304 CATALYZING INQUIRY
Constructing these structures will require the ability to fabricate individual devices and the
ability to assemble these devices into a working system, since it is likely to be very difficult to
assemble a system directly from scratch. One approach to an assembly facility is to use a mostly
passive scaffold, consisting of selectively self-assembling molecules that can be used to support the
fabrication of molecular devices that are appropriately interconnected. Indeed, DNA molecules and
their attendant enzymes are capable of self-assembly. By exploiting that capability, it has been pos-
sible to create a number of designed nanostructures, such as tiles and latticed sheets. Although the
characteristics of these biomaterials need further exploration, postulated uses of them include as
scaffolds (for example, for the crystallization of macromolecules); as photonic materials with novel
properties; as designable zeolite-like materials for use as catalysts or as molecular sieves; and as
platforms for the assembly of molecular electronic components or biochips.^5 Uses of DNA as a
molecular “Lego” kit with which to design nanomachines, such as molecular tweezers and motors on
runways, are also under investigation.
The relevance of synthetic cell engineering to nanofabrication is driven by the convergence of
developments in several areas, including the miniaturization of biosensors and biochips into the na-
nometer-scale regime, the fabrication of nanoscale objects that can be placed in intracellular locations
for monitoring and modifying cell function, the replacement of silicon devices with nanoscale, molecu-
lar-based computational systems, and the application of biopolymers in the formation of novel
nanostructured materials with unique optical and selective transport properties. The highly predictable
hybridization chemistry of DNA, the ability to completely control the length and content of oligonucle-
otides, and the wealth of enzymes available for modification of DNA make nucleic acids an attractive
candidate for all of these applications.
Furthermore, by designing and implementing synthetic cells, a much better understanding will be
gained of how real cells work, how they are regulated, and what limitations are inherent in their
machinery. Here, the discovery process is iterative, in that our understanding and observations of living
cells serve as “truthing” mechanisms to inform and validate or refute the experimental constructs of
synthetic cells. In turn, the mechanisms underlying synthetic cells are likely to be more easily under-
stood than comparable ones in natural cells. Using this combined information, the behavior of biologi-
cal processes in living cells can slowly be unraveled. For such reasons, the process of creating synthetic
cells will spin off benefits to biology and science, just as the Human Genome Project led to dramatic
improvements in the technology of molecular biology.
To proceed with the creation of synthetic cells, three separate but interrelated problems must be
addressed:
- The theoretical and quantitative problem of formulating, understanding, and perhaps even opti-
mizing the design of a synthetic cell; - The biological problem of applying lessons learned from real cells to such designs and using
synthetic cells to inform our understanding of more complicated natural cells; and - The engineering and chemistry problem of assembling the parts into a physical system (or to
design self-assembling pieces).
One approach to building such a cell de novo is to start with a set of parts and assemble them into
a functional biomolecular machine. Conceiving a cell de novo means that cellular components and their
assembly are predetermined, and that the cell engineer has a quantifiable understanding of events and
outcomes that can be used to predict the behavior of the components and their interactions at least
probabilistically. A key aspect of de novo construction is that a de novo cellular design is not con-
strained by evolutionary history and hence is much more transparent than cells found in nature. Be-
(^5) E. Winfree, F. Liu, L.A. Wenzler, and N.C. Seeman, “Design and Self-Assembly of Two-Dimensional DNA Crystals,” Nature
394(6693):539-544, 1998.