A Blog Around The Clock

Basics: Biological Clock

Considering I’ve been writing textbook-like tutorials on chronobiology for quite a while now, trying always to write as simply and clearly as possible, and even wrote a Basic Concepts And Terms post, I am surprised that I never actually defined the term “biological clock” itself before, despite using it all the time.

Since the science bloggers started writing the ‘basic concepts and terms’ posts recently, I’ve been thinking about the best way to define ‘biological clock’ and it is not easy! Let me try, under the fold:

A biological clock is a structure that times regular re-occurence of biochemical, physiological and behavioral events in an organism in constant environmental conditions

Perhaps the best way to explain this is to dissect the definition word-by-word, explaining my choice of words included (and those omitted) in the definition. But first, I need to make it clear that I am NOT trying to invent a new definition, or to impose my views on others. Instead, I am trying to capture the sense in which the term has actually been used by the practitioners in the field, and the way such usage may have changed over time.

What a Biological Clock isn’t

- I need to stress once again that the term “biological clock” is not a real entity, but a metaphor used by the researchers to describe a real entity in shorthand. This metaphor was very useful throughout the history of the field, though on occasion it locks people into frames of mind that may prevent them from seeing a problem as clearly as it could be.

- A biological clock is certainly not to be taken literally, as a real machine with gears or pendulums ticking somewhere inside a living organism.

- A biological clock does not refer to the pseudoscience of biorhythms, one of many ways to extract money from the gullible, either in its original Wilhelm Fliess version or its more recent and spiced-up Oriental variety.

- Colloquially, people often use the term ‘biological clock’ in the sense of “mine is ticking” meaning that time for having kids is running out. That is fine in conversation, but it is not a scientific use of the term.

- Biological Clock should not be confused with the Molecular Clock, a measure of the rate of nucleotide substitution in the DNA over evolutionary time periods, used to infer times of divergence between lineages.

…in an organism…

There are rhythms in nature that occur at levels higher than the organism, e.g., the cycles of population booms and busts in ecology (hare and lynx examples are most famous). Such rhythms are never refered to in the scientific literature as driven by any kind of clocks. The term ‘biological clock’ is sometimes used interchangeably with the term ‘physiological clock’.

This is also the reason I left out of the definition any references to adaptive or evolutionary factors and focused on the way the term is used in the literature – as a sources of a physiological mechanism.

…in constant environmental conditions…

If I give you an electroshock every two hours, you will exhibit a 2-hour cycle of convulsions. This does not mean that your rhythm is endogenously generated by an internal biological clock. It is directly induced by a recurring event in the environment. Many rhythms in living organisms are a result of a direct effect of some environmental factor. A biological clock is responsible only for recurring events that are not direct responses to the envrionmental cycles.

Yet, I did not use a term “environmentally independent” or some such phrase, because the rhythms generated by endogenous clocks are malleable to environmenal factors, especially to light (and very few hormones and other chemicals) – the phase, period and amplitude of the rhythms can be modified by environmental cues. They just don’t dissappear once the organism is held in completely constant conditions for prolonged periods of time (at least 2-3 times longer than the period of a single cycle).

…biochemical, physiological and behavioral events…

I did not want to say “everything”, although it comes close in reality. Again, this excludes ecological cycles. It also leaves it somewhat vague if developmental events are to be included or not, which is a good thing, because some developmental events are (e.g., insect eclosion, bird hatching, somite development, developmental timing in Nematodes), while others are not regulated by various types of biological clocks.

Also, not every clock in the body controls every event. A clock in the liver times events in the liver, a clock in the lungs controls events in the lungs. Only the pacemakers control everything, by synchronizing peripheral clocks, which in turn drive local rhythms. A pacemaker in the suprachiasmatic area (SCN) of the mammalian brain may entrain other local clocks in the brain which in turn drive rhythms of various behaviors.

…times regular re-occurence…

I did not really want to use the word “rhythm” because it may suggest only rhythms of a high frequency (as in music rhythms). I also did not want to limit the definition only to daily/circadian rhythms. Other kinds of rhythms, e.g,. tidal, lunar and circannual, are also driven by biological clocks. The term “calendar” is sometimes seen in popular articles, though not as a specific scientific term, and only in reference to photoperiodism.

…a structure…

This was the hardest part of making the definition. What is a clock? A mechanism? An organ system?

Throughout the 20th century, this was easy. You take an organism, you put it in some kind of setup in which you can continuously monitor some kind of output (usually behavioral activity) and you document a rhythm in constant conditions. Then you systematically lesion or remove various organs or nuclei in the brain, until the rhythm disappears. The organ, which when removed results in arrhytmicity is, you publish, the biological clock in that organism. Thus, you discover the SCN in mammals or the pineal or retina in non-mammalian vertebrates, various brain-nuclei, optic lobes or eyes in invertebrates, etc.

But the world has changed since then. We are now investigating biological clocks at the molecular level. Is the transcription-translation feedback loop among a dozen or so canonical clock genes itself a clock? No, because it is only a neccessary but not sufficient part of the clock. Or is a cell that contains such a molecular mechanism a clock? I’d say yes. Or is the tissue composed of such cells a clock? Different people in the field use this term differently, so I wanted to remain vague. But it is a structure.

At the same time, the distinction between a clock and a pacemaker is becoming more and more important, yet more and more difficult to define.

The clock in each cell of the liver is entrained by the signals from the pacemaker in the SCN. The SCN is, in turn, entrained by the light-dark cycles detected in the environment by the eyes. Is the only distinction between a pacemaker and the peripheral clock in the ability to directly (vs.indirectly) tap into environmetal information? Does that mean that we have pacemakers and clocks, while fruitflies and zebrafish have only pacemakers as every cell of their bodies is a pacemaker directly entrained by environment? Those are some of the current problems in the field. This is the reason why more and more chronobiologists tend to use the term “circadian system” instead of “circadian clock”, in order to imply the underlying complexity.

In many animals, there are not just clocks in every cell in the body, but also multiple pacemakers, each getting information from the environment. These multiple pacemakers affect each other as well as peripheral clocks and are also affected by the feedback from the periphery.

And that is just vertebrates! We know much less about clocks and circadian organization in invertebrates, fungi and plants.

And then, there are unicellular organisms, both bacteria and protists, many of which contain, or should we say, ARE biological clocks. There is no distinction there between the clock and everything else the cell does.

Recently, it has been discovered that biological clocks (or at least clock genes) are also directly involved in regulation of (not just timing of) development, metabolism, appetite, thermoregulation, reproduction, sleep, cocaine addiction and behavior. Thus, the borderlines between the circadian system and other organ systems are getting increasingly fuzzy.

So, whatever structure (cell or higher) that controls the timing of oscillations in everything happening in the body devoid of environmental cues is a biological clock.

Update: A Pacemaker Is A Network

Comments

  1. #1 Jonathan Vos Post
    January 28, 2007

    That seems to me to be a VERY good definition.

    Earlier, on another thread, you rejected the term “chronomics.” I presume that the “Chronome” is at least as bad? Any relevance to your studies of this week’s publication online of the human metabolome?

    By the way, I wrote 3 papers for a 2006 international conference on computational systems biology, in Italy, submitted 2, and referees agreed that both were out of scope. So I never submitted the 3rd paper anywhere. It is my take on chronobiology, with extensive bibliography, and an original copious logarithmic table of chronobiological events by time span. Would you be willing to have me email it to you for informal review, as a (sorry) single big Word file?

  2. #2 Bill
    January 28, 2007

    I vote “structure” off the island — to me, the word connotes a single physical thing, which I don’t think is accurate.

    How about being explicit about the metaphor — “A biological clock is a metaphor for a mechanism that governs the timing of regular, recurring biochemical, physiological and behavioral events in an organism in constant environmental conditions”?

  3. #3 coturnix
    January 28, 2007

    But clock is not a mechanism – it is a place in the body that houses the mechanism – at least the way the term has been used by the field for the past several decades. We have moved down fromorgans and tissues to cells, but clock genes themselves are only part of a celluluar clock (an important, i.e., neccessary but not sufficient part).

  4. #4 Bill
    January 31, 2007

    The “clock” is a place? That makes no sense to me — the mechanism is dispersed over all the cells that show periodic gene expression. I am going to have to read your tutorials more carefully before I can make useful comments on this.

  5. #5 coturnix
    January 31, 2007

    Yup – that’s how it has been used for the past several decades. It is a tissue, a brain nucleus, or an organ. Lately, it is also used sometimes to denote a single cell as well as the tissue of which that cell is a part.

    When you talk about the ‘diffuse’ complexes of clocks, we talk about “circadian systems”, i.e., these are not clocks any more, they are systems or networks composed of multiple clocks which are themselves anatomically discrete units.

  6. #6 Jonathan Vos Post
    January 31, 2007

    In case you hadn’t heard, there’s now the amazing: Human Metabolome Database.
    see it starting at its home page
    http://www.hmdb.ca/

    The following is 2 years old, but an example that clarifies some of this discussion. I’d be interested to hear what experts think of this a couple of years later, i.e. now.

    http://www.sciencedaily.com/releases/2005/02/050201104044.htm

    Source: New York University
    Date: February 3, 2005

    NYU Researchers Simulate Molecular Biological Clock

    Science Daily � Researchers at New York University have developed a model of the intra-cellular mammalian biological clock that reveals how rapid interaction of molecules with DNA is necessary for producing reliable 24-hour rhythms. They also found that without the inherent randomness of molecular interactions within a cell, biological rhythms may dampen over time. These findings appeared in the most recent issue of the Proceedings of the National Academy of Sciences (PNAS).

    Daniel Forger, an NYU biologist and mathematician, and Charles Peskin, a professor at NYU’s Courant Institute of Mathematical Sciences and Center for Neural Science, developed a mathematical model of the biological clock that replicates the hundreds of clock-related molecular reactions that occur within each mammalian cell.

    Biological circadian clocks time daily events with remarkable accuracyoften within a minute each day. However, understanding how circadian clocks function has proven challenging to researchers. This is partly because the 24-hour rhythm is an emergent property of a complex network of many molecular interactions within a cell. Another complication is that molecular interactions are inherently random, which raises the question how a clock with such imprecise components can keep time so precisely. One way to combat molecular noise is to have large numbers of molecular interactions, but this is limited by the small numbers of molecules of some molecular species within the cell (for instance, there are only two copies of DNA).

    To simulate the random nature of the biochemical interactions of the mammalian intra-cellular circadian clock, Forger and Peskin used the existing Gillespie method. The method tracks the changes in the integer numbers of each type of molecule of the system as these biochemical reactions occur. Modeling each type of molecule separately helped avoid mathematical assumptions in their model that may not be valid in real-life cells. Their model was validated with a large library of data on the concentrations of the molecular species within the mouse molecular clock at different times of the day and data on the behavior of mice with circadian clock mutations.

    The results of their computer simulations showed that reliable 24-hour timekeeping can only be achieved if the regulatory molecules that influence gene expression bind and unbind to DNA quicklytypically, within a minute. In this way, the large number of bindings and unbindings helps to compensate for the small numbers of molecules involved. The researchers also found that having more molecules in the cell does not necessarily lead to more accurate timekeeping. Removing all the CRY1 molecules (CRY1 mutant) or removing all the CRY2 molecules (CRY2 mutant), while keeping all other molecular species unchanged, leads to more accurate timekeeping. While simulating the PER2 mutation, they found that circadian oscillations could only be sustained in the presence of molecular noise. This may help explain some of the conflicting experimental reports about the PER2 mutant.

    “Without the rapidity of molecular interactions within these cells, the precision of the biological clock would be lost,” explained Forger. “It is remarkable that a process occurring on the time scale of minutes can have such a profound effect on one that occurs over 24 hours.”

    Note: This story has been adapted from a news release issued by New York University.

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