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Accuracy of direct gradient sensing by single cells

Robert G. Endres∗†‡ and Ned S. Wingreen∗§

Department of Molecular Biology, Princeton University, Princeton, NJ 08544-1014; † Division of Molecular Biosciences, Imperial College London, London SW7
2AZ, United Kingdom; and ‡ Centre for Integrated Systems Biology at Imperial College, Imperial College London, London SW7 2AZ, United Kingdomb;

Edited by José N. Onuchic, University of California at San Diego, La Jolla, CA, and approved August 27, 2008 (received for review May 14, 2008)

Many types of cells are able to accurately sense shallow gradients Here, we derive the fundamental limits of gradient sensing
of chemicals across their diameters, allowing the cells to move by using two models for cells: a perfectly absorbing sphere and
toward or away from chemical sources. This chemotactic ability a perfectly monitoring sphere. Within the theory, gradients are
relies on the remarkable capacity of cells to infer gradients from estimated by comparing the discrete positions of particles, either
particles randomly arriving at cell-surface receptors by diffusion. absorbed on the surface of the sphere or measured inside the
Whereas the physical limits of concentration sensing by cells have spherical volume, with the expected continuous distribution origi-
been explored, there is no theory for the physical limits of gradient nating from a particular gradient. We find that a perfectly absorb-
sensing. Here, we derive such a theory, using as models a perfectly ing sphere is superior to a perfectly monitoring sphere for sensing
absorbing sphere and a perfectly monitoring sphere, which, respec- both concentrations and gradients (Table 1), because previously
tively, infer gradients from the absorbed surface particle density observed particles are never remeasured. Quantitatively, our the-
or the positions of freely diffusing particles inside a spherical vol- ory (Fig. 1, solid curves) compares favorably with recent mea-
ume. We find that the perfectly absorbing sphere is superior to the surements of Dicty cells migrating to a cAMP-filled pipette (6),
perfectly monitoring sphere, both for concentration and gradient suggesting that the chemotactic ability of Dicty approaches the
sensing, because previously observed particles are never remea- fundamental limits set by diffusion.
sured. The superiority of the absorbing sphere helps explain the
presence at the surfaces of cells of signal-degrading enzymes, such Limits of Concentration Sensing
as PDE for cAMP in Dictyostelium discoideum (Dicty) and BAR1 In this section, we consider the limits of concentration sensing set
for mating factor α in Saccharomyces cerevisiae (budding yeast). by particle diffusion. Consider as a measurement device a spher-
Quantitatively, our theory compares favorably with recent mea- ical cell of radius a that can measure the local concentration of
surements of Dicty moving up a cAMP gradient, suggesting these a certain dissolved chemical. Such an idealized device may make
cells operate near the physical limits of gradient detection. measurements by using two different strategies: (i) The device
can either act as a perfectly absorbing sphere and record the num-
chemotaxis | receptors | noise ber of absorbed particles on its surface or (ii) act as a perfectly
monitoring sphere and count the number of particles inside its vol-

C ells are able to sense gradients of chemical concentration with

extremely high sensitivity. This is done either directly, by mea-
suring spatial gradients across the cell diameter, or indirectly, by
ume. In either case, from the number of particles, an estimate
of the chemical concentration can be obtained. However, these
estimates have an intrinsic uncertainty due to the randomness of
temporally sensing gradients while moving. In temporal sensing, a particle diffusion.
cell modifies its swimming behavior according to whether a chem-
ical concentration is rising or falling in time (1). This mode of Perfectly Absorbing Sphere. For the perfectly absorbing sphere the
sensing is typical of small, fast moving bacteria such as Escherichia uncertainty in measuring a background chemical concentration
coli, which can respond to changes in concentration as low as 3.2 c is straightforward to derive. At steady state, the average parti-
nM attractant aspartate (2). In contrast, direct spatial sensing is cle current impinging on the sphere is J = 4πDac, where D is
prevalent among larger, single-celled eukaryotic organisms such the chemical diffusion constant. The average number of particles
as the slime mold Dictyostelium discoideum (Dicty) and the yeast absorbed in time T is N = 4πDacT. Because the particles are inde-
Saccharomyces cerevisiae (3, 4). Dicty cells are able to sense a pendent, N is Poisson distributed, i.e., (δN)2  = N. Therefore,
concentration difference of only 1–5% across the cell (5), cor- the perfectly absorbing sphere has a concentration-measurement
responding to a difference in receptor occupancy between front uncertainty of
and back of only five receptors (6). Spatial sensing is also per- (δc)2  (δN)2  1
formed with high accuracy by cells of the immune system including = = . [1]
neutrophils and lymphocytes (7), as well as by growing synap- c2 N2 4πDacT
tic cells and tumor cells. While there has been great progress in
understanding the limits of concentration sensing and signaling Perfectly Monitoring Sphere. The perfectly monitoring sphere was
in bacteria such as E. coli (8–13), very little is know about the introduced by Berg and Purcell (8) as a parameter-free model
theoretical limits of direct gradient sensing by eukaryotic cells. for a cell that “perfectly” binds and releases all ligands that con-
In a recent set of experiments, van Haastert and Postma (6) tact its surface. To quantify the time a diffusing particle spends
measured the Chemotactic Index of Dicty cells in a cAMP gradi- in the cell’s vicinity and is therefore capable of being measured,
ent (Fig. 1, symbols). Chemotactic Index is defined as the distance Berg and Purcell treated the cell as a permeable sphere that infers
moved in the direction of the cAMP gradient divided by the the particle concentration by counting the number of particles N
total distance moved. To obtain the data in Fig. 1, van Haastert
and Postma used a pipette containing different concentrations of
cAMP. Diffusion of cAMP out of the pipette established a steady- Author contributions: R.G.E. and N.S.W. designed research, performed research, con-
state cAMP gradient, with magnitude a function of distance from tributed new analytic tools, analyzed data, and wrote the paper.
the pipette. Chemotaxis was observed for cells as far as 700 µm The authors declare no conflict of interest.

from a pipette filled with 10−4 M cAMP, corresponding to a mean This article is a PNAS Direct Submission.
concentration of 7 nM and a gradient of only 0.01 nM/µm. This § To whom correspondence should be addressed. E-mail:
remarkable chemotactic ability raises the question – how closely This article contains supporting information online at
does gradient sensing by Dicty cells compare with the fundamental 0804688105/DCSupplemental.
limits on gradient sensing set by diffusion? © 2008 by The National Academy of Sciences of the USA / cgi / doi / 10.1073 / pnas.0804688105 PNAS October 14 , 2008 vol. 105 no. 41 15749–15754
However, notice that the concentration-measurement uncer-
tainty of the perfectly absorbing sphere is actually smaller than
that of a perfectly monitoring sphere of the same size, because the
perfectly absorbing sphere removes particles from the environ-
ment, and hence does not measure the same particle more than

Limits of Gradient Sensing

Now consider the perfectly absorbing sphere and the perfectly moni-
toring sphere as devices for measuring the local gradient of a certain
dissolved chemical. In both cases, measurements of discrete par-
ticles can be compared with the expected continuous distribution
of particles originating from a particular gradient (Fig. 2A), and
hence, the gradient can be estimated. Here, we present, in brief, a
theoretical derivation of the intrinsic uncertainty of gradient sens-
ing [for details see supporting information (SI) Appendix (PDF)].
We find that the intrinsic uncertainty is independent of the actual
Fig. 1. Comparison between the Chemotactic Index determined by experi-
gradient present, and is always much smaller (by a factor of 7/60
ment (symbols and dashed lines) and our theory (solid curves). Chemotactic  12%) for the perfectly absorbing sphere.
Index is defined as the distance moved by a cell in the direction of a gradi-
ent divided by the total distance moved. Experimental data were obtained Perfectly Absorbing Sphere. The average particle current density j =
by van Haastert and Postma (6) from Dictyostelium discoideum cells migrat- −D∇c  impinging on the surface of a perfectly absorbing sphere
ing toward pipettes containing four different cAMP concentrations, 0.1 µM of radius a at steady state follows from the diffusion equation,
(squares), 1 µM (triangles), 10 µM (diamonds), 100 µM (circles). The theoret-
∇ 2 c = 0, and is given in polar coordinates by
ical curves were obtained for a perfectly absorbing sphere by using a single
fitting parameter Da3 T = 1.2 · 105 µm5 , corresponding to, e.g., a cAMP diffu-
sion constant of D = 300 µm2 /s, a cell radius of a = 5 µm, and an averaging Dc0
time T = 3.2 s, using the gradient profiles from ref. 6 and the Chemotac- j(θ, φ) = + 3Dcr · e(θ, φ), [4]
tic Index from Eq. 21. Experimentally, the Chemotactic Index only reaches
approximately 0.9 at zero distance, so we rescale our theory curves by 0.9.
(Inset) Chemotactic Index as a function of (cz0 ) /c0 in units of nM/(µm)2 , where c0 is a constant background concentration, cr is the back-
where cz and c0 are the gradient and concentration, respectively. ground gradient, and e(θ, φ) = (cos φ sin θ, sin φ sin θ, cos θ ) is a
unit vector normal to the surface of the sphere (see Fig. 2A). To
best estimate the chemical gradient from an observed discrete den-
sity of particles absorbed at the surface of the sphere during time
inside its volume, and improves accuracy by averaging over sev- 
T (Fig. 2B), fit the observed density σTobs = N r −ri ), where N
i=1 δ(
eral statistically independent measurements. A simple estimate is the total number of absorbed particles, to the expected density
for the resulting uncertainty in concentration can be obtained as j(θ, φ)T from Eq. 4. Because the estimates of the components of
follows: the number N is Poisson distributed and the cell counts the gradient in the x, y, and z directions are independent, without
appoximately N = a3 c particles in its volume at any time. During loss of generality, we consider only the gradient estimate in the
a time T, the cell can make Nmeas = T/(a2 /D) independent mea- z direction, i.e., cz = ∂c/∂z, and later generalize to an arbitrary
surements, where a2 /D is the typical turnover time for particles gradient. From the best fit, the estimate for the gradient in the
inside the sphere, leading to z direction after absorption of particles for a time T is given by
(δc)2  (δN)2  1 1  N
= = ≈ . [2] σTobs cos θ dA
c2 N2 Nmeas N DacT i=1 cos θi
cz = 2
= , [5]
4πDa T 4πDa2 T
Berg and Purcell (8) derived the exact concentration-
measurement uncertainty for a perfectly monitoring sphere (“per- where θi is the polar angle of the ith absorbed particle. We are inter-
fect instrument”) from the time correlations of particles inside the ested in the uncertainty (accuracy) of the gradient measurement,
sphere, and obtained which is given by the variance
(δc)2  3    2
= , [3] (δcz )2  = c2z − cz
c2 5πDacT
i=1 cos θi +
which is identical to the estimate in Eq. 2 up to a numerical i=1 i =j cos θi cos θj i=1 cos θi
prefactor. = −
(4π Da2 T)2 (4π Da2 T)2

Table 1. Uncertainty of concentration and gradient sensing

Measurement uncertainty Perfect absorber Perfect monitor Ratio absorber/monitor

(δc)2  1 3 12
Concentration: (8) = 2.4
c02 4πDac0 T 5π Dac0 T 5
(δcr )2  1 15 60
Gradient: ≈ 8.6
(c0 /a)2 4πDac0 T 7π Dac0 T 7

15750 / cgi / doi / 10.1073 / pnas.0804688105 Endres and Wingreen

i=1 cos2 θi Ncos2 θ  c0
= = = . [6]
(4πDa2 T)2 2
(4πDa T) 2 12π Da3 T
The derivation of Eq. 6 made use of the independence of the parti-
cles to factorize the expectation value as  N
i=1 i=j cos θi cos θj  =
N(N − 1)cos θ2 = N2 cos θ 2 , because the number of
absorbed particles N is Poisson distributed. We also used N =
4πDac0 T, as well as cos2 θ  = 1/3. (The relation cos2 θi  =
cos2 θ  for absorbed particles holds even in the presence of a
true gradient in the z direction because the gradient-weighted
contribution cos3 θ  is zero.)
In three dimensions, the total uncertainty of the gradient,
normalized by c0 /a, is given by
(δcr )2  3(δcz )2  1
= = , [7]
(c0 /a)2 (c0 /a)2 4πDac0 T
with the factor of 3 arising because each component of the gradi-
ent contributes independently to the total uncertainty. This result
for the uncertainty in gradient sensing is independent of the mag-
nitude of the actual gradient present, including the case when
no actual gradient is present. Curiously, the result is numerically
identical to the concentration-measurement uncertainty (Eq. 1).

Perfectly Monitoring Sphere. Here, we extend Berg and Purcell’s

analysis of the perfectly monitoring sphere (“perfect instrument”)
to include gradient sensing. Specifically, we assume that the moni-
toring sphere measures not only the number, but also the positions
of all particles in its volume (Fig. 2C). The best estimate of the
gradient is obtained by fitting a concentration gradient with a
c = c0 + cr · r to the observed time-averaged number density
dtρobs (t) = T1 dt N r − ri (t)), obtained by measuring the
i=1 δ(
exact positions of all the particles inside the volume of the sphere
for a time T. As above we focus on one component of the gradi-
ent, namely the gradient in the z direction cz , and obtain as a best
dt dV z ρobs (t)
cz = T  , [8]
dV z2

where the integral dV is over the volume of the sphere. We are
interested in the variance of this estimated gradient
(δcz )2  = c2z − cz 2 [9]

= m2z,T − mz,T 2 ,

where we have used dVz2 = 4πa5 /15 and have defined

mz,T = dt dV z ρobs (t), [10]
T Fig. 2. Idealized models for gradient sensing by a cell. The gradient points
along the z axis, which is shown horizontally. (A) Continuum model for a
namely, mz,T is the time-averaged total z coordinate of particles perfectly absorbing sphere. The mean particle current density j(θ) imping-
inside the sphere. The expectation values in Eq. 9 are therefore ing on the sphere has axial symmetry; θ measures the angle with respect to
given by the z axis. At steady state, the particle concentration c is zero immediately
 2 outside the perfectly absorbing sphere, as shown schematically by the red
 2  1 curve superposed on the dotted background gradient. (B) Discrete particle
mz,T = 2 dt dV z ρobs (t) [11] model for the perfectly absorbing sphere. From the number and positions
of particles absorbed during time T , the background particle concentration
1 and gradient can be estimated. (C) Perfectly monitoring sphere. Particles dif-
= 2 dt dt mz (t)mz (t ), fuse in and out of the sphere without resistance. By monitoring, for a time
T 0 0
  T , the number and positions of particles inside the sphere, the background
1 concentration and gradient can be estimated.
mz,T  = dt dV z ρobs (t)


1 T
= dtmz (t), consider the sphere embedded inside a much larger volume con-

T 0
taining a total of M particles. Then, mz (t) = M i=1 zi (t), where zi
where the quantity mz (t) is the total of the z coordinates of all is the z coordinate of particle i if this particle is inside the sphere
the particles inside the sphere at time t. To calculate mz (t), we and is zero otherwise. On average there will be N = 43 π a3 c0

Endres and Wingreen PNAS October 14 , 2008 vol. 105 no. 41 15751
particles inside the sphere at any time t. The auto correlation func- Now, consider the contribution from an additional gradient with
tion mz (t)mz (t ) of particles inside the sphere at time t and time zero mean over the volume of the sphere. We need to perform the
t can consequently be calculated as integrals over a non uniform distribution in Eq. 17. Because a gra-
M M dient along the z axis
 π contributes a factor cos θ, which leads to the
 vanishing integral 0 sin θ cos3 θdθ = 0, we conclude that only the

mz (t)mz (t ) = zi (t)zj (t ) constant background contributes to the uncertainty in the gradient
i=1 j=1 measurement. Therefore, Eq. 19 for τz remains true even when an
4 actual gradient is present.
= π a3 c0 u(t − t ) + mz (t)2 , [12] The result for τz in Eq. 19 can be used in Eq. 14 to obtain the
normalized uncertainty of gradient measurement by the perfectly
where we have defined u(t − t ) = z(t)z(t ) for a single particle. monitoring sphere
Substituting Eqs. 11 and 12 into Eq. 9 results in
(δcr )2  3(δcz )2  15
T T = = , [20]
75c0 (c0 /a) 2 (c0 /a)2 7πDac0 T
(δcz )2  = dt dt u0 (t − t ). [13]
4πa7 T 2 0 0
where all three components of the gradient contribute indepen-
By defining a correlation time τz = (1/a2 ) 0 dτ u(τ ) for the dently. Hence, the perfectly monitoring sphere is not only inferior
coordinate z(t), the double time integral in Eq. 13 can be sim- to the perfectly absorbing sphere for concentration sensing by a
plified, provided the time T is much larger than τz . By using factor of 12/5 in variance (cf. Eqs. 1 and 3), but is also inferior by
time-reversal symmetry u(τ ) = u(−τ ) for equilibrium diffusion an even larger factor of 60/7 for gradient sensing (cf. Eq. 7).
(assuming small gradients), the variance simplifies to Comparison with Experiment
75c0 τz Van Haastert and Postma (6) recently measured the Chemotac-
(δcz )2  = . [14] tic Index of Dicty cells in a cAMP gradient (6) (Fig. 1, symbols).
2π a5 T
They used a pipette containing different concentrations of cAMP
The remaining task is to calculate τz , the probability that a par- to establish a distance-dependent steady-state cAMP gradients.
ticle with coordinate z inside the sphere at time t = 0 is still (or The Chemotactic Index was defined as the distance moved by the
again) inside the sphere at a later time τ . We first consider the case cell in the direction of the cAMP gradient divided by the total dis-
in which the background chemical concentration is uniform, and tance moved. How does the observed chemotactic ability of Dicty
later consider the presence of an actual gradient. Based on the compare with the fundamental limits on gradient sensing set by
solution of the diffusion equation in three dimensions, if a unit diffusion? To facilitate comparison with the results of van Haastert
amount of chemical is released at point r , the concentration at and Postma (6), we have calculated the optimal Chemotactic Index
point r at a later time τ is given by for a cell acting as a perfectly absorbing sphere.
  To obtain the optimal Chemotactic Index CI, we assume that
−r |2
exp − |r4Dτ after averaging for a time T, a cell moves at a constant velocity

f (|r − r |, τ ) = 3
. [15] in the direction of the estimated gradient. If we take the actual
(4πDτ ) 2 gradient to point in the z direction, then the chemotactic index for
one run i is simply cos θi , where θi is the angle between the true
By using the result for the time integral from ref. 8, gradient and the estimated gradient. If the velocity and run time
∞ are the same for each run, leading to a constant run length l, then
dτ f (|r − r |, τ ) = , [16] the average Chemotactic Index is given by
0 4πD|r − r | N 
i lz l Ni cos θi
the correlation time τz can be expressed as a volume inte- CI = N = = cos θi . [21]
i l
gral over the sphere (the initial coordinate r is uniform in
the sphere because we assume a uniform background chemical To evaluate cos θi  for a perfectly absorbing sphere, we use our
concentration) result (Eq. 7) for the variance of the estimated gradient in each
∞ direction, e.g., (δcx,y,z )2  = c0 /(12πDa3 T). Assuming a Gaussian
τz = 4 dτ dV z dV z f (|r − r |, τ ) distribution with these variances, as well as an actual gradient with
π a5 0 mean value c0z in the z direction, the two-dimensional distribution
of estimated gradients cr = (cx , cz ) is given by
3 z
= dV z dV    2  
16π Da 5 |r − r | 1
Pc0 (cx , cz ) =
2 2 0
e−cx 2σx − cz −cz 2σz2
, [22]
3 z 2πσx σz
= dV zψ(r, θ ), [17]
16π 2 Da5 
where σx,z = (δcx,z )2 . From this distribution, we can obtain the
where r = |r |. The function optimal Chemotactic Index

z r cos θ
ψ(r, θ) = dV = dV [18] CI = cos θ = cz c2x + c2z
|r − r | |r − r |

is analogous to the potential of a charge density in electrostatics, πy −y
= e [I0 (y) + I1 (y)], [23]
specifically the charge density ρ(z ) = z = ρ(r , θ ) = r cos θ 2
for r ≤ a and ρ(r ) = 0 for r > a. To solve the final inte-
gral in Eq. 17, we perform a multipole expansion of ψ(r, θ) in where y = (c0z )2 /(4σz2 ) and I0(1) is the first (second)-order modi-
terms of Legendre polynomials Pl (cos θ ), exploiting the rotational fied Bessel function of the first kind. Fig. 1 shows a comparison of
symmetry of ψ(r, θ ) about the z axis (14), leading to the optimal CI (solid curves) with the data of ref. 6. Importantly,
the comparison relies on only a single global fitting parameter
2a2 representing gradient-sensing ability, namely, the product Da3 T,
τz = . [19] where D is the diffusion constant, a is the cell diameter, and T is

15752 / cgi / doi / 10.1073 / pnas.0804688105 Endres and Wingreen

the averaging time. Based on the estimates D = 300µm2 /s and phosphodiesterase (PDE), which degrade external cAMP (19–
a = 5µm (6), the averaging time is predicted to be about T = 3.2 21). One form is membrane-bound (mPDE) and effectively turns
s. (The perfect-monitor model yields an identical curve, but with Dicty into an absorber, whereas the other form is soluble (ePDE).
a longer inferred averaging time T = 27.5 s.) The theory for the The membrane-bound form mPDE only accumulates during cell
optimal Chemotactic Index matches the experiment rather well. aggregration, supporting the idea that degradation of cAMP at
Eq. 23 further predicts that the Chemotactic Index depends on the membrane helps accurate gradient sensing and navigation.
the gradient c0z and the concentration c0 only  through the com- Indeed, cells lacking mPDE display cell-autonomous chemotaxis
bination (c0z )2 /c0 (Fig. 1 Inset). Intuitively, (c0z )2 /c0 measures defects even in mixed aggregates with isogenic wild-type cells (21).
the signal-to-noise ratio—the signal is proportional to the true Interestingly, there is good evidence that Dicty cells do carry out
√ |c0z |, whereas the noise from particle diffusion scales as G protein-coupled receptor-mediated endocytosis of folic acid,
c0 . More generally, the optimal Chemotactic Index depends on another major Dicty chemoattractant (22). (ii) In budding yeast,
all variables only through the combination (c0z )2 Da3 T/c0 . More- the receptor Ste2 binds α-factor pheromone, initiating a mating
over, the theory predicts the full distribution of run angles (see response including directed growth (“shmooing”) toward a poten-
SI Appendix, Fig. S1 Inset), which can be obtained by integrating tial mating partner. Ligand-bound Ste2 undergoes internalization
Eq. 22 in the radial direction for each angle θ . by endocytosis (23). Furthermore, the protease Bar1 degrades
α-pheromone externally (24, 25), and may be largely membrane
associated (26). (iii) There are many examples of ligand–receptor
Discussion internalization in developmental biology. For example, primordial
Many types of cells are known to measure spatial chemical gra- germ cells in zebrafish migrate toward the chemokine SDF-1a that
dients directly with high accuracy. In particular, D. discoideum activates the receptor CXCR4b. Ligand-induced CXCR4b inter-
(Dicty) is well known to measure extremely shallow cAMP gradi- nalization is required for precise arrival of germ cells at their target
ents important for fruiting body formation (3, 5, 6) and S. cerevisiae destination (27). These examples suggest a correlation between
(budding yeast) detects shallow gradients of α mating pheromone ligand internalization/degradation and the accuracy of cell polar-
(15). Accurate spatial sensing is also performed by cells of the ization and movement. In presenting these admittedly speculative
immune system including neutrophils and lymphocytes (7). The examples, our hope is to raise interest, across fields, in how the
question arises: What are the fundamental limits of gradient sens- constraints of gradient sensing accuracy may have shaped cellular
ing set by chemical diffusion? Here, we derived such limits by using sensing systems.
as model cells a perfectly absorbing sphere and a perfectly mon- Although the absorption of ligands can improve gradient sens-
itoring sphere (8). Within the theory, gradients are estimated by ing, there is an inherent problem for an absorbing cell to measure a
comparing the discrete distribution of observed locations of par- gradient while moving. An absorbing cell moving in a uniform con-
ticles, either absorbed on the surface of the sphere (Fig. 2B) or centration creates an apparent gradient because of an increased
measured inside the sphere (Fig. 2C), with the expected continu- flux of incoming particles at its front and a decreased flux of parti-
ous distribution originating from a gradient (Fig. 2A). We find that cles at its back (8). By using the model of a spherical cell, the ratio
a perfectly absorbing sphere is superior to a perfectly monitoring of fluxes between front and back hemispheres is given by
sphere for concentration and gradient sensing by respective factors
of 12/5 (= 2.4) and 60/7 (≈ 8.6) (Table 1), because the perfectly R=1+ , [24]
absorbing sphere prevents rebinding of already measured parti- D
cles. Indeed, the results presented here for the perfectly absorbing where v0 is the cell velocity, a is the cell radius, and D is the particle
sphere represent the true fundamental limits of both concentra- diffusion constant. On the other hand, the flux ratio of a sta-
tion and gradient sensing by cells. Our theory for the limits of tionary spherical cell in a gradient |∇c| with uniform background
gradient sensing compares favorably with recent measurements by concentration background c0 is given by
van Haastert and Postma (6) of Dicty cells migrating to a cAMP-
filled pipette (Fig. 1), suggesting that Dicty chemotaxis approaches 
the fundamental limits set by cAMP diffusion. R=1+ . [25]
The marked superiority of the perfect absorber for concentra-
tion and gradient sensing leads us to conjecture that cells may Hence, a moving cell sees an apparent gradient
have developed mechanisms to absorb ligands so as to prevent v0 c0
their rebinding. Such absorption could be implemented by ligand  =
|∇c| . [26]
or ligand–receptor internalization or by degradation of bound lig- D
ands. Even degradation of ligands without measurement could As an example, chemotaxis of Dicty to cAMP is observed at a mean
be advantageous. For example, a perfect absorber that measures concentration of 7 nM in a gradient of only 0.01 nM/µm (6). A
only a fraction f of incident particles has the same uncertain- Dicty cell moving with a typical speed of 0.2 µm/s at the same mean
ties given in Table 1 but with an effective measurement time concentration but without a gradient creates an apparent gradi-
Teff = fT. Such an absorbing cell that measures only 12% of ent of about half the real gradient. There are several ways out of
absorbed particles can still measure gradients as accurately as this dilemma. (i) Cells could separate measurement from move-
a perfectly monitoring sphere. Similarly, an absorbing sphere ment at low gradients, e.g., by stopping, measuring the gradient,
of radius a with two small measurement patches at its poles of and then moving. Dicty would only need to stop for approximately
radius s (s a), i.e., with a measuring surface-area fraction a2 /D ≈ 0.1 s based on cell radius of a = 5 µm and diffusion con-
s2 /(2a2 ), effectively reduces the averaging time for pole-to-pole stant D = 300 µm2 /s. (ii) Cells could sense gradients transverse
gradients to 3s2 T/(2a2 ) (SI Appendix). Consequently, a measur- to their direction of motion. This is particularly advantageous for
ing surface fraction as small as 4% yields the same uncertainty as fast–moving cells (e.g., bacteria) for which the apparent gradi-
the monitoring sphere. ent can become >100 times steeper than the actual gradient (8).
In fact, there are numerous examples in biology of ligand– (Indeed, the oxygen-sensing marine bacterium Thiovulum majus

receptor internalization (16) and ligand degradation on cell sur- directly senses gradients transverse to its direction of motion (29).)
faces, which we speculate might be related to gradient sensing. Interestingly, Dicty cells moving on agar in the absence of a gra-
(i) Although many G protein-coupled receptors are internalized dient appear to combine these two strategies. Qualitatively, the
by endocytosis (17), the cAMP receptor cAR1 in Dicty is not tips of elongated moving cells slow down and flatten, often pro-
(18). However, Dicty produces two forms of cyclic nucleotide ducing two or more distinct pseudopods. Cells then elongate and

Endres and Wingreen PNAS October 14 , 2008 vol. 105 no. 41 15753
move (approximately one cell length) in the direction of one of A number of mechanistic models for gradient sensing and chemo-
the pseudopods before the process is repeated (Liang Li and Ted taxis have addressed the important questions of cell polariza-
Cox, personal communication). By this strategy, Dicty may avoid tion, signal amplification, and adaptation (30–36), cell move-
locking onto a false, movement-generated gradient. (iii) In prin- ment of individual cells (37, 38), cell aggregation with cAMP
ciple, cells could compensate for the apparent motion-generated degradation by PDE (39), as well as sensing of fluctuating con-
gradient, either by internal signal processing or by external chem- centrations (10, 40, 41). Our results on the fundamental limits
ical secretion. In fact, Dicty cells do secrete cAMP, primarily from of gradient sensing complement these models, and may ulti-
their trailing edge during movement (4), but this cAMP secretion mately help lead to a comprehensive description of eukaryotic
serves dominantly to facilitate cell aggregation, including cells fol- chemotaxis (42).
lowing cells during streaming. Given the complex role of cAMP Finally, we remark that the experiments by van Haastert and
in Dicty aggregation, studies of Dicty chemotaxis using gradients Postma used stationary spatial gradients (6). Cells in such gra-
of folate, which is absorbed (22) but apparently not secreted by dients might profit from remembering their direction of motion
Dicty, may ultimately prove simpler to interpret. (43), and evidence for such internal memory was recently obtained
Our models of the absorbing and the monitoring spheres neglect (28, 44, 45). It therefore might prove interesting to measure the
all biochemical reactions, such as particle–receptor binding and chemotactic index for randomly changing gradients, to find out
downstream signaling, which could significantly increase measure- whether cells indeed use their memory to improve chemotaxis.
ment uncertainty beyond the fundamental limits described here.
To study the effects of particle–receptor binding, we extended a ACKNOWLEDGMENTS. We thank Naama Barkai, John Bonner, Rob Cooper,
formalism for the uncertainty of concentration sensing, recently Ted Cox, Liang Li, Trudi Schupbach, Stanislas Shvartsman, and Monika Skoge
developed by Bialek and Setayeshgar (10), to gradient sensing. We for helpful suggestions. This work was supported by the Human Frontier
Science Program. R.G.E. was supported by Biotechnological and Biological
found that the measurement uncertainty allowing ligand rebind- Sciences Research Council Grant BB/G000131/1 and the Centre for Integrated
ing is larger than the measurement uncertainty without rebind- Systems Biology at Imperial College. N.S.W. was supported by National Science
ing, confirming the superiority of the absorber over the monitor. Foundation Grant PHY-065017.

1. Berg HC (1999) Motile behavior of bacteria. Phys Today 53:24–29. 24. Hicks JB, Herskowitz I (1976) Evidence for a new diffusible element of mating
2. Mao H, Cremer PS, Manson MD (2003) A sensitive versatile microfluidic assay for pheromones in yeast. Nature 260:246–248.
bacterial chemotaxis. Proc Natl Acad Sci USA 100:5449–5454. 25. Barkai N, Rose MD, Wingreen NS (1998) Protease helps yeast find mating partners.
3. Arkowitz RA (1999) Responding to attraction: Chemotaxis and chemotropism in Nature 396:422–423.
Dictyostelium and yeast. Trends Cell Biol 9:20–37. 26. Ciejek E, Thorner J (1979) Recovery of S. cerevisiae a cells from G1 arrest by α factor
4. Manahan CL, Iglesias PA, Long Y, Devreotes PN (2004) Chemoattractant signaling in pheromone requires endopeptidase action. Cell 18:623–635.
dictyostelium discoideum. Annu Rev Cell Dev Biol 20:223–253. 27. Minina S, Reichman-Fried M, Raz E (2007) Control of receptor internalization, sig-
5. Mato JM, Losada A, Nanjundiah V, Konijn TM (1975) Signal input for a chemotactic naling level, and precise arrival at the target in guided cell migration. Curr Biol
response in the cellular slime mold Dictyostelium discoideum. Proc Natl Acad Sci USA 17:1164–1172.
72:4991–4993. 28. Li L, Nørrelykke SF, Cox EC (2008) Persistent cell motion in the absence of external
6. van Haastert PJM, Postma M (2007) Biased random walk by stochastic fluctuations signals: A search strategy for eukaryotic cells PLoS One 3:e2093.
of chemoattractant-receptor interactions at the lower limit of detection. Biophys J 29. Thar R, Kühl M (2003) Bacteria are not too small for spatial sensing of
93:1787–1796. chemical gradients: An experimental evidence. Proc Natl Acad Sci USA 100:
7. Zigmond SH (1977) Ability of polymorphonuclear leukocytes to orient in gradients of 5748–5753.
chemotactic factors. J Cell Biol 75:606–616. 30. Meinhardt H (1999) Orientation of chemotactic cells and growth cones: Models and
8. Berg HC, Purcell EM (1977) Physics of chemoreception. Biophys J 20:193–219. mechanisms. J Cell Sci 112:2867–2874.
9. Bray D, Levin MD, Morton-Firth CJ (1998) Receptor clustering as a cellular mechanism 31. Skupsky R, Losert W, Nossal RJ (2005) Distinguishing modes of eukaryotic gradient
to control sensitivity. Nature 393:85–88. sensing. Biophys J 89:2806–2823.
10. Bialek W, Setayeshgar S (2005) Physical limits to biochemical signaling. Proc Natl Acad 32. Narang A (2006) Spontaneous polarization in eukaryotic gradient sensing: A math-
Sci USA 102:10040–10045. ematical model based on mutual inhibition of frontness and backness pathways.
11. Mello BA, Tu Y (2005) An allosteric model for heterogeneous receptor complexes: J Theor Biol 240:538–553.
Understanding bacterial chemotaxis responses to multiple stimuli. Proc Natl Acad Sci 33. Levine H, Kessler DA, Rappel WJ (2006) Directional sensing in eukaryotic chemotaxis:
USA 102:17354–17359. A balanced inactivation model. Proc Natl Acad Sci USA 103:9761–9766.
12. Keymer JE, Endres RG, Skoge M, Meir Y, Wingreen NS (2006) Chemosensing in 34. Krishnan J, Iglesias PA (2007) Receptor-mediated and intrinsic polarization and their
Escherichia coli: Two regimes of two-state receptors. Proc Natl Acad Sci USA 103:1786– interaction in chemotaxing cells. Biophys J 92:816–830.
1791. 35. Onsum M, Rao CV (2007) A mathematical model for neutrophil gradient sensing and
13. Endres RG, Wingreen NS (2006) Precise adaptation in bacterial chemotaxis through polarization. PLoS Comput Biol 3:e36.
“assistance neighborhoods.” Proc Natl Acad Sci USA 103:13040–13044. 36. Otsuji M et al. (2007) A mass conserved reaction-diffusion system captures properties
14. Jackson JD (1975) in Classical Electrodynamics (Wiley, New York), 2nd Ed, Chap 4.4. of cell polarity. PLoS Comput Biol 3:e108.
15. Segall JE (1993) Polarization of yeast cells in spatial gradients of α mating factor. Proc 37. Dawes AT, Bard Ermentrout G, Cytrynbaum EN, Edelstein-Keshet L (2006) Actin fila-
Natl Acad Sci USA 90:8332–8336. ment branching and protrusion velocity in a simple 1D model of a motile cell. J Theor
16. Mukherjee S, Ghosh RN, Maxfield FR (1997) Endocytosis. Physiol Rev 77:759–803. Biol 242:265–279.
17. Ferguson SS (2001) Evolving concepts in G protein-coupled receptor endocytosis: The 38. Dawes AT, Edelstein-Keshet L (2007) Phosphoinositides and Rho proteins spatially
role in receptor desensitization and signaling. Pharmacol Rev 53:1–24. regulate actin polymerization to initiate and maintain directed movement in a
18. Caterina MJ, Hereld D, Devreotes PN (1995) Occupancy of the Dictyostelium cAMP one-dimensional model of a motile cell. Biophys J 92:744–768.
receptor, cAR1, induces a reduction in affinity which depends upon COOH-terminal 39. Pálsson E et al. (1997) Selection for spiral waves in the social amoebae Dictyostelium.
serine residues. J Biol Chem 270:4418–4423. Proc Natl Acad Sci USA 94:13719–13723.
19. Malchow D, Nägele B, Schwarz H, Gerisch G (1972) Membrane-bound cyclic AMP phos- 40. Goodhill GJ, Urbach JS (1999) Theoretical analysis of gradient detection by growth
phodiesterase in chemotactically responding cells of Dictyostelium discoideum. Eur J cones. J Neurobiol 41:230–241.
Biochem 28:136–142. 41. Wylie CS, Levine H, Kessler DA (2006) Fluctuation-induced instabilities in front prop-
20. Shapiro RI, Franke J, Luna EJ, Kessin RH (1983) A comparison of the membrane- agation up a comoving reaction gradient in two dimensions. Phys Rev E Stat Nonlin
bound and extracellular cyclic AMP phosphodiesterases of Dictyostelium discoideum. Soft Matter Phys 74:016119.
Biochim Biophys Acta 785:49–57. 42. Iglesias PA, Devreotes PN (2008) Navigating through models of chemotaxis. Curr Opin
21. Sucgang R, Weijer CJ, Siegert F, Franke J, Kessin RH (1997) Null mutations of Cell Biol 20:35–40.
the Dictyostelium cyclic nucleotide phosphodiesterase gene block chemotactic cell 43. Andrews BW, Iglesias PA (2007) An information-theoretic characterization of the
movement in developing aggregates. Dev Biol 192:181–192. optimal gradient sensing response of cells. PLoS Comput Biol 3:e153.
22. Rifkin JL (2001) Folate reception by vegetative Dictyostelium discoideum amoebae: 44. Samadani A, Mettetal J, van Oudenaarden A (2006) Cellular asymmetry and individ-
distribution of receptors and trafficking of ligand. Cell Motil Cytoskeleton 48:121–129. uality in directional sensing. Proc Natl Acad Sci USA 103:11549–11554.
23. Schandel KA, Jenness DD (1994) Direct evidence for ligand-induced internalization of 45. Skupsky R, McCann C, Nossal R, Losert W (2007) Bias in the gradient-sensing response
the yeast α-factor pheromone receptor. Mol Cell Biol 14:7245–7255. of chemotactic cells. J Theor Biol 247:242–258.

15754 / cgi / doi / 10.1073 / pnas.0804688105 Endres and Wingreen