to make materials that have a combination of functional properties, including protection, coloration, transport of materials, structural strength, texture, etc. As we push forward in synthetic biology, we can combine engineered living and nonliving materials to provide similar functions, though we are a long way off from this goal. DARPA's Engineered Living Materials (ELM) program was a start.
3	Cell-based chemical detection and logging	Biology is able to perform molecular recognition at a level of concentration and specificity that in many cases exceed what is possible with traditional chemical and electronic means. Cells can also be engineered to provide persistent "situational awareness" (of their environment) and to log the history of what they have seen in their environment (via a variety of DNA recording technologies that are being developed).
3	Cell-free chemical detection	There is lots of excitement (and a couple of startup companies) that are looking at cell-free (often paper-based) detection of biomolecules that hold promise as an inexpensive, durable (?), and lightweight sensors. Cell-free sensors also have the advantage that they don't require the use of living organisms in an open environment.
2	Gut microbiome engineering	As scientists have discovered more and more about the role that the gut microbiome plays in the overall systems within the human body (including the immune system and the nervous system), it has become more evident that there maybe opportunities in manipulating the microbiome through combinations of diet and probiotics. In particular, introducing engineered (non-pathogenic) bacteria into the gut may provide a means for increase detection, logging, and regulation of the gut microbiome. There are some startup companies in this space (two that I know of are Synlogic and Persephone Biome) and several recent calls for proposals from government funding agencies.
2	Wound microbiome engineering	Another microbiome where engineered bacteria might be useful is in the skin microbiome around wounds. This is a very complicated environment that involves a variety of different types of cells and signals, but it may be possible to engineer bacterial that can detect the "operating condition" within the wound and try to improve the healing process by manipulating the local environment. My group as a project as part of the DARPA Biological Control program that is using this as a (long term) motivation for some of our work.
2	Plant microbiome engineering	Another fascinating microbial environment is in the soil system around plants. Pivot Bio just announced a product in which they make use of bacterial that fix nitrogen as a means of getting more efficient use of fertilizers. As we get more sophisticated in what we can engineer into bacterial, there should be other opportunities for improving the environment around plant roots to improve productively and robustness.
4	Environmental bioremediation	Bacteria break down chemical substances and turn them into other substances. Waste processing already makes use of (natural) bacterial to perform recycling of materials. There are many opportunities to expand on this to process "waste" biomass into something useful. The DARPA ReSource program is focused on this opportunity, as one example.
1	Engineered (biological) surface coatings	Multi-cellular organism use cells to create surface properties tune to the organisms needs: skin, feathers, scales, and bark are all examples. In addition, bacterial films use spatially structured interactions that allows the films to survive and protect/degrade surfaces. Can we engineer bacteria in a manner that allows them to create surface properties such as texture and color that are engineered for a specific purpose?
1	Environmentally responsive materials	Building on the idea of engineered functional materials, can we build biological materials whose properties depend on their environment? Simple examples would be materials that change color or texture when the temperature changes. More complex examples might be materials that secrete a chemical when they detect a certain environmental condition (similar to the wound microbiome example).
3	Point-of-need manufacturing	Biology can be programmed and biology can process materials ⇒ we can program biology to produce the materials we need, when and where we need them. Think about a 100 liter tank that can produce any one of a 100 different types of chemicals depending on what you tell the bacteria (or yeast) inside it to do. There are also opportunities in the area of cell-free point-of-need manufacturing that groups at MIT and Northwestern (among others) have demonstrated.
2	Hybrid silicon cell sensors	Biology can't (quite) do everything and electronics and do some things that biology is not optimized for. Can we get the best of both words by combining the unique features of biology (detection, production) with the strengths of electronics (computing, communications)? SRC and NSF have a big program in this area and there are other activities looking at the interface between cells and silicon.
6	Metabolic engineering/materials production	The use of engineered metabolic pathways to make (relatively simple) chemicals is an active area of business, with chemicals ranging from insulin to spider silk to food products. The basic technology is implementation of a enzymatic pathway to produce a biologically tractable chemical in a fermentable organism (e.g., yeast, E. coli).

Technologies

TRL	Technology	Comments
3	Circuit design libraries and tools	Many of the applications above will require relative complex circuits and pathways to be designed, built, tested, and implemented. Current design tools for engineering biological circuits and pathways are limited and not very predictive. My current favorite tool to talk about is Cello, which seems to hit the right balance of modeling and empirical data, although it is currently limited just to logic circuits. It will be important for tools in this area to handle different host organisms, effects of resource limits and crosstalk, as well as robustness analysis (including mutation).
1	Subsystem engineering and modularity	At the present time, most biological circuits and pathways are engineered and built by a single group/company, and the notation of a "subsystem" is not really available. We need to move over time to a model where different groups/companies build subsystems that are designed to work with other subsystems, and provide subsystems that meet specifications and allow modularity and interconnection.
3	Cell-free prototyping	The DARPA Living Foundries program supported work in the use of cell-free systems for prototyping biological circuits and pathways, but this approach has not yet matured to the point where it is useful (or used). The biggest missing piece seems to be in obtaining results in cell-free settings that are representative of cell-based operations. Using cell-free for prototyping could provide substantial speedup in implementing circuits and serve as a stop-gap until model-based approaches are more reliable.
2	Model-based design	The ultimate goal for an engineering approaach to synthetic biology would be to have models that can be used for design that are predictive of what happens in implementation (cell-based or cell-free). This is largely the situation in other disciplines and it has enabled to design and implementation of very complex systems by virtue of the ability to cretae systems that match their models. Until we get to this point with biology, the size of systems that we can design will continue to be limited.
3	Microbial consortia and engineered commensals	For a variety of synthetic biology applications it will make sense to distributed the functionality of the system across multiple cells that distribute the different elements of the system. This approach has the advantage that circuits/pathways in individual cells can be simpler and are isolated from each other (so they can re-use parts). Related to this, being able to establish engineered cells are part of natural multi-cellular systems (bacterial films, microbiomes, etc) will be an important capability for moving microbiome applications forward.
0	Engineered multi-cellular organisms	Moving beyond collections of micro-organisms, engineering multi-cellular systems in which different cells carry out a set of integrated, yet distinct, functions is a potential pathway to implementing complex behaviors such as engineering plants and (simple) animals. The level of complexity here is well beyond what is currently available, though some combination of additive manufacturing and engineered microbes might provide an initial path forward.
2	Engineered macromolecular machines	Moving in the other direction for multi-cellular systems, building macro-molecular machines consisting of multiple proteins, small molecules, and RNA could serve as a platform for more complex processing of information and materials. The ribosome is a prototypical example of a biomolecular machine in which a variety of molecular components work together to carry out a complex function (translation). While we are far from being able to build such macro-molecular machines from scratch, work on artificial ribosomes may give some glimpse of what is possible.
2	Programmable (and orthogonal) sensing and communications	In a variety of applications it will be important to sense multiple molecules and environmental conditions, as well as communication information between cells. These types of information processing will require engineering membrane bound proteins (and more complex machinery) to allow information and matter to be communicate into and out of cells (and synthetic cells). Orthogonality (or some method for deconvolution) may also be a key technical capability.
2	Mutation-resistant systems/mutation compensation	For circuits and pathways implemented in living organisms, there is a constant issue due to mutation and burden. In particular, if a poinnt mutation leads to an increase in growth rate at the expense of a decrease in the desired function of a cell, that mutation has a growth advantage that can allow it to take over a population of engineered cells. Figuring out how to get long lasting stability in the presence of mutation will be needed for applications in which the engineered cells must function for long periods (hundreds of cell divisions). Some initial work on measuring burden and regulating burden provides one possible approach to dealing with this issue.
1	Non-exponential phase circuitry	Most implementations of engineered circuits and pathways are demonstrated during exponential growth of cells, usually growing on rich media. But for many of the applications we envision, exponential growth is not likely and so we will need to figure out how to get circuits that work when cells are in a some sort of "steady state" (either stationary phase or equivalent rates of cell proliferation and cell elimination)
3	Electronic interfaces	To date, many (most?) biological circuits are implemented completely biologically. Figuring out how to harness "multi-modal" operations in which some portions of a system function are implemented biologically and others portions are implemented electronically could open up the space of potential applications for synthetic biology. Some initial investments in this are ahave been made by NSF and SRC.