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A. M. P.
SEMINARI 1998 - '99
N. Zurak, E. Klain *

Freud's theory of thanatos and the concept of programmed cell death

* N. Zurak, E. Klain
Zagreb School of Medicine
Department of Neurology.
Department of Psychological Medicine
University Hospital Rebro
Zagreb, Kiöpaticeva 12.

In his famous publication Beyond the pleasure principle , published in 1920, Sigmund Freud presented his theory describing thanatos-death instinct , determined to bring an organism back into the anorganic state od existence.
According to Freud, since the very beginning of the life the presence of an instinct of disintegration of elements within very complex biological molecular structure is leading to autodestructive tendency carried on by the structure of the ego and superego. Tha authors are presenting their opinion starting that the modern molecular biology offers impressive arguments in favor of the Freud`s theory. These arguments are based on the discovered phenomenon of the programmed death on the cellular level. In historical aspect it seems that the concept of thanatos on the cellular level represents the fundamental theoretical hypothesis anticipating the existence of the programmed cellular death. Cellular death is a biological program recognized as an active physiological genetically-coded process.
Key words:
thanatos, death instinct, programmed cell death

The fate of great ideas frequently illustrates the gap between their scope and receptivity of the time of their emergence. One of such examples certainly is the fate of Freud's concept of thanatos. Following the painstaking breakthrough of the theory of libido, it was met with scepticism and incredulity, resentment and denial even by the most faithful followers of Freud's teaching. Considered as a psychological concept, it was from the beginning understood as something profoundly speculative and hardly demonstrable in the realm of biology. "Only believers, who demand that science shall be a substitute for the catechism they have given up, will blame an investigator for developing or even transforming his views", says Freud defending himself from the rigid views of orthodox Freudians 9.
Although the expectations and interpretation of Freud's idea pursued a psychological direction, emphasizing the clinico-psychological experience in the concept of genesis, the biological level was directly implicated by Freud himself 9.
According to our opinion, with the discovery of the existence of programmed death at the cellular level, current molecular biology has provided strong evidence to support Freud's theory of thanatos. Historically, it could be stated that the concept of thanatos at the cellular level is the initial theoretical hypothesis anticipating the existence of programmed cell death. In molecular biology, cell death as a biological program has been recognized as a genetically encoded process which is both physiologic and active2,3,21,23.

Freud's concept
Death instinct was first elaborated by Freud in his paper Beyond the Pleasure Principle (1920) 9. He has described it as a biological instinct directed toward the organism's return to the inorganic state 9. According to Freud, an instinct or tendency toward own death, via the re-establishment of the state of nirvana, state of equilibrium, return, regression of the organism as a chemically organic colloid into an inorganic substance, is inherent to human beings as well as to all living creatures 9.
From the very beginning of life, the disintegrating instinct of elements in the highly complex biological molecule has been immanently active, constituting the core of autodestructive tendencies subsequently superimposed by the functional structures of ego and superego. As differentiated from the animal instinct (Eros, libido), intended to combine elements into larger units to serve life and its propagation, the instinct of death serves destructuralization, dissolution, and death in a limited sense 9. Freud emphasized the biological aspect of death instinct, thus his theory has been understood as a partially defensive biological speculation 19.
Living creatures die without exception for intrinsic reasons, and "the sense and purpose of all lives is death. Retrospectively, after all, inanimate substances were existing even before the occurrence of life." 9 Freud says: "We may be astonished to find how little agreement there is among biologists on the subject of natural death and in fact that the whole concept of death melts away under their hands." The fact that there is a fixed life expextancy in higher animals, naturally implies that death should be due to natural causes 9. Consequentially, death as a universal phenomenon and physiological process should inevitably be structured as an instinct 8.
In The Ego and the Id (1923), Freud has explained the psychological aspect of death instinct and its role in the concept, not only for melancholia and masochism but also generally in neuroses 10.
Namely, death as a physical fact must affect our mental system, i.e. become an instinct in the psychoanalytical sense. Therefore, there is mental representation of death at the symbolic and imaginary level 10. In Inhibitions, Symptoms, and Anxiety (1926), Freud says that the fear from annihiliation is the primordial human fear 10.
Freud includes castration, and Grunberger so-called return to the womb, in mental representations of the somatic death pressure 9,7,14.
Freud describes the melancholic superego as a pure death instinct. In his Civilization and Its Discontents (1930), Freud states that the organism is defending itself from the instinct of death by shunting and converting it into aggression 12.
From the very beginning of Freud's elaborating the idea of thanatos, the psychopathological phenomena of sadism and masochism attracted Freud's attention as the possible manifestations of death instinct. He tackled the question of how the sadistic instinct aiming at hurting the object, could derive from Eros, the protector of life. Many people are irresistibly attracted by the sense of imperilment. There is a surprising readiness for masochistic behavior of the ego, seeking suffering and pain without any tactical purpose 9,10,11. The question is whether such behavioral patterns necessarily imply the existence of death instinct?
Doesn't it appear plausible to presume that sadism esentially is a death instinct that has been forcibly estranged from the ego under the influence of narcissistic libido, and could thus only occur in relation to the object?
Let us return to masochism, a complex sadism-like instinct, initially understood by Freud as sadism directed toward the subject's own ego. Later on, Freud also admitted the possible existence of primary masochism, and concluded that it was actually irrelevant whether the instinct had an outward (sadism) or inward (masochism) orientation 9.
Freud's view of the fusion of the instincts of Eros and Thanatos makes the explanation of erotic elements found even in destructive processes (e.g., masochistic gratification) possible.
The mental life, and perhaps the neural life as a whole (neural activities) is predominated by a tendency to diminish, maintain constant or eliminate the inner tension caused by stimuli (the so-called nirvana principle). This tendency finds expression in the pleasure principle and our recognition of this fact as one of the strongest reasons to believe in the existence of death instinct, says Freud 9. He has described the reality principle as the pleasure principle tested and improved by reality. It stands for an intelligently organized conduct of the instinctive life directed by the aim of obtaining the greatest possible ultimate sum of pleasure and the smallest possible sum of pain. The way in which this is achieved is that the ego, with the aid of its testing of reality, confronts with other external facts and possibilities and instinctive demands. In this function, the ego is partially a representative of reality, even though at bottom it may sympathize with the instinctive demands of id 9. Under the pressure of a more powerful reality, it has had, willy-nilly, to identify itself in part with this, and now it demands in turn from the instinctive life due regard for this factor of paramount power. If then it voluntarily seeks out painful sensations, it does so in the interest of a pleasure gain, or, at least of lessened pain. The ego thus originates from the id as a differentiation product of the latter, through identification with external reality, but only for the purpose of thus securing a more complete satisfaction of instinctive demands. The differentiation of the superego from the ego, which comes later in the history of development, involves, however, a very similar process, an identification with a special part of reality: with social requirements. The relations of the superego to the ego constitute a parallel phenomenon to the relations of the ego to reality. Just as the ego arose from the id, in so far as the psychic apparatus, turning at least one of its parts toward external reality, acknowledges their distinctive characters.
With the extension of the libido concept to individual cells, a mirror analogy of a biologically opposite sign, manifesting through destructuralization and dissolution of cells, could be hypothesized for Thanatos 9.
Interestingly enough, Freud found common origins and analogies for his dualistic concept of instinct interaction in the teaching of an ancient philosopher, physician and polyhistor, Empedocles from Agrigento. He even wonders whether his dualistic theory may simply be a cryptomnesia of Empedocles' concept 9.
Empedocles from Acragas (Agrigentum) explained the substance diversity by the mixing of four elements, i.e. earth, air, fire and water. He considered the universum as having an equally living nature as indiviudal organisms. According to him, the events occuring both in the life of the universe and in the spiritual life are governed by two permanently opposed principles. He termed them love and fight (war). One of them is fighting to agglomerate the pieces of the four elements into single units, whereas the other, opposite to this, separates primary particles. The two elementary Empedocles' principles correspond to our principles of Eros and destructivity both terminologically and functionally, says Freud, and continues: "For a long time now we do not have the four Empedocles' elements as our basic substance; the living is clearly demarcated from the non-living. For a long time we do not think about the mixing and separation of the substance particles anymore, but about the fusion and dissolution of instinctual components. The more so, we have been provided with a sort of biological basis for the principle of "fight", reducing our destruction instinct to death instinct, i.e. to the instinct of returning everything living to the non-living (inorganic) state."9

Programmed cell death
A half a century ago, Viktor Hamburger and Rita Levi Montalcini were the first to demonstrate that the degeneration and death of specific cells, fibers and synaptic endings were an integral part in the process of embryonic development 20. In a large number of cases, cell death has been found to coincide with the time at which the cells of the respective brain region establish synaptic connections with their target. This has given rise to a hypothesis that there is competition for innervation of neuronal targets, and that dying cells are those which have failed to establish the given contact. Inversely, the surviving cells must receive a signal or continuing trophic factor from the cells with which they are going to establish synaptic contact. The establishment of synaptic contacts, at least in some cases involves competition for the targets, validation of successful synapses, and elimination of unsuccessful or redundant connections. This mechanism holding for individual cells has also been observed at the level of particular endings and synapses 2,3,15,21.
In 1972, Kerr, Wyllie and Curie proposed the term apoptosis to describe the "by then poorly recognized mechanism of cell elimination control which, as it seems, plays a role complementary but opposite to that of mitosis in the regulation of animal cell population" 15. Nowadays, the term apoptosis includes morphological and structural alterations accompanying most of programmed cell deaths in the embryonic development 15,2,5,18,23. This phenomenon is found in all cell types, however, the one occurring in neurons is especially interesting for this presentation. As differentiated from a cell undergoing necrotic death, in apoptosis the cells show abnormal shriveling, while electron mircography reveals condensed cytoplasm with the organelles appearing normal. The nucleus generally shrivels, while its chromatin becomes very dense (pyknotic), collapsing into patches adjacent to the nucleus membrane. Eventually, it dissolves into dense pellets named apoptotic corpuscles. These cellular remnants are exposed to phagocytosis by resident macrophages via the mechanism of endocytosis. It is important to note that there is no reactive inflammation around the apoptotic cells, which means that the cell is eliminated without any stimulus from the immune system 2,3,4,5,13,18,22,24.
Caenorhabditis elegans (CE), a worm from the family Nematodes, has been most frequently used in the experiments conducted to elucidate the molecular biology of the apoptotic process 5,23.
Fourteen incomplete cell death genes (cell-defective genes /ced/) were found in CE, some of them also identified in mammalian homologues. It has been postulated that the apoptotic process may be activated by the inhibition of growth factors, denervation, DNA defects and impairments of the cellular metabolic cycle as well as by oxidation-reduction and excitotoxic stress. All these factors activate death receptors (FAS) located on cell membrane 2,5,21. The activation of endonucleases (so-called caspases) via proteases leads to cell surface alterations and cytoskeletal reorganization with changes of the cell nucleus described above, and subsequently also of the cytoplasm. It is impressive indeed that this program of cell death has been preserved all along the evolutional sequence, from the worm through the man 2,3,5,23.
During the embryonic development, there are redundant neurons and glial cells relative to the limited number of their final connections. The development of individual neurons and of the brain as a whole is characterized by progressive cellular events aiming at achievement of various phenotypes, neuronal connections and functions 2,3,5,23. In this context, it appears almost paradoxical that extensive programmed cell death is one of the major features of the embryonic development of the central nervous system. The realization of certain systems (system-matching), correction of errors, elimination of unnecessary cells and of cells that have served particular transient roles within the scope of developmental function, pattern formation, morphogenesis, and elimination of cells of inappropriate phenotype, have been mentioned as the possible roles of this physiological process 5,13,23.
As neurons are in a continuing postmitotic state upon the completion of embryogenesis, one of the crucial issues concerning mitosis polarity and programmed cell death refers to the possibilities of expression of these two processes in adult human brain 23. At the level of glial cells, excessive cell division with cell immortalization occurs in tumor growth (gliomas), while at the neuronal level it is substituted by the possibilities of synaptic plasticity, mostly as physiologic responses to neuron parenchymal lesions 23. Excessive destruction of the groups of neurons assuming the pattern of apoptotic death has been demonstrated in a number of degenerative diseases of the central nervous system, e.g., Down's syndrome, retinitis pigmentosa, spinal muscular atrophy of Werdnig-Hoffman type, cerebellar degeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple systemic atrophy, and AIDS dementia complex. Apoptosis is also present in cases of axotomy and denervation states, as well as in toxic neuropathies and encephalopathies 3,4,13,21,23.
It should be emphasized that programmed cell death is a general biological strategy preserved during individual life, whereas apoptosis is one of its executive modi 23. The two terms have usually been used as synonyms, however, there is evidence that programmed cell death may also follow a different micromorphological presentation 18,23.
Figure 1 shows a simplified flow-chart of the process of apoptosis. The factors with antiapoptotic action are listed on the left, and those with proapoptotic action on the right, along with analogies of the former and latter with eros and thanatos, respectively.
Molecular biology provide us continuously with ever new discoveries of so far unknown biochemical mediators and protagonists of the process of programmed cell death, thus such schematic presentations become obsolete very soon. For the purpose of this paper, however, the very concept that has remained unchanged in spite of the complicated scenery rather than the biological molecular details appears to be important.

Would it be an exaggeration to say that the discovery of the existence of programmed encoded death at the cellular level as an active process opposing the tendency of cell replication (mitosis) is a definite evidence for Freud's concept of Thanatos? The question is by no means easy to answer, however, it appears worthwile to compare the arguments used by Freud and some of his followers to defend their concept of Thanatos, and those employed by the concept opponents, with the evidence pointing to the existence of programmed encoded cell death.
These arguments could be divided into psychologic-philosophical, physico-cosmological, and biological arguments.

Psychologic-philosophical arguments
The main objection to the concept of death instinct is that it is an unnecessary idea 17. Living organisms undergo gradual decay and then die, which should be axiomatically clear and therefore unnecessary to prove. Another objection is that it cannot be clinically observed, and the next one that the concept is philosophical rather than clinical by nature 17.
Freud's concept of death instinct has frequently been viewed as a pure biological speculation, and only few psychoanalysts consider it clinically usable. In contrast, Freud developed the concept on the basis of his clinical experience 1,7,8,9,10,17,19.
Instinct is a permanent disposition or tendency of the organism to act in an organized and biologically adjusted manner characteristic of a certain species, and also an irrational impulse to take some purposeful action without being immediately conscious of the goal toward which the action has been directed. In the psychoanalytical theory, the instincts are powers that are supposed to underlie the tensions caused by the needs of id 8,22.
Instinct as a dynamic process has the origin in bodily stimulation. Its goal is elimination of the state of tension at the instinct origin. The instinct fulfils its purpose on the object, i.e. owing to the object. The object of death instinct is the subject itself. This is a unique situation in the psychology of instincts, where the instinct gratification becomes its ultimate frustration 8.
It should be noted that all instincts and drives are biological programs, while not all biological programs are instincts. It is quite unusual to talk about instincts at the cellular level; after all, the above mentioned definitions of instinct speak against it. It should be stressed, without entering an epistemological discussion, that Freud has radicalized the issue to the cellular level, for both Eros and Thanatos 9,10,11,12. Therefore, it may be better to talk about the concept of thanatos rather than the instinct of death at the cellular level, in order to avoid any possible misunderstanding.
The man's pathway of communication with death as a narcissistic wound has been characterized by his refusal to accept it; death is always caused by the preternatural. Beside this, children exhibit manifestations of narcissistic behavior before becoming aware of the inevitability of death. In adults, the fact that the awareness of unavoidability and certainty of individual death acts concomitantly with the instinctive, unconscious effects of thanatos, should be taken in consideration. The difference is that the unconscious, instinctive pulsions seek and find their symbolic expression which the awareness of death inevitability does not need. Although the instinctive purpose of Eros in narcissistic states is opposite as a defense against Thanatos, the purpose of death in narcissism is submitted to special distortion due to what has happened in the instinctive life of the narcissistic individual. Narcissistic adherence is characterized by the feeling of incompleteness; absence of something in everything. In other words, narcissistic adherence might be the symbolism of death, i.e. the object's death 8,14.
Narcissism as the passion of existence is the passion of death. Love implies the desire for death, a desire that could be described in an imaginary way as a longing for return into the lifeless state that preceded the birth 8,14,16.
According to Freud, the instinct of death mostly acts in silence, within the body. Its purely psychologic manifestations are quite rare, while the manifestations resulting from its fusion with libido are more common. Likewise the instinct of life, the instinct of death demands gratification. Libidinization is always present as part of the fusion between the instincts of life and death. Where the instinct of death prevails, libido serves the instinct of death. This is especially apparent in perversions, masochism in particular 8,9,10,19.
Based on his clinical experience, Freud also speaks about an opposite process, separation. In clinical practice with severe psychopathologic events, the action of death instinct in its almost pure form can frequently be detected in the conflict with other living powers, more commonly than in fusion 9,10.
According to Klein, both anxiety and guilt originate from death instinct. The desire of death and fear from death, with the possibility of symbolic survival, are later and more diversified experiences than the primordial fear from annihilation and the related horror. The activity of death instinct produces fear, pain and feeling of guilt in the self that wants to live and remain intact 19.
The conflict between the instincts of life and death can be formulated in purely psychological terms. With the birth, we are faced with the experience of needs. There could be two types of response to this experience, which are uniformly present in all of us, although in a variable ratio. One type demands satisfaction of the requirements, and it is life-promoting, oriented toward the object. The other is the instinct of annihilation of the need, annihilation of the empirically perceived self, and of everything other perceived. In some of his papers, Freud describes refusal of the impairment as the nirvana principle. Originally, he thought the nirvana principle to be part of the comfort-discomfort (pleasure-pain) principle, this being the search for constancy. Later on, however, Freud equalized this impairment refusal with death instinct, the instinct of return to the inorganic or death in the literal sense 19.
The shortcomings of such psychologic-philosophical argumentation are always present when trying to explain a general biological problem by the armamentarium of the humanities. The success of such a way of argumentation is actually reduced to the receptivitiy of the audience, which is at least partially a fully irrational process. Using this way, the number of followers or, in case of denial, of opponents of a concept or idea, can be increased, however, the solution of the problem is extremely difficult to achieve.

Physico-cosmological arguments
In Freud's biography by Jones, it is stated that the second law of thermodynamics, used to interpret Freud's theory, is in fact inapplicable to this stuff 17. Saul thinks that there are sufficient reasons for which the second thermodynamic law might still apply to one aspect of Freud's death instinct 17.
The second law of thermodynamics formulates the direction of all processes in nature. The heat always flows from the warmer toward the cooler, unless there is some external power acting on the process. However, there is an exception to the law. A tendency toward the loss of heat, descent, equilibrium, stability, and irreversibility is expressed in the concept of entropy 6,17. The author of this concept was Clausius, a German physicist (1850) 6. Entropy is a measure of system energy that cannot be converted to action, i.e. entropy is a measure of irreversibility or randomization of a dynamic system 6. The essence of the second law is that all processes in nature, provided the system includes what is involved in the process, produce irreversibility. As there is no process in nature which would be completely free from friction or heat conduction, all processes that actually take place in nature are, if the second law is correct, irreversible in reality. The form of the ideally reversible processes is a single, ideally limiting case 6,17. These considerations can be applied in all systems, e.g., mechanical, thermic, electrical, chemical, etc. In his argumentation along this line, Saul says that entropy, likewise temperature, pressure and density, cannot be defined as absolute, constant values but as a certain mean value of a large number of individual variables. Thus, as long as one or more minor variables are observed, entropy cannot be defined otherwise but as temperature or pressure, so that the second law has neither been applied nor proven. All the processes sustaining an organism, be it an ameba or human body, are chemical processes and as such, of course, they are liable to the regularities of nature, and the second law is such a regularity. This law, as we have seen, claims that irreversibility (and this is what is measured by the entropy formula) shows a continuous tendency to increase 17. The living protoplasm is a chemical system of high fragility and irreversibility, i.e. low entropy, which regularly turns into a more inert, inorganic state, i.e. a state of higher entropy, in accordance with the tendency of all physical processes to behave in agreement with the second law of thermodynamics. It seems to Saul that Freud's intuition was correct and that dissolution of the organism is the outcome of the physicochemical characteristics, and that all living processes act while facing a tendency opposite to reversibility 17. Ultimately, the second law of thermodynamics theoretically anticipates the thermodynamic death of the universe, through the concept of entropy.
In our opinion, such argumentation does not contribute to the solution of the problem for two reasons. In the first place, there should be clear differentiation between the open and closed as well as between biological and inorganic or inanimate systems. Accordingly, the universe should be considered as a closed system. However, the most relevant reason appears to be the fact that this is an explication of the inevitability of death in living beings rather than argumentation of the existence or the need of existence of the biologically active instinct of death. Namely, the death of a living organism could also be explained by the wear and weakening of vital instincts governing and controlling the living processes, with a progressively increasing rate of irreversibility (entropy). It seems to us that this very standpoint served as a premise upon which the opponents of the idea of thanatos have built (with good reasons) their resentment.
The inevitability of death in living beings really need not have been substantiated in this way, so we agree with the above citation from Saul, stating that in such a context, the concept of death instinct was and is unnecessary.
Using the psychological, physical, and cosmological arguments as well as comparability of the microcosmic with the macrocosmic, according to F. Alexander, it might lead to a conclusion in favor of Freud's consideration: "The surface tension which arrests the growth of the drop of liquid and disrupts it, the decomposition of the biological molecule into its elements during the catabolic phase of metabolism, the self-destruction of the psychic apparatus, the breaking up of states and cultures, all these are expressions of the same regressive dynamic principle, which counteracts growth and life just as the momentum of inertia opposes the formation of higher dynamic units, and which we should all so much like to forget or deny in its biological manifestation, is the death instinct." 1
If we strictly adhere to the conservative nature of the instinct, we cannot reach the origin and purpose of life.

Biological arguments
It has already been said that critics have qualified Freud's concept of death instinct as a biological speculation. If we agree that the psychological phenomena are cerebral function derivatives, then the psychological arguments could be classified as one of the biological classes. Well, let us agree with the mentioned objection. At that time, the objection was correct; the concept of death instinct was a biological speculation indeed 19. However, likewise any other speculation, the biological ones may later on be proved or rejected. We believe that Freud's biological speculation has now been demonstrated in the territory of exact molecular biology by the discovery of programmed cell death as a genetic program, i.e. a programmed cell suicide. This program is a general regularity present in the animal world from tiny nematodes through primates to humans, in all cells without exception. The evidence for the existence of this genetic program in human neurons, permanently postmitotic cells, the cells emanating and creating, via their activity through complex and stratified processes of interaction, the subconscious and consciousness in man, is of utmost importance in this presentation 23 . The problem mentioned with the definition of instinct and its difficult application in the instinct of death should, according to our opinion, be solved by recognition of the fact that a genetic program, which is the biological basis of the instinct, exists at the cellular level. In the abstract, and in this particular case also in reality, neither realization nor nonrealization of the genetic program can have any affective gratification at the cellular level. At the level of an individual's death, the gratification of death instinct as a psychic projection is simply impossible, because the substrate of its possible gratification disappears with death.
All instincts are by definition species specific genetic programs, whereas the instinct of death, likewise the instinct of life, is a general biological phenomenon of the animal world.
The ingenuity of Freud's thought of the inevitable existence of death instinct as an active physiological process is presently easier to comprehend in the light of the above mentioned discoveries in the field of molecular biology of neuronal and glial cells. Nowadays, when we know that cell mitosis and programmed cell death are active, physiological and counterpoised processes occurring at the cellular level, and that both processes also clinically manifest their pathology, it could be said that neuronal mitosis in the embryonal life and its plasticity in the postnatal life are analogous to Eros' libido, while the programmed death of neurons in the perspective and manifestation is identical to the role of Thanatos. In his paper Beyond the Pleasure Principle, Freud directly addresses cellular level: "With the hypothesis of narcissistic libido and the extension of the concept of libido to the individual cells, the sexual instinct was transformed for us into Eros, which seeks to force together and hold together the portions of living substance." 9 In the light of these facts, it seems to us that the building of psychoanalysis, which has been constructed upon the theory of libido and Eros, requires a supplementation and enrichment with the identification of psychic representations and symbolic manifestation of the instinct of death (thanatos). On this way too, however, just the pathways paved by Freud himself, differentiating from the clinical aspect in their possible psychopathological manifestations the projections of these antagonistic instincts, and recognizing the cases of their interaction and interference, should be followed.
Avoiding any speculation on whether or not the biological molecular argument will be appreciated and its value recognized at the psychological level, there is something that is beyond any dispute. Freud was the first to propose theoretically that death was an active and physiological process, and he built the concept of thanatos on this premise.
It was only decades later that his prophetic considerations could be confirmed at the molecular biology cellular level, by the discovery of programmed cell death. Therefore, it can be said with good reason that Freud was a predecessor of the discovery of programmed cell death. This is best illustrated by his expectations, written in Beyond the Pleasure Principle (1920): "The deficiencies in our description would probably vanish if we were already in a position to replace the psychological terms by physiological or chemical ones." 9 And then: "Biology is truly a land of unlimited possibilities. We may expect it to give us the most surprising information and we cannot guess what answers it will return in a few dozen years to the questions we have put to it." 9


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