The footprints of neuroscience in Alexandria during the 3rd-century BC: Herophilus and Erasistratus

Introduction

In the first half of the 3rd-century BC in Alexandria, Herophilus of Chalcedon (ca. 330 to ca. 260 BC) and Erasistratus of Chios (ca. 315 to ca. 240 BC) became the first and last scientists in antiquity to perform systematic dissections of human cadavers. ¹ The magnitude of their anatomical and physiological discoveries remains an ‘intriguing historical puzzle’ that has been acknowledged as ‘a stunning moment in the history of science’. ² During the lifetimes of Herophilus and Erasistratus, the performance of anatomical dissection over a short period of almost 40 years led to extraordinary scientific advances, especially in the field of neuroscience. Anatomical dissection then mysteriously ceased for almost 18 centuries. ²

In the present manuscript, the neuroscientific achievements of the Hellenistic period (mostly the work of Herophilus and Erasistratus) will be examined in association with the exceptional historical circumstances that rendered the neuroscientific research of this era unique and revolutionary. Furthermore, the course of neuroscientific progress during the Hellenistic years will be explored in parallel with some of the most influential contemporary philosophical and cultural currents. In addition to the cultural framework, the particular socio-political dynamics of Alexandria in the 3rd-century BC will be portrayed as potent influences that enabled Herophilus and Erasistratus to introduce the scientific human dissection. Finally, after a concise review of the literature, the resonance of the anatomical and scientific work of these two physicians in the post-Hellenistic periods will be critically discussed.

The Hellenistic culture of Alexandria

Since its founding by Alexander the Great in 331 BC and for a period of over 600 years, Alexandria was the cultural metropolis of the world. Its strategic location, as a large seaport in the vicinity of the Nile Delta, allowed the unhindered confluence of civilizations and harboured the intermingling of Greek, Egyptian, Persian, Babylonian and Hebrew cultures. During the 3rd-century BC, under the reign of the first two kings of the Ptolemaic Dynasty, Ptolemy I Soter (367 to 283/2 BC) and Ptolemy II Philadelphus (309 to 246 BC), ¹ this convergence of civilizations facilitated an unprecedented social and scientific dialogue. The renowned Musaeum and the Great Library of Alexandria were the seat of a thriving scientific production. There are numerous examples (from different scientific domains such as astronomy, physics, mathematics and medicine) that indicate the remarkable quality of scientific achievements from this period.^2,3

During the 3rd-century BC, the scientists in Alexandria developed a cross-field dialogue and introduced—under the influence of analogous socio-political practices—standards of shared scientific argumentation. ³ Among the eminent scholars concerned with the analysis of ancient Greek science, Lloyd ⁴ suggested that the researchers of the Hellenistic period worked in a highly competitive, argumentative atmosphere and that they were under the influence of culturally absorbed dialectic and democratic ideological principles.

Despite the prevalence of democratic principles in the argumentation and the dialectic cross-scientific interaction, it was (paradoxically) the absence of political democracy in Ptolemaic Egypt that allowed the development of some of the most radical concepts of the 3rd-century BC. ⁵ As von Staden suggested, the political structure of the Ptolemaic monarchy in Alexandria (though it retained the ideals of pluralistic debate and critical scrutiny of arguments) deviated from the Greek democratic systems, which had significant effects on scientific research. ² During the 3rd-century BC, the centralization of power enhanced the political influence on research. The monarch controlled all political and economic actions—as well as moral and religious life. In the case of the Ptolemies, this allowed ad hoc interventions in research and translated into abundant support, either in financial terms or in the form of social and ethical patronage of scientific and scholarly production. ⁶ Furthermore, in contrast to the classical democratic Greek communities, scientists in Ptolemaic Alexandria no longer accounted to the democratic majority. They were allowed to operate on an ‘uncensored’ research agenda.

In a critical analysis on the works of Herophilus and Erasistratus, von Staden focused on the remarkable ‘scientific audacity’ of these two scientists, who contradicted prominent contemporary taboos as well as the cultural, religious and ethical constrains of their time—they dared to introduce cadaveric dissection for scientific purposes. In this case, von Staden noted that the political privileges granted by the Ptolemaic monarchs to the scientists of the 3rd-century BC became transparent: ‘In Alexandria, a scientist’s associates could not vote, ostracize or exile him on grounds of impiety, as they could—and did—in democratic Athens’. ²

In addition to the socio-political context, the spread of cultural phenomena, such as the appreciation of experimental findings and the subsequent emergence of evidence-based science, was prominent in Alexandria. ³ The shared need of argumentation in diverse fields led to a maturation of the reasoning processes, through methodological demonstration and development of proof, which was shared by rhetoric, philosophy, mathematics and medicine. ⁵ Particularly in the domain of medicine, this led to a reappraisal of experiments as tools to understand the causality behind pathological processes. ³ These circumstances provided fertile ground for the development of systematic experimental research in the field of brain sciences. In this domain, Herophilus and Erasistratus became the founders of scientific methodology, experimentation and argumentation in neural sciences, and they conducted some of the first documented studies in the field of neuroscience. ⁷ According to historical sources, their original treatises were lost in the fire of the Great Library of Alexandria; however, significant fragments of their work survived and were presented in the comprehensive writings of Galen (ca. 130 to 201 AD) and Caelius Aurelianus (5th-century AD).^8–10

Biographical notes: Herophilus and Erasistratus

Herophilus (ca. 330 to ca. 260 BC), often referred to as the ‘Father of Anatomy’, ¹¹ was a Greek physician who was born in Chalcedon, a city located on the Asiatic side of Bosphorus. During his adolescence, he apprenticed under Praxagoras, a highly regarded physician and anatomist, who taught at the Hippocratean medical school on the island of Kos almost 65 years after the death of Hippocrates. ¹¹ Herophilus remained a Hippocratean throughout his life, imbued with the principles of rationalistic medicine and scientific argumentation. He endorsed the scientific position, which maintained that pathological physical processes imposed on bodily functions account for disease propagation. It is thought that Herophilus received part of his medical training in Athens; in 300 BC, he moved to Alexandria, where he spent the remainder of his life. ¹¹ In Alexandria, he became the first physician to perform scientific dissections of human cadavers systematically, which resulted in original anatomic and physiologic discoveries. ¹²

Erasistratus (ca. 315 to ca. 240 BC) was a younger contemporary of Herophilus. Erasistratus was born in Chios (or Ceos), an island in the eastern Aegean Sea. Limited evidence exists regarding Erasistratus’s early life. ¹³ According to Plutarch, ¹⁴ he practiced medicine at the court of Seleucus I Nicator in Syria and later in Alexandria, where (along with Herophilus) he pursued anatomical studies based on human cadaveric dissection, attempting to enunciate the principles of neural structures and brain functions. Erasistratus, like Herophilus, was evidently attracted by the vigorous climate of inquiry that was fostered in Alexandria by the first two Ptolemies. His discoveries in physiology established him as a renowned physician and reputed naturalistic scientist of the Hellenistic period. ¹⁵

Nothing comes from nothing: The leading doctrines about the origin of human cognition in the pre-Hellenistic and Hellenistic eras

Herophilus and Erasistratus engaged in sophisticated scientific inquiries in the field of brain sciences, under the influence of preceding Greek philosophers’ leading doctrines. Since the 5th-century BC, two controversial theories had polarized the philosophical and medical community in Greece; the theories attempted to approach the origin of conceptual activity: encephalocentrism and cardiocentrism. The former considered the brain to be the seat of consciousness, sensation and intellect; the latter attributed all these faculties to the heart. ³ Both being prominent exponents of encephalocentrism, Herophilus and Erasistratus were influenced by conjectures concerning the essence of rational soul and the causes of neurological and psychiatric disorders. ¹⁶

Among the first scientists to appraise the sensory and cognitive significance of the brain was Alcmaeon of Croton; this was no later than the beginning of the 5th-century BC. ¹⁷ Alcmaeon was an esteemed physician and one of the most eminent natural philosophers and medical theorists of antiquity. He is thought to have been a pupil of Pythagoras in the Greek colony of Croton in southern Italy.^17,18 He addressed scientific and philosophical problems regarding bodily and cognitive processes based on the observation of natural phenomena.

According to Alcmaeon, bodily states depend upon rivalling forces, which affect the natural body equilibrium. He endorsed analogies of social and political images and projected familiar concepts derived from the functional system of the polis (city)—such as the sense of supremacy, distribution of power and interaction of opposing forces—to analyse the balance of bodily functions. He interpreted the manifestation of disease as a disruption of the natural equilibrium. He viewed bodily states as analogous to the citizens of a polis—exhibiting collaborating and antagonizing tendencies within an operational system. The preponderance of one bodily constituent was imposed by external forces, which would allow that constituent to prevail over the others; this was acknowledged as the cause of disease. ¹⁸ His rationalistic conceptualization of disease processes was eventually verified by anatomical studies and experimental reasoning.

Alcmaeon performed the first documented anatomical dissection on animal corpses in medical history. Based on his anatomical observations in the nervous system, he maintained that ‘all senses are connected to the brain’ through structures called ‘poroi’ (channels). He described the poroi that connected the eyes to the brain, acknowledging the optic nerves for the first time in history. ¹⁷ Through his observational studies, he maintained the hierarchical superiority of the brain in the bodily functional system. ¹⁷

In the 4th-century BC, Hippocrates of Cos considered the brain to be the seat of the human intellect and neurological disease. ² The Hippocratic Corpus, which holds a prominent position in the history of medicine, consists of a heterogeneous medley of medical treatises; these treatises are attributed to several Hippocratic authors, mainly dating from the second half of the 5th-century to the end of the 4th-century BC. ¹⁹ According to the Hippocratic view, the disruption of bodily equilibrium was a causal factor for the manifestation of disease and, accordingly, brain dysfunction. In one of the treatises of the Hippocratic Corpus, epilepsy (called ‘the sacred disease’ in antiquity due to its attributed divine origin) was recognized as having a natural cause located in the brain.^19,20

Subsequently, Plato (427 to 347 BC) became one of the leading advocates of encephalocentrism, arguing that the brain was the organ of sensual perception, judgement and reasoning. Plato’s most critical analysis on the nature of sense perception and ontology of reasoning is found in Theaetetus, Timaeus and Philebus, where he claims that ‘pathe’ (the physical changes in the perceiving human body, impinged by external stimuli) yield sense perception and cognition, thereby inducing bodily awareness and conscious reactions. ²¹ In contrast, Aristotle (384 to 322 BC) maintained that all perceptual faculties reside in the heart. ¹³ Despite endorsing the cardiocentric doctrine, Aristotle contributed significantly to the anatomical elaboration of the brain, mostly by observing animal brain dissections; he distinguished for the first time the meninges (dura mater, pia mater and arachnoid) and the cerebrum from the cerebellum. Furthermore, Aristotle abandoned previous ideas of transmigration and reincarnation of the soul, and, instead, postulated that the soul endows the matter of the animate organism only. ² Thus, according to Aristotle’s view, the corpse should be considered a human being in name only; therefore, the traditional notions of the inviolable sanctity of body and skin could no longer apply after death. ²

Eventually, two schools of philosophy ascended in Athens at the time of Herophilus and Erasistratus: Stoicism and Epicureanism. Although fundamentally different on many philosophical issues, both Stoics and Epicureans appeared to agree that all entities (animate and inanimate) are nothing but matter. ² According to both Stoics and Epicureans, neither death nor corpses were to be feared, as death is simply a change or rearrangement of matter. These philosophical positions facilitated the demystification of corpses and offered the required cultural foundations for the introduction of cadaveric dissection.

The rise and fall of anatomical dissection

Under the influence of these emblematic philosophical figures, Herophilus and Erasistratus commenced their scientific work in Alexandria, attempting to translate philosophical inquiries into concrete and testable scientific problems that were addressed through anatomical dissection. The extensive studies on animals, conducted by Greek natural scientists, had already demonstrated the incomparable value of first-hand observation in scientific analyses. Dissection of animals had been previously performed in ancient Greece (i.e. by Alcmaeon of Croton and Aristotle). Nevertheless, there is no historic account that human dissections had ever been conducted by Greeks or Egyptians for scientific reasons. Important knowledge had already been acquired through the long history of mummification in Egypt, which also had, to a certain extent, relieved the religious fear of the corpse. ²² Furthermore, on ethical grounds, the mummification in Egypt had already created a ‘legitimating precedent’ for the introduction of cadaveric dissection. ²³ Perhaps this interplay of Greek and Egyptian civilizations in Alexandria, assisted by the determination of Ptolemy I and II to make their city a scientific frontier and cultural centre of the world, facilitated the initiation and performance of revolutionary human anatomical studies by the two Hellenistic researchers.

Notably, during the reign of the two Ptolemies, executed criminals were systematically sent to Herophilus and Erasistratus’s labs for dissection. According to historical accounts, Herophilus and Erasistratus performed, under royal patronage, hundreds of anatomical dissections on animals and condemned criminals. ¹¹

There is also an ongoing historical discussion concerning whether human vivisection had also been performed in Alexandria by the two physicians. ¹¹ Although no unequivocal historical consensus exists, Celsus implied that Herophilus and Erasistratus acquired supreme anatomical knowledge ‘opening men while still alive, observing parts before nature had concealed their position, colours, shape’. ¹¹ Yet, Galen, who remains the main historical source for the treatises of the two Greek physicians, albeit expressing abundantly his polemical fervour (especially towards Erasistratus’s physiological theories), never mentioned of either of them having performed vivisection. ¹⁰ According to historians of science, no consistent written evidence exists that human vivisection had ever been practiced in the ancient world. Many scholars attribute the rumours of vivisection to defamation attempts, which have been attributed to scientific or political enemies. ² In any case, after its introduction, human anatomical dissection was performed by these two physicians for almost 40 years. Because it was generally disapproved by the rest of the scientific community, it ceased completely (at least in the Western world) for almost 18 centuries until the Renaissance, when it was restored by Andreas Vesalius (1514 to 1564 AD). ²

The treatises of Herophilus of Chalcedon

According to Galen, Herophilus’s original anatomical discoveries expanded to almost every anatomical system of the body. ¹⁰ His descriptions of the liver, arteries, veins, pancreas, reproductive systems, digestive system and lymphatic system are a few of the reported results of his dissection studies. ²⁴ His fundamental observations of the nervous system are considered unparalleled for his time. In particular, it is the discovery of the confluence of the sinuses, named Torcular Herophili, to which he owes the perpetuation of his name. ¹²

Among the noteworthy discoveries attributed to Herophilus are the following:

○ The differentiation between arteries and nerves. Before Herophilus’s time, nerves, tendons, arteries and veins had been jointly referred to as ‘cords’. He provided the first detailed description of their structure and discussed their functional differences. Aristotle, for instance, believed that arteries carried pneuma, which was thought to mediate nerve impulses. Herophilus was the first to attribute to nerves the function of conducting nerve impulses. ¹¹

The treatises of Erasistratus of Chios

Similar to the disclosures of Herophilus, most of the fragments of Erasistratus’s numerous works survived through the writings of Galen. ¹⁰ Galen, although generally hostile to Erasistratus’s medical theories, praised Erasistratus’s anatomical accuracy. ¹⁰ Erasistratus (Figure 2) was mostly renowned for his physiological studies, especially on the heart, where he accurately elucidated the function of heart valves and the irreversibility of blood flow through them. ²⁷ He offered an accurate account of the heart as a mechanical pump and studied the vascular system, distinguishing veins from arteries. Furthermore, his studies involved medical topics such as hygiene, paralysis and fevers. ¹⁵ Although he was proficient in anatomy, his work in physiology was more influential. Philosophically, he denounced ‘hidden’ causes of phenomena and attempted their interpretation based on the observation of natural interactions imbued by physical laws. ¹³ In this regard, he developed a mechanistic interpretation of the function of the body, which was underwritten by dissection and experimentation on the principle that ‘matter moves towards that which is being emptied’. ²⁸ For example, air must enter the lungs after exhalation, as there is a potentially empty space that must be filled. Air (pneuma) has a critical role in Erasistratean and Hellenistic physiology. ²⁹ OPEN IN VIEWER

OPEN IN VIEWER

Figure 2.

Erasistratus discovers the cause of the illness of Antiochus. Painting by Jacques-Louis David (1774). École nationale supérieure des beaux-arts, Paris.

Among the noteworthy discoveries attributed to Erasistratus are the following:

He appraised the brain as the seat of consciousness and controlling centre of the body. ¹³

Discussion

Many theoretical pursuits of modern neuroscience find their origin in the scientific and philosophical accomplishments of Hellenistic neuroscience. The treatises of Herophilus and Erasistratus illustrate the first historically documented systematic attempts to unravel crucial issues concerning the origin of neural processes and the cause of neurological diseases. The contribution of these scientists in the development of innovative concepts about the faculties of mind, the structure and function of the brain, their original methodological approach, and their highly accurate inferences of neural processes laid the foundation of brain sciences. Beyond their accurate neuroanatomical descriptions of the brain, cranial nerves, meninges, dural sinuses and ventricles, these physicians introduced a rationalistic approach of neurologic disease to the medical practice. Furthermore, they acknowledged the hierarchical superiority of the brain and attempted for the first time in scientific history to link neuronal function to specific anatomical structures, undertaking the first documented endeavour towards localisation in brain studies. ¹⁶ More than this, through their empirical investigations, grounded in the observation of what actually constitutes the mental processes, they pursued the exploration of the self-conscious individual in a particular social and cultural environment. ³⁰

The legacy of Greek philosophy and the intellectual impetus of Hellenistic Alexandria of the 3rd-century BC shaped the course of history of many scientific fields beyond neuroscience. In principle, Hellenistic culture was uniquely occupied with foundational issues of methodology, and during this era, science evolved as a generalised cultural phenomenon of critical investigation, explanation, argumentation and validation of reasoning in the face of vibrant social criticism. ³ Through the work of scientists in the Hellenistic era, the interrelation of aim and method, as a means to improve our understanding of nature, becomes evident in the broader scientific environment—particularly in the fields of medicine and brain sciences. ¹² This remarkable scientific flourishing in the 3rd-century BC poses significant questions: What are the unique circumstances in the Hellenistic Alexandria of the 3rd-century BC that allowed the conception of such extraordinary scientific research? What might have been the cultural and socio-political interplays that enabled the introduction of revolutionary scientific techniques, such as the establishment of anatomical dissection studies? Why, after the monumental discoveries of Herophilus and Erasistratus, did neuroscientific research degrade so abruptly?

According to science historians, a wide spectrum of contributing factors may have resulted in the Hellenistic era’s rise in pioneering scientific practices, which deviated from the traditional approaches to classical Greek science. In contrast to the religious, moral and social taboos that had previously confined the Greeks, the scientific community of the Hellenistic period dared to contravene entrenched beliefs and cultural habits. In respect to the anatomical dissection, for example, the act of cutting through human skin and into the human body for heuristic and scientific purposes would had been obscene in classical Greek societies. In fact, according to many ancient Greek civil and sacred laws, human corpses were considered sources of pollution for all who came into contact with them or stood in relation or kinship to them. ² Greek historiography, poetry and drama also resonated with the perversion and the perilous impurity of the contact with corpses, which would inflict divine and civic penalties on both the individual and the community. ²

Although strong connections exist between the Hellenistic and classical Greek culture, Alexandria during the 3rd-century BC provided a new and intellectually liberated environment, where not only Greek but also Macedonian and indigenous Egyptian populations converged to create a common cultural identity. ⁶ Although a Greco-Macedonian surface was imposed on Egypt, this surface sought to create a unifying tradition. The Ptolemaic emphasis on Greek culture, asserted by the establishment of the Musaeum and the Great Library of Alexandria, indicated the political aspiration to enforce a Greek tradition in Alexandria. ⁶ It was a strategy for political control, which ensured not only Egyptian submission but also the cultural prevalence of the Ptolemaic dynasty in Egypt. ³¹ In this society, the converging cultural currents were still allowed to survive through progressive and dynamic interactions. The political motives expressed in the Ptolemaic Alexandria had mainly descended from Alexander the Great’s policies of cultural fusion. ³

Notably, the glorious Musaeum and the Great Library of Alexandria reflect the intention of Ptolemies to implement a socio-political leadership that was subserved by cultural imperialism. This aspiration of the Ptolemies to emphasize their leadership applied not only in Egypt but also to the Greeks. The political goal of the Ptolemies in the 3rd-century BC was the establishment of a cultural superiority over the Greek mainland cities. ⁶ Eventually, the power and reputation of Alexandria exceeded the fame of Athens, and, with the intention of cultural submission, the cultural and conservative taboos of Greek communities were challenged.

Thus, Alexandria became a new frontier city where customary Greek beliefs were no longer considered intrinsically superior. ² Perhaps the liberation from old taboos and religious prejudice, the cultural intermingling in Alexandria and the abundant political support for scientific research facilitated the radical thinking and scientific production during the Hellenistic era. Furthermore, the unique and short historical circumstances allowed for the performance of anatomical dissections. Through their remarkable skills of observation and scientific reasoning, Herophilus and Erasistratus made unique anatomical and physiological discoveries during their lifetimes.

The work of these two Greek physicians has been little appropriated by historians and had remained, until recently, neglected by the neuroscientific community. According to historical sources, some circumstances that may account for this could be traced back to the social and political upheaval that followed during the late Ptolemaic period. Although the Ptolemaic dynasty officially ended with Cleopatra’s suicide in 30 BC, after her naval defeat by Rome at Actium in 31 BC, Ptolemaic Egypt had already since the 2nd-century BC been severely impacted by ethnic tensions, administrative corruption, succession wars, burdensome state taxation, revolts against the Ptolemaic rule, famine and rural depopulation. ³² The Ptolemaic economy was almost completely agriculturally dependent upon the Nile flooding. During the reign of the later Ptolemies, a documented, prolonged drought and Nile failure are considered to have affected the intrastate conflicts in Egypt and the interstate warfare with the great Near Eastern Seleukid Empire. ³² The Third Syrian War (246 to 241 BC) between the Seleucid and Ptolemaic empires and the unsteady political situation shifted the political interests and support, dramatically impairing scientific research and eventually lead to the expulsion of intellectuals from Alexandria. ⁸ In addition, the original works of Herophilus and Erasistratus, along with important works of other scholars of the Hellenistic period, were destroyed in the fire of the Great Library of Alexandria, only to be recited in the critical writings of Galen.^10,22 Eventually, in the domain of medicine, there was a turbulent controversy between the sects of Rationalists (also called Herophileans or Erasistrateans) and the opposing Empiricists. On ethical and epistemological grounds, the Empiricists claimed that human dissection was scientifically unnecessary and maintained that understanding causality was not a prerequisite for the practice of medicine. They developed their argument against dissection on the notion that the parts in the deceased have undergone alteration and, hence, cannot provide meaningful information concerning the living human body. ² Finally, the demise of anatomical studies and the ascendancy of empirical medicine in the following centuries led to an unfortunate and prolonged stagnancy in the field of brain sciences.

Concluding remarks

The present analysis of the works of Herophilus and Erasistratus and the unravelling of Hellenistic neuroscience has intended to explore the historical roots of some abiding neuroscientific inquiries (such as the exploration of conceptual activity and the elaboration of the physiological underpinnings of human intellect). Perhaps, if the doctrines of Herophilus and Erasistratus had been properly accredited and investigated in their time, the history of neuroscience could have unfolded differently. After the ephemeral scientific progress during the Hellenistic era, neural sciences stagnated, propagating the dichotomy between Rationalists and Empiricists as well as the dualism between encephalocentrism and cardiocentrism for almost 18 centuries. Many of the scientific theories and concerns raised by the scientists of the Hellenistic period would only be revisited during the Renaissance and post-Renaissance periods through the works of Leonardo da Vinci (1472 to 1519 AD), Andreas Vesalius (1514 to 1564 AD) and René Descartes (1596 to 1650 AD). ³³

In conclusion, the interpretation of Hellenistic neuroscience, as a socially entangled scientific activity, indicates that the approach to the history of science should, in every historical period, entail cultural discursivity. Modern neuroscience appears to be just as historically contingent as ancient science, encompassing philosophical and intellectual challenges, the emergence of new concepts, cross-scientific theoretical debate and dialogue and unique historical consequences in social, political and cultural contexts. Through the unfolding of the short history of Hellenistic neuroscience, we can witness some of the first milestone achievements in the field of neural sciences, which marked one of the most celebrated periods of science: the 3rd-century BC.