The article below is extractedfrom:  N. Zurak, E. Klain, "Freud's theory of Thanatos and the concept of programmed cell death" Click the Link for the complete article with footnotes. 

In  Beyond the pleasure principle (1920), Sigmund Freud presented his theory describing Thanatos or the death instinct--a psycho-biological mechanism bringing an organism back into the inorganic state of existence.

Since the very beginning of the life, Freud explained, the presence of an instinct of disintegration of elements within very complex biological molecular structures generate an autodestructive tendency. The authors suggest that modern molecular biology offers impressive arguments in favor of  Freud`s theory. 

These arguments are based on the discovery of programmed death on the cellular level. It seems that the concept of Thanatos represented the fundamental 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.

Although the interpretation of Freud's idea pursued a psychological direction, emphasizing the clinico-psychological experience, the concept of genesis on the biological level was directly implicated by Freud himself.

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. We suggest 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 active.

Freud's concept

The concept of the death instinct was first presented by Freud in his paper Beyond the Pleasure Principle (1920). He described it as a biological instinct directing toward the organism's return to the inorganic state. An instinct or tendency toward death, Freud argued, via 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 .

From the very beginning of life, the disintegrating elements in highly complex biological molecules has been active, constituting the core of autodestructive tendencies subsequently superimposed on the 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. Freud emphasized the biological aspect of death instinct.

The fact of a fixed life expectancy in higher animals implies that death should be due to natural causes. Consequentially, death as a universal phenomenon and physiological process is be structured as an instinct.

In The Ego and the Id (1923), Freud  explained the psychological aspect of death instinct and its role in the concept and its role for melancholia and masochism. 

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. In Inhibitions, Symptoms, and Anxiety (1926), Freud stated that the fear annihilation is the primordial human fear.

It is plausible to theorize that sadism essentially is a death instinct that has been forcibly estranged from the ego under the influence of narcissistic libido.

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, Freud says, finds expression in the pleasure principle. Our recognition of this fact as one of the strongest reasons to believe in the existence of death instinct.
 

Programmed cell death

A half a century ago, Viktor Hamburger and Rita Levi Montalcini were the first to demonstrate the degeneration and death of specific cells, fibers and synaptic endings were an integral part in the process of embryonic development. 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 the 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 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.

In 1972, Kerr, Wyllie and Curie proposed the term apoptosis to describe the "by then poorly recognized mechanism of cell elimination which, it seems, plays a role complementary but opposite to that of mitosis in the regulation of animal cell population." Nowadays, the term apoptosis includes morphological and structural alterations accompanying most of programmed cell deaths in embryonic development. 

This phenomenon is found in all cell types. However, the one occurring in neurons is especially interesting. As differentiated from a cell undergoing necrotic death, in apoptosis the cells show abnormal shriveling, while electron micrography reveals condensed cytoplasm with the organelles appearing normal. The nucleus 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.

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. 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.

Excessive destruction of  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.

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. The two terms have usually been used as synonyms, however, there is evidence that programmed cell death may also follow a different micromorphological presentation

Discussion

We theorize 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 evidence for Freud's concept of Thanatos.

Psychologic-philosophical arguments

The main objection to the concept of death instinct is that it is an unnecessary idea. 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.

According to Freud, the instinct of death mostly acts in silence, within the body. It’s purely psychologic manifestations are quite rare, while the manifestations resulting from its fusion with libido are more common. Like 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 and masochism.

Physico-cosmological arguments

The second law of thermodynamics formulates the direction of all processes in nature. 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. 

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. 

According to F. Alexander:

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.

Biological arguments

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 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.
 
The problem of 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. Freud's theory of the existence of the death instinct as an active physiological process is easier to comprehend in the light of the discoveries in the field of molecular biology of neuronal and glial cells.

Nowadays, 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 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 addresses the 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." 

Avoiding 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 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."  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."