stuart r. hameroff- a new theory of the origin of cancer: quantum coherent entanglement, centrioles,...

8/3/2019 Stuart R. Hameroff- A new theory of the origin of cancer: quantum coherent entanglement, centrioles, mitosis, and differentiation

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BioSystems 77 (2004) 119136

A new theory of the origin of cancer: quantum coherententanglement, centrioles, mitosis, and differentiation

Stuart R. Hameroff Departments of Anesthesiology and Psychology, and Center for Consciousness Studies, The University of Arizona, Tucson, AZ, USA

Received 30 January 2004; received in revised form 27 April 2004; accepted 28 April 2004

Abstract

Malignant cells are characterized by abnormal segregation of chromosomes during mitosis (aneuploidy), generally con-sidered aresult of malignancy originating in genetic mutations. However, recent evidence supports a century-old concept thatmaldistribution of chromosomes (and resultant genomic instability) due to abnormalities in mitosis itself is the primary causeof malignancy rather than a mere byproduct. In normal mitosis chromosomes replicate into sister chromatids which are thenprecisely separated and transported into mirror-like sets by structural protein assemblies called mitotic spindles and centrioles,both composed of microtubules. The elegant yet poorly understood ballet-like movements and geometric organization occurringin mitosis have suggested guidance by some type of organizing eld, however neither electromagnetic nor chemical gradientelds have been demonstrated or shown to be sufcient. It is proposed here that normal mirror-like mitosis is organized byquantum coherence and quantum entanglement among microtubule-based centrioles and mitotic spindles which ensure pre-

cise, complementary duplication of daughter cell genomes and recognition of daughter cell boundaries. Evidence and theorysupporting organized quantum states in cytoplasm/nucleoplasm (and quantum optical properties of centrioles in particular) atphysiological temperature are presented. Impairment of quantum coherence and/or entanglement among microtubule-basedmitotic spindles and centrioles can result in abnormal distribution of chromosomes, abnormal differentiation and uncontrolledgrowth, and account for all aspects of malignancy. New approaches to cancer therapy and stem cell production are suggestedvia non-thermal laser-mediated effects aimed at quantum optical states of centrioles. 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Aneuploidy; Cancer; Centrioles; Differentiation; Genomic instability; Laser therapy; Malignancy; Microtubules; Mitosis; Mitoticspindles; Neoplasm; Quantum coherence; Quantum computation; Quantum entanglement; Quantum optics; Quantum theory; Stem cells

1. Theories of the origin of cancer: mutation,aneuploidy, genomic instability

Malignant cells divide and multiply uncontrollably.They evade built-in autodestruct mechanisms, stimu-late formation of blood vessels to feed themselves, andcan invade other tissues. Proper differentiationtheprocess by which genetic expression leads to spe-

E-mail address: [email protected] (S.R. Hameroff).URL: http://www.consciousness.arizona.edu/hameroff.

cic cell types (phenotypes)is lost. Despite intenseefforts and recognition of predisposing factors (e.g.carcinogens, reactive oxidants, genetic/family history)cancer remains an enormous problem.

In the early 20th century German biologist TheodorBoveri observed cell division (mitosis) in normaland cancerous cells (Boveri, 1929). Whereas nor-mal cells exhibited symmetrical, bipolar division of chromosomes into two equal mirror-like distribu-tions (Fig. 1), Boveri noticed that cancer cells weredifferent. Cancer cells showed imbalanced divisions

0303-2647/$ see front matter 2004 Elsevier Ireland Ltd. All rights reserved.doi:10.1016/j.biosystems.2004.04.006


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120 S.R. Hameroff/ BioSystems 77 (2004) 119136

Fig. 1. Modications to the centriole in the normal cell cycle and mitosis (not to scale: centrioles are750nm in length and 200 nm outerdiameter, much smaller than mitotic spindles). Center: centriole as two perpendicular cylinders. Clockwise from center (G1, S, and G2occur during Interphase which precedes and follows mitosis): in G1 phase centriole cylinders separate. In S phase centrioles replicate,each cylinder forming a new perpendicular cylinder via connecting lamentous proteins. G2 phase: centrioles separate and begin to migrate.Prophase: centrioles move apart and microtubules form the mitotic spindles between the centrioles. Metaphase: mitotic spindles attach tocentromeres/kinetochores on opposite sides of each paired chromosome (only four of which are shown). Anaphase: paired chromosomes

separate into sister chromatids and are moved by (and move along) mitotic spindles to newly forming daughter cells. Modied fromHaganet al. (1998)by Dave Cantrell.

of chromosomes, with asymmetrical and multipolarunequal (aneuploid) distributions (Figs. 2 and 3).Boveri suggested that aberrant processes in mitosisitself caused abnormal distribution of chromosomesand genes. He reasoned that most abnormal distri-butions would be non-viable, but some would leadto viable cells and cancerous differentiation withuncontrollable proliferation. But because no recur-rent pattern occurredthe aneuploidy changed fromgeneration to generation (what is now called ge-nomic instability)the majority of scientists as-sumed the abnormal distribution of chromosomeswere effects, rather than causes of malignancy andthat cancer originated from intrinsic chromosomalchanges. In retrospect, genomic instability is a log-ical consequence of abnormal mitosis. Nonethe-less, the belief that cancer resulted from geneticmutations became the standard dogma (Gibbs,2003).

As DNA and genetics became understood andprominent, the idea that cancer is the result of cumu-lative mutations became entrenched. Specic alter-ations in a cells DNA, spontaneous or induced bycarcinogens, change the particular proteins encodedby cancer-related genes at those spots. Two particularkinds of genes were identied as being potentiallyrelevant to cancer. The rst included tumor suppres-sor genes which normally restrain cells tendencies todivide. Presumably mutations affecting these genesdisabled them, removing benecial effects of suppres-sors. The second group included oncogenes whichstimulate growth, or cell division. Mutations lead-ing to cancer were thought to lock oncogenes into apermanently active state.

However, in the era of genetic engineering, onco-gene/suppressor theory has failed to explain cancer.No consistent set of gene mutations correlate withmalignancy; each tumor may be unique in its ge-


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S.R. Hameroff/ BioSystems 77 (2004) 119136 121

Fig. 2. Abnormal centriole activities in mitosis leading to aneuploidy. As inFig. 1 except that during metaphase the centriole/spindlebinding of chromatids is defective and asymmetrical leading to maldistribution of chromosomes in the anaphase daughter cells. Eachdaughter cell is missing an entire chromosome and has an extra chromatid, hence an abnormal genotype. By Dave Cantrell.

Fig. 3. Abnormal centriole activities in mitosis leading to aneuploidy. As inFigs. 1 and 2except that defective centriole replication continuesin G2 producing three centrioles which form abnormally distributed spindles in prophase and abnormal chromosome distribution/genotypesin metaphase and anaphase. This results in chromosomes maldistributed among three daughter cells. By Dave Cantrell.


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netic makeup. In fact tremendous genetic variabil-ity occurs within individual tumors, and genomicinstabilitychanges in the genome with subsequent

cycles of mitosisis now seen as the major pathwayto malignancy (Marx, 2002).Some specic DNA factors are indeed related to

genomic instability. These include unrepaired DNAdamage, stalled DNA replication forks processed in-appropriately by recombination enzymes, and defec-tive telomeres which protect ends of chromosomes.But again, inherent DNA mutation and sequelaethestandard dogmado not explain the entire picture.Other approaches suggest that a combination of DNAdefects and other problems are responsible for ge-nomic instability and malignancy.

One approach is called modied dogma whichrevives an idea fromLoeb et al. (1974)who notedthat random mutations, on average, would affectonly one gene per cell in a lifetime. Some otherfactorcarcinogen, reactive oxidants, malfunction inDNA duplication and repair machineryis proposedto increase the incidence of random mutations (Loebet al., 2003). Another approach is early instability(Nowak et al., 2002) which suggests that master genesare critical to cell divisionif they are mutated, mi-tosis is aberrant. But master genes are still merely

proposals.Another idea returned to Boveris suggestion thatthe problems lie with the molecular machinery of mi-tosis which, under normal circumstances, results inprecisely equal separationof duplicated chromosomes.The all-aneuploidy theory (Duesberg et al., 2000)proposes that cells become malignant before any mu-tations or intrinsic genetic aberrancy. With the excep-tion of leukemia, nearly all cancer cells are aneuploid.Thus, malignancy is more closely related to maldistri-bution of chromosomes than to mutations on the genes

within those chromosomes. Experiments show that ge-nomic instability correlates with degree of aneuploidy.What causes aberrant mitosis? Asbestos bers and

other carcinogenic agents are known to disrupt normalmitosis. Certain genes trigger and regulate mitosis,and experimentally induced mutations in these genesresult in abnormal mitosis and malignancy. However,such mutations in mitosis-regulating genes have notbeen found in spontaneously occurring cancers. Thus,mitosis itself , the dynamical, ballet-like mechanicalseparation of chromosomes into two perfectly equal

paired sets, may be at the heart of the problem of cancer. However, the organization of mitosis is notunderstood.

2. Mitosis and differentiation

Under normal conditions chromosomes replicateinto sister chromatids which remain attached toeach other at a single point via a structure called acentromere/kinetochore.

Chromatids are then separated and pulled apart intotwo identical sets by remarkable molecular machinescalled mitotic spindles which attach to the chro-matid centromere/kinetochore (Hagan et al., 1998).The spindles are composed of microtubules (cen-tromere/kinetochores also contain microtubule frag-ments). Once separated, sister chromatids are knownas daughter chromosomes.

The microtubule spindles pull the daughter chro-mosomes toward two poles anchored by microtubuleorganizing centers (MTOCs), or centrosomes (as theyare known in animal cells). Centrosomes are com-posed of structures called centrioles embedded in anelectron-dense matrix composed primarily of the pro-tein pericentrin. Each centriole is a pair of barrel-like

structures arranged curiously in perpendicular tan-dem (Figs. 4 and 5), and (like mitotic spindles) arecomprised of microtubules, self-assembling polymersof the protein tubulin. In centrioles, microtubulesare fused longitudinally into triplets; nine triplets arealigned, stabilized by protein struts to form a cylin-der which may be slightly skewed (Dustin, 1984).New cylinders self-assemble/replicate perpendicularto existing cylinders, and centriole replication in-volves self-assembly of two new cylinders from eachpre-existing cylinder of the pair which constitutes

the centriole (Figs. 13, G1, S, and G2 phases). Thetwo perpendicular pairs then separate resulting in twocentrioles.

Centrioles are the specic apparatus within livingcells which trigger and guide not only mitosis, butother major reorganizations of cellular structure occur-ring during growth and differentiation. Somehow cen-trioles have command of their orientation in space, andconvey that information to other cytoskeletal struc-tures. Their navigation and gravity sensation have beensuggested to represent a gyroscopic function of cen-


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Fig. 4. A centriole is comprised of two cylinders (as shown inFig. 5) arranged in perpendicular tandem. Each cylinder is 750 nm (0.75m)in length. By Dave Cantrell.

trioles (Bornens, 1979). The mystery and aesthetic el-egance of centrioles, as well as the fact that in certaininstances they appear completely unnecessary, havecreated an enigmatic aura Biologists have long beenhaunted by the possibility that the primary signicanceof centrioles has escaped them (Wheatley, 1982).

The initiation of mitosis (S of interphase intoprophase) involves centriole replication, separation

and migration to form the mitotic poles to whichspindles attach (Nasmyth, 2002). The opposite endof each spindle afxes to centromeres/kinetochoreson specic chromatids, so that proper separation of centrosomes/centrioles results in separation of chro-mosomes into equal sets forming the focal point of the two daughter cells (Fig. 1).

There are a number of questions regarding mito-sis, but one compelling issue is how all the intricateprocesses are coordinated in space and time by centri-oles to generate a geometric structure that maintains

itself at steady state. Indeed, the mitotic apparatusresembles a crystalline structure, however it is alsoa dynamic, dissipative system. A review inScienceconcluded: Robustness of spindle assembly mustcome from guidance of the stochastic behavior of microtubules by a eld (Karsenti and Vernos, 2001).Without any real evidence some conclude that chro-mosomes generate some type of eld which organizes

the centrioles and spindles. However, Boveri and laterMazia (1970)believed the opposite, that spindle andcentrosome/centriole microtubules generated an orga-nizing eld or otherwise regulated the movement of chromosomes and orchestration of mitosis.

As centrosomes/centrioles organize the spindles(which anchor in the pericentrin matrix surround-ing centrioles), it seems most likely that centro-somes/centrioles are the primary organizers of mitosis.

Cultured cells in which centrosomes are removedby microsurgical techniques, leaving the cell nucleus


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Fig. 5. Centriole cylinder (one half of a centriole) is comprised of nine microtubule triplets in a skewed parallel arrangement. Eachmicrotubule is comprised of tubulin proteins (Fig. 6), each of which may be in one or more possible conformational states (illustrated ase.g. black or white). The cylinder inner core is approximately 140 nm in diameter and the cylinder is 750 nm in length. By Dave Cantrell.

and cytoplasm, are called karyoplasts.Maniotis andSchliwa (1991)found that karyoplasts reestablish amicrotubule organizing center near the nucleus and

form mitotic spindles. Karyoplasts can grow but donot undergo cell division/mitosis.Khodjakov et al. (2002)destroyed centrosomes by

laser ablation in cultured cells and found that a randomnumber (214) of new centrosomes formed in cloudsof pericentrin.

In any case centrosomes/centrioles are essen-tial to normal mitosis (Marx, 2001; Doxsey, 1998;Hinchcliffe et al., 2001) and impairment of theirfunction can lead to genomic instability and cancer(Szuromi, 2001; Pihan and Doxsey, 1999). Multiple

and enlarged centrosomes have been found in cells of human breast cancer and other forms of malignancy(Lingle et al., 1998, 1999; Pihan et al., 2003). Wongand Stearns (2003)showed that centrosome number,hence centriole replication, is controlled by factorsintrinsic to the centrosome/centrioles (i.e. rather thangenetic control). Referring to the centrosome as thecell brain,Kong et al. (2002)attributed malignancyto aberrant centrosomal information processing.

In other forms of intracellular movement and or-ganization, microtubules and other cytoskeletal struc-

tures are the key players. So it is logical that they alsoorganize mitosis. But something is missing. What typeof organizational eld, information processing or prin-

ciple might be occurring in mitosis? Recent attemptsto explain higher brain functions have suggested thatmicrotubules within neurons and other cells processinformation, and may utilize certainquantum proper-ties. If so, these same properties could also explainaspects of mitosis and normal cell functions lost inmalignancy.

Subsequent to mitosis, embryonic daughter cellsdevelop into particular types of cells (phenotypes),e.g. nerve cells, blood cells, intestinal cells, etc., aprocess called differentiation. Each (normal) cell in

an organism has precisely the same set of genes. Dif-ferentiation involves expressing a particular subsetof genes to yield a particular phenotype. Neighborcells and location within a particular tissue somehowconvey signals required for proper gene expressionand differentiation. For example an undifferentiatedstem cell placed in a certain tissue will differ-entiate to the type of cell in the surrounding tis-sue. However, the signaling mechanisms conveyedby surrounding cells to regulate differentiation areunknown.


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Cancer cells are often described as poorly differ-entiated, or undifferentiatedlacking rened prop-erties characteristic of a particular tissue type, and

unmatched to the surrounding or nearby normal tis-sue. Abnormal genotypes (e.g. from aberrant mito-sis or mutations) can disrupt normal differentiation,but again the mechanisms of normal differentiation(genotype to phenotype) are unknown.

It seems likely that centrioles play key roles indifferentiation. Situated close to the nucleus, centri-oles can transduce intra-cellular signals to regulategene expression (Puck and Krystosek, 1992). Ascommander of the cytoskeleton, centrioles candetermine cell shape, orientation and form. And cen-trioles have the information storage and processingcapacity to record the blueprints for a vast numberof phenotypes, all possible states of differentiation ina specic organism. The key question in differentia-tion is how signals/communication from neighboringand surrounding tissues mediate gene expression.While chemical messengers and chemical gradientsare possible mechanisms (e.g.Niethammer et al.,2004), a more elegant, efcient and practical methodmay involve non-local quantum interactions (e.g. en-tanglement) among microtubules and centrioles inneighboring and nearby cells.

3. Microtubules and centrioles

Interiors of eukaryotic cells are structurally or-ganized by the cell cytoskeleton which includesmicrotubules, actin, intermediate laments andmicrotubule-based centrioles, cilia and basal bodies(Dustin, 1984). Rigid microtubules are interconnectedby microtubule-associated proteins (MAPs) to forma self-supporting, dynamic tensegrity network which,

along with actin laments, comprises a negativelycharged matrix on which polar cell water moleculesare bound and ordered (Pollack, 2001).

Microtubules are cylindrical polymers of the pro-tein tubulin and are 25 nm (1 nm= 10 9 m) in diam-eter (Fig. 6). The cylinder walls of microtubules arecomprised of 13 longitudinal protolaments whichare each a series of tubulin subunit proteins (Fig. 6).Each tubulin subunit is an 8nm 4 nm 5 nmheterodimer which consists of two slightly differ-ent classes of 4 nm, 55,000 Da monomers known as

Fig. 6. Microtubules are hollow cylindrical polymers of tubulinproteins, each a dimer of alpha and beta monomers.

alpha and beta tubulin. The tubulin dimer subunits

within the cylinder wall are arranged in a hexagonallattice which is slightly twisted, resulting in differingneighbor relationships among each subunit and itssix nearest neighbors (Dustin, 1984). Pathways alongneighbor tubulins form helices which repeat every 3,5, and 8 rows (the Fibonacci series).

Each tubulin has a surplus of negative surfacecharges, with a majority on the alpha monomer; thus,each tubulin is a dipole (beta plus, alpha minus). Con-sequently microtubules can be considered electrets:oriented assemblies of dipoles which are predicted to

have piezoelectric, ferroelectric and spin glass prop-erties (Tuszynski et al., 1995). In addition, negativelycharged C-termini tails extend outward from eachmonomer, attracting positive ions from the cytoplasmand forming a plasma-like Debye layer surroundingthe microtubule (Hameroff et al., 2002).

Biochemical energy is provided to microtubulesin several ways: tubulin-bound GTP is hydrolyzedto GDP in microtubules, and MAPs which attach atspecic points on the microtubule lattice are phos-phorylated. In addition microtubules may possibly


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utilize non-specic thermal energy for laser-like co-herent pumping, for example in the GigaHertz rangeby a mechanism of pumped phonons suggested by

Frhlich (1968, 1970, 1975). Simulation of coherentphonons in microtubules suggest that phonon maximacorrespond with functional microtubule-MAP bindingsites (Samsonovich et al., 1992).

In centrioles (as well as cilia, agella, basal bod-ies, etc.) microtubules fuse into doublets or triplets.Nine doublets or triplets then form larger barrel-likecylinders (Fig. 5) which in some cases have in-ternal structures connecting the doublets/triplets.The nine doublet/triplets are skewed, and centriolesmove through cytoplasm by an Archimedes screwmechanism.

Albrecht-Buehler (1992)has shown that centriolesact as the cellular eye, detecting and directing cellmovement in response to infrared optical signals.(Cilia, whose structures are nearly identical to centri-oles, are found in primitive visual systems as well asthe rod and cone cells in our retinas.) The inner cylin-drical core of centrioles is approximately 140 nm indiameter and 750 nm in length, and, depending on therefractive index of the inner core, could act as a waveg-uide or photonic band gap device able to trap photons(Fig. 8). Tong et al. (2003)have shown that properly

designed structures can act as sub-wavelength waveg-uides, e.g. diameters as small as 50nm can act aswaveguides for visible and infrared light.

Historic work by Gurwitsch (1922) showedthat dividing cells generate photons (mitogeneticradiation), and recent research byLiu et al. (2000)demonstrates that such biophoton emission is max-imal during late S phase of mitosis, correspondingwith centriole replication.Van Wijk et al. (1999)showed that laser-stimulated biophoton emission(delayed luminescence) emanates from peri-nuclear

cytoskeletal structures, e.g. centrioles.Popp et al.(2002) have shown that biophoton emission is due toquantum mechanical squeezed photons, indicatingquantum optical coherence. The skewed helical struc-ture of centrioles may be able to detect polarization orother quantum properties of photons such as orbitalmomentum.

Unlike centrioles, cilia and agella bend by meansof contractile proteins which bridge between dou-blets/triplets. The coordination of the contractilebridges are unknown, howeverAtema (1973)sug-

gested that propagating conformational changes alongtubulins in the microtubule doublet/triplets signaledcontractile proteins in an orderly sequence.Hameroff

and Watt (1982)suggested that microtubules may pro-cess information via tubulin conformational dynamics(coupled to dipoles) not only longitudinally (as Atemaproposed) but also laterally among neighbor tubulinson the hexagonal microtubule lattice surface, account-ing for computer-like capabilities.Rasmussen et al.(1990) showed an enormous potential computationalcapacity of microtubule lattices (and microtubulesinterconnected by MAPs) via tubulintubulin dipoleinteractions, with the dipole-coupled conformationalstate of each tubulin representing one bit of in-formation. The regulation of protein conformationalstates is an essential feature of biological systems.

4. Tubulin conformational states

Within microtubules, individual tubulins may existin different states which can change on various timescales (Fig. 7). Permanent states are determined bygenetic scripting of amino acid sequence, and multi-ple tissue-specic isozymes of tubulin occur (e.g. 22tubulin isozymes in brain;Lee et al., 1986). Each tubu-

Fig. 7. Tubulin protein subunits within a microtubule can switchbetween two (or more) conformations, coupled to London forcesin a hydrophobic pocket in the protein interiort. Right bottom:Each tubulin is proposed to also exist in quantum superpositionof both conformational statesPenrose and Hameroff (1995; cf.Hameroff and Penrose, 1996a, 1996b).


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lin isozyme within a microtubule lattice may be struc-turally altered by post-translational modicationssuch as removal or addition of specic amino acids.

Thus, each microtubule may be a more-or-less stablemosaic of slightly different tubulins, with altered prop-erties and functions accordingly (Geuens et al., 1986).

Tubulins also change shape dynamically. In oneexample of tubulin conformational change observedin single protolament chains, one monomer can shift27 from the dimers vertical axis (Melki et al., 1989)with associated changes in the tubulin dipole (openversus closed conformational states).Hoenger andMilligan (1997) showed a conformational changebased in the beta tubulin subunit.Ravelli et al. (2004)demonstrated that the open versus closed conforma-tional shift is regulated near the binding site for thedrug colchicine. Dynamic conformational changes of particular tubulins may be inuenced, or biased, bytheir primary or post-translational structures.

In general, conformational transitions in which pro-teins move globally and upon which protein functiongenerally depends occur on the microsecond (10 6 s)to nanosecond (10 9 s) to 10ps (10 11 s) time scale(Karplus and McCammon, 1983). Proteins are onlymarginally stable: a protein of 100 amino acids isstable against denaturation by only 40kJmol 1

whereas thousands of kJ mol

1 are available in aprotein from amino acid side group interactions. Con-sequently protein conformation is a delicate balanceamong powerful countervailing forces (Voet andVoet, 1995).

The types of forces operating among amino acidside groups within a protein include charged interac-tions such as ionic forces and hydrogen bonds, as wellas interactions between dipolesseparated charges inelectrically neutral groups. Dipoledipole interactionsare known as van der Waals forces and include three

types:(1) Permanent dipolepermanent dipole.(2) Permanent dipoleinduced dipole.(3) Induced dipoleinduced dipole.

Type 3 induced dipoleinduced dipole interactionsare the weakest but most purely non-polar. They areknown as London dispersion forces, and althoughquite delicate (40 times weaker than hydrogen bonds)are numerous and inuential. The London force at-traction between any two atoms is usually less than a

few kJ mol 1, however thousands occur in each pro-tein. As other forces cancel out, London forces in hy-drophobic pockets can govern protein conformational

states.London forces ensue from the fact that atoms andmolecules which are electrically neutral and (in somecases) spherically symmetrical, nevertheless have in-stantaneous electric dipoles due to asymmetry in theirelectron distribution: electrons in one cloud repel thosein the other, forming dipoles in each. The electriceld from each uctuating dipole couples to othersin electron clouds of adjacent non-polar amino acidside groups. Due to inherent uncertainty in electronlocalization, the London forces which regulate tubulinstates are quantum mechanical and subject to quantumuncertainty.

In addition to electron location, unpaired electronspin may play a key role in regulating tubulin states.Unpaired electron spin is basically a tiny magnet andmicrotubules are ferromagnetic lattices which alignparallel to strong magnetic elds, accounted for bysingle unpaired electrons per tubulin. Atomic struc-ture of tubulin shows two positively charged areas( 100150 meV) near the alpha-beta dimer neckseparated by a negatively charged area of about1.5nm (Hameroff and Tuszynski, 2003). This regionconstitutes a double well potential which should en-able inter-well quantum tunneling of single electronsand spin states since the energy depth is signicantlyabove thermal uctuations (1 kT= 25meV at roomtemperature). The intra-tubulin dielectric constantis only 2, compared to roughly 80 outside the mi-crotubule. Hence neither environmental nor thermaleffects should decohere quantum spin states in thedouble well. Spin states and superposition of un-paired tunneling electrons should couple to excesstubulin electrons and global tubulin conformational

states including tubulin quantum superposition states(Fig. 7). Tubulin subunits within microtubules maybe regulated by quantum effects.

5. The strange world of quantum reality

Reality seems to be described by two separatesets of laws. At our everyday large scale classical,or macroscopic world, Newtons laws of motion andMaxwells equations for electromagnetism are suf-


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cient. However, at small scales in the quantumrealm (and the boundary between the quantum andclassical realms remains elusive) paradox reigns.

Objects may exist in two or more states or placessimultaneouslymore like waves than particles andgoverned by a quantum wave function. This prop-erty of multiple coexisting possibilities, known asquantum superposition, persists until the superposi-tion is measured, observed or decoheres via inter-action with the classical world or environment. Onlythen does the superposition of multiple possibili-ties reduce, collapse, actualize, choose, ordecohere to specic, particular classical states.

The nature of quantum state reductiontheboundary between the quantum and classicalworldsremains mysterious (Penrose, 1989, 1994).

Another quantum property is entanglement in whichcomponents of a system become unied, governedby one common quantum wave function. The quan-

Table 1Classical and quantum superposition states for electrons/electron pairs (top), tubulins/tubulin pairs (middle), and centriole cylinders/centrioles(bottom)

tum states of each component in an entangled systemmust be described with reference to other components,though they may be spatially separated. This leads to

correlations between observable physical properties of the systems that are stronger than classical correla-tions. Consequently, measurements performed on onecomponent may be interpreted as inuencing othercomponents entangled with it.

Because of the implication for non-local, instanta-neous (therefore faster than light) inuence, Einsteindisliked entanglement (and quantum mechanics ingeneral) deriding it as spooky action at a distance.Einstein et al. (1935)f ormulated the EPR paradox,a thought experiment intended to disprove entangle-ment. Imagine two members of a quantum system(e.g. two paired electrons with complementary spin: if one is spin up, the other is spin down, and vice versa;Tables 1 and 2, top). If the paired electrons (both insuperposition of both spin up and spin down) are sep-


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Table 2Quantum superposition, reduction, and entanglement for electron pairs (top), tubulin pairs (middle), and centrioles (bottom)


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arated from each other by being sent along differentwires, say to two different locations miles apart fromeach other, they each remain in superposition of both

spin up and spin down. However, when one superpo-sitioned electron is measured by a detector at its des-tination and reduces/collapses to a particular spin (sayspin up), its entangled separated twin (according toentanglement) must instantaneously reduce/collapseto the complementary spin down. The experimentwas actually performed in 1983 with two detectorsseparated by meters within a laboratory (Aspectet al., 1982) and showed, incredibly, that comple-mentary instantaneous reduction did occur! Similarexperiments have been done repeatedly with not onlyelectron spin pairs, but polarized photons sent alongber optic cables many miles apart and always re-sult in instantaneous reduction to the complementaryclassical state (Tittel et al., 1998). The instantaneous,faster than light coupling, or entanglement remainsunexplained, but is being implemented in quan-tum cryptography technology (Bennett et al., 1990).(Though information may not be transferred via en-tanglement, useful correlations and inuence may beconveyed.)

Another form of entanglement occurs in quantumcoherent systems such as BoseEinstein condensates

(proposed by Bose and Einstein decades ago but re-alized in the 1990s). A group of atoms or moleculesare brought into a quantum coherent state such thatthey surrender individual identity and behave likeone quantum system, marching in step and governedby one quantum wave function. If one component isperturbed all components feel it and react accord-ingly. BoseEinstein condensates (clouds) of ce-sium atoms have been shown to exhibit entanglementamong a trillion or so component atoms (Vulsgaardet al., 2001).

There are apparently at least two methods to cre-ate entanglement. The rst is to have componentsoriginally united, such as the EPR electron pairs,and then separated. A second method (mediatedentanglement) is to begin with spatially separatednon-entangled components and make simultaneousquantum measurements coherently, e.g. via laserpulsations which essentially condense components(BoseEinstein condensation) into a single systemthough spatially separated. This technique was usedin the cesium cloud entanglement experiments and

other quantum systems and holds promise for quan-tum information technology.

Quantum superposition, entanglement and reduc-

tion are currently being developed technologicallyfor future use in quantum computers which promiseto revolutionize information processing. First pro-posed in the early 1980s (Benioff, 1982), quantumcomputers are now being developed in a variety of technological implementations (electron spin, photonpolarization, nuclear spin, atomic location, magneticux in Josephson junction superconducting loops,etc.). Whereas conventional classical computers rep-resent digital information as bits of either 1or 0, inquantum computers, quantum information may berepresented as quantum superpositions of both 1and 0 (quantum bits, or qubits). While in superposition,qubits interact with other qubits (by entanglement) al-lowing computational interactions of enormous speedand near-innite parallelism. After the computationis performed the qubits are reduced (e.g. by environ-mental interaction/decoherence) to specic classicalstates which constitute the solution (Milburn, 1998).

6. Are microtubules quantum computers?

Quantum dipole oscillations within proteins wererst proposed byFrhlich (1968, 1970, 1975)to regu-late protein conformation and engage in macroscopiccoherence.Conrad (1994)suggested quantum super-position of various possible protein conformationsoccur before one is selected.Roitberg et al. (1995)showed functional protein vibrations which dependon quantum effects centered in two hydrophobicphenylalanine residues, andTejada et al. (1996)haveevidence to suggest quantum coherent states exist inthe protein ferritin. In protein folding, non-local quan-

tum electron spin interactions among hydrophobicregions guide formation of protein tertiary confor-mation (Klein-Seetharaman et al., 2002), suggestingprotein folding may rely on spin-mediated quantumcomputation.

In the context of an explanation for the mecha-nism of consciousness,Penrose and Hameroff (1995;cf. Hameroff and Penrose, 1996a, 1996b; Hameroff,1998; Woolf and Hameroff, 2001)have proposed thatmicrotubules within brain neurons function as quan-tum computers. The basic idea is that conformational


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states of tubulins, coupled to quantum van der WaalsLondon forces, exist transiently in quantum superpo-sition of two or more states (i.e. as quantum bits, or

qubits). Tubulin qubits then interact/compute withother superpositioned tubulins by non-local quantumentanglement. After a period of computational entan-glement tubulin qubits eventually reduce (collapse)to particular classical states (e.g. after 25 ms) yieldingconscious perceptions and volitional choices whichthen govern neuronal actions. The specic type of reduction proposed in the PenroseHameroff modelinvolves the Penrose proposal for quantum gravitymediated objective reduction (Penrose, 1998). De-spite being testable and falsiable, the proposal forquantum computation in neuronal microtubules hasgenerated considerable skepticism, largely because of the apparent fragility of quantum states and sensitivityto disruption by thermal energy in the environment(decoherence). Quantum computing technologistswork at temperatures near absolute zero to avoid ther-mal decoherence, so quantum computation at warmphysiological temperatures in seemingly liquid mediaappears at rst glance to be extremely unlikely. (Al-though entanglement experiments are done at roomtemperature.)

Attempting to disprove the possibility of quan-

tum computation in brain microtubules, University of Pennsylvania physicist MaxTegmark (2000)calcu-lated that microtubule quantum states at physiologicaltemperature would decohere a trillion times too fastfor physiological effects, with a calculated decoher-ence time of 10 13 s. Neurons generally function inthe range of roughly 10100ms, or 10 2 to 10 1 s.

However, Tegmark did not actually address specicsof the PenroseHameroff model, nor any previous the-ory, but rather proposed his own quantum microtubulemodel which he did indeed successfully disprove. For

example Tegmark assumed quantum superposition of a soliton wave traveling along a microtubule, sepa-rated from itself by 24 nm. The PenroseHameroff model actually proposed quantum superposition of tubulin proteins separated from themselves by the di-ameter of their atomic nuclei. This discrepancy aloneaccounts for a difference of 7 orders of magnitudein the decoherence calculation. Further correctionsin the use of charge versus dipoles and dielectricconstant lengthens the decoherence time to 10 5to 10 4 s. Considering other factors included in the

PenroseHameroff proposal such as plasma phasescreening, actin gel isolation, coherent pumping andquantum error correction topology intrinsic to micro-

tubule geometry extends the microtubule decoherencetime to tens to hundreds of milliseconds, within theneurophysiological range. Topological quantum errorcorrection may extend it signicantly further. Theserevised calculations (Hagan et al., 2002) were pub-lished in Physical Reviews E , the same journal inwhich Tegmarks original article was published.

The basic premise that quantum states are de-stroyed by physiological temperature is countered bythe possibility of laser-like coherent pumping (Frh-lich mechanism) suggested to occur in biologicalsystems with periodic structural coherence such asmicrotubules. Moreover,Pollack (2001)has shownthat water in cell interiors is largely ordered due tosurface charges on cytoskeletal actin, microtubulesand other structures.

Thus, despite being largely water, cell interiors arenot aqueous but rather a crystal-like structure. Per-haps most importantly, experimental evidence showsthat electron quantum spin transfer between quantumdots connected by organic benzene molecules ismoreefcient at room temperature than at absolute zero(Ouyang and Awschalom, 2003). Other experiments

have shown quantum wave behavior of biological por-phyrin molecules (Hackermller et al., 2003). In bothbenzene and porphyrin, and in hydrophobic aromaticamino acid groups in proteins such as tubulin, delo-calizable electrons may harness thermal environmen-tal energy to promote, rather than destroy, quantumstates.

Furthermore, PaulDavies (2004)has suggested thata post-selection feature of quantum mechanics putforth byAharonov et al. (1996)may operate in livingsystems, making the decoherence issue moot.

7. Quantum entanglement in mitosis anddifferentiation?

Centriole replication and subsequent coordinatedactivities of the mitotic spindles appear to be key fac-tors in forming and maintaining two identical sets of chromosomes, thus avoiding aneuploidy, genomic in-stability and cancer. Viewing mitosis as a dissipative,clock-like process which, once set in motion has no


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adaptive recourse, seems unlikely to account for thenecessary precision. Some organizing communicationbetween replicated centrioles and daughter cell spin-

dles seems to be in play (Karsenti and Vernos, 2001),and would certainly be favored in evolution if feasible.The perpendicular centriole replication scheme haslong been enigmatic to biologists. Alternative mech-anisms such as longitudinal extension (budding),or longitudinal ssion with regrowth (akin to DNAreplication) would seem to be more straighforward. InDNA replication each component of a base pair is indirect contact so direct binding of the complementarymember of the base pair is straightforward. However,in centrioles replication by neither extension/buddingnor ssion would permit direct contact/copying of each component tubulin because of the more complexthree dimensional centriole geometry. The enigmaticperpendicular centriole replication provides an op-portunity for each tubulin in a mature (mother)centriole to be transiently in contact, either directlyor via lamentous proteins, with a counterpart in theimmature (daughter) centriole. Thus, the state of each tubulin (genetic, post-translational, electronic,conformational) may be relayed to its daughter coun-terpart tubulin in the replicated centriole, resulting inan identical or complementary mosaic of tubulins, and

two identical or complementary centrioles. Assum-ing proteins may exist in quantum superposition of states, transient contact of tubulin twins during centri-ole replication would enable quantum entanglementso that subsequent states and activities of originallycoupled tubulins within the paired centrioles wouldbe unied (Tables 1 and 2, middle). Then if a par-ticular tubulin in one centriole cylinder is perturbed(measured), or its course or activities altered, itstwin tubulin in the paired centriole would feel theeffect and respond accordingly in a fashion analogous

to quantum entangled EPR pairs. Thus, activities of replicated centrioles would be mirror-like, preciselywhat is needed for normal mitosis. InTables 1 and2 the state of each centriole is euphemistically repre-sented as either spin up or down (right or left). In ac-tuality the states of each centriole would be far morecomplex, since each tubulin could be in one particularbinary state. There are approximately 30,000 tubulinsper centriole cylinder. If each tubulin can be in oneof two possible states, each centriole could be in oneof 230, 000 possible states. Considering variations in

isozymes and post-translational modications, eachtubulin may exist in many more than two possiblestates (e.g. 10), and centrioles may therefore exist

in up to 1030, 000

possible stateseasily sufcientto represent each and every possible phenotype. Butregardless of their specic complexity, replicated cen-trioles would be in identical (or complementary, i.e.precisely opposite) entangled states.

How could entanglement actually occur? Centri-oles are embedded in an electron dense protein matrix(pericentrin) to which mitotic spindle microtubulesattach; the opposite ends of the spindles bind specicchromatids via centromere/kinetochores. The centri-ole/pericentrin (centrosome) and spindle complexare embedded in protein gel and ordered water so thatthe entire mitotic complex may (at least transiently)be considered a pumped quantum system (e.g. a Frh-lich BoseEinstein condensate) unied by quantumcoherence.

As described previously, quantum optical coher-ence (laser coupling) can induce entanglement. Al-though photons generally propagate at the speed of light, recent developments in quantum optics haveshown that photons may be slowed, or trapped inphase coherent materials, or phaseonium (Scully,2003). In these situations photons are resonant with

the materials (which may be at warm temperatures)but not absorbed. Quantum properties of the light canbe mapped onto spin states of the material, and laterretrieved (read) by a laser pulse (or Frhlich coher-ence). The dimensions of centrioles are close to thewavelengths of light in the infrared and visible spec-trum (Fig. 8) such that they may act as phase coherent,resonant waveguides (Albrecht-Buehler, 1992). Frh-lich coherence may then play the role of laser retrieval,coupling/entangling pairs of centrioles. As describedpreviously, experimental evidence shows an associa-

tion between centriole replication and photon emission(Liu et al., 2000; Van Wijk et al., 1999; Popp et al.,2002).

How would quantum entanglement work in nor-mal mitosis? Binding of a particular chromatid cen-tromere/kinetochore by a spindle connected at itsopposite end to a centriole may be considered a quan-tum measurement of the anchoring centriole, causingreduction/collapse and complementary action in itsentangled twin (thus, binding the complementarychromatid centromere/kinetochore). Although the ac-


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Fig. 8. Cutaway view of centriole cylinder showing (to scale) wavelengths of visible and infrared light suggesting possible waveguidebehavior. By Dave Cantrell.

tion is complementary, and thus in some sense oppo-site, the operations are identical from an informationstandpoint (and because centriole orientations areopposite, the actions may be considered equivalent).Consequently, precise complementary mirror-like ac-tivities of tubulins in the two entangled centrioleswould ensue, and each member of a sister chro-matid pair would be captured for each daughter cell.Two precisely equal genomes would result following

mitosis.How would failed quantum entanglement lead toaneuploidy and malignancy? Defects during mitosiscan occur in two ways. As shown inFig. 2 spin-dle attachment to chromatids during metaphase (re-ecting entangled information in the centrioles) maygo awry, resulting in abnormal separation of chromo-somes. This may result from improper communicationbetween the two centrioles (the right handed centri-ole does not know what the left-handed centriole isdoing). Another type of defect may occur in the repli-

cation and entanglement as shown inFig. 3, resultingin three (or more) centrioles which separate chromo-somes into three portions rather than two preciselyequal portions.

Measurement of standard EPR pairs apparentlydestroys entanglement. Once complementary actionsoccur, members of separated pairs behave indepen-dently. In centrioles, one measurement/operationper tubulin would be useful in mitosis and differ-entiation, allowing approximately 30,000 measure-ments/operations per centriole cylinder and ensuring

precise division of daughter chromosomes and sub-sequent differentiation. However, an ongoing seriesof measurement operations (chromatid interactions,movements and binding of other cytoskeletal struc-tures, differentiation, etc.) persisting after completionof mitosis could be even more useful.

Could persistent entanglement (re-entanglement)occur in biological systems? Unlike standard EPRpairs (e.g. electron spin) whose underlying states are

random, the conformational state of each member of paired tubulin twins has identical specic tendenciesdue to genetic and post-translational structure. In thesame fashion that laser pulsing mediates entanglementamong cesium clouds and other quantum systems,quantum optical (and/or Frhlich) coherence couldmediate ongoing entanglement (re-entanglement)among tubulin twins in separated centrioles. Becausedynamic conformational states are transient, the quan-tum state may be transduced to, and stored as, a spinstate or other more sustainable parameter. Thus, cen-

trioles throughout a tissue or entire organism mayremain in a state of quantum entanglement. Impair-ment or loss of such communicative entanglementmay correlate with malignancy.

8. Implications for cancer therapy

Current therapies for cancer are generally aimedat impairing mitosis and are thus severely toxic.Many cancer drugs (vincristine, taxol, etc.) bind to


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microtubules and prevent their disassembly/assemblyrequired for formation and activities of the mitoticspindles. In addition to generalized toxicity due to

impairment of non-mitotic microtubule function, par-tial disruption of mitosis can cause further aneuploidy(Kitano, 2003). Radiation is also a toxic process withthe goal of impairing/destroying highly active ma-lignant cells more than normal cells. Recognizingcentrosomes as the key organizing factor in mitosis,Kong et al. (2002)proposed disabling centrosomesby cooling/freezing as a cancer therapy.

Low level laser illumination apparently en-hances mitosis.Barbosa et al. (2002)using 635 and670 nm lasers, andCarnevalli et al. (2003)using an830 nm laser both showed increased cell division inlaser-illuminated cell cultures. Using laser interfer-ence Rubinov (2003)showed enhanced occurrence of micronuclei (aberrant multipolar mitoses) althoughspecic interference modes decreased the number of micronuclei. It may be concluded that non-specic,low intensity laser illumination enhances centriolereplication and promotes cell division (the oppositeof a desired cancer therapy). On the other hand if centrioles are sensitive to coherent light, then higherintensity laser illumination (still below heating thresh-old) may selectively target centrioles, impair mitosis

and be a benecial therapy against malignancy.However, laser illumination may also be usedin a more elegant mode. If centrioles utilize quan-tum photons for entanglement, properties of cen-trosomes/centrioles approached more specicallycould be useful for therapy. Healthy centrioles for agiven organism or tissue differentiation should thenhave specic quantum optical properties detectablethrough some type of readout technology. An afictedpatients normal cells could be examined to determinethe required centriole properties which may then be

used to generate identical quantum coherent photonsadministered to the malignancy. In this mode the ideawould not be to destroy the tumor (relatively lowenergy lasers would be used) but to reprogram orredifferentiate the centrioles and transform the tumorback to healthy well differentiated tissue.

Stem cells are totipotential (or pluripotential) un-differentiated cells with a wide variety of potentialapplications in medicine. Zygotes, or fertilized eggsare totipotential stem cells, and embryonic cells ingeneral are relatively undifferentiated. Thus, fetal em-

bryos have been a source for stem cells though se-rious ethical considerations have limited availability.Perhaps normally differentiated cells could be undif-

ferentiated (retrodifferentiated) by laser therapy asdescribed above, providing an abundant and ethicalsource of stem cells for various medical applications.

9. Conclusion: quantum entanglementand cancer

It is suggested here that normal mitosis is orga-nized by quantum entanglement and quantum coher-ence among centrioles. In particular, quantum opticalproperties of centrioles enable entanglement in nor-mal mitosis which ensures precise mirror-like activi-ties of mitotic spindles and daughter chromatids, andproper differentiation, communication and boundaryrecognition between daughter cells.

Defects in the proposed mitotic quantum entangle-ment/coherence can explain all aspects of malignancy.Analysis and duplication of quantum optical prop-erties of normal cell centrioles could possibly leadto laser-mediated therapeutic disruption and/or repro-gramming of cancerous tumors as well as abundant,ethical production of stem cells.

Acknowledgements

I am grateful to Dave Cantrell for illustrations, toMitchell Porter and Jack Tuszynski for useful discus-sions, and to Patti Bergin for manuscript preparationassistance.

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