September 12, 2008 | David F. Coppedge

Animals Got Rhythm; Scientists Don’t

Here’s a biological puzzle with plenty of room for young researchers to solve: the workings of biological rhythms.  All animals respond to rhythms in periods of hours, days, weeks, months, and years, but as George E. Bentley (UC Berkeley) wrote in Current Biology,1 how they do it is only partially understood.  “Sometimes the questions are simple and the answers are complicated,” he ended his article.
    And complicated it is.  Here’s just a portion of the caption to one of his diagrams called “Proposed novel pathways of photoperiodic timing in birds and mammals” to glaze your eyeballs:

(A) A diagrammatic representation of the proposed novel pathway for photoperiodic timing in birds.  (1) The light signal enters the brain via the skull and is detected by extra-retinal, deep brain photoreceptors (2), the exact identity and location of which are not yet known.  Long day lengths induce TSH and Dio2 expression (3) in the pars tuberalis (red) and mediobasal hypothalamus, respectively, thereby causing a local increase in T3.  This increase in T3 is conveyed via an unknown pathway to promote the release of gonadotropin-releasing hormone (GnRH) from neurons (4) in the pre-optic area.  GnRH then induces the release of gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland into the bloodstream to cause gonadal activation (5).  Note the lack of involvement of melatonin in this proposed pathway, even though the pineal gland in birds is light-sensitive in its own right. 

(There will be no quiz.)  That was just the bird part.  A different complex system exists in mammals.  But the complexity does not end there.  Animals, with their widely differing gestation periods, exhibit many variations on the theme.  Some respond to melatonin and thyroid hormones in different ways, at different rates, and from different parts of the brain.  There appears to be no unifying mechanism.  From hamster to elephant, animals have not told evolutionists what rules or natural law govern their rhythms (see footnote 3 for two attempts). Bentley commented, “However exciting and potentially important these recent findings might be from the perspectives of ecology, physiology and evolution, it’s obvious that they do not provide us with the full picture.  For example, how is this common mechanism tweaked so as to cause short-day breeding in some species and long-day breeding in others?”  He did not explain who or what does the tweaking.
    Bentley’s article was one of several in a special issue of Current Biology devoted to the phenomenon of animal and plant rhythms.  In an Editorial in the same issue,2 Albert Goldbeter (U of Brussels) began, “The development and harmonious functioning of an organism depend on the exquisite coordination of myriad intertwined biological processes.”  Just one of those is biological timing.  Animals need to know when to eat, when to sleep, when to hibernate, when to reproduce, and much more.  “The period of biological rhythms spans more than ten orders of magnitude, from a fraction of a second up to tens of years,” he added.  These rhythms are tightly coupled to regulatory processes in the cell and the animal as a whole.
    Only now are scientists beginning to understand the multiple feedback loops and regulatory processes that begin at the molecular level and extend up to the visible behavior of a whole population.  This is a field ripe for systems biology – a new approach to biology that keeps the big picture in mind.  Goldbeter explained: “Because rhythmic behavior cannot be ascribed to a single gene or enzyme, and rather constitutes a systemic property originating from regulatory interactions between coupled elements in a metabolic or genetic network, cellular rhythms represent a prototypic field of research in systems biology.”  For instance, the big-picture look has revealed a phenomenon called the limit cycle.  This concept is a central figure in the study of biological rhythms, he said.  How do limit cycles work? 

Models help unraveling the dynamics of cellular rhythms and show that sustained oscillatory behavior often corresponds, in the concentration space, to the evolution toward a closed curve known as a limit cycle.  Cycling once around this trajectory takes exactly one period.  The closed trajectory is generally unique in a given set of conditions, and is particularly stable as it can be reached regardless of initial conditions.

His use of evolution here (one of only two mentions in the two papers) does not refer to Darwinian evolution, but to the unfolding of the limit cycle as a consequence of multiple inputs.  The only other mention of evolution, by Bentley, was only a passing reference – and that in the most general terms (see quote in paragraph 2, above).  Other papers in the series mentioned evolution only in passing; only two tried to discuss it in some detail, with questionable success.3
    In his final paragraph, Goldbeter described the pervasive and intertwined nature of biological rhythms with an analogy.  Again, don’t cram for a quiz.

The ubiquity and physiological significance of biological rhythms can be illustrated by one last example, which shows how rhythms are often nested in a manner reminiscent of Russian dolls.  In the process of reproduction, several rhythms play key roles at different stages and with markedly distinct periods.  Fertilization of an egg triggers a train of Ca2+ [doubly ionized calcium] spikes that are essential for successful initiation of development.  Prior to these Ca2+ oscillations of a period of the order of minutes, ovulation requires appropriate levels of LH and FSH established through pulsatile signaling by GnRH with a period close to one hour (the response of pituitary cells to GnRH also involves high-frequency Ca2+ oscillations).  The ovulation cycle is itself periodic, and takes the form of the menstrual cycle in the human female.  Capping these various periodicities, in many animal species reproductive activity varies according to an annual rhythm controlled by the photoperiod, through modulation of the circadian secretion of melatonin.  In a final manifestation of the ticking of the biological clock, ovulation stops at menopause.  At the very core of life, the reproductive process highlights the deeply rooted links between rhythms and time in biological systems.

1.  George E. Bentley, “Biological Timing: Sheep, Dr. Seuss, and Mechanistic Ancestry,” Current Biology, Volume 18, Issue 17, 9 September 2008, Pages R736-R738.
2.  Guest editorial by Albert Goldbeter, “Biological rhythms: Clocks for all times,” Current Biology, Vol 18, R751-R753, 09 September 2008.
3.  A quick word search on “evolution” in the other six papers in the series found only two discussing it in some detail.  One European team’s analysis, however, did not explain how these complex systems actually originated by mutation and natural selection.  They provided only a just-so story on how the different mechanisms in different groups of animals might have been related ancestrally.  Their language glossed over the origin of a multitude of complex systems with phrases like “the evolution of” and “the development of” sprinkled with doubt-words like probably, likely, may have and our interpretation.  They also spoke of the “flow of information” and repeatedly mentioned function without explaining those design-theoretic concepts in Darwinian terms.  Overall, it was clear they were assuming evolution rather than demonstrating it; they assumed that natural selection was capable of providing whatever structure that the “evolutionary pressures” were demanding.  Here is their complete citation (reiterated with diagram in their Figure 4); it can be considered representative of the other 5 papers in the series that mentioned evolution (most of them with just a passing reference that was not germane to their subject matter, and some with contrary evidence and damaging admissions). 

The unusual direction of information flow described here probably reflects an ancestral mechanism preceding the evolution of a separation between the hypothalamus and pituitary and the development of a local portal blood system linking the tissues.  In ancestral vertebrates (Figure 4, left), it is likely that photoreceptor expression in multiple sites in the central nervous system (CNS) served discrete principal functions: control of vision (lateral eyes), circadian rhythms (pineal structures), and photoperiodism (deep brain and pituitary).  In mammals (Figure 4, right), photoreceptor loss has led to the lateral eyes’ assuming all light-sensing functions, with pineal melatonin secretion becoming a humoral relay for photoperiodic information to pituitary and deep-brain sites.  Additionally, distinct regions of the ancestral brain have become specialized for different functions, notably the hypothalamus for integration of environmental cues and the pituitary for hormone production.  Our interpretation is that photoperiodic control has been assumed by TSH expression at the PT-brain interface, allowing information encoded in the melatonin signal to reach hypothalamic sites.  Birds may be viewed as an intermediate scenario in which compartmentalization of endocrine control into sites of integration (hypothalamus) and output (pituitary) has occurred, but extraretinal photoreceptor sites persist.  The highly derived state of the photoperiod-transduction pathway in mammals may well reveal the constraints imposed by their nocturnal ancestry.

Hanon et al, “Ancestral TSH Mechanism Signals Summer in a Photoperiodic Mammal,” Current Biology, Volume 18, Issue 15, 5 August 2008, Pages 1147-1152.
The other paper that discussed evolution in detail arguably only spun just-so stories uneasily in the face of contrary evidence:

A re-evaluation of the role of the TTFL [transcriptional/translational feedback loops] in eukaryotes is underway.  Can the cyanobacterial clock system [a complex clock in the simplest of unicellular organisms] tell us anything about clocks in eukaryotes?  Eukaryotic circadian genes have no detectable homology to kaiABC sequences, so if there is an evolutionary relationship between the bacterial and eukaryotic systems, it is so diverged as to be genetically invisible.  But what about the possibility of convergence to a fundamentally similar biochemical mechanism?  It might seem implausible that clocks of independent origin would converge upon an essentially similar core PTO [post-translational oscillator] made more robust by an overlying TTFL.  However, the advantages that accrue to the cyanobacterial system by having a post-translational mechanism at its core are also relevant to eukaryotic clocks.  For example, individual mammalian fibroblasts express cell-autonomous, self-sustained circadian oscillations of gene expression that are largely unperturbed by cell division in a fashion reminiscent of cyanobacteria.  Could the necessity for imperturbability, even when buffeted by the massive intracellular changes provoked by cell division, provide an evolutionary driving force for circadian clock mechanisms to converge on a relatively similar core mechanism?  The results from cyanobacteria, combined with recent results from eukaryotic systems that do not easily fit into the original TTFL formulation, embolden such speculations.

Foster and Roenneberg, “Human Responses to the Geophysical Daily, Annual and Lunar Cycles,” Current Biology, Vol 18, R816-R825, 09 September 2008.

Clocks within clocks within clocks – wouldn’t William Paley be astonished.  Pay no mind to those Darwinian storytellers in the footnotes; they are assuming 99% of what they need to prove, and still scrambling to come up with plots that thinking people would not laugh at.

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Categories: Amazing Facts, Birds, Mammals

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