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Positive feedback is a ubiquitous signal transduction motif that allows systems to convert graded inputs into decisive, all-or-none outputs. Here we investigate why the positive feedback switches that regulate polarization of budding yeast, calcium signaling, Xenopus oocyte maturation, and various other processes use multiple interlinked loops rather than single positive feedback loops. Mathematical simulations revealed that linking fast and slow positive feedback loops creates a “dual-time” switch that is both rapidly inducible and resistant to noise in the upstream signaling system.

The term “signal transduction” has been in use for over 40 years, originating in biological studies of cellular photoreceptors and chemotaxis, and elaborated through discoveries of signaling systems such as the protein kinases ( 1 ). In engineering, “signaling” has a precise meaning that defines the notion of “information” ( 2 ), and quantifies the capabilities of a signaling system in terms of its channel capacity, measured in bits ( 3 ). Despite the attractive analogy, a number of obstacles have thwarted attempts to apply information theory quantitatively to cellular signal transduction networks. On page 354 of this issue, Cheong et al. ( 4 ) succeed in doing so, making rigorous and quantitative measurements of information capacities in a biochemical signaling system.

I read with great interest the Report “Allometry of alarm calls: black-capped chickadees encode information about predator size” by C. N. Templeton et al. (24 June, p. [1934][1]), who show that black-capped chickadees utilize a graded-response alarm call to warn against predators with differences in risk as measured by predator size. I was struck by the similarity between the findings of this work and the graded-response aggressive calls of Eleutherodactylus frogs. Similar to the chickadees'” chick-a-dee” calls, where increasing repetition of the “dee” note denotes increased threat, the two-note “co-qui” call of the Puerto Rican coqui, Eleutherodactylus coqui , is used with increasing repetition of the second “qui” note during increasingly aggressive interactions with conspecific nest predators ([1][2]). Other Eleutherodactylus species also use a similar aggressive call system when confronted with conspecific or other predators ([2][3], [3][4]). A possible difference between these signaling systems may be in the interpretation of the calls by the receiver (in the case of the chickadees, this would include other birds at risk of predation, and in the case of the coquis, this would include the predator itself). In either case, this type of sophisticated, graded-response acoustic communication that implies knowledge of the level of threat posed by a predator and conveys this information to a receiver is not limited to birds and mammals, but is also used by lower vertebrates. ![Figure][5] An Eleutherodactylus frog and a black-capped chickadee. CREDITS: RAFAEL I. MARQUEZ/CALPHOTOS; DONNA DEWHURST/USFWS 1. 1.[↵][6] 1. M. M. Stewart, 2. S. A. Rand , Copeia 1991, 1013 (1991). [OpenUrl][7][CrossRef][8] 2. 2.[↵][9] 1. K. E. Ovaska, 2. J. Caldbeck , Anim. Behav. 54, 181 (1997). [OpenUrl][10][CrossRef][11][PubMed][12][Web of Science][13] 3. 3.[↵][14] 1. S. F. Michael , J. Herpetol. 31, 453 (1997). [OpenUrl][15] # A "Chick-a-dee" or a "Co-qui"? {#article-title-2} We thank Michael for pointing out graded alarm signaling by some Eleutherodactylus frogs. We suspect that many other species, from a wide variety of taxonomic groups, may employ similar graded signaling systems. However, one exciting aspect of the chickadee alarm call communication system is that it incorporates not only a graded signaling system, where subtle variations in the “chick-a-dee” call reflect the degree of threat a perched predator represents, but also aspects of a functionally referential signaling system, where different types of vocalizations, “chick-a-dee” or “seet,” refer to the type of predator encounter. Careful examination of other species that are faced with challenging selection pressures from multiple predators may even reveal more complex communication systems. [1]: /lookup/doi/10.1126/science.1108841 [2]: #ref-1 [3]: #ref-2 [4]: #ref-3 [5]: pending:yes [6]: #xref-ref-1-1 "View reference 1. in text" [7]: {openurl}?query=rft.jtitle%253DCopeia%26rft.volume%253D1991%26rft.spage%253D1013%26rft.atitle%253DCOPEIA%26rft_id%253Dinfo%253Adoi%252F10.2307%252F1446096%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [8]: /lookup/external-ref?access_num=10.2307/1446096&link_type=DOI [9]: #xref-ref-2-1 "View reference 2. in text" [10]: {openurl}?query=rft.jtitle%253DAnimal%2BBehaviour%26rft.stitle%253DAnimal%2BBehaviour%26rft.aulast%253DOvaska%26rft.auinit1%253DK.%2BE.%26rft.volume%253D54%26rft.issue%253D1%26rft.spage%253D181%26rft.epage%253D188%26rft.atitle%253DVocal%2Bbehaviour%2Bof%2Bthe%2Bfrog%2BEleutherodactylus%2Bantillensison%2Bthe%2BBritish%2BVirgin%2BIslands%26rft_id%253Dinfo%253Adoi%252F10.1006%252Fanbe.1996.0414%26rft_id%253Dinfo%253Apmid%252F9268448%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [11]: /lookup/external-ref?access_num=10.1006/anbe.1996.0414&link_type=DOI [12]: /lookup/external-ref?access_num=9268448&link_type=MED&atom=%2Fsci%2F310%2F5748%2F620.2.atom [13]: /lookup/external-ref?access_num=A1997XM49800019&link_type=ISI [14]: #xref-ref-3-1 "View reference 3. in text" [15]: {openurl}?query=rft.jtitle%253DJ.%2BHerpetol.%26rft.volume%253D31%26rft.spage%253D453%26rft.atitle%253DJ%2BHERPETOL%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx

Cell Signaling If you have driven a car with a manual transmission, you are aware that the response to the throttle is quite different when the drive train is connected to a “load” (when the clutch is engaged and the engine drives the wheels) than when it is not (when the engine spins freely with the clutch disengaged). Jiang et al. explored whether a similar concept of “load” applies to biochemical signaling systems; that is, whether the dynamic properties of a signaling mechanism were altered in the presence or absence of substrate molecules that are targets of the system. Combined experiments and mathematical modeling showed that the presence of substrate could alter the response time of the system, increasing it when one of the enzymes in the signaling system was operating at a maximal rate (saturated) but decreasing it when the enzymes were operating in a linear manner. The authors discuss how such effects of downstream targets on the responsiveness of signaling systems might be used to design appropriate responses when modifying biological systems or designing synthetic ones. Sci. Sig. 4 , ra67 (2011).

[Figure][1] CREDIT: F. GIUDICELLI ET AL. , PLOS BIOLOGY 5 , 6 (7 JUNE 2008) Complicated biochemical signaling pathways regulate the function of living cells. Such regulatory networks often have “downstream” components that provide input to components that act earlier in a pathway, creating feedback loops. These feedback loops have the potential to greatly alter the properties of a pathway and how it responds to stimuli. To fully understand these regulatory systems and exploit their vast potential as targets of therapeutic strategies, we need quantitative information on the flow of signals through a pathway and on the timing and location of signaling events within cells. We need to explore the properties that determine, for example, whether a system shows a graded response to a stimulus or turns on and off like a switch, how long a pathway stays activated, whether its output oscillates, which components can be perturbed to control the output of the system, and so on. The papers assembled in this special issue and in the companion issue of Science Signaling highlight recent progress in tackling these challenges. The systems-level approaches required to understand signaling networks often integrate mathematical modeling with traditional biochemical analysis. Brandman and Meyer (p. 390) describe the ways in which feedback loops allow sophisticated regulatory responses, such as adaptable sensors that respond to changes in the amplitude of an input signal rather than the absolute amount of that signal. Lewis (p. 399) summarizes recent examples in which modeling approaches allow new insights into classical problems in development. Spemann's organizer, for example, emits a gradient of signaling molecules, and recent work explains how the system adjusts when an embryo is damaged, to recreate a complete body axis. Tools that allow precise noninvasive control and monitoring of biochemical components facilitate sorting out how a system responds. As Gorostiza and Isacoff explain (p. [395][2]), it is now possible not only to sample the output of signaling systems by monitoring the fluorescence of reporter molecules but also to engineer proteins with light-dependent isomerization switches that, when reintroduced into cells, can be controlled precisely in time and space by exposure to light. At Science Signaling (see [www.sciencemag.org/cellsignaling08][3]), an original research paper by Abdi et al. takes strategies that engineers use to understand the vulnerability of digital circuits and applies them to biological systems to identify key elements of cellular signaling networks. In Perspectives, Dohlman discusses how scaffolding molecules can determine the graded or switchlike response of a pathway. Elston summarizes how responses to pulsatile inputs are used to understand the dynamic behavior of a signaling system in yeast. Chiang and Muir outline advances in chemical approaches providing deeper insight into signaling mechanisms. Getting your loops straight—or understanding how a complicated signaling network might respond in any given situation—does not come easily or intuitively. But the approaches mentioned here are clearly opening a large area of investigation of enormous practical potential. [1]: pending:yes [2]: /lookup/doi/10.1126/science.1166022 [3]: http://www.sciencemag.org/cellsignaling08