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QUANTUM MECHANICS AND CANCER BIOLOGY

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DOI: 10.13140/RG.2.2.34417.79209

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 QUANTUM MECHANICS AND CANCER BIOLOGY

By

Aggrey Aningu Wakhule

Medical Physicist

Kenyatta National Hospital

( M Sc Medical Physics – University of Surrey, UK)

ABSTRACT

The quest for clear understanding of cancer and hence the ultimate search for a
logical way to prevent, diagnose and cure has been an elusive area of research
amongst scientists. The complexity of mutations during replication in the human cell
has made the situation more puzzling to researchers who have made contributions in
this area.

This matter, seen as the preserve of biologists, has attracted the interest of
physicists who have argued that mutations may be guided by quantum mechanical
phenomena such as proton tunnelling and decoherence. This work examines
previous works advanced by Physicists in this field and argues for a relationship
between mutations and proton tunnelling. Quantum mechanics has been briefly
discussed in away understandable to Biologists while the cell and cancer biology is
covered to the extent of understanding of Physicists.

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The author of this work claims no originality but strongly suggests for further
research on the extent to which external risk factors may influence quantum
mechanical events within the cell’s environment to cause mutations.

CONTENTS

TITLE PAGE

ABSTRACT …………………………………………………………… i

TABLE OF CONTENTS……………………………………………… ii

1. INTRODUCTION ……………………………………………………. 1

2. QUANTUM MECHANICS …………………………………………… 2

2
 2.1 Historical background …………………………………………… 2
2.2 General Overview ……………………………………………….. 2
2.3 Superposition of Quantum States……………………………… 3
2.4 Decoherance……………………………………………………… 3
2.5 Quantum Measurements and Uncertainties…………………… 4
2.6 Quantum Tunnelling……………………………………………… 4

3. QUANTUM BIOLOGY………………………………………………… 6

3.1 Overview……………………………………………………………. 6
3.2 Some Applications of Quantum Mechanics in Biology………… 6

4. THE CELL ……………………………………………………………. 8

4.1 Structure and Function………………………………………….. 8

4.2 The DNA………………………………………………………….. 11
4.3 The Cell Division…………………………………………………. 15

5. CANCER………….……………………………………………………. 20

5.1 Overview……………………………………………………………. 20
5.2 Mutation……………………………………………………………... 20
5.3 Hallmarks of Cancer……………………………………………….. 26
5.4 Cancer Risk Factors……………………………………………….. 30

6. QUANTUM MECHANICAL APPROACH TO CANCER BIOLOGY... 32

6.1 Overview………………………………………………………………. 32
6.2 The Lӧwdin Model and Proton Tunnelling…………………………. 32

7. CONCLUSION……………………………………………………………. 40

8. APPENDIX….…………………………………………………………….. 41

9. ACKNOWLEDGEMENT…………………………………………………... 48

10. REFERENCES ……………………………………………………………… 49

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 1. INTRODUCTION

The traditionally held view that cancer research is a preserve of biologists is facing
challenges by new novel theories from physicists. Although much of the physics
predictions remain speculative, there is growing consensus amongst scientists to
explore more on the theories developed through well modelled experimental
approach.

The widely held perspective remains that cancer is caused by mutations occurring
during the replication of deoxyribonucleic acid (DNA). The mechanism through which
these mutations occur are too complex to be explained by the available biological
knowledge. Some Physicists and Chemists claim that the mutations may be as a
result of quantum events occurring during cell division.

Erwin Schrödinger (1944) [1], suggested that genetic information was contained in
“aperiodic crystal” in its configuration of covalent chemical bond and argued that
mutations are linked to a jump in quantum system from one energy level to another
in what is known as quantum leaps. This theoretical prediction was acknowledged
independently by James Watson and Francis Crick [2] who co-discovered the
structure of deoxyribonucleic acid (DNA) now referred to as the Watson-Crick Model.

4
Chan J.Y.,(2011) [3] suggests that new evidence supporting the existence of a
mutator phenotype in cancer cells, is as a result of amplified measurement
uncertainty on genetic information during DNA replication. Chan J.Y further argues
that ‘genetic information is contained in the sequence of DNA bases, each existing
due to proton tunnelling, as a coherent superposition of quantum states composed of
both the canonical and rare tautomeric forms until decoherence by interaction with
DNA polymerase’.

McFadden J. and Al-Khalili J. [4] argue that spontaneous mutations are instigated by
such events as a shift of single proton from one site to another of the DNA hydrogen
bond through a quantum process (proton tunneling). The wave function describing
the genome quantum state is presumed to be in a coherent linear superposition
which is destroyed by a process of decoherence through the interaction of the
genome wave function and the environment which acts as a measurement tool. They
have shown that the ‘accelerated rate of decoherence may significantly increase the
rate of production of mutated state’.

These arguments point to a possible role for a quantum process in DNA mutations
responsible for cancer. This work is an exploration into the quantum process that
may be responsible for DNA mutations and examines previous works done on the
same.

2. QUANTUM MECHANICS

2.1 General Overview

Quantum Mechanics has experienced rapid expansion from its beginnings in the
early 20th century to define itself as a unique branch of Physics dealing with physical
phenomena at atomic and subatomic levels.

Various interpretations have been developed to explain our understanding of nature

at the microscopic level through Quantum mechanics. The Copenhagen
Interpretation is one of the earliest and most taught. Developed by pioneer
Quantum Physics scientists such as Niels Bohr, Werner Heisenberg and others at
the Niels Bohr’s Institute in the 1920’s, there seems to be no concise statement
which defines the full Copenhagen Interpretation.[5]

However, there are basic principles generally accepted as being part of the
interpretation:

1. A system is completely described by a wave function Ψ, representing the

state of the system, which evolves smoothly in time, except when a

5
 measurement is made, at which point it instantaneously collapses to an
eigenstate of the observable that is measured.
2. The description of nature is essentially probabilistic, with the probability of a
given outcome of a measurement given by the square of the modulus of the
amplitude of the wave function. (The Born rule, after Max Born)
3. It is not possible to know the value of all the properties of the system at the
same time; those properties that are not known exactly must be described by
probabilities. (Heisenberg's uncertainty principle)
4. Matter exhibits a wave–particle duality. An experiment can show the particle-
like properties of matter, or the wave-like properties; in some experiments
both of these complementary viewpoints must be invoked to explain the
results, according to the complementarity principle of Niels Bohr.
5. Measuring devices are essentially classical devices, and measure only
classical properties such as position and momentum.
6. The quantum mechanical description of large systems will closely
approximate the classical description. (This is the correspondence principle of
Bohr and Heisenberg.)

According to the Copenhagen Interpretation, a Quantum system exists in a

superposition state and when a measurement is made, it causes decoherence.

2.2 Superposition of Quantum States

This is a concept in quantum mechanics which asserts that a quantum system exists
in all its possible states simultaneously, but gives an outcome of only one state when
measured.

The system is said to be in a linear superposition of several eigenstates and a

measurement on the system causes the wave function of several eigenstates to
collapse to a single eigenstate. This destroys the coherence of the system in a
process called decoherence, leading to entanglement of the system with the
environment. The environment plays the role of a measurement device.

According to Paul Dirac [6], ‘The general principle of superposition of quantum

mechanics applies to the states [that are theoretically possible without mutual
interference or contradiction] ... of any one dynamical system. It requires us to
assume that between these states there exist peculiar relationships such that
whenever the system is definitely in one state we can consider it as being partly in
each of two or more other states. The original state must be regarded as the result of
a kind of superposition of the two or more new states, in a way that cannot be
conceived on classical ideas. Any state may be considered as the result of a

6
superposition of two or more other states, and indeed in an infinite number of ways.
Conversely any two or more states may be superposed to give a new state...’

The interference peaks from electrons in a double-split experiment is a good

example of superposition.

2.3 Decoherence
When a quantum system existing in a state of superposition gets entangled with the
environment, the wave function representing the system collapses into a definite
outcome of a single observable. This is what is referred to as a quantum
measurement. The environment acts as a measurement tool on the system. The
interaction between the system and the environment is an irreversible process, thus
preventing various components in the quantum superposition of the overall system’s
wave function from interfering with each other. This is referred to as decoherence.

Heinz-Dieter Zeh [8] claims that quantum decoherence identifies the boundary
between classical limit and quantum mechanics. The environment as a
measurement tool causes the classical appearance of macroscopic objects.

Zeh [8], Zurek [9] and Schlosshauer [10] have argued that quantum decoherence
does not explain actual wave function collapse but provides explanation for
conversion of quantum probabilities to classical probabilities.

2.4 Quantum Measurement and Uncertainties

Quantum measurement is characterized by indeterminism and the results are
probabilistic according to Copenhagen interpretation. The measurement of
observables are subject to uncertainties as postulated by Werner Heisenberg in his
well-known Heisenberg Uncertainty Principle. The principle puts fundamental limit to
the precision with which certain pair of complementary variables such as position (x)
and momentum (p) can be known simultaneously.

Measurements in quantum mechanics are viewed differently depending on the

interpretation of quantum mechanics. The major conflict is in the concept of wave
function collapse. While it is postulated from Copenhagen interpretation that during
measurement, a non-linear collapse of the wave packet occurs, it contradicts linear
dynamics of quantum mechanics as envisaged from the well-known Schrödinger
equation. This is what has become to be known as ‘the measurement problem’.
David Albert [11] puts it thus ‘The dynamics and the postulate of collapse are flatly in
contradiction with one another ... the postulate of collapse seems to be right about
what happens when we make measurements, and the dynamics seems to be
bizarrely wrong about what happens when we make measurements, and yet the

7
dynamics seems to be right about what happens whenever we aren't making
measurements.’

The Copenhagen interpretation seems to offer a solution to this problem through

John Von Neumann’s postulate who suggested in 1932 that the entangled state of
the quantum system and instrument collapses to a determinate state whenever a
measurement takes place.

However, the Many-world interpretation proposed by Hugh Everet [12] claims to

solve the measurement problem by denying the existence of wave function collapse
associated with measurement. The phenomena of wave function collapse is
explained by quantum decoherence.

2.5 Quantum Tunnelling

One of the most striking features of quantum mechanics is the probability of a
particle going through a potential barrier that could otherwise be impossible from a
classical mechanics point of view [13]. This is the tunnel effect or barrier penetration
and the process is referred to as quantum tunnelling. The particles involved could be
protons or electrons. This work gives more emphasis on proton tunnelling due to its
application in DNA mutations.

Quantum tunnelling plays essential role in physical phenomena such as nuclear

fusion occurring in main sequence stars like the sun. It has applications in tunnel
diode, quantum computing and scanning tunnelling microscope. It has been argued
that spontaneous mutation of DNA occurs when normal DNA replication takes place
after a proton in the hydrogen bond in base sequence overcomes a potential barrier
and shifts in the process of quantum tunnelling that is refered to as proton tunnelling.

Studies in radioactivity provoked interest in this phenomena and led to the

development of quantum tunnelling. This was clearly demonstrated in a
mathematical explanation of alpha decay where a case was considered of the alpha
particle tunnelling out of the nucleus. Before decay, the alpha particle is confined by
a potential barrier within the nucleus. The energy of the emitted alpha particle and
the average lifetime of the nucleus can be measured before the decay. The lifetime
of the nucleus is a measure of the probability of the tunnelling through the barrier.
The probability being higher for shorter lifetime. The escape of the alpha particle is
due to the wave-like aspect of the particle and also due to the phenomena of
uncertainty principle explained in section 2.4

Tunnelling effect occurs when the particle energy, E is less than the potential energy,
V of the barrier (E<V). See figure 2.5.1 below.

8
Figure 2.5.1: Quantum tunnelling through a barrier. The energy of the tunnelled
particle is the same but the amplitude is decreased. Note the exponential decay of
the wave function through the barrier.

3. QUANTUM BIOLOGY

3.1 Overview
Quantum biology is an emerging field of research that investigates biological
processes from a quantum mechanical point of view. It usually refers to the
application of ‘non-trivial’ quantum features such as superposition, non-locality,
tunnelling and entanglement [15].

Biological systems can be said to be open systems requiring continuous supply of

energy. Open systems are subject to environmental fluctuations resulting in fast
decoherence thus suppressing quantum dynamics. However, there are arguments
that at the level of molecular complexes and proteins, processes of fundamental
importance for biological functions can be very fast and well localised and may
exhibit quantum phenomena before interaction with the environment [15].

Early work in quantum information science has shown that thermal noise in
stationary equilibrium systems may support existence of quantum coherence and

9
entanglement thus making quantum processes be enhanced or regenerated by the
interaction with the environment [16][17].

In recent years, quantum biology has benefited from experimental tools that provide
an insight of quantum dynamics in biological systems [18][19][20][21]. These new
technologies have elevated quantum biology from a theoretical endeavour to an
experimentally verifiable field [15].

There is recent evidence to suggest that a variety of organisms may harness some
unique features of quantum mechanics to gain a biological advantage [22]

3.2 Some Applications of Quantum Mechanics in Biology

Most biological processes involving conversion of energy to forms usable for
chemical transformations can be explained by quantum mechanics. These
processes involve chemical reactions, light absorption, formation of excited
electronic states, transfer of excitation energy and the transfer of electrons and
protons in chemical processes such as photosynthesis and cellular respiration [23].

Quantum mechanics has been applied in the study of various biological processes
such as absorbance of frequency-specific radiation (photosynthesis and vision),
conversion of chemical energy into motion, magnetoreception in animals and DNA
mutation.

Experimental evidence shows that enzymes use quantum tunnelling to speed up

biochemical reactions that would otherwise take thousands of years to occur. This is
achieved through some kind of teleportation (a process by which quantum
information can be transmitted) whereby enzymes are presumed to influence
disappearance of electrons and protons from one position in a biomolecule and
reappearance in another position without passing through the gap in between. This
can be visualised by treating the electron and proton as a wave due to the concept of
wave-particle duality principle (where a particle can behave as a wave and vice-
versa [24])

Photosynthesis, a process whereby light energy is converted into chemical energy

usable by plants is another important biological process making use of quantum
mechanics. Photosynthesis involves the capture of a tiny packet of sunlight energy
which is transported through the chlorophyll molecule with an efficiency of almost
100% to a reaction centre where its energy is stored. The packet of light finds the
quickest route through the chlorophyll molecules by sampling all possible routes at
once quantum mechanically like a spread out wave to find the quickest way.

Birds and other animals are known to utilize earth’s magnetic field for navigation. A
most notable observation has been made through the studies of the European robin
bird believed to have some internal chemical compass [25] where a protein in the

10
bird’s eyes enables quantum entanglement (a phenomena that enables two
separated particles remain connected irrespective of the distance through some
‘mysterious’ quantum link) to make a pair of electrons sensitive to the angle of
orientation of the earth’s magnetic field.

Quantum mechanical phenomena has also been observed in the sense of smell. It
has been long held in olfaction theory that smell is determined by the shape of
molecules in the air. However, recent findings have shown that fruit flies can
distinguish odorants with exactly the same shape but made of different isotopes of
the same element. This has led to the argument that molecular vibrations with
frequencies unique to different scents promote quantum tunnelling of electrons in the
olfactory system, thus strengthening Turin’s [26] suggestion that olfactory receptors
respond not to the shape of the molecules but to their vibrations.

The role of quantum mechanics in DNA mutation has received wide

acknowledgement by scientists and forms the central argument in this work. It shall
be discussed in greater details in a later chapter.

4. THE CELL

A cell is the smallest functional and biological unit of all living organisms that can
replicate independently. All cells are composed primarily of carbon, hydrogen,
nitrogen, and oxygen.

The cell was discovered by Robert Hooke in 1665. It was until the 1830s when
Matthias Schleiden and Theodor Schwann proposed that all living things composed
of cells. Rudolf Virchow proclaimed that cells arise only from other cells challenging
the widely accepted theory of spontaneous generation which held that organisms
arise spontaneously from garbage or other non-living matter [27].

From the late 1800s, cell research has provided four concepts in what constitutes the
Cell Theory. These concepts are;

1. The cell is the fundamental unit of structure and function in all living
organisms. Therefore defining cell properties is in fact defining properties of
life.

11
 2. The activity of an organism depends on both the individual and the collective
activities of its cells.
3. The biochemical activities of cells are dictated by the relative number of their
specific subcellular structures. This is according to the principle of
complementarity of structure and function.
4. All living cells arise from pre-existing cells by division.

4.1 Structure and Function

Cells differ in structure according to the function which they perform. These
differences are quantitative rather than qualitative such that most intracellular
structures or organelles can be found in any cell [28]

A generalized human cell contains the plasma membrane, the cytoplasm, and the
nucleus as shown in figure 4.1.1 below.

Figure 4.1.1: Structure of the generalized cell [27].

The Plasma Membrane

Sometimes called the cell membrane, it consists of two layers of phospholipids (fatty
substances) with protein and sugar molecules embedded in them. The membrane
also contains the lipid cholesterol [29].

12
The structure of the plasma membrane is best described by the fluid mosaic model.
According to the model, the molecular arrangement of the plasma membrane
resembles an ever-moving sea of fluid lipids that contains a mosaic of many different
proteins [30] [31].

Some membrane proteins form ion channels through which specific ions such as
sodium ions (Na+) flow into or out of the cell. The channels are selective and allow
only a single type of ion to pass through. Other integral proteins selectively move a
polar substance or ion from one side of the membrane to the other thus acting as
transporters [32].

Cholesterol has been shown to regulate ion pumps, which in some cases show an
absolute dependence on cholesterol for activity. These studies suggest that an
essential role that cholesterol plays in mammalian cell biology is to enable crucial
membrane enzymes to provide function necessary for cell survival [33].

Cytoplasm

Cytoplasm comprises of all the cellular contents enclosed by the plasma membrane.
It is composed of the cytosol and the organelles.

The cytosol is a gel-like intracellular fluid surrounding the organelles and constitutes
about 55% of total cell volume. It comprises of 75-90% water, plus various dissolved
and suspended components including different types of ions, glucose, amino acids,
fatty acids, proteins, lipids, ATP and waste products. Many chemical reactions
required for cell existence occur in the cytosol. Some cytosolic reactions provide the
binding blocks for maintenance of cell structures and for cell growth [30].

The organelles in cell biology are specialized subunits within a cell with
characteristic shapes and specific functions including cellular growth, maintenance
and reproduction. Each organelle is separately enclosed within its own lipid bilayer
and has its own set of enzymes carrying out specific reactions without interfering
with other reactions in different organelles [30].

The human cell contains different kinds of organelles performing different functions.
Examples of organelles found in the human cell include; the nucleus, mitochondria,
endoplasmic reticulum (ER), Golgi complex, ribosomes, lysosomes, peroxisomes,
proteasomes, centrioles, cilia and flagella, cytoskeleton [27- 30,32, 34 -38].

The nucleus is the largest and most prominent organelle of a cell [39]. It has a
spherical or oval-shaped structure. Most cells have a single nucleus while others like
mature red blood cells, gametes and germ cells do not have the nucleus. Some cells
like those of the skeletal muscles have multiple nuclei.

13
The nucleus is enclosed within a double membrane lipid bilayer known as the
nuclear envelope which separates the nuclear contents with the cytoplasm. It is
similar to the plasma membrane and its outer membrane is continuous with the
rough ER and resembles it in structure as shown in figure 4.1.2. The nuclear
envelope contains tiny pores which control the movement of substances between the
nucleus and the cytoplasm. Small molecules and ions pass through the pores
passively by diffusion [40]. However, macromolecules such as RNA and proteins
require association karyopherins (a group of proteins involved in transporting
molecules between the cytoplasm and the nucleus of a eukaryotic cell) called
importins to enter the nucleus and exportins to exit. The proteins that must be
translocated from the cytoplasm to the nucleus contain short amino acid sequences
known as nuclear localization signals, which are bound by importins, while those
transported from the nucleus to the cytoplasm carry nuclear export signals bound by
exportins [41]. The molecules are recognized and selectively transported through the
nuclear pore into or out of the nucleus.

Figure 4.1.2: The nucleus according to Hickman et al. [37]

Within the nucleus is a spherical structure called the nucleolus involved in the
synthesis and assembly of the components of ribosomes. The most distinguishing
feature that sets up the nucleus as the most important organelle is its storage of
genetic information in form of DNA.

4.2 The DNA

Deoxyribonucleic acid (DNA) is the hereditary material in humans and almost all
other organisms. It contains the genetic information necessary for the production of
other cell components and for the reproduction of life. Most DNA is located in the cell
nucleus (nuclear DNA) but a small amount can be found in the mitochondria
(mitochondrial DNA or mtDNA). A detailed study of DNA is the basis of
understanding of cancer and mutations.

14
The DNA was first isolated in 1869 by a Swiss physician Friedrich Miescher [42].
Later works by Albrecht Kossel, 1897 [43], Phoebus Levene in 1919 [44] and William
Astbury in 1937 [45] [46], led to the first accepted correct double-helix model of the
DNA structure suggested by James Watson and Francis Crick in 1953 [47], based
on a single X-ray diffraction image (labeled as "Photo 51" - Figure 4.2.1), as well as
the information that the DNA bases are paired - obtained from Chargaff’s rules
discovered by Austrian chemist Erwin Chargaff. These rules state that DNA from any
cell of all organisms should have a 1:1 ratio (base Pair Rule) of pyrimidine and
purine bases and, more specifically, that the amount of guanine is equal to cytosine
and the amount of adenine is equal to thymine. This pattern is found in both strands
of the DNA [48][49]. The discovery by Watson and Crick has been called "The
Double Helix".

Figure 4.2.1: Photo 51, showing x-ray diffraction pattern of DNA [50]

DNA is made up of two chains of nucleotide. The nucleotides consist of the

phosphate group, a pentose sugar and a nitrogen base as shown in figure 4.2.2.

Figure 4.2.2: DNA structure [51]

The phosphate group forms one of the DNA backbones. In the phosphate group,
four oxygens surround a central phosphorous. The phosphorous is single-bonded to
three of the oxygens and double-bonded to the fourth. Due to the nature of the
chemical bonds, there is a negative charge on each single-bonded oxygen atom.
This negative charge accounts for the overall negative charge on the phosphate
backbone of a DNA molecule [52]. Figure 4.2.3 is a sketch of the phosphate group.

The phosphate group attaches to the 5’ carbon atom replacing the –OH group. The
3' carbon of a sugar molecule is connected through a phosphate group to the 5'
carbon of the next sugar. This linkage is also called 3'-5' phosphodiester linkage. All

15
DNA strands are read from the 5' to the 3' end where the 5' end terminates in a
phosphate group and the 3' end terminates in a sugar molecule. If the ‘P’ is on the
left of a base, then it is attached to the 5’ – carbon and if it is on the right, then it is
attached to the 3’ – carbon [53]. This gives a repeated pattern of the DNA backbone.

O
HO_ P _
OH
_
OH
Figure 4.2.3: The phosphate group (sketched based on Bryce, C. F. A and Pacini, D
[53])

The pentose sugar is a five-carbon monosaccharide sugar molecule. Nucleic acids

contain only two types of sugars; ribose present in RNA (Ribonucleic Acid) and
deoxyribose present in DNA. The prefix ‘deoxy’ in deoxyribose means ‘without
oxygen’ [53] because it is lacking a hydroxyl group at the 2' position. Instead there is
just a hydrogen. This work is mainly focused on the DNA.

In the deoxyribose sugar in DNA, four carbons and an oxygen make up the five-
membered ring; with the fifth carbon branching off the ring. As with the numbering of
the purine and pyrimidine rings (discussed later), the carbon constituents of the
sugar ring are numbered 1'-4' (pronounced "one-prime carbon"), starting with the
carbon to the right of the oxygen going clockwise. The fifth carbon (5') branches from
the 4' carbon. This is illustrated in figure 4.2.4

Figure 4.2.4: Deoxyribose Sugar [52]

The DNA gets its polarity from this numbering system of the sugar group. The
linkages between nucleotides occur between the 5' and 3' positions on the sugar
group. One end has a free 5' end and the other has a free 3' end.

An oxygen-containing hydroxyl group (-OH) is attached to the remaining free

carbons at the 1', 3' and 5' positions.

The nitrogen bases attach in place of the -OH group on the 1' carbon atom in the
sugar ring [54]

The DNA contains four distinct nitrogen bases: adenine (A), cytosine (C), guanine
(G) and thymine (T). Uracil replaces thymine in RNA. There are two categories of
nitrogen bases: adenine and guanine are purines while thymine and cytosine are
pyrimidines [52]. Purines consist of a six-membered and a five-membered nitrogen-

16
containing ring, fused together. Pyridmidines have only a six-membered nitrogen-
containing ring [55]. See figure 4.2.5

Figure 4.2.5: DNA Bases [52]

The double-strand of DNA is formed by the nitrogen bases through weak hydrogen
bonds. The base pairing rules determine the bonding of nitrogen bases through
specific shapes and hydrogen bond properties so that guanine and cytosine only
bond with each other, while adenine and thymine also bond exclusively. The purine
pairs with the pyrimidine in what is called base pairing complementarity. In order for
hydrogen bonding to occur at all, a hydrogen bond donor must have a
complementary hydrogen bond acceptor in the base across from it. Common
hydrogen bond donors include primary and secondary amine groups or hydroxyl
groups. Common acceptor groups are carbonyls and tertiary amines [52]. See figure
4.2.6

Figure 4.2.6: Common Hydrogen Bond Donors and Acceptors [52]

The G:C base pair has three hydrogen bonds. The first hydrogen bond forms
between the 6' hydrogen bond accepting carbonyl of the guanine and the 4'
hydrogen bond accepting primary amine of the cytosine. The second between the 1'
secondary amine on guanine and the 3' tertiary amine on cytosine. And the third
between the 2' primary amine on guanine and the 2' carbonyl on cytosine [52]. This
is illustrated in figure 4.2.7

17
 Figure 4.2.7: Guanine: Cytosine Base Pair [52]

For the A:T base pair, only two hydrogen bonds exist. One is found between the 6'
primary amine of adenine and the 4' carbonyl of thymine. The other between the 1'
tertiary amine of adenine and the 2' secondary amine of thymine [52]. This is
illustrated in figure 4.2.8

Figure 4.2.8: Adenine: Thymine Base Pair [52]

The structure of the DNA according to Watson - Crick Model is illustrated by figure
4.2.9.

Figure 4.2.9: A depiction of a section of the sugar-phosphate backbone of DNA

which conforms into one strand of the double helix [56]. The bases may be attached

18
in any order, giving the vast number of possibilities of arrangements which are
possible in the genetic code. In the double helix, bases are only attached by
hydrogen bonds to their complementary base, that is A-T and G-C. This
arrangement makes possible the separation of the strands and the replication of the
DNA double helix.

The role of DNA is the storage of information through the coding established in the
base pairing order and is replicated during cell division.

4.3 The Cell Division

Cell division is the process by which cells reproduce themselves. There are two
types of cell division; somatic or vegetative cell division and reproductive or reductive
cell division [30] [57]. In somatic cell division, a cell undergoes a nuclear division
called mitosis and a cytoplasmic division called cytokinesis, producing two
identical cells each with same number and kind of chromosomes (microscopic,
threadlike part of a cell that carries hereditary information in the form of genes) as
the original cell. Somatic cell division replaces dead, injured or worn out cells and
adds new ones during tissue growth. Reproductive cell division involves a two-step
process called meiosis where the number of chromosomes in the nucleus is
reduced by half. The reproductive cell division produces gamates – cells responsible
for production of a new organism or offspring. This work considers somatic cell
division in more details due to its relevance in cancer study.

Somatic cell division is an orderly sequence of events where a parent cell divides
into more daughter cells [58]. The human cell contain 23 pairs of chromosomes
making a total of 46, with each member of a pair being inherited from each parent.
The two chromosomes that make up each pair are called homologous chromosomes
and contain similar genes arranged in mostly the same order. Cell division involve a
cell cycle consisting of two major phases; Interphase, when the cell is not dividing,
and the mitotic (M) phase, when the cell is dividing. Refer to figure 4.3.1

19
Figure 4.3.1: The Cell cycle indicating various checkpoints [30].

At the interphase phase, the cell replicates its DNA and produces additional
organelles and cytosolic components in anticipation of cell division [30]. It involves
three separate stages;

The first stage is the gap phase (G1) and is the interval between the mitotic and the
synthesis (S) phase. The cell is metabolically active and replicates most of its
organelles and cytosolic components. The cell grows in size and volume. It is usually
the longest and variable in length. Cells that cannot proceed with the cycle enter the
resting phase known as G0 indicated in figure 4.3.1 [29] [30].

The second stage of interphase is the synthesis (S phase). During this phase DNA
replication occurs leaving the cell with 92 chromosomes - enough for two cells and is
almost ready for mitosis [29].

The third stage is the second gap phase (G2). The cell continues to grow, enzymes
and other proteins are synthesized ready for cell division. Replication of centrosomes
is completed at this stage [30].

During the mitotic (M) phase, there is nuclear division (mitosis) and cytoplasmic
division (cytokinesis) forming two identical cells [30]. Mitosis is a continuous process
involving five distinct stages; prophase, prometaphase, metaphase, anaphase and
telophase.

Prophase is the first stage in mitosis, occurring after the conclusion of the G2 portion
of interphase. During prophase, the parent cell chromosomes condense and become
thousands of times more compact than they were during interphase [59]. The

20
centrioles form and move towards opposite ends of the cell ("the poles"). The
nuclear membrane dissolves. The mitotic spindle forms from the microtubules.
Spindle fibers from each centriole attach to each sister chromatid at the kinetochore
[60]

Prometaphase: During prometaphase, phosphorylation of nuclear lamins by M-CDK

causes the nuclear membrane to break down into numerous small vesicles. As a
result, the spindle microtubules now have direct access to the genetic material of the
cell. This stage has been referred to as early metaphase by various authors.

At metaphase the centrioles complete their migration to the poles and the
chromosomes line up in the middle of the cell attached by their centromeres [29]
[60].

In anaphase stage the paired chromosomes separate and move to opposite sides of
the cell. The motion results from a combination of kinetochore movement along the
spindle microtubules and through the physical interaction of polar microtubules.

Telophase is the final stage of mitosis. During this stage, chromatids arrive at
opposite poles of the cell. The chromosomes uncoil and revert to threadlike
chromatin form. A nuclear envelope forms around each chromatin mass. The mitotic
spindle breaks up.

Cytokinesis refers to the division of the cytoplasm and organelles into two identical
cells. During cytokinesis, the cell membrane pinches in at the cell equator, forming a
cleft called the cleavage furrow. The position of the furrow depends on the position
of the astral and interpolar microtubules during anaphase.

A summary of the mitotic phase during the cell cycle is illustrated in figure 4.3.2.

21
Figure 4.3.2: A summary of mitotic phase of the cell cycle [61]

Throughout the cell cycle, there are multiple checkpoints that help the cell determine
if and when it should divide, whether it's time to advance to the next phase, or
whether it's time to die and make room for a younger, healthier cell.

The various checks on cell growth that occur during interphase allow tissues to
revitalize themselves without increasing in size. When these restraints fail,
devastating results can occur, including the growth and spread of cancer [59].

These checkpoints are initiated by Cyclin-dependent protein kinases (Cdks)

enzymes within a cell, which can transfer a phosphate group from ATP to a protein
to activate the protein while other enzymes can remove the phosphate group from
the protein to deactivate it. This activation and deactivation of Cdks is important in
the initiation and regulation of DNA replication, mitosis, and cytokinesis. The
switching on and off of the Cdks is done by cellular proteins called cyclins. The
timing and sequence of events in cell division is determined by the levels of cyclins in
the cell [30].

The main checkpoints that control the cell division include; G1 or restriction
checkpoint, G2 checkpoint and metaphase checkpoint.

22
G1 or restriction checkpoint is located at the end of the cell cycle’s G1 phase before
entry into S phase. The decision as to whether the cell cycle should proceed or enter
a resting stage G0 is made at this point. This checkpoint was demonstrated by Arthur
Pardee in 1973 [62]. The restriction point is controlled mainly by action of the CKI
p16 (CDK inhibitor p16) protein which inhibits CDK4/6 blocking interaction with cyclin
D1 to cause cell cycle progression. In other words, the CDK inhibitor p16 inhibits
another CDK from binding to its cyclin (D).

The G2 checkpoint is located at the end of G2 phase, triggering the start of the
mitotic (M) phase. At this point the cell checks such factors as DNA damage by
radiation to ensure the cell is ready for mitosis. The G2 checkpoint ensures that DNA
replication in S phase has been completed successfully. The CDKs associated with
this checkpoint are activated by phosphorylation of the CDK by the action of a
Maturation promoting factor (MPF).

The metaphase checkpoint (spindle checkpoint) ensures that all of the

chromosomes are attached to the mitotic spindle by a kinetochore and be under
bipolar tension. This tension is what is sensed and initiates entry into anaphase. This
is done by the sensing mechanism ensuring that the anaphase-promoting complex
(APC/C) is no longer inhibited, which is now free to degrade cyclin B, which harbours
a D-box (destruction box), and to break down securin [63]

These checkpoints are illustrated on figure 4.3.1. Note that the metaphase
checkpoint is not indicated.

23
 5. CANCER

5.1 Overview
According to World Health Organisation (WHO) Cancer Fact sheet Number 297 [64],
cancer is defined as … ‘a generic term for a large group of diseases that can affect
any part of the body. Other terms used are malignant tumours and neoplasms. One
defining feature of cancer is the rapid creation of abnormal cells that grow beyond
their usual boundaries, and which can then invade adjoining parts of the body and
spread to other organs. This process is referred to as metastasis. Metastases are
the major cause of death from cancer.’

The preceding chapter on the cell has examined various aspects of the cell including
the DNA and cell division with the attendant checkpoints that can be explored further
to understand the nature of cancer. Disruption or fundamental failure of the
checkpoints during cell division can be seen as a major cause of mutations (to be
discussed later). Cancer is fundamentally a disease of tissue growth regulation
failure. In order for a normal cell to transform into a cancer cell, the genes which
regulate cell growth and differentiation must be altered [65].

Uncontrolled cell division leads to excess tissue called tumour or neoplasm. When
the tumour is cancerous, it is referred to as a malignant tumour or malignancy
which has the ability to spread to other parts of the body in a process called
metastasis. It is otherwise a benign tumour if it does not metastasize e.g. a wart
[30]. Malignant tumours grow rapidly and continuously spread to other parts of the
body by local infiltration through lymphatic system, blood and body cavities [29]. As
the malignant cells invade the surrounding tissues, they trigger growth of new
network of blood vessels – a process known as angiogenesis. The proteins that
stimulate angiogenesis in tumours are called Tumour Angiogenesis Factors (TAFs).
The malignant cells detached from the initial tumour and invade other parts of the
body through metastasis establish secondary tumours.

Cancer develops through a multistep process in which many distinct mutations may
have to accumulate in a cell before it becomes cancerous. This partly explains why it
takes a long time for cancer to develop and why most cancers occur in old age. The
fact that many mutations must occur for cancer to develop is also an indication that
the cell growth is controlled by many sets of checks and balances [30]

5.2 Mutation
A mutation is a permanent change in the DNA base sequence. Mutations occur from
damaged DNA or RNA genomes mostly caused by radiation or chemical mutagens,

24
replication process errors, or from the insertion or deletion of segments of DNA by
mobile genetic elements [66] [67] [68]. Even though organisms have mechanisms
such as DNA repair to prevent or correct mutations, it is not always the case and the
effects of mutations will still occur.

Mutations can be beneficial as the source of new variations important for evolution
and development of the immune system. Indeed today, biologists consider mutations
as one of the ways that evolution happens. Mutations can also be harmful since they
can lead to various human medical conditions including various types of cancer.

Mutations can happen on a number of different scales. Mutations involving only a

single base pair in a DNA molecule are called point mutations. Other mutations
involve rearrangements in big regions of chromosomes. These are called
chromosomal mutations [69].

Point mutations, are mostly caused by chemicals or malfunction of DNA replication,

exchanging a single nucleotide for another [70]. Exchanging a purine for a purine (A
↔ G) or a pyrimidine for a pyrimidine, (C ↔ T) is referred to as a transition and is the
most common. A transition can be caused by nitrous acid, base mis-pairing, or
mutagenic base analogues such as 5-bromo-2-deoxyuridine (BrdU). The less
common exchanges involving a purine for a pyrimidine or a pyrimidine for a purine
(C/T ↔ A/G) e.g. the conversion of adenine (A) into a cytosine (C) is called a
transversion [71]. A point mutation can be reversed by another point mutation. Point
mutations are classified in terms of frameshift and substitutions mutations. In frame
shift mutations, a nucleotide is either deleted from or inserted into the DNA, while in
substitution mutations a nucleotide with a different nitrogen base replaces a
nucleotide in the DNA.

Since in frame shift mutations a base is either added or removed from a codon, the
effect is to shift the codons as read during translation by one position. Therefore the
frame shift mutation changes all the amino acids after the first one because codons
are in groups of three non-overlapping RNA bases [69]. See figure 5.2.1

25
Figure 5.2.1: Point mutations [69]

Substitution mutations may vary in effect on the polypeptide resulting from

translation. The major types of substitution mutations are;

 A missense mutation where a change in a single base in the DNA template

results in a change in a single amino acid in the final polypeptide. The original
glycine is replaced by arginine, a basic amino acid.
 Neutral mutations are a type of missense mutation in which the new amino
acid is chemically similar to the one it is replacing. The resulting polypeptide
will not be much different from the original polypeptide, in terms of how well it
functions, hence the term neutral mutations.
 Silent mutations are a type of substitution mutations in which a base
substitution in the DNA template results in no change in the amino acid. This
is because the substitution simply results in another codon for the same
amino acid. Thus these mutations are silent, since they cannot be detected by
looking at the protein's sequence of amino acids.
 A nonsense mutation is a mutation that replaces a codon for an amino acid
with one of the three stop codons. This cause an early termination of
transcription resulting in a shortened and usually non-functional polypeptide.

Figure 5.2.2 illustrates the main types of substitution mutations discussed above.

TAC GTG ATA CCA AAG TAG ACT

AUG CAC UAU GGU UUC AUC UGA
met his tyr gly phe ile -
Original DNA

26
TAC GTG ATA GCA AAG TAG ACT
AUG CAC UAU CGU UUC AUC UGA
met his tyr arg phe ile -
Missense mutation

TAC GTG ATA CGA AAG TAG ACT

AUG CAC UAU GCU UUC AUC UGA
met his tyr ala phe ile -
Neutral mutation

TAC GTG ATA CCG AAG TAG ACT

AUG CAC UAU GGC UUC AUC UGA
met his tyr gly phe ile -
Silent mutation

TAC GTG ATT CCA AAG TAG ACT

AUG CAC UAA GGU UUC AUC UGA
met his - - - - -
Nonsense Mutation

Figure 5.2.2: Types of substitution mutations. The changes are shaded [69]

Chromosomal mutations occur on a large scale involving many genes.

Chromosomal mutations are important in human biology as an important cause of
birth defects. For example in Downs syndrome, a chromosomal disorder causing
mental retardation can be caused by an extra copy of chromosomal 21 often called
trisomy [69]. Chromosomal mutations can occur with chromosomal rearrangements
without change in chromosome number or with changes in chromosome number.

Chromosomal rearrangements include the following types:

 Duplications: This involves the insertion of an extra copy of a region of a

chromosome into a neighboring position. As shown in figure 5.2.3 gene D has
become duplicated.
 Deletions: This occurs when a gene is mistakenly removed from a
chromosome, mostly as a result of unequal crossing over leading to loss of
the genes within those regions. Zygotes produced by gametes involving
deletions are not viable since they do not have the full complement of genes.
 Inversions: This happens when a whole region of genes on a chromosome
gets flipped around. In paracentric inversions the centromere is not included
in the inversion. In pericentric inversions, the centromere is involved in the
inversion.

27
  Translocations: This is the movement of part of a chromosome to another part
of the genome. An intrachromosome translocation is where the translocation
happens with the same chromosome. When a translocation involve transfer of
a region of a chromosome to a non-homologous chromosome, it is called an
interchromosomal translocation. Chromosomal translocations are considered
to be primary cause of lymphomas and leukaemia [72].
 Transposable elements: These are stretches of DNA which can insert
themselves into new regions of a chromosome and are therefore often called
jumping genes.

Figure 5.2.3: Types of Chromosomal rearrangement [69]

Changes in chromosome number sometimes happen in addition to the chromosomal

rearrangements discussed previously. This occurs in various forms as follows;

 Aneuploidy: This is a condition in which the number of chromosomes in the

nucleus of a cell is not an exact multiple of the monoploid number of a
particular species. An extra or missing chromosome is a common cause of
genetic disorders including human birth defects. Some cancer cells also have
abnormal numbers of chromosomes [73]. Aneuploidy originates during cell
division when the chromosomes do not separate properly between the two
cells. This generally happens when cytokinesis begins while karyokinesis
(division of the nucleus, usually an early stage in the process of cell division,
or mitosis) is still under way.
 Polyploidy: Polyploid cells and organisms are those containing more than
two paired (homologous) sets of chromosomes. Polyploidy can happen
because of a failure of the spindle fibres in mitosis or meiosis to segregate
chromosomes into separate groups. Indeed many organisms have specialized
polyploid tissues (even organisms we typically consider as diploid). There are

28
 two types of polyploidy; Autopolyploidy is polyploidy in which all the
chromosomes originate from the same diploid parent species and
Allopolypoidy is a polyploidy in which the sets of chromosomes are from
different species.

Mutations can be spontaneous or induced by chemical agents or radiation.

Spontaneous mutations arise from errors in the DNA duplication process. As part of
this process there is a proof reading mechanism involving one of the DNA
polymerases. Spontaneous mutations on the molecular level can be caused by;
Tautomerism (A base is changed by the repositioning of a hydrogen atom, altering
the hydrogen bonding pattern of that base, resulting in incorrect base pairing during
replication), Depurination (Loss of a purine base (A or G) to form an apurinic site -
AP site), Deamination (Hydrolysis changes a normal base to an atypical base
containing a keto group in place of the original amine group), Slipped strand
mispairing (Denaturation of the new strand from the template during replication,
followed by renaturation in a different spot ("slipping"). This can lead to insertions or
deletions). This discussion shall focus more on tautomerism due to its role in the
discussion on quantum mechanics in cancer in a later chapter.

Tautomerism is a special case of structural isomerism and can play an important role
in non-canonical base pairing in DNA and especially RNA molecules. Tautomers
are constitutional isomers of organic compounds that readily interconvert by a
chemical reaction called tautomerization [74] [75] [76]. This reaction commonly
results in the formal migration of a hydrogen atom or proton, accompanied by a
switch of a single bond and adjacent double bond. The concept of tautomerization is
called tautomerism. Because of the rapid interconversion, tautomers are generally
considered to be the same chemical compound.

The most common form of tautomerism is Prototropy and refers to the relocation of
a proton [77]. It may be considered as a subset of acid-base behaviour. Prototropic
tautomers have the same empirical formula and total charge. Annular tautomersim is
a type of prototropic tautomerism where a proton can occupy two or more positions
of a heterocyclic system, for example, 1H- and 3H-imidazole; 1H-, 2H- and 4H-
1,2,4-triazole; 1H- and 2H- isoindole [78]. Ring–chain tautomersim occur when the
movement of the proton is accompanied by a change from an open structure to a
ring, such as the open chain and pyran forms of glucose and furan form of fructose.

Induced mutations can be triggered by chemicals or radiation. Chemicals which can

cause mutations are called mutagens. Mutagens can act on the genetic material in a
number of different ways. For example certain carcinogens mimic the shape of the
nitrogen bases in DNA and confuse the duplication process. Other mutagens modify
the structure of the DNA bases themselves and thus lead to errors in base pairing.
Still other mutagens called intercalating agents insert themselves in between bases
in the DNA molecule and again confuse the duplication process [69].

29
Radiation that has sufficient energy to break chemical bonds and create ions is
called ionizing radiation while non-ionising radiation has insufficient energy to break
chemical bonds and create ions. X-rays are a good example of ionizing
radiation. Ionizing radiation can seriously damage DNA molecules and whole
chromosomes. Non ionizing radiation cannot typically lead to the formation of ions
and is less likely to induce mutations. However there are some exceptions.
Ultraviolet (UV) radiation is typically considered to be non-ionizing radiation but it is
absorbed by DNA and especially affects thymine. Two thymine side by side can join
together to form a so called dimer when exposed to UV resulting in confusion of the
duplication process.

The goal in public health is to minimize additional mutations induced by mutagens

and radiation added to the environment by human activity because many agents that
induce mutations also cause cancer. For example, the tars in cigarettes are both
mutagens and carcinogens (cancer causing chemicals). The same is true
for radiation such as UV and radiation produced by naturally occurring unstable
isotopes and elements such as radon.

A somatic cell genetic mutation or acquired mutation is a change in the genetic

structure that is neither inherited nor passed to the offspring. This happens all the
time in living organism and is difficult to measure the rate. Measurement of such a
rate is important in predicting the rate at which people may develop cancer [79]

5.3 Hallmarks of Cancer

The initiation and progression of cancer is a multistep process in which successive
mutation accumulate to form a cancerous mass of cells. This process involves
acquisition of specific characteristics that are unique to cancer and sets them apart
from the normal cells. The characteristics have become to be known as the
hallmarks of cancer [80]. Today these ideas are widely accepted as established facts
[81].

US cancer experts Doug Hanahan and Bob Weinberg published a seminal paper
called “The Hallmarks of Cancer” in January 2000 [82] which outlined six
characteristics that were unique to cancer cells. The six traits as proposed by
Hanahan and Weinberg were; sustaining proliferative signalling, resisting cell death,
evading growth suppressors, inducing angiogenesis, activating invasion and
metastasis and enabling replicative immortality. Figure 5.3.1 is an illustration of the
six hallmarks.

30
Figure 5.3.1: The six hallmarks originally proposed by Hanahan and Weinberg in
2000 [83]

Hanahan proposed four new hallmarks in his 2010 NCRI conference talk [81]. The
proposed four were; deregulating cellular energetics, avoiding immune destruction,
genome instability and mutation, tumour promoting inflammation. This four were
captured in a revised paper by Hanahan and Weinberg in 2011 titled, “Hallmarks of
cancer: The Next Generation” [83].

In their revised paper [83], Hanahan and Weinberg thus remarked (in reference to
the original six hallmarks)….. ‘Underlying these hallmarks are genome instability,
which generates the genetic diversity that expedites their acquisition, and
inflammation, which fosters multiple hallmark functions. Conceptual progress in the
last decade has added two emerging hallmarks of potential generality to this list—
reprogramming of energy metabolism and evading immune destruction. In addition
to cancer cells, tumors exhibit another dimension of complexity: they contain a
repertoire of recruited, ostensibly normal cells that contribute to the acquisition of
hallmark traits by creating the ‘‘tumor microenvironment.’’ Recognition of the
widespread applicability of these concepts will increasingly affect the development of
new means to treat human cancer’.

The six hallmarks original proposed by Hanahan and Weinberg [82] are briefly
discussed as follows;

31
Sustaining proliferative signalling: The most fundamental trait of cancer cells is
the ability to sustain proliferation than would be expected for normal cells which
carefully control their progression through the cell cycle to maintain homeostasis
within the cell. Cancer cells sustain proliferation due to growth factors, which are
able to bind to cell surface-bound receptors that activate an intracellular tyrosine
kinase-mediated signalling cascade, ultimately leading to changes in gene
expression and promoting cellular proliferation and growth [80][82].

Resisting cell death: Cancer cells have a mechanism to resist cell death. While
normal cells initiate programmed cell death (apoptosis) cancer cells evade apoptosis
thus maintaining the growth of the tumour and allowing cancerous cells to form in the
first stage of the disease development and spread to other parts of the body
(metastasize)

Evading growth suppressors: Cancer cells have the ability to evade programs that
hinder cell proliferation. Most of this programs are dependent on the action of tumour
suppressor genes. The tumour suppressors, operating in different ways to suppress
cell growth and proliferation have been found through their inactivation in any type of
human cancer. In the words of Walker, Colledge, et al (2014) [80]… ‘Growth-
inhibitory factors can modulate the cell cycle regulators and produce activation of the
CDK inhibitors, causing inhibition of the CDKs. Mutations within inhibitory proteins
are common in cancer. Loss of restriction by disruption of pRb regulation can be
found in human tumours, which produces a loss of restraint on transition from G 1 to
S phase of the cell cycle. Disruption of p53 function will have downstream effects on
p21 that alter the coordination of DNA repair with cycle arrest and that result in the
affected cell accumulating genomic defects. Down-regulation of p21 and p27, which
can be found in tumours with normal p53 function, correlates notably with high
tumour grade and poor prognosis’.

Inducing angiogenesis: Tumour cells, just like normal cells, require a constant
supply of oxygen and nutrients. The cancer cells also need to get rid of metabolic
wastes and carbon dioxide. This is achieved through angiogenesis, a process by
which new blood vessels are formed. Hanahan and Weinberg through their revised
article of 2011 [83] cited earlier work by Hanahan and Folkman, 1996 [84] and stated
that…‘in the adult, as part of physiologic processes such as wound healing and
female reproductive cycling, angiogenesis is turned on but only transiently. In
contrast, during tumor progression, an “angiogenic switch” is almost always activated
and remains on, causing normally quiescent vasculature to continually sprout new
vessels that help sustain expanding neoplastic growth.’ Angiogenic switch is
controlled by factors that induce or inhibit angiogenesis [85] [86]. Vascular
endothelial growth factor A (VEGF-A) is a well-known inducer while thrombospondin-
1 (TSP-1) is a well-known inhibitor.

Activating invasion and metastasis: This hallmark is a characteristic of the cancer

cell’s ability to break away from their original site and invade other tissues through
metastasis. The invasion and metastasis is a multistep process involving a sequence
of discrete steps, usually termed as the invasion-metastasis cascade [87] [88]. This
process begins with local tissue invasion, subsequent infiltration of nearby blood and
lymphatic vessels by cancer cells. The malignant cells are eventually conveyed
through haematogenous and lymphatic spread to distant parts in the body, forming

32
micro metastatic lesions that eventually grow into macroscopic metastatic lesions in
what is termed ‘colonization’ [83]

Enabling replicative immortality: Normal cells have a limit referred to as Hayflick

limit which they can divide. Evidence has shown that the telomeres associated with
each cell’s DNA shorten with subsequent cell divisions until a critical length is
reached where no further division can occur [89] [90]. In contrast cancer cells evade
this limit and are capable of indefinite divisions making them immortal. This is due to
a specialised polymerase enzyme called telomerase, which adds nucleotides to
telomeres allowing continued cell division. The telomerase enzyme is expressed at
significant levels in many human cancer [80]

Hanahan and Weinberg [83] revised their earlier work of 2000 [82] and stated that
these hallmarks had two enabling characteristics: Genome instability and mutation,
and tumor promoting inflammation. They also added two new emerging hallmarks
as: reprogramming of energy metabolism, and evading immune destruction. These
two emerging hallmarks are briefly discussed below. Some authors have classified
the two enabling characteristics as hallmarks [80] making them ten in number but
this work shall focus only on the eight as proposed by Hanahan and Weinberg [83]

Reprogramming energy metabolism: Cancer cells exhibit an abnormal metabolic

pathway to generate energy. This fact was postulated by Warburg [91]. Warburg
hypothesized in 1924 that cancer is caused by the fact that tumour cells generate
energy mainly by non-oxidative breakdown of glucose (glycolysis) as opposed to
normal cells which generate energy mainly by oxidative breakdown of pyruvate
which is an end product of glycolysis and is oxidized within the mitochondria.
Currently it is believed that cancer cells ferment glucose while keeping up the same
level of respiration that was present before the process of carcinogenesis, and thus
the Warburg effect would be defined as the observation that cancer cells exhibit
glycolysis with lactate secretion and mitochondrial respiration even in the presence
of oxygen [92]

Evading immune destruction: The role played by the immune system in ‘resisting
or eradicating formation and progression of incipient neoplasias, late-stage tumors
and micrometastases’ is still unresolved [83]. A striking increase of certain cancers in
immunocompromised individuals has been observed [93] though majority of these
cancer are virus-induced implying a reduced viral burden on the infected individuals.
Recently evidence has been provided to suggest that the immune system is a
significant barrier to tumour formation and progression in some forms of non-virus
induced cancers [83]. However, cancer cells still appear to be invisible to the body’s
immune system.

Scientists have used these hallmarks to develop therapeutic drugs. The description
of hallmark principle has informed therapeutic developments of drugs targeting one
or more hallmark capabilities. These drugs are deliberately directed to specific
molecular targets involved in enabling a particular capability. It should be noted
however that a particular targeted drug may enhance another capability. For

33
example a drug targeting angiogenesis may enhance metastasis [83]. Figure 5.3.2
illustrates the concept of targeted cancer drugs based on hallmark capabilities.

Figure 5.3.2: Therapeutic targeting of the hallmarks of cancer

5.4 Cancer Risk Factors

Several factors may work collectively or individually to induce mutation in a normal
cell making it become cancerous. These factors may be environmental or genetic.
Environmental factors account for the majority of cancers; about 90-95% while
genetic factors account for about 5-10% [94].

Environmental factors refer to any cause that is not genetically inherited according to
Kravchenko et al [95]. Common environmental factors and their proportional
contribution to cancer death are; tobacco (25-30%), diet and obesity (30-35%),
infections (15-20), radiation (around 10%), stress, lack of physical activity and
environmental pollutants [94]. See attached appendix.

34
The environmental risk factors can be classified as chemical, biological and
radiation.

Chemical substances that produce cancer are called carcinogens. Tobacco smoke
contains over fifty known carcinogens, including nitrosamines and polycyclic
aromatic hydrocarbons [96] and is believed to contribute to about 90% of lung
cancers [97]. It is also known to cause cancer in the larynx, head, neck, stomach,
bladder, kidney, oesophagus and pancreas [98].

Environmental risk factors that can be classified as biological are viruses and some
bacteria. The human papillomavirus (HPV) is directly mutagenic as it induces the
viral genes E6 and E7 [99]. The HPV is believed to cause all cervical cancers in
women. The virus produces a protein that causes proteasomes to destroy p53, a
protein responsible for suppressing unregulated cell division.

Induced radiation, both ionising and non-ionising, may cause upto 10% of cancers
[100]. This radiation may be from radioactive substances and ultraviolet (UV), pulsed
electromagnetic fields. Cancers induced by radiation include some types of
leukaemia, lymphoma, thyroid cancers, skin cancers, sarcomas, lung and breast
carcinomas [94]. X-rays used in medical settings for diagnostic or therapeutic
purposes is another source of radiation exposure.

Genetically inherited cancers account for about 5-10% of cancers. They mostly arise
from a genetic defect. A small percentage of the population are carriers of a genetic
mutation with a large effect on cancer risk and causing less than 10% of all cancers
[101]. Some of these include: certain inherited mutations in the genes BRCA1 and
BRCA2 with a high risk of breast cancer and ovarian cancer, and hereditary
nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) which is present in
some people with colorectal cancer, among others.

35
 6. QUANTUM MECHANICAL APPROACH TO CANCER
BIOLOGY

6.1 Overview
The previous chapters have made introductory remarks first on quantum mechanics,
mentioning non-trivial quantum effects such as superposition, decoherence and
tunnelling. A brief reference was made on quantum biology in reference to the non-
trivial effects on biological systems. The discussion of the cell and its DNA
composition provided the basis to make informed exploration into the concept of
mutations in relation to cancer biology.

This chapter is a culmination of previous discussions and focuses on the role, if any,
of quantum mechanics in cancer biology. Al-Khalili, 2010 [102] referring to Erwin
Schrödinger’s book, What is Life [1], writes that Schrödinger… ‘speculated that the
behaviour of living matter at the cellular level can be thought of in terms of pure
physics and chemistry and that at such scales, even quantum mechanics would play
a role. He also introduced the idea of an “aperiodic crystal” that contained genetic
information in its configuration of covalent chemical bonds.’

The Schrödinger’s book [1] was to form a basis for future discourses on the role of
quantum mechanics in biology. Much work has since been published to advance the
view that quantum mechanics is indeed fundamental to biological processes. The
most active research areas in quantum biology being on photosynthesis [22] [24] and
avian magnetoreception [103]. This work focuses particularly on the role of quantum
mechanics on DNA mutation as first advanced by Lӧwdin [104] in 1963.

6.2 The Lӧwdin Model and Proton Tunnelling

Based on Watson-Crick model of DNA [47], Lӧwdin [104] in 1963, stated that;
‘...According to this model, the genetic code is essentially contained in the
arrangements of the hydrogen bonds, and the purpose of this note is to study these
bonds quantum mechanically and show that, after a DNA replication, the protons are
necessarily in nonstationary states which implies that there is a certain probability for
“quantum jumps” which will lead to discontinuous changes of the code which will
show up and get manifested at the next DNA replication. This mechanism may be
responsible for the occurrence of spontaneous mutations, the phenomenon of aging
considered as a loss of useful genetic information, and the spontaneous occurrence

36
of tumors (and cancer) as a consequence of somatic mutations depending on the
accumulated effects of code changes in a certain direction.’

In the Watson - Crick Model discussed in section 4.2, the base pairs are held
together by hydrogen bonds obeying Chargaff’s rule [49]. See figure 6.2.1.

Figure 6.2.1: Linear representation of DNA molecule [104]

The hydrogen bond is basically a proton H shared between two electron pairs on
either the nitrogen or oxygen atoms [104].

Lӧwdin examined in detail the parts of the bases that take part in the hydrogen bond,
figure 6.2.2 and introduced a short-hand notation for the ‘proton-electron’ pair’ code
shown in figure 6.2.3a emphasizing the electron lone pair and the protons H.

Figure 6.2.2: The nucleotide bases occurring in DNA. The arrows indicate the bonds
towards the sugar groups in the strands; the upper parts of the molecules form the
bottom of the “deep groove” of the double helix [104]

37
Figure 6.2.3a: Shorthand for the “proton-electron pair” code [104]

Similarly, he considered the tautomeric forms by moving a proton from the upper
lone pair to the middle one. He denoted the “imine” forms of A and C by A * and C*
and the “enol” forms of T and G by T* and G* and obtained the “proton-electron pair”
code as shown in figure 6.2.3b below;

Figure 6.2.3b: Shorthand for the tautomeric form of “proton-electron pair” code [104]

From figure 6.2.3b it becomes apparent the A* will combine with C and G* will
combine with T, giving the combination of;

A* – C, A – C* and G* – T, G – T*

The complementarity between the bases is now destroyed meaning the shift of a
single proton within a base in this way will affect the genetic information and
introduce an error at the first cell duplication [104]. Watson and Crick [47] suggested
that this mechanism could be used to explain mutation.

Lӧwdin [104] argued that the tautomeric form of a DNA base could be explained
quantum mechanically using the concept of proton tunnelling and proposed that this
tautomeric form could give rise to point mutations.

The attraction of each electron lone pair on a proton in a hydrogen bond is

represented by a deep single-well potential. The superposition of two such deep
single well potentials forms a highly asymmetric double-well potential with a potential
barrier in the middle [3]. See figure 6.2.4a.

Due to the inherent quantum nature of the proton, there is intrinsic probability that it
will quantum tunnel through the barrier as shown in figure 6.2.4b. Proton tunnelling
makes the proton exist in a linear superposition state between two adjacent sites
with the DNA bases. A measurement made on the system, gives a 50-50 probability
of the proton being tunnelled and of being non-tunnelled, representing the probability
of the DNA base being in the rare and canonical tautomer respectively.

38
Figure 6.2.4a: Asymmetric double-well potential showing energy eigenvalues [105]

Figure 6.2.4b: Proton tunnel through the barrier from one eigenstate to the next [105]

Lӧwdin argued that tunnelling time is dependent on the height and form of barrier.
He further stated that the form of the double-well potential, in DNA, controlling the
hydrogen bond depends on the neighbouring pairs, their net charges and the entire
electric environment and not only on the base pair involved alone. Addition of extra
charge on one base pair increases the probability of tunnelling due to a change in
energy added. The tunnelling time is also influenced by the position of the base pair
in the DNA molecule involved. Even though the protons are well shielded in the
double helix, Lӧwdin suggested a likelihood of temperature dependency of the
tunnelling time.

The temperature dependence has been well investigated by Godbeer et al [106].

The Godbeer team in a recent paper remarked… ‘it has been established in recent
years that under certain conditions quantum processes such as tunnelling can
actually be enhanced (thermally assisted) when the system couples to its
environment, as this allows transitions to higher energy eigenstates closer to the top

39
of the potential barrier. Here we show for the first time that, over a specific
temperature range, increasing the temperature of the heat bath to encourage such
thermally-induced tunnelling is equivalent to increasing the frequency of a von
Neumann-type measurement on the system by the environment (an anti-Zeno
effect). However, this correspondence between these two independent pictures of
quantum measurement breaks down above a certain limit: increasing the frequency
of measurement above this limit leads to a reversal from an anti-Zeno to a Zeno
effect and the tunnelling rate decreases again, whereas raising the temperature
further leads to a levelling off in the tunnelling probability’. This seems to contradict
the often held view that the temperature of the surrounding environment of a
quantum system affects the efficacy of quantum tunnelling negatively.

It is worthwhile to note that the DNA exists in a wet and warm environment which
influences the quantum effects. Therefore, if increased temperature were to derail
quantum tunnelling, then the now held view amongst some scientists that proton
tunnelling could be the basis of mutations is null and void. But this is not the case
currently. Godbeer et al. considered the relationship between quantum
measurements and decoherence using numerical simulations. Initial studies based
on such model showed conflicting conclusion as to whether repeated measurements
derail the tunnelling process (quantum Zeno effect - QZE) or enhance the process
(the anti-Zeno effect - AZE). Using temperature as a parameter of quantum
measurement, Godbeer et al. however, have shown that within a certain range of
temperature anti-Zeno effect (AZE) is observed.

Further investigations based on Lӧwdin’s work was done by Zhao et al [107] who
used computational method to calculate the potential energy surface of the H13
proton in the base cytosine of the DNA molecule and found two potential wells; one
corresponding to the normal cytosine while the other corresponding to its imino
tautomer. They showed that the bindings of the proton in these wells are stable
enough against the thermo-disturbance. The protons in these wells oscillate around
the nearest nitrogen atom and may move away from the nitrogen atom to form the
hydrogen bond with other bases. The estimated lifetime of the proton staying in one
of these wells was calculated to be about 6 x 102 years.

Zhao et al argued that the four bases (A, T, C, G) in a DNA molecule will rarely
transfer to their unusual configurations with transitions from A ↔ Aimino, T ↔ Tenol,
G ↔ Genol and C ↔ Cimino. These imino/enol tautomers will be paired as Aimino…C,
A…Cimino, Genol…T, and G…Tenol making possible changes; C…G ↔ T…A of the
base pairs in DNA during its double replication.

Using a coordinate system based on the cytosine known structure formula Zhao et al
obtained a map of the potential energy surface of the proton H13 as shown in figure
6.2.5a.

40
Figure 6.2.5a :Contour diagram for the potential energy of the proton H13 in
cytosine. The energy is in atom unit (a.u.), and the length is in the unit of pico-metre
(pm). The darker the blue shade in the figure the lower the potential at that point.
The number attached to the line represents the single point energy along the
contour. Two potential wells are clearly seen, with the left one corresponding to the
cytosine and the right one to its imino tautomer. The difference between these two
tautomers of cytosine lies mainly in the different positions of the proton H13 [107]

According to Zhao et al, from a quantum mechanics point of view, there is a

possibility of the proton tunnelling from one well to another well. They used the
following equation to find the path of lowest potential connecting the centres of the
wells in figure 6.2.5a by changing the length units from pico-metre to angstrom.

y(x) = 1.1417352+0.71244583x +0.3508047x2+0.04422011x3 + 0.06419875x4 -

0.56534255x5+0.25248558x6

The potential energy in atom unit along the path was given by the following formula;

V (x)=−393.908877+0.103691x − 0.102525x2 −0.3063312x3 +0.102250x4

+0.355250x5 −0.195806x6

Figure 6.2.5b indicates the potential barrier between the two wells of the proton H13.

41
Figure 6.2.5b: The potential barrier between two wells of the H13 proton [107]

Applying WKB formula, the penetration probability of the proton through this barrier
is;
2
𝑊 = 𝑒𝑥𝑝 {− ∫ √2𝑚𝑝 [𝑉(𝑥) − 𝐸] 𝑑𝑙}
ħ
𝑠

𝑏
2 𝑑𝑦 2
√
= 𝑒𝑥𝑝 {− ∫ 2𝑚𝑝 [𝑉(𝑥) − 𝐸] [1 + ( ) ] 𝑑𝑙}
ħ 𝑑𝑥
𝑎

≈ 𝑒𝑥𝑝[−54.85] ≈ 1.50929 × 10−24

Where E = - 393.9496 a.u is the total energy of the proton H13 in cytosine-imino, a
and b are the x coordinates of the proton to be determined by the condition E = V (x)
with b > a, and s is the lowest potential path terminated by points x = a and x = b.
This was used to calculate the penetration probability in unit time as;

P =fW = 3.427 x 1013 x 1.50929 x 10-24 Hz = 5.168 x 10-11 s-1

This implies that the mean lifetime for a proton staying in one of these wells is 6 x
102 years. This means that it will take 600 years for thermo-equilibrium to be
reached. Therefore, there must be another way to explain the large ratio between
populations of cytosine and its imino tautomer in nature.

Studying quantum dynamics of the hydrogen bonds in the adenine-thymine base

pair, Giovanni Villani [108] has argued that, …. ‘Due to the position of hydrogen
atoms, different tautomers are possible: the stable Watson–Crick A–T, the imino-
enol A*–T* and the zwitterionic (the form with charge separation) A+ –T- and A- –T+

42
structures. The common idea in the literature is that only A–T exists either because
the difference of energy among this tautomer and the others is large or because the
other structures are transformed quickly in A–T.’ In this studies Giovanni has
suggested the conclusion that A – T is the most stable tautomer and a small amount
of the A* - T* tautomer is present at any time.

It has been suggested by Home and Chattopadhyaya [109] that DNA could stay in a
superposition of mutational states in a biomolecular version of Schrödinger’s cat
paradox (where a thought experiment by Erwin Schrödinger presupposes a cat
confined in a box containing a radioactive source could be dead and alive at the
same time). This implies the living cell elements may remain an ordered structure in
line with maintaining quantum coherence at high temperatures above those that
would otherwise destroy the quantum state of inanimate systems [4]. According to
Patel [110] nucleotide bases can remain in a quantum superposition for a long period
to take part in replication process. However, the state of quantum superposition can
be destroyed when the DNA interacts with the environment. The environment plays a
measurement role.

In a recent paper published in the European journal of Biophysics, Rahman et al

[111] have argued that proteins, genes and all molecules in a cell are within the
same quantum system. They have stated that, …‘Both genes and proteins will be
affected simultaneously due to the quantum state alteration. The protein
modifications become the phenocopies. The interaction of the environmentally
affected cellular quantum system with the genetic apparatus leads to gene mutation,
which itself is a quantum process. The mutated genes remain as uncollapsed
coherent superposition’s while such mutations accumulate in possibility. They are
amplified by the measurement apparatuses of the protein producing machinery but
still remain in possibility.’

McFadden and Al-Khalili [4] have suggested that the environment can accelerate
generation of mutant state out of the quantum superposition through accelerated
decoherence. Rahman et al argue that when a pattern emerges that merit
phenotypical expression, the wave functions collapse and the genetic material
becomes fixed in one configuration only.

43
 7. CONCLUSION

This work has been an attempt to relate quantum mechanical principles to biological
processes. Much emphasis was put on the role of non-trivial quantum events such
as proton tunnelling to explain mutations in relation to cancer.

All work done on this relationship between quantum mechanics and cancer is still
speculative and there is lack of supportive experimental evidence. The theoretical
predictions however look plausible and are worthy of further study. Also the
assumption made is that mutations are due to a shift in proton position within the
DNA base. There could be other possibilities of explaining mutation, like
reconfiguration of electronic arrangements within the DNA. Such ways too, deserve
particular attention.

But still focused on the proton tunnelling as the means by which mutations occur
leading to cancer, then it is imperative to investigate the role carcinogens may play
to enhance or speed up proton tunnelling. Do chemical carcinogens contains specific
elements that can move through the nuclear envelope and affect DNA replication
quantum mechanically? And does radiation impart the necessary energy to make a
proton in the hydrogen bond to cross over the potential barrier classically? The DNA
lies within an environment consisting of so many different materials including
enzymes with varying degree of different elements each of which may play a role in
the tunnelling process. This may be a worthy cause to look into.

It would also be an interesting area of research to investigate how non-trivial

quantum events affect our general human health both physically and mentally. Do
quantum events such as entanglement affect our perception of the environment and
our consciousness? Indeed there are still more studies to be done on the
relationship between quantum mechanics and biological processes.

Subject to the aforementioned risk factors of cancer, it is also reasonably debatable

to suggest that viral-induced cancer, could be as a result of mutations occurring in
the viral DNA itself and not within the host cell. This is because a virus is basically a
DNA or RNA which depends on the host cell to replicate and as such is subject to
mutations.

44
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