Cell Systems
Peer Review
Evaluation of Husain et al.: On the Use
of Kalman Filtering by Cells
Jordi Garcia-Ojalvo1,*
1Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona Biomedical Research Park, Dr. Aiguader 88, 08003
Barcelona, Spain
*Correspondence: jordi.g.ojalvo@upf.edu
https://doi.org/10.1016/j.cels.2019.11.003
One snapshot of the peer review process for ‘‘Kalman-like Self-Tuned Sensitivity in Biophysical Sensing’’
(Husain et al., 2019).
Editor’s Note: This is a first-round review
of ‘‘Kalman-like Self-Tuned Sensitivity in
Biophysical Sensing’’ by Kabir Husain,
Weerapat Pittayakanchit, Gopal Patta-
nayak, Michael J. Rust, and Arvind Mur-
ugan; it was written for Cell Systems as
part of the peer review process. We
chose to feature it because it is an
example of a review that is quite positive
yet extremely incisive in that it pinpoints
precisely the main changes the authors
needed to make to move the paper
forward to publication. These sugges-
tions led to a superb alignment between
author intentions and editorial expecta-
tions for the revised paper. After the first
round of review, Husain et al. (2019) was
revised to take the reviewers’ comments
into account, re-submitted, re-reviewed,
accepted for publication, and then pub-
lished in this issue of Cell Systems. For
comparison, an earlier version of Husain
et al. was deposited on arXiv ahead of
review and can be found here: https://
arxiv.org/abs/1903.07103. Garcia-Ojalvo
blinded his identity during the peer re-
view process but has chosen to reveal
it here. Husain et al. support the publica-
tion of this Peer Review; their permission
to use it was obtained after their paper
was officially accepted. This Peer Re-
view was not itself peer reviewed. It
has been lightly edited for stylistic polish
and clarity. Callouts to cited literature,
equations, and figures refer to the orig-
inal submission. No scientific content
has been substantively altered.
This paper suggests that the response
of certain biological systems to a chang-
ing environment can take the form of an
adaptive Kalman filter. This is a compel-
ling idea, which the authors aim to sup-
port by examining two different systems:
the circadian clock in cyanobacteria and
the osmotic stress response in yeast. I
enjoyed reading the paper, and I think it
will be a valuable addition to the systems
biology literature. I was at times a bit
confused, however, by the presentation
and organization of the manuscript.
Specifically:
1. The title of the paper mentions
only circadian clocks, which are
not the central focus of the work.
This feeling is also reinforced by
the abstract, whose first half is
basically centered on circadian
oscillators.
2. The connections of the two sys-
tems with each other (sections I
and II) and with the Kalman para-
digm (section III) are rather vague.
Although the authors have made
an effort to highlight the similarities
among the three systems (Figures
2b, 3c, and 4b), in many cases the
correspondence is weak. For
instance, although Figure 2b ap-
pears to indicate that the sensitivity
coefficient g in the circadian model
should be compared with the gain
parameter g in the Kalman model
(Figure 4b), mathematically it
seems that the indicator variable a
in Equation 9 of the Supplemental
Information would be a more
adequate analogy. On the other
hand, although the weight factor a
in the osmotic stress model
(Figure 3c) seems to be an
adequate analogy to the Kalman
gain g from the mathematical point
of view, it is unclear how that
parameter is associated with the
sensitivity of the system. The fact
that the molecular mechanism un-
derlying the feedback in the os-
Cell Systems 9, November 27, 2019 ª 2019 Elsevier Inc. 415
motic stress case is unknown con-
tributes to the confusion.
Because the interpretation in
terms of an adaptive Kalman filter
brings together the two very
different phenomena studied in
this paper (circadian rhythmicity
and osmotic stress response), a
stronger effort should be made in
showing the analogy between the
two systems. Otherwise, the paper
looks like a juxtaposition of two
different studies in different sys-
tems, whereas the loose analogy
between them would seem more
appropriate for an opinion paper.
If, on the other hand, the authors
could strengthen the similarities
(both conceptual and mathemat-
ical) between the two models, in
particular by identifying clearly the
Kalman gain in each case, the pa-
per would in my opinion improve
substantially.
I would also like to point out these
other minor issues:
3. References 1–5 in the first para-
graph of the introduction seem to
be cited as examples of works
showing that biological systems
have internal models of the
external world, but they’re rather
general references of the systems
being listed (with the exception of
receptor signaling cascades,
which for some reason have no
reference associated with them).
4. In the paragraph preceding
Equation 1, the authors say:
‘‘Data shown in Fig. 1C from
S. elongatus [11] grown in constant
light shows that glycogen is pro-
duced only when it is both objec-
tively and subjectively day, and

degraded otherwise.’’ But to prove
that the two inputs act according to
an ‘‘AND’’ logic, the behavior for
constant darkness should also be
shown (or dismissed in a reasoned
manner).
5. It would be helpful to explain in the
caption of Figure 1 what the yellow
regions in (d) are.
6. In the second paragraph after
Equation 1, the authors say, ‘‘We
explored this in a minimal model
of a generic circadian clock, con-
sisting only on a phase oscillator
q(t) entrained by external light
signal s(t).’’ They should refer to
the Supplemental Information
here. They should also better
define s(t) in the paragraph
following Equation 1 or refer to
the Supplemental Information
there as well.
7. It would be helpful to mark clearly
sint in Figure 2d and to explain in
416 Cell Systems 9, November 27, 2019
the caption what the gray shadow-
ing is.
8. I would also ask the authors to
comment on the vertical stripes
that appear in Figure 2e and to
relate them with the intrinsic
period of the oscillator if appro-
priate.
9. The meaning of b x should be given
as soon as it’s introduced, in line
11 of the second paragraph of
section III of the main text.
10. Introducing the Kalman filter in
terms of a moving particle is a bit
too far from the applications
presented in the paper. It might
be clearer if a simple system
closer to the topic of the paper
(such as a time-varying protein
concentration) were used. But
this is certainly a matter of taste.
11. In the paragraphs surrounding
Equation 4, the authors refer to
the same situation (high sint) in
Cell Systems
Peer Review
very different terms, namely that
predictions are too noisy or that
the stressful environment is suffi-
ciently adverse. Whereas the first
description is rather clear, the sec-
ond is a bit cryptic and system
dependent.
12. In the Discussion section, the au-
thors say that tg is of the order of
several days for clocks. This
seems a rather large timescale;
can the authors discuss briefly
the implications of this?
In any case, this is in my opinion a very
interesting piece of work, and I would like
to congratulate the authors for it.
REFERENCES
Husain, K., Pittayakanchit, W., Pattanayak, G.,
Rust, M.J., and Murugan, A. (2019). Kalman-like
self-tuned sensitivity in biophysical sensing. Cell
Syst. 9, this issue, 459–465.