ORIGINAL PAPER

Fundamental paradox of survival determinism:the ur-etiology disease paradigm

Pavle Krsmanovic

Received: 2 December 2011 / Accepted: 29 October 2012 / Published online: 6 November 2012

� Springer-Verlag Berlin Heidelberg 2012

Abstract Following a common practice in medicine,

biomedical researches tend to view various disease condi-

tions as direct results of preceding, disease-causing events.

Such events are commonly those that could have been

previously detected and which have given the history of

studies of particular diseases, been previously recognized as

playing an important role in an onset and/or progression of

the disease in question. Although such practice is justified

from the very principles of experimental investigation and

scientific observation, it comes short of finding the funda-

mental causes behind these disease conditions. This man-

uscript proposes a different view to the origin of some types

of diseases as well as some other biological phenomena.

Namely, the focus of the concept relates to a notion of

survival determinism, proposed to have been in the very

core of evolution of primordial organisms. Thereby, as

various disease models are discussed in the light of the

proposed mechanisms for adaptation, they could be seen as

relicts of the early evolutionary history of life on Earth.

Keywords Survival determinism � Cancer � Protein �Parthenogenesis � Protein aggregation � Mitochondria �Aging � Evolution

Introduction

In his article on the pillars of life (Koshland 2002), proposed

seven attributes inherent to all living entities: program,

improvisation, compartmentalization, energy, regeneration,

adaptability, and seclusion. Although outlining these char-

acteristics in such fashion does aid in our attempt to define

‘‘life’’ it remains focused on the perceptible, i.e., tangible,

capacities of living entities. In other words, even though

some of the outlined characteristics do concentrate on the

functional characteristics of life, such as adaptability and

improvisation, they remain derived based on descriptions of

the observable phenomena rather than the nature of the

processes themselves. Another, supplementary approach

would be to extrapolate on the known available scientific

facts to describe the fundamental nature of any living entity.

Thereby, one would implicitly focus on the purpose of

processes, i.e., what is aimed to be accomplished by them,

which characterize living entities rather than solely their

observable and detectable outcome. To do so, one would

need to maintain that the inherent aim and purpose of each

living system is the preservation of itself and its kind

through self-survival and reproduction.

In an earlier paper (Krsmanovic 2011), I have outlined a

view on cancer as a disease originating from a stochastic

survival determinism program. Such program was pro-

posed to have been in the very core of early development of

unicellular organisms, which remained active in the sub-

sequent stages of evolution. In the conventional approaches

to discuss cancer it is usually interpreted as a disease lar-

gely arising due the direct effects of the carcinogens, such

as particular chemicals, radiation, etc., or (epi) genetic

mutations. On the contrary, the hypothesis I have outlined

proposes that carcinogenesis stems from a process that was

initially developed for the purpose of survival under con-

ditions of rapidly changing environment. The model is

based on the concept of survival determinism, proposed to

be inherent to all of the living systems. Therefore, as the

discussed program was indeed indicated to be abundant

P. Krsmanovic (&)

Functional Architecture of the Cell (B065),

German Cancer Research Centre (DKFZ),

Im Neuenheimer Feld 580, 69120 Heidelberg, Germany

e-mail: p.krsmanovic@dkfz.de

123

Theory Biosci. (2013) 132:65–71

DOI 10.1007/s12064-012-0169-9

throughout the living world, one could extent the discus-

sion beyond cancer and speculate that such, or related,

processes would be causing other diseases or some related

biological phenomena.

Thereby, some of the diseases would be seen to occur

not primarily due to the previously recognized mutations or

other defects in the organisms suffering from the respective

diseases. On the contrary, diseases would be primarily

discussed with respect to the inability of individual cells to

comply with the needs of the organism as a whole.

Therefore, the first premise of subsequent discussions

would be that cells always act in response to the changes in

their environment by implementing genetic programs they

possess. In addition, a multicellular organism would be

perceived as a result of a highly structured and elaborate

symbiosis of individual cells—a rationale which consti-

tutes the second premise of these discussions. Thereby,

origins of some diseases would be discussed with respect to

the evolutionary mechanisms of the most fundamental,

single living systems—the cells.

Stochastic survival determinism

The variant of survival determinism program that was

proposed to give rise to cancer would have an aim to

generate a novel functionality, i.e., enzyme(s) or path-

way(s). Such novel functionalities could have eventually

enabled the organism(s) subjected to a rapid and/or drastic

change in the environment to remain viable. The aim of the

process would be to generate many different offspring

organisms with different genetic backgrounds. As only

some of the offspring would be expected to survive the

program was termed stochastic. The processes proposed to

play a role in generating such variability were all previ-

ously characterized to occur in different types of cancers.

For example, various degrees of (epi) genetic mutations,

which were proposed to occur at the initial stages of the

stochastic survival determinism process, were found in all

known tumour types. The significance of such epigenetic

changes was in the focus of many scientists, whereby

Feinberg et al. 2006 proposed it to be in the core of the

development of cancer progenitor cells. Subsequently,

genomic instability found in many, if not all, types of

cancer (Duesberg et al. 2000) was proposed to be a con-

sequence of massive genomic changes occurring during the

process. Finally, as activity of transposable elements can be

induced in cells by treatment with various stress factors

(reviewed by Slotkin and Martienssen 2007), they were

also proposed to have a role in the discussed process.

Thereby, the occurrence of these events was proposed to

be guided by the cell(s) themselves for the purpose of

survival in what they would sense as a hostile and/or

changing environment. Subsequently, the stochastic sur-

vival determinism model is correlated to some forms of

parthenogenesis, such as the one experimentally induced in

mice (Kono et al. 2004). The correlation is supported by

several similarities between such forms of parthenogenesis

and the proposed model. Namely, many of the cases of

experimental inductions of parthenogenesis by treatments

with different forms of stress indeed bear some similarities

with what is proposed in the model (some examples were

previously reviewed by Mittwoch 1978). A direct support

for the proposed correlation between cancers and parthe-

nogenesis also comes from a study, which reported that the

mice from a strain where parthenogenesis occurred regu-

larly were susceptible to developing ovarian teratomata

(Stevens and Varnum 1974).

Hence, the notion of survival determinism was previ-

ously developed as a concept to address the question of role

of evolution of single cells in the context of a multicellular

organism. By further discussing such capacity of the indi-

vidual cells in a body of a large organism one could address

the role of innate survival programs in etiologies of various

diseases. Nevertheless, the concept of survival determinism

does not presuppose the process of propagation of partic-

ular traits: for example by evolution by selection1 or, in

case of selectively neutral mutants, by genetic drifts2. In

other words, it does not represent an alternative mechanism

for evolution but merely a mechanism for offspring gen-

eration: in the case of stochastic survival determinism, its

focus is on generation of the offspring with varied genetic

background. In the following chapters related survival

determinism programs are correlated to other types of

diseases and/or some observations and experimental data.

Thereby they address the relevance of the proposed model

in cases of other processes or known diseases for the pur-

pose of providing a novel conceptual framework for

interpretation of the available data.

Survival determinism role in some genetic diseases

Among different means for cancer initiation, genomic

instability or epimutations in the cancer progenitor cells

(reviewed by Feinberg et al. 2006) would imply that

cancer could originate due to different (epi) genetic

mutations. However, similarly as to previous discussion

on origins of cancer, loss of essential proteins, or effects

1 Initially introduced by Charles Darwin in the book titled: On theOrigin of Species by Means of Natural Selection, or the Preservationof Favoured Races in the Struggle for Life (1859).2 The neutral theory of molecular evolution was introduced in the late

1960 and 1970s by Motoo Kimura to address the question of vast

genomic differences between different species which are selectively

neutral.

66 Theory Biosci. (2013) 132:65–71

123

of some other disease-causing mutations on the cell via-

bility could also be interpreted in the context of a related

survival determinism program. For example, cardiomyo-

cyte death in desmin-null mice is mitigated by overex-

pression of an antiapoptotic bcl-2 gene (Weisleder et al.

2004). As previously indicated, the final aim of the sur-

vival determinism program would be to allow propagation

of life. Thereby, apoptotic sacrifices of some cells in a

population of many would be seen as a means to distribute

the available nutrients away from the cells that have a

very poor likelihood for survival. As desmin filaments are

fundamental for proper functioning of cardiac cells

(reviewed by Paulin and Li 2004) their loss could initiate

such survival program. Furthermore, cell death is one of

the commonly observed phenotypes in various forms of

myofibrillar myopathies, such as in the case of aB-crys-

tallin desmin-related cardiomyopathy (Maloyan et al.

2005). Similarly, mutations in or lack of other essential

proteins could lead to the activation of a similar survival

determinism program. Thereby, the disease phenotypes

characterized by massive cell death, on one side, or

increased cell proliferation on the other (as it is the case in

some neurodegenerative diseases, some of which will be

subsequently discussed) would be an indication that the

disease condition occurred due to the activation of sur-

vival determinism programs in somatic cells.

Another approach to directly correlate the original

causes of some diseases to the survival determinism

program would be to determine if the patients bearing

mutations leading to such diseases would be more sus-

ceptible to developing cancer. Thereby, one would dem-

onstrate that, apart from some mutation-specific effects in

the particular diseases, those mutations would subse-

quently lead to the activation of the same or related

survival determinism program. One of such examples is

the expression of a truncated version of Lamin A, prog-

erin, in a number of human cancer cell lines (Tang et al.

2010). Progerin causes Hutchinson–Gilford progeria syn-

drome (HGPS), a rare premature aging disorder. Lamin A,

on the other hand, is a nuclear intermediate filament

protein which has an important role in maintaining

nuclear stability, elasticity, and organising nuclear chro-

matin (reviewed by Prokocimer et al. 2009). Truncation

of such a vital protein would clearly lead to some

mutation-specific effects, such as nuclear shape defects

and chromatin disorganisation. Nevertheless, its presence

in cancer cells indicates that one of the effects of the

mutation could be associated with activation of the sur-

vival determinism process. Furthermore, reports of HGPS

patients developing malignant cancers (King et al. 1978;

Shalev et al. 2007) indicate that the respective mutations

might indeed make them susceptible to developing some

forms of cancers.

Effects of the immune system and pathogens

Infections with various pathogens elicit an immune

response in humans, as well as other higher animals.

However, the role of the immune system in the progression

of some solid tumors, as reviewed by Pollard (2004), indi-

cates its versatility: although it was developed to counteract

infectious pathogens as broadly as possible, it responds to

the stimuli of other cells and has a broad spectrum of

potential targets, whereby it could also act against the host

cells themselves. Hence, a conceptual analogy between the

carcinogenesis model and autoimmune diseases has been

indicated in an earlier paper (Krsmanovic 2011). The

effects of the survival determinism program in this case are

reflected by the program of the cells developed for the

purpose of the survival of their colony, i.e., the organism,

regardless of what the actual consequences would be. In a

broader sense, the cells of an organism simply respond to

changes in their environment or in themselves, in accor-

dance with the survival programs they have.

Following the survival determinism paradigm, origin of

viruses was also traced to the activity of the same program

to further illustrate that various biological phenomena

could be effectively discussed in the context of such or a

related mechanism. In other words, in the context of sur-

vival determinism viruses were proposed to have initially

been designed as transport vesicles of the genetic material

between different organisms in a colony. Similarly, one

could also extend the discussion further to the symbiotic

relationship between mitochondria and their eukaryotic

host cells or the problems that could arise if their symbiotic

relationship is obstructed. For example, calcium perturba-

tion in mitochondria could lead to the opening of mito-

chondrial permeability transition pore (mPTP) to cause its

efflux (Halestrap 2006). As mitochondria are considered to

have originated by endosymbiosis, the role of mPTP might

have been derived from a similar complex found in bacteria

Legionelle pneumophila (Khemiri et al. 2008). Such com-

plex in these bacteria was postulated to be involved in

induction of apoptosis during infection.

Aged or dysfunctional mitochondria are digested in the

cell by autophagy (reviewed by De Meyer and Martinet

2009), which one could also assume to be initiated under

mitochondrial stress conditions. Therefore, opening of the

mPTP could be, in fact, a mitochondrial response which

mimics its role from the early pathogenic bacteria.

Thereby, whereas under non-stress conditions mitochon-

dria and the host cell would foster their mutual interde-

pendence, under prolonged stress conditions both

mitochondria and their host cells might be expected to

activate their ancient self-survival mechanisms thereby

overriding their symbiotic paradigm. In such case, mito-

chondria could be acting in response to what they perceive

Theory Biosci. (2013) 132:65–71 67

123

as stress in their environment, i.e., the eukaryotic cell host

attempting to discard them. Accordingly, their response

would involve an initiation of a survival mechanism still

remaining from their pre-mitochondrial ancestors, the early

pathogenic bacteria. Thereby, the respective mechanism

could be extended beyond the interaction and evolution of

individual cells: all the way down to the individual cellular

components.

A case study: survival determinism in protein

aggregation diseases

As indicated previously, one group of diseases, which could

be effectively discussed in the context of survival determinism

is the class of protein aggregation diseases. In the context of

such discussion, protein aggregation might be perceived as a

means to concentrate the misfolded or otherwise dysfunc-

tional proteins in a single location inside a cell. The cell could

do so in order to discard the protein aggregates in one of the

offspring cells upon division, whereby it would attempt to

generate a subset of offspring cells with fewer or no aggre-

gates. Thereby, in order to be able to constantly discard the

protein aggregates, the cells harboring aggregation-prone

proteins would remain in the replication competent state. In

case of unicellular organisms in their growth phase such

condition would already be fulfilled. However, in case of

single cells that are part of a multicellular organism, the cells

which activate their survival determinism program would

need to bypass their original altruistic disposition. Thereby,

they would place their own survival as higher priority to that of

the organism they are a part of.

Several lines of evidence support the proposed model of

etiology of this type of diseases. For example, active pro-

tein aggregate stabilisation could be mediated by some

small heat-shock proteins, which were already found to

accumulate in aggregates of glial fibrilary acidic protein

(GFAP) mutants in neurodegenerative Alexander disease

(Perng et al. 2006). This observation indicates that protein

aggregation could be an active process. Furthermore, the

pathological form of prion protein (PrPSc), which causes

protein aggregation in case of prion diseases, stimulates

astrocyte proliferation in the presence of the non-toxic

protein PrPc, as indicated by Brown (2001). The offspring

cells that accumulate the protein aggregates would be

expected to be eventually sacrificed and undergo apoptosis.

In support of such notion, astrocytes treated with PrP106-

126, a prion toxic peptide which mimics the PrPSc activity

during prion disease pathology, but prevented from pro-

liferating show increased cell death. Similarly, PrP106-126

is not toxic in myoblasts, which could divide further, unlike

in myotubes, which are fully differentiated cells and for

which it is toxic (Brown et al. 1998).

To trace the possible origins of the proposed mechanism

of stress response in case of protein aggregation, one could

discuss its role in the early biotic life on earth similarly to

the proposed model of the cancer origin. In other words, in

the cases when massive protein misfolding and/or aggre-

gation could not be mitigated by the existing cellular

machinery the early unicellular organisms could have

activated their survival determinism program. Thereby they

would have been more likely to remain viable and propa-

gate further. However, although hypothetically the process

could be initiated due to a rapid change in the cells’

environment, the causes of protein aggregation could occur

due to a mutation in some proteins (discussed by Brown

2001). Thereby, the mutant proteins might not be able to

fold properly and could instead promote further protein

aggregation. As a cell might have too few tools to precisely

differentiate the actual causes of protein aggregation, the

activation of the survival determinism program under

conditions of prolonged protein aggregation would appear

to be one of the last options it has to prevent a fatal

outcome.

Different forms of survival determinism

The mechanism outlined above is related to the one proposed

to lead to cancer but is characterized by a targeted, rather than

stochastic, survival determinism. Namely, although the

choice of the offspring, which would be sacrificed might still

be random, the targeted survival determinism involves the

accumulation of defects, such as protein aggregates, only in a

subgroup of the offspring cells. Thereby, a specific sub-

population of cells, such as the cells accumulating protein

aggregates, would eventually be sacrificed for the benefit of

the rest of the cell population. Furthermore, as the two forms

of survival determinism are likely interconnected, they could

represent the two stages of the same survival determinism

process (Fig. 1). In other words, the principal mechanism of

the early unicellular organisms would have had to respond to

the prolonged stress conditions would involve the targeted

survival determinism. The cells would remain in the process

of cell division, whereby they would attempt to dispose of the

stress-causing agent through sacrificing some of the off-

spring cells.

In addition to the process already discussed in several

different types of diseases, such mechanism could also be

characteristic for the initiating stages of benign and non-

invasive tumors. In the subsequent stages of tumor growth

it would still remain active to give rise to a lineage of

cancer stem cells (the concept of which is discussed by

Clevers 2011) and a subpopulation of cells undergoing

stochastic survival determinism. Accordingly, the two

forms of survival determinism, targeted and stochastic

68 Theory Biosci. (2013) 132:65–71

123

ones, were indicated above to be likely related with respect

to the diseases they could cause. Thereby, as asymmetrical

cell division was indicated to operate under the stochastic

(discussed in Krsmanovic 2011) as well as the targeted

survival determinism they both likely reflect subdivisions

of a more general pathway.

In addition to application of the concept in the context of

disease one could further implement it in discussing cel-

lular aging. The origin of biological aging would simply be

a consequence of the division of labor by the cells of a

multicellular organism. Most of the differentiated cells are

replaceable and thereby any aging-related defects that

would affect the organism before it has produced offspring

would have been the subject of gradual evolution by

selection. Therefore, there has been no significant selective

pressure to counteract aging more thoroughly. Since the

selection operates on organisms prior to or shortly after

their reproduction, the mechanism discussed is not

incompatible with the process of evolution by selection.

In that respect, aging could also be discussed as a pro-

cess resulting from the division of functions among the

cells, whereby cell differentiation would be seen to repre-

sent a form of biological altruism. Namely, as differenti-

ated cells are committed to only a subset of particular

functions, they would need to activate mechanisms only, or

largely, related to those functions. Nevertheless, unlike in

the case of the rest of the cells in the body, genome

diversity in germline cells would be predominantly gen-

erated via meiotic recombination or de novo base muta-

tions. The occurrence of spontaneous aneuploidies would

likely lead to conception failure (Wang et al. 2012, and

references therein), indicating that under stable conditions

the germ line cells would foster rather stable preservation

of the genome. In this case, such protection would be

necessary as the sole purpose of these cells is dissemination

of the genetic material.

Finally, the survival determinism processes in some cases

could in fact reflect the general state of colonies of some

organisms such as insects. For example, queen bees could lay

fertilised and unfertilised eggs, which would give rise to the

worker or queen bees, in case of the former, or male drones,

in case of the later (reviewed in Mittwoch 1978). Such form

of reproduction would reflect the altruistic form of survival

determinism. Thereby the organisms not designed for further

proliferation would not simply accumulate the defects as in

the case of survival determinism initiated under the stress

conditions. They would, in fact, act to better sustain those

organisms in the colony whose sole purpose is further

Cell Death

Simple mitosis and activation of the stress-response

Unicellular organisms

If the cells still cannot adapt

Continual propagation of the offspring

Stochastic survival determinism

Targeted survival determinism

Cells harbouring random defects

Prolonged stress or rapid change of the environment

Additional Stress

Spontaneous Mutations

CellDeath

Cell DeathCell Death

Simple mitosis and activation of the stress-response

Simple mitosis and activation of the stress-response

Unicellular organismsUnicellular organismsUnicellular organisms

If the cells still cannot adaptIf the cells still cannot adapt

Continual propagation of the offspring

Continual propagation of the offspring

Stochastic survival determinismStochastic survival determinism

Targeted survival determinismTargeted survival determinism

Cells harbouring random defectsCells harbouring random defects

Cells accumulating defects

CellDeathCellDeath

Fig. 1 Different stages of survival determinism. Model of two

different stages of survival determinism (targeted and stochastic): one

being activated as the first response of the organism to the stress or

change in the environment; the second form of survival determinism

would be activated if the first process does not allow for the stable

survival of the offspring. The final aim of these processes is survival

of some of the offspring, whereas a fraction of it would be sacrificed

(either directly, by accumulating defects as in case of the targeted

survival determinism, or indirectly, as a byproduct of the program

aiming at producing random survivors as in the case of the stochastic

survival determinism). Dashed lines leading to the stochastic survival

determinism indicate it could get activated in a subpopulation of the

offspring cells due to additional stress or accumulation of some

spontaneous mutations during the process of targeted survival

determinism. The feedback loop is omitted for simplicity

Theory Biosci. (2013) 132:65–71 69

123

propagation. Nevertheless, through the sacrifice of their own

reproductive potential, organisms living in such colonies

would display an altruistic form of survival determinism.

Such form would appear to be characteristic not for the

organisms facing drastic change in the environment: it would

rather represent the steady state for the organisms which

reproduce under stable conditions.

A teleological paradox

The outlined survival determinism models could in fact

reflect the rapidly changing environment that the early life

on Earth was subjected to. Thereby, whereas an unstable

and rapidly changing environment would favor fast-pro-

liferating organisms with a capacity for rapid adaptability,

stable environment would favor slowly developing, stable

and durable organisms. Activation of the targeted or per-

haps stochastic survival determinism programs would in

fact reflect the general state of an organism under unstable,

harsh living conditions. Nevertheless, the concept of sur-

vival determinism still harbors a fundamental, teleological3

paradox: whereas such mechanism was developed to

guarantee propagation of life, it remains the cause of var-

ious diseases, which would eventually lead to death of

organisms. Hence as the initial cause of many, if not most,

of the diseases could be traced to their survival determin-

ism, it could be said to reflect their ur-etiology4. In this

context, ur-etiology denotes an original common cause in

some of the diseases to be due to the cells survival deter-

minism overriding their biological altruism.

The paradox is, however, not due to the survival deter-

minism itself but due to a broader discord between dif-

ferent approaches to achieve survival and propagation of

life. On one hand, battle for survival or survival of the

fittest represent two modes of evolution by selection and

thereby focus on the advantages and benefits of individual

organisms. On the other hand, organization of organisms

into groups and biological altruism both promote propa-

gation of life but through a direct benefit for the entire

colony. Whereas, the organization of organisms into groups

also promotes survival of each individual one, biological

altruism requires individual sacrifice. However, in the

context of the early unicellular organisms, survival of

individual cells through survival determinism pathways

might have been one of very few means life had to be able

to foster its propagation. Therefore, the apparent discord is

due to the cellular context and the mode of survival the

cells would utilize. Such discord would thereby reflect a

more paradigmatic antagonism: although survival egoism

was initially necessary to guarantee perpetuation of the first

unicellular organisms, it remains an obstacle for sustain-

able viability of more sophisticated forms of symbiosis of

cells, i.e., the multicellular organisms.

Conflict of interest The author declares that he has no conflict of

interest.

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