Drew Endy is an assistant
professor in the biological
engineering division and
cofounder of Massachusetts
Institute of Technology's synthetic
biology working group.
Creation implies an act that is based on some combination
of perfect knowledge, unlimited power, and infinite
resources. Gods create. Engineers on the other hand,
from structural to electrical and now biological, are
always constrained by (1) an imperfect understanding
of raw materials, (2) limited abilities to manipulate these materials,
and (3) a budget. As a result, engineers construct. The art of engineering
is to reliably construct useful and beautiful artifacts despite
In synthetic biology, there is now tremendous excitement about
constructing fully functioning cells from scratch. Unlike past scientific
research - for example, sequencing of the human genome - the race
to construct synthetic cells has no finish line. Instead, synthetic cells
will be judged on their elegance of design, functional prowess, and
safety features, all characteristics that can be continuously improved.
For comparison, would you want to drive your car across the world's
first "minimal" bridge?
As one or more of the remarkably diverse approaches to
construct synthetic cells succeed, the resulting organisms will define
the "power supplies and chassis" of our future synthetic biological
systems. A biological engineer working today cannot predict which
approaches are likely to produce the dominant cellular platforms for
future synthetic biology. But, consider the following possibilities:
The common E. coli, today's favorite bacterial chassis, is being heavily
re-engineered to improve its properties and function. for example,
fred blattner, György Pòsfai, and colleagues are constructing a
reduced E. coli genome, removing cryptic prophages, transposons,
and other genetic elements of "ill repute." The resulting changes
produce a genome that doesn't mutate as much as the natural cell.
As a second example, George Church and colleagues are working
to recode the E. coli genome in order to implement a new genetic
code. Alternative genetic codes should facilitate protein production
and engineering and could eventually improve genetic safety - for
example, by enabling orthogonal DNA programs executable only
inside the synthetic cell.
At least two groups are working to construct "minimal" cells from
some of the smallest known natural bacteria, the Mycoplasmas.
On the next page, scientists J. Craig Venter, Hamilton Smith, and
Clyde Hutchison explain their goal of rebuilding and then extending
the genome of the slow-growing, human pathogen, Mycoplasma
genitalium. A less well-known example is engineer Thomas F. Knight,
Jr.'s work to understand and rebuild the genome of Mesoplasma
florum. Although the M. florum genome is slightly larger than M.
genitalium's, M. florum grows as fast as E. coli and is a biosafety level
1 organism, which means that it is not known to cause disease in
healthy people. Choosing such a potential cellular chassis for synthetic
biological systems appears nearly as rational as choosing a
small transparent worm - caenorhabditis elegans - to study development,
as Sydney Brenner did in June of 1963.
Artificial Cells & Virtual Machines
As described throughout this issue, many groups are working to
construct synthetic cells from raw materials. It's exciting to imagine
using such cells as platforms for operating our future synthetic biological
systems. By only including components of known function, it
may be easier to avoid issues of component crosstalk and compatibility.
A more modest approach, however, involves the idea that
"virtual machines" can be engineered inside existing cells to isolate and
insulate the operation of our synthetic biological systems. In computer
programming, "virtual machines" provide environments for running
software independent of the underlying details of the computer itself.
For example, Java is a language for programming any computer, so
long as that computer can provide a Java Virtual Machine. The first
synthetic biology Virtual Machines might only include the T7 RNA
polymerase - an enzyme that can transcribe genes in nearly any
organism - coupled to orthogonal ribosomes, but could eventually
involve a synthetic organelle, which installs inside any natural organism
to provide a common and independent biological operating system.
Regardless of which approaches work first, our ability to design
and build novel genomes and cells will directly aid our study of
nature's designs, and enable the construction of useful synthetic