Research on Intelligent Design

To put together scientific advances from the perspective of Intelligent Design.

Wednesday, October 05, 2005

Intelligent Design for the Mechanism of the Centrioles

Do Centrioles Generate a Polar Ejection Force? Jonathan Wells. Rivista di Biologia, 98 (2005), pp. 71-96.

Title in Italian: I Centrioli Generano Una Forza Di Espulsione Polare?

Excerpts from the Abstract:

"In the hypothesis proposed here a polar ejection force is generated by centrioles, which are found in animal cells but not in the cells of higher plants."

"Instead of viewing centrioles through the spectacles of molecular reductionism and neo-Darwinism, this hypothesis assumes that they are holistically designed to be turbines."

"Orthogonally oriented centriolar turbines could generate oscillations in spindle microtubules that resemble the motion produced by a laboratory vortexer."

"A rise in intracellular calcium at the onset of anaphase could regulate the polar ejection force…"

"… defective regulation could result in an excessive force that contributes to the chromosomal instability characteristic of most cancer cells."
Fragment of Abstract in Italian:

Riassunto:
"L’Autore propone che una tale forza di espulsione sia generata dai centrioli, che si trovano negli animali ma non nelle piante superiori."
"I centrioli consistono di nove triplette di microtubuli disposte come le pale di una minuscola turbina."
"Turbine centriolari orientate ortogonalmente determinerebbero oscillazioni nei microtubuli del fuso. Si genererebbe così una forza di espulsione mediata dai microtubuli che tenderebbe ad allontanare i cromosomi dall’asse del fuso e dai poli."
"Un innalzamento della concentrazione intracellulare di calcio all’inizio dell’anafase potrebbe regolare la forza di espulsione polare attraverso la disattivazione delle turbine centriolari."
"Difetti nella regolazione potrebbero risultare in un eccesso di forza e contribuire così all’instabilità cromosomica tipica della maggior parte delle cellule tumorali."

Excerpts from the Full Text (in PDF):

"The polar ejection force depends on microtubules that extend from the spindle pole…"

"In the hypothesis proposed here, centrioles produce a microtubule-mediated polar ejection force by generating oscillations in the spindle that resemble the motion of a laboratory vortexer."

"Bornens [1979] suggested that rapidly rotating centrioles, powered by an ATPase at their proximal ends, function like gyroscopes that provide an inertial reference system for the cell and generate electrical signals to coordinate cellular processes."

"Since 1980 there has been relatively little interest in hypotheses about the structure and function of centrioles. This may be due partly to the dominance of neo-Darwinian theory: because all centrioles appear to be equally complex, there are no plausible evolutionary intermediates from which to reconstruct phylogenies (Fulton [1971]), so centrioles have attracted little interest from neo-Darwinian biologists."

"Furthermore, the reductionist approach to living cells that is implicit in neo-Darwinian theory has focused attention on individual molecules rather than the centriole’s overall structure and function."

"…Various authors, starting with de Harven [1968], have noted that the triplet microtubules have a turbine-like disposition." [Detailed structural description of centrioles in PDF's page 5, paragraph 3]

"What if centrioles really are tiny turbines?"

"This is much easier to conceive if we adopt a holistic rather than reductionistic approach, and if we regard centrioles as designed structures rather than accidental by-products of neo-Darwinian evolution (Wells [2004])."

"If centrioles really are turbines, then fluid exiting through the blades would cause them to rotate clockwise when viewed from their proximal ends (Fig. 1)."

> Figure 1 Shows - A centriole viewed from its proximal end. The broad, wavy arrows indicate fluid flow through one of the nine slits between the triplet microtubule turbine blades. The long narrow arrow shows the direction of rotation of the centriole as a whole. (In a real centriole, each blade is slightly twisted so that it lies much flatter at the distal end.)

"In order for a centriolar turbine to turn, there must be a mechanism to pump fluid through its blades."

"If the helix inside a centriole rotates like the central apparatus of an axoneme, it could function as an “Archimedes’ screw”, a pump well suited to the low Reynolds number conditions that prevail at subcellular dimensions (Purcell [1977])." [Detailed helical structures described in page 6, after Fig. 1]

"The pump would draw fluid in through the proximal end and force it out through the tripletmicrotubule turbine blades (Fig. 2), causing the turbine to rotate." Figure 2 – Cross-section of a single centriole. In the hypothesis proposed here, the helical structure functions as an Archimedes’ screw driven by dynein molecules in the internal columns lining the wall of the lumen (ic). The rotating screw would pump fluid in from the proximal end and force it laterally outward between the turbine blades.

"Dynein molecules in the centriole’s internal columns (“ic” in Fig. 2) could drive the Archimedes’ screw pump by interacting with its helical blades. If the helix is right-handed (as in Fig. 2), then dynein molecules in the internal columns would not only drive the helix but also start the turbine rotating in the proper direction."

"Since the centriolar pump is a small, self-contained structure that does not have to produce flagellar waveforms several micrometers long, its angular velocity could easily be at the high end of this range." [Detailed description, end of page 8 to page 9.]

"Most centrosomes contain a pair of centrioles oriented at right angles to each other…" [Details, page 9, Chapter 3.]

"… the movement of one centriole [is] constrained."

"The older member (“mother”) of a centriole pair is distinguished from the younger (“daughter”) by various structures (Rieder and Borisy [1982])…"

"…In centrioles isolated under low calcium conditions, the distal appendages are connected to the wall of the centriole while the subdistal appendages are clearly dissociated from it (Paintrand et al. [1992])."

"These characteristics are consistent with a model in which the subdistal appendages form a bearing connected to the cell’s cytoskeleton, and the distal appendages form a flange. The mother centriole could thus rotate within the bearing provided by its subdistal appendages, as originally suggested by Bornens [1979], while being held in place by the flange formed by its distal appendages (Fig. 3)."

Figure 3 – Cross-section of an orthogonal centriole pair. The mother (M) and daughter (D) centrioles are connected at their proximal ends. The subdistal appendages (a) would function as a bearing around the distal end of the mother centriole and also as an anchor for spindle microtubules (b). The distal appendages (c) would form a flange that holds the mother centriole in place as it rotates. The large ellipse is the centromatrix.

"The centriole pair is surrounded by a structural network of 12- to 15-nm diameter filaments called the “centromatrix” (Schnackenberg et al. [1998])."

"The daughter centriole, constrained by its connection to the mother, cannot rotate on its own axis; instead, it would swing bodily around the long axis of the mother centriole (Fig. 4)."

Figure 4 – A three-dimensional view of the centriole pair. The mother centriole would rotate in the direction indicated by the short solid arrow. The daughter centriole would not rotate about its own axis but would revolve around the axis of the mother (long solid arrow). The torque produced by the daughter would press the mother laterally against its bearing (short open arrow, top left), introducing an eccentricity or “wobble” into the revolutions of the pair.

"Nevertheless, the daughter would still function as a turbine, producing a torque that would press the mother centriole laterally against the inner wall of its bearing (open arrow in Fig. 4). The daughter’s torque would cause the centriole pair to revolve eccentrically, producing a wobble resembling the motion of a laboratory vortexer."

"The fluid inside the centromatrix capsule would not remain stationary, but would be stirred in a circle by the revolving daughter centriole. It might seem that friction against the inner wall of the centromatrix would offer enormous resistance to such movement."

"Surprisingly, however, the resistance could be quite low. A hydrophobic surface in water tends to be covered by microscopic, pancake-shaped “nanobubbles” with diameters of the order of 200 nm and thicknesses of the order of 20 nm (Tyrrell and Attard [2001]; Steitz et al. [2003]; Ball [2003]). Such nanobubbles could render a surface composed of hydrophobic 12-15 nm filaments almost frictionless."

"With power being continually supplied by the helical pump inside the mother centriole, the centriole pair could thus accelerate to a very high angular velocity inside the centromatrix capsule."

"In the hypothesis proposed here, the centriole pair would begin revolving inside the centromatrix capsule at the start of prometaphase."
"Several live imaging studies have shown that centrioles in prophase cells are stationary within the centrosome (Waters et al. [1993]; Piel et al. [2000]), but those studies stopped imaging at the beginning of prometaphase – precisely when centriole revolutions would begin."

"If the only thing rotating were the centrioles themselves, the moment of inertia would be approximately the sum of a cylinder rotating about its long axis (the mother centriole) and a cylinder rotating about an axis perpendicular to one end (the daughter centriole)."

"…the effective moment of inertia [I] of the revolving centriole pair would be somewhere between 10^-30 kg m^2 and 10^-28 kg m^2."

"If the effective moment of inertia of the revolving centriole pair is of the order of 10^-29 kg m^2, the angular acceleration (from Equation 5) produced by the torque of the mother centriole (from Equation 4) would be 'alpha', aproximately: 10 sec^-2."
"Assuming negligible friction, this would cause the angular velocity of the centriole pair to increase about 10 Hz every second. Within one minute of starting their turbines the centriole pair would be revolving hundreds of times per second. Ten minutes after start-up the pair would be revolving thousands of times per second, and twenty minutes after start-up it would be revolving more than ten thousand times per second."

"…Spindle microtubules would… undergo small amplitude, high frequency oscillations that are mechanical, not electrical as Bornens [1979] proposed." [Details, page 13, Chapter 4.]

"…Objects within the spindle would… undergo high frequency, small amplitude circular movements perpendicular to polar microtubules, as originally proposed by Wells [1985]."

"Such objects would experience a centrifugal acceleration that is proportional to their radius of rotation and the square of their angular velocity."

"The radius of rotation of an object surrounded by polar microtubules would be approximately the product of its distance from the centrosome (d) and the tangent of the eccentricity of the centrosome’s wobble (E symbol at the end of Equation 6)."

"The object’s angular velocity would be the product of the angular acceleration of the centriole pair (alpha) and the number of seconds that have elapsed since the turbines started (t). So the centrifugal acceleration (beta) experienced by an object in the spindle would be: Equation 6.

"If the eccentricity of the wobble is 1 degreeand 'alpha', approximates10 sec^-2 (as estimated above), then twenty minutes after turbine startup an object 20 micro-m from the spindle pole would be subjected to a centrifugal acceleration of approximately 50 m sec^-2, or about five times the acceleration due to gravity."

"Most of this centrifugal acceleration would be perpendicular to a line between the object and the spindle pole. Objects in the middle of a bipolar spindle would thus experience a force laterally away from the long axis of the spindle (large open arrow in Fig. 5)."

"The conical arrangement of spindle microtubules, however, would convert part of this to a component tending to move objects radially away from the pole (small open arrow in Fig. 5)."

Figure 5 – A cone of spindle microtubules extending from a centrosome. The centriole pair would impart a wobble to the spindle microtubules resembling the motion of a laboratory vortexer. An object within the spindle (solid sphere near top) would be subjected to a small-amplitude rotary motion (solid arrow) and experience a centrifugal force laterally away from the spindle axis (large open arrow to left). The cone-shaped arrangement of the microtubules, however, would produce a component of force directed radially away from the spindle pole (small open arrow, top center). The angle at the vertex of the cone is exaggerated for clarity.

"The wobble produced by a revolving centriole pair would thereby generate a polar ejection force that depends on the presence of microtubules but not on microtubule elongation or kinesin-like proteins."

"The force would originate in spindle poles; it would affect objects in the spindle even if they were not attached to microtubules; and it would make those objects appear to move as though they were being blown or carried by a current – classical characteristics of the polar wind."

"A centriole-generated polar ejection force could be regulated in part by intracellular calcium levels. In dividing animal cells, the onset of anaphase is normally accompanied by a transient rise in intracellular Ca^2+ concentration (Poenie et al. [1986]). This increase could act in three ways to turn off the polar ejection force:
(1) by stopping or reversing the direction of the helical pump inside a centriole;
(2) by retracting the pump away from the proximal end; [and/or]
(3) by causing the subdistal appendages to tighten like brake shoes around the mother centriole." [Details, pages 15-16, PDF's Chapter 5.]

"Calcium regulation of the polar ejection force would play an important role in cell division."

"Once chromosomes have been properly positioned at the metaphase plate, the polar wind is no longer necessary, and reducing or eliminating it would facilitate the poleward movement of chromosomes. In fact, if the revolving centrioles are not shut down they might continue to accelerate, generating a polar ejection force of sufficient magnitude to damage chromosomes."

6. IMPLICATIONS FOR CANCER

"An almost ubiquitous finding in cancer cells is chromosomal instability (Lengauer et al. [1998]). This instability manifests itself as the gain, loss, or rearrangement of material in single chromosomes (translocation), and in the loss of entire chromosomes or the presence of extra ones (aneuploidy). These defects are typically accompanied by centrosomal defects as well. Indeed, centrosome defects may be the primary cause of chromosomal instability (Brinkley and Goepfert [1998]; Pihan et al. [1998]; Lingle and Salisbury [2000])."

"Although extra centrosomes can form multipolar spindles and lead to aneuploidy, the most important factor in producing chromosomal instability is probably not multiple spindle poles but the presence of extra centrosomes and excess centrosomal material at the poles of normal-looking bipolar spindles (Pihan and Doxsey [1999]; Brinkley [2001])."

"If centrioles generate a polar ejection force, the presence of too many centriole pairs at either pole could result in an excessive polar ejection force that subjects chromosomes to unusual stresses and leads to breaks and translocations."

"Even more serious than the presence of extra centrioles would be a failure of control mechanisms that normally shut down centriolar turbines at the beginning of anaphase, since centriole pairs would continue to accelerate and generate polar ejection forces far greater than normal."

"As suggested above, one or more of these control mechanisms could be calcium-regulated. It is worth noting in this regard that recent studies have reported a link between calcium and vitamin D deficiency and various types of cancer."

"Geographical patterns suggest that reduced exposure to sunlight (resulting in lower vitamin D levels) increases the risk for prostate, colon and breast cancer (Hanchette and Schwartz [1992]; Garland et al. [1999])."

"Dietary calcium supplements can modestly reduce the risk of colorectal cancer (McCullough et al. [2003]), and there appears to be an inverse correlation between vitamin D levels and prostate cancer (Konety et al. [1999])."

"Analogs and metabolites of vitamin D inhibit the growth of prostate cancer cells in vitro (Krishnan et al. [2003]) and in vivo (Vegesna et al. [2003]), and they have similar inhibitory effects on breast cancer cells (Flanagan et al. [2003])."

"If centrioles generate a polar ejection force, the correlation between calcium and vitamin D levels and cancer could be a consequence – at least in part – of the role of calcium in turning off centriolar turbines at the onset of anaphase."

7. CONCLUSIONS

"The polar ejection force that plays an important role in dividing animal cells could be generated by centrioles. In the hypothesis presented here, these organelles are literally tiny turbines that pump fluid through their triplet microtubule blades with a dynein-powered Archimedes’ screw located in their proximal lumens."

"A mother centriole would rotate about its long axis within a bearing of subdistal appendages, held in place by a flange of distal appendages."

"A daughter centriole, projecting at a right angle from the mother, would not rotate about its own axis but would revolve around the latter inside the capsule formed by the centromatrix."

"The daughter would also function as a turbine, however, generating a torque that introduces an eccentricity or “wobble” into the revolutions of the mother-daughter pair."

"The resulting wobble, resembling the motion of a laboratory vortexer, would generate a centrifugal-like force several times stronger than the force of gravity, affecting every object within the spindle."

"Although most of the force would be directed laterally away from the spindle axis, the conical arrangement of microtubules would produce a component directed radially away from the spindle pole."

"The resulting microtubule-mediated centrifugallike force could account for many of the characteristics of the polar ejection force observed in dividing animal cells."

"This hypothesis is consistent with a large body of evidence."

"It also makes testable predictions.

For example:

A. It predicts that spindle microtubules in animal cells begin to oscillate at the beginning of prometaphase, and that those oscillations rapidly accelerate until metaphase, at which point they decelerate or cease. By metaphase the oscillations may be of such high frequency that they would be difficult to detect, but the lower frequency oscillations early in prometaphase should be detectable by immunofluorescence microscopy and high-speed camera technology.

B. It predicts that the centriole contains a helical pump powered by dynein molecules located in the inner wall of its lumen. Improved imaging techniques may make it possible to elucidate the complex internal structure of centrioles, characterizing more fully the helical structures in their lumens and determining the precise localization of dynein in their inner walls.

C. It predicts that the polar ejection force is regulated, at least in part, by intracellular calcium concentration. It should be possible to test this by observing chromosome behavior in the spindles of dividing animal cells while artificially raising the concentration of intracellular calcium during prometaphase or blocking its rise at the beginning of anaphase."

"If the hypothesis presented here withstands these and other experimental tests, then it may contribute to a better understanding not only of cell division, but also of cancer. [See Chapter 6, above]"

2 Comments:

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