Studies in History and Philosophy of Biological and Biomedical Sciences 44 (2013) 158169

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Studies in History and Philosophy of Biological and

Biomedical Sciences
journal homepage: www.elsevier.com/locate/shpsc

Basic science through engineering? Synthetic modeling and the idea of

biology-inspired engineering
Tarja Knuuttila a, Andrea Loettgers b
a
b

University of Helsinki, Fabianinkatu 24 (P.O. Box 4), 00014, Finland

California Institute of Technology, 1200 E. California Blvd., MC 114-96, Pasadena, CA 91125, USA

a r t i c l e

i n f o

Article history:
Available online 17 April 2013
Keywords:
Synthetic modeling
The Repressilator
Engineering
Integration
Design principles
Network motifs

a b s t r a c t
Synthetic biology is often understood in terms of the pursuit for well-characterized biological parts to
create synthetic wholes. Accordingly, it has typically been conceived of as an engineering dominated
and application oriented eld. We argue that the relationship of synthetic biology to engineering is far
more nuanced than that and involves a sophisticated epistemic dimension, as shown by the recent practice of synthetic modeling. Synthetic models are engineered genetic networks that are implanted in a natural cell environment. Their construction is typically combined with experiments on model organisms as
well as mathematical modeling and simulation. What is especially interesting about this combinational
modeling practice is that, apart from greater integration between these different epistemic activities, it
has also led to the questioning of some central assumptions and notions on which synthetic biology is
based. As a result synthetic biology is in the process of becoming more biology inspired.
2013 Elsevier Ltd. All rights reserved.

When citing this paper, please use the full journal title Studies in History and Philosophy of Biological and Biomedical Sciences

1. Lego bricks . . . over and over again?

On the cover of the September 2011 issue of Science that is dedicated to synthetic biology, grayish agglomerations depicted as
consisting of Lego-bricks oat in the lilac-black space. The picture,
belonging to a ourishing genre of Lego-inspired synthetic biology
pictures, was produced by Equinox Graphicsa company specialized in producing science and engineering images. On page 1193
of the special issue one nds the following description of what is
depicted on the picture: Bacteria constructed from toy bricks represent the potential of synthetic biology to design and construct
genetic modules that can be used to introduce new functions into
existing organisms or even to engineer new biological systems.
(see Fig. 1).
The Lego-brick has become almost the epitome of synthetic
biology, understood as a kind of engineering science, which pursues designing and constructing well-characterized biological
parts to create synthetic wholes. It is displayed by the goal of creating standard biological parts, BioBricks,1 that are interchangeable
sequences of DNA with specic function, and in an attempt to

apply to biology the practices of standardization, decoupling, and

abstraction (Endy, 2005). While this understanding of synthetic
biology, built on a metaphor of construction, has received the most
popular attentionas also the cover of the recent issue of Science
showsthe place and role of engineering in synthetic biology is
much more nuanced than that. In fact the cover of Science actually
contradicts some of the most central points presented in the articles
of the issue. Firstly, Nandagopal and Elowitz (2011, pp. 12441248)
address the question of how one could integrate the engineered genetic circuits with the rest of the cell environment to attain more
robust functioningthe strict modularity of the Lego-bricks is
clearly left behind. On the other hand Ruder, Lu, and Collins
(2011, pp. 12481252) argue that while synthetic biology initially
arose from the combined efforts and insights of a small band of
engineers, physicists, and computer scientists . . . for the eld to
reach its full clinical potential, it must become better integrated
with clinicians (Ruder et al., 2011, p. 1251). Thus integration seems
to be the key word; the synthetic biologists in question aim for a
more integrated approach on both the systems and the disciplinary
levels.

E-mail addresses: tarja.knuuttila@helsinki. (T. Knuuttila), loettger@caltech.edu (A. Loettgers).

<http://biobricks.org/> Accessed 10.08.12.

1369-8486/$ - see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.shpsc.2013.03.011

T. Knuuttila, A. Loettgers / Studies in History and Philosophy of Biological and Biomedical Sciences 44 (2013) 158169

159

synthetic models; that is to say engineering synthetic networks

constructed from genetic material. Before going into the cases we
will briey discuss the different conceptions of engineering in synthetic biology and describe some general features of synthetic
modeling. Our study is partly based on an empirical study on the
Elowitz lab, which is one of the leading synthetic biology
laboratories.2
2. Engineered artifacts vs. biological systems
2.1. Engineering as the study of functions and system dynamics

Fig. 1. Cover of the September 2011 issue of Science featuring a special section on
synthetic biology.

While these synthetic biologists are calling for more integration

OMalley and Soyer (2012) have recently argued that systems and
synthetic biology already display a wide variety of integrative practices. As such, systems and synthetic biology may provide an
exemplary case of the various kinds of integration taking place in
contemporary science. In our paper we will concentrate on one
particular type of integration discussed by OMalley and Soyer:
methodological integration. It involves directing a range of methods at a particular biological system or research problem in order
to gain multidimensional understanding of how the system works
(OMalley & Soyer, 2012, p. 60). Such methodological integration is
characteristic of combinational modeling whereby synthetic biologists combine the experimentation on model organisms and mathematical modeling/simulation with a new type of a model: a
synthetic model. Clearly, this kind of modeling practice involves
the attempt to gain more multidimensional understanding as it
combines three different methods, all of which are able to deliver
different kinds of knowledge, and all of which are partial and in
need of triangulation with other kinds of evidence. Thus the concept of integration seems to referas the mere word already suggeststo the convergence of more complete and uniform
explanations of phenomena often via repeated rounds of piecemeal
adjustment and re-engineering (Chang, 2004; OMalley, 2011).
Such development captures without doubt a great deal of what is
happening in systems and synthetic biologyand in science, more
generally. However, in this paper we wish to also emphasize another aspect of combinational modeling that points towards its
reexive character.
Combinational modeling may not just lead to greater integration but also to the questioning of some central assumptions and
notions on which synthetic biology is based. This reexivity is perhaps most vividly exhibited by the practice of synthetic modeling
and the way in which synthetic models are used to explore the
appropriateness of some features of mathematical models and
their theoretical grounding. In a relatively short period of time,
work on synthetic models has made synthetic biologists aware of
some fundamental differences between human engineered artifacts and biological systems. In what follows we will discuss
through our example casesthe insights provided by engineering
2

In synthetic biology one can distinguish two main approaches:

an application-oriented approach and a basic-science approach.
The application-oriented approach, which aims for instance to design novel biological parts or organisms for the production of vaccines (Ro et al., 2006), biofuels (Bond-Watts, Bellerose, & Chang,
2011), and cancer-killing bacteria (Anderson, Clarke, Arkin, & Voigt, 2006), is often construed as comprising the whole eld of synthetic biology. Less visible than this application-oriented approach
is the basic-science approach, which uses synthetic biology and
especially synthetically designed biological parts as a tool for
investigating the basic design principles of gene regulatory networks (e.g., Elowitz & Leibler, 2000; Gardner, Cantor, & Collins,
2000). When this line of research took its rst steps, one of the
main requirements was to reduce the complexity of biological systems. The reason for this strategy was not necessarily due to the
reductive vision of the scientists in question but rather their aim
of studying some aspects of biological organization in isolation of
other aspects. This was deemed indispensable for the purposes of
exploring various possible design principleslater to be called
motifs (see below). Another important motivation for this approach, we suggest, was to explore the concepts, methods, and
techniques imported to systems and synthetic biology from other
disciplines, notably from engineering and physics. This is precisely
the reexive dimension of the material practice of synthetic
biology.
On the level of modeling methods, the basic-science approach
has been heavily physics-inuenced, although many of the central
concepts come from engineering. This raises the question of what
triggered this use of engineering concepts. Interestingly, physicists themselves have advocated the use of engineering concepts
in biology. For example, in the mid-1990s there was some discussion about the appropriateness of transferring concepts from
physics to biology exemplied by programmatic articles such as
From molecular to modular cell biology by Hartwell, Hopeld,
Leibler, and Murray (1999).3 All four authors, two of whom are
physicists (John Hopeld and Stanislas Leibler) and the other two
biologists (Leland Hartwell and Andrew Murray), have made
important contributions in their respective elds of research. In this
article the four authors argue for turning away from the prevailing
reductionist approaches in molecular biology that reduce biological phenomena to the behavior of molecules (Hartwell et al., 1999,
p. C47). According to the authors these approaches fail to take into
consideration that biology-specic functions cannot be attributed
to one molecule, but that [. . .] most biological functions arise from
the interaction among many components (Hartwell et al., 1999, p.
C47). To describe biological functions, they go on to claim, we
need a vocabulary that contains concepts such as amplication,
adaptation, robustness, insulation, error correction, and coincidence
detection (Hartwell et al., 1999, p. C47).4 Analogies to engineered

One of the authors spent four years in the Elowitz lab at the California Institute of Technology observing the daily research practice in this lab.
Of course, this issue is as old as the mathematical approach to biology; for an overview, see e.g., Kingsland (1985).
4
It deserves to be noted that Hartwell et al. (1999) paint a too reductionist picture of molecular biology also largely ignoring the early attempts to apply engineering concepts
to biologyoften side-by-side with concepts adapted from physics (e.g., Jacob & Monod, 1961).
3

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artifacts were considered appropriate as such items are typically

constructed to fulll a certain functionlike the parts of biological
organisms.
Interestingly, this amalgamation of engineering concepts and
methods of dynamic systems analysis is understood as the engineering approach by many practicing systems biologists. Thus for
instance Wolkenhauer, in discussing what systems biology can
learn from engineering, more or less equates the engineering approach to the systems-theoretic approach that studies what
role components have in the functioning of the cell (Wolkenhauer,
2006, p. 19; italics added). The focus of this engineering approach
is not just on the components but also, importantly, on their nonlinear interactions and the temporal dynamics of these interactions. This is quite a different understanding of the engineering
approach than that offered by the construction-metaphor and the
pursuit of BioBricks.5 However, as a result of combining this systems-theoretic line of research with the design, manipulation, and
exploration of synthetic biological systems, synthetic biologists have
also begun to consider the limits of some central engineering concepts covering also the basic assumptions of the associated mathematical models. In the following sections we discuss how the
practice of combinational modeling has led scientists to discover
important differences between the control mechanisms of biological
and engineered things.
2.2. Providing control in engineered and biological systems
Control is of central importance in engineered as well as in biological systems.
However, already early on it was discovered that there are fundamental differences between controlling the living behavior of
biological systems and that of engineered articial systems. Engineered systems typically rely on autonomous control mechanisms.
A thermostat is a good example. In this case the room temperature
(input) is measured, compared to a reference temperature (output), and in the next step the heater is changed in such a way that
the room temperature is adjusted to the reference temperature.
The biological solution is more elegant and makes use of an organisms internal oscillating cycles that interact and harmonize their
behavior by coupled oscillations.6 Biological systems need this cyclic organization, since they are autonomous entities able to maintain,
repair, and build themselves using the matter and energy of their
environments.7 Thus biological systems differ crucially from articial, engineered systems when it comes to the role of oscillations
in their functioninga point addressed by Brian Goodwin already
in 1960s.
Goodwin was an early mathematical modeler of feedback
mechanisms in biological systems such as metabolic and gene regulatory control cycles, showing that such mechanisms allowed for
periodic oscillations. Goodwin contrasted the behavior of biological oscillators with engineered control systems writing: The
appearance of such oscillations is very common in feedback control
systems. Engineers call them parasitic oscillations because they
use up a lot of energy. They are usually regarded as undesirable
and the control system is nearly always designed, if possible, to
eliminate them (Goodwin, 1963, p. 5). Thus decades before the
emergence of synthetic biology it was already clear that biological
organisms organize their living behavior differently than the way
the engineered artifacts are designed.

Goodwins model and its extensions have been used as basic

templates for various models of oscillatory behavior, including
the circadian clock, which is one of the most studied gene regulatory systems. Instead of one clock it actually consists of a large
orchestra of clocks that, on the basis of oscillations on the molecular level, synchronize the functions of the organs in a biological
organism (see e.g., Bechtel & Abrahamsen, 2010, 2011). Although
in comparison to circadian clocks, humanly engineered control systems such as thermostats appear rather simple, but they are still
thought to have something important in common: both make
use of feedback mechanisms. One of the most basic assumptions
in the modeling of control in biological systems is that they make
use of feedback mechanisms. Such feedback mechanisms and their
dynamic properties are typically modeled by using nonlinear differential equations, which give rise to oscillations.8 This reliance
of systems and synthetic biology on the engineering notion of the
feedback system, on the one hand, and the realization that oscillations play a different role in biological systems than in engineered
artifacts, on the other hand, points to the kind of productive double
bind synthetic biology has over engineering.
This double bind is seen in the continuous dialectic between the
positive and negative analogies drawn between engineered artifacts and biological organisms, as the case of feedback systems
and oscillations already shows. Such dialectic prompts scientists
to retrieve resources from different elds of studyand to devise
new strategies to explore the appropriateness of these analogies.
Synthetic modeling can be seen as one such novel strategy.
Namely, up until recently researchers have been uncertain
whether the kinds of feedback systems depicted by the various
mathematical models proposed are really realizable in biological
systems. There remained the possibility that the well-established
ways of mathematically depicting feedback systems and their
dynamics developed by physicists and systems theorists (see e.g.,
Strogatz, 1994) may not be suitable for accounting for how naturally evolved organisms organize themselves. But with the advent
of synthetic biology and synthetic modeling, it became possible to
demonstrate that biological systems may make use of the kinds of
feedback systems earlier studied by mathematical modeling.
Moreover it became possible to demonstrate that these feedback
loops can indeed produce the kind of oscillatory behavior exhibited
by gene regulatory systems. Yet this synthetic strategy simultaneously yielded new unexpected ndings and surprising insights
and, although partially successful, it also made researchers acutely
aware of the differences between biological and engineered
systems. Such recent topics as noise and integration can be directly
related, we suggest, to the combinational, mathematical-cummaterial, strategy of synthetic biology.
3. The Repressilator and the combinational strategy
Some of the rst synthetic models were constructed to study
how gene regulatory systems could bring about circadian oscillations, i.e. the day and night rhythms of the organisms. In their review article, The Pedestrian Watchmaker: Genetic Clocks from
Engineered Oscillators, Cookson et al. describe the typical construction process of a synthetic model in the following way: First,
genetic wiring diagrams are translated into equations that can be
analyzed. [. . .] Next, tools from applied math and computer science
are used to analyze the model in order to extract the design criteria

See Knuuttila & Loettgers (in press) for use of various analogies and metaphors in synthetic biology.
Christiaan Huygens (16291695) rst observed the phenomenon of coupled oscillators. The pendulum clocks he mounted on the same non-rigid wall synchronized their
oscillations.
7
To what extent biological organisms gain control over their functioning by self-organization arising from interacting oscillations is an open question. Living systems do also
rely on such decoupled controllers as genes (see Bechtel & Abrahamsen, 2011; Bechtel, 2011, for excellent discussions on the role of different oscillations in biological systems).
8
Also thermostats produce temperature oscillations but they are designed so as to keep the temperatures close to the target.
6

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161

Fig. 2. Combinational modeling according to Sprinzak and Elowitz (2005). The upper part of the diagram depicts the combinational modeling strategy. The lower part
compares a natural gene regulatory network and a synthetic one.

for a desired output. Then, modern recombinant DNA techniques

are used to construct gene-regulatory networks in living cells
according to the design specications. [. . .] Lastly, micro- and
nano-technologies are developed to acquire the precise single-cell
measurements that are needed for comparison with model predictions and design renement (Cookson, Tsimring, & Hasty, 2009, p.
3931). What seems already clear in the light of this brief characterization is that apart from being constructed on the basis of mathematical models, synthetic models are supposed to be used in
combination with them. Sprinzak and Elowitz (2005) call the synthetic paradigm a combinational use of experimentation on model
organisms, mathematical modeling, and synthetic modeling.
This combinational modeling is one of the dening strategies of
the basic-science approach of synthetic biology. The basic idea of
the combinational modeling strategy is shown in Fig. 2, which is
taken from a review article on synthetic biology by Sprinzak and
Elowitz (2005). As the upper part (a) of the diagram suggests, in
combinational modeling the results gained from the three different
epistemic activities inform each other.
Why do researchers make use of such a combinational modeling strategy in studying the organizational principles in biology?
A clue can be found from the lower part (b) of the diagram. The
left-hand side of the diagram depicts our present understanding
of the natural gene regulatory circuit of the circadian clock of
Drosophila (fruit y) consisting of interacting genes and proteins.
The right-hand side in turn depicts a synthetic model of the circadian clock, the Repressilator, which is an oscillatory genetic circuit
introduced in 2000 by Elowitz and Leibler (2000).9 The diagram
indicates the two main differences between the natural and the synthetic system:

1. The natural system exhibits a much higher degree of complexity than the synthetic system.
2. The synthetic circuit has been designed by using different genes
and proteins.
Consequently, synthetic models have the advantage of being
less complex than model organisms. On the other hand, in contrast
to mathematical models they are of the same materiality as biological systems (although the Repressilator was constructed from different genetic material than the naturally occurring circadian
clocks, a point to which we will return below). This fact of being
of the same materiality as natural systems is crucial for the epistemic value of synthetic modeling, since synthetic models are expected to work in the same way as biological systems. Due to
their right kind of materiality combined with their tightly constrained nature, synthetic models have led researchers to discover
such features of the functioning of biological systems that were not
anticipated by mathematical modeling or experimentation with
model organisms.10
3.1. From circuit diagrams to mathematical models
The rst step in constructing the Repressilator consisted in
designing a mathematical model used to explore the known basic
biochemical parameters and their interactions through computer
simulations. Synthetic biologists often refer to their mathematical
model as the blueprint for the design and construction of the
synthetic model. What exactly do they mean by that? Is it possible
to say more about the construction of the mathematical model and
how it relates to the synthetic model? Clearly, what is at stake can-

9
The Repressilator and the genetic toggle switch (Gardner et al., 2000) were the two rst synthetic models. They were published in the same issue of Nature independently of
each other.
10
See Nersessian & Chandrasekharan, (2009) for another discussion on analogical reasoning and combinational modeling involving a physical model, its computational model,
and an intermediary, hybrid computational model. Green (this volume) also contains an excellent discussion of the use of multiple models focusing on the work of Uri Alon and
his group.

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Fig. 3. Two network motifs: b depicts a negative feedback loop and c a positive
feedback loop (Alon, 2007, p. 451).

not simply be called translation due to the manifold of construction decisions and assumptions involved. To get a more informative account of the transition from a mathematical model to a
synthetic model one needs to answer several questions. How was
the mathematical model arrived at? How is the mathematical
model used to inform the construction of the synthetic model?
And what is the contribution of the other tools, including also technological artifacts and methods, for the specic construction of a
synthetic model? Here we try shedding some more light on these
questions by rst taking a closer look at the design of the mathematical model underlying the Repressilator.
In designing the mathematical model Elowitz and Leibler made
use of the body of theoretical work on regulation mechanisms and
their dynamics in theoretical biology. The systems biologist Uri
Alon calls such simple regulation mechanisms network motifs.
They can be depicted by simple diagrams as shown in Fig. 3. The
diagram on the left-hand side shows a negative feedback loop
and on the right-hand side a positive feedback loop.
The challenge consists in giving those diagrams an appropriate
mathematical form. This challenge is twofold: Firstly, such seemingly simple mechanisms are represented mathematically by
nonlinear, coupled differential equations leading to complex
dynamics. Secondly, the attempt to give them more biological content is far from any straightforward procedure. On the one hand,
although there is a large amount of known biochemical details,
most of that knowledge cannot be included in the model for tractability reasons. On the other hand, many crucial mechanisms and
details still remain unknown and the data is often of a wrong kind.
For the kind of dynamic modeling approach of systems and synthetic biology one would need e.g. quantitative time-course data,
which is hard to come by (see e.g., Wolkenhauer, 2007).
What the researchers in the basic-science branch of synthetic
biology are after here are the general design principles of gene regulatory networks. The network motifs of Uri Alon are made up of
such design principles. Alon characterizes network motifs as
recurring circuits of interactions from which the network is built
(Alon, 2007, p. 542). As Alon describes, such network motifs were
rst systematically dened in Escherichia coli, in which they were
detected as patterns that occurred in the transcription network
much more often than would be expected in random networks
(ibid.). A prominent network motif that occurs in about half of
the repressors in E. coli is negative autoregulation, or as it is also
called, a negative feedback loop.
A central point in designing a mathematical model of gene regulation for example consists in translating simple diagrams, as
shown in Fig. 3, to a mathematical model. Regulation via negative
or positive feedback are of such a general character that various
mathematical models can be designed to describe these mechanisms and study their dynamics. A good example of this line of
work is provided by the theoretical biologists Ren Thomas and
Richard dAri, who have been studying general types of regulation
mechanisms describing their architecture, interaction, and dynamics. Their book Biological Feedback (1990)11 develops a formal
methodology for analyzing dynamic systems (see also Thomas,
1998). Although directed primarily to biologists the models
presented can be used in other areas of inquiry. As such these
11

mathematical models of possible regulation mechanisms provide

an important resource for modelers, offering a good example of what
has been called computational templates by Humphreys (2004; see
also Knuuttila & Loettgers, 2012). Computational templates are genuinely cross-disciplinary computational devices such as sets of equations, functions, and computational methods, which can be applied
to different problems in various disciplines. These formal templates
are used by adjusting them to the specic process under investigation; in the case of gene regulation they are adjusted and enriched
by providing more biochemical details. In the following we are going
to examine this process in more detail.
In a simple regulation diagram, of which Fig. 3 provides the
most schematic example, the details of the mechanism are still
invisible. In constructing a mathematical model a rst step consists
of describing some basic parts and relations of the mechanism. In
its simplest form such description could be as follows: Firstly a
gene becomes transcribed resulting in the production of mRNA,
from which a protein is produced. In the next step the protein
binds to its own transcription site and by doing so represses the
transcription of its own gene. This leads to a decrease of mRNA
and protein concentration. When the concentration becomes very
low there are not enough proteins to bind at the transcription site
to repress their own production. The production of mRNA and proteins will start again because an increasing number of transcription
sites will not be occupied by the protein and the transcription of
the gene can take place again. This mechanism will lead to oscillations in the concentration of the mRNA and protein.
How is this process rendered into a mathematical model? A
very common way of describing regulatory interactions makes
use of differential equations. In such a model the concentrations
of mRNA and proteins at a given time t are described by a continous variable xi(t). The regulatory interactions are represented by
kinetic equations introduced from chemical kinetics.

dxi
fi x;
dt

1  i  n;

where fi(x) is the rate law.

The rate of change of variable xi is a function fi of the other concentration variables x = [x1,. . .xn]. The function fi can be of different
forms, depending on how the rate of change is related to the
concentration.
In the case of negative feedback the concentration of mRNA and
proteins is described by x1 and x2. The associated regulatory interactions are given by the following set of coupled differential
equations:

dx1
j1 f x2  c1 x1
dt
dx2
j2 x1  c2 x2 ;
dt
with:

j1 ; j2 = production rate constants

c1 ; c2 = degradation rate constants
The rate law is given by the so-called Hill function:

f x2

Hn
n

H xn2

; H > 0:

with:

H = genes repression coefcient

x2 = protein concentration
n = Hill coefcient.

Thomas and DAris book inspired the construction of the Repressilator; see the end of Section 3.1.

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163

Fig. 5. The main components of the Repressilator (left-hand side) and the Reporter
(right-hand side) (Elowitz & Leibler, 2000, p. 336).

Fig. 4. Parameter space of the coupled differential equations of the Repressilator

(Elowitz & Leibler, 2000, p. 336).

The Hill function is used in biochemistry for describing the

binding of a ligand12 to a macromolecule. In the case of gene regulation the production rate of the protein is related to the protein concentration in such a way that the maximal production rate is reached
when the promoter site is unbound. Half-maximal repression is
reached when the repressor activity is equal to H.
Coming back to the case of the Repressilator the negative feedback between the three genes is described by a set of six coupled
differential equations.

dmi
a
mi
a0
dt
1 pnj
dpi
bpi  mi
dt


i lacl; tetR; cl
with
j cl; lacl; tetR
In this set of differential equations pi is the concentration of the
proteins suppressing the function of the neighbor genes and mi
(where i is lacI, tetR, or cl) the corresponding concentration of
mRNA. The parameter a0 describes what is called leakiness. Even
in the presence of a saturating amount of proteins suppressing
their own production, a slight increase in mRNA can be observed.
a + a0 describes the maximal production rate in the absence of
any repressors and n is the Hill coefcient. The form of the coupled
set of six differential equations looks different from the general
form introduced before. But it has been already adjusted to the
case of three genes repressing each other via negative feedback.
A further important step in adjusting the general form to the
context of biology consisted in nding values for parameters such
as the Hill coefcient n as well as a and a0. This has been done by
performing computer simulations and exploring the kinds of effects a change of those parameters has on the solution of the differential equations. Elowitz and Leibler did show that there are two
possible types of solutions: The system may converge toward a
stable steady state, or the steady state may become unstable, leading to sustained limit-cycle oscillations (Elowitz & Leibler, 2000, p.
336). The solutions are depicted in Fig. 4. Furthermore, the numerical analysis of the model gave insights into the experimental
parameters showing that [...] oscillations are favoured by strong
promoters coupled to efcient ribosome binding sites, tight
12
13

transcriptional repression (low leakiness), cooperative repression

characteristics, and comparable protein and mRNA decay rates
(ibid., p. 336).
In sum, in designing and analyzing their mathematical model
Elowitz and Leibler had at their disposal the research on mathematical modeling of regulatory systems. Apart from Thomas and
dAris Biological Feedback (1990), they refer to Winfree (1990)
and Goldbeter (1996). The dynamics of such regulatory systems
can be quite complex and difcult to analyze because of the nonlinear character of the differential equationscaused by the fact
that the rate of the controlled process is a nonlinear function of
the concentration of the regulator.
3.2. The Repressilator and the functional meaning of noise
The structure of the Repressilator is depicted in the Fig. 5.
In the diagram the synthetic genetic regulatory network, the
Repressilator, is shown on the left-hand side and it consists of
two parts. The outer part is an illustration of the plasmid constructed by Elowitz and Leibler. The plasmid is an extra-chromosomal DNA molecule integrating the three genes of the
Repressilator. Plasmids occur naturally in bacteria. In the state of
competence, bacteria are able to take up extra chromosomal DNA
from the environment. In the case of the Repressilator this property
allowed the integration of the specic designed plasmid into E. coli
bacteria. The inner part of the illustration represents the dynamics
between the three genes, TetR, LacI and kcl. The three genes are
connected by a negative feedback loop. The left-hand side of the
diagram shows the Reporter consisting of a gene producing green
uorescent protein (GFP), which is fused to one of the three genes
of the Repressilator. The GFP oscillations in the protein level made
visible the behavior of transformed cells allowing researchers to
study them over time by using uorescence microscopy.
The construction of the Repressilator was enabled by the development of new methods and technologies, such as the construction
of plasmids and Polymerase Chain Reactions (PCR). It is important
to note that the components of the Repressilator (and their number)
had to be chosen in view of what would be optimal for the behavior under study.13 This means that such networks need not be part
of any naturally occurring system. For example the genes used in the
Repressilator do not occur in such a combination in any biological
system, but were chosen and tuned on the basis of the simulations
of the underlying mathematical model and other background knowledge in such a way that the resulting mechanism would allow for
(stable) oscillations.

A ligand is a signal-triggering molecule.

In the case of the Repressilator the order in which the genes are connected to each other turned out to be crucial as well.

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What, then, was the point of constructing the Repressilator if it

clearly was an engineered synthetic network with no counterpart
in naturally evolved genetic networks? The answer we have already hinted at was that it was an epistemic tool designed for
answering certain kinds of theoretical questions (Knuuttila, 2011,
see below). One question addressed by the Repressilator was due
to the fact that the model templates, methods, and concepts used
in systems and synthetic biology were not originally devised with
biological organisms in mind. Another question concerned the abstract and highly idealized nature of these models and their underdetermination by the available data (see Knuuttila & Loettgers,
2011). As such, mathematical models, even combined with experimental evidence, were unable to settle the question of whether
the various network designs proposed, for example in the context
of circadian clock research, could actually work in biological organismseven though they were able to create the sought-after oscillations. Moreover by implementing the synthetic genetic network
into a cell it is exposed to some further constraints of natural biological systems, thus providing insight into the modularity of the
circadian mechanisms (see below).
In fact the Repressilator sparked a new line of research as a direct result of its limited success. In contrast to the mathematical
model underlying it the Repressilator did not show the expected
behavior: regular oscillations. Instead the oscillations turned out
to be noisy. As a result Elowitz and Leibler constructed a stochastic
version of the original deterministic model. Computer simulations
of this model suggested that stochastic uctuations in gene expression could be the cause of this noisy behavior. Spudich and Koshland (1976) had already suggested that stochastic uctuations
could be due to the low number of molecules in cells. However,
at that time no means existed for the direct observation of such
uctuations on a molecular level. This only became possible with
the introduction of Green Fluorescent Proteins and synthetic modeling, which contributed importantly to the emergence of a new
research program examining the sources and role of noise in biological systems (e.g., Elowitz, Levine, Siggia, & Swain, 2002; Swain,
Elowitz, & Siggia, 2002; see also Loettgers, 2009). As a result of this
new line of research noise has also gained a functional meaning:
Biological systems appear to make good use of noise in diverse processes, including development (Neildez-Nguyen et al., 2008), differentiation (e.g., genetic competence; see Cagatay et al., 2009),
and evolution (Eldar & Elowitz, 2010). This contrasts with engineering where noise is usually considered as a disturbance. In thus
allowing noise also a functional meaning, this new research program actually draws a further negative analogy to engineered control systems (apart from the different role of oscillations in
engineered artifacts and natural systems, pointed out already by
Goodwin, see above). And the studies on noise point towards still
another difference. Namely, apart from internal noise, there remained the possibility that the noisy behavior could also have been
caused by external noise coming from the cell environment. The
Repressilator was probably not so modular as it was supposed to
be, that is, it did not form as isolated a module in its host system
as was expected. Indeed, apart from noise, modularity is another
engineering concept whose limits have been questioned by recent
research in synthetic biology. This line of research has made synthetic biologists more concerned with the integration of synthetic
parts with the rest of the cell.

relationship to the assumption of modularity: on the one hand

synthetic biology relies on the assumption of modular organization
in view of its aim to design autonomous modules of interacting
components that would give rise to a specic function/behavior.
On the other hand each synthetic biological system also functions
as a test to which extent the assumption of the modular organization is justied. In interpreting such experiments one should keep
in mind, though, a distinction between the modular organization in
biological systems, which are outcomes of a long evolutionary process, and the modular organization of synthetic systems, which
have been designed in the lab. The modular design of synthetic
systems does not necessarily presuppose that natural biological
systems are organized in a modular way. But it has been generally
supposed that for the synthetic modular strategy to succeed,
biological systems have to allow for the integration of synthetic
systems in a modular fashion. As in the case of noise, if nonmodular organization should turn out to be an advantage in realizing specic functions in synthetic systems, it would be a good
strategy to make use of it. Looking at recent developments in
synthetic biology there are indeed attempts to make use of more
integrated structures. However, as in the case of noise, one has to
pay the price of losing partial control over the synthetic system.
4.2. Dual-feedback oscillator
Another good example of how synthetic modeling can lead to
unexpected ndings is provided by the work Jeff Hasty and his
co-workers. They designed a dual-feedback oscillator which, by
connecting more tightly with the host cell, shows surprisingly robust behavior. As to the number of genes, the design of the dualfeedback oscillator is even simpler than that of the Repressilator.
It consists of only two genes: an activator and a repressor. The
expression of either gene can be enhanced by the activator protein
and blocked by the repressor protein. Both proteins function as
transcription factors for both genes. As such in this synthetic oscillator two motifs, a positive and a negative feedback, are combined: a promoter drives the production of both its own activator
and repressor (see Stricker at al., 2008). In a later review article
the group expanded the earlier discussion of the synthetic oscillator (Cookson et al., 2009). In this latter article they introduce the
synthetic oscillator by explaining how it was based on both experimental work on the Drosophila melanogaster (fruit y) clock and
earlier theoretical work, i.e. a mathematical model set forth by
Hasty, Dolnik, Rottschfer, and Collins (2002) which, as they put
it, is theoretically capable of exhibiting periodic behavior (Cookson et al., 2009, p. 3932). Fig. 6 shows the network diagram of the
dual-feedback oscillator.
The synthetic network consists of two genes: araC and lacI. A
hybrid promoter plac/ara1 (the two small adjacent boxes) drives
transcription of araC and lacI, forming positive and negative feedback loops. It is activated by the AraC protein in the presence of
arabinose and repressed by the LacI protein in the absence of

4. From modularity to integration

4.1. Investigating the modularity assumption
Modular organization is among the most basic and important
assumptions of synthetic biology but also one of the most contested. Since its beginning synthetic biology has had a complex

Fig. 6. A diagrammatic representation of the dual-feedback oscillator (Stricker

et al., 2008, p. 516).

T. Knuuttila, A. Loettgers / Studies in History and Philosophy of Biological and Biomedical Sciences 44 (2013) 158169

isopropyl b-D-1thiogalactopyranoside (IPTG). As in the case of the

Repressilator the oscillations are made visible by a green uorescent protein (GFP). This synthetic system provides a material system allowing for the study of the oscillatory dynamic of the
dual-feedback system: the basic properties and conditions of the
oscillatory dynamic can be estimated on the basis of the components of the model and their interactions. By adding arabinose
and IPTG to the system the promoter becomes activated and the
systems two genes, araC and lacI, become transcribed. An increased production of the protein AraC in the presence of arabinose
results in a positive feedback loop that increases the promoter
activity. On the other hand, the increase in LacI production results
in a linked negative feedback loop that decreases promoter activity. The difference in the promoter activities of the two feedback
loops leads to the oscillatory behavior.
On the basis of the analysis of the synthetic system the
researchers made several observations that were both unexpected
and difcult to reconcile with the original mathematical model
that nevertheless formed the basis of the synthetic model. The
problem was, quite surprisingly, that the oscillator performed almost too well as Nandagopal and Elowitz put it (2011, p. 1244).
Two of the observations proved particularly important in this respect. First, the time delays inherent in the process of gene expression that were initially ignored were shown to be critical for the
robust oscillations (Stricker et al., 2008). They were rst overlooked because they are shorter than the overall period of the oscillator. Second, perhaps the most drastic of the surprising ndings is
the relationship of the parameter set and the robustness of the
oscillations. While the mathematical model predicted robust oscillations only for a small set of parameters, the synthetic model contradicted the mathematical model by showing robust oscillations
for a much larger set of parameter values. The researchers were
perplexed by the fact that [i]t was difcult to nd inducer levels
at which the system did not oscillate! (Cookson et al., 2009, p.
3934; italics in the original).
These contradictory results led the researchers in question to
reconsider the original model. Cookson et al. wrote about this as
follows: In other words, it became increasingly clear that the observed oscillations did not necessarily validate the model, even
though the model predicted oscillations. We were able to resolve
the discrepancy between the model and theory by reevaluating
the assumptions that led to the derivation of the model equations
(Cookson et al., 2009, p. 3934). The key nding in the reevaluation
of the mathematical model was that a component in the complex
biochemical process that had been underestimated and left out
from the mathematical model turned out to be of central importance for the robustness of the observed oscillations in the synthetic model. Without going into greater detail, the processes
involved in the production of the transcription factors led to a posttranslational coupling between the activator (AraC) and the repressor (LacI), which is a consequence of an unintended interaction with
the host cell.
These unintended interactions with the host cell show that synthetic systems need not comprise perfect modules; instead interactions with the cell environment may occur and can even be
advantageous, as the case of the dual-feedback oscillator shows.
In fact there is a new trend in synthetic biology targeting the question of how synthetic systems could be designed in such a way that
they are more closely integrated with the endogenous cellular processes of the host organisms (e.g., Nandagopal & Elowitz, 2011, see
below). Hence somewhat paradoxically, although the program of
synthetic biology was originally based on the idea of constructing
isolated synthetic circuits from well-characterized components, it

14

This article appeared in the September 2011 issue of Science, see above.

165

seems actually to accumulate evidence on how loosening the

assumption of modularity can lead to new and unexpected possibilities. Following this route means the development of new strategies for designing and probing synthetic systems. A rst step in
this direction is taken by Nandagopal and Elowitz (2011) who, in
a recent article, discuss the various strategies for integration.14
4.2.1. Strategies for integration
The recent research on noise and integration in the eld of synthetic biology points toward new challenges and the need for novel
strategies. In regard to the question of noise, the use of noise in the
design and engineering of synthetic systems could become critical.
Likewise, when it comes to the (non)modular organization, the
question becomes one of how to integrate the components of synthetic systems with those of the host cell to support the performance of the synthetic system. Nandagopal and Elowitz (2011)
put forward one possible strategy. The two authors explicate what
they mean by integration on the systems level by asking: Does a
synthetic circuit need to operate independently of its host to function reliably? (Nandagopal & Elowitz, 2011, p. 1244) and go on to
discuss the work of Jeff Hasty and his co-workers on a simple dualfeedback oscillator (Section 3.2, see above). What is especially
interesting about Nandagopal and Elowitzs discussion is that they
make explicit the importance of the cellular milieu for the functioning of the synthetic gene circuits. Neither Stricker et al. (2008)
nor Cookson et al. (2009) spell that out, although it is implicit in
their ndings. Stricker et al. (2008) show that time delays inherent
to the process of gene expression were critical for the robust functioning of the oscillator. In addition Cookson et al. (2009) discussed
unintended interactions with the host cell components that improved the precision of the oscillator. Yet neither Stricker et al.
(2008) nor Cookson et al. (2009) discuss the consequences of their
ndings regarding the basic assumption of synthetic biology that
synthetic systems can be integrated into a host cell without interfering with/or disrupting each others functions.
To be sure, the question of modularity is a tricky one. Synthetic
biology creates circuits that would not survive in the natural
world. Such a synthetic system makes use of specic processes
provided by the host cell, which are needed to keep the synthetic
system alive. Thus the synthetic system depends in a vital fashion
on the host cell but despite this dependency the two systems can
be claimed to remain independent on the level of network dynamics, and on the level of the functions arising from the dynamic
interaction between the components of the network. Such interrelationship between a host cell and a synthetic system has been
considered a necessary requirement for retaining control over the
synthetic system and its function once it has become part of a host
cell. This central assumption of synthetic biology is based on the
more general assumption of modular organization of biological
systems. Nandagopal and Elowitz give the following description
of the relationship between synthetic systems and host cells:
The view was that underlying cellular processes could be used
to support the synthetic circuits, for example, by providing the
gene expression machinery, but that the two layers could function
independently (Nandagopal & Elowitz, 2011, p. 1244).
What do Nandagopal and Elowitz mean by this? In order to
exemplify the situation one can draw an analogy to computer programs. Many computer programs make extensive use of standard
routines for calculating specic mathematical functions. These
routines are called upon when needed in the course of the program. They are programmed and connected to the computer program in such a way that the interaction is restricted to calculate
the function from a given input and to deliver the result. But the

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T. Knuuttila, A. Loettgers / Studies in History and Philosophy of Biological and Biomedical Sciences 44 (2013) 158169

Fig. 7. The continuum of synthetic biology (Nandagopal & Elowitz, 2011, p. 1244).

program will not change the routine it calls upon, nor the other
way around.
The crucial question is what happens with the assumption of
the respective independent functioning of the synthetic system
and the host cell in the light of the ndings of Hasty and his coworkers? Do these ndings give reason enough to announce the
breaking down of the modular relationship between a synthetic
and a biological systemor, to go one step further, to question
the assumption of a modular organization of biological systems
in general? When discussing the possible consequences of these
ndings, Michael Elowitz stated:
I think its hard to say in general what the implications of these
kinds of interactions are. One way to look at them is as problems that need to be eliminated through good design. Another
way is as opportunities to implement non-canonical designs.
A nal possibility is that these are coupling mechanisms that
are actually used physiologically at least in some cases. Its
interesting in this light that in competence there is a somewhat
analogous mechanism whereby the protease adapter MecA
mediates an effective interaction between two of its substrates,
ComS and ComK.15
It is interesting that synthetic biologists, like Nandagopal and Elowitz, do not rush to question the modularity assumption as such
but instead invoke the idea of integration and the possible ways
of dealing with host cell interactions.16 If there is a coupling between a synthetic system and a host cell, then there are two possible
ways of handling them. Either one has to come up with novel designs that avoid such couplings or, if they turn out to be advantageous, one needs to look for ways to integrate them into the
design of synthetic systems. Nandagopal and Elowitz are clearly opting for a second route. They call for synthetic systems that integrate
more closely with endogenous cellular processes (Nandagopal &
Elowitz, 2011, p. 1244). With this step, they suggest, the eld would
move away from its original aim of designing autonomous genetic
circuits that could function as independently as possible from
endogenous cellular circuits or even functionally replace endogenous circuits (ibid., p. 1244).
Nandagopal and Elowitz use a tri-partite picture (Fig. 7) to depict what they think will be one of the big changes in the practice
15

of synthetic biology: Future progress will require work across a

range of synthetic levels, from rewiring to building autonomous
and integrated circuits de novo (ibid., p. 1244).
In the diagram depicted in Fig. 7 Elowitz and Nandagopal introduce what they call the continuum of synthetic biology. In this
continuum one moves from the wild type towards fully autonomous synthetic systems increasing the degree of the synthetic part
of the system. How is this increase in the synthetic part achieved?
There are several options. One can follow the traditional approach of designing an assumedly modular genetic circuit and
introducing it into the wild type. As the example of Stricker et al.
(2008) and Cookson et al. (2009) nevertheless showed, unintended
interactions can occur (gray arrows) that could be difcult to control. An alternative approach, propagated by Nandagopal and Elowitz, consists in rst rewiring the genetic circuit in the wild type
and then, in a second step, implementing a synthetic circuit into
the rewired circuit. This rewiring of the existing genetic circuits offers, rstly, a way to explore the design principles on which the genetic circuit is based and, secondly, a possibility of using these
insights to avoid unintended interactions with the host cell. Interestingly, as has been shown in a number of studies in which the
strategy of rewiring has been used, the actual biological design
principles are often counter-intuitive (see for example agatay,
Turcotte, Elowitz, Garcia-Ojalvo, & Sel, 2009). Nature appears to
have used solutions that differ from those of engineers.
As a consequence of the rewiring strategy the resulting engineered circuit is only partially independent. However, for the engineering purposes, as high a modularity as possible is usually
sought because of its controllability. In order, then, to get an independent circuit that would be based on the insights gained from
the exploration of the rewired circuit, one would integrate the
function of the rewired circuit design into an autonomous genetic
circuit. This strategy allows for suppressing unwanted interactions
with the host cell but also implementing interactions, which support the function in question. In more general terms the proposed
strategy tries to balance the need for control and the possibility of
taking advantage of the interactions with the host cell. In such a
way the engineering of synthetic systems becomes increasingly inspired by biological systemsa point that has recently been
stressed by several synthetic biology research programs.17

Personal communication by email.

In an interview, Elowitz also discussed the fact that the cells in which the rst generation synthetic models were implanted tended to grow more slowly, which may also
point towards some interactions taking place.
17
See e.g., http://wyss.harvard.edu/viewpage/264/a-new-model (Accessed 5 January 2012).
16

T. Knuuttila, A. Loettgers / Studies in History and Philosophy of Biological and Biomedical Sciences 44 (2013) 158169

In sum, there are different ways in which one can deal with host
cell interactions. The ndings of Stricker et al. (2008) and Cookson
et al. (2009) can also prompt researchers to perceive natural systems in novel ways and actively search for similar couplings and
mechanisms in biological systems as suggested by the behavior
of the synthetic models. This could lead to some unexpected ndings regarding the organization of biological systems. Thus the discussion on host cell interactions shares some important
similarities with the case of noise. It seems that in synthetic biology the engineering concepts are changing their meanings and
becoming more and more adjusted to biological systemspartly
as a result of the practice of synthetic modeling.

5. Conclusions: Basic science through engineering

Integration is a word that characterizes many things taking
place in systems and synthetic biology, from the level of the construction of synthetic systems to the level of research methodology
and interdisciplinary relationships. The synthetic biologists, whose
work we have studied here, focus on biological integration, that is,
how to integrate synthetic systems more closely with their host
organisms. We have in turn examined combinational modeling,
which is one form of methodological integration characteristic of
synthetic biologyand also utilized by synthetic biologists to study
biological integration (see OMalley & Soyer, 2012).18 Combinational modeling refers to a process whereby synthetic biologists
use experimentation with model organisms, mathematical modeling, and synthetic modeling to inform each other. Through combinational modeling synthetic biologists have often gained unexpected or
otherwise surprising insights into the organization of biological
organisms. While there is a long story to be told on how mathematical modeling and experimentation on model organisms have contributed to each other in circadian-clock research (see e.g., Bechtel,
2010; Bechtel & Abrahamsen, 2010), we have focused here on the
relationship between mathematical modeling (and simulation) and
synthetic modeling.
What is the kind of integration that happens in combinational
modeling? Two notions presented in the previous philosophical
literature seem especially relevant: triangulation and iteration.
Triangulation is the use of different epistemic means to study
the same phenomenon. It is often conceptualized as the combinational use of independent means to triangulate the existence
and character of a common phenomenon, object or result
(Wimsatt, 2007, p. 43; see also Wimsatt, 1981). There has been
some discussion on how independent these triangulated epistemic methods can be (e.g., Orzack & Sober, 1993); because, often,
as in the cases presented here, this is not the case. Quite the
contrary, in combinational modeling, mathematical models and
synthetic models are closely linkedwhile, on the other hand,
the materiality of synthetic models simultaneously brings in an
independent component. It seems that it is precisely this dialectic of relatedness and independence that gives combinational
modeling its epistemic leverage leading to iterative cycles of
modeling.
Epistemic iteration refers to a process of corrective evolution whereby the step-wise cyclic application of different methods and new layers of knowledge gradually enhance the
achievement of the epistemic goals sought for (Chang, 2004).
Such iterative process is indeed discernible in the cases we have
discussed. Both in the case of the Repressilator and the dualfeedback oscillator the behavior of the synthetic model led to

167

the improvement or modication of the mathematical model

that informed the construction of it. Elowitz and Leibler resorted
to a stochastic version of their original deterministic model to
explain the noisy oscillations of the Repressilator. Hasty and his
co-workers in turn complemented and revised their mathematical model in view of the unexpected importance of the time
delays and the interactions with the host organism (Stricker
et al., 2008; Cookson et al., 2009). Consequently, these cases
conrm OMalleys observation that again and again in synthetic biology [. . .] false assumptions about the system are
revealed in the construction of devices (OMalley, 2011,
p. 408). But these assumptions being questioned may also point
beyond the iterative cycle, towards new questions, novel research agendas and, importantly, the re-evaluation of the basis
on which synthetic biology is built.
Namely the material-cum-theoretical nature of synthetic
models, such as the Repressilator and the dual-feedback oscillator, and the possibility of directly manipulating biological components and networks offered by them, hasapart from many
valuable insights into biological organizationalso disclosed the
limitations of any single-minded engineering approach. Novel research topics such as noise and integration can be directly related to synthetic modeling and the way it is combined with
mathematical modeling. Consequently, then, it seems partly misguided to claim that synthetic biology aims at construction,
whereas the objective of systems biology is to understand existing biological systems (Calvert & Fujimura, 2011, p. 160). While
this may be a correct observation as regards even a major part of
synthetic biology, material construction can also be a way to
take the systems and synthetic biology approach a step further,
even theoretically.
The construction of synthetic systems may be epistemically
informative in several ways. Clearly, a lot of knowledge, partly
embedded in the technologies and techniques used is needed to
construct synthetic systems in the rst place. A well-functioning
tool validates the theoretical knowledge it embodies and, even
failures, say, of the various visions of standardization also teach
us something about biological systems (e.g., OMalley, 2011,
p. 409). This seems to be the insight behind the idea of thing
knowledge and the way it is juxtaposed with theoretical knowledge (Baird, 2004; on thing knowledge, see also Gelfert this
volume). But here we have been dealing with a material construction strategy that appears also to go beyond mere thing
knowledge being more directly involved in really exploring the
theoretical assumptions made in modeling the gene regulatory
behavior.
In this respect it is instructive to consider how the synthetic
biologists, whose work we have studied, themselves conceive of
what they are doing. Cookson et al. (2009) consider the construction of synthetic oscillators as basic science through engineering.
They write:
The possibility of a minimal core network driving robust cellular behavior has inspired the development of an alternative
approach to the study of gene-regulatory networks: create the
network, beginning with a one or two-component system and
then rebuild the network from the bottom up. In this way, we
can gradually assemble increasingly complex systems that
mimic the native network, while maintaining at each stage
the ability to model and test the network in a tractable experimental system. (Cookson et al., 2009, p. 3933)

18
It would be interesting to study to which extent biological integration (non-modularity, or soft modularity) requires methodological integration. Our hunch is that as
biological integration increases the complexity of biological organization, its study also requires multiple methods due to the fact that each method has its own characteristic
constraints. We wish to thank the anonymous referee for raising this interesting question.

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T. Knuuttila, A. Loettgers / Studies in History and Philosophy of Biological and Biomedical Sciences 44 (2013) 158169

In an interview Michael Elowitz explained to us his motivation for

engaging in synthetic modeling in the following way:
It seemed like what we really wanted to do is to build these circuits to see what they really are doing inside the cell . . . that
would be in a way the best test of it . . . of what kind of circuits
were sufcient for a particular function.
From the perspective of modeling what seems especially interesting is the stress Elowitz, Hasty and their co-workers place on
minimality, sufciency and tractability. In this synthetic models
are like mathematical models that are tightly constrained systems
that, by their design, enable the study of certain pending scientic questions. What is important for this kind of modeling strategy is precisely its minimality and tractability. One seeks to
implement only those kinds of principles and assumptions that
are supposed to be sufcient and/or necessary to produce the
behavior under investigation. The synthetic model can then be
considered as an epistemic tool constructed to explore some basic
assumptions and network architectures used in the study of gene
regulatory systems (see Knuuttila, 2011).
There is also a sense in which synthetic modeling comes close
to experimenting with theory, as discussed in the context of simulation (e.g., Dowling, 1999; Fox Keller, 2003; Winsberg, 2003). Yet
as opposed to simulation models transformed into a computational
algorithm and run on a digital computer, here the theoretical model rendered as a synthetic model is of the same natural kind as
the native networks as well as being embedded in a simulation
environment of the same materiality, i.e., the host organism
(on the same materiality see e.g., Morgan, 2003, 2005; Guala,
2002). In being constructed from genetic material and embedded
in a natural cell environment, the synthetic model is supposed to
be subject to the same constraints as the natural gene regulatory
networks. It seems that it is precisely this combination of theoretical and material constraints that make synthetic modeling and
combinational strategy so fruitful in studying some theoretical
questions.
To conclude, in this article we have discussed the basic-science
approach to synthetic biology and showed how the purposefully
designed synthetic parts can function as powerful epistemic tools
in studying biological organization. This line of research exhibits
a sophisticated reexive double bind to engineering: engineering
approaches are made use of in constructing synthetic networks,
but at the same time these engineering principles are also explored
in an attempt to nd out whether and to which extent they apply
to biological organisms. The recent concerns on noise and integration are related to this line of research, which seeks the ways in
which biology could increasingly inform and inspire engineering.
It also shows that some traditional engineering aims, like controllability, may need to be compromised or implemented in novel,
and so far largely unforeseen ways, in view of attaining robust biological functioning. The toy-biology of Lego-bricks is thus as far removed from these visions and associated challenges as one can
even imagine.
Acknowledgements
We are grateful to Maureen OMalley for her important comments on this paper. We also thank the participants of the symposium on Philosophical Perspectives on Synthetic Biology,
Helsinki, May 2011, for stimulating discussions on synthetic biology that have proved benecial for this work. We also wish to
thank the Equinox Graphics for permission to use their image
on the cover of the September 2011 issue of Science free of
charge.

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