BIO254:Pacemaker

Due Date: 11/20

Overview

Pacemakers are internal biological oscillators (see below) in organisms that control the period and phase of certain biological rhythms (see below) such as the circadian rhythm and the heart beat. These rhythms involve many separate oscillating systems (or cells in the case of the heartbeat) that are coordinated by the pacemaker. Thus pacemakers are ‘master clocks’. This controlling feature distinguishes pacemakers from the many other types of oscillators. The two most studied pacemakers are the circadian pacemaker and the cardiac pacemaker, although there are certainly other pacemakers that control other biological rhythms.

Biological rhythms

Pacemakers control certain (but not all) biological rhythms. The study of biological rhythms is one of the oldest fields of biology. They are mentioned in the writings of Aristotle (384-322 BC) (Ward, 1971), and the human heartbeat has surely been known to humans for as long as we have existed (130,000 years of anatomically modern humans). The periods of biological rhythms range from sub-microsecond in the electric organ of eels (Moortgat, 1998), to 24 hours in circadian rhythm, to 1 month in the menstrual cycle, to 12 months in hibernation, to longer than 1 year in the flowering cycle of bamboo (Fig. 1).

Figure 1. Image from (Engelmann, 2004).

Rhythms also underlie sensory coding, attention, memory and sleep (Fontanini, 2006). Biological rhythms are found in all organisms including bacteria (Engelmann, 2004), fungi, plants, insects, and mammals. Rhythms that are linked to external phenomena are called circa and the rest are called non-circa (Hosn, 1997). Non-circa pacemakers are not synchronized to external cycles but may still be influenced by external cues. Non-circa pacemakers include the heartbeat pacemaker in the sinus node in humans.

Biological oscillators

Pacemakers are a subset of biological oscillators; they are oscillators that control other oscillators. Biological oscillators are also called rhythm generators. There are many types of biological oscillators that use different mechanisms that can roughly be grouped according to the length of their periods (Fig. 2)

Figure 2. Image from (Buhusi, 2006).

Circadian pacemaker

Circadian pacemakers coordinate the timing of biological events in an organism with the day/night cycle caused by the rotation of the Earth about its axis. Circadian rhythms are found in fungi, mammals, insects, fish, bacteria, and plants (Panda, 2002). Synchronizing an organism with the day/night cycle conveys selective advantages. For example, priming photosynthesis in plants before the sun comes up allows the maximum amount of light to be converted to useable energy (Merrow, 2005).

Defining Characteristics

Circadian pacemakers are self-sustaining, have a characteristic period, are capable of entrainment, and are temperature compensated.

Self-sustaining

Pacemakers will continue to oscillate in the absence of external cues. This is in contrast to external regulators of activity such as thermoregulation of lizard activity level by the warming of the sun.

Characteristic period

Circadian pacemakers have a period of approximately 24 hours, . If kept in constant darkness, some mice will have a period of activity and rest that is slightly less than 24 hours (Pittendrigh, 1993).

Entrainment

Circadian pacemakers would not be much use if they were not synchronized with the day/night cycle. Therefore, despite being self-sustaining, circadian pacemakers can be entrained (synchronized) by input from external cues such as light or social activity. For more information on light entrainment see Term 8.1 in the BIOSCI 154/254 Wikipedia.

Temperature compensation

Despite being based on biochemical processes that are individually temperature sensitive, the circadian pacemaker is relatively insensitive to temperature variations.

History

The earliest record of an observation of a circadian pacemaker was made by de Mairan, a French astronomer, in 1729 (Hosn, 1997). He observed that clover leaves moved even in total darkness, despite the fact that the purpose of their movement seemed to be to track the sun. Linaeus (1707-1778) introduced the concept of a ‘flower clock’. In 1914 Szymanski showed that even under constant conditions goldfish had a circadian rhythm. A genetic basis for the circadian rhythms was indicated in experiments in bean plants by Bunning in 1932. Experiments by Pittendrigh around 1954 showed that the circadian rhythm in Drosophila was temperature compensated. Experiments by Ronald J. Konopka in Seymour Benzer’s lab identified a gene in which mutations caused an alteration of the circadian pacemaker’s period, and was thus named Period abbreviated as Per. Different mutations of Per either shortened or lengthened the period, or abolished the rhythm altogether (Chandrashekaran, 1999). Since then many other genes involved in circadian pacemaker have been identified in various species.

Examples of mechanisms

Here we describe examples of the mechanisms of pacemakers in various types of organisms.

1) Mice

In mammals, the suprachiasmatic nuclus (SCN) of the hypothalamus contains the circadian pacemaker. The SCN controls circadian oscillators in the retina, liver, heart, lung (Peirson, 2006), and kidney (Merrow, 2005). Circadian pacemakers control circulating hormone levels, cognitive and locomotor activity levels. Circadian pacemakers make use of a transcription/translation feedback loop. Several experiments in which single cells are isolated have shown that single cells can generate circadian rhythms of gene expression and circadian pacemakers are thus composed of a collection of single-cell circadian rhythm generators. The mechanism within each cell is diagrammed in Fig. 3.

Figure 4. Image from (Ko, 2006).

2) Drosophila

Since the per gene was discovered (see History above), the mechanism underlying the circadian pacemaker in Drosophila has largely been elucidated. It is believed to depend on multiple phosphorylations of one component as a key timing mechanism. The proposed mechanism is outlined in Fig. 4.

Figure 4. Image from (Bae, 2006).

3) Fish

Many of the clock genes in mammals have homologs in zebrafish and the interactions are largely similar with a few differences (Cahill, 2002).

Cardiac pacemakers

There are actually two cardiac pacemakers, a primary and secondary; the secondary acts as a backup in case the primary ceases to function. The cardiac pacemaker uses a different mechanism than the circadian pacemaker, which makes sense since they have very different periods. The cardiac pacemaker is similar to the circadian pacemaker in that it controls many other oscillators: specifically, the cells of the heart, each of which has the ability to generate spontaneous rhythmic depolarization. Only the cardiac pacemaker cells in the sinoatrial node control the heart rate because they have a faster rhythm than the other cells in the heart, and thus their signal causes the other cells to depolarize before they get a chance to depolarize. The primary cardiac pacemaker is in the sinoatrial node, and the secondary cardiac pacemaker, which is a backup in case the primary pacemaker fails, is in the atrioventricular node. The mechanisms that causes spontaneous depolarization is based on the unique properties of the potassium, sodium, and calcium channels in the pacemaker cells of the heart. The cells spontaneously depolarize due to a feedback mechanism in which the rate of potassium eflux decreases as the cell depolarizes, depolarizing it further, and due to the ‘funny current’ which is due to sodium leaking in.

Artificial pacemakers

Artificial pacemakers are currently made useing microelectronics however genetically engineered pacemakers may begin to replace microelectronic pacemakers (Boink, 2006).

Cardiac

Artificial pacemakers made with microelectronics are used in patients with deficient pacemakers, for example when the sinus node of the heart does not function correctly.

Neural

Micoelectronic pacemakers implanted in the brain of epilepsy patients at the precise (with 1 mm accuracy) locations that are the origins of seizures in a given patient create signals that help prevent seizures (http://www.clevelandclinic.org/health/health-info/docs/1900/1937.asp?index=8782).

Other pacemakers

It is likely that many of the other biological rhythms described in Fig. 2 are controlled by oscillators that have the defining characteristics of pacemakers listed above, however it has not been common to refer to them as pacemakers. For example, few articles refer to a pacemaker for the menstrual cycle ().

References

Boink GJ, Seppen J, de Bakker JM, Tan HL (2006) .Gene therapy to create biological pacemakers.Med Biol Eng Comput. Oct 18; [Epub ahead of print]

Cahill GM (2002) Clock mechanisms in zebrafish. Cell Tissue Res. 2002 Jul;309(1):27-34. Epub 2002 May 25.

Fontanini A, Bower JM.Slow-waves in the olfactory system: an olfactory perspective on cortical rhythms.Trends Neurosci. 2006 Aug;29(8):429-37. Epub 2006 Jul 13.

Moortgat KT, Clifford H. Keller§, Theodore H. Bullock, and Terrence J. Sejnowski (1998) Submicrosecond pacemaker precision is behaviorally modulated: The gymnotiform electromotor pathway. PNAS Vol. 95, Issue 8, 4684-4689.