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then the combined promise of systems
scale up (a microorganism), researchers
decode them. Biological systems can
whether we understand biological sys-
logy—the notion that one can assemble
(Haynes and Silver, 2009). Further anal-project required an investment of over
$25million and 150 person-years of highly
trained researcher effort. This investment
larity but exhibits nonmodular features
as well. For many years the gene was
regarded as a fundamental modular unit
Approaches to Synthetic Biology
Given that the goals of synthetic biology
are to make the engineering of biologycannot realistically be replicated for every
chemical or material to which we would
of biology. As such, a gene is capable of
transferring a particular phenotype to the
faster and more predictable, and to
harness the power of biology for thewere able to develop a process that en-
abled cheaper supply of this drug, pro-
viding a more accessible cure for a
disease devastating third world countries.
However, the research phase of this
tems sufficiently to be able to redesign
them to fulfill specific requirements.
Engineers enjoy the concept of inter-
changeable parts and modularity. Biology
offers many sources of potential modu-
yses provided by systems biology may
help to guide the development of stan-
dard strategies for assembling genetic
modules into functional units.biology and synthetic biology that may
drive transformative advances in our
ability to program biological function.
One recent example of the successful
engineering of a biological system to
address a global challenge in health and
medicine is the creation of microbes that
produce a precursor to the antimalarial
drug artemisinin (Ro et al., 2006). By shift-
ing synthesis from the natural production
host (a plant) to one more optimized for
rapid production times and inexpensive
send and receive signals rapidly and in a
highly specific manner. Pathways exist
to sense and respond to the environment.
Plants and microbes can use sunlight as
an energy source. However, biological
systems are also uniquely capable of
self-replication, mutation, and selection,
leading to evolution. Synthetic biologists
aim to take advantage of these parallels
and develop engineering principles for
the design and construction of biological
systems. However, an open question is
biological systems from well-defined
‘‘parts’’ or modules (Endy, 2005). How-
ever, modular assembly approaches
have largely remained confounded by
the effects of context—that is, the non-
modular aspects of biology. For example,
where a gene or an associated regulatory
element is located in the genome can
impact expression and thus its function.
In addition, the location of regulatory
elements relative to each other and
ORFs can impact their encoded functionEssay
Informing Biolog
of Systems and
Christina D. Smolke1,* and Pamela A. S
1Department of Bioengineering, Stanford Uni
2Department of Systems Biology and Wyss In
Boston, MA 02115, USA
*Correspondence: csmolke@stanford.edu (C
DOI 10.1016/j.cell.2011.02.020
Synthetic biology aims to make
systems biology focuses on the
dynamic and complex behavior
these two fields.
Biology is the technology of this century.
The potential uses of biology to improve
the human condition and the future
of the planet are myriad. Over the last
century, humans have used biology to
make many useful things, in part based
on discoveries from molecular biology.
In addition, researchers have redesigned
biological systems to test our funda-
mental understanding of their compo-
nents and integrated functions. However,
the complexity and reliability of engi-
neered biological systems still cannot
approach the diversity and richness ex-
hibited by their natural counterparts. It isical Design by In
ynthetic Biolog
ver2,*
rsity, 473 Via Ortega, Stanford, CA 94305-420
titute of Biologically Inspired Engineering, Har
.S.), pamela_silver@hms.harvard.edu (P.A.S.)
e engineering of biology faster a
nteraction of myriad component
f biological systems. Here, we
apply this approach. Instead, imagine
a time when a bioengineer designs a sys-
tem at the computer, orders the neces-
sary DNA encoding the specified system,
and then begins the actual experiment of
turning it into life. Thus, one overarching
goal of synthetic biology is to make the
engineering of biology faster, affordable,
and more predictable.
Biological systems and their underlying
components offer a number of functional
parallels with engineered systems. For
example, biological sensors are exqui-
sitely sensitive; the olfactory system can
detect single odorant molecules andCell 14tegration
, USA
rd Medical School, 200 Longwood Avenue,
d more predictable. In contrast,
and how these give rise to the
xamine the synergies between
organism. However, we now know that
genes display more fine-grained modu-
larity in the form of promoters, open
reading frames (ORFs), and regulatory
elements. mRNAs contain sequences
important for proper intracellular targeting
and degradation. Proteins often contain
targeting sequences, reactive centers,
and degradation sequences. And lastly,
entire pathways are modular in that
some signaling pathways can be trans-
ferred from one organism to another to
reconstruct a new state in the engineered
organism. This modularity underlies one
of the core concepts of synthetic bio-4, March 18, 2011 ª2011 Elsevier Inc. 855

common good, the development of new
approaches that support the design and
construction of genetic systems has
been a core activity within the field. Al-
though advances have been made in
both areas (fabrication and design), our
ability to construct large genetic systems
currently surpasses our ability to design
such systems, resulting in a growing
‘‘design gap’’ that is a critical issue that
synthetic biologists must address.
The ability to synthesize large pieces of
DNA corresponding to operons, entire
pathways, chromosomes, and genomes
in a rapid and predictable way is a key
approach to system fabrication. Systems
biology has provided numerous tem-
plates with the abundance of sequenced
genomes being deposited daily into
publicly accessible databases. Some
progress has recently been reported,
including the resynthesis of a bacterial
genome and its successful insertion into
a different bacterial host (Gibson et al.,
2010). However, it took researchers
nearly 15 years and approximately $30
million to develop various fundamental
aspects of this project. Much of this time
and cost was methods development that
will hopefully reduce the resources
needed to carry out such projects in the
future. In addition, new high-throughput
methods for large-scale DNA synthesis
have been recently described (Matzas
et al., 2010; Norville et al., 2010; Tian
et al., 2009). However, much more work
is still needed to develop these technolo-
gies to the point where they are acces-
sible to the majority of researchers (that
is, in terms of cost and reliability), and
systems biology may provide important
clues. For example, faster and more reli-
able ways to synthesize large pieces of
DNA may be uncovered by examination
of new organisms and thereby reveal
new nonchemical methods for DNA
synthesis.
A second approach is to develop the
methods to generate new component
functions that can act as sensors, regula-
tors, controllers, and enzyme activities,
for example. These components will in
turn extend the set of parts from which
synthetic biologists can build genetic
devices and systems. Synthetic biologists
work not only with design of DNA that
encodes genetic circuits but also with
molecular design of biomolecules, such
856 Cell 144, March 18, 2011 ª2011 Elsevieras RNAs and proteins, to perform new
functions. Substantial efforts in the field
of protein engineering have contributed
to the diversity of functions exhibited
by protein components (Dougherty and
Arnold, 2009). However, even with these
advances, the diversity of component
activities that is currently available as
parts has been limited, thus limiting
the design of genetic circuits. Systems
biology may aid in the development of
effective strategies for generating new
component functions by providing infor-
mation on how Nature has evolved
different functions for macromolecules.
A third approach is the predictable
design of complex genetic circuits that
lay the foundation for new biological
devices and systems. Many circuits
designed and built thus far have relied
on our fairly detailed knowledge of how
gene transcription is regulated. For
example, synthetic circuits have applied
concepts of positive and negative feed-
back to generate systems that sense
stimuli, remember past events, and pro-
mote cell death in both prokaryotic and
eukaryotic cells (Burrill and Silver, 2010;
Sprinzak and Elowitz, 2005). However,
many of these systems have been built
in a fairly ad hoc manner, requiring sub-
stantial troubleshooting and iterative
design to exhibit desired functions, and
lack the robust performance standards
one might expect as an engineer. Going
forward, synthetic biologists need to
better understand the parts underlying
system design, how to predict their func-
tion in a particular genetic context, and
how to predict their integrated function
with other system parts (Ellis et al., 2009;
Savageau, 2011). This biological under-
standing will then be integrated with com-
putational models to develop computer-
aided design tools.
What Does Systems Biology Mean
to Synthetic Biology?
As with synthetic biology, many different
types of research have been categorized
as systems biology. Broadly speaking,
systems biology represents an approach
to biological research that focuses on
the interactions between components of
a biological system and how those inter-
actions give rise to the dynamic behavior
of the system in contrast to themore tradi-
tional molecular biologists’ reductionist
Inc.approach of studying components in
isolation from each other (Alon, 2007).
Systems biology has been associated
with new technologies and methods that
allow for quantitative measures of com-
ponents and component interactions
within biological systems, particularly
those that allow for genome-wide mea-
surements. In addition, because many of
these technologies result in large data-
sets, systems biology has also been
associated with computational tools that
support the integration and analysis of
these datasets to identify static relation-
ships and interactions between compo-
nents. Finally, as one of the ultimate goals
of systems biology is to be able to predict
a system’s dynamic behavior from the
component parts, computational tools
that can model biological systems-level
function from underlying components
are associated with this field.
However, there are currently a number
of challenges and limitations facing the
field of systems biology. Paramount is
determining how to correctly analyze
and draw valid conclusions from large
amounts of different types of data ranging
from genomics and metabolomics to
molecular dynamics in many single cells.
Effectively addressing this problem may
require new mathematical and computer
science approaches. A second key chal-
lenge is knowing what kind of measure-
ments to make and how accurate these
measurements need to be to fully under-
stand a biological system. Effectively
addressing this challenge will require a
re-evaluation of how measurements
have been made over the past 10 years
in systems biology (for instance, the
movement from two-hybrid interactions
to mass spectrometry to measure protein
interactions). It will also require the devel-
opment of even more sensitive strategies
to make time-dependent measurements
inside many cells simultaneously. Taken
together, systems biology is confronted
with the problem of both sensitivity and
scale.
Does the ultimate goal of synthetic bio-
logy of the predictable design, construc-
tion, and characterization of biological
systems rely on findings and approaches
from systems biology? Design, analysis,
and understanding are integrally linked in
engineering methodology. Therefore, it is
reasonable to assume that advances