It is doubtful that there has ever been a lecture on liver regeneration that began without showing an artistic depiction of the punishment of Prometheus. The painting usually chosen to illustrate the regenerative capacity of the liver is the dramatic early 17th-century Baroque masterpiece by Peter Paul Rubens (no relation to the author) PrometheusBound, which hangs in the Philadelphia Museum of Art (Fig. 1). Before discussing the intricacies of liver regeneration and its regulation, the lecturer usually mentions in passing that according to Greek mythology, Prometheus was tortured each day by a huge eagle that tore out and devoured his liver, which then grew back each night in readiness for fresh “hepatophagy” on the morrow. But who was Prometheus, for what crime was he being punished, and by whom? How did the story end, and why was the liver the target organ of his punishment? The tale is a fascinating one that not only conveys an ancient familiarity with the liver's remarkable reparative powers but also, throughout the ages, has provided in Prometheus a resistance hero in the struggle for freedom from tyranny and oppression, a representative of individuality against conformity, and a champion of conscience against authority. The legend of Prometheus has captured the imagination of poets, playwrights, writers and visual artists starting with the 8th-century BCE poet Hesiod, in whose poetry the myth first appeared.1 Æschylus crafted the story in the 5th-century BCE as a classic Greek tragedy,2 and the 6th-century BCE Laconic ceramic goblet that is housed in the Gregorian Etruscan Museum (of the Vatican Museums) shows both Prometheus's torture and his brother Atlas bending under the weight of the sky (Fig. 1). Prometheus appealed to Goethe and Byron; to the Shelleys—Percy Bisshe and Mary Wollstonecraft; and to Longfellow and the Earl of Shaftesbury.3 It has even been suggested that Herman Melville's maniacal Captain Ahab in Moby Dick is a latter-day Prometheus.3 In this obsession with Prometheus, visual artists have not been outdone. Besides the work of Rubens and the ceramist of ancient Sparta, Prometheus has been brought to life on canvas and in sculpture, respectively, by Dirck van Baburen, Gustave Moreau, Jean Delville, Briton Rivière, and Paul Manship, and by one of the most acclaimed and innovative sculptors of the 20th century, Jaques (Chaim) Lipschitz.
The superficial explanation of the crime for which Prometheus was punished is that he stole fire from the gods and gave it to mankind; in fact, the events leading up to his punishment were much more complex. Incidentally, politically sensitive readers should note that the foregoing sentence is socially correct, for at the time of these happenings womankind had yet to be invented. Prometheus was one of the four sons of Iapetos of the Titans, those vague quasigod-like beings who ultimately lost their terrible struggle against the gods of Olympia led by Zeus. The defeated Titans were bound with chains and cast into the abysmal depths of the earth, except for Atlas, who was condemned to stand forever on the edge of the world and bear upon his shoulders the vault of the heavens. Prometheus, the visionary (whose name means “foreteller”), escaped the fate of the others of his kind by maintaining judicious neutrality in the Titans' revolt. He and his scatterbrained brother Epimetheus (whose name “Afterthought” indicated that he only thought things out after they happened) were charged with the creation of mortals to replace an earlier humanity that had been destroyed in a deluge. Later, in dividing up the carcass of a sacrificial ox, Prometheus tricked Zeus, against whom he still harbored a grudge, into accepting fleshless bones and fat while giving the succulent meat to mankind, whom Prometheus greatly favored and protected. Zeus's retaliation deprived men of fire, which Prometheus then stole back and returned to them. Zeus's wrath against Prometheus expressed itself as a 13 generation–long ordeal of agonizing continual aquiline partial hepatectomy while he was chained to a lofty crag in the Caucasus mountains. Zeus punished mankind more deviously by giving the imprudent Epimetheus, who lived among them, the gift of an exquisite beauty blessed by the divinities, Pandora, who carried a closed jar that contained evils not yet seen in man's world. Needless to relate, Prometheus had warned his feckless myopic brother against accepting gifts from Zeus, but to no avail. Overcome with curiosity about its contents, Pandora lifted the lid of her jar, which is often erroneously called “Pandora's Box,” and released the terrible afflictions within it on all mankind. Despite the unfortunate coincidence that misery entered the world with the arrival of the first woman, hope was not lost but remained inside her jar. Prometheus's ill fortune was reversed 30,000 years later, when Zeus allowed his own son, Hercules, to kill the eagle and release the chains. The wise centaur Chiron, wounded accidentally by Hercules's poison arrow, longed for death and therefore accepted descent into Hades in place of Prometheus, who, reconciled with Zeus by revealing the secret of a potential lethal plot against him, took up a permanent position on Mt. Olympus with the rest of the gods.
At first glance, the choice of the liver as a focus of punishment seems somewhat arbitrary, even capricious, but it should not be so surprising, considering the esteem in which the liver was held in the Ancient World, as the “seat of the soul” and more.4 (Parenthetically it must be noted that a long-winged eagle was indeed Zeus's instrument of torture and not a vulture as sometimes mistakenly stated,5 since the latter is a scavenger and not a bird of prey, and as such would not eat living animals or Titans.) It has been reasoned that the liver was also selected for injury rather than another visceral organ to avoid killing or maiming the hero in order to maximize the inflicted pain by prolonging the process indefinitely.6 These considerations possibly explain why the brain, the heart or other visceral organs were not chosen. Irrespective of whether the eagle came to feed daily or on alternate days to allow for hepatic repair, one wonders whether the ancient Greeks really knew about liver regeneration or whether this was simply a dramatic device. On the other hand, perhaps Prometheus was a foreteller in more ways than one, since sound and quantitative experimental proof of hepatic regeneration and a measure of its tempo were ultimately furnished in the early part of the 20th century.7
In 1931, Higgins and Anderson published their landmark study on restoration of the liver following its partial surgical removal,7 almost 100 years after the French physicians Léon Jean Baptiste Cruveilhier8 and Gabriel Andral9—the founder of the science of hematology, who coined the term anæmia—first suggested in the early 1830s that hepatic regeneration was feasible. Despite initial opposition or, at best, lukewarm acceptance of the idea that the liver has regenerative capacity,10 astute observers did notice macroscopic signs of liver regeneration in patients with extensive hepatic necrosis due to acute or subacute yellow atrophy, and in those with localized parenchymal loss from hydatid cysts, abscesses, and syphilitic vascular occlusion, as reviewed in detail by Milne10 and Fishback.11 Support for the notion that the liver is capable of self-replication was also found microscopically in the form of mitoses in hepatocytes10, 12, 13 and proliferation of bile ducts,14, 15 which initiated a debate that is still in vogue more than a century later concerning the identity of the progenitor cells of hepatocellular regeneration.16–21 Regardless of the flurry of late 19th- and early 20th-century investigative activity into the nature of hepatic regeneration, which mostly consisted of studies in rats, mice, rabbits, and dogs, on the effects of removing small to large pieces of liver,22, it was not until Higgins and Anderson introduced their safe, simple model of two-thirds surgical hepatectomy in the rat7 that the way was paved for the myriad reproducible quantitative scientific studies that followed. For example, Brues et al. soon used this model to show that although liver mass increases within a few hours of partial hepatectomy (to reach normal size by 72 hours7), hepatocyte proliferation lags by 24 hours.23
The limitations of space and, not to mention, the author's meager experience in this field do not permit an exhaustive discussion here of liver regeneration. Fortunately, experts abound, and reviews of their chosen topic seem to proliferate too.24–41 It would, however, be remiss not to draw the reader's attention to the enduring contribution of the unassuming nonagenarian Nancy Bucher, whose pioneering career in liver regeneration research started shortly after the Second World War.42, 43 Spanning almost six decades,25–27, 31 and still active, her lifework includes one of the longest uninterrupted periods of individual research funding (46 years) that the National Institutes of Health has supported. During the majority of the 73 years since Higgins and Anderson devised their rat model of liver regeneration7 (perhaps better referred to as compensatory hyperplasia, because the resected lobes do not grow back), Bucher has been responsible for establishing most of the variables involved in the process.25–27, 31 Research into liver regeneration began by defining the morphological, ultrastructural, cell kinetic, biochemical, physiological, and nucleic acid changes in regenerating liver.24–26, 37 Why, calculations were even made to show that replicating mature hepatocytes could indeed support Prometheus's eagle.36 Next to be examined was the role of endocrine and other circulating regulatory factors,31, 44 including humors in portal blood45 and hepatic blood flow, per se46 in the quest for key growth factors that turn on and switch off liver regeneration.28, 31, 47 More recently, attention has turned to immediate early genes, delayed early genes, and cell cycle genes, as well as transcription factors, which all play permissive roles in DNA replication and hepatocyte mitosis, since it appears that liver cells must first be “primed” to take advantage of growth factor effects.34, 35, 38, 47 And not to be overlooked is the importance of the liver extracellular matrix and its dynamic effect on hepatocyte growth, gene expression, and liver regeneration.27, 32
Beyond the intellectually exciting cellular and molecular pathways that presently mesmerize devotees of the science of liver regeneration are two subjects of great clinical importance and scientific interest that also have strong social and ethical implications. The topics of living donor liver transplantation48, 49 and stem-cell research50 frequently invoke the name of Prometheus's erstwhile sister-in-law, Pandora, and the mischief she summoned when she opened her “box.” Regarding living donation and split-liver transplantation, it has been observed that the regeneration expected according to Higgins's and Anderson's model7 and previous experience reported in deceased donor transplant recipients51 may not be realized in partial liver recipients and especially in their living donors52, which introduces another nuance of regeneration into the transplant arena that has yet to be fully explored. The role that stem cells play in human liver regeneration has still to be decided, but the option to obtain stem cells and use them to repopulate diseased or deficient livers could be the hope left in Pandora's jar, or it could turn out to be one of the evils that escaped from it. In the case of liver regeneration, it now seems that Prometheus and Pandora will be together again, awhile at least.