Catalyzing Inquiry at the Interface of Computing and Biology

306 CATALYZING INQUIRY

• Stability and robustness in the face of varying environmental conditions and noise. For example, it is
  well known that nature provides a variety of redundant pathways for biological function, so that (for
  example) the incapacitation of one gene is often not unduly disruptive to the cell.


• Improvement in the libraries of DNA-binding proteins and their matching repressor patterns. These are
  at present inadequate, and good data about their kinetic constants are unavailable (hence signal transfer
  characteristics cannot be predicted). Any specific combination of proteins might well interact outside
  the genetic regulatory mechanisms involved, thus creating potentially undesirable side effects.


• Control point design and insertion.


• Data measurement and acquisition. To facilitate the monitoring of a synthetic cell’s behavior, it is
  desirable to incorporate into the structure of the cell itself methods for measuring internal state param-
  eters. Such measurements would be used to parameterize the functionality of cellular elements and
  compare performance to specifications.


• Deeper understanding of biomolecular design rules. Engineering of proteins for the modification of
  biointeractions will be required in all aspects of cell design, because it is relevant to membrane-based
  receptors, protein effectors, and transcriptional cofactors. Today, metabolic engineers are frequently
  frustrated in attempts to reengineer metabolic pathways for new functions because, at this point, the
  “design principles” of natural cells are largely unknown. To design, fabricate, and prototype cellular
  modules, it must be possible to engineer proteins that will bind to DNA and regulate gene expression.
  Current examples of DNA binding proteins are zinc fingers, response regulators, and homeodomains.
  The goal is to create flexible protein systems that can be modified to vary binding location and strength
  and, ultimately, to insert these modules into living cells to change their function.


• A “device-packing” design framework that allows the rapid design and synthesis of new networks inside
  cells. This framework would facilitate designs that allow the reuse of parts and the rapid modification
  of said parts for creating various “modules” (switches, ramps, filters, oscillators, etc.). The understand-
  ing available today regarding how cells reproduce and metabolize is not sufficient to enable the inser-
  tion of new mechanisms that interact with these functions in predictable and reliable ways.


• Tool suites to support the design, analysis, and construction of biologic circuits. Such suites are as yet
  unavailable (but see Box 9.3).

9.4 Neural Information Processing and Neural Prosthetics,

Brain research is a grand challenge area for the coming decades. In essence, the goal of neuroscience
research is to understand how the interplay of structural dynamics, biochemical processes, and electri-

Box 9.3

Tool Suites

One tool suite is a simulator and verifier for genetic digital circuits, called BioSPICE. The input to BioSPICE is

the specification of a network of gene expression systems (including the relevant protein products) and a small

layout of cells on some medium. The simulator computes the time-domain behavior of concentration of

intracellular proteins and intercellular message-passing chemicals. (For more information, see http://

http://www.biospice.org.)

A second tool would be a “plasmid compiler” that takes a logic diagram and constructs plasmids to implement

the required logic in a way compatible with the metabolism of the target organism. Both the simulator and the

compiler must incorporate a database of biochemical mechanisms, their reaction kinetics, their diffusion

rates, and their interactions with other biological mechanisms.