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Apud concept: Hypothesis or tautology?
Medical
Hypotheses
APUD CONCEPT
6: 437-440,
: HYPOTHESIS
I980
Comment
OR TAUTOLOGY?
Petr Skrabanek, Mater Misericordiae
Hospital, Dublin,
Ireland
Dr Leong and Dr Matthews (Med. Hypotheses 5, 265, 1979) suggested that the pineal gland is an APUD organ. They also indicated that the APUD concept has been "scientifically accepted". I think that Drs. Leong and Matthews unnecessarily introduced the APUD concept into their very interesting review of the pineal function. In my opinion, their statement that the pineal gland is an APUD organ means no more than that the pineal gland produces peptides and/or amines, which is well known. The APUD concept has had a tortuous history. Its unifying theme has been, as Drs. Leong and Matthews pointed out, a wish "to unite a physically widely dispersed and apparently unconnected series of qlandular structures by a common embryological derivation." This has been shown to be either false or untestable. To parry criticisms based on experiments, the concept has been continuously modified by ad-hoc hypotheses, finally reaching the stage of a non-falsifiable dogiiiZ.Tquick look at the history of the concept shows that originally Pearse (1) noted comnon cytochemical properties in peptide-producing cells in the pituitary (corticotrophs, melanotrophs), pancreas (p cells) and thyroid (C cells) and proposed that these four cells developed from a comnon cell of neural origin. Two years later, other cells were added, including endcells of the GIT. The latter cells shifted the balance and Pearse suggested that all APIJD cells were of entodermal origin (2). Meanwhile it has been shown that the parafollicular cells of the thyroid originated in the neuroectoderm (3). Pearse and Polak (4), therefore suggested that all APUD cells are of the neuroectodermal, or more specifically, of neurocristal origin. It was also suggested that the APUD cells are modified nerve cells (5) and that all endocrinology is a part The concept has been enthusiastically accepted of neuroendocrinology. since it "explained" ectopic hormones, multiple endocrine neoplasiss,etc. In 1974, Pearse and Polak (6) classified all "apudomas" (i.e., tumours arising from the APUD cells) as a subgroup of "neurolophomas" ( i.e., tumours arising from the neural crest). The pituitary somatotroph Takor Takor and Pearse was a problem since it arised from the ectoderm. (7) showed that the pituitary originated from the ventral neural ridge. This however, did not solve the problem of the pituitary fully since gonad0 trophs and thyrotrophs were lacking APUD cytochemical properties (8). Another "outstanding exception" was the parathyroid chief cell which had neither APUD characteristics nor neuroectodermal origin. Despite these obstacles, the hypothesis was stronger than facts. "We can now reincorporate in the APUD series those peptide-producing cells which lack the APUD facility"(8).
437
Strong criticism of the postulated neurocristal origin of many APUD cells (9,10,11,12,13) led Pearse to abandon the idea (14) but he still insisted on using the misleading terms "neurocristopathy" and "neurocristoma" because of "the contribution which can be made to dissemination and acceptance of a discovery or concept by the attachment of However, in 1977 Pearse (15) finally admitted that an attractive name". "the possession of APUD characteristics is not, nor ever has been, evidence for a cellular origin from the neural crest.(...)The assumption is no longer tenable". When it was untenable, Pearse and Polak (16) acknowledged the priority of the neurocristal concept to Pag&s. The current formulation of the APUD concept postulates that "the endocrine cells of the APUD series, producing peptides and/or amines active as hormones or as neurotransmitters are all derived from neuroendocrine-programmed cells originating in the embryonic ectoblast" (16). The ectoblastic origin, unfortunately, is not accesible to experiment. The untestability is, in fact, incorporated into the concept since it was postulated that the migration of the APUD ancestors occurs in such an early stage that "they could not be prevented by any conceivable operative technique" (14). It would have to take place before th??end of gastrulation since at this stage gastrointestinal endocrine cells are already in the endodetm (17).
In summary, the APUD concept is an elusive animal. The postulated comnon or-m untestable and therefore unfalsifiable, and the cytochemical part of the concept is inconsistent and arbitrary. Cells which exhibit APUD characteristics (mast cells, Paneth cells, basophils) are not included, while cells without APUD characteristics (parathyroid chief cells, gonadotrophs, thyrotrophs) are included. At the same time, not all cells producing hormonal peptides belong to the APUD system, for example placental cytotrophoblast producing chorionic gonadotrophin, and other placental peptide-producing cells. "The sole present exception . ..of a cholecystokinin-like peptide in some neurons of the cerebral cortex" (16) can be extended by analogy to numerous other peptidergic neurons. The conclusion that the APUD concept is of little value has been reached by others, too. (18). Since neither the cytochemical criteria nor the origin matter, the statement that an organ or a cell belongs to the APUD system means only that the organ or cell produces hormone-like peptides and/or amines, which is a tautological description of a hormone-producing cell. This was admitted by Pearse and Takor Takor (19) when they stated that "the onset of true APUD characteristics in a cell that can reasonably he postulated to be or can be shown to be an endocrine cell precursor signifies endocrine or neuroendorine determination." The close connection between the endocrine and nervous systemsis not a new idea. Cawadias (20) showedthat "to unify these systems into one, the extended nervous system, or the neurohumoral system, and thus include endocrinology in neurology" was an accepted trend of thought before the 2nd World War. From the common function, i.e., transfer of information, the common embryological origin does not follow (21). For example, cancer cells in various organs have common functional and biochemical characteristics though it does not mean that the precursors of the cancer cells are of the common embryological origin, except the unhelpful truism that all cells ultimately originated from the zygote. 438
Theories which cannot be disproved are usually very popular because they appear to explain everything. "The study of any of them seemed to have the effect of an intellectual conversion or revelation, opening your eyes to a new truth hidden from those not yet initiated. Once your eyes were thus open you saw confirming instances everywhere."(22). Theories which explain everything, explain nothing. REFERENCES 1. Pearse AGE. Common cytochemical properties of cells producing polypeptide hormones, with particular reference to calcitonin and the thyroid C cells. Veterinary record 79, 587, 1966. 2. Pearse AGE. Common cytochemical and ultrastructural characteristics of cells producing polypeptide hormones (the APUD series) and their relevance to thyroid and ultimobranchial C cells and calcitonin. Proceedings of the Royal Society B 170, 71, 1968. 3. Le Douarin N, Le Lisvre C. Demonstration de l'origine neurale des cellules 2 calcitonine du corps ultimobranchial chez l'embryon de poulet. Comptes-rendus de l'Acad&nie des Sciences 270, 2857, 1970. 4. Pearse AGE, Polak JM. Neural crest origin of the endocrine polypeptide (APUD) cells of the gastrointestinal tract. Gut 12, 783, 1971. 5. Pearse AGE, Polak JM. The neural crest origin of the endocrine polypeptide cells of the APUD series. p 145 in Endocrinology 1971 (S Taylor,ed), Heinemann, London, 1972. 6. Pearse AGE, Polak JM. Endocrine tumours of neural crest origin: neurolophomas, apudomas and the APUD concept. Medical Biology 52, 3, 1974. 7. Takor Takor T, Pearse AGE. Neuroectodermal origin of avian hypothalamo-hypophyseal complex: the role of the ventral neural ridge. Journal of Embryology and Experimental Morphology 34, 317, 1975. 8. Pearse AGE, Takor Takor T. Neuroendocrine embryology and the APUD concept, Clinical Endocrinology (Oxford) 5, Suppl., 229s, 1976. 9. Andrew A. Further evidence that enterochromaffin cells are not derived from the neural crest. Journal of Embryology and Experimental Morphology 31, 589, 1974. 10. Andrew A. An experimental investigation into the possible neural crest origin of pancreatic APUD (islet) cells. Journal of Embryology and Experimental Morphology 35, 577, 1979. 11. Pictet RL, Rall LB, Phelps P, Rutter WJ. The neural crest and the origin of the insulin-producing and other gastrointestinal hormone-producing cells. Science 191, 191, 1976. 12. Fontaine J, Le Douarin NM. Analysis of endoderm formation in the avian blastoderm by the use of quail-chick chimaeras. Journal of Embryology and Experimental Morphology 41, 209, 1977. 13. Sidhu GS. The endodermal origin of digestive and respiratory APUO cells. America1 Journal of Pathology 96, 5, 1979.
tract
14. Pearse AGE. Neurocristopathy, neuroendocrine pathology, and the APUD concept. Zeitschrift filr Krebsforschung 84, 1, 1975.
439
15. Peat-seAGE. The diffuse neuroendocrine system and the APUD concept. Related "endocrine" peptides in brain, intestine, pituitary, placenta, and anuran cutaneous glands. Medical Biology 35, 115, 1977. 16. Pearse AGE, Polak JM. The diffuse neuroendocrine system and the APUD concept. p 33 in Gut Hormones (SR Bloom, ed) Churchill Livingstone, Edinburgh, 1978. 17. Le Douarin NM. The embryological origin of the endocrine cells associated with the digestive tract. Experimental evidence based in the use of a stable cell marking technique. p 49 in Gut Hormones (SR Bloom,ed) Churchill Livingstone, Edinburgh, 1978. 18. Bennett&HS. A review of "Chromaffin, enterochromaffin and related cells" with some comments on the APUD and paraneuron concepts. Archives of Histology (Japan) 40, Supp1.,317, 1977. 19. Pearse AGE, Takor Takor T. Embryology of the diffuse neuroendocrine system and its relationship to the common peptides. Federation Proceedings 38, 2288, 1979. 20. Cawadias AP. The history of endocrinology. Proceedings of the Royal Society of Medicine 34, 303, 1941. 21. Powell D, Skrabanek P. Brain and gut. Clinics in Endocrinology and Metabolism 8, 299, 1979. 22. Popper KR. Conjectures and refutations. Growth of scientific knowledge. p. 34, Routledge and Kegan Paul, London, 5th edition, 1974.
440
Hypotheses
APUD CONCEPT
6: 437-440,
: HYPOTHESIS
I980
Comment
OR TAUTOLOGY?
Petr Skrabanek, Mater Misericordiae
Hospital, Dublin,
Ireland
Dr Leong and Dr Matthews (Med. Hypotheses 5, 265, 1979) suggested that the pineal gland is an APUD organ. They also indicated that the APUD concept has been "scientifically accepted". I think that Drs. Leong and Matthews unnecessarily introduced the APUD concept into their very interesting review of the pineal function. In my opinion, their statement that the pineal gland is an APUD organ means no more than that the pineal gland produces peptides and/or amines, which is well known. The APUD concept has had a tortuous history. Its unifying theme has been, as Drs. Leong and Matthews pointed out, a wish "to unite a physically widely dispersed and apparently unconnected series of qlandular structures by a common embryological derivation." This has been shown to be either false or untestable. To parry criticisms based on experiments, the concept has been continuously modified by ad-hoc hypotheses, finally reaching the stage of a non-falsifiable dogiiiZ.Tquick look at the history of the concept shows that originally Pearse (1) noted comnon cytochemical properties in peptide-producing cells in the pituitary (corticotrophs, melanotrophs), pancreas (p cells) and thyroid (C cells) and proposed that these four cells developed from a comnon cell of neural origin. Two years later, other cells were added, including endcells of the GIT. The latter cells shifted the balance and Pearse suggested that all APIJD cells were of entodermal origin (2). Meanwhile it has been shown that the parafollicular cells of the thyroid originated in the neuroectoderm (3). Pearse and Polak (4), therefore suggested that all APUD cells are of the neuroectodermal, or more specifically, of neurocristal origin. It was also suggested that the APUD cells are modified nerve cells (5) and that all endocrinology is a part The concept has been enthusiastically accepted of neuroendocrinology. since it "explained" ectopic hormones, multiple endocrine neoplasiss,etc. In 1974, Pearse and Polak (6) classified all "apudomas" (i.e., tumours arising from the APUD cells) as a subgroup of "neurolophomas" ( i.e., tumours arising from the neural crest). The pituitary somatotroph Takor Takor and Pearse was a problem since it arised from the ectoderm. (7) showed that the pituitary originated from the ventral neural ridge. This however, did not solve the problem of the pituitary fully since gonad0 trophs and thyrotrophs were lacking APUD cytochemical properties (8). Another "outstanding exception" was the parathyroid chief cell which had neither APUD characteristics nor neuroectodermal origin. Despite these obstacles, the hypothesis was stronger than facts. "We can now reincorporate in the APUD series those peptide-producing cells which lack the APUD facility"(8).
437
Strong criticism of the postulated neurocristal origin of many APUD cells (9,10,11,12,13) led Pearse to abandon the idea (14) but he still insisted on using the misleading terms "neurocristopathy" and "neurocristoma" because of "the contribution which can be made to dissemination and acceptance of a discovery or concept by the attachment of However, in 1977 Pearse (15) finally admitted that an attractive name". "the possession of APUD characteristics is not, nor ever has been, evidence for a cellular origin from the neural crest.(...)The assumption is no longer tenable". When it was untenable, Pearse and Polak (16) acknowledged the priority of the neurocristal concept to Pag&s. The current formulation of the APUD concept postulates that "the endocrine cells of the APUD series, producing peptides and/or amines active as hormones or as neurotransmitters are all derived from neuroendocrine-programmed cells originating in the embryonic ectoblast" (16). The ectoblastic origin, unfortunately, is not accesible to experiment. The untestability is, in fact, incorporated into the concept since it was postulated that the migration of the APUD ancestors occurs in such an early stage that "they could not be prevented by any conceivable operative technique" (14). It would have to take place before th??end of gastrulation since at this stage gastrointestinal endocrine cells are already in the endodetm (17).
In summary, the APUD concept is an elusive animal. The postulated comnon or-m untestable and therefore unfalsifiable, and the cytochemical part of the concept is inconsistent and arbitrary. Cells which exhibit APUD characteristics (mast cells, Paneth cells, basophils) are not included, while cells without APUD characteristics (parathyroid chief cells, gonadotrophs, thyrotrophs) are included. At the same time, not all cells producing hormonal peptides belong to the APUD system, for example placental cytotrophoblast producing chorionic gonadotrophin, and other placental peptide-producing cells. "The sole present exception . ..of a cholecystokinin-like peptide in some neurons of the cerebral cortex" (16) can be extended by analogy to numerous other peptidergic neurons. The conclusion that the APUD concept is of little value has been reached by others, too. (18). Since neither the cytochemical criteria nor the origin matter, the statement that an organ or a cell belongs to the APUD system means only that the organ or cell produces hormone-like peptides and/or amines, which is a tautological description of a hormone-producing cell. This was admitted by Pearse and Takor Takor (19) when they stated that "the onset of true APUD characteristics in a cell that can reasonably he postulated to be or can be shown to be an endocrine cell precursor signifies endocrine or neuroendorine determination." The close connection between the endocrine and nervous systemsis not a new idea. Cawadias (20) showedthat "to unify these systems into one, the extended nervous system, or the neurohumoral system, and thus include endocrinology in neurology" was an accepted trend of thought before the 2nd World War. From the common function, i.e., transfer of information, the common embryological origin does not follow (21). For example, cancer cells in various organs have common functional and biochemical characteristics though it does not mean that the precursors of the cancer cells are of the common embryological origin, except the unhelpful truism that all cells ultimately originated from the zygote. 438
Theories which cannot be disproved are usually very popular because they appear to explain everything. "The study of any of them seemed to have the effect of an intellectual conversion or revelation, opening your eyes to a new truth hidden from those not yet initiated. Once your eyes were thus open you saw confirming instances everywhere."(22). Theories which explain everything, explain nothing. REFERENCES 1. Pearse AGE. Common cytochemical properties of cells producing polypeptide hormones, with particular reference to calcitonin and the thyroid C cells. Veterinary record 79, 587, 1966. 2. Pearse AGE. Common cytochemical and ultrastructural characteristics of cells producing polypeptide hormones (the APUD series) and their relevance to thyroid and ultimobranchial C cells and calcitonin. Proceedings of the Royal Society B 170, 71, 1968. 3. Le Douarin N, Le Lisvre C. Demonstration de l'origine neurale des cellules 2 calcitonine du corps ultimobranchial chez l'embryon de poulet. Comptes-rendus de l'Acad&nie des Sciences 270, 2857, 1970. 4. Pearse AGE, Polak JM. Neural crest origin of the endocrine polypeptide (APUD) cells of the gastrointestinal tract. Gut 12, 783, 1971. 5. Pearse AGE, Polak JM. The neural crest origin of the endocrine polypeptide cells of the APUD series. p 145 in Endocrinology 1971 (S Taylor,ed), Heinemann, London, 1972. 6. Pearse AGE, Polak JM. Endocrine tumours of neural crest origin: neurolophomas, apudomas and the APUD concept. Medical Biology 52, 3, 1974. 7. Takor Takor T, Pearse AGE. Neuroectodermal origin of avian hypothalamo-hypophyseal complex: the role of the ventral neural ridge. Journal of Embryology and Experimental Morphology 34, 317, 1975. 8. Pearse AGE, Takor Takor T. Neuroendocrine embryology and the APUD concept, Clinical Endocrinology (Oxford) 5, Suppl., 229s, 1976. 9. Andrew A. Further evidence that enterochromaffin cells are not derived from the neural crest. Journal of Embryology and Experimental Morphology 31, 589, 1974. 10. Andrew A. An experimental investigation into the possible neural crest origin of pancreatic APUD (islet) cells. Journal of Embryology and Experimental Morphology 35, 577, 1979. 11. Pictet RL, Rall LB, Phelps P, Rutter WJ. The neural crest and the origin of the insulin-producing and other gastrointestinal hormone-producing cells. Science 191, 191, 1976. 12. Fontaine J, Le Douarin NM. Analysis of endoderm formation in the avian blastoderm by the use of quail-chick chimaeras. Journal of Embryology and Experimental Morphology 41, 209, 1977. 13. Sidhu GS. The endodermal origin of digestive and respiratory APUO cells. America1 Journal of Pathology 96, 5, 1979.
tract
14. Pearse AGE. Neurocristopathy, neuroendocrine pathology, and the APUD concept. Zeitschrift filr Krebsforschung 84, 1, 1975.
439
15. Peat-seAGE. The diffuse neuroendocrine system and the APUD concept. Related "endocrine" peptides in brain, intestine, pituitary, placenta, and anuran cutaneous glands. Medical Biology 35, 115, 1977. 16. Pearse AGE, Polak JM. The diffuse neuroendocrine system and the APUD concept. p 33 in Gut Hormones (SR Bloom, ed) Churchill Livingstone, Edinburgh, 1978. 17. Le Douarin NM. The embryological origin of the endocrine cells associated with the digestive tract. Experimental evidence based in the use of a stable cell marking technique. p 49 in Gut Hormones (SR Bloom,ed) Churchill Livingstone, Edinburgh, 1978. 18. Bennett&HS. A review of "Chromaffin, enterochromaffin and related cells" with some comments on the APUD and paraneuron concepts. Archives of Histology (Japan) 40, Supp1.,317, 1977. 19. Pearse AGE, Takor Takor T. Embryology of the diffuse neuroendocrine system and its relationship to the common peptides. Federation Proceedings 38, 2288, 1979. 20. Cawadias AP. The history of endocrinology. Proceedings of the Royal Society of Medicine 34, 303, 1941. 21. Powell D, Skrabanek P. Brain and gut. Clinics in Endocrinology and Metabolism 8, 299, 1979. 22. Popper KR. Conjectures and refutations. Growth of scientific knowledge. p. 34, Routledge and Kegan Paul, London, 5th edition, 1974.
440