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Biological Research

versión impresa ISSN 0716-9760

Biol. Res. v.34 n.2 Santiago  2001 

Jaime Alvarez and the case against slow axoplasmic
transport: some epistemological reflections


Facultad de Medicina, Universidad de los Andes, Santiago, Chile

Corresponding author: Alejandro Serani-Merlo, Facultad de Medicina, Universidad de los Andes, San Carlos de Apoquindo 2200, Las Condes, Santiago 6782468, Chile. Phone: 56-2-2141258. Fax: 56-2-2141752. E mail:

Received: April 18, 2001. Accepted: April 18, 2001


The 'slow axoplasmic transport theory' has been the prevailing view over the last forty years in order to explain the metabolic maintenance of neuronal axons and nerve endings. A significant amount of evidence against this theoretic interpretation of the existing experimental data has been presented by J. Alvarez, A. Giuditta and E. Koenig in an exhaustive review. They propose an alternative theoretical interpretation called the 'local synthesis model', integrating recent evidence for axon biology and regeneration. We present some epistemological considerations that reinforce the above criticisms and propositions.

Key terms: axon biology, biological epistemology, neuron, slow axonal transport


Biological research is a vast and complex human endeavor whose comprehension does not seem to fit adequately into a monolitical conceptual scheme designated by a single univocal term. In fact 'science' and 'scientific method' are analogical notions that can be legitimately applied in varying ways to different intellectual approaches of reality and to different types of subject matter (Maritain, 1932). In our previous work, we have distinguished at least five epistemological levels in the scientific study of living beings: 1) naturalist observations and descriptions; 2) empirio-schematic experimental biology; 3) empiriometric experimental biology; 4) theoretical biology; 5) philosophical biology (Serani-Merlo, 1986; Serani-Merlo, 2000a).

Science is constructed upon evidence, and even in quite concrete experimental matters an overly-narrow consideration of what constitutes sound scientific evidence can give rise to misconceptions. The fate of research on the metabolic and structural maintenance of neurons and the transport of substances through their axonic prolongations over the past forty years constitutes a particularly illustrative case of epistemological misunderstandings that have hindered the attainment of a prompt scientific consensus and slowed the progress in that field of neurobiology. The analysis of the role played by the scientific work of the Chilean neurobiologist Jaime Álvarez-Marín in this episode of the history of neurobiology is the main object of this communication.

The nervous system, the nerve cell and its axon

The collective anatomical parts of the encephalic mass, the spinal cord and the peripheral nerves, constitute what can be conceptualized as the organ subserving nervous system functions. We propose to classify nervous system functions in three orders or categories of functions: behaviorally related, integrative, and metabolic. The first is composed of those activities directly involved in animal behavior. These activities comprise themselves three group of functions which constitute by their unity what we call animal behavior (Serani-Merlo, 2000b; Serani-Merlo, 2000c), and so could be called 'behaviorally-related nervous activities'. They are represented by i) perceptive and cognitive functions; ii) appetitive and emotional functions; and iii) executive (skeletal) motor functions.

The second category of nervous functions is represented by those activities involved in making the link between the behavioral adaptations of the animal and the metabolic requirements of the organism, needed to subserve the energetic demands imposed by behavior, and so they could be called 'integrative nervous activities'. This group of activities consists of: i) the autonomic (sympathetic and parasympathetic systems) and ii) the neuroendocrine functions.

The third category of nervous functions is represented by the ensemble of cellular and molecular processes involved in satisfying the metabolic requirements needed to make possible both behaviorally related and integrative functions.

The specific material structure involved in all these actions is the nervous tissue composed primarily of neurons and glia. Neurons are a rather specialized type of cells, specifically designed to transmit signals from one cell to another through the propagation of transient local electrochemical changes in the cell.

Axons are cylindrical neuronal extensions especially adapted to transmit those electrochemical transients from one cell to another. From a structural point of view, axons are variable in length, and their mass volume can vary from a fraction of the size of the neuronal body to various orders of magnitude greater than that.

The slow axoplasmic transport theory

The current extended view, acritically accepted in textbooks and even in specialized literature, is that there are two types of systems transporting substances from the body cell to the axon and axonic terminals: one is a fast axoplasmic transport system, and the other is a slow axoplasmic flow. This model supposes that the axon is not metabolically active in terms of structural and functional protein production, as the axon is unable to satisfy even its own structural rechange.

There seems to be sufficient positive empirical evidence at present for the existence of a fast axoplasmic flow of materials from the neuronal cell body to the axon, and there is also some specific knowledge about the nature of the transporting mechanism. However, the affirmation of the existence of a slow axoplamic flow of substances responsible to afford the complete rechange of structural and functional proteins of the axon and axonic terminals is based on scant direct positive experimental evidence.

'Slow axoplasmic transport theory' is a conceptual framework constructed upon three kinds of evidence and a scientific prejudice. As early as 1894, in the immediate vicinity of the intellectual revolution of Santiago Ramon y Cajal's new conceptions about the structure of the nervous system, Mathias Duval (1894/1990) affirmed: "The dendrites...end freely, often in contact with capillaries, so that their branches serve a nutritive role, like a root system for the nerve cell. It thus plays no role in neuronal conduction, and the cell body itself plays only a secondary role. The major function of the cell body would thus be trophic. Neural activity passes almost entirely through the reticulum of short axons and the collaterals of longer axons." The separation between a trophic cell body and a merely conducting axon is then explicitly affirmed. The experimental observation of reversible ballooning of axons above experimental nerve constrictions and its thinning below them contributed to reinforcing that opinion. In the context of that prejudice and the recent discovery of a fast axoplasmic flow of materials from the cell body to the nerve terminals, two another bits of evidence, one negative and one positive, practically imposed the slow axoplasmic flow theory as an official doctrine.

The evidence was 1) the non-observation of ribosomal structures in axons; 2) the observation of the fate of radioactive protein precursors injected in the vicinity of the perikaryon. The first negative evidence was considered as a confirmatory proof for the non-trophic nature of the axoplasm, and the decreasing curves of radioactivity in the perykaryon and the progression of the label through the axon were interpreted as the slow and progressive passage of the labeled proteins to the axons in transit to nerve terminals. The specific theory was then based upon a negative evidence and an indirect positive evidence i.e. the interpretation of the real meaning of the temporal fate of a radiolabel.

The local synthesis model

During the last forty years a small group of scientists have patiently accumulated a significant amount of positive evidence pointing to a rational impossibility of sustaining the slow axoplasmic transport theory in neurons and of a positive affirmation of a metabolically active and functionally autonomous axon. The detailed account of the accumulated empirical and rational evidence has recently been prepared by Álvarez, Giuditta and Koenig (Álvarez et al., 2000; Álvarez, 2001), three of the most conspicuous protagonists of this story.

Our objective here is to propose a loose outline for an epistemological categorization and a logical rearrangement of the general arguments utilized in the above mentioned work in order to highlight the plurality of strategies commonly involved in experimental biology, the obstacles that derive from a too-narrow consideration of experimental biology and the acritical acceptance of predominant ideas.

Is the accepted theory credible?

As J. Álvarez repeatedly affirms, and contrary to intuitive sensory intuition, axoplasm volume in neurons with long axons can be as much as four orders of magnitude greater than the total volume of the large neuronal cell body. If the cell body had to afford the entire metabolic needs of the axon and its terminals, one would expect to see a large initial segment that would progressively decrease in size as the flow of material necessarily decreases, and not an axon which maintains its dimensions fairly constant over long distances, as is the case.

For axons that can measure more than one meter long, proteins in transit to nerve endings at a rate of a millimeter per day could take a couple of years of transit time. In order to make the hypothesis plausible, an extremely long ad hoc survival must arbitrarily be assigned to transported proteins.

Is there direct evidence concordant with the accepted theory?

As von Bernhardi and Álvarez (1989) elegantly showed in anurians, the axoplasm is not revealed to be the kind of metabolic burden to the protein-synthesizing machinery of the cell body that the theory requires.

Is the negative evidence of the theory really negative?

As Álvarez et al. (2000) show in their review there is currently a sufficient amount of physiological and morphological evidence for the existence of ribosomes in axons, the presence of the necessary RNA, and for the incorporation of amino acids into proteins.

Is the positive evidence of the theory really positive?

The temporal fate of incorporated radio labeling of amino acids to the cell body and its transit to the axon has been one of the fundamental supporting factors of the slow axoplasmic theory. This evidence, however, depends on the correct interpretation of the real meaning of the curves. Álvarez and Torres (1985) have convincingly shown that there is an alternative means of interpreting the curves; an interpretation which in fact yields the exact opposite result of the slow axoplasmic theory. The decay curves of radio labeling fit much better into a model of distributed protein synthesis along the axon without the need to incorporate ad hoc arbitrary survival times for proteins.

Is there an alternative theory?

There is in fact an alternative conceptual view, which Álvarez, et al (2000) call the local synthesis model. This new and alternative theoretical framework not only overcomes all the inconvenience of the commonly accepted one, but also incorporates an important amount of new evidences on the biology of axons and its response to physiological and pathological conditions that cannot be reasonably interpreted in the old one.


Modern experimental biology is but a part of a larger human effort directed toward the rational understanding of living beings (Serani-Merlo, 2000a). The recognition of the existence of different formerly autonomous conceptual and methodological strategies in order to attain a scientific rational understanding of living beings must not obscure the fact that human understanding is ultimately unitary. What seems valid for a large scale consideration of biological human understanding applies also to the lower scale consideration of strictly empirical biological knowledge. The vicissitudes of empirical neurobiological research on the understanding of the structure and function of the neuron provide an illustrative example of this last statement.

In their exhaustive review of the empirical research in the field in the last forty years, Jaime Álvarez and his coworkers furnish us with convincing, rational and empirical evidence suggesting that the time has come to abandon the theory of slow transport of materials from the neuronal cell body to axons and nerve endings. The history of ideas on axonal transport of substances would be a clear example of the permanence in time of an unsound scientific doctrine as an accepted official dogma. Our analysis reinforces their proposal in the sense that we contend that their data solidly establish that the accepted theory has poor rational support. In fact we have shown that: 1) even before it was experimentally tested, the theory was in itself unconvincing in face of expected morphological predictions and of known biological principles; 2) the theory is in contradiction with well-proven direct experimental results; 3) the negative evidence on which it stands has been disproven by a considerable amount of positive direct and indirect empirical evidence; 4) the positive indirect interpretation of empirical data that gave rise to the theory can be completely reinterpreted within a new conceptual framework in better accordance with actual experimental data; 5) an alternative conceptual framework, called the local synthesis model, fits the existing evidence much better and allows for the coherent incorporation of an entire new field of evidence on axonal plasticity and regeneration.

The history of biology provides a long list of poorly-based scientific statements that have persisted as official doctrine long after being reasonably disproven. Our tenet is that a wider and stronger critical consideration of accepted biological doctrines could hasten the scientific progress avoiding conceptual confusions and useless experimentation.


This work was partially financed by FONDECYT grant 1000499 to ASM.


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