Part Recent Research and

Development in Molecular
Communication Technology
Molecular Communication: Biological
Communications Technology
NAKANO Tadashi, Michael Moore, ENOMOTO Akihiro, and SUDA Tatsuya
This article provides a comprehensive overview of state-of-the art research on molecular
communication a molecule-based communication paradigm for biological machines. Unlike current telecommunications based on electric or optical signals, molecular communication exploits
biological molecules as information carriers. In molecular communication, senders of communication encode information onto molecules and transmit to the environment. The information
coded molecules then propagate in the environment to reach receivers of communication, which
capture and biochemically react to the molecules (i.e., decode the information from the information carrying molecules). Since biological molecules are compatible with biological systems, molecular communication is expected to impact medical domains such as human health monitoring
where implant biological machines interact with biological cells through molecular communication. This article describes key concepts, architecture, potential applications of molecular communication as well as existing research on engineering molecular communication components
and systems.

Keywords
Molecular communication, Biological communications, Communication engineering

1 Introduction
Biological nanomachines (or nanomachines, for short) are nanoscale to microscale
devices that either exist in the biological world
or are artificially created from biological
materials and that perform simple functions
such as sensing, logic, and actuation. Example
nanomachines from the biological world
include biological cells[4], molecular motors
that produce mechanical work using chemical

energy[46], and any biochemical molecules,

complexes, circuits that act as processing
units[10] while examples of synthetic biological nanomachines are artificial molecular
machines[35] and genetically engineered biological cells that are programmed to produce
intended functions[15][19][23][56].
Molecular communication is a new paradigm for communication between nanomachines over a short (nanoscale or microscale)
range[28]. In molecular communication, infor-

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75

mation is encoded to and decoded from molecules, rather than electrons or electromagnetic
waves. Using electrons or electromagnetic
waves for communication is particularly limited at the nanoscale and microscale range
because of power constraints and physical
limitations in the size and nature of communication components (i.e., biological nanomachines). Because nanomachines are too small
and simple to communicate using electrons or
electromagnetic waves, molecular communication provides a novel mechanism for
nanomachines to communicate by propagating
molecules that represent information.
A promising area that molecular communication contributes to is medical domains[36].
Imagine that a biological system (e.g., the
human body) is composed of a large number
of cells (i.e., nanomachines), that each cell
performs simple and specific operations such
as uptake, processing, and release of molecules, and that cells interact to perform various functions of the body (e.g., distributing
molecules for metabolism and replication of
cells). Molecular communication provides
mechanisms to transport molecules between
cells, and thus, it may help perform targeted
delivery of drugs by providing mechanisms to
transport drugs (information-encoded molecules) between drug repositories embedded in
a human body (sender nanomachines) and
specific cells in a human body (receiver
nanomachines). Molecular communication
also provides mechanisms for nanomachines
to communicate, and thus, it may help drug
repositories (sender nanomachines) to coordinate and control the amount and timing of
drug release. Targeting delivery of drugs to
specific cells in a human body and creating
molecular communication for such applications involve understanding how molecules
are transported within a biological system,
how molecules are addressed to specific locations within a biological system (i.e., molecule-addressing mechanisms in a biological
system), or even adding receptor molecules to
a biological system to produce an addressing
mechanism[5][32][40][47].

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Research on molecular communication has

started since the initial idea of molecular communication was presented in 2005[29]. Existing research on artificially creating molecular
communication is based on understanding the
design of molecular communication in biological systems and on modifying the functionality of existing molecular communication in
biological systems (e.g., [20][28][39][42] ).
Research on theoretical foundations of molecular communication is also underway. The
importance of information theory for small
scale communication systems is addressed
in[2], and research efforts are currently being
made for addressing information theory for
various classes of molecular communication
(e.g., [17][18][33][34][38].)
This article is organized in the following
manner. Section 2 gives an overview of various forms of molecular communication in biological systems. Section 3 describes a generic
architecture of molecular communication
where senders and receivers communicate
using molecules through key communication
processes. Section 4 describes existing
research on engineering molecular communication components and systems, and Section 5
concludes this article.

2 Molecular communication in
biological systems
Molecule-based communication or molecular communication is a common and ubiquitous method by which biological nanomachines communicate. Various modes and
mechanisms of molecular communication are
found within and between cells. In the following, modes and mechanisms of molecular
communication are categorized based on how
signal molecules are propagated, namely,
whether signal molecules simply diffuse in the
environment or they directionally propagate
by consuming chemical energy. The former
type of communication is called passive transport-based molecular communication, and the
latter type active transport-based molecular
communication.

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2.1 Passive transport-based

molecular communication
Passive transport provides a simple
method of propagating signal molecules within a cell and between cells. In passive transport, signal molecules randomly diffuse in all
available directions, making it particularly
suited to environments that are highly dynamic and unpredictable. Passive transport is also
suited to situations in which infrastructure for
communications is not feasible. Passive transport, however, requires a large number of signal molecules to reach a distant destination,
and owing to the random movement of molecules, the time to reach a destination increases
with the square of the distance. Passive transport is also not suitable to propagate large signal molecules in a crowded environment such
as the interior of cells.
In the following, we describe three examples of passive transport-based molecular
communication from biological systems,
including (a) free diffusion-based molecular
communication, (b) gap junction mediated diffusion-based molecular communication, and
(c) reaction-diffusion-based molecular communication.
(a) Free diffusion-based molecular communication: In this mode of molecular communication, cells release signal molecules
(e.g., proteins and peptides) into the extracellular environment, and neighboring
cells capture the signal molecules with protein receptors, resulting in the activation of
a chemical reaction (e.g., increased metabolism or transcription of cellular proteins).
An example of free diffusion-based molecular communication is quorum sensing, a
communication mechanism for bacterial
cells. In quorum sensing, bacterial cells
release an autoinducer, acyl homoserine
lactone (AHL) into the environment, and
detect the concentration of AHL in the
environment, to estimate the number of
nearby bacteria. When the AHL concentration is sufficiently high in the environment,
the bacteria interpret this as a large number
of bacteria in the environment, and thus,

the bacteria start transcribing DNA to perform group functions (e.g., enough bacteria
to generate an infection, form a biofilm, or
generate luminescence)[16].
(b) Gap junction mediated diffusion-based
molecular communication: Diffusion of
signal molecules can be guided through
cell-cell communication channels called
gap junction channels [4] . Gap junction
channels are physical channels formed
between two adjacent cells, connecting the
cytoplasm of the two cells. Gap-junction
channels allow only connected cells to
communicate, enabling coordinated actions
among adjacent cells, such as synchronized heart-beating by cardiomyocytes.
(c) Diffusion-reaction-based molecular
communication: Diffusion of signal molecules can involve biochemical reactions to
achieve a different mode of communication that allows propagation of impulses.
As a result of the quick increase and
decrease of signal molecules in their concentrations, the signal molecules appear as
an impulse that propagates in the environment. For instance, some glial cells produce impulses of calcium ions (Ca2+) for
intercellular communication. The endoplasmic reticulum (ER) in a cell gathers
and stores calcium ions, and when a cell is
stimulated (e.g., by a physical stimulus), it
releases the stored calcium ions from the
ER and the calcium diffuses to adjacent
cells through cell-cell junction channels.
The diffused calcium in turn stimulates the
adjacent cells, causing a chain reaction of
calcium stimulation. Shortly after being
stimulated and releasing calcium, a cell
pumps calcium within the cell back into
the ER and suppresses further stimulation,
thus creating a short impulse of calcium
through the cell. Because the communication propagates in a short impulse of calcium concentration, cells can communicate
at a higher frequency. Neurons similarly
produce ion impulses (called action potentials) that propagate over the length of the
neuron.

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2.2 Active Transport-Based Molecular

Communication
Active transport provides a communication mechanism to directionally transport signal molecules to specific locations. Active
transport can propagate signal molecules over
longer distances (up to meters in length) as
compared with diffusion-based passive transport. Large signal molecules and vesicles diffuse poorly in passive transport because of
their size; on the other hand, active transport
consumes chemical energy and generates sufficient force to directionally transport large
signal molecules [11] . Active transport provides a communication mechanism with a
high degree of reliability even when the number of signal molecules to transport is small.
Because the transport of signal molecules is
directional, the probability of signal molecules
reaching the destination is higher than when
using passive transport, and thus active transport requires fewer signal molecules to perform communication. However, active transport often requires communication infrastructure to produce and maintain the transport,
guide, and interface molecules (e.g., molecular
motors, microtubules filaments, and vesicles).
Active transport of molecules also requires a
regular supply of energy to overcome the
chemical interactions between signal molecules and molecules in the environment.
In the following, we describe two examples of active transport-based molecular communication from biological systems, including
(a) molecular motor-based molecular communication and (b) bacterial motor-based molecular communication.
(a) Molecular motor-based molecular communication: This type of molecular communication is found within a cell where
molecular motors are used to transport signal molecules. A molecular motor is a protein or a protein complex that converts
chemical energy (e.g., ATP hydrolysis)
into mechanical work at the molecular
scale. Inside a cell, molecular motors transport signal molecules or large vesicles
(e.g., liposomes, cell organelles) that con-

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tain signal molecules[46][49][53]. Molecular

motors consume chemical energy (e.g.,
ATP) to transport signal molecules or the
vesicles along the preestablished guide
molecules (e.g., along a star-shaped topology that the guide molecules form inside a
cell).
(b) Bacterial motor-based molecular communication: Bacteria move directionally
based on chemical concentrations in the
environment. Bacteria also exchange DNA
through the process of conjugation. In this
process, two types of bacteria, a sender
bacterium with an F-plasmid (i.e., a genetic sequence that enhances the transfer of
genetic information) and a receiver bacterium without F-plasmid, transfer a DNA
chromosome through a pilus (i.e., a projection from the sender bacterium to the
receiver bacterium forming a bridge for
transmitting DNA). Transfer of DNA
between bacteria may allow the receiver
bacterium to acquire DNA that produces
some useful cellular functionality (e.g.,
protein production, antibiotic resistance).
Therefore, bacteria essentially transport
DNA to other bacteria in the environment[9][52]. The receiver bacterium may
also release pheromones that form a chemical gradient that guides a sender bacterium toward a receiver bacterium (i.e. the
closer to the receiver, the higher the chemical concentration).

3 Molecular communication
architecture
As described in Section 2, there exist varieties of modes and mechanisms of molecular
communication in biological systems. One
may ask whether it is possible to generalize
necessary components and processes for molecular communication. Establishing a generalized architecture for molecular communication may help understand design principles of
biological systems as well as help engineer
artificial biological systems. In this section,
we attempt to describe an abstract architecture

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for molecular communication.

3.1 Generic representation of
molecular communication
Figure 1 depicts a generic molecular communication architecture. It consists of components functioning as information molecules
(i.e., signal molecules such as proteins or ions)
that represent the information to be transmitted[50], sender nanomachines that release the
information molecules (e.g., cells, cellular
organelles, protein machinery), receiver
nanomachines that detect information molecules, and the environment in which the information molecules propagate from the sender
nanomachine to the receiver nanomachine[51].
It may also include transport molecules (e.g.,
molecular motors) that transport information
molecules, guide molecules (e.g. microtubule
or actin filaments) that direct the movement of
transport molecules, and interface molecules
(e.g., vesicles) that allow any type of information molecule to be transported by a transport
molecule[39].
Components of molecular communication
are made up of molecules, and must be
designed with the thought in mind that molecular communication occurs in an aqueous or
air environment, which generates a significant
amount of noise. The noise in the environment
comes from a number of factors. For instance,

the environment contains energy and forces

that constantly interact with the various molecular communication components. Such energy and forces include thermal energy, electrical fields, magnetic fields, and electromagnetic waves (e.g., light energy that is absorbed by
molecules). The environment also contains
molecules and nanomachines that do not participate in molecular communication, and
these generate noise. Such molecules and
nanomachines include solvent molecules (e.g.,
water molecules), solute molecules (e.g., energy molecules necessary to support the
nanomachines), and other nanomachines (e.g.,
nanomachines to maintain chemical concentrations in the environment or act as structural
components). The noise in the environment
determines the degree of randomness in molecular communication (e.g., randomness in the
movement of information molecules and randomness in the timing of, rate of, and energy
for chemical reactions).
3.2 Molecular communication
processes
The components in molecular communication perform the following general phases of
communication (Fig. 1): encoding of information into an information molecule by the
sender nanomachine, sending of the information molecule into the environment, propaga-

Fig.1 Generic representation of molecular communication

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tion of the information molecule through the

environment, receiving of the information
molecule by the receiver nanomachine, and
decoding of the information molecule into a
chemical reaction at the receiver nanomachine.
Encoding
Encoding is the phase during which a
sender nanomachine translates information
into information molecules that the receiver
nanomachine can detect. Information may be
encoded onto the type of information molecules used. Information may also be encoded
in various characteristics of information molecules such as the three-dimensional structure
of the information molecule, in the specific
molecules that compose the information molecules, or in the concentration of information
molecules (the number of information molecules per unit volume of solvent molecules).
The amount of information that a sender
encodes onto a single information molecule is
limited by the molecular structure of a receiver nanomachine. A receiver nanomachine is
capable of only a limited number of configurations; thus, when a receiver nanomachine
receives an information molecule, the receiver
nanomachine receives only the amount of
information corresponding to the number of
configurations possible in the receiver
nanomachine[48]. If a receiver nanomachine
achieves only two configurations, the receiver
nanomachine only understands one bit of
information at a time.
A sender nanomachine may transmit information about which a receiver nanomachine
does not have information. For instance, in
biological systems, certain types of cells communicate through exchanging DNA molecules. An arbitrary DNA sequence is decoded
at a receiving cell into proteins that introduce
new functionality into a receiver cell. If a
sender nanomachine in molecular communication can transmit arbitrary information molecules, it is possible to send new functionality
to the receiver nanomachine.
Sending
Sending is the phase during which a

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sender nanomachine releases information molecules into the environment. A sender

nanomachine may release information molecules by either unbinding the information molecules from the sender nanomachine (e.g., by
budding vesicles from a biological cell if a
sender nanomachine is a biological cell with
endoplasmic reticulum), or by opening a gate
that allows the information molecule to diffuse away (e.g., by opening a gap junction
channel in the cell membrane of a sender
nanomachine). A sender nanomachine may
also catalyze a chemical reaction that produces transport molecules elsewhere.
Because of its size, a sender nanomachine
contains a limited amount of energy and information molecules. This results in a limited
communication capability that the single
sender nanomachine alone can generate. Thus,
the sender nanomachine of molecular communication generally relies on the environment
for supplying (chemical) energy and information molecules. In addition, multiple sender
nanomachines may release the same information molecules, resulting in a stronger signal
in the environment.
Propagation
The sender and receiver nanomachines are
at different locations in the environment, and
propagation is the phase during which the
information molecule moves from the sender
nanomachine through the environment to the
receiver nanomachine. The information molecule may diffuse passively through the environment without using chemical energy or
may bind to a transport molecule (e.g., a molecular motor that generates motion [7] ) and
actively propagate through the environment
using energy.
In passive transport, information molecules randomly move according to forces in
the environment. Large information molecules
or high-viscosity environments result in slower diffusion through the environment. In active
transport, a transport molecule carries information molecules through the environment,
and it consumes chemical energy to reduce the
randomness in its movement in the environ-

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ment. By providing more control over the

movement of information molecules, active
transport may decrease the time necessary for
information molecules to reach the receiver
nanomachine and also increase the probability
of information molecules successfully reaching the receiver nanomachine.
During propagation, an interface molecule
may also be necessary to protect information
molecules from noise in the environment. For
instance, information molecules may be contained in a vesicle-based interface molecule
and propagate through the environment[39].
The vesicle prevents the information molecules from chemically reacting with other
molecules outside the vesicle.
Receiving / Decoding
Receiving is the phase during which the
receiver nanomachine captures information
molecules being propagated in the environment. Decoding is the phase during which the
receiver nanomachine, upon capturing information molecules, decodes the received molecules into a chemical reaction. One option for
capturing information molecules is to use
receptors that are capable of binding to a specific type of information molecule. Another
option for capturing them is to use channels
(e.g., gap-junction channels) that allow them
to flow into a receiver nanomachine without
using receptors. Chemical reactions for decoding at the receiver nanomachine may include
producing new molecules, performing a simple task, or producing another signal (e.g.,
sending other information molecules).
3.3. Characteristics of Molecular
Communication
A variety of communication characteristics result from using biological nanomachines
as senders and receivers, using molecules as
an information carrier, and from the propagation of information molecules through an
aqueous environment. First, the environment
noise causes the propagation of information
molecules to be fundamentally stochastic and
to have a relatively large communication
delay. Second, information is encoded onto

molecules and the amount of information that

a receiver nanomachine can receive is limited
by the number of possible configurations in
the receiver nanomachine. Third, the biological molecules and materials used to create
components for molecular communication
cause communication to exhibit characteristics
of biocompatibility and energy efficiency.
Each of the unique characteristics of molecular communication is described below.
Stochastic communication
The stochastic behavior of molecular communication arises from environmental factors
such as unpredictable movement of molecules
in the environment, as well as from communication component factors such as nanomachines stochastically reacting to information
molecules and nanomachines and information
molecules degrading over time. Environmental factors and communication component factors inherently affect the design of molecular
communication. For instance, in order to be
robust to the environmental noise, the sender
nanomachines increase the signal-to-noise
ratio by releasing a large number of information molecules, and receiver nanomachines
chemically react to information molecules
only when a relatively large number of information molecules are present in the environment. Sending a large number of information
molecules is highly redundant, so that degradation of a few information molecules during
propagation does not impact communication.
In addition, noninformation molecules (noisecausing molecules) in the environment may
not trigger chemical reaction at a receiver
nanomachine as long as the noise from those
molecules is significantly less than the signal
from a large number of information molecules.
Large communication delay
Molecules in the environment that do not
participate in molecular communication cause
information molecules to propagate slowly
through the environment. In both passive and
active transport, the speed of propagation is
bounded at a relatively lower speed (i.e.,
micrometers per second in an aqueous environment) because of the large amount of inter-

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ference with the molecules in the environment. In addition, because of the possibly
large delay in the environment, information
molecules may remain in the environment for
a period of time and arrive at a receiver
nanomachine after a widely varying amount of
time (e.g., hours after release at the sender
nanomachine).
The delay in an information molecule
propagating from a sender to a receiver
nanomachine determines various communication characteristics of molecular communication. If the information molecules stay in the
environment for an extended length of time
(e.g., DNA molecules can be chemically stable for months), a sender nanomachine must
delay a new communication until the information molecules used in an old communication
degrade in the environment to prevent the old
communication from interfering with the new
communication. Thus, the frequency at which
a sender nanomachine sends information molecules is determined by the length of time
information molecules stay in the environment
before degrading.
Molecule based coding
In molecular communication, information
is encoded in various characteristics of information molecules such as the type of information molecules used, three-dimensional structure, chemical structure (e.g., protein),
sequence information (e.g., DNA), or concentration (e.g., calcium concentration) of information molecules[48]. A physical substance
(i.e., the information molecule) propagates
from a sender nanomachine to a receiver
nanomachine, and the receiver nanomachine
chemically reacts to incoming information
molecules. Because information is encoded
onto molecules in molecular communication,
the amount of information that a sender
encodes onto a single information molecule
(or the amount of information that a receiver
nanomachine receives) is limited by the number of possible configurations in the receiver
nanomachine.
Biocompatibility
Sender and receiver nanomachines in mol-

82

ecular communication communicate through

sending, receiving, and decoding (chemically
reacting to) information molecules. Since molecular communication uses the same communication mechanisms as biological systems,
nanomachines in molecular communication
can directly communicate with various natural
components in a biological system using
encoding and decoding methods available to
the biological system. Biocompatibility of
molecular communication may enable applications such as inserting nanomachines into a
biological system for medical applications that
require biologically friendly nanomachines.
Energy efficiency
Through the fine-tuning of natural evolution, molecular communication in biological
systems has achieved a high degree of energy
efficiency. For example, under some conditions, myosin (a type of a molecular motor)
converts chemical energy (i.e., ATP) to
mechanical work with 90 percent energy efficiency[30][57]. Chemical energy may be possibly supplied by the environment in which
nanomachines operate. For example, molecular communication systems deployed in a
human body may harvest energy (e.g., glucose) from the human body, requiring no
external energy sources.

4. Engineered molecular
communication
Advanced bio-nanotechnology and
improved understanding in cell and molecular
biology have made it possible to design and
engineer molecular communication systems.
A common approach for designing and engineering molecular communication systems is
to extend or modify existing biological systems. Accordingly, many molecular communication systems are engineered by exploiting
biological systems. This section overviews the
state-of-the-art research in engineering of molecular communication components and systems. A collection of molecular communication research including that in related areas is
categorized below into (1) engineering of

Journal of the National Institute of Information and Communications Technology Vol.55 No.4 2008

sender and receiver nanomachines, (2) engineering of transport mechanisms for propagating information molecules, and (3) engineering of communication mechanisms that are
necessary to build larger-scale integrated molecular communication systems.
4.1 Engineering of sender and
receiver nanomachines
Sender and receiver nanomachines need
communication functionality such as that to
synthesize, store and release information molecules for sender nanomachines, and to capture and react to specific information molecules for receiver nanomachines. There are
two basic classes of approaches for developing nanomachines: they are modifying existing biological cells, or producing simplified
cell-like structures using biological materials
that achieve communication functionality.
4.1.1 Synthetic biological cells
The area of synthetic biology has demonstrated that new communication capabilities
can be added to biological cells through genetic engineering [6][14][55][56] . In [6] , sender
nanomachines are engineered to synthesize
and release information molecules (AHL molecules) using specific metabolic pathways.
Receiver nanomachines are also engineered to
respond to the information molecules by synthesizing specific reporter proteins in a concentration dependent manner (if the concentration of the information molecule falls in a certain concentration range.) The information
molecules that sender nanomachines release
are membrane permeable and freely diffuse
from senders to receivers; therefore, they communicate through free-diffusion-based molecular communication.
Synthetic biology has also demonstrated that
many other capabilities can be introduced into
biological cells through genetic engineering.
Demonstrated functionality in the area
includes the following:
Logic functions: In [56] , computational
building blocks were engineered based on
DNA transcription and translation processes.
An example of building blocks is a biochem-

ical inverter, where the input mRNA generates a repressor protein that prevents DNA
transcription processes, producing no output
mRNA. In the absence of the input mRNA,
DNA transcription processes proceed to generate an output mRNA. Other building
blocks were designed. Similarly, in[15], signal transduction pathways in eukaryotic cells
were modified by synthetic signaling proteins to demonstrate gating behaviors such as
AND or OR gates.
Toggle switches: In[23], a one bit memory
was implemented with two genes inserted
into a bacterium. Its bistability is achieved
by the two genes under the control of promoters that are mutually repressed by the
product of the other gene. Two inducers are
also introduced to suppress the product of
one of the two genes, which are used to
switch from one state to the other.
Oscillators: In[19], a bacterium has inserted
DNA sequences that cause the bacterium to
oscillate the concentration of three protein
products (TetR, cI, LacI) over time. The
DNA sequences to be inserted into the bacterium were selected, so that TetR blocked
the promoter sequence of cI, cI blocked the
promoter sequence of LacI, and LacI
blocked the promoter sequence of TetR.
Thus, at time t, TetR is active; cI is blocked;
and LacI starts being produced. At time t_1,
LacI becomes active; TetR is blocked; and cI
starts being produced.
These functions can be used to increase
the complexity of senders and receivers of
molecular communication. For example, logic
functions can be used at receiver nanomachines to produce programmed responses
based on received information molecules;
Toggle switches (i.e., 1 bit memories) can be
used to retain a communication-related memory inside cells (e.g,. a communication status
of whether sending or waiting); oscillators
(i.e., clocks) can be used at sender nanomachines to control the timing of release. However, it is noted that introducing multiple functions faces a technical difficulty of a possible
interference with existing functions (e.g., at

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the protein level), and it is not technically

easy.
4.1.2 Artificial cells
The other approach to engineering sender
and receiver nanomachines is to create simplified cell-like structures using biological materials (e.g., through embedding of proteins in a
vesicle). Simplification of biological systems
(e.g., cells) may lead to components that are
easier to engineer.
One example of the approach of simplification is to start with a lipid bilayer and then
add functionality as necessary [21][31] . The
lipid bilayer is similar to the membrane that
encloses a cell. The lipid bilayer forms into a
vesicle (a spherical lipid bilayer), and functional proteins (e.g., a receptor) are either
embedded into the vesicle or are captured
inside the vesicle. In[21], chemical components for a minimal cell that is capable of
replication are proposed. In [31] , an active
receptor and enzyme are successfully embedded into a lipid bilayer, producing sender and
receiver functionalities. By restricting the
number of functionalities that are embedded in
the vesicle, it is not necessary to consider the
various complex processes (e.g., other metabolic pathways in the cell and processes to
maintain the structure of the cell) occurring in
a natural biological nanomachine. For
instance, it is possible to select chemicals to
cause the vesicles to form tubular projections
to connect the vesicles without concern for the
various other chemical processes[3][45].
4.2 Engineering of transport
mechanisms
Research in engineering molecular communication includes developing transport
mechanisms for propagating information molecules. This section describes engineering of
passive transport mechanisms and active
transport mechanisms. As described in
Section 2, passive transport propagates information molecules freely in the environment
while active transport propagates information
molecules directionally using motors.

84

4.2.1 Engineered passive transport

mechanisms
4.2.1.1 Free-diffusion based molecular
communication
One type of engineered passive transport
is to use free diffusion based molecular communication, where communication is inherently a broadcast or random walk of information
molecules. In free diffusionbased passive
transport, a receiver may have receptors that
are specific and that respond only when a certain type of information molecule is present in
a high enough concentration[24][55]. Thus, the
sender may select the receiver nanomachine
by sending the information molecules that
cause a response at the receptors of the desired
receiver nanomachine. The sender may also
set the concentration of information molecules
(by adjusting the number of information molecules to transmit) so that only nearby receivers
with the specific receptor are capable of
responding, and distant receivers do not
respond. For instance, an engineered bacterium produces VAI (Vibrio fischeri autoinducer)
information molecules, and the VAI information molecules diffuse through the environment and bind to VAI-specific receptors (i.e.,
a specific DNA sequence that binds VAI) in a
receiver bacterium that produces a response
(e.g., GFP expression).
An example communication sequence
based on this type of molecular communication is illustrated in Fig. 2, where the sender of
communication specifies receivers of communication in a concentration-dependent manner.
The sender synthesizes and transmits information molecules in the environment (encoding
and sending). The information molecules
transmitted into the environment create a concentration gradient with its highest concentration value around the sender as shown in
Fig. 2. The receivers implement a band detector[6]; i.e., they produce a reaction if its concentration falls in a specific concentration
range. Therefore, those receivers that are within the concentration range (receiver 2) respond
(receiving and decoding), but those that are
outside the concentration range (receivers 1

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Fig.2 An example communication sequence based on free-diffusion based molecular communication

and 3) do not produce any reactions (receiving

only and no decoding).
4.2.1.2 Gap junction mediated
diffusion-reaction based
molecular communication
Another type of engineered passive transport is to use diffusion-reaction-based molecular communication, where information molecules react in the environment to increase and
decrease their concentrations while diffusing.
This form of transport can cause a wave-like
impulse of information molecules that propagate through the environment.
In[44], cell wires have been demonstrated
to propagate calcium waves over a line of patterned cells. Diffusion of calcium waves are
mediated by diffusion of calcium signals
through gap junction channels, and therefore,
this is gap junction mediated diffusion-reaction-based molecular communication. Inside a
cell, a calcium store (e.g., ER) has calcium
release channels. The calcium release channels release calcium signals from the calcium
store when calcium signals activate the calcium channels. Released calcium signals diffuse
inside a cell and activate nearby calcium channels, which, in turn, release calcium signals
from their calcium stores. The concentration

of calcium inside a cell increases through this

positive feedback. When the concentration of
calcium becomes high, the cell uses various
calcium pumps to remove calcium signals
from the cell. This acts as a negative feedback.
The positive and negative feedback produce a
propagating impulse wave of calcium signals
inside a cell. In addition, if multiple cells are
coupled through cell-cell channels called gapjunction channels, Ca2+ increase of one cell
can propagate to the other cell, allowing a
longer distance molecular communication
between nanomachines. Since gap junction
channels can have different selectivity and
permeability, this property can be used to
implement filters and switching mechanisms
to control the direction and range of propagation[43].
An example communication sequence
based on this type of molecular communication is illustrated in Fig. 3. The sender synthesizes some stimulating molecules that can initiate cell-cell signaling at intermediate cells
(encoding). The sender then emits the stimulating molecules (sending), which trigger cellcell signaling at intermediate cells. Upon
receiving the stimulating molecules, intermediate cells generate diffusive molecules and

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Fig.3 An example communication sequence based on gap junction mediated diffusion-reaction based molecular communication

propagate them through gap junction channels

intercellularly (propagation). During propagation, diffusive molecules may be directed
toward target receivers (switching) or amplified for longer distance propagation (amplification). The receiver reacts to nearby intermediate cells that receive the diffusive molecules
and initiates biochemical processes (receiving
and decoding).
4.2.2 Engineered active transport
mechanisms
4.2.2.1 Molecular motor-based
molecular communication
One type of engineered active transport is
to use molecular motors to transport information molecules or interface molecules containing information molecules. Biological systems
include a variety of molecular motors (e.g.,
kinesin, myosin, cilia, flagella, etc.). Existing
research on engineering active transport, however, focuses on only a few types of molecular
motors (i.e., kinesin, dynein). Two examples
of active transport using molecular motors
introduced here are molecular motors walking
on filaments and filaments propagating on a
patterned surface coated with molecular
motors.
In the first example, engineered active
transport uses molecular motors, guide molecules (e.g., microtubule filaments) that selforganize into a network, and molecular motors
(e.g., dynein, kinesin) that actively transport

86

information molecules along the guide molecules[37][51]. This first example uses components and processes similar to the active transport mechanisms in biological systems. In biological systems, a network of guide molecules
(e.g., actin or microtubule filaments) is created
within a cell in a self-organizing manner
through dynamic instability of guide molecules, and molecular motors (such as dynein
and kinesin) transport information molecules
to specific locations within the cell by walking
along a network of guide molecules. Engineering of the self-organization of the filaments
can produce simple patterns of filaments (e.g.,
a star-shaped pattern or a random mesh pattern)[12][20]. Through designing self-organization processes of creating filament patterns
and through selectively transporting on the
designed filament pattern, molecular motors
may be guided to desired locations (e.g.,
desired receiver nanomachine or a desired set
of receiver nanomachines).
In the second example of engineered
active transport using molecular motors, the
arrangement of microtubules and motors is
inverted. A surface of a glass is coated with
the molecular motor (e.g., kinesin), and the
motors push the filaments along the surface.
In this arrangement, transport molecules (i.e.,
the filament) load information molecules at a
sender nanomachine and unload the information molecules at a receiver[26][28]. The direc-

Journal of the National Institute of Information and Communications Technology Vol.55 No.4 2008

tion of filament movement is guided by

adding walls (e.g., deposited proteins) onto the
glass surface through lithographic techniques.
Various patterns may be generated that gather
filaments toward a receiver nanomachine. For
instance, an arrow-shaped wall pattern acts a
directional rectifier to ensure that filaments
propagate in a single direction (e.g., only
clockwise) by rectifying filaments that are
propagating opposite the arrowhead direction[27].
An example communication sequence
based on the first example is illustrated in
Fig. 4. The sender encodes information using
information molecules, and injects into interface molecules (e.g., vesicles). The sender
then emits the interface molecules to molecular motors (e.g., through a budding mechanism). The interface molecules are then
attached to and loaded on molecular motors.
The interface molecules are propagated by
molecular motors that move along guide molecules (e.g., rail molecules). During propagation, molecular motors may switch guide molecules to reach destination receivers. When
molecular motors approach to the receiver,
interface molecules containing information
molecules are fused into the receiver. This
allows receivers to receive information molecules and invoke reactions in response to
information molecules.
4.2.2.2 Bacterial motor-based
molecular communication
In another type of engineered active transport, a transport molecule itself is a nanoma-

chine using molecular motors to move itself

toward a receiver nanomachine along chemical gradients in the environment. This example uses components and processes similar to
self-propulsion of single-cell organisms (e.g.,
a bacterium) through an aqueous solution. In
biological systems, a bacterium (i.e., a transport nanomachine) uses cilia or flagella (molecular motors that generate propeller-like
forces) to move itself along chemical gradients toward favorable conditions (e.g., food
source, light) and away from unfavorable conditions (e.g., harmful chemicals, light). With
the engineered transport nanomachine with
molecular motors, the receiver may generate
guide molecules (similar to a gradient of a
food source or pheromone in the environment
in the bacterium example) to indicate where
the receiver is and to influence the direction in
which the transport nanomachine moves
through the environment. The transport
nanomachine does not require preestablished
filament networks, since guide molecules
emitted by a receiver randomly diffuse to form
the chemical gradient around the receiver. For
instance, the pseudopodia of a cell (projections from a cell) can form complex shapes
such as a structure that links the entrance and
exit of a maze[41]. The pseudopodia form the
structure by growing toward a chemical gradient of food originating from both the entrance
and the exit of the maze. Active transport
using pseudopodia is robust, since the
pseudopodia adapt match to the shape of the
maze. Another example of this type of molec-

Fig.4 An example communication sequence based on molecular motor-based molecular

communication

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ular communication is found in bacterial cells,

E. faecalis that perform conjugative plasmid
transfer [ 5 4 ] . Female E. faecalis secretes
pheromones to the environment, and male
E. faecalis respond to the pheromones in the
environment. Once male E. faecalis receive the
pheromones, they activate gene transcriptions
to express cell surface adhesion proteins,
allowing male and female E. faecalis to aggregate, so that the plasmid is transferred from
male to female E. faecalis.
An example communication sequence
based on this type of molecular communication is illustrated in Fig. 5. In this type of molecular communication, the sender and
receivers contain information molecules in
them (e.g., DNA or RNA molecules within
cells). The sender of communication emits
guide molecules (e.g. pheromones) to attract
receivers. The receivers of communication
propel to move closer to the sender, representing the propagation process. Once the sender
and receivers are physically touched (aggregated), the sender and receiver exchange
information molecules (encoding, sending,
receiving, decoding).

4.3 Engineering of communication

mechanisms
Existing research in molecular communication focuses on building components for
molecular communication as overviewed in
this section. Such components, however, must
work together to produce useful molecular
communication. Existing research in creating
integrated molecular communication systems
includes developing a generic interface for
interacting with a biological system and creating an addressing mechanism to enhance communications, each of which is briefly reviewed
in this subsection.
4.3.1 Communication interfaces
A communication interface provides a
generic abstraction for communication that is
reused by a variety of communication mechanisms. In molecular communication, a generic
and abstract communication interface allows
sender and receiver nanomachines to transport
a variety of molecules using the same communication mechanism. Creating a generic and
abstract communication interface is important
in a molecular communication network, since,
with such a communication interface, a communication component is designed without
requiring details of other communication components[39].

Fig.5 An example communication sequence based on bacterial motor-based molecular communication

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Journal of the National Institute of Information and Communications Technology Vol.55 No.4 2008

One example of a generic and abstract

communication interface is found in drug
delivery [32] . In drug delivery, varieties of
drugs are encapsulated in nanoscale capsules
and target some location in the human body.
Targeting molecules embedded in the
nanoscale capsule bind to a specific receptor
embedded in the target location inside the
human body. The location of the receptor molecule in the human body thus determines the
eventual location of the nanoscale capsules.
With this interface, drug targeting mechanisms
do not rely on characteristics of the drug (i.e.,
the information molecule) being transported.
Nanoscale capsules act as a generic and
abstract communication interface. The interface molecules allow any type of information
molecule to concentrate at the correct location,
which reduces the amount of drug necessary
for results, and thus reduces side effects from
drugs reaching undesired locations. The
nanoscale capsule also protects information
molecules from environmental noise and prevents the information molecules from chemically reacting with molecules outside the
interface during the propagation.
4.3.2 Addressing mechanisms
One important feature in communication is
the ability to send information to a specific
receiver. In molecular communication, an
addressing mechanism allows a sender
nanomachine to specify the receiver nanomachine. With a generic addressing mechanism,
the sender nanomachine would have a generic
abstraction for specifying receiver nanomachines. In diffusion-based communication in
biological systems, a receiver nanomachine is
addressed according to which information
molecule is being used. On the other hand, a
molecular communication system using a
generic addressing mechanism is more flexible and imposes fewer constraints on which
information molecules are used in molecular
communication.
One approach for a generic addressing
mechanism is using DNA sequences[28]. In
the addressing mechanism investigated, the

information molecule includes a single-stranded DNA with a sequence that specifies the
address of a receiver nanomachine. The
receiver nanomachine has an address DNA
that is complementary to and thus binds to the
single-stranded DNA on the information molecule. Using DNA sequences in addressing
provides a method for generating a large number of addresses, since DNA sequences may
be arbitrarily produced (with existing technology, DNA up to 10,000 base pairs in length)
and binding of DNA sequence is understood
(as evidenced by construction of various
shapes from designed DNA sequences).
Adding an addressing mechanism to molecular communication would allow the creation
of more complex molecular communication
networks.

5 Conclusions
Molecular communication integrates techniques from biology to interact with biological
systems, from nanotechnology to enable
nanoscale and microscale interactions, and
from computer science to integrate into largerscale information and communication processing systems. Although research in molecular
communication is in its infancy and has only
reproduced functionality already available in
biological systems, continuing research in
molecular communication will lead to integrated molecular communication systems in
which various components of molecular communication work together to provide full communication functionality. Molecular communication has significant potential, since it
interacts directly with biological systems at
nanoscales and microscales, and it may potentially impacts various technological domains
including health (e.g., nanomedicine[22] and
tissue engineering[8][25]), environment (e.g.,
environmental monitoring), IT (e.g., unconventional computing[1] and body sensor networks [57] ), and military (e.g., biochemical
sensors).

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NAKANO Tadashi, Ph.D.

Assistant Adjunct Professor, Department
of Computer Science, University of
California, Irvine
Internet Technology, Molecular
Communication

Michael J. Moore
Department of Computer Science,
University of California, Irvine
Computer Systems and Networking,
Design and Development of
Communication Systems using
Biological Molecules

ENOMOTO Akihiro
Department of Computer Science,
University of California, Irvine
Computer Systems and Networking,
Design and Development of
Communication Systems using
Biological Molecules

SUDA Tatsuya, Ph.D.

Professor, Department of Computer
Science, University of California, Irvine
Distributed Systems, Sensor Networks,
Molecular Communication

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