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Review

Tityus: A forgotten myth of liver regeneration

Dina G. Tiniakosa,*, Apostolos Kandilisa, Stephen A. Gellerb aLaboratory of Histology & Embryology, Medical School, National & Kapodistrian University of , Athens, Greece; bDepartment of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

Abstract abound including the sacrifice of self for the sake of mankind The ancient Greek myth of Tityus is related to liver regenera- and the price of knowledge [5]. In different eras, the fight tion in the same way as the well known myth of between and Prometheus has represented battles between is. Depictions of the punishment of Prometheus are frequently freedom and oppression, individual against state, man versus used by lecturers on liver regeneration; however, Tityus remains God, and sense against absurdity [6]. unknown despite the fact that he received the same punishment As long as a millennium or more before the Prometheus myth, and his myth could also be used as a paradigm for the organ’s the Sumerian water god, Enki, also defied the king of the gods, his extraordinary ability to regenerate. Nevertheless, there is no con- brother, the air-god, Enlil [7,8]. Sumeria was where modern Iraq is vincing evidence that ancient Greeks had any specific knowledge now located. Indeed, one depiction of Enki shows two streams of about liver regeneration, a concept introduced in the early 19th water emanating from his shoulders, representing the Tigris and century. We describe and analyze the myth of Tityus and com- the Euprhates rivers. Enlil decides to destroy humanity, angered pare it to the myth of Prometheus. We also explore artistic and by the sounds of their mating which offends him. Enlil sends literary links and summarize recent scientific data on the mech- drought, famine, and plague to eliminate humanity, but Enki inter- anisms of liver regeneration. Finally, we highlight links of the leg- feres by teaching the human, Arahasis, about irrigation, granaries, end of Tityus with other sciences. and medicine. Enraged, Enlil unleashes a great 7-day deluge (sim- Ó 2010 European Association for the Study of the Liver. Published ilar to the Noah story of the Old Testament) but Enki again provides by Elsevier B.V. All rights reserved. relief for the humans. The parallelism between the myths of Pro- metheus and Enki, protectors of mankind, indicates a possible Introduction Sumerian influence on the genesis of the Greek myth, a hypothesis supported by the known commercial and cultural exchanges The ancient Greek myth of Titan Prometheus and his punishment between Greece and the Near East since the Late Bronze Age. for deceiving Zeus and protecting mankind is known to most While Prometheus is well recognised, less is known about members of the scientific community who study hepatic dis- another figure in legends who received the same punishment eases, mainly because Prometheus’ liver was the target of torture. and whose myth could also be used by modern hepatologists as However, the myth of Prometheus is known and cherished by an ancient example of the phenomenon of liver regeneration. many, because, according to one version, Prometheus created According to , Tityus (Nistó1 or Nista1 in the first man. The ancient poet (8th century BC) [1] Greek), son of Zeus and Elara, was a gigantic being, living records that Prometheus twice tricked the gods. First, he offered in and Euboea [2,3]. When Elara became pregnant by Zeus, mortals the best meat from a slaughtered cow and gave the fat he hid her deep in the earth so that his wife would not learn and bones to the gods. Then, when an infuriated Zeus punished of this. There Elara gave birth to Tityus, who was nursed by man by taking fire, Prometheus stole it back for mankind. Accord- ( of earth) and grew to enormous proportions. Tityus ingly, Zeus punished him in two ways. First, Prometheus was was so large that his body was said to cover nine acres [2,3].In bound on the mountain . More explicitly, for students another version of the myth, Tityus was gigantic even as a fetus of the liver, an eagle fed from his liver each day, but the liver and, because he ruptured his mother’s womb, he had to be carried regenerated overnight. Secondly, Zeus sent Pandora to the world to term by Gaia herself; most likely making her the first surrogate where she released all hitherto unknown evils to humans [2,3]. mother in human ‘‘myth-history”. When Tityus grew up he made The legend of Prometheus is so steadfast that it has survived the mistake of assaulting goddess , mother of , the god throughout the centuries. Prometheus became an archetypal cul- of light, and of , goddess of hunting. Specifically, when ture hero in the West [4]. Similarities with Christian religion Leto was traveling from in Phocis on her way to , Tityus attempted to rape her, possibly encouraged by Hera. Leto cried out to her children who immediately came to her rescue Keywords: Liver regeneration; Prometheus; Tityus. and tried to kill the giant with their arrows. Tityus, however, Received 26 November 2009; received in revised form 4 February 2010; accepted 8 February 2010 was immortal but could be punished by Zeus who had him bound * Corresponding author. Address: Laboratory of Histology & Embryology, Medical in , the ancient kingdom of the Dead, where two vultures School, National & Kapodistrian University of Athens, 75, M. Asias str, Goudi, were fed on his liver which, as in the Prometheus legend, regener- 11527 Athens, Greece. Tel.: +30 210 7462302; fax: +30 210 7462340. ated perpetuating the torture eternally [2,3]. E-mail address: [email protected] (D.G. Tiniakos).

Journal of Hepatology 2010 vol. 53 j 357–361 Review The name of Tityus, probably deriving from the ancient Greek according to most sources, was eaten by a mighty eagle [15]. Vul- word ‘‘tisis”, means ‘‘he who suffers retribution”. Alternatively, it tures are scavengers mainly eating carrion because of their may be related to ‘‘Tityros”, a name for a flute-playing . The weaker beak and the lack of strength compared to other birds myth of Tityus is probably older than that of Prometheus. While of prey [15]. Paralleling the two myths, the choice of vultures Prometheus is not mentioned by and first appears in Hes- as attackers, better suits the criminal Tityus, while punishment iod’s works, Homer refers twice to Tityus in the . First, a by an eagle seems more appropriate for the heroic Prometheus. hero called Rhadamanthys is said to stop in Euboea to pay him a In the Tityus myth the vultures come to devour the giant’s visit (chapter 7) and then Odysseus, in his descent to Hades, liver every new moon [2,3]. In contrast, says that the describes how he saw Tityus being tortured (chapter 11): ‘‘I eagle came every other day to feed on Prometheus’ liver, whereas saw Tityus too, son of the mighty Goddess Earth—sprawling there Hesiod comments that the ‘‘long-winged” bird came every day on the ground, spread over nine acres—two vultures hunched on [1,16]. These versions of hepatic regenerative capacity indicate either side of him, digging into his liver, beaking deep in the blood- a time-span for the liver’s reparative activity from one night to sac, and he with his frantic hands could never beat them off, for he 28 days. Irrespective of the mythic time-frame of liver regenera- had once dragged off the famous consort of Zeus in all her glory, Leto, tion, both legends raise the possibility that ancient Greeks may threading her way toward Pytho’s ridge over the lovely dancing- have had some knowledge not only of the organ’s potential for rings of Panopeus” [9]. Tityus and his myth are also referred to repair but also of the quantitative and temporal aspects of liver by many other ancient poets and writers like , Apollonius regeneration. Nevertheless, the concept of liver regeneration Rhodius, Strabo, , , and Virgil, his legend being was introduced in modern medicine in the early nineteenth cen- symbolic of the harsh punishment that could be applied to a tury [17,18]. Different possible explanations exist as to how the criminal. Indeed, according to experts in the field of Greek understanding of liver regeneration may have come about more mythography, he may have been the vilest of criminals among than two and a half millennia ago. It may be that the ancients worshippers of the Olympians; this is the way Homer knew of observed the growth of livers as a part of the practice of him [10], in stark contrast to the heroic figure of Prometheus liver divination, using the liver to predict the future. Alternatively and the virtues he represented. there may have been opportunities to study liver healing after Tityus and Prometheus, two tragic mythic figures linked by superficial liver wounds following battle or by observation of their similar punishment, never met according to ancient healing after draining liver abscesses [6]. However, in a recent mythography. However, their stories are linked through Tityus’ in-depth review on the subject, Power and Rasko could not find grandson Euphemos (his name meaning ‘‘he with the good repu- convincing evidence that ancient Greeks had a special knowledge tation”), son of Tityus’ daughter . Euphemos, in contrast to of liver regeneration [18]. his delinquent grandfather, had a kind personality, was a famous The myths of Tityus and Prometheus reveal only one aspect of runner, and an Argonaut. It is said that, during his trip with Jason liver regeneration, namely the organ’s ability to reconstitute its and the other Argonauts, Euphemos saw the eagle who fed on mass after partial removal. Twenty-seven centuries passed before Prometheus’ liver cycling above their boat, the [11].We the first experimental model of liver regeneration following par- can only speculate that Euphemos, gazing at the Promethean tial hepatectomy, the pioneering work of Higgins and Anderson eagle, may have thought of his grandfather, condemned in eter- was published in 1931 [19]. They developed a simple and easily nity, while the more fortunate Prometheus was to be freed gen- reproducible surgical procedure in which two-thirds of a rat liver erations later by Hercules [2]. is removed. This model has been widely used in order to study In the Prometheus myth, the liver was chosen as the focus of mechanisms that govern liver regeneration after partial hepatec- torture because the ancient Greeks regarded the liver as the seat tomy. The concepts of ancient mythographers were confirmed in of life, soul, and intelligence [1]. The indestructibility of the soul observations that showed that liver mass increases a few hours is, in this way, connected to the regenerative capacity of the liver, after partial hepatectomy and, at least in rats, reaches normal size referred to as ‘‘immortal” by Hesiod [1]. Furthermore, by choos- by 72 h [19]. The increasing utilization of live donor and split- ing the liver, the punishment of Prometheus becomes even more liver transplantation has triggered the need to better understand heinous since, because of the capacity of the liver to regenerate, the mechanisms that regulate and promote liver regeneration the suffering of the hero is perpetuated. Similarly, the liver is also [20–24]. Many studies have shed light on the molecular basis chosen as the site of punishment of Tityus. His liver is referred to of liver regeneration, which involves at least three pathways: as ‘‘inexhaustible” and ‘‘always-replenishing” by the Roman poet (i) a cytokine pathway, responsible for the priming of the regen- Virgil in his epic ‘‘Aeneid” [12] and ‘‘constantly growing afresh” erative process, namely the transition of quiescent hepatocytes by the Roman dramatist and philosopher Seneca in ‘‘Phaedra” into the cell cycle, (ii) a growth factor pathway, responsible for [13]. However, according to experts in mythology, in the case the cell-cycle progression, and (iii) a metabolic pathway that of the lustful giant there is also another explanation for wounding links liver function with cell growth and proliferation [20,23]. the liver [6]. In ancient Greek, the word ‘‘gpaq” (hepar), also At the cellular level, hepatocytes are the main proliferating cells, spelled ‘‘gdaq” (hedar), may have its root in ‘‘gdomg” (hedoni) but non-parenchymal cells proliferate as well to maintain the which means pleasure. This is not unexpected since, in antiquity, intercellular relationships of the regenerated liver [22]. However, the liver was also thought to be the seat of passion and desire full comprehension of the phenomenon of liver regeneration [14]. In the case of Tityus, his punishment may have been viewed awaits increased understanding of the pivotal role of the liver by the ancient Greeks as a kind of castration, a scenario that in the regulation of body homeostasis and in its complex interac- would not be appropriate for the tale of Prometheus. Emascula- tions with other tissues and organs. New important data, such as tion was deemed a fitting retribution for Tityus’ crime of rape the implication of platelet-derived serotonin [25], the involve- [6]. In addition, two vultures were chosen to punish the sinner ment of caveolin-1 [26], and the crucial role of stem cells in liver in the legend of Tityus, in contrast to Prometheus whose liver, regeneration [27] continue to emerge.

358 Journal of Hepatology 2010 vol. 53 j 357–361 JOURNAL OF HEPATOLOGY In general, the Promethean myth is mostly employed in liver us (c.1532). This drawing hangs in the British Royal Collection, at scientific meetings where transplant surgeons often show the Windsor Castle. In this version a vulture violates the bound giant grand painting of Peter Paul Rubens (1618) as the unofficial (Fig. 1). For reasons unknown Michelangelo rotated the paper emblem of their profession. Rubens majestic work portrays a with his drawing of Tityus 90 degrees and traced at the back of giant eagle piercing Prometheus’ right hypochondrium and hold- it an upright form of the figure, entitling this new work The Risen ing a portion of his liver in its beak. This painting is probably the Christ (c.1532) (Fig. 2). The tortured giant became the risen Christ, most common depiction of the punishment of Prometheus used stepping from his tomb. Art critics still wonder about the intent by lecturers on hepatic regeneration, along with that of an of the painter: was he implying another, darker side of Christ, a ancient Spartan kylix (560–550 BC) showing exhausted suggestion of human desire rewarded by bodily resurrection? from holding the sky on his shoulders and a hero tied on a pole Or was it just a depiction of Christ rising to save the immoral whose liver is eaten by an eagle [4]. giant who represented sinful mankind [28]? Michelangelo’s Tity- Prometheus has inspired many other painters, such as Luca us sketch may have inspired another Renaissance master, Titian Giordano, Salvator Rosa, Dirck van Baburen, Gustave Moreau, (1490–1576), who then depicted the agonizing chained giant suf- Giorgio de Chirico, Oscar Kokoschka, Max Beckman, Jose Clement fering as a bird of prey tore at his flesh to eat the liver (Fig. 3). Orozco, Barnett Newman, and others, as well as sculptors such as Later, others also used the Tityus legend. Examples include Corn- Nicola Sebastian Adam, Konstantin Brancuzi, Henry Moore, Paul elis Cort (1533–1578), a Dutch engraver who studied with Titian Manship, and Jacques Lipschitz. Interestingly, Lipschitz imagined in Venice and produced engravings (copperplates) of Titian’s Tity- Prometheus strangling the eagle, an act that would fit better to us (1566), and Cornelis Cornelis van Haarlem (1562–1638) who the hero’s personality. The shiny gold Prometheus statue by Man- drew a sketch of Tityus (1588) that now hangs in the Albertina, ship, at New York’s Rockefeller Center, has been seen by many Vienna, Austria. (1591–1652) painted the tor- millions of people. ture of Tityus in a series entitled Furies of the Condemned Tityus, although not a heroic figure like Prometheus, also (1632), including , , and Sishyphus, all of whom also influenced ancient Greek artists such as Polygnotos and the Pen- suffered in Hades after having offended Zeus. The Ribera series thesilea and Aegisthus painters who depicted scenes from the hangs in the Museo del Prado, Madrid, Spain. myth on ceramic pots and vases. Tityus was also popular in the These works of art personified the reigning dynasty’s implaca- Renaissance, his punishment interpreted as an allegory of the ble powers against the infidelity, pride and arrogance of those consequences of unrestrained love. Michelangelo Buonarroti who attacked the supremacy of the monarchy. The scene por- (1475–1564), inspired by the myth of the lustful giant, sketched trayed by the paintings, where a chained opponent is devoured a nude Tityus reclining on a bed of rock in The punishment of Tity- by a huge bird, was a favourite theme of the Baroque era’s rulers,

Fig. 1. Tityus (c.1532), Michelangelo Buonarroti, Royal Collection, Windsor Castle, U.K. In contrast to the original myth according to which two vultures attack Titus, Michelangelo erroneously painted only one.

Journal of Hepatology 2010 vol. 53 j 357–361 359 Review

Fig. 3. Tityus (1549), Titian, Museo del Prado, Madrid, Spain. Titian drew a bird of prey tearing Tityus’ flesh to eat his liver. However, in the relevant myth the giant is punished by two vultures.

D. tityus is a very large beetle (up to 5.5 cm), contributing to its name, it is harmless. A homonymous insect can, however, be deadly. The Tityinae, a subfamily of , are the most poisonous in humans, and can cause dramatic circulatory and respiratory system effects [32]. The Tityus species of scorpions are found in Central and and the Caribbean [32,33]. Most scorpions reproduce sexually via males and females. Ironically, some of the Tityus species, despite bearing the name of the mythical sexual offender, reproduce through par- Fig. 2. The Risen Christ (c.1532), Michelangelo Buonarroti, Royal Collection, Windsor Castle, U.K. thenogenesis. The venom of , a neurotoxin known as Tityustoxin, is the most potent of scorpions’ venoms. In addi- tion to its neurotoxicity, Tityus venom produces a severe inflam- some of who compared themselves with Zeus. On the other hand, matory syndrome with histopathological changes at the site of the artists may have chosen to depict Prometheus’ and Tityus’ inoculation. The venom also affects distant organs, including myths in an effort to criticize the merciless exercise of power the liver, the pancreas, the intestines, and the lungs [34]. Exper- by the monarchs who ruled in Europe during the 16th and 17th iments in rats have shown that Tityustoxin (TSTX-1), increases century. It is believed that Peter Paul Rubens was influenced by serum levels of aspartate aminotransferase, decreases liver glyco- Titian’s ‘‘Tityus”—either the prototype or Cort’s engraving—in gen and causes hepatic congestion and degenerative changes to painting his classical depiction of (1618) [29]. hepatocytes [35]. venom is reported Why has the myth of Prometheus flowered while Tityus´ to cause hepatocyte injury with Mallory–Denk body formation seems to be forgotten? Prometheus, of course, was heroic and [35]. noble, while Tityus was venal. In contrast to Prometheus, Tityus’ The name of Prometheus will, no doubt, remain attached to name is rarely mentioned in medical literature [18,30] and is human liver regeneration because of the richness of the artistic generally unknown to clinical and laboratory doctors and scien- representations of Prometheus’ punishment as well as because tists. There are, however, many allusions to Tityus’ chthonic of the identification of Prometheus as a benefactor of mankind. name among entomologists. Furthermore, some of the descriptions of Prometheus’ torture Dynastes tityus is the name used in the Linnaeus could be used to demonstrate some understanding of the rela- system for the largest of United States beetles, also known as tively short time required for liver regeneration. Tityus, another Eastern Hercules, Rhinoceros, or Unicorn Beetle [31]. While mythical figure providing evidence of the liver’s capacity to

360 Journal of Hepatology 2010 vol. 53 j 357–361 JOURNAL OF HEPATOLOGY regrow, will, perhaps appropriately in view of his attempting to [11] . The voyage of Argo: the . 2nd ed. Lon- commit the despicable act of rape, remain best linked to a harm- don: Penguin Books; 1971. [12] Virgil. Aeneid (Oxford World’s Classics). New York: Oxford Paperbacks; less, but very large, beetle and a highly dangerous of 1998. scorpions. [13] Boyle AJ. Seneca’s Phaedra: introduction, text, translation and The ancient Greek myths of the vilain giant Tityus and heroic notes. Leeds: Francis Cairns Publications; 1987. Titan Prometheus are probably based on tales of supernatural [14] Apostolides PD. Interpretative dictionary of all Hippocratic words. Ath- vitality, rather than on actual knowledge of the liver’s ability to ens: Gabrielides Editions; 1997. [15] Garcia-Olmo D, Garcia-Olmo . The vulture and stem cells. N Engl J Med regenerate. The contrasts between the two myths are more than 2003;349:1480. Authors reply: 1481. the resemblances, mainly because the first underlines the severe [16] Aeschylus. Prometheus bound. New York, USA: Oxford University Press; punishment of a criminal, while the second describes the sacrifice 1990. of a god for mankind. However, both have inspired poets, writers, [17] Reuben A. Prometheus and Pandora—together again. Hepatology 2004;39:1460–1463. and artists across the centuries, with the Prometheus legend sur- [18] Power C, Rasko EJ. Whither Prometheus liver? Greek myth and the science of viving to date as that of an archetypal hero, while Tityus is largely regeneration. Ann Int Med 2008:421–426. forgotten. Nevertheless, according to the myth, Tityus still lies in [19] Higgins JM, Anderson RM. Experimental pathology of the liver. I. Restoration the underworld providing his ‘‘immortal” liver for the vultures. of the liver of the white rat following partial surgical removal. Arch Pathol 1931;12:186–202. [20] Fausto N, Riehle KJ. Mechanisms of liver regeneration and their clinical implications. J Hepatobiliary Pancreat Surg 2005;12:181–189. Financial disclosure [21] Florman S, Miller CM. Live donor liver transplantation. Liver Transpl 2006;2:499–510. [22] Malik R, Selden C, Hodgson H. The role of non-parenchymal cells in liver All authors declare no conflict of interest. growth. Semin Cell Dev Biol 2002;13:425–431. [23] Michalopoulos GK. Liver regeneration. J Cell Physiol 2007;213:286–300. Acknowledgement [24] Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 2004;5:836–847. [25] Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, et al. Platelet- We thank Dr. Elizabeth M. Brunt for critically reading the derived serotonin mediates liver regeneration. Science 2006;312:104–107. manuscript. [26] Fernandez MA, Albor C, Ingelmo-Torres M, Nixon SJ, Ferguson C, Kurzchalia T, et al. Caveolin-1 is essential for liver regeneration. Science References 2006;313:1628–1632. [27] Duncan AW, Dorrell C, Grompe M. Stem cells and liver regeneration. Gastroenterology 2009;137:466–481. [1] Hesiod. -. New York: Oxford University Press; [28] Benfey C. Fanciful traces: Michelangelo’s whimsical sketches. Slate Mag 1999. 1996, 27 Nov. [2] Morfrod MPO, Lenardon RJ. Classical mythology. 8th ed. New York, [29] Kimball F. Rubens’ Prometheus. Burlington Mag 1952;94:67–70. USA: Oxford University Press; 2006. [30] Rosenthal N. Prometheus’s vulture and the stem-cell promise. N Engl J Med [3] Smith W. Dictionary of Greek and Roman biography and mythology. Lon- 2003;349:267–274. don: IB Tauris & Co Ltd.; 2007, p. 1161. [31] Arnett Jr RH, Thomas MC, Skelley PE, Frank JH. American beetles. Boca Raton, [4] Kerenyi C. Prometheus, archetypal image of human existence. New Jer- FL: CRC Press; 2002. sey: Princeton University Press; 1997. [32] Brownell P, Pollis G. Scorpion biology and research. New York: Oxford [5] Dontas NA. The sacrifice of Prometheus. Kathimerini-7 Days; 2002. p. 2–31. University Press; 2001. [6] Chen TS, Chen PS. The myth of Prometheus and the liver. J R Soc Med [33] Linsenmaier W. Insects of the World. New York: McGraw-Hill Book 1994;87:754–755. Company; 1972. [7] Kramer SN. Sumerian mythology—a study of spiritual and literary achieve- [34] D’Suze G, Salazar V, Diaz P, Sevcik C, Azpurua H, Bracho N. Histopathological ment in the third millennium B.C. revised ed. Philadelphia: University of changes and inflammatory response induced by Tityus discrepans scorpion Pennsylvania; 1972. venom in rams. Toxicon 2004;44:851–860. [8] Kramer SN, Maier JR. Myths of Enki, the crafty god. Oxford: Oxford [35] Correa MM, Sampaio SV, Lopes RA, Mancuso LC, Cunha OA, Franco JJ, et al. University Press; 1989. Biochemical and histopathological alterations induced in rats by Tityus [9] Homer, Fagler RT. Odyssey. 1st ed. New York: Viking Penguin; 1996. serrulatus scorpion venom and its major neurotoxin tityustoxin-I. Toxicon [10] Harrison JE. Prolegomena to the study of Greek religion. New Jersey: Prince- 1997;35:1053–1067. ton University Press; 1991.

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