Sensors: Biological Oscillators in Nanonetworks-Opportunities and Challenges

sensors
Review
Biological Oscillators in
Nanonetworks—Opportunities and Challenges
Ethungshan Shitiri 1 ID
, Athanasios V. Vasilakos 2 and Ho-Shin Cho 1, *
1 School of Electronics, Kyungpook National University, Daegu 41566, Korea; ethungshan@ee.knu.ac.kr
2 Department of Computer Science, Electrical and Space Engineering, Lulea University of Technology,
93187 Lulea, Sweden; athanasios.vasilakos@ltu.se
* Correspondence: hscho@ee.knu.ac.kr; Tel.: +82-53-950-7577

Received: 20 March 2018; Accepted: 9 May 2018; Published: 13 May 2018
Abstract: One of the major issues in molecular communication-based nanonetworks is the provision
and maintenance of a common time knowledge. To stay true to the definition of molecular
communication, biological oscillators are the potential solutions to achieve that goal as they generate
oscillations through periodic fluctuations in the concentrations of molecules. Through the lens of a
communication systems engineer, the scope of this survey is to explicitly classify, for the first time,
existing biological oscillators based on whether they are found in nature or not, to discuss, in a
tutorial fashion, the main principles that govern the oscillations in each oscillator, and to analyze
oscillator parameters that are most relevant to communication engineer researchers. In addition,
the survey highlights and addresses the key open research issues pertaining to several physical
aspects of the oscillators and the adoption and implementation of the oscillators to nanonetworks.
Moreover, key research directions are discussed.
Keywords: nanonetworks; molecular communication; biological oscillators; clocks; survey
1. Introduction
Nanomachines are to a nanonetwork what transceivers are to a cellular network or what sensors
are to a wireless sensor network. In other words, they are considered to be the functional units for the
new and emergent nanonetwork [1]. In a nanonetwork, the communication between the nanomachines
is envisioned to occur through either the traditional electromagnetic communication [2] or the more
recent molecular communication [3]. On one hand, the traditional method is a well-established
method for terrestrial environments. However, the attenuation and losses that the electromagnetic
waves suffers in a fluidic molecular environment makes its application seem bleak [4]. Nonetheless,
the electromagnetic communication in the terahertz band are being investigated as a viable radio wave
technology for non-fluidic, nanoscale communications [5]. Molecular communication, on the other
hand, is favorable, as it already exists in fluidic environments. For example, signal exchanges between
neurons [6], cell division [7], and metabolic signals [8] are different forms of molecular communication.
Naturally, molecular communication is readily compatible for fluidic, nanoscale communications [9].
In this study, we strictly consider the molecular communication-based nanonetwork. Besides the duo,
other communication techniques envisioned for nanonetworks (but less researched upon) are acoustic
and nanomechanical communications [1,2]. Unless specified, the term “nanonetwork” in this article
refers to a molecular communication-based nanonetwork.
From a communication systems engineer’s perspective, it would be desirable for nanomachines
to have components and modules similar in function to those presently used in communication
transceivers. A good illustration of such nanomachine architecture can be found in [1]. Currently,
molecular nanomachines are restricted to simple tasks and are therefore characterized by low
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Sensors 2018, 18, 1544 2 of 30
power, basic functionality, and limited capability [9–11]. Simple tasks include generating a response
(e.g., fluorescence) upon sensing a target (e.g., toxic chemical) [12] or delivering a package (e.g., drugs)
to a target site (e.g., infected area) [13]. Such tasks, however, may sometimes heavily rely on an
external controller (humans or a more powerful device). For instance, in targeted drug delivery [11],
the external controller has to routinely inject the drug with high precision so that the surrounding
healthy tissues are not affected. Nanonetworks can leverage targeted drug delivery provided the
nanomachines can be programmed to either release the drug periodically after a certain period or when
a behavioral change in the target is sensed. In both scenarios, the nanonetwork has to know “when to”
release the drug. The former requires the knowledge of the duration between each release and the
latter requires knowledge on the precise time required for the behavioral change to communicate to
the network for a coordinated release. Common to both, a “time keeper” is required [11].
1.1. Motivation
Several reasons drive the motivation of this study and are listed below:
• Need for a biologically compatible time keeper: Quartz crystal oscillators provide and maintain
the time information in almost every electronic device [14]. To stay true to the definition of
molecular communication, however, it would be meaningful to integrate oscillators that are
made with biological components (e.g., molecules) and are driven by biochemical processes
(e.g., gene translation and transcription) or, in other words, oscillators that are biocompatible [15].
Fortunately, to begin with, nature has an abundance of such oscillators. The sleep-wake cycle
driven by the circadian oscillator [16], cell division controlled by mitotic oscillators [17,18], and the
periodical break-down of glucose to sugar that is maintained by glycolytic oscillators [19] are few
examples of biological oscillators in nature. In this study, we refer to them as natural oscillators.
For many decades, biologists, physicists, and mathematicians have extensively studied natural
oscillators, mainly to understand the underlying principles of the oscillators, which, as we will
see in Section 2.1, are of a very complex nature, even though we outline only the main principles.
• Avenues for developing a simpler system: While the understanding of the complex mechanism that
drives natural oscillators is a challenge, to engineer such mechanisms was another challenge until
the birth of a field called synthetic biology [20]. Ironically, the successful realization of the first
in-vivo, artificially-realized oscillator, namely, the repressilator [21] represented the beginning
of synthetic biology. The repressilator laid the path for other novel designs to follow [22,23].
In this study, we refer to them as synthetic oscillators. Synthetic biology offers several advantages
to nanonetworks. Firstly, it has led to the development of oscillators that involve much simpler
mechanisms than their natural counterparts [24] and such oscillators could be embedded within a
nanomachine. Secondly, such an engineering feat is a benefit to nanonetwork applications that
are targeted towards living tissues, where biocompatible components that can be biologically
engineered are preferred. Although these systems are still far from perfection, recent studies have
shown that they can indeed be improved [25–28].
• Investigations from a communication systems engineer perspective: Nearing two decades since the
inception of nanonetworks, few studies on oscillators in the literature have surfaced from the
nanonetwork research community [29–31]. Taking cues from nature, these studies have presented
oscillatory systems that will be suitable, in particular, for molecular nanomachines and, in general,
for a nanonetwork. The first two oscillator systems were designed to allow a nanonetwork
to achieve synchronization by converging the period of oscillations [29,30], while the third
system was designed to align the clock times and extend the purpose of the oscillator beyond
synchronization, to provide timing information for scheduling channel access and decoding the
signals or for coordinating other communication modules in a nanomachine [31]. We will present,
for the first time, qualitative comparisons between them.
• Lack of a consolidated study: To date, a consolidated literature that brings biological oscillators under
one single study is lacking. Motivated by the gaps in the literature regarding biological oscillators,
Sensors 2018, 18, 1544 3 of 30
more specifically to nanonetworks, we provide a comprehensive review of biological oscillators

from the earliest to the latest developments. Additionally, unlike other recent surveys [32],
we study each oscillator using parameters that are significant in the eye of a communication
systems engineer.
On a side note, readers are encouraged to refer the literature [33] for detailed explanations and
visuals of the chemical reactions of the natural oscillators, supported by a rich background on historical
facts and significances. Moreover, for the sake of brevity, we leave out the mathematical expressions
for both the natural and synthtic oscillators as these can be found in much detail in the literature,
particularly, in ref. [32].
1.2. Main Contributions

Based on the aforementioned rationales, the main goal of this survey is to introduce biological
oscillators, in a tutorial fashion, to the nanonetwork research community and additionally, to act as
a small window into the complex and intriguing world of biological oscillators to communication
system engineers. The main contributions of this paper are summarized as follows:
• Consolidating the biological oscillators into a single work, which, to the best of our knowledge,
no work has ever done, making this survey the first one.
• Classification of the biological oscillators based on whether they are found in nature or not.
• Reviewing the natural oscillators and their underlying mechanisms with sufficient detail, bearing
in mind that not all researchers working in nanonetworks have biology backgrounds.
• Reviewing the synthetic oscillators and their design principles and properties, supported with
simple and accurate visuals of the system’s schematics, bearing in mind that not all researchers
working in nanonetworks have synthetic biology backgrounds.
• Reviewing the recent works on oscillatory systems proposed by the nanonetwork
research community.
• Comparative analysis of the oscillators.
• Identification of open research issues for both the physical and communication aspects of
the oscillators.
The remainder of this paper is organized as follows: In Section 2, we discuss the natural
and synthetic oscillators in terms of their working mechanisms. Substantiating each oscillator,
figures illustrating each oscillator’s oscillations are also provided. Section 3 highlights the current
research issues in the physical aspects, such as molecular noise, design, and sustainability and in the
communication aspects, such as adoption and implementation. The tradeoffs and future research
directions are also presented. Finally, Section 4 concludes the paper.
2. Biological Oscillators
Any biological system, wherein there exists a source of excitation, a restorative process, and a
delay element, with appropriate system parameters that lead to a cyclic behavior, can be regarded
as a biological oscillator [34]. This section enumerates on biological oscillators that we believe are
of significant interest to the nanonetwork research community. The section is divided into three
subsections—the first subsection is dedicated to natural oscillators, the second subsection is dedicated
to synthetic oscillators, and the third subsection is dedicated to synthetic oscillators that have been
proposed by the nanonetwork research community.
We explicitly classify, for what we believe is the first time, the biological oscillators into two broad
categories depending on their existence in nature. Figure 1 shows the classification of the biological
oscillators into natural and synthetic oscillators.
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Sensors 2018, 18, x FOR PEER REVIEW 4 of 30
Biological oscillators
Natural oscillators Synthetic oscillators
Glycolytic oscillator Goodwin oscillator
cAMP oscillator Repressilator
Circadian oscillator Hasty oscillator
Calcium oscillator Dual feedback oscillator
Mitotic oscillator Metabolator
Fussenger oscillator
miRNA-regulated oscillator
Displacillator
Moore oscillator
Akgül oscillator
Shitiri oscillator
Figure
Figure 1. 1. Classification of
Classification of biological
biologicaloscillators.
oscillators.
2.1. Natural Oscillators
2.1. Natural Oscillators
Natural oscillators are those that exist in nature and their primary function is to regulate various
processes and activities in living beings. Here, we review a list of such oscillators that have been
Natural oscillators are those
extensively studied and arethat exist inimportance
of significant nature and
to thetheir
field ofprimary
biology. function is to regulate various
processes and activities in living beings. Here, we review a list of such oscillators that have been
2.1.1. Glycolytic Oscillators
extensively studied and are of significant importance to the field of biology.
Glycolytic oscillators produce periodic fluctuations in the concentration of the molecules
(metabolites) that are involved in the process of glycolysis [35,36]. The oscillatory phenomenon was
2.1.1. Glycolyticfirst
Oscillators
reported in 1957 by Duysens and Amesz [37] who were conducting studies to understand the
process of glycolysis. Glycolysis is considered to be the most ancient and powerful bioenergetics (the
Glycolyticstudy
oscillators produce inperiodic
of energy transductions fluctuations
living organisms [38]) processin the concentration
prevailing of the molecules
in all living beings [19],
from are
(metabolites) that bacteria to mammals,
involved and process
in the is the mostofstudied control system
glycolysis [35,36]. (see The
[38], supplementary
oscillatory phenomenon
materials). Although first reported by Duysens and Amesz, the experimental work by Betz and
was first reported
Chancein is,
1957 by Duysens
however, regarded to beand Amesz
the first [37] who
work conducted were on
specifically conducting studies
glycolytic oscillators [35]. to understand
the process of glycolysis. Glycolysis is considered to be the most ancient and powerful bioenergetics
Of the many studies undertaken to identify the main molecule that causes the oscillations [39–44],
the enzyme phosphofructokinase (PFK) has been generally found to be the dominant factor. How
(the study of energy transductions in living organisms [38]) process prevailing in all living beings [19],
PFK is considered the dominant factor may be attributed to its different conformational responses to
from bacteria toadenosine
mammals, and is(ATP)
triphosphate the most studied
and adenosine control(ADP).
diphosphate system This(see [38],behavior
particular supplementary
makes materials).
PFK an allosteric enzyme as it is allosterically inhibited by ATP and activated by ADP. Allosteric is
Although first reported by Duysens and Amesz, the experimental work by Betz and Chance is, however,
the property by which the behavior of the enzyme is affected by a molecule binding to a specific part
regarded to be the
of thefirst
enzyme work
[38]. conducted specifically on glycolytic oscillators [35].
In total, glycolysis
Of the many studies undertaken involvesto
11 identify
intermediary steps
the [45], all
main of which involve
molecule that an oscillatory
causes theregime.
oscillations [39–44],
We, however, outline here the simplified model of glycolysis as reviewed in [45], which involves
the enzyme phosphofructokinase
PFK. When PFK is in a state (PFK)
calledhas the been generally
active state, found
it catalyzes to be the dominant
the phosphorylation factor. How PFK
of fructose-6-
is considered the dominant
phosphate factor may beusing
to fructose-1,6-bisphosphate attributed to itsthisdifferent
ATP [46]. During phosphorylationconformational
process, ATP is responses to
adenosine triphosphate (ATP) and adenosine diphosphate (ADP). This particular behavior makes PFK
an allosteric enzyme as it is allosterically inhibited by ATP and activated by ADP. Allosteric is the
property by which the behavior of the enzyme is affected by a molecule binding to a specific part of
the enzyme [38].
In total, glycolysis involves 11 intermediary steps [45], all of which involve an oscillatory regime.
We, however, outline here the simplified model of glycolysis as reviewed in [45], which involves PFK.
When PFK is in a state called the active state, it catalyzes the phosphorylation of fructose-6-phosphate
to fructose-1,6-bisphosphate using ATP [46]. During this phosphorylation process, ATP is converted to
ADP and causes a rise in the level of ADP and a decline in the level of ATP. ADP is then converted back
to ATP by adenosine monophosphate (AMP) and consequently, reverses the levels of ADP and ATP.
Interestingly, for every ATP consumed, two ATPs are produced. The net increase in ATP levels forces
PFK to become inactive, inhibiting it from catalyzing the phosphorylation. PFK resumes its action
when AMP, which is present in small amounts, removes the inhibition by ATP. Thus, the cycle is reset.
The period of the oscillation range is in the order of minutes, from 1.8 min (as shown in Figure 2) to
converted to ADP and causes a rise in the level of ADP and a decline in the level of ATP. ADP is then
converted back to ATP by adenosine monophosphate (AMP) and consequently, reverses the levels
of ADP and ATP. Interestingly, for every ATP consumed, two ATPs are produced. The net increase
in ATP levels forces PFK to become inactive, inhibiting it from catalyzing the phosphorylation. PFK
Sensors 2018, 18, 1544 5 of 30
resumes its action when AMP, which is present in small amounts, removes the inhibition by ATP.
Thus, the cycle is reset. The period of the oscillation range is in the order of minutes, from 1.8 min (as
8.6 shown in Figure
min [33]. Recent2)works
to 8.6 min [33].have
[47,48] Recent works [47,48]that
demonstrated have demonstrated
sustained that sustained
oscillations oscillations
can occur in a single
cellcan occur inthey
whereas a single
werecell whereas they
previously were previously
thought thoughtthrough
to be generated to be generated through
a population a population [49].
[49].
Figure 2. Oscillations produced in the phosphofructokinase (PFK) concentrations by a glycolytic

Figure [41].
oscillator 2. Oscillations produced in the phosphofructokinase (PFK) concentrations by a glycolytic
oscillator [41].
2.1.2. Cyclic Adenosine Monophosphate (cAMP) Oscillator

2.1.2. Cyclic Adenosine Monophosphate (cAMP) Oscillator
TheThecyclic adenosine
cyclic adenosine monophosphate
monophosphate (cAMP)
(cAMP) oscillator
oscillator produces
produces oscillatory
oscillatorybehavior
behavior through
throughthe
cyclic synthesis of cAMP [33,50]. The oscillation formed is in fact a mode
the cyclic synthesis of cAMP [33,50]. The oscillation formed is in fact a mode of intercellularof intercellular communication
which is found among
communication theisDictyostelium
which found among discoideum amoeba
the Dictyostelium species [51–53].
discoideum amoeba The amoeba
species forages
[51–53]. Thefor
food either as
amoeba an independent
forages cell orasasan
for food either a group of cells, cell
independent depending
or as aon the availability
group or scarcityon
of cells, depending of the
food,
respectively [54–56]. To transit to the group phase during times of food scarcity,
availability or scarcity of food, respectively [54–56]. To transit to the group phase during times of a periodic mechanism
of intercellular
food scarcity,communication
a periodic mechanismis mediated by periodic
of intercellular secretion ofisthe
communication secondary
mediated messenger
by periodic cAMP
secretion
andofleads to oscillations
the secondary [33,51,55–57].
messenger cAMP and leads to oscillations [33,51,55–57].
WeWe describe
describe thethe operation
operation ofofthe
thecAMP
cAMPoscillator
oscillatoras as described
described inin [33].
[33].Adenylate
Adenylatecyclase,
cyclase,which
which
synthesizes intracellular cAMP from ATP, is activated when extracellular
synthesizes intracellular cAMP from ATP, is activated when extracellular cAMP binds to a receptor cAMP binds to a receptor
of the
of the cell
cell [58,59].The
[58,59]. The secretion
secretionofofintracellular
intracellular cAMP
cAMP outoutof the
of cell
thefollows its synthesis;
cell follows cAMP binds
its synthesis; cAMP
to its
binds toreceptor
its receptorand further promotes
and further its ownits
promotes synthesis [60]. The[60].
own synthesis accumulation of cAMP isof
The accumulation generally
cAMP is
considered
generally to be regulated
considered through through
to be regulated the desensitization of the cAMP
the desensitization receptors
of the cAMP when cAMP
receptors binds
when to
cAMP
them, which can be reversed through phosphorylation [61,62]. Once
binds to them, which can be reversed through phosphorylation [61,62]. Once the receptors return the receptors return to the
sensitive state, cAMP can bind to them, and the synthesis of cAMP is restarted, thereby forming the
to the sensitive state, cAMP can bind to them, and the synthesis of cAMP is restarted, thereby
cAMP oscillations. Another form of cAMP regulation is the degradation of cAMP through
forming the cAMP oscillations. Another form of cAMP regulation is the degradation of cAMP
phosphodiesterase [63,64]. The temporal changes in the concentration of external cAMP cause
through phosphodiesterase
Sensors [63,64]. The temporal changes in the concentration of external cAMP
2018, 18, x FOR PEER REVIEW 6 of 30cause
relaxation oscillations with periods in the order of tens of minutes, as shown in Figure 3.
relaxation oscillations with periods in the order of tens of minutes, as shown in Figure 3.
Figure 3. Oscillations
Figure of extracellular
3. Oscillations of extracellularcyclic
cyclicadenosine monophosphate
adenosine monophosphate (cAMP)
(cAMP) generated
generated usingusing
the the
model in [60].
model in [60].
2.1.3. Circadian Oscillator

The circadian oscillator refers to an internal biological oscillator that has a free-running period
of about 24 h (an oscillator with a ~24 h period but one that does not follow the day–night cycle). The
term circadian, coined by Franz Halberg in 1959, 230 years after the classic experiment of 1729 that
Figure 3. Oscillations of extracellular cyclic adenosine monophosphate (cAMP) generated using the
Sensors 2018, 18, 1544 6 of 30
model in [60].
2.1.3.Circadian
2.1.3. CircadianOscillator
Oscillator
Thecircadian
The circadianoscillator
oscillatorrefers
referstotoananinternal
internalbiological
biologicaloscillator
oscillatorthat
thathashasa afree-running
free-runningperiodperiod
ofofabout
about24 24hh (an
(an oscillator with
with aa ~24
~24hhperiod
periodbut butoneone that does
that notnot
does follow
followthetheday–night
day-night cycle). The
cycle).
term circadian, coined by Franz Halberg in 1959,
The term circadian, coined by Franz Halberg in 1959, 230 years after 230 years after the classic experiment of
classic experiment of 1729 that1729 that
demonstratedthat
demonstrated thateven
evenininthetheabsence
absenceofofsunlight,
sunlight,the thedaily
dailymovements
movementsofofthe theleaves
leavesofofthe
theMimosa
Mimosa
plantwere
plant were maintained
maintained [65],[65], loosely
loosely translates
translates to “about
to “about a day”.a Sleep-wake
day”. Sleep–wake
cycles arecycles
a good are a good
example
example of circadian oscillators [16]. A pivotal study in the understanding of
of circadian oscillators [16]. A pivotal study in the understanding of the circadian oscillators was the the circadian oscillators
was the identification
identification of the gene
of the per (period) per (period)
[66] thatgene [66] that
expresses expresses
the PER proteinthein aPER protein
periodic in a leading
manner, periodic
tomanner, leading
oscillations to oscillations [67–70].
[67–70].
ToTounderstand
understandthe theoperation
operationofofcircadian
circadianoscillation,
oscillation, wewediscuss
discussGoldbeter’s
Goldbeter’smodel model[71].
[71].ItItbegins
begins
withthe
with the transportation
transportation of of the
theperpermessenger
messenger ribonucleic
ribonucleic acidacid
(mRNA)
(mRNA) fromfromthe nucleus to the to
the nucleus cytosol
the
cytosol [56]. The mRNA is then translated into the PER protein, causing a rise in the PER level.is
[56]. The mRNA is then translated into the PER protein, causing a rise in the PER level. This PER
saidPER
This to beisinsaid
the to
inactive state.
be in the Over time,
inactive state.PER
Over undergoes
time, PER phosphorylation [72] and is transformed
undergoes phosphorylation [72] and isto
the active state.
transformed to theOnce
activeinstate.
the active
Once in state, it is transported
the active back to theback
state, it is transported nucleus
to thewhere
nucleus it where
begins itto
represses the transcription of the per gene [73]. PER, therefore, inhibits its own
begins to represses the transcription of the per gene [73]. PER, therefore, inhibits its own transcription. transcription. The cycle
resumes
The cycle when
resumes the when
PER levels
the PERin the nucleus
levels are nucleus
in the too low and are the
too inhibition
low and the is removed.
inhibition Figure 4 shows
is removed.
the oscillatory
Figure 4 shows the behavior of the
oscillatory per gene.
behavior of Period
the per of oscillations
gene. Period ofare generallyare
oscillations in the order of
generally in hours.
the order
of hours.
Figure4.4.Circadian
Figure Circadianoscillations
oscillationsformed theper
formedbybythe pergene
genewith
withGoldbeter’s
Goldbeter’smodel
model[33,71].
[33,71].
2.1.4. Calcium Oscillator

The calcium (Ca2+ ) oscillator generates periodic temporal fluctuations in the concentration levels
of Ca2+ that arise either from the entry of external calcium into a cell or from the periodic release of
intracellular calcium to the cytosol from internal stores [74]. The former is commonly found in excitable
cells while the latter are found in non-excitable cells [75]. The first observations of the calcium oscillator
were made in 1985 by Cuthbertson and Cobbold in fertilized mouse oocytes [76] and in hepatocytes in
1986 and 1987 by Woods et al. [77,78]. Over the years, several models have been developed to describe
the mechanisms and dynamics of the Ca2+ oscillations. For example, while some models consider
Ca2+ oscillations with a constant inositol 1,4,5-triphosphate (IP3 ) concentration [79–82], other models
consider Ca2+ oscillations with a varying IP3 [83–86].
Here, we review the workings of the oscillator as presented by Höfer et al. [85]. It involves the
interplay between Ca2+ , inositol trisphosphate (IP3 ), and the biphasic IP3 receptors (IP3 Rs). The IP3
molecules bind to the biphasic IP3 receptors (IP3 Rs) located on the membrane of the endoplasmic
reticulum (ER)—the internal storage site for Ca2+ ions. The binding allows the IP3 Rs, which act like a
gate, to open up, releasing the Ca2+ ions stored inside the ER, thereby increasing the levels of cytosolic
[79–82], other models consider Ca2+ oscillations with a varying IP3 [83–86].
Here, we review the workings of the oscillator as presented by Höfer et al. [85]. It involves the
interplay between Ca2+, inositol trisphosphate (IP3), and the biphasic IP3 receptors (IP3Rs). The IP3
molecules bind to the biphasic IP3 receptors (IP3Rs) located on the membrane of the endoplasmic
Sensors 2018, 18,(ER)—the
reticulum 1544 internal storage site for Ca2+ ions. The binding allows the IP3Rs, which act7 of 30 a
like
gate, to open up, releasing the Ca2+ ions stored inside the ER, thereby increasing the levels of cytosolic
Ca2+. Two processes follow. First, when the cytosolic Ca2+ level is sufficiently high, the Ca2+ ions begin
Ca2+ . Two processes follow. First, when the cytosolic Ca2+ level is sufficiently high, the Ca2+ ions begin
to inhibit the IP3Rs, effectively inhibiting the release of Ca2+ from the ER and consequently reducing
to inhibit the IP3 Rs, effectively inhibiting the release of Ca2+ from the ER and consequently reducing
cytosolic Ca2+. In addition, simultaneously, the majority of the cytosolic Ca2+ are pumped backed into
cytosolic Ca2+ . In addition, simultaneously, the majority of the cytosolic Ca2+ are pumped backed into
the ER through natural pump-like structures on the ER called Na+–Ca2+ exchangers, adding to the
the ER through natural pump-like structures on the ER called Na+ -Ca2+ exchangers, adding to the
reduction of cytosolic Ca2+. Second, the cytosolic Ca2+ triggers the regeneration of IP3 through PLCδ,
reduction of cytosolic Ca2+ . Second, the cytosolic Ca2+ triggers the regeneration of IP3 through PLCδ ,
which is also a secondary messenger, setting the oscillator up for the next cycle. Calcium oscillations
which is also a secondary messenger, setting the oscillator up for the next cycle. Calcium oscillations
can have periods in the order of seconds, shown in Figure 5, to several minutes.
can have periods in the order of seconds, shown in Figure 5, to several minutes.
Figure 5. Calcium oscillations generated based on mathematical models by De-Young and Keizer [79]
Figure
and 5. Calcium
Li and oscillations generated based on mathematical models by De-Young and Keizer [79]
Rinzel [80].
and Li and Rinzel [80].
2.1.5. Mitotic Oscillators
2.1.5. Mitotic Oscillators
Mitotic oscillators generate oscillations through periodic fluctuations in the level of cdc2 kinase,
Mitotic
a cell cycle oscillators
regulator. generate
Mitotic oscillations
oscillators through
regulate the periodic
process offluctuations in the
cell division, level of
namely cdc2 kinase,
mitosis [87].
a cell cycle regulator. Mitotic oscillators regulate the process of cell division,
More specifically, they determine the onset of the cell division [88]. Walther Flemming discoverednamely mitosis [87]. More
specifically,
mitosis in 1878they
[89].determine
Since then,thetheonset
ideaof thea cell
that division [88].
biochemical Walther
oscillator mayFlemming
be in control discovered mitosis
of the onset of
in 1878 [89]. Since then, the idea that a biochemical oscillator may be in control
mitosis had long been speculated [90,91]. This speculation was validated in experiments, where of the onset of mitosis
cell
had long
division in been speculated
the slime [90,91]. Thisoccurred
mold, Physarum, speculationwithwas validated
periods of 12 hin[92,93].
experiments, where cell division
in the slime mold,
To explain Physarum,
the workings of occurred
a mitotic with periods
oscillator, we of 12 h [92,93].
describe here the minimal model for a mitotic
oscillator [94]. A protein (cyclin) is synthesized at a constant rate tohere
To explain the workings of a mitotic oscillator, we describe the minimal
generate an enzyme model for kinase),
(cdc2 a mitotic
oscillator
whose active[94]. A protein
form (cyclin)
produces is synthesized
a substance that at a constant
degrades rate toresetting
cyclin, generatethean enzyme
oscillator(cdc2 kinase),
[17,95,96].
whose active form produces a substance that degrades cyclin, resetting the oscillator
More specifically, cyclin activation of the cdc2 kinase causes the transformation of cdc2 kinase from [17,95,96]. More
specifically, cyclin activation of the cdc2 kinase causes the transformation
the inactive, tyrosine-phosphorylated form, denoted as M+, into the active, dephosphorylated form, of cdc2 kinase from the
inactive,
denoted as tyrosine-phosphorylated
M [88,94]. A negative feedback form,loop
denoted as M+,
is created whenintoM the active,
triggers thedephosphorylated
activation of a proteaseform,
that specifically degrades cyclin. Mitotic oscillation periods have been observed to be generally in the
order of tens of minutes (as shown in Figure 6), but can range to the order of hours as well [33].
Natural oscillators could provide the necessary timing information to a nanonetwork in a
broadcasting manner without having to be embedded within a nanomachine. This is a key advantage
as it would allow nanomachines to simply sense and extract the timing information from the ubiquitous
natural oscillators. Applications such as the periodic release of drugs can monitor the periodic changes
in the oscillations and time their release accordingly. However, each nanomachine will be required to
be in close proximity to the oscillator and/or require an additional interface to read the oscillations.
In Table 1, we summarize the characteristics of the natural oscillators and list them in the increasing
order of oscillation frequency.
denoted as M [88,94]. A negative feedback loop is created when M triggers the activation of a protease
that specifically degrades cyclin. Mitotic oscillation periods have been observed to be generally in the
order2018,
Sensors of tens of minutes (as shown in Figure 6), but can range to the order of hours as well [33].8 of 30
18, 1544
Figure6.6.Oscillations
Figure Oscillations generated
generated from from the minimal
the minimal cascadeillustrating
cascade model model illustrating
the temporalthe temporal
fluctuations
fluctuations in the concertation
in the concertation of cyclin [94].of cyclin [94].
Natural oscillators could Table

provide the necessary
1. Overview timing
of natural information to a nanonetwork in a
oscillators.
broadcasting manner without having to be embedded within a nanomachine. This is a key advantage
as it would allow nanomachines
Year of to simply sense and extract the timing Process information from the
Regulating
Oscillator Cell/Organism Frequency
DiscoveryApplications such as the periodic release of drugs
ubiquitous natural oscillators. the Oscillations
can monitor the
periodic changes in the oscillations and time their
Unicellular andrelease accordingly. However, each nanomachine
Circadian oscillator 1729 [65] 11.57 µHz Transcription regulation
will be required to be in close proximitymulticellular
to the oscillator and/or require an additional interface to read
the oscillations. In Table 1, we summarize the characteristics 11.57ofµHz
the to
natural oscillators and list them
Mitotic oscillator 1974 [92] Eukaryotic cells Enzyme regulation
in the increasing order of oscillation frequency. 1.7 mHz
Yeast cells; heart
Glycolytic Table 1.cells; muscleof natural oscillators.
Overview
1965 [35] 0.3–16.7 mHz Enzyme regulation
oscillator extracts; Pancreatic
Year of beta cells; Process Regulating the
Oscillator Cell/Organism Frequency
Discovery Dictyostelium Receptor-enzyme
Oscillations
cAMP oscillator 1974 [50] 1.7–3.33 mHz
discoideum interactions
Circadian Unicellular and
1729 [65] 11.57 μHz Transport between
Transcription cells
regulation
oscillator multicellular and their environment or
Calcium oscillator 1985 [76] Variety of cells 16.7 mHz to 1 Hz between various
Mitotic 11.57 μHz to 1.7 intracellular
1974 [92] Eukaryotic cells Enzyme regulation
oscillator mHz compartments
Yeast cells; heart
2.2. Synthetic Oscillators cells; muscle
Glycolytic
1965 [35] extracts; 0.3–16.7 mHz Enzyme regulation
Synthetic oscillators are the oscillatory systems that are developed in a laboratory setting in the
oscillator
Pancreatic beta
field of synthetic biology. Regarded as the intersection of protein and genetic engineering with systems
cells;
biology, the basic idea of synthetic biology is to engineer an artificial gene circuit that can be inserted
intocAMP
a host cell to perform Dictyostelium
1974 [50]new tasks [97]. As mentioned1.7–3.33
earlier, the
mHzrealization ofReceptor–enzyme
the repressilator [21]
oscillator discoideum
(and the toggle switch [98]) is said to have sparked the beginning of synthetic biology interactions
[20,99]. For an
in-depth introduction to synthetic biology, readers are directed to literature Transport
[97]. We between cellsa
review here
set of synthetic oscillators that are significantly important, including the first and their
ever environment
theoretical or
model,
Calcium
which is considered 1985
to [76] Variety
be a critical step inofthe
cells
design 16.7 mHz
of the to 1 Hz
synthetic oscillators between
we knowvarious
of today.
oscillator
intracellular
2.2.1. Goodwin Oscillator compartments
In 1963, B.C. Goodwin proposed a model to capture the oscillatory behavior in genetic regulatory
2.2. Synthetic
networks Oscillators
[100,101]. In his model, a single gene, x, periodically represses itself through a self-negative
feedback loop leading to oscillations (Figure 7a). Specifically, gene x expresses (transcribes) a messenger
We review here a set of synthetic oscillators that are significantly important, including the first ever
theoretical model, which is considered to be a critical step in the design of the synthetic oscillators
2.2.1. Goodwin Oscillator
we know of today.
In 1963, B.C. Goodwin proposed a model to capture the oscillatory behavior in genetic
2.2.1. Goodwin
regulatory networksOscillator
[100,101]. In his model, a single gene, 𝑥, periodically represses itself through a
Sensors 2018, 18, 1544 9 of 30
self-negative feedback
In 1963, loop leading
B.C. Goodwin to oscillations
proposed (Figure the
a model to capture 7a).oscillatory
Specifically, genein𝑥genetic
behavior expresses
(transcribes)
regulatory a messenger RNA, X,Inwhich
networks [100,101]. is translated
his model, into an
a single gene, enzyme, Y, represses
𝑥, periodically which initself
turnthrough
catalyzes
a the
self-negative
production of a feedback
metabolite, Z,
loop leading
which to
causes oscillations
the (Figure
inhibition of the7a). Specifically,
expression of Xgene 𝑥
[56,100]
RNA, X, which is translated into an enzyme, Y, which in turn catalyzes the production of a metabolite, expresses
(Figure 7b).
(transcribes) a messenger RNA, X, which is translated into an enzyme, Y, which in turn catalyzes the
Z, which causes the inhibition of the expression of X [56,100] (Figure 7b).
production of a metabolite, Z, which causes the inhibition of the expression of X [56,100] (Figure 7b).
_
𝑥 _
𝑥
_ _
𝑥
(a) (b) 𝑥
(a) (b)
Figure 1. Goodwin Oscillator: (a) symbolic representation; (b) schematics with intermediary steps
Figure 7. Goodwin Oscillator: (a) symbolic representation; (b) schematics with intermediary steps
Figurethe
illustrating 1. Goodwin Oscillator:
self-negative (a) symbolic
feedback loop. representation; (b) schematics with intermediary steps
illustrating the self-negative
illustrating feedback
the self-negative loop.
feedback loop.
In principle, the Goodwin oscillator can generate sustained oscillations (Figure 8), yet it requires
In principle,
In principle, the Goodwin
the Goodwin oscillator
oscillator cancan generatesustained
generate sustained oscillations
oscillations(Figure(Figure 8),8),
yetyet
it requires
it requires
an unrealistically
an large
unrealistically HillHill
large coefficient
coefficientvalue
value (n(n>>8)
8) [102].
[102]. Nonetheless,
Nonetheless, it it
is is
thethe first
first model
model that that has
has has
an unrealistically
demonstrated how large Hill coefficient
sustained value
oscillations (n > be
could 8) [102].
obtainedNonetheless,
through a itself-negative
is the first model
feedbackthat loop
demonstrated how sustained oscillations could be obtained through a self-negative feedback loop
demonstrated
[56] and how sustained oscillations could be obtained through afollow
self-negative feedback loop [56]
[56]has
andundoubtedly
has undoubtedly laid thethe
laid groundwork
groundworkfor for other models
other models totofollow suit.
suit. In In addition,
addition, this this
typetype
and has undoubtedly
of negative feedback
of negative
laid the
looploop
feedback waswas groundwork
later discovered
later
for
discoveredin
other
inthe
models
thecircadian
to follow
oscillators
circadian oscillators
suit.
ofof
In addition,
Drosophila
Drosophila
this type of
melanogaster
melanogaster
negative
andfeedback
Neurospora
and Neurospora loop
crassa was
crassa later discovered
[68,103,104],
[68,103,104], in the
leveraging
leveraging thecircadian
the work of
work oscillators of Drosophila melanogaster
of Goodwin.
Goodwin.
and Neurospora crassa [68,103,104], leveraging the work of Goodwin.
Figure 8. Oscillations formed by temporal concentration changes in mRNA(X) by the Goodwin

oscillator.
Figure8.8.Oscillations
Figure Oscillations formed
formed by temporal
by temporal concentration
concentration changes
changes in mRNA(X) by theXGoodwin
in mRNA( ) by the oscillator.
Goodwin
oscillator.
Although no wet lab experiments were carried out, Goodwin remarked that the period of
oscillation would be between 4–8 h [104]. However, in a recent wet lab experiment carried out
by Stricker et al. [22], periods that were under an hour, averaging 30 min, were observed, (see [22],
supplementary materials), far less than what Goodwin had remarked. The Goodwin oscillator also
showed consistency in period to isopropyl β-D-1-thiogalactopyranoside (IPTG), a substance that
can inhibit the repressor [22]. A far more realistic model of the Goodwin oscillator was realized by
Smith [105], wherein a time delay was included in the negative feedback loop, mitigating the need for
the unrealistic Hill’s coefficient value.
2.2.2. Repressilator
The repressilator [21] was the first synthetic gene oscillator to be successfully engineered.
It consists of three genes, x, y, and z, that can repress each other forming a negative feedback loop
(Figure 9a), making it a multi-gene variant of the Goodwin oscillator [32]. The loop begins with the
first gene, x, which performs the translation of the repressor protein, X. X inhibits the transcription
of the second repressor gene, y, whose protein product, Y, in turn, inhibits the expression of a third
[105], wherein a time delay was included in the negative feedback loop, mitigating the need for the
Theunrealistic Hill’s coefficient
repressilator [21] wasvalue.
the first synthetic gene oscillator to be successfully engineered. It
consists of three genes, 𝑥, 𝑦, and 𝑧, that can repress each other forming a negative feedback loop
2.2.2. Repressilator
first gene, 𝑥The repressilator [21] was the first synthetic gene oscillator to be successfully engineered. It
, which performs the translation of the repressor protein, X. X inhibits the transcription of
Sensors 2018, 18, 1544 of three genes, 𝑥, 𝑦, and 𝑧, that can repress each other forming a negative feedback loop
consists 10 of 30
the second repressor gene, 𝑦, whose protein product, Y, in turn, inhibits the expression of a third
gene, z.first
Finally,
gene, 𝑥the protein
, which product
performs of 𝑧, Z, inhibits
the translation the first
of the repressor gene,X.𝑥X, inhibits
protein, from performing X translation,
the transcription of
completing the
the secondloop [21].
repressor gene, 𝑦,9b
Figure illustrates
whose protein the Y, in feedback
negative
product, process.
turn, inhibits the expression of a third
gene, z. Finally, the protein product of z, Z, inhibits the first gene, x, from performing X translation,
gene, z. Finally, the protein product of 𝑧, Z, inhibits the first gene, 𝑥, from performing X translation,
completingcompleting
the loop the
[21]. Figure
loop 9b illustrates
[21]. Figure the
9b illustrates thenegative feedback
negative feedback process.
process.
_
_ 𝑦
𝑧 _𝑦
𝑧 _
_ _ _
_ _ _
𝑥 𝑥 𝑥 y 𝑧
_ 𝑥 y 𝑧
_
(a) (a) (b) (b)
Figure
Figure Figure
9. 9. Repressilator:
9. Repressilator:
Repressilator: (a)(a) (a) symbolic
symbolic
symbolic representation; (b)
representation;
representation; (b)
(b)schematic
schematicrepresentation
schematic representation
representationdepicting the pathsthe
depicting
depicting thepaths
paths
of the proteins, X, Y, and Z, responsible for causing repression of genes y, z, and x, respectively.
of the proteins,
of the X, Y,
proteins, X, and
Y, and
Z, Z,
responsible
responsible forforcausing
causingrepression
repressionof genes y,
ofgenes y, z, and x, respectively.
z, and
Oscillations generated through simulations were found to have average periods of 150 min (Figure
Oscillations generated
10), whilegenerated
wet through simulations
lab experiments periodswere thefound to 160
have average periods of 150ofmin (Figure
Oscillations throughshowed
simulations inwere range of
found to± have
40 min average
with at least 40%
periods the
of 150 min
10), while wet lab experiments showed periods in the range of 160 ± 40 min with at least 40% of the
engineered cells reported to generate oscillations successfully [21]. Further, significant variation in
(Figure 10),the
while wet lab experiments showed periods in the range of 160 ± 40 min with at least 40%
engineeredoscillation amplitudes
cells reported was observed
to generate (Figure 2c successfully
oscillations in [21]). [21]. Further, significant variation in
of the engineered cells reported to generate oscillations successfully [21]. Further, significant variation
the oscillation amplitudes was observed (Figure 2c in [21]).
in the oscillation amplitudes was observed (Figure 2c in [21]).
Figure 10. Oscillations formed by the temporal fluctuations in the concentration of protein X.
Figure
Figure 10. 10. Oscillations
Oscillations formed
formed bybythe
thetemporal
temporalfluctuations
fluctuations in
in the
the concentration
concentration of proteinXX.
ofprotein .
2.2.3. Atkinson Oscillator

The Atkinson Oscillatorconsists of two genes, x and y, where gene x expresses both its own
oscillator
2.2.3. Atkinson
transcription and that of gene y (Figure 11a) [106]. Specifically, gene x expresses X, which, in turn,
The Atkinson oscillator consists of two genes, 𝑥 and 𝑦, where gene 𝑥 expresses both its own
promotes its own expression
transcription and
and that of the𝑦 expression
gene of Y through
(Figure 11a) [106]. Specifically, geney.𝑥 As
gene the level
expresses of Y rises,
X, which, in turn,it begins to
inhibit thepromotes
transcription
its own of the firstand
expression gene
the expression Y through
causing aofdecline the 𝑦.level
ingene As theoflevel of Y rises,
X, which resets the oscillator
it begins
to inhibit the transcription
and a new cycle begins (Figure 11b). of the first gene causing a decline in the level of X, which resets the
oscillator and a new cycle begins (Figure 11b).
_
𝑥 𝑦 _
𝑥 y
(a) (b)
Figure 11.Figure 11. Atkinson

Atkinson oscillator:
oscillator: (a) symbolicrepresentation;
(a) symbolic representation; (b)(b)
schematic depictingdepicting
representation the the
internal pathways.
internal pathways.
In both the simulations and wet lab experiments, the period of the oscillations remains the same
~10 h (Figure 12), suggesting very good agreement between the theoretical simulation and the
experiments. However, the oscillations formed were damped owing to the oscillator’s design [106].
In particular, the authors postulated that the damping was caused either by the longer lifetime of the
activator, X, or by the shorter lifetime of the repressor gene, 𝑦.
𝑥 𝑦 _
𝑥 y
(a) (b)
Sensors 2018, 18, 1544 11 of 30
Figure 11. Atkinson oscillator: (a) symbolic representation; (b) schematic representation depicting the
internal pathways.
In both the simulations and wet lab experiments, the period of the oscillations remains the
same ~10Inhboth the simulations
(Figure and wet
12), suggesting labgood
very experiments, the period
agreement of the
between oscillations
the theoreticalremains the same
simulation and the
~10 h (Figure 12), suggesting very good agreement between the theoretical simulation and the
activator, X, orX, by
activator, thethe
or by shorter
shorterlifetime
lifetimeof
of the
the repressor gene,𝑦.y.
repressor gene,
Figure Damped
12. 12.
Figure Damped oscillations
oscillations formed
formed by the Atkinson
by the Atkinsonoscillator.
oscillator.TheThe
solid solid
line line represents
represents the the
simulated
simulated results
results and and
thethe squaresrepresent
squares represent the
the wet
wetlab
labexperiment
experimentresults [106].
results Reprinted
[106]. from Cell,
Reprinted from Cell,
113, 113, Mariette
Mariette R. Atkinson,
R. Atkinson, MichaelA.
Michael A.Savageau,
Savageau, Jesse
JesseT.T.Myers,
Myers,Alexander
Alexander J. Ninfa, Development
J. Ninfa, of
Development of
Genetic Circuitry Exhibiting Toggle Switch or Oscillatory Behavior in Escherichia coli, 11,
Genetic Circuitry Exhibiting Toggle Switch or Oscillatory Behavior in Escherichia coli, 11, Copyright Copyright
(2018), with permission from Elsevier.
(2018), with permission from Elsevier.
2.2.4. Hasty Oscillator

2.2.4. Hasty Oscillator
The Hasty oscillator [107] consists of two genes, one of which exhibits a switch-like behavior
The Hastyonoscillator
depending its protein[107] consists
product of two genes,
concentration one 𝑥ofexpresses
level. Gene X at low concentrations
which exhibits of X
a switch-like behavior
depending
and does onnot proteinXproduct
its express concentrationoflevel.
at high concentrations X giving
Gene it x expressesbehavior
switch-like X at low(see
concentrations of X and
Figure 13a). The
doesHasty oscillator
not express X atis high
therefore also referredoftoXasgiving
concentrations the variable link oscillator
it switch-like [32].(see
behavior At low concentrations
Figure 13a). The Hasty
ofofprotein
oscillatorX.isThus,X,in
gene
therefore 𝑥manner,
expresses
thisalso theXto
referred and triggers
as the the
of Xexpression
variable
concentration link oscillator
is regulated, [32]. AtYlow
of protease
resulting inthrough 𝑦. Asofthe
gene Figure
concentrations
oscillations. protein
13b
concentration
X, gene x expresses
illustrates of X increases,
X and triggers
the oscillator as
in morethe well
detail. as at some high concentrations of X, X represses
expression of protease Y through gene y. As the concentration its own of
transcription
Unlike andthe that of Y. Protease
previous Y degrades
oscillators, X, further
the Hasty adding
oscillator to the decline
generates in the concentration
oscillations resembling a
X increases, as well as at some high concentrations of X, X represses its own transcription and that of Y.
relaxation
Protease oscillator
Y degrades (Figure adding
X, further 14). Although
to the not shown
decline in here, the average period
the concentration of the in
of X. Thus, oscillations
this manner,
ranges between 8–44 min when driven by another process that exhibits a oscillating behavior
the concentration of X is regulated, resulting in oscillations. Figure 13b illustrates the oscillator [107]. in
To the best of our knowledge, no wet lab experiments have been carried out to verify the model.
more detail.
_
𝑥 𝑦
_
𝑥 y
(a) (b)
Figure
Figure 13. Hasty
13. Hasty oscillator:
oscillator: (a)(a) symbolicrepresentation;
symbolic representation; (b)
(b) schematic
schematicrepresentation elucidating
representation the the
elucidating
intermediary steps. Lines with squared heads indicate the variable
intermediary steps. Lines with squared heads indicate the variable links. links.
Unlike the previous oscillators, the Hasty oscillator generates oscillations resembling a relaxation
oscillator (Figure 14). Although not shown here, the average period of the oscillations ranges between
8–44 min when driven by another process that exhibits a oscillating behavior [107]. To the best of our
knowledge, no wet lab experiments have been carried out to verify the model.
(a) (b)
Figure 13. Hasty oscillator: (a) symbolic representation; (b) schematic representation elucidating the
intermediary
Sensors steps. Lines with squared heads indicate the variable links.
2018, 18, 1544 12 of 30
Figure
Figure14.
14.Oscillations observedby
Oscillations observed bythe
theHasty’s
Hasty’s oscillator.
oscillator.
2.2.5. Metabolator
2.2.5. Metabolator
TheThe metabolator,
metabolator, as asthethename
namesuggest,
suggest, isisaa synthetic
synthetic oscillator
oscillator that
that generate
generateoscillations
oscillations in
in metabolites through the integration of metabolism and transcription
metabolites through the integration of metabolism and transcription regulation [108]. regulation [108]. It was It was
constructed to show that metabolic flux could control system-wide oscillations.
constructed to show that metabolic flux could control system-wide oscillations. The metabolator was The metabolator
was conceived to consist of a flux-carrying network with two interconverting metabolite pools (M1 and
conceived to consist of a flux-carrying network with two interconverting metabolite pools (M1 and
M2) that are catalyzed by two enzymes (X and Y). In turn, M2 is responsible for the expression of the
M2) that are catalyzed by two enzymes (X and Y). In turn, M2 is responsible for the expression of the
two enzymes. The expression of X is inhibited by M2, and the expression of Y is promoted by M2
Sensors
two(Figure 2018, 18,
enzymes. 15a).
Thex FOR PEER REVIEW
expression of X is inhibited by M2, and the expression of Y is promoted 13 of 30
by M2
(Figure 15a).
1
1
𝑥 𝑦
_ 𝑥 y
_
2
2
(a) (b)
Figure 15. Metabolator:

Figure 15. (a) symbolic
Metabolator: (a) symbolic representation;
representation; (b)
(b) schematic
representation illustrating
illustrating the
the
signaling pathways.
signaling pathways.
At low concentration
concentration levels
levelsofofM2, gene𝑥 xisisnot
M2,gene notinhibited
inhibited from
fromexpressing
expressing X, while gene
X, while 𝑦 is ynot
gene is
promoted
not promoted to express Y. Since
to express X catalyzes
Y. Since M1 toM1
X catalyzes M2,tothe
M2, concentration of M2 of
the concentration increases which results
M2 increases which
in the decline
results of the concentration
in the decline of M1.of
of the concentration AsM1.
theAsconcentration of M2 of
the concentration rises, rises, 𝑥gene
M2 gene is inhibited from
x is inhibited
expressing
from X, while
expressing X, while 𝑦 is promoted
gene gene to express
y is promoted Y. With
to express the increase
Y. With in the
the increase in concentration
the concentration of Y,ofM2
Y,
is converted
M2 is convertedback to M1
back to M1(Figure
(Figure15b). The
15b). Theresultant
resultanteffect
effectisissimultaneous
simultaneousrise riseand
and decline
decline in the
concentrations of
concentrations of M1 and M2, respectively,
respectively, bringing
bringing thethe metabolator
metabolator backback to
to the
the initial
initial stage.
stage. Periods
averaged about
averaged about 4040 min
min inin simulations
simulations(as (asshown
shownin inFigure
Figure16)16)and
and45 45±± 10 min in wet lab experiments
with 60%
with 60% ofof the
the engineered
engineered cells
cells showing
showing oscillations
oscillations[108].
[108].
expressing X, while gene 𝑦 is promoted to express Y. With the increase in the concentration of Y, M2
is converted back to M1 (Figure 15b). The resultant effect is simultaneous rise and decline in the
concentrations of M1 and M2, respectively, bringing the metabolator back to the initial stage. Periods
averaged about 40 min in simulations (as shown in Figure 16) and 45 ± 10 min in wet lab experiments
withSensors
60%2018,
of the engineered cells showing oscillations [108].
18, 1544 13 of 30
Figure
Figure16.
16.Oscillations observedininthe
Oscillations observed the metabolator.
metabolator.
2.2.6. Dual
2.2.6. Feedback
Dual Oscillator
Feedback Oscillator
TheThedualdual feedback
feedback oscillator
oscillator consistofoftwo
consist genes,𝑥xand
twogenes, and𝑦,
y, that
that are
are opposite
opposite in
in nature
nature[22].
[22]. The
oscillator is based on the theoretical model [109] but with a common promoter [110]. Gene 𝑥 promotes
The oscillator is based on the theoretical model [109] but with a common promoter [110]. Gene x its
Sensors 2018,its
promotes 18,own
x FORtranscription
PEER REVIEW as well as that of y (positive feedback loop), while y represses its14own
of 30
own transcription as well as that of 𝑦 (positive feedback loop), while 𝑦 represses its own transcription
transcription as well as that of x (negative feedback loop) (Figure 17a).
as well as that of 𝑥 (negative feedback loop) (Figure 17a).
Proteins X and Y, respectively, mediate promotion and repression in the following manner.
Firstly, the transcription of protein X by gene 𝑥 occurs. X can express both 𝑥 and 𝑦 simultaneously,
thereby increasing their concentrations. Concurrently, protein Y is expressed by gene 𝑦. Unlike X,
protein Y represses both 𝑦 and 𝑥 simultaneously (Figure 17b) and brings about a decline in the
𝑥 𝑦 _ 𝑥 _ 𝑦
concentration of X. _ _
(a) (b)
Figure 17. Dual feedback oscillator: (a) symbolic representation (b) schematics depicting the
Figure 17. Dual feedback oscillator: (a) symbolic representation (b) schematics depicting the
intermediate positive and negative loops through the proteins X and Y.
intermediate positive and negative loops through the proteins X and Y.
Proteins X and
Oscillations Y, respectively,
were mediate
generated with promotion
periods and
of about 44repression
min (Figurein the
18).following
In wet labmanner. Firstly,
experiments,
the transcription of protein X by gene x occurs. X can express both x and y simultaneously,
periods of approximately 40 min have been observed, suggesting a good relationship between the thereby
increasing
model andtheir concentrations.
the experiment Concurrently,
[22]. The protein
dual feedback Y is expressed
oscillator is extremely gene y.owing
by robust UnliketoX,
theprotein
positiveY
represses both y and x simultaneously (Figure 17b) and brings about a decline
and negative feedback loops—more than 99% of the engineered cells exhibited oscillations in the concentration
of X.
successfully [22]. Unlike the Goodwin oscillator, the dual feedback oscillator also showed varying
Oscillations
periods were
in the range generated
of 13–58 with periods
min when the ITPGofconcentration
about 44 minwas (Figure 18).
varied In wet
[22], lab experiments,
indicating tunability.
periods of approximately 40 min have been observed, suggesting a good relationship between the
model and the experiment [22]. The dual feedback oscillator is extremely robust owing to the
positive and negative feedback loops—more than 99% of the engineered cells exhibited oscillations
periods in the range of 13–58 min when the ITPG concentration was varied [22], indicating tunability.
model and the experiment [22]. The dual feedback oscillator is extremely robust owing to the positive
and negative feedback loops—more than 99% of the engineered cells exhibited oscillations
periods in the range of 13–58 min when the ITPG concentration was varied [22], indicating tunability.
Sensors 2018, 18, 1544 14 of 30
Figure
Figure Oscillationsin
18.18.Oscillations in the concentrationofofx by
the concentration thethe
x by dual feedback
dual oscillator.
feedback oscillator.
2.2.7.
2.2.7. Fussenegger
Fussenegger Oscillator
Oscillator
TheThe Fussenegger oscillator is a synthetic mammalian oscillator based on an autoregulated
Fussenegger oscillator is a synthetic mammalian oscillator based on an autoregulated sense–
sense-antisense transcription control circuit encoding a positive and a time-delayed negative feedback
antisense transcription control circuit encoding a positive and a time-delayed negative feedback loop,
loop, enabling autonomous, self-sustained oscillatory gene expression [23]. The sense strand of RNA
enabling autonomous, self-sustained oscillatory gene expression [23]. The sense strand of RNA (or
(or antisense strand of DNA) is the strand used for the translation of a protein (or transcription of
antisense strand
the mRNA), of DNA)
whereas is the strand
the antisense strandused for the
of RNA translation
(or sense strand ofof DNA)
a protein
does(or transcription
nothing. However,of the
mRNA), whereas the antisense strand of RNA (or sense strand of DNA) does
when the sense and antisense strands of RNA form a complex just like a double helix DNA, translation nothing. However,
whencan the sense and
be inhibited. Thisantisense strands
is the underlying of RNA
principle form
of the a complex
negative feedbackjust like
of the a doubleoscillator.
Fussenegger helix DNA,
translation can be oscillator
The Fussenegger inhibited.comprises
This is two
the genes,
underlying
x and principle of theinvolves
y, one of which negativebothfeedback
sense andof the
Fussenegger oscillator. The
antisense transcription Fussenegger
(Figure oscillator
19a). The sense comprises
transcript two genes,
of x is translated, the𝑥resulting
and 𝑦, protein
one of Xwhich
feeding
involves backsense
both to itself
and byantisense
promotingtranscription
transcription and activating
(Figure 19a). the
Thesecond
sense gene,
transcript of 𝑥19b).
y (Figure In a
is translated,
first for a synthetic genetic network, this second gene activates the antisense
the resulting protein X feeding back to itself by promoting transcription and activating the secondtranscription of the first
gene;
gene, the transcript
𝑦 (Figure Inisanot translated, insteadgenetic
it hybridizes withthis
the second
sense transcript, repressing the
Sensors 2018, 18, 19b).
x FOR PEER first
REVIEWfor a synthetic network, gene activates the
15 antisense
of 30
production of X at translation [32].
transcription of the first gene; the transcript is not translated, instead it hybridizes with the sense
transcript, repressing the production of X at translation [32].
_
𝑥 𝑦 _
𝑥 y
(a) (b)
Figure 19. Fussenegger oscillator: (a) symbolic representation (b) schematic representation depicting
the internal pathways. The grey colored lines represent
represent the
the hybridization
hybridization path.
path.
The Fussenegger
The Fussenegger oscillator
oscillator has
has one
one ofof the
the highest
highest periods
periods obtained
obtained from
from aa synthetic
synthetic oscillator,
oscillator,
averaging in the order of hours (~15 h), as shown in Figure 20. On the contrary, wet
averaging in the order of hours (~15 h), as shown in Figure 20. On the contrary, wet lab experiments lab experiments
show average
show average periods
periods ranging
ranging inin the
the order
order ofof minutes
minutes (170(170 ±
± 71
71 min),
min), far
far less that the
less that the simulated
simulated
oscillations. To match the simulation results to those of the experimental results,
oscillations. To match the simulation results to those of the experimental results, a refined mathematical a refined
mathematical
model model
(Equations (1.1)(Equations (1.1) and
and (1.5) were (1.5) by
replaced were replaced
Equations by and
(1.21) Equations
(1.22), (1.21) and (1.22),
respectively [23])
respectively [23]) with estimated parameter values (see [23], supplementary materials)
with estimated parameter values (see [23], supplementary materials) was designed and matching was designed
and matching
results results were
were obtained (seeobtained
Figure 4c (see Figure
[23]). An4calternative
[23]). An alternative
oscillator oscillator was developed
was developed in
in [111] to
[111] to make the first-generation oscillator [23] insensitive to component fluctuations. This resulted
in a low-frequency oscillator.
show average periods ranging in the order of minutes (170 ± 71 min), far less that the simulated
oscillations. To match the simulation results to those of the experimental results, a refined
mathematical model (Equations (1.1) and (1.5) were replaced by Equations (1.21) and (1.22),
respectively [23]) with estimated parameter values (see [23], supplementary materials) was designed
Sensors 2018, 18, 1544 15 of 30
and matching results were obtained (see Figure 4c [23]). An alternative oscillator was developed in
[111] to make the first-generation oscillator [23] insensitive to component fluctuations. This resulted
in amake the first-generation
low-frequency oscillator [23] insensitive to component fluctuations. This resulted in a
oscillator.
low-frequency oscillator.
Figure
Figure20.
20. Oscillations obtained
Oscillations obtained byby
thethe Fussenegger
Fussenegger oscillator.
oscillator.
2.2.8. miRNA-Regulated
2.2.8. miRNA-RegulatedOscillator
Oscillator
AsAs thethe namesuggest,

name suggest, aa miRNA-regulated
miRNA-regulated oscillator
oscillator is one whose
is one whoseoscillations
oscillationsare regulated by
are regulated by
miRNAs (microRNAs) where the miRNA regulation is coupled with feedback
miRNAs (microRNAs) where the miRNA regulation is coupled with feedback loops—either positive loops—either positive
or negative
or negative ororboth.
both.miRNA
miRNA is is an
an RNA
RNAwhich
whichisisnotnottranslated
translatedintointo
a protein
a protein but instead, through
but instead, through
base-pairing with a target mRNA, leads to post-transcriptional/translational repression, thereby
base-pairing with a target mRNA, leads to post-transcriptional/translational repression, thereby
inhibiting protein generation [112,113]. Based on this feature of miRNA, an oscillator model was
inhibiting protein generation [112,113]. Based on this feature of miRNA, an oscillator model was
proposed by Gerard and Novak [25]. The model rests on a negative feedback loop where mRNA (X)
proposed
encodesby theGerard
Sensors 2018, 18, and
of aNovak
x FOR PEER
synthesis
REVIEW [25]. The model rests on a negative feedback loop where16mRNA
protein (Y), which acts as the repressor. The latter represses the synthesis of
of 30 (X)
encodes
messengerthe synthesis of a protein
RNA. By forming (Y), which
an inhibitory acts as
complex withthemRNA,
repressor.
miRNA The(Xlatter represses
i ) inhibitsby
the synthesis
the expression
in Figure 22, the oscillations are formed with n = 4, which is half that of required the original
of of
messenger
the proteinRNA. (FigureBy forming an inhibitory complex with mRNA, miRNA (Xi) inhibits the
21b).
Goodwin oscillator.
expression of the protein (Figure 21b).
This model resembles the Goodwin oscillator but with the addition of the miRNA process
_
(Figure 21a). In fact, the additional process introduces a larger delay which relaxes the need for an
𝑥
_
unrealistically large Hill coefficient value (n > 8) to generate the oscillations i (at least eight molecules
of repressors must bind in a complex to be able to repress the expression of the gene [25]). As shown
_
(a) (b)
Figure 21. miRNA-regulated oscillator: (a) symbolic representation; (b) schematic representation
depicting the internal pathways.
This model resembles the Goodwin oscillator but with the addition of the miRNA process
(Figure 21a). In fact, the additional process introduces a larger delay which relaxes the need for an
unrealistically large Hill coefficient value (n > 8) to generate the oscillations (at least eight molecules of
repressors must bind in a complex to be able to repress the expression of the gene [25]). As shown
in Figure 22, the oscillations are formed with n = 4, which is half that of required by the original
Goodwin oscillator.
Figure 22. Oscillations formed in the concentration of the protein by the miRNA-regulated
Goodwin oscillator.
(a) (b)
_
Figure 21. miRNA-regulated𝑥 oscillator: (a) symbolic representation;i (b) schematic representation
_
_
Sensors 2018, 18, 1544 16 of 30
𝑥
(a) (b)
Figure
Figure Oscillations
22.22. formed
Oscillations in the
formed inconcentration of the protein
the concentration by the miRNA-regulated
of the protein oscillator.
by the miRNA-regulated
Figure 22. Oscillations formed in the concentration of the protein by the miRNA-regulated
oscillator.
oscillator.
2.2.9. Displacillator
Unlike2.2.9.
theDisplacillator
2.2.9. Displacillator aforementioned oscillators, the displacillator [114] is based on a molecular interaction
between DNAUnlike strands called strand
the aforementioned displacement
oscillators, [115]. [114]
the displacillator Fundamentally, a strand
is based on a molecular displacement
interaction
Unlike the
interaction aforementioned
between
involves DNAtwostrands oscillators,
called
DNA strands strand the displacillator
displacement
that compete [115].
with [114]to is
Fundamentally,
each other based
bind a to onsame
strand
the a molecular
displacement interaction
complementary
between
strand.DNA
As shown strands
interaction called
involves
in Figure
two strand 1 displacement
DNA
23, strand competes with[115].
strands that compete
strandFundamentally,
with each other to bind a strand displacement
to the
2 to bind to the complementary
same
strand
complementary strand. As shown in Figure 23, strand 1 competes with strand 2 to bind to the
interaction
resulting involves
incomplementary twostrand
the displacement DNA of strands
strand 2. that
The compete
displacement with
can each
occur in other
the to
reverse
resulting in the displacement of strand 2. The displacement can occur in the
bind
directionto the same
where
complementary strand.
strand 2 displaces
reverse strand
directionAs 1.shown
where strand 2in Figure
displaces 23,1.strand 1 competes with strand 2 to bind to the
strand
complementary strand resulting in the displacement of strand 2. The displacement can occur in the
Strand 1 Strand 2
reverse direction where strand 2 displaces strand 1.
+ ⇌ ⇌ ⇌ ⇌ +
Strand 2 Strand 1
Strand 1 Complementary Strand 2

strand
+ ⇌ ⇌ ⇌
Figure 23. Illustration of a DNA strand displacement between two strands that share the same ⇌ +
Strand
Figure Strand
23. 2Illustration of a DNA strand displacement between two strands that share the same 1
sequence
sequence (black line), allowing them to bind the same complementary strand.
(black line), allowing them to bind the same complementary strand.
Complementary Based on the aforementioned mechanism, three strands or molecules become interlinked with
strand
Based on other
each (Figure 24a). The displacillator
the aforementioned mechanism, involves
three several strand
strands ordisplacement
moleculesinteractions that are
become interlinked with
cascaded, as shown in Figure 24b. In the first reaction of the cascade, strand (or molecule) X is
each other
Figure 23. (Figure
consumed
24a).
Illustration The
of amore
to generate
displacillator
DNA strand
Y, which
involves
displacement
is further
several
consumed in
strand
between
the secondtwo
displacement
strands
reaction
interactions
that more
to generate share that
Z, the same
are cascaded,
sequence and as shown
finally,
(black line), in Figure
Z isallowing
consumed in 24b.
them toIn
the third the the
firstto
reaction
bind reaction
generate
same of the
more
complementary cascade,
X, completing strand (or molecule)
the cascading
strand. loop. X is
consumedHowever,
to generate this figure
more isY,anwhich
oversimplification of the reaction,
is further consumed in as
thethesecond
strands reaction
on the lefttoside of the more Z,
generate
and finally,
Based on Z theis aforementioned
consumed in the third reaction to
mechanism, generate
three strands more orX, completing
molecules the cascading
become loop. with
interlinked
each other (Figure 24a). The displacillator involves several strand displacement interactionsthe
However, this figure is an oversimplification of the reaction, as the strands on the left side of that are
reaction do not2018,
Sensors directly
18, x FORinteract
PEER REVIEWwith one another. Instead, additional DNA complexes called fuels
17 of 30
cascaded, as shown in Figure 24b. In the first reaction of the cascade, strand (or molecule) X is
are used to facilitate the reaction. These fuel complexes undergo a two-step stand displacement on
consumed toreaction
generate do not more Y, interact
directly whichwith is further consumed
one another. in the DNA
Instead, additional second reaction
complexes calledto generate more Z,
fuels
each side of the reaction aided by the strands themselves or other fuel strands, as depicted in Figure 25.
are used to facilitate the reaction. These fuel complexes undergo a two-step stand displacement on
andThe
finally, Z is
oscillations consumed in the third reaction to generate more X,
26. as depicted in Figure 25. cascading loop.
completing the
each sideobserved in the
of the reaction displacillator
aided are shown
by the strands themselves in Figure
or other fuel strands,
However, this figure is an oversimplification of the reaction, as the strands on the left side of the
+ →2
+ →2
+ →2
(a) (b)
Displacillator:
Figure 24.Figure (a) symbolic
24. Displacillator: representation;
(a) symbolic (b)
representation; (b) schematic
representation of the cascading
of the cascading
strand displacement
strand displacement interactions.
interactions.
Strand Y
+ Strand X
⇌ Strand Y
+ Strand Y
Strand Y
Strand Y
(1) Fuel 1 complex Waste complex

+ →2
(a) (b)
+ →2
Figure 24. Displacillator: (a) symbolic representation; (b) schematic representation of the cascading
Sensorsstrand
2018, 18, 1544
displacement interactions. 17 of 30
+ →2
+
Strand Y
+ Strand X
⇌ Strand Y
+ →2Strand Y
(a) (b) Strand Y
Strand Y
Figure 24. Displacillator: (a) symbolic representation; (b) schematic representation of the cascading
(1)
strand displacement Fuel 1 complex
interactions. Waste complex
(4)
Fuel 2 strand Fuel 4 strand
Strand Y
+ Strand X
⇌ Strand Y
+ Strand Y
Strand Y
Strand Y
Strand X Strand Y
(1) Fuel 1 complex Waste complex
(4)
Fuel 2 strand Fuel 4 strand
(2) Fuel 3 strand Fuel 3 strand (3)
Waste complex Fuel 3 complex
Strand X Strand Y part of the cascade. (1) Strand Y

Figure 25. Strand displacement implementation illustrating the first
Figureto25.
binds theStrand
Fuel 1displacement implementation
complex through illustrating
strand displacement. the firstXpart
(2) Strand also of the to
binds cascade. (1)1 Strand
the Fuel complex Y
binds to the
through Fueldisplacement,
strand 1 complex through strand
releasing displacement.
the Fuel 3 strand. (2)(3) The X
Strand also3binds
Fuel strandtobinds
the Fuel 1 complex
to the Fuel 3
(2) Fuel 3 strand (3)
through strand
complex throughdisplacement, releasingreleasing
strand displacement, the Fuelthe firstFuel
3 strand. 3 strand
(3) TheYFuel
Y strand from3thestrand binds(4)
complex. to The
the Fuel
Fuel 34
complex through strand displacement, releasing the first Y strand Y from the complex.
strand also binds to the Fuel 3 complex through strand displacement, releasing the second Y strand. (4) The Fuel 4
strand also binds to the Fuel 3 complex through strand displacement, releasing the second Y strand.
Waste complex Fuel 3 complex
Unlike their natural counterparts, the synthetic oscillators described above could be embedded
within a nanomachine allowing constant availability of the timing information to a nanomachine and
Concentration (nM)
Figure 25. Strand displacement

This implementation illustrating such
the first part ofastheit cascade. (1) Strand Y
its communication modules. 10 main advantage of Y
is the systems allows network-related
binds
services to the
such asFuel
data1 complex through strand scheduling
aggregation/fusion, (2) Strand X time-divided
displacement.techniques, also binds to thechannel
Fuel 1 complex
access, etc.
to be realized. However, it may require the oscillators to beZsynchronized relatively, meaning
through strand displacement, releasing the Fuel 3 strand. (3) The Fuel 3 strand binds to the Fuel 3 each
through strand displacement, 5 releasing the first Y strand Y
oscillator may synchronize with other oscillators using the information about clock drift Fuel
complex from the complex. (4) The and4clock
offsetstrand
or to also binds to the Fuel
be synchronized 3 complexmeaning
absolutely, through strand displacement,
the oscillators releasingto
synchronize thea second
global Y strand.
time.
X
0
0 30 60
Concentration (nM)
Time (hours)
10 Y
Figure 26. Oscillations observed in individual strands of the displacillator (see [114], supplementary
Z
materials). From Niranjan Srinivas, James Parkin, Georg Seelig, Erik Winfree, David Soloveichik,
5
X
0
0 30 60
Time (hours)
Figure 26. Oscillations

Figure 26. observed in
Oscillations observed in individual
individual strands
strands of
of the
the displacillator (see [114],
displacillator (see [114], supplementary
supplementary
materials). From Niranjan Srinivas, James Parkin, Georg Seelig, Erik Winfree,
materials). From Niranjan Srinivas, James Parkin, Georg Seelig, Erik Winfree, David David Soloveichik,
Soloveichik,
Enzyme-free nucleic acid dynamical systems, Science, 358, December, 2017. Reprinted with permission
from AAAS.
In Table 2, we summarize the characteristics of the synthetic oscillators and list them in the
ascending order of oscillation frequency. In terms of the number of cells that successfully oscillate,
the dual feedback oscillator can achieve a very high success rate, with 99% of the cells achieving
oscillations. The metabolator comes in second with a success rate of 60%. Common to both these
Sensors 2018, 18, 1544 18 of 30
oscillators are the positive and negative feedback loops inherent in the models. With a success rate
below 50%, the repressilator is third and interestingly, it does not involve a positive feedback loop.
While there could be other intrinsic factors such as the values of the system design parameters, having
both positive and negative feedback loops seems to have a positive impact on the success rate.
Table 2. Overview of synthetic oscillators.
Frequency: Oscillations Process Involved

Oscillator Year
Theoretical/Experimental Observed in the Oscillations
miRNA-regulated Post-transcription
2013 [25] 11.57 µHz/n.a n.a.
oscillator regulation
Strand
Displacillator 2017 [114] 0.0139 mHz/0.0139 mHz n.a.
displacement
Fussenegger Post-transcription
2009 [23] 0.019 mHz/0.098 ± 0.23 mHz n.a.
Transcription
Atkinson oscillator 2003 [106] 0.028 mHz/0.02 mHz n.a.
regulation
Transcription
Repressilator 2000 [21] 0.11 mHz/0.1 ± 0.42 mHz 40%
regulation
Dual feedback Transcription
2008 [22] 0.38 mHz/0.42 mHz 99%
Transcription
Hasty oscillator 2001 [107] (0.38–2.08) mHz/n.a. n.a.
regulation
Metabolic and
Metabolator 2005 [108] 0.42 mHz/1.67 ± 0.37 mHz 60% transcription
regulation
Transcription
Goodwin oscillator 1963 [100] 0.56 mHz/n.a. n.a.
regulation
2.3. Oscillators Specific to the Nanonetwork

In Section 2.2, we examined and reviewed the synthetic oscillators that were strictly developed by
biologists and, in a way, can be thought of as endeavors to identify new methods of engineering systems
at the molecular level. Having said that, the nanonetwork research community have also proposed
oscillatory systems whose mechanisms are largely inspired by natural oscillators or mechanisms
to perform and provide functions pertaining to communication devices. We discuss them in the
subsequent paragraphs.
2.3.1. Moore Oscillator

In [29,116], the authors proposed a system with auto-inhibitory molecules to generate oscillations.
The mechanism that drives the oscillator is based on a naturally occurring phenomenon, wherein,
the coupling of two feedback signals, excitatory and delayed inhibitory, results in oscillations [117].
The excitatory path is formed when the type x molecules chemically react to release a pulse of type X
molecules. Type X molecules are of inhibitory nature and therefore, once released into the environment,
they begin to inhibit the type x from further generation of X pulses, forming delayed inhibitory
feedback (Figure 27). Then, as the type X molecules disperse into the environment, their concentration
around x decreases. Beyond a certain concertation level, they can no longer inhibit x, and therefore,
x can then release the next pulse of type X molecules. The attainment of the lower threshold marks
the completion of one oscillation cycle. The quick release and slow dispersion gives the oscillation
a relaxation oscillator attribute. These processes keep repeating, forming oscillations. The period of
oscillation can range between 15–25 s (Figure 28). In some ways, the Moore oscillator resembles the
Goodwin oscillator [100,101].
𝑥, and therefore,
the oscillation 𝑥 can oscillator
a relaxation attribute.
then release the next These type X molecules.
processes
pulse of keep repeating, forming
The attainment of oscillations.
the lower
threshold marks the completion of one oscillation cycle. The quick release and slow dispersion
The period of oscillation can range between 15–25 s (Figure 28). In some ways, the Moore oscillator gives
the oscillation
resembles the Goodwina relaxation oscillator
oscillator attribute. These processes keep repeating, forming oscillations.
[100,101].
The period of oscillation can range between 15–25 s (Figure 28). In some ways, the Moore oscillator
resembles
Sensors 2018, the Goodwin
18, 1544 oscillator [100,101]. 19 of 30
𝑥 _
𝑥 _
Figure 27. Schematic diagram of the Moore oscillator.
Figure 28. Time evolution of the period of oscillation obtained by Moore oscillator.
FigureFigure
28. Time evolution
28. Time of the
evolution period
of the of of
period oscillation
oscillationobtained
obtained by
by Moore oscillator.
Moore oscillator.
2.3.2. Akgül Oscillator
In another study [30], the authors proposed an oscillatory system that is regulated by auto-
Ininducing
another study study
In another
molecules. [30],Besides
the
[30],authors
the proposed
authors
the fact that proposedan oscillatory system
an oscillatory
the auto-inducers that that
system
facilitate their is regulated
own isgeneration,
regulated by the
auto-
by
auto-inducing
inducing molecules.
proposed molecules.
systemBesidesworks atthe Besides
thefact the fact
that level.
network that the auto-inducers
the auto-inducers
The basis of this facilitate
facilitate their
oscillator their
is alsoown own
from generation,
generation,
a naturallythe
the proposed
occurring
proposed systemat
systemphenomenon
works works at theasnetwork
known
the network level.level.
quorum The The
sensing basis
[118].
basis of this
of When
this aoscillator isis also
nanomachine
oscillator alsosenses
from
froma athe naturally
auto-
naturally
occurring
inducers
occurring phenomenon
in the environment,
phenomenon known
known as as quorum
it immediatelysensing
quorum sensing [118].
releases When
the When
[118]. a nanomachine
auto-inducer. senses the
The releasedsenses
a nanomachine auto-inducers
auto-inducing
the auto-
in the environment,
molecules propagate it immediately
via diffusion releases
to otherthenanomachines,
auto-inducer. The released
causing themauto-inducing
to release molecules
more auto-
inducers in the environment, it immediately releases the auto-inducer. The released auto-inducing
propagate via diffusionEvery to other nanomachines, causingthis
them to release more auto-inducing molecules.
molecules propagate via diffusion to other nanomachines, causing them to release more the
inducing molecules. nanomachine performs type of chain reaction process until auto-
Every nanomachine
concentration performs this
of the auto-inducer type of
reaches chain upper
a certain reaction process Once
threshold. until the
the concentration
concentrationreaches of the
inducing molecules.
Sensors
auto-inducer
Every
2018, 18, x a
reaches FOR nanomachine
PEER REVIEW
certain
performs this type of chain reaction
upper threshold. Once the concentration reaches the upper
process until the
20 of 30 threshold,
concentration of the auto-inducer
the nanomachine halts the releasereaches a certain
of the upper threshold.
auto-inducers, Once the
and this action causes concentration
a decrease in reaches
the
the upper threshold, the nanomachine halts the release of the auto-inducers, and this action causes a
concentration of the
decrease auto-inducers.
in the concentration of As the concentration
the auto-inducers. falls to a lower
As the concentration falls tothreshold, the nanomachines
a lower threshold, the
nanomachines begin to release the auto-inducers, causing a rise in the concentration
begin to release the auto-inducers, causing a rise in the concentration again (Figure 29). again (Figure
The resultant
29). The resultant periodic increase and decrease in the concentration of the auto-inducers constitutes
periodic increase and decrease in the concentration of the auto-inducers constitutes the oscillations.
the oscillations. An oscillation period of about 10 s can be achieved, as shown in Figure 30.
An oscillation period of about 10 s can be achieved, as shown in Figure 30.
is sensed and concentration

is below threshold
is sensed and
concentration reaches
threshold
Figure 29. Schematic diagram of the Akgül oscillator. The arrow with the crossed line indicates that X
Figure 29. Schematic diagram of the Akgül oscillator. The arrow with the crossed line indicates that
is not generated.
X is not generated.
threshold
Figure 29. Schematic diagram of the Akgül oscillator. The arrow with the crossed line indicates that
X is not
Sensors generated.
2018, 18, 1544 20 of 30
Figure 30. 30.

Figure Global
Globaloscillations
oscillationsgenerated
generated in the
the concentration
concentrationofof
thethe auto-inducing
auto-inducing molecule
molecule by the
by the
Akgül
Akgül oscillator.
oscillator.
2.3.3.
2.3.3. Shitiri
Shitiri Oscillator
Oscillator
A more
A more recent
recent study[31]
study [31]has
has proposed
proposed aa system
systemthat thatuses
usesexcitatory
excitatorymolecules
molecules to generate
to generate
oscillations with a higher frequency. It draws inspiration from Ca 2+ oscillators [85]. It employs three
oscillations with a higher frequency. It draws inspiration from Ca oscillators [85]. It employs three
2+
types of excitatory molecules (X, Y, and Z) that work in tandem to generate oscillatory patterns in
types of excitatory molecules (X, Y, and Z) that work in tandem to generate oscillatory patterns in the
the concentration of molecule Y. In addition, the system consists of an internal store of Y molecules.
concentration of molecule Y. In addition, the system consists of an internal store of Y molecules. When
When the X molecules bind to the biphasic receptors that are in the internal store [79], the Y molecules
the X
aremolecules bind to the
released, increasing biphasic receptors
the concentration that are
of Y outside in theAsinternal
the store. store
Y increases, [79],
this causes Y molecules
thethe receptors are
released, increasing
to shut, the concentration
thereby stopping any further of Y outside
outflow the store. As
of Y molecules. ThisY step,
increases, this causes
along with the receptors
the Y molecules
to shut,
beingthereby
pumped stopping
back intoany thefurther outflow
store, forms of Y molecules.
the negative feedbackThisloopstep, along
of the system.withAtthe Y stage,
this molecules
being pumped back into the store, forms the negative feedback loop of
the concentrations of the X and Y molecules decline. However, during the increase in Y molecules,the system. At this stage, the
concentrations
the Y moleculesof the X and
trigger theYreproduction
molecules decline. However,
of X molecules during the
by chemically increase
reacting withinthe YZ molecules.the Y
molecules,
molecules trigger the reproduction of X molecules by chemically reacting with the Z molecules.
This causes the concentration of X molecules to increase, and the whole cycle begins again. Figure 31 This
illustrates
causes the process.
the concentration Axof
Sensors 2018, 18, FORX
period of oscillation
molecules
PEER REVIEW of about 2 and
to increase, s can the
be achieved
whole cycle (Figurebegins
2132).
of 30 again. Figure 31
illustrates the process. A period of oscillation of about 2 s can be achieved (Figure 32).
Figure 31. Schematic diagram of the Shitiri oscillator. The rectangular box represents the storage unit
Figure 31. Schematic diagram of the Shitiri oscillator. The rectangular box represents the storage unit of Y.
of Y.
These oscillators have been designed with consideration of the nanonetwork and its applications.
Similar to the synthetic oscillators presented in Section 2.2, the aforementioned oscillators could be
embedded into a nanomachine. In addition to the communication-related services mentioned in
Section 2.2, the aforementioned oscillators could allow the correct decoding of signals or even allow
faster data rates. However, what they lack is laboratory validation.
Figure 32. Oscillations in the concentration of the Y molecule generated by the Shitiri oscillator.
These oscillators have been designed with consideration of the nanonetwork and its
applications. Similar to the synthetic oscillators presented in Section 2.2, the aforementioned
Figure 31. Schematic diagram of the Shitiri oscillator. The rectangular box represents the storage unit
of Y.2018, 18, 1544
Sensors 21 of 30
Figure
Figure 32.32. Oscillationsininthe
Oscillations the concentration theY Ymolecule
concentration ofofthe moleculegenerated by the
generated byShitiri oscillator.
the Shitiri oscillator.
Tableoscillators
These 3 summarizes the characteristics
have been designed of the aforementioned
with consideration oscillators
of and,
the asnanonetwork
one would expect, and its
none of them
applications. share the
Similar to same process foroscillators
the synthetic generating the oscillations.
presented Interestingly,
in Section 2.2, these oscillators
the aforementioned
have higher
oscillators could frequencies
be embeddedcompared
into atonanomachine.
those listed in Table 2, at least
In addition to in
theprinciple.
communication-related services
mentioned in Section 2.2, the aforementioned oscillators could allow the correct decoding of signals
Table 3. Overview of oscillators specific to the nanonetwork.
or even allow faster data rates. However, what they lack is laboratory validation.
Table 3 summarizes
Oscillator Year
the characteristics
Frequency: of the Oscillations
aforementioned oscillators and, as one would
Process Involved in the Oscillations
Theoretical/Experimental Observed
expect, none of them share the same process for generating the oscillations. Interestingly, these
Moore oscillator 2013 [29] 50 mHz–mHz/n.a. n.a.
oscillators have higher
Akgül oscillator
frequencies
2014 [30]
compared to those listed
100 mHz/n.a. n.a.
in Table 2, atAuto-inhibition
least in principle.
Auto-inducer
Shitiri oscillator 2016 [31] 500 mHz/n.a. n.a. Molecule-receptor interactions
Table 3. Overview of oscillators specific to the nanonetwork.
Table 4 provides a qualitative comparison of the synthetic oscillators presented in this study.
Frequency: Oscillations Process Involved in
Oscillator is a measure
Robustness Year of the number of oscillators in a nanonetwork that achieve oscillations. Simply
Theoretical/Experimental
put, it is the ability of an oscillator to overcome the molecularObserved
noise (more details the Oscillations
in Section 3.1) and
Moore oscillations
produce 2013 as desired. Tunability is the ability of an oscillator to modify the frequency of
50 mHz–mHz/n.a. n.a. Auto-inhibition
oscillator
oscillations when [29]a specific trigger is applied. This feature enables the rectification of clock skew, if it
Akgülbetween2014
exists, the oscillators. From Table 4, we can infer that the combination of a positive and a
100 mHz/n.a. n.a. Auto-inducer
negative
oscillator feedback
[30]loop improves the robustness. When more than one of these combinations exists,
the robustness is
Shitiri very high, as in the case of the dual feedback oscillator. However,
2016 we can also infer
Molecule–receptor
that when more than one negative 500 mHz/n.a.
feedback loop is combined n.a.sufficient delay, improvements
with
oscillator [31] interactions
in the robustness are observed, as in the case of the repressilator. From these inferences, we can
cautiously acquire some insight into the robustness of the Moore and Shitiri oscillators—i.e., they are
highly robust. With regard to tunability, less than half of previous works analyzed tunability in
their experiments, with two-thirds reporting tunability. Although not shown in the Table 4, natural
oscillators, in general, are tunable. With that being said, Moore, Akgül, and Shitiri oscillators should be
able to exhibit tunability as they are based on natural oscillators. To some degree, the Shitiri oscillator
has been shown to modify the oscillations in response to changes in the initial concentrations of the
stimuli. Table 5 presents a summary of the advantages, disadvantages, types (manner in which the
oscillators convey the time information), and frequencies of the biological oscillators.
Sensors 2018, 18, 1544 22 of 30
Table 4. Qualitative comparisons of the synthetic oscillators.
Model-to-Wet
Oscillator Feedback Loops Robustness Tunability Oscillations
Lab Agreement
Goodwin oscillator One self-(−) Bad Low No Sustained
Repressilator Three (−) Good Medium n.a. Sustained
One self-(−) and
Atkinson oscillator Excellent n.a. n.a. Damped
one (−)
One self-(±), one (±),
Hasty oscillator n.a. n.a. n.a. Sustained
and one (−)
Metabolator One (−) and one (+) Good Medium n.a. Sustained
One (−), one self-(−),
Dual feedback
one (+), and one Good High Yes Sustained
oscillator
self-(+)
Fussenegger One self-(−) and Good after
n.a. n.a. Damped
oscillator one (−) revision
miRNA-regulated One self-(−) and one
n.a. n.a. n.a. Sustained
oscillator coupled (−)
Displacillator Three (+) Good n.a. Yes Damped
Two self-(−) and
Moore oscillator n.a. n.a. n.a. Sustained
two (−)
Akgül oscillator One self-(+) n.a. n.a. n.a. Sustained
Two self-(−) and
Shitiri oscillator n.a. n.a. Yes Sustained
one (+)
Table 5. Summary of biological oscillators.
Oscillator Advantages Disadvantages Type Frequencies

Not embedded into
Close proximity
a nanomachine
Natural Additional Broadcasting only Low
Simpler to
interfacing
implement
Embedded into a
nanomachine Synchronization Peer-to-peer or
Synthetic Low–medium
Allows more required broadcasting
functionalities
Embedded into a Synchronization
Synthetic nanomachine required Peer-to-peer or
Medium–high
nanonetwork Allows more Lacks laboratory broadcasting
functionalities validation
3. Open Research Issues
3.1. Noise
Gene expression, which is one of the main processes that is responsible for the oscillations
in the synthetic oscillators discussed in Section 2.2, involves a series of biochemical processes that
are discrete in nature, causing molecular noise [119]. This noise is fundamentally made up of two
components—intrinsic and extrinsic noises. Intrinsic noises, also referred to as the inherent stochasticity,
are the variations in the rate of a particular gene’s expression among identical cells due to microscopic
events that govern which reaction occurs and in what order [119]. On the other hand, extrinsic noises
are the fluctuations in the output of the gene due to the fluctuations in the amount or activity of
the regulatory molecules (proteins and polymerases). This is because the expression of each gene
Sensors 2018, 18, 1544 23 of 30
is controlled by the concentrations, states, and locations of the regulatory molecules [119]. In fact,
√
molecular noise is inversely proportional to the (number of molecules) [120].
To take into account the effects of molecular noise on the oscillatory behavior, stochastic
numerical models [121,122] are preferred over deterministic differential equation models. Nonetheless,
deterministic models provide good approximations for oscillatory behavior when molecules in
quantities greater than hundred are present in the oscillatory mechanism [123,124].
The molecular noise can be controlled to a lower level by producing fewer proteins from
numerous mRNA (low translation rate and high transcription rate) or by producing fewer mRNAs
(low transcription rate) but this comes with an energy cost [125]. A further reduction in noise can
be achieved using a negatively auto-regulated transcription system to form a negative loop [126],
echoing why the negative feedback loops are so vital in generating sustained oscillations (as seen in
Section 2). Using a larger amount of molecules can also reduce the noise levels [120]. However, while
the molecular noise may be reduced by using a large number of molecules, the interference between
different species of molecules may increase. Therefore, a tradeoff between noise and interference
arises. Finding the optimal number of molecules that a system can handle without significant noise
and interference remains an open research challenge.
3.2. Design
The oscillators discussed in Section 2.3 lack validation in wet lab experiments. While mathematical
models have been very effective in capturing the complex physical behaviors of the oscillatory systems
and realizing them in computer simulations, it would be highly beneficial for such systems to be
further validated in wet lab experiments. As seen in the case of the Fussenegger oscillator, a significant
difference in the period of oscillation between the results obtained in from computer and wet lab
experiments was obtained. However, a minor revision to the mathematical model corrected the
difference. On the contrary, a very good agreement between the mathematical model and the wet
lab experiments was observed for the Atkinson oscillator. From the latter, it is safe to infer that with
mathematical models, if done correctly, it is possible to replicate results exactly as one would obtain in
the wet lab experiments. Such precise modelling can in fact reduce the requirement of validating the
model in wet lab experiments, at least in the developmental stages, as it should be noted that the time
and cost involved in wet lab experiments is higher than in computer simulations.
One way to ensure that a model will indeed oscillate is to adhere to specific design guidelines,
such as those presented by Novak and Tyson [24]. Four fundamental requirements for the design of an
oscillator are negative feedback, time delay, sufficient non-linearity of reaction kinetics, and proper
balancing of time scales of opposing chemical reactions. An oscillatory system should be able to
return to its starting point, which is achieved through negative feedback. To ensure the chemical
reactions involved in the oscillations do not settle at a stable steady state (no oscillations), the negative
feedback signal must be sufficiently delayed in time, and thereby, obtain sustained oscillations.
Non-linearity is essential to destabilize the steady state and therefore, the kinetic rate laws of the
reaction mechanism must be sufficiently “nonlinear”. The reactions that produce and consume the
interacting chemical species must occur on appropriate timescales that permit the network to generate
oscillations. Such guidelines, therefore, lay the framework for new and novel oscillatory systems to
be designed in principle without having to worry about the correctness of the design, as long as the
requirements are met.
Arguably, a tradeoff between time, cost, and ease of rectification and validation arises. However,
it should also be noted that both techniques complement, rather than oppose, each other. Therefore,
as much as wet lab experiments allow for practical realizations, it would be sufficiently enough to fully
develop and test an oscillatory system using computer simulations as mistakes in the model can be
corrected much easier than in the wet lab.
Sensors 2018, 18, 1544 24 of 30
3.3. Sustainability
Molecules are associated with a finite lifetime. They undergo degradation over the course of time
and as such, oscillations cease to exist. This makes the selection of molecules of utmost importance.
Two methods can be used to enhance the lifetime of the molecules and guarantee the sustainability of
an oscillator. First, molecules that have very long lifetimes or more specifically, longer half-lives must
be carefully selected, such as Ca2+ which can have a half-life of up to months or years [127]. Second,
the degraded molecules must be replaced frequently with newly synthesized molecules of the same
kind. This mechanism is commonly found, as seen in synthetic oscillators, where the periodic process of
transcription and translation generates new molecules of mRNA and protein/metabolites, respectively.
To have an energy efficient system, it would be desirable to use the first method. However,
this requires some sort of storage facility, such as the endoplasmic reticulum found in calcium
oscillators, to store, release, and absorb back a particular molecule—a higher complexity in the
design. On the contrary, the second method does not have the need for a storage facility. However,
due to the constant synthesis of new molecules, a sufficient amount of ATP needs to be available at all
times to carry out the synthesis—a higher or constant energy demand. This creates, to some degree,
a tradeoff between energy and complexity.
3.4. Adoption and Implementation to Nanonetworks

To date, no experimentation validation has been found that shows how an actual transceiver-like
nanomachine works and interacts with other nanomachines or within its communication modules.
This leaves us to cautiously step into the unknown future in the actual realizations of such
nanomachines. Nonetheless, the recent developments in nanotechnology assure us a better future.
Considering this, we outline here a couple of key implementation issues.
3.4.1. Interfacing
As pointed out in Section 3.1, one of the pressing issues is to provide an interface between
a nanomachine and an oscillator. This could be achieved through a special unit, namely the
biomolecule detector, to read the changes in the oscillations and convey the message to a nanomachine.
Such interfacing mainly applies for oscillators that are not embedded within a nanomachine but
can also be extended to those oscillators that are be embedded within a nanomachine. For the ones
embedded in a nanomachine, the challenge lies in passing the information about time in a secure
and fast manner to every communication module. Molecular motors, which are proteins or protein
complexes that transform chemical energy into mechanical work, could act as potential carriers
of timing information [1]. However, investigations into the engineering of biological oscillators to
molecular communication systems and specifics into how these technologies can be incorporated for
potential applications of nanonetworks still remain research challenges.
3.4.2. Matched Oscillators

As pointed out in Section 3.2, another pressing issue is the need to synchronize the oscillators.
We envision two methods to achieve that goal—internal and external. The internal method refers to
cases where a special module, namely the period checker, ensures a constant desired period of oscillations
(or zero clock drift). Equipped with biological sensors, the period checker routinely checks the period
between two consecutive oscillations. If deviations from the desired period are observed, then it will
release a specific molecule to counteract the deviation. Such modifications to the period have been
observed in calcium oscillators [128]. However, this increases the design complexity and may not be
able to handle clock offsets. The external method refers to cases where algorithms and protocols are
designed to estimate the clock drifts and the clock offsets. These methods already exist in traditional
communication networks and are beginning to emerge in the literature for nanonetworks [29,129,130].
Sensors 2018, 18, 1544 25 of 30
Such methods are much simpler to implement but could be prone to channel variation and may have
high energy requirements. Therefore, suitable protocols still need to be developed.
4. Conclusions
Oscillators essentially act as “heartbeats” and provide the necessary timing information to
electronic devices [14]. On that note, it is pertinent for nanomachines to be embedded with oscillators
as nanomachines are envisioned to perform functions such as periodic measurements, coordinated
activity, and scheduled transmissions, etc., all of which are required to be regulated with precise timing.
In a tutorial fashion, we have presented the recent advancements in biological oscillators. We have
broadly classified biological oscillators into two groups—natural and synthetic. As expected, in most
cases, synthetic oscillators have much simpler mechanisms than their natural counterparts. Frequencies
greater than 1.67 mHz have been obtained in-vivo for synthetic oscillators, and frequencies of up
to 1000 mHz have been obtained in natural oscillators. Moreover, in principle, synthetic oscillators
could achieve up to 500 mHz and it remains to be seen if the same can be achieved through wet
lab experiments.
With the necessary framework [24] set up to act as a guide in the design of the oscillators,
we outlined the issues in the physical aspects with regard to molecular noise, the precision of models,
and the lifetime of molecules. To counteract molecular noise without incurring a higher energy cost,
there remains a tradeoff between the number of molecules and the tolerable interference between
different molecules. Another challenge that remains is the precision of the models in comparison to
wet lab experiments. While computer models are easier to correct and require less time to generate
results, adequate care is needed to ensure the precision of the model. Arguably, a tradeoff between
time, cost, and ease of rectification and validation arises. Finally, the effects of the degradation of the
molecules employed in the oscillatory system has to be sufficiently long, and similarly, the lifetime of
the network or suitable molecule replacement mechanisms, such as synthesis, should be incorporated.
This leads to a tradeoff between energy and complexity. We believe that these challenges and issues
will serve as a guide for future research development in biological oscillators.
Additionally, we provided discussions on the issues related to the communication aspects of
the oscillators. Two key issues—namely interfacing and matched oscillators—were identified and
presented as potential future research directions.
Author Contributions: E.S. conducted the literature survey, carried out the computer simulations, and wrote the
paper. A.V.V. and H.-S.C. supervised the research and participated in the data analysis and revision processes.
Funding: This study was supported by the National Research Foundation of Korea (NRF) grant funded by the
Korean Government (MSIP) (2017R1A2B4002622) and the BK21 PLUS project funded by the Ministry of Education,
Korea (21A20131600011).
Conflicts of Interest: The authors declare no conflict of interest.
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Keywords: nanonetworks; molecular communication; biological oscillators; clocks; survey

Sensors 2018, 18, 1544; doi:10.3390/s18051544 www.mdpi.com/journal/sensors

more specifically to nanonetworks, we provide a comprehensive review of biological oscillators

1.2. Main Contributions

Natural oscillators Synthetic oscillators

Glycolytic oscillator Goodwin oscillator

cAMP oscillator Repressilator

Circadian oscillator Hasty oscillator

Calcium oscillator Dual feedback oscillator

Mitotic oscillator Metabolator

Figure 2. Oscillations produced in the phosphofructokinase (PFK) concentrations by a glycolytic

2.1.2. Cyclic Adenosine Monophosphate (cAMP) Oscillator

2.1.3. Circadian Oscillator

2.1.4. Calcium Oscillator

Natural oscillators could Table

Figure 8. Oscillations formed by temporal concentration changes in mRNA(X) by the Goodwin

2.2.3. Atkinson Oscillator

Figure 11.Figure 11. Atkinson

2.2.4. Hasty Oscillator

Figure 15. Metabolator:

AsAs thethe namesuggest,

Strand 1 Complementary Strand 2

(1) Fuel 1 complex Waste complex

Waste complex Fuel 3 complex

Strand X Strand Y part of the cascade. (1) Strand Y

Figure 25. Strand displacement

Figure 26. Oscillations

Table 2. Overview of synthetic oscillators.

Frequency: Oscillations Process Involved

2.3. Oscillators Specific to the Nanonetwork

2.3.1. Moore Oscillator

is sensed and concentration

Figure 30. 30.

Table 4. Qualitative comparisons of the synthetic oscillators.

Table 5. Summary of biological oscillators.

Oscillator Advantages Disadvantages Type Frequencies

3. Open Research Issues

3.4. Adoption and Implementation to Nanonetworks

3.4.2. Matched Oscillators

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