PHYD01 Research Project

Chemical reactions in dividing cells: Partitioning noise and dilution buffering

Tim Henley, 1000234506∗

UNIVERSITY OF TORONTO SCARBOROUGH
Department of Physical and Environmental Sciences
(Dated: Monday, April 8, 2019)

In the living, chemical reaction systems are highly stochastic and mean values such as concentra-
tion fluctuate under constant conditions [20]. Additional noise is added to these mean values when
the population is randomly partitioned between two daughter cells at division [12]. Importantly,
the growth and division of a population of molecules over the cell cycle corresponds to a growth and
division of the volume of the cell. If we reframe the reaction system in terms of concentration (per
growing volume) much of the partitioning noise is buffered. This research used exact sample path
simulations of coupled reaction systems to study the effects on noise in the system due to random
partitioning (Cyclo-Stationary) and partitioning reframed with growing volume as concentration
(Quasi-Stationary). We compared results for these two systems to a conventional model (Station-
ary) system for equivalent ranges of parameters. In our Cyclo-Stationary system partitioning caused
significant noise, particularly in the RNA. Surprisingly, noise due to partitioning was negligible for
protein in this system. In our Quasi-Stationary system, buffering due to dilution significantly re-
duced noise in RNA. Global behaviour of the Quasi-Stationary system, as characterized by basic
relations between mean values and variances for the system, is restored to the behaviour seen in the
Stationary case.

1. INTRODUCTION and rate of production of a given protein) fluctuates ran-

domly under constant conditions [16]. Fluctuations in

Genetic chemical reaction systems in cells are typically these average values arise from stochastic generation and

modelled in a highly deterministic way, but are in fact degradation of species present at low numbers (intrinsic

essentially stochastic. Biochemical reaction depend on noise) but also from stochastic effects of the physical and

conformation, orientation, velocity and trajectory of any biological environment (extrinsic noise) [9]. In practice it

pair of interacting species, each adding another element is non-trivial distinguishing between the two analytically

of randomness in the noisy Brownian cellular matrix. and experimentally [9,12, 20].

Most experimental measurements of gene expression lev-

els are averaged over large populations of cells, and at
all phases of growth, masking much of the variation[20].
On the single cell level, even within an isogenic popula-
tions, gene expression (measured as the average values
∗ Electronic address: tim.henley@mail.utoronto.ca
The gene expression (and the average values of con-
centration and rate of production by which it is charac-
terized) are highly dependent on the cell cycle, and vary
drastically between two cells a different phases of their
cell cycle [20]. One source of noise tied to the cell cycle
is stochastic partitioning of molecules between daughter
cells at cell division [11,12]. A goal of the present study is
 2

to characterize how random partitioning of populations

causes fluctuations in different components of a chemi-
cal reaction system, and how this noise differs from that
normally attributed to gene expression.

Another cell cycle dependent global variable is the

changing volume of the cell as it grows and then divides.
The principle hypothesis of the present study is that re-
framing a chemical system with random partitioning in
terms of concentration will serve to buffer the noise due
to partitioning. When counting molecules in a system
we define a discrete system with absolute size and defi-
nite step size (as one molecule is generated or degraded.)
Our original theoretical model developed below is based
FIG. 1: Stationary Model: Sample time series for the cou-
on such a discrete joint probability distribution. Refram- pled birth-death system in (1): hRN Ai = 20.05 ± 0.03 and
ing in terms of a constant volume would simply rescale hP roteini = 40.1 ± 0.1 (molecules per cell).
the system trivially. By shifting to a continuous concen-
tration system, in which volume increases and is divided
RNA Protein
in parallel to the partitioning (as in a living cell), we z }| { z }| {
λ1 λ2 x
expect the system would effectively stabilized and result x −−→ x + 1 y −−→ y + 1 (1)
β1 x β2 y
in reduced variance about its mean values. That is, if x −−→ x − 1 y −−→ y − 1
the volume and populations are doubled and halved at a
dhxi
common rate, their ratio should remain constant. = λ1 − β1 hxi
dt (2)
dhyi
= λ2 hxi − β1 hyi
dt
Here x (RNA) in produced by Poisson process, born
1.1. Stationary Model: Birth-Death independently with a constant probability per unit time.
y (protein) is born at a rate proportional to the number
We employed an exact sample path approach to sim- of RNA (x), but also fluctuates if the number of RNA
ulate time series for coupled chemical reaction systems is constant [9]. Fluctuation in RNA number can cause
as shown in Figure 1. One of the key working strategies significant fluctuation in protein number, particularly for
in all of our simulations was implementing a variety of low copy numbers of RNA [10]. Much of the fluctuation
checks to ensure each feature was operating as intended. is time averaged out and for long timescales the system
As an overall sanity check and reference frame for anal- has a characteristic stationary distribution.
ysis we also completed a set of simulations on a conven- This model is necessarily a simplification of a limited
tional stationary model, against which we could compare section of a larger network (note that DNA was conspic-
our results. A common model for stochastic gene expres- uously omitted). However, the differential equations for
sion is given by the classic birth-death system: averages and variances (such as those in (2)) only depend
 3

directly on the birth and death of the species involved
[10]. Previous research has shown that it is possible to
exactly relate average abundances, lifetimes, step sizes
and covariances for any pair of components in a complex
stochastic reactions system without specifying larger sys-
tem [5,6,9].
The Chemical Master Equation (CME), which deter-
mines the dynamics of average abundances for the RNA
and protein system in (1) is given by [9]:
These equations directly relate fluctuations and aver-
age responses in the system, the perturbations and re-
sponse to perturbations, and show their tight intercon-
nection [9,10]. They also highlight how noise in one part
of the system propagates to effect other parts of the sys-
tem. We hope to show through our analysis and com-
parison how certain types of fluctuation arise and how
they are transmitted, amplified or suppressed [10]. The
covariance relations in (5) and (6) summarize the noise

dP (x, y) in our model system, by conveying how variances in our

= λ1 P (x − 1, y) − λ1 P (x, y)
dt | {z } model system scale with mean values and the covariance.
transcription
They were used in our study to gauge the impact on noise
+ β1 (x + 1)P (x + 1, y) − β1 xP (x, y)
| {z
RNA degradation
} due to stochastic partitioning and partitioning reframed
(3)
in terms of concentration, where we expect some suppres-
+ λ2 xP (x, y − 1) − λ2 xP (x, y)
| {z }
translation sion of noise due to dilution [20]. They will also help to

+ β2 (y + 1)P (x, y + 1) − β2 yP (x, y) distinguish the effect of noise on the independent species,
| {z }
Protein degradation RNA, as compared to protein whose generation is depen-
Such networks of chemical reactions in biological sys- dent on the RNA population.
tems can be modelled as a continuous-time discrete-state
Markov processes, a random memoryless walk on an ar-
bitrary dimensional lattice [10]. For a two part system
like (1), the dynamics are governed by a joint probability
distribution P(x,y). Each P(x,y) determines a state for
the system, each with its own governing CME [10]. The
variance for such a system is expressed in the form of the
covariance matrix, which generalizes variance to multiple
dimensions:

cov(xi , xj )
ηij = (4)
hxi ihxj i

For our stationary case this is simply:

cov(x, x) var(x) 1
ηxx = = = (5)
hxihxi hxi2 hxi FIG. 2: Stationary Model Comparing RNA (x) and Protein
| {z }
RNA (y) elements of covariance matrix, equation (6).

cov(y, y) var(y) 1 cov(x, y) The plots in Figures 2 compare both sides of equali-
ηyy = = = + (6)
hyihyi hyi2 hyi hxihyi
| {z } ties (5) and (6) for RNA and Protein respectively based
Protein
on simulations of our static model. These visualize

how well the equalities holds over a range of popula-
tion sizes. We include these plots chiefly for compari-
son with our Cyclo-Stationary (partitioning) and Quasi-
Stationary (concentration-partitioning) models. Essen-
tially the equalities hold over a broad range of mean pop-
ulation sizes for the stationary model.
2. RESULTS AND DISCUSSION
2.1. Cyclo-Stationary Model: Binomial partitioning
In living cells active degradation is typically slow or
absent and most species are partitioned randomly at cell
division [11, 20]. For our simulations incorporating cell
division we removed the degradation terms in (1) leaving:
RNA Protein
z }| { z }| {
λ λ2 x
x −−1→ x + 1 y −− →y+1 (7)
In place of degradation we implemented a binomial divi-
sion of the populations at a fixed time step in order to
approximate stochastic partitioning of species between
daughter cells at cell division. A hard constant doubling
time was used to eliminate additional variance due to a
varying doubling time. We used 134 hours based an av-
erage cell division time for E. coli but the model can be
rescaled trivially [19]. The resulting system produces a
time series where the mean populations are roughly dou-
bled and then halved at fixed intervals (Figure 3).
For the Cyclo-Stationary model, the equalities at very
low copy numbers (1 to 3 species per cell) hold very
closely for both RNA and protein (Figure 4, upper two
plots). For RNA the two sides of the covariance equal-
ity quickly drift apart: differing by 42% at hRN Ai =
20.17 ± 0.02 and 88% at hRN Ai = 201.4 ± 0.1. This de-
viation was expected in the Cyclo-Stationary case, par-
ticularly at higher mean population sizes where the pop-
ulation fluctuates over broader ranges between each divi-
sion. The covariance due to binomial division is typically
4
FIG. 3: Cyclo-stationary Model: Sample time series
for cyclo-stationary binomial partitioning system in (7):
hRN Ai = 20.17 ± 0.02 and hP roteini = 39.00 ± 0.03
(molecules per cell).
characterized as extrinsic noise, from outside the chemi-
cal reaction system itself [9]. Due to the high covariance
this stochastic partitioning causes (cov(x, y) = 50.5 ± 0.1
for hRN Ai = 20.17 ± 0.02 and cov(x, y) = 3223 ± 6 for
hRN Ai = 201.4±0.1), the mean population size for RNA
is centred within a broad fluctuation and thus this mean
does not reflect the variation in RNA number. Equation
(5) reduces to var(x) = hxi, and clearly does not hold
for the Cyclo-Stationary case.
In the Cyclo-Stationary simulations, the covariance
equality for protein held surprisingly well over all. We
had expected the binomial division to disrupt this
relation considerably but the equality remains quite
close over several orders of magnitude: within 5% for
hproteini = 3.780 ± 0.004 molecules per cell, within 5%
for hproteini = 39.00±0.03 molecules per cell and within
4% for hproteini = 390.1 ± 0.3 molecules per cell. This
can be explained by the variance in mean protein popula-
tion being tied closely to the covariance between the two

FIG. 4: Cyclo-Stationary Model Comparing RNA (x) and
protein (y) elements of covariance matrix, equation (6).
populations. In system (1) x is said to be double stochas-
tic, since it is generated randomly but also depends on
the random generation of y, hence the covariance term in
equation (6). However, in the Cyclo-Stationary case, the
partitioning, although independently random for each
species, averages to a highly temporally synchronized
degradation in both, inflating the covariance in the sys-
tem. Importantly, there is still more noise than the Sta-
tionary case and perhaps enough that partitioning noise
could be distinguished in these values, or similar data,
depending on the resolution.
In figures 5 and 6 we plot the contributions of the
two terms on the right hand side of equation (6) sep-
arately. Comparing these two components of the protein
equality, we can see that the covariance term dominates
even at the lowest mean copy numbers (Figure 11). For
hproteini = 9.722 ± 0.0073 molecules per cell, the covari-
ance term contributes 58%. At higher mean populations
this pattern increases (Figure 12), with covariance term
contributing 96% for hproteini = 390.1 ± 0.3 molecules
per cell. It appears that this connection between the
5
variance in protein number and the covariance between
the populations serves to buffer the effect of partitioning
noise in the protein populations across several orders of
magnitude.
This connection can be clarified considerably by rear-
ranging equation (6) as follows:
hyi
var(y) = hyi + cov(x, y) (8)
hxi
Two points are important to note here. First the con-
variance is relatively large in the cyclo-stationary system
and increases with population size: cov(x, y) = 50.5 ± 0.1
for hproteini = 39.00 ± 0.03 and cov(x, y) = 3223 ± 6 for
hproteini = 390.1 ± 0.3 . As in the case of RNA, the
mean number of protein does not reflect the variance in
the population, but the dominant covariant term in this
equality does. The same covariance which acts as noise
disrupting the equality for RNA, is an essential compo-
nent of the equality for protein and effectively sustains
it. Second, in general hyi
> 1. That is, in general in
hxi
RNA-protein systems, there are several copies of a given
protein present compared to the number of associated
RNA. In our simulations as well, the mean value of pro-
tein increased with increasing rate of protein generation
(figure 11).
2.2. Quasi-Stationary Model: Concentration
Next we modified our cyclo-stationary model by adding
a volume component. In our initial simulations the vol-
ume increases linearly so that it roughly doubles and then
is halved in sync with the binomial division of the popula-
tions. We used 0.63µm3 based on an average cell volume
for E. coli but the model can be rescaled trivially[666].
We then divided the discrete molecule number for each
species by volume at each step in order to reframe the sys-
tem in terms of concentration. This implies also refram-
ing the discrete joint probability (number of molecules of

FIG. 5: Cyclo-Stationary Model: Comparing components
of right hand side of equality for protein (y) entry of covari-
ance matrix, equation (6), for the cyclo-stationary binomial-
partitioning system for mean populations 1 to 10 per cell.
FIG. 6: Cyclo-Stationary Model: Comparing components
of right hand side of equality for protein (y) entry of covari-
ance matrix, equation (6), for the cyclo-stationary binomial-
partitioning system for mean populations 20 to 100 per cell.
species per cell with discrete jumps) as a continuous prob-
ability distribution (concentration of species per cell with
continuous jumps). Because volume and molecule num-
6
ber double at the same over-all rate, the large jumps at
division in the cyclo-stationary case are ’smoothed’ out
here, resulting in a concentration fluctuating stochasti-
cally about a it’s mean (Figure 13). It is important to
note that, because the partitioning is random, there are
still occasional large drops in concentration at cell divi-
sion, thus the noise cancellation incomplete (Figure 7).
FIG. 7: Quasi-stationary Model: Concentration Sample
time series for quasi-stationary binomial partitioning in terms
of concentration system in (7) for RNA and protein.
To explore noise buffering due to dilution we again
compared the elements of the covariance matrix to quan-
tify the noise of this system over a similar range of
molecules per cell (which became concentrations in this
model). The reduction in noise was most dramatic in
the RNA case, over a broad range of concentrations and
in particular as concentration increased (compare Fig-
ures 4 and 8 for RNA). The equality for RNA holds
within 5 % for hRN Ai = 2.212 ± 0.004, within 9% for
hRN Ai = 21.31 ± 0.01 copies per µm3 and 10% for
hRN Ai = 212.9 ± 0.1 copies per µm3 . This is a re-
markable reduction in noise, over several orders of mag-

nitude. In the quasi-stationary system, with the parti-
tioning noise buffered by dilution, the variance in RNA
concentration is equivalent to the mean RNA concentra-
tion, as expressed by equality (5), to within 10 % for
a broad range of biologically relevant concentrations of
RNA.
FIG. 8: Quasi-Stationary Model Comparing RNA (x) and
protein (y) elements of covariance matrix, equation (6).
For protein as well, the equality holds within 10% for
hproteini = 4.080 ± 0.005 molecules per µm3 , within
5% for hproteini = 41.12 ± 0.04 molecules per µm3 and
within 10% for hproteini = 412.1 ± 0.3 molecules per per
µm3 . The equality does not appear to hold as closely
as in the cyclo-stationary case for protein, at least for
the lower end and higher end of concentrations tested
(Figures 8). Indeed, it should be expected that the dras-
tic reduction in noise in RNA was accompanied by an
increase in noise elsewhere in the system.
If we look again at the relative contribution of the right
hand terms in (6), Figures 9 and 10, they are nearly
equal, particularly below 20 and above 200 molecules
per cell. Their relative contributions are within 2% for
hproteini = 6.144 ± 0.005 molecules per µm3 and within
7
8% for hproteini = 123.3 ± 0.1 molecules per µm3 . The
contribution to variance proportional to the mean con-
centration of protein and to the covariance between the
populations is relatively equalized, to within 10% for all
concentrations tested. If we return to equation (8), for
this quasi-stationary system:
hyi
hyi ≈ cov(x, y) (9)
hxi
However, this reduction in the relative contribution of
covariance is clearly tied to greater deviation seen in
the equality. Interestingly, rearranging equation (9) does
roughly equate the mean behaviour in RNA to the co-
variance in this Quasi-stationary system.
FIG. 9: Quasi-Stationary Model: Concentration Com-
paring components of right hand side of equality for Protein
(y) entry of covariance matrix, equation (6), for the concen-
tration system for mean populations 1 to 10 per cell.
It is perhaps most interesting to note that the actual
value of the matrix elements is restored to very close
to the stationary case values in this Quasi-Stationary
system. Qualitatively, comparing Figures 1 and 7, the
overall noise of the system is quite similar. On a short
timescale there is a clear differences in terms of the size
of the continuous jumps in concentration compared to

FIG. 10: Quasi-Stationary Model: Concentration Com-
paring components of right hand side of equality for Protein
(y) entry of covariance matrix, equation (6), for the concen-
tration system for mean populations 20 to 200 per cell.
the discrete jumps in number for the stationary case and
the occasional partitioning drop in population mentioned
above, but these are mostly cancelled out over long time
scales. Comparing the average values and fluctuations of
the two systems, they are nearly identical across several
orders of magnitude. It is difficult to characterize this
precisely as noise cancellation related to dilution.
What can be said is relations in equalities (5) and (6)
do hold well in dilution, despite the effects of partition-
ing noise, as seen in the Cyclo-Stationary case. In fact,
if these relations do characterize global behaviour of the
system, the global behaviour of the Stationary system
is very close to the global behaviour of Quasi-Stationary
case for similar parameters. To ensure this did hold over
a range of relative rates we completed a systematic varia-
tion for a spread of values and the results are remarkably
stable for all values tested (Figure 11). The pattern of
equalities, disturbed by partitioning and restored glob-
ally by dilution is clearest in this comparison.
8
3. CONCLUSIONS
The Stationary and Quasi-Stationary systems are so
alike they would likely be difficult to distinguish experi-
mentally. What this suggests is that noise due to random
partitioning would be difficult to distinguish from genetic
noise, particularly when buffered by dilution. It is likely
that in a cell multiple sources of noise would interact
and mask each other, but all of them would be buffered
simply by being dispersed over a growing volume. This
points to intense difficulty in distinguishing among any
source of systematic noise without the aid of carefully de-
signed experiments [20]. Previous research has show that
the effects of partitioning noise is often misattributed to
genetic noise [11,12].
Our results also to confirm previous research, which
has suggested that dilution does effectively buffer noise
caused by the random partitioning [20]. In the spe-
cial case, where change in volume is highly synchronized
with partitioning, the noise cancelling is substantial how-
ever dilution would likely buffer other types of systematic
noise to varying degrees. In similar systems, any noise
which roughly scales with the size of the system (ie. with
the size of the population) or varies in sync with the cell
cycles, would be buffered significantly by dilution effects.
In the same way that a number of molecules in a cell
was converted to concentration, dilution of any variable
effectively spreads its impact out over the extent of the
growing system. Trivially, the same absolute fluctuation
divided over a larger region will represent a smaller rela-
tive variation.
Little progress was made deriving an equivalent theo-
retical limits for the Cyclo and Quasi-Stationary. Since
the variance and mean values for the system, as summa-
rized by covariance matrix, were restored by reframing
in terms of concentration, the overall dynamics of these
values would be similar and that similar bounds could be
 9

FIG. 11: Comparing results for Stationary, Cyclo-Stationary and Quasi-Stationary for RNA (x) and Protein (y) elements of
covariance matrix, equation (6), for values of rate r2 for Protein with r1 for RNA varying on x-axis.

established, at least for our Quasi-stationary case. As an
example, we were shown a derivation of a limit for this
Cyclo-stationary case (the derivation is not reproduced
here) [8]. For high copy number, equality (6) should ap-
proach 1/27 and we confirmed that as populations in-
crease to 1000 per cell and beyond, it does appear to
approach this limit.
To extend the research summarized here we should
consider other ways that the production of a given pro-
tein actually scales with the cell cycle. For volume as
well, we initially adopted a linear increase in order to
limit sources of noise. We also did some preliminary
work with probabilistic and exponential growth but due
to the computational demands of the time-series, we did
not have sufficient time to complete a similar analysis for
these systems. Perhaps distinguishing the type of noise
in the system due to various growth regimes would help
to better fit a given model to data from living cells. We
should also consider the effects of variance in total vol-
ume and random volume partitioning as well as variation
in the doubling time at which both types if partitioning
occur. By comparing various hybrid implementations to
our work so far, we could better distinguish the subtle dif-
ference on noise in the system each modification causes.
A crucial open question is how well can we charac-
terize and distinguish noise caused by various sources in
a given system. For instance, the dependence on covari-
ance could be used to distinguish noise in an independent
variable such as our RNA from that in a doubly stochas-
tic variable like protein. On the other hand, we also saw
how this dependance on covariance actually reduced the
noise caused by partitioning in this same species. Di-
lution clearly does buffer noise due to partitioning and
render it difficult to distinguish from other types of noise
in the system. What is most clear in our work is that
sources of noise and average responses of the system to
10
noise must be analyzed together [8]. Dilution could also
increase the variance in species with slow rates of gener-
ation relative to the cell cycle time-scale.
4. METHODS
Our simulations were based on the Gillespie algorithm,
an exact sample path approach which uses random num-
bers to simulate time series of coupled reactions in in-
dividual cells [13]. We used one random number to de-
termine the time of next reaction and one to determine
which reaction would occur and then tracked average val-
ues and fluctuations from large numbers of such path [9].
The time of next reaction, the probability of which reac-
tion occurs and the effect on the system given the state
are all determined by the equations such as equations (1)
and (2) [9]. Our simulations were completed in Python.
For our original analysis we set the rate of protein gen-
eration to be 1 varied the RNA rate over a range of values.
We used finer resolution, varying the RNA rate from 0 to
10 and then by 10 from 10-100 and 200 from 200-1000 (al-
though the results for the highest rate simulations were
no reproduced here). For each pair of rates in the se-
quence we ran 10 trials with 106 steps. The mean values
were taken form each set of series and the error taken to
be the standard deviation among trials over the square
root of the number of trials. Twenty such make up the
plots in Figures such as 1, 4 and 8. For the over-all
comparison in Figure 11, the protein rate was varied to
produce a larger set of systems. Here 5 time-series with
106 steps were completed for each data point.
In order to simulate partitioning the populations were
divided at a fixed doubling time. It was thought that
this constant time scale would allow for cleaner interpre-
tations without adding extra noise to the system. For
the simulations discussed here, the volume was modelled
using a simple linear function, which doubled the volume
 11

at the same fixed doubling time. Essentially, volume was
calculated at each time step in order to reframe the joint
distribution in term of concentration, dividing the num-
ber of molecules present by the current volume.
10. A. Hilfinger, J. Paulson. (2014) Systems Biology
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Academy of Sciences, Vol. 108, pg. 15004-9.

12. D. Huh, J. Paulsson. (2011) Non-genetic het-

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