GENETIC CODE CHANGES INDUCED BY ISOTOPE
SUBSTITUTIONS AND LOW-INTENSITY-LOW-DOSE
RADIATION, THEIR REPRESENTATION AND
CONSEQUENCES
A. Ya. Temkin
Department of Interdisciplinary Studies
Faculty of Engineering
Tel-Aviv University
Ramat-Aviv
Tel-Aviv 69978
Israel
E-mail: temkin@eng.tau.ac.il
January 8, 2002
1
ABSTRACT
Low-intensity-low-dose radiation (ionizing and laser light, as well) and isotope
substitutions in chemical groups (adenine, guanine, cytosine and thymine) of the
DNA molecule may cause changes in genetic information carried by a DNA molecule
even when no rupture of its polymer chains occurs. It is shown that in such cases the
formal language based on 4-letter alphabet (A-adenine, G-guanine, C-cytosine and Tthymine) used for genetic information writing must be replaced by another formal
language with more than 4-letters alphabet (probably with another grammar). The
number of letters in the new alphabet may be so large that the use of such a formal
language becomes practically impossible. So it would be desirable to avoid the use of
any formal language, in general, i. e., to express the genetic information by, so to say,
a "no-language" way. By this reason it is proposed to use with this purpose the
general method of the Ch. 7 of the book [20]. This method allows one to express the
physical properties associated with rotational, vibration and electronic quantum states
of the DNA molecule and transitions between them in terms of the information and
the information processing, correspondingly. Thus, this method is fit, in particular, for
the treatment of low-intensity-low-dose-radiation and isotope substitution biological
effects because all properties of the DNA molecule and all processes occurring in this
molecule are expressed uniformly in terms of the information and information
processing. The considered distortion of the genetic information by the low-intensitylow-dose radiation and isotope substitutions is expected to be an important (maybe the
main) mechanism being the basis of their biological effects.
2
INTRODUCTION
In review [1] the DNA strand breaks are considered as only one of possible
mechanisms of genomic instability induced by ionizing radiation. In the present paper
we shall consider another possible mechanism of genomic changes and instability.
This mechanism is originated from the genetic code changes arising at isotope
substitutions (see, for example, [2-9] and references there) of elements in adenine,
guanine, cytosine and thymine bases of DNA molecules, as well as at low-intensitylow-dose ionizing particle, gamma-, X-ray, laser light etc. irradiation. They arise also
as result of natural processes occurring in any living being even when there is no
external factor such as radiation, isotope substitution etc.. Such distortion of the
genetic code even by very low-intensity-low-dose irradiation may lead to a
considerable increase of cases of malignant diseases as well as hereditary deviations
and abnormalities among the following generations' populations. However, at the
same time it may lead to harmful consequences for malicious cells etc., which,
possibly, opens the way to low-intensity-low-dose laser and ionizing radiation
medical treatment [10-16].
GENETIC CONSEQUENCES OF DNA CHEMICAL GROUPS
IDENTITY VIOLATIONS
Let us begin from the consideration of the genetic information change
provoked by substitution of some elements of adenine, guanine, cytosine and thymine
chemical groups of a DNA strand by their isotopes. It is interesting in itself and also
3
will help to understand how to approach to more complicated case of similar effects
provoked by the low-intensity-low-dose radiation action.
The genetic information is written on a DNA molecule by 4-letter alphabet of
a formal language. Each letter means one of 4 type chemical group: A denotes
adenine, G denotes guanine, C denotes cytosine and T denotes thymine. It is
supposed that all chemical groups of the same
type are identical.
This simplifying assumption allowed one to obtain extremely important and
impressive results in the study of genome. However, it must be kept in mind that it is
only, so to say, the zero-order approximation to genetic properties of DNA molecules.
For example, what is to be happened if nuclei of a certain part of atoms of a certain
number of these chemical groups be substituted for their isotopes, e. g., p would be
replaced by d in atoms H, i. e., at certain places deuterium will be placed instead
hydrogen? This example shows that our question is not only an abstract theoretical
question, but is connected with a real situation when the light water is replaced by the
heavy water that reaches the DNA in different places substituting hydrogen for
deuterium. An isotope substitution breaks the identity of chemical groups of the same
type remaining, however, their chemical identity unaffected. This violation of identity
is displayed, for example, in magnetic field, e. g., 0.3 Oe magnetic field on the surface
of Earth. In this field the splitting of proton's levels is about 0.16 eV, while for the
deuton ones it is about 0.05 eV between states with spin values -1 and +1, and 0.025
eV between states with spin values -1 and 0, or 0 and +1. This fact is especially
important because all living beings on the Earth live in this magnetic field, their living
processes, reproduction and evolution occur under the influence of this field. The
violation of identity of bases by the isotope substitution of H atom for D influences
4
these processes. Note that the described effect of magnetic field is not the only one
displaying this identity violation. For example, isotope substitution changes the
selection rules in chemical reactions that because of it occur differently from those
with non-substituted bases. Now, after the described isotope substitution, each two
chemical groups are identical when they were not subjected of isotopic substitution or
when the substitution (by the same isotope) was at the same place in each group. As a
consequence of this one obtains instead 4-letter alphabet, the one containing more
(maybe much more) letters. They are the 4 letters existed from the beginning (i. e.,
before the substitution) plus letters representing chemical groups (chemically the
same as mentioned above, but isotope substituted) classified according substituting
isotopes and their places in chemical groups. The information written by this new
alphabet forms the new genome.
It is important that the considered effect differs profoundly from the kinetic
isotope effect, well known in many fields of chemistry. The kinetic isotope effect
depends on the mass and spin of the element that is substituted for its other isotope, it
decreases when the mass number of this element increases. For example, it can be
important for the hydrogen substitution for deuterium, but negligible for the oxygen16 substitution for oxygen-18. In distinct, the considered effect produced by the
genetic code change at the isotope substitution does not depend on mass and spin of
substituted and substituting isotopes of a certain element.
Let us consider the simplest example when in a number of thymine groups
CH3 is replaced by CH2D. Denote the corresponding letter TD. Now there is the fiveletter alphabet 5 = {T, TD, A, C, G}. The formal language built on the grounds of this
alphabet will be a new one. The genetic information written on the non-deuterated
DNA molecule by the language with the alphabet 4 = {T, A, C, G} can be rewritten
5
by the new language with the alphabet 5 = {T, TD, A, C, G}. Then the information
carried by a non-deuterated and deuterated (as it was described) DNA molecule will be
written by the same language with the alphabet 5 = {T, TD, A, C, G}. It allows one to
compare the genetic information in these both cases, and by this way to understand to
what genetic changes leaded this isotope substitution and at what degree these changes
are important. It is correct also, if not the whole DNA molecule is considered, but only
one gene.
Whether a copy obtained by the replication of a deuterated DNA molecule
could be deuterated? This is a very important question for the genetics. There are two
possibilities: 1) the copy will not be deuterated, in general, and 2) the copy may be
deuterated by the H - D exchange with the original deuterated DNA molecule or the
protoplasm. It is very not probably that in the case (2) the deuterium substitution will
occur namely at the same places of the new DNA molecule than it was on the original
one. In other words, the identity of the initial DNA molecule and its copy in that what
concerns the isotope substitution places, practically is not accessible. This means, the
genetic information carried by the copy (written by 5-letter-alphabet language) will be
not the same that the one carried by the original molecule. Really, the situation is even
more complicated because the new alphabet may contain more than five letters.
Indeed, the substitution of H by D is a stochastic process and so can occur not only in
CH3 of thymine, but also in other places of thymine and even in other three types of
chemical groups. It creates more than 5 types of groups distinguished from the original
ones and between themselves, which means that the new more-than-5-letters alphabet
and, therefore, the new formal language will be created. The number of letters of
such an alphabet may be enormous. For example, if all possible versions of atom H
substitution for atom D in four types of bases in DNA molecule are taken into account,
6
it is necessary to use an alphabet containing more than 500000 letters. It makes the use
of any formal language practically impossible.
In the case (1) the new DNA molecule will not be deuterated and, therefore,
all the following generations of DNA obtained by subsequent replications will be not
deuterated. However, it is correct only, if in a certain generation of DNA molecule the
isotope exchange with the protoplasm does not occur. Thus, the influence of the
deuteration will be ended at the initial generation. As opposed to this, in the case (2) it
will remain for all generations. It is to expect that the case (2) will be realized when the
protoplasm contains deuterium. For example, drinking the heavy water can create such
a situation.
GENERAL CASE
Violations of identity of chemically identical DNA bases can be created not
only by isotope substitutions, but, for example, by ionization. It is evident that an
ionized base is not identical to those non-ionized. The same is correct for an excited
(electronically, vibrationally or rotationally) base that is non-identical to those nonexcited. As a consequence, the similar consideration would be valid also in the case of
radiation- and photochemical processes occurring with DNA molecules. In particular,
it opens a way to the consideration of such "delicate" genetic effects of low-intensitylow-dose ionizing radiation or light, when only a number of bases in a DNA polymer
chain were changed, while the polymer chain itself is not broken. Such situations may
arise in radiation and photobiology. Then ionizing radiation or light, e. g., laser light,
may induce, for example, one atom H abstraction from CH3 group of thymine in a
number of places of a DNA strand. Thymine groups with CH2 instead CH3 will be
7
different from those with CH3. From the point of view of formal language it will be a
case similar to the one of the substitution of CH3 for CH2D, and, therefore, all written
above remains valid. Of course, changes that are results of the formal language
changes do not exhaust all changes of the genetic information produced by this
reaction of the H atom abstraction. This means, when one considers genetic changes
produced by irradiation, it is to divide them into those based on the formal language
change and those based on changes of physical and chemical properties of DNA
molecules. Their dependence on the type of radiation, dose and dose rate may be
different. The first type is especially important at low dose and low dose rate. Indeed,
it is enough a few of cases of the chemical group identity breaking to provoke serious
hereditary aberrations of the future generations or such diseases as, for example,
cancer of the irradiated person himself. The realization of different effects, arising as
consequences of the chemical groups' identity breaking, depends essentially on the
value of the information [17-19] carried by the DNA molecule or by its segments
where this identity breaking occurred.
The situation is expected to be much more complicated than the described
above, when the identity breaking of chemically identical groups occurs by "labeling"
a certain part of them by nuclear spin inversions or excitations of molecular quantum
levels. In such cases this "labeling" is rapidly changed as function of time (notice that
isotope exchange may also lead to the time dependence of the "labeling"). Under such
condition the new alphabet must contain an enormous number of letters and the "text",
i. e., the genetic information, would be rapidly changed as function of time. In such a
situation the writing of the genetic information by a certain formal language becomes
impossible. As a consequence of this fact the new question arises: what, in general, is
in such a situation the genetic information, in other words, how this concept can be
8
defined, and under what conditions this concept is not nonsense? A criterion that this
concept is not nonsense is as follows. Let I0 is the total amount of the genetic
information carried by the original DNA double helix, and I is the maximum change
of the total amount of this information provoked by different factors, as it is written
above. Let I reaches its maximum in time . Denote  the characteristic time of life of
a DNA strand from its appearance up to its replication. Then the concept of the genetic
information has meaning, if I  I 0 during the time , or, when this inequality is
not fulfilled, if >>. In fact, this criterion is not enough, and a number of other criteria
must be found that take into account not only the total amount, but also different
components of the genetic information and their values. For example, the criterion
written above may be fulfilled, but at a certain segment of the DNA strand, e. g., a
certain gene, the local change of the information would be too large and would reach
its maximum in too short time. Then a gene (or genes) may be distorted or destroyed.
The criterion can be rewritten as follows to take this effect into account. Let L denotes
a segment of the DNA strand. Then one can introduce local information amount and its
change, as well as the corresponding time necessary to reach the maximum of this
change: I0,L, IL and L, correspondingly. It must consider the set {L} of all possible
segments covering the considered DNA strand, and to formulate the above written
criteria for each L: the concept of the genetic information has meaning, iff for all L be
IL<<I0,L during the time , or, when this inequality is not fulfilled, iff for all L be
L>>. Possibly, there other criteria can be found which take into account the values of
different kinds of information [17-19] carried by segments. However, we have used
"iff" because the task to determine values of different types of genetic information is
extremely difficult, complicated and not clear, and we shall not consider it in this
paper. What means "all possible segments"? It is not arbitrary set of any segments, but
9
that taking into account their genetic meaning. One possibility is that each segment
must be a gene or its part, or a number of whole genes, but cannot consist of a part of a
certain gene and a part of its neighbor one.
If some factors provoke changes of the information carried by DNA double
helix, as it was explained above, but the criteria written above are satisfied, the concept
of the genetic information is not nonsense and it is to search for a relevant method of
its expression. It is evident that the use of an alphabet expanding simultaneously with a
corresponding change of the formal language grammar would be not practical. It must
search for other methods.
Let us indicate some ways of possible influence molecular genetic processes
by processes occurring on the level of molecular quantum states. The realization of the
genetic information usually occurs by chemical reactions. These reactions or, at least, a
part of them occur via activated complex. Among the channels of its decay there are
those of the excitation transfer (to other parts of the DNA molecule, to the
surroundings etc.). If such an excitation transfer was occurred, reactions corresponding
to other (than the excitation transfer) channels of the activated complex decay will be
suppressed. Such an excitation transfer can be increased or provoked also artificially
by a corresponding addition of inhibitors (acceptors of excitations) to protoplasm. By
this way it is possible to suppress completely concrete, chosen by us, reactions
occurring with a certain base at a certain place of DNA molecule. It would produce
effects like the ones of the methilation, but it can be applied to any base, not only to
cytosine. Perhaps, it can open it can open new ways of medical a. o. applications of the
molecular genetics. On the other hand, the transfer of the energy from donors (excited
molecules added to the protoplasm) to a considered part of DNA or mRNA molecules
can create an activate complex that in natural conditions should not exist because there
10
is not necessary amount of the energy. The decay of this complex may open new ways
of the information realization by reactions. The changes of the probabilities of different
channels of the activated complex decay may be also results of changes of electronic
and nuclear spin states by a magnetic field because it may change selection rules.
GENERAL CONCLUSIONS CONCERNING GENETIC
INFORMATION AND GENOME
The written above allows one come to very general conclusions concerning
genetic information and genome representation. We have seen that there are situations
when the information carried by a DNA molecule cannot be represented in terms of
formal languages. Each of such situations considered above corresponded to a kind of
direct action changing the DNA structure issued from external factors (some types of
radiation, isotope substitutions etc.). Such situations can be created artificially, but they
arise also naturally at space flights because the irradiation by cosmic rays. It is
especially important that they exist perpetually for the living beings on the surface of
Earth as well as under water because the natural background of the low-intensity
ionizing radiation. It is created by the natural radioactivity of the soil and by cosmic
rays reaching the Earth surface. All the evolution processes occur under this radiation,
so all living beings adapted themselves to its actions. At the same time this radiation is
an important factor provoking spontaneous genetic changes and, therefore, the one of
the evolutionary development. Genetic changes are provoked also by the Sunlight that
is also a part of normal conditions of the life.
However, the abovementioned problem with the genetic information
representation arises also when there is no external factor provoking directly changes
of DNA molecule structure or state. For example, the realization of genetic
11
information concerning the nervous system is usually done by nervous pulses, or, more
generally, molecule excitation propagation through nervous of the peripheral nervous
system or of the brain. The thinking, i. e., the information processing by the brain, is
done by this way. The ability itself to think as well as intellectual abilities to different
fields are contained among the genetic information that is realized as it was described.
Thus, the genetic information, in general, cannot be represented in terms of formal
languages even in absence of abovementioned external factors.
As a consequence of it, genome cannot be represented in terms of formal
languages, the information contained in genome can be represented by a certain way
where the concept of language is not defined.
NOT FORMAL LANGUAGES, BUT WHAT INSTEAD?
A GENERAL METHOD OF THE GENETIC INFORMATION
REPRESENTATION
As it is seen from the previous Section, it is very probably that quantum states
(rotational, vibrational and electronic) of a DNA and mRNA molecules as well as
transitions between them influence genetics. With the purpose to approach this
problem and to study the involvement of such states and transitions between them to
molecular genetic processes, it would be desirable to express them in terms of the
information and information processing. Then the whole problem, which begins from
the information written by genetic code on the DNA chain and continues by internal
molecular quantum states, would be expressed homogeneously in terms of information
and information processing. It was done in the general form in Ch. 7 of the book [20]
12
on the grounds of information processing by activated chains of relations (ACR) [20,
Chs. 1-3] applied to the molecular genetics. Try to discuss whether it is fit for the
considered problem.
Each chemical group (base) a of a DNA molecule has a number of quantum
states
 . Consider a certain chemical group (base) a in a state  as a special entity
a  and represent the group a not as a chemical group in different states  , but as the
  . Note that in the case of isotope substitution  labels the considered
set a  a 
chemical group substituted at certain places for certain isotopes; one value of
 labels
this chemical group without substitution. This pure formal change of notations (which
does not affects the meaning) allows one to apply the method of the book [20] to the
  of a DNA molecule form a set
considered problem. All such elements a  a 
AS  a . If AS  a be ordered [20, §7.1], it is none other than the source set
defined in [20, Ch.1]. If the ordering throughout the DNA molecule is impossible, it is
to divide it into a number of segments such that each segment could be ordered
independently of others [20, Ch. 7]. After the set AS  a was ordered the
mathematical formalism of [20, Chs. 1-3 and 7] can be applied to the considered
problems. Note that a  may be not only different quantum states (vibration,
rotational, electronic), but they may be ionized states, states when one (or more) atom
was abstracted from the group, isotope substituted group etc.. Therefore, the theory of
Ch. 7 of the book [20] can be applied to a DNA molecule subjected of isotope
substitution, excitation of its different degrees-of-freedom, ionization, atom abstraction
etc.. In the many cases of low-intensity-low-dose laser irradiation only the excitations
of rotations are to be taken into account. However, some times (it depends on photon
energy) also excitations of vibrations and electronic levels are to be taken into account.
13
In the case of low-intensity-low-dose-ionizing-radiation action upon DNA molecule
also the excitation of electronic levels and ionization customarily must be taken into
account.
The theory proposed in [20, Ch.7] leads to the new definition of the gene that
includes not only the information expressed by the genetic code, but also the
information carried by nuclear and electronic motion in DNA molecule. In the book
[20, Ch. 7] the gene defined so is called C-GENE (complete gene). Its part that does
not include the information written by the genetic code is called S-GENE (soft gene).
The s-gene expresses in terms of the information and information processing the
physical properties and processes on the levels of nuclear and electronic motion of the
DNA molecule. This is comfortable for the consideration how these states and
processes influence genetics, for example, for the consideration of genetic changes
induced by the excitation of rotations, vibrations or of electronic levels by radiation.
However, it must be kept in mind that "influence genetics" means "creation inherited
genetic changes". This note must be taken into account at the consideration of each
concrete case. Then one can state that the proposed method expands the concept of
epigenetics (see, for example, [21-24] and references there) and even proposes its
most general definition.
It seems that our consideration is in agreement with review [1], in which is
showed that for the explanation of experimental results it is to suppose the existence of
other mechanisms of the radiation induced genomic instability than the DNA strand
breaks, and even the contribution of epigenetics is considered.
14
CONCLUSIONS
In the present paper we consider the genetic information
distortion arising without DNA molecule rupture at
the isotope substitutions of elements in DNA molecule 4 bases or at the low-intensitylow-dose-laser- or ionizing radiation, or at the natural processes, for example, in
central and peripheral nervous systems of living beings. It was shown that the
approach based on the use of formal languages could be realistic only for the several
simplest cases of isotope substitution. Namely, when new formal languages with the
number of letters in alphabet more then 4, but not large, should be used instead the
usual 4-letters one (A - adenine, G - guanine, C - cytosine and T - thymine). However,
usually the consideration of the isotope substitution demands the use of formal
languages with too large number of letters in the alphabet, even more than 500000, that
makes the use of this approach practically impossible. For the consideration of effects
created by the irradiation the number of letters in the alphabet of the relevant formal
language may be so large that practically should be consider as infinite. The similar
situation is created also without an external factor (radiation, isotope substitution etc.)
intervention by natural processes inside a living organism. These processes represent
the genetic information realization and their existence itself means non other that the
organism lives.
We proposed to use for the treatment of the genetic information in such cases
the method of the information representation and processing by DNA molecule
described in Ch. 7 of the book [20], which is based on the corresponding general
method of Chs. 1-3 of this book. This method allows one to express physical properties
15
and processes on the level of molecular quantum states of DNA polymer molecule in
terms of the information and information processing. Then these properties and can be
included into the common framework with the genetic information written by the
genetic code. As a consequence of this the concept of gene was extended [20, Ch. 7] so
that it includes, in particular, the dynamics produced by physical processes occurring
on the levels of intramolecular nuclear and electronic motion (transitions between
rotational, vibration and electronic states of the molecule). This representation is fit,
for example, for the consideration of the genetic information radiation damage because
it is homogeneous and does not demand the "sewing together" such heterogeneous
characteristics as those expressed in terms of the genetic code and those expressed in
terms of physical properties and processes.
Probably, the described mechanism based on the genetic information
distortion is, in particular, essential for biological effects produced by low-dose-lowdose rate radiation and for isotope substitutions. However, it must be taken into
account that other physical, biochemical and biological mechanisms also contribute to
these effects and cannot be neglected.
16
REFERENCES
1.
W. F. Morgan, J. P. Day, M. I. Kaplan, E. M. McGhee, C. L. Limoli,
Genomic Instability Induced by Ionizing Radiation, Radiation Research
146, 247-258 (1996); B. M. Sutherland, P. V. Bennett, O. Sidorkina, J.
Laval, Clustered DNA Damages Induced in Isolated DNA and in Human
Cells by Low Doses of Ionizing Radiation, Proc. Nat'l Acad. Sci. 97, 103108 (2000)
2.
A. L. Lehninger, BIOCHEMISTRY; THE MOLECULAR BASIS OF
CELL STRUCTURE AND FUNCTION. Second Edition. Worth
Publishers, Inc., New York, 1975; p.p. 892-894
3.
E. S. West, W. R. Todd, H. S. Mason, J. T. Van Bruggen,
TEXTBOOK OF BIOCHEMISTRY. Fourth Edition, The Mcmillan
Company, 1966; p.p. 684, 1087
4.
D. E. Metzler, BIOCHEMISTRY; THE CHEMICAL REACTIONS
OF LIVING CELLS. Academic Press, Inc., New York, 1977; p.p. 124,
405
5.
Argon National Laboratory, Chemistry Division, Research Areas,
Photosynthesis, Biological Materials Growth Facility. Available on-line:
http://chemistry.anl.gov./photosynthesis/algaefarmpub.html
6.
A. Hengge, Biology and Heavy Water, MadSci Network:
Biochemistry. Available on-line:
http://www.madsci.org/post/archives/oct98/904868255.Bc.r.html
17
7.
G. A. Sowa, A. C. Hengge, W. W. Cleland, 18O Isotope Effects
Support a Concerted Mechanism for Ribonuclease A, J. Am. Chem. Soc.
119, 2319-2320 (1997)
8.
R. A. Hess, A. C. Hengge, W. W. Cleland, Kinetic Isotope Effects for
Acyl Transfer from p-Nitrophenyl Acertate to Hydroxylamine Show a pHDependent Change in Mechanism, J. Am. Chem. Soc. 119, 6980-6983
(1997)
9.
A. C. Hengge, B. L. Martin, Isotope Effect Studies on the Calcineurin
Phosphoryl-Transfer Reaction: Transition State Structure and Effect of
Calmodulin and Mn2+, Biochemistry 36, 10185-10191 (1997)
10. T. I. Karu, On Molecular Mechanism of the Therapeutic Action of the
Low-Intensity Laser Light, Doklady Akademii Nauk SSSR 291, 12451249 (1986) (in Russian)
11. T. I. Karu, Photobiological Fundamentals of Low-Power Laser
Therapy, IEEE J. Quantum Electronics QE-23, 1703-1717 (1987)
12. M. Kurisaka, M. Arisawa, T. Mori, T. Sakamoto, M. Seike, K. Mori,
T. Okada, H. Wakiguchi, T. Kurashige, Combination Chemotherapy
(cisplatin, vinblastin) and Low-Dose Irradiation in the Treatment of
Pineal Parenchymal Cell Tumor, Child's Nervous System 14, 564-569
(1998)
13. A. Safwat, The Role of Low-Dose Total Body Irradiation in Treatment
of Non-Hodkin's Lymphoma: a New Look at an Old Method,
Radiotherapy and Oncology 56, 1-8 (2000)
18
14. Y. Ozawa, N. Shimizu, G. Kariya, Y. Abiko, Low-Energy Laser
Irradiation Stimulates Bone Nodule Formation at Early Stage of Cell
Culture in Rat Calvarial Cells, Bone 22, 347-354 (1998)
15. M. Yamamoto, K. Tamura, K. Hiratsuka, Y. Abiko, Stimulation of
MCM3 Gene Expressions in Osteoblast by Low Level Laser Irradiation,
Lasers in Med. Sci. 16, 213-217 (2001)
16. M. Walker, S. Rumpf, G. D. Baxter, D. G. Hirst, A. S. Lowe, Effect of
Low-Intensity Laser Irradiation (660 nm) on a Radiation-Impaired
Wound-Healing Model in Murine Skin, Lasers in Surgery and Medicine
26, 41-47 (2000)
17. M. Eigen, Selforganization of Matter and the Evolution of Biological
Macromolecules, Naturwissenschaften 58, 465-523 (1971)
18. M. V. Volkenstein, The Amount and Value of Information in Biology,
Found. Phys. 7, 97-109 (1977)
19. W. E. Packel, J. F. Traub, H. Woźniakowski, Measures of Uncertainty
and Information in Computation, Inf. Sci. 65, 253-273 (1992)
20. A. Ya. Temkin, SOME IDEAS ON INFORMATION PROCESSING,
THINKING AND GENETICS. Tel-Aviv, 1999; available also on-line
(free) on author's Web site: http://www.eng.tau.ac.il/~temkin
21. J. Lederberg, The Meaning of Epigenetics, The Scientist, September
17, 2001, p. 6
22. B. A. Maher, Researchers Focus on Histone Code, ibid. p. 15
23. A. P. Wolffe, M. A. Matzke, Epigenetics: Regulation Through
Repression, Science 286, 481-486 (1999)
19
24. R. A. Martienssen, V. Colot, DNA Methylation and Epigenetic
Inheritance in Plants and Filamentous Fungi, Science 293, 1070-1074
(2001)
20