East Africa and India have recently been proposed as places of origin for leprosy, based primarily on the geographical mapping of sixteen single-nucleotide polymorphism subtypes (snps). When comparing these data with historical texts, however, obstacles become apparent for both interpretations. Large population movements, a lack of divergence date ranges for some snp subtypes, and the discovery of a second strain of leprosy further complicate the geography of the disease. Dated skeletons with snp subtypes and molecular data, along with the informed collaboration of historical evidence, are key to determining the place of origin for both leprosy species.
Leprosy was the scourge of ancient societies and continued to be a significant health problem in a number of countries until quite recently. A combination of early diagnosis and treatment with multi-drug therapy has greatly reduced the number of cases of leprosy worldwide, especially in the last twenty-five years. Today, nearly 83 percent of the more than 200,000 new cases reported annually are from three countries—India, Brazil, and Indonesia. Nevertheless, many Western countries have not yet been able to eradicate leprosy completely. In the United States, the appearance of three strains of M. leprae—snp subtypes 3K (nine cases), 3J (one case), and 3M (one case)—indicates that new cases continue to arrive from abroad. Another occasional source of infection is apparent contact with armadillos, ranging from Texas to Florida and Georgia. Hence, leprosy continues to remain a health concern even in developed countries. Employing a variety of methods—with attention to both historical sources and molecular data—this article examines the likely origins of leprosy, indicating what we can know about the spread of a disease that has social as well as medical consequences.1
Prior to 2005, India was widely accepted as the country of origin for Mycobacterium leprae primarily due to detailed descriptions of the progressive forms of leprosy in the Sushruta Samhita, an Indian medical text dating to c. 600 b.c. In 2005, Monot et al. greatly increased our understanding of M. leprae and our ability to map it geographically based on the discovery that four single-nucleotide polymorphisms (snps) correlated with general geographical regions consistent with an origin for M. leprae in either East Africa or India. In 2009, Monot et al. proposed an origin for M. leprae in East Africa (henceforth, the East African model) after comparing Brazilian and Indian genome sequences, allowing them to define sixteen snp-subtypes (1A–D, 2E–H, 3I–M, 4N–P). They proposed that the geographical locations of these subtypes were consistent with migration patterns of early humans and trade routes. snp-subtype 2H was the earliest in East Africa, leading to 2F in Iran and finally 1A in India. Subtype 2F would have evolved into 3K, leading to 3M in Europe. Since type 3 is associated with European populations, and only 3K was reported in China, it must have spread from either Iran or Turkey via the Silk Road, instead of via maritime routes from India to southern China (Figure 1).2
Weng et al. found that 3K was the most common type of M. leprae in both coastal and inland provinces of China, whereas subtypes 1D (seventeen cases) and 1A (one case) appeared only in the coastal provinces of Guangdong, Fujian, and Guangxi, and only snp type 2 (subtype unknown, 1 case) appeared in the autonomous province of Xinjiang. Based on these data, Weng et al. proposed that M. leprae could have originated in East Africa and spread to China via southern maritime routes mainly through Guangzhou in Guangdong province, a port of entry that likely dates to the Han dynasty (202 b.c.–a.d. 220). According to Paine, however, ports along the southern coast of China were importing goods as early as the eighth century b.c.3
Schuenemann et al. challenged the East African model after comparing five M. leprae samples from medieval skeletons with eleven modern samples that had longer branch lengths from accumulated substitutions. The authors calculated average distances between strains. Using a strict clock model, which assumes that all strains evolve at the same evolutionary rate, they calculated the most likely divergence date for the most recent common ancestor for all known M. leprae strains to have been 3,126 years ago, or 1114 b.c. (within a range of 4,562 to 1,975 years ago, or 2546 b.c. to a.d. 43). They also calculated a most likely date and date ranges for some snp subtypes. Subtype 3K was the oldest (782 b.c., 2157 b.c. to a.d. 389), followed by 3L (no date or range given) and 3I (a.d. 516, 35 b.c. to a.d. 908). Branch 1 (1D=a.d. 621, a.d. 46 to 1106; 1B=a.d. 810, a.d. 292 to 1246; 1A=a.d. 1317, a.d. 959 to 1612) and Branch 2 (2F=a.d. 735, a.d. 466 to 964) possibly diverged at the same time; the latest is branch 4 (4N=a.d. 1045, a.d. 558 to 1467; 4P, 4O=a.d. 1246, a.d. 842 to 1610). A most likely date or date range was not given for subtype 3J, 3M, 1C, 2E, 2G, or 2H. Schuenemann et al. proposed that these data supported an origin in India (henceforth, the Indian model). Additional evidence derived from a skeleton from India exhibiting lesions diagnosed as leprous, dating to c. 2000 b.c. This date is consistent with the earliest date in their date range for subtype 3K of 2157 b.c.4
Singh et al. discovered a second species that caused leprosy, Mycobacterium lepromatosis. Comparing a near-complete genome sequence of M. lepromatosis with that of M. leprae, they calculated a divergence time for the most recent common ancestor for all M. leprae strains as 3,607 years ago (1592 b.c.) with a range of 5,525 to 2,204 years ago (3508 to 187 b.c.). They also stated that subtype 3K was in a separate branch 0 from all other snp 3 subtypes.5
The most recent common ancestor for all known strains of M. leprae has never been found in any species. However, chimpanzees and some species of monkeys and Eurasian red squirrels (Sciurus vulgaris) are susceptible to M. leprae, and Eurasian red squirrels are also susceptible to M. lepromatosis. Hence, some researchers propose that M. lepromatosis and M. leprae diverged from their most recent common ancestor about 13.9 million years ago, when each acquired a new host, possibly different species of monkeys or apes, or even a rodent vector. Sometime around 1592 b.c. or 1114 b.c., or within the previously cited date ranges of 3508 to 187 b.c. or 2545 b.c. to a.d. 42, humans were probably first infected with M. leprae from contact with an infected animal, beginning the divergences of known snp types and subtypes. M. lepromatosis also reached humans in a similar manner at an unknown time and place as migrations and long-distance trade spread both species of leprosy around the world. This interpretation is consistent with both the East African and Indian models.6
Unfortunately, molecular studies have largely ignored the earliest historical data for the origin and spread of leprosy; they might have provided a framework to evaluate the strengths and weaknesses of each theory. One of the most effective methods to do so is to compare historical accounts of leprosy with the geographical distribution of each snp subtype and molecular data from the earliest dated skeletons in each region. This strategy not only helps to verify or refute the accuracy of the date ranges for each strain of M. leprae, but it also identifies gaps in the molecular data, which can be a factor in the evaluation of the earliest skeletons diagnosed with leprosy but not verified molecularly. Molecular analysis of ancient skeletons is an expensive process, and dna is often too degraded in ancient skeletons to confirm a case of leprosy. For these reasons, many of the earliest skeletons diagnosed with leprosy are still untested.
This review of the historical and molecular data raises the possibility that M. leprae did not originate in either India or East Africa but somewhere else, like Myanmar. It also reveals two obstacles in determining a place of origin and spread of M. leprae. Population migrations throughout the centuries were more complex than the previously cited molecular studies suggest. Hence, the sixteen snp subtypes alone are inadequate to map the origin and spread of M. leprae in some regions. However, snp variable number tandem repeat (snp vntr) genome sequencing has been used to differentiate earlier from later versions of the same snp subtypes, though only with caution because the reliability of this technique for this purpose has yet to be proven. This technique or another one is necessary to clarify this issue.7
A second obstacle to mapping the origin and spread of M. leprae is the recent discovery of M. lepromatosis. All of the earlier studies about the origin and spread of leprosy assumed that ancient medical texts describe only M. leprae, but since both species can develop into all forms of leprosy, and each species could have had a different country of origin, the study of these texts must proceed circumspectly. The use of both historical and molecular data is warranted.8
Leprosy, or Hansen’s disease, is a slow, progressive, and highly infectious chronic disease produced by the bacilli M. leprae and M. lepromatosis. M. leprae t-cell-mediated immunity typically protects more than 95 percent of a modern population, although this percentage varies by population to some degree, especially when first introduced. Seventeen years after the first person was infected with M. leprae on the island of Nauru in the South Pacific, 35 percent of the population was infected with it. M. lepromatosis may be even more virulent than M. leprae, since it has a shorter doubling time.9
The lack of detail in most of the ancient texts means that we can distinguish only the disfiguring features that developed during the later stages of lepromatous leprosy from other possible conditions; thickening of facial skin, hypertrophied lips and nose, pronounced wrinkles, and a yellow cast are also characteristics of leonine facies or lion face. Leprosy also removes facial hair (especially eyelashes and the lateral third of eyebrows), as well as the ears. When the eyes are infected, blindness sometimes follows. The absorption of the nasal bones typically makes the bridge of the nose collapse; further damage to the throat can result in a hoarse whisper. Concurrently, the hands and feet become swollen and deformed and lose sensation. Persistent injury, due to this lack of sensation, and the absorption of bone leads to a loss of fingers and toes. When ancient texts describe a condition with a combination of these facial disfigurements, concurrent with a loss of fingers or toes, lepromatous leprosy is undoubtedly the cause.10
The diffuse form of lepromatous leprosy is rarely discussed outside of Central America. Diffuse lepromatous leprosy uniquely invades the endothelial cells, typically leading to a vascular occlusion and cyanotic lesions; the resulting swollen or spotted appearance derives from an inadequate blood supply. These lesions can eventually become necrotic, as evidenced by ulceration and discoloration from gray to black. They are most common on the extremities but occasionally spread to the chest and back. When first discovered in Mexican patients, the close association between M. lepromatosis and diffuse lepromatous leprosy, determined solely on the basis of molecular data, was attributed to M. lepromatosis as the root cause and M. lepromatosis the derivative within this region. A later study comparing historical records and molecular data, however, showed that both species arrived on European ships, illustrating the importance of comparing detailed historical accounts with molecular data. Although both species of leprosy can develop into all of the various forms, M. lepromatosis seems responsible for the presence of diffuse lepromatous leprosy more often than does M. leprae, though in some populations, M. lepromatosis develops into only standard forms of leprosy.11
Osseous leprous lesions, which typically appear in the later stages of lepromatous leprosy, are also important in mapping the spread of the disease. Møller-Christensen noted three pathological changes to facial bones: endonasal inflammation, atrophy of the anterior nasal spine, and atrophy and recession of the alveolar process of the maxilla confined to the incisor region. Endonasal inflammatory changes, together with one or both of the other two symptoms, were necessary for a diagnosis of facies leprosa (Bergen syndrome or rhinomaxillary syndrome), but facies leprosa alone does not confirm leprosy; some conditions—syphilis, tuberculosis, leishmaniasis, and cancer—can mimic it.12
According to Møller-Christensen, a relatively firm diagnosis of leprosy was possible when facies leprosa was accompanied by tibiae and fibulae exhibiting bilateral and symmetrical periostitis and vascular grooves (transverse striations usually on the distal third of both bones), but a reasonably certain diagnosis also required changes in the bones of the hands and feet, consisting of bilateral but rarely symmetrical diaphyseal remodeling. In the hands, the terminal phalanges erode to points due to concentric resorption, presenting a tapered appearance beginning at the distal end of a bone. Resorption continues proximally but rarely extends to the metacarpal; eventually, only stumps may remain. In the feet, bone absorption typically begins in the metatarsophalangeal joints at, or near, the distal end of a metatarsal; the diaphysis gradually thins, sometimes becoming knife-shaped, until a fine, conical needle of bone appears at the distal end.13
Frostbite, diabetes mellitus, psoriatic arthritis, and pyogenic osteomyelitus caused by trauma or ulceration can mimic osseous leprous lesions in the hands and feet. Thus, the combination of facial lesions and bilateral lesions in extremities is required to identify leprosy. The importance of this check on diagnoses is illustrated by a skeleton diagnosed with leprosy from burial 11 at the site of Dryburn Bridge in Scotland, c. 2000 to 1600 b.c. The skeleton exhibited osseous lesions consistent with facies leprosa, but neither hands nor feet survived, making a diagnosis impossible. This individual, however, was only six-to-eight years old; such extensive facial lesions in young children lacks a medical parallel. Instead, bone absorption is typically confined to the incisors. Furthermore, osseous leprous lesions in children usually arise in endemic populations. In this case, no evidence exists to suggest that leprosy was endemic. Tuli noted that osseous lesions from tuberculosis appear early in life, including facial lesions, developing in the first three decades. Furthermore, this Scottish skeleton tested positive only for Mycobacterium tuberculosis, which is consistent with the lesions.14
Møller-Christensen’s observations and caveats have stood the test of time, widely cited in the paleopathology literature. Most recently, as a case in point, Donoghue et al. stated, “A clear diagnosis of leprosy based solely on paleopathology can be made only if the typical facial changes are found in combination with atrophy and truncation of the fingers and toes.”15
The argument that leprosy is mentioned in the Atharva Veda is controversial. The Atharva Veda is one of four vedas; based on linguistic and archaeological evidence, it could date as late as 500 b.c. The word for leprosy appears in the Charak Samhita, c. 800 b.c., but without any mention of symptoms. By c. 600 b.c., the Sushruta Samhita described the various forms of leprosy in detail. The most extreme form exhibits a “contraction of the skin, local anesthesia, a copious flow of perspiration, swelling, and piercing or cutting pain in the affected part, together with a deformity of the limbs and hoarseness,” “falling off of fingers,” “sinking of the nose and ears,” and “redness of the eyes.” The detail of the description suggests that it had been fairly common in parts of India at least and under observation for a considerable period, which is consistent with the leprosy mentioned in the Charak Samhita 200 years earlier. No historical evidence exists for leprosy in India before 800 b.c.16
Individual 1997-1 from Balathal, India (c. 2000 b.c.), and nine additional skeletons from Harappa, India (c. 1900 to 1300 b.c.), have been diagnosed with leprosy, but none of them appear to have undergone molecular testing. According to Robbins et al., Individual 1997-1 exhibits osseous lesions consistent with facies leprosa or with tuberculosis, as well as vertebral ankylosis, which also is associated with tuberculosis. Nonetheless, Robbins et al. conclude that since this individual lacks other classical pathognomonic changes associated with tuberculosis, leprosy was a likely cause of the facial lesions, but in the process, they fail to exercise this same standard for leprosy. As previously noted, a definitive diagnosis of leprosy requires not only pathognomonic changes to the face, which it exhibited, but also changes to the extremities, which it lacked. Facial lesions and vertebral ankylosis more properly pertain to tuberculosis. Furthermore, Individual 1997-1 also exhibits anterior wedging on the C4-C7 and possibly L3-L5 vertebrae, which also imply tuberculosis. Hence, no reason exists to prefer a diagnosis of leprosy over tuberculosis.17
Robbins Schug et al. identified an additional nine individuals from Harappa, India (c.1900–1300 b.c.), with osseous lesions consistent with leprosy, but eight had only cranial lesions. The ninth exhibited some postcranial lesions but none unique to leprosy, allowing for a diagnosis of tuberculosis for all of them, especially since three other skeletons exhibited lesions consistent with only tuberculosis. Thus, until these skeletons receive molecular testing, they should be considered probable cases of tuberculosis. Finally, although some of these skeletons might date earlier than a most likely date of 1592 b.c., all of them are older than a most likely date of 1114 b.c.18
Even if all of these individuals had only tuberculosis, M. leprae may still have originated in India. If the most recent common ancestor of M. leprae came from an animal vector around 1114 b.c., and subtype 3K diverged around 782 b.c., it must have infected a number of individuals before doing so. Hence, it would be consistent with M. leprae appearing in the Charak Samhita, around 800 b.c., leading to its detailed description in Sushruta Samhita in 600 b.c. Thus, the historical and most of the molecular data fit together well, but a major obstacle still stands in the way. The earliest snp subtype in India is 1D with a most-likely divergence date of a.d. 621 and date range of a.d. 46 to 1106. Therefore, either the most recent common ancestor and subtype 3K still exist in India but have not yet been found or both strains once existed but have since disappeared, emphasizing the need for molecular testing of ancient skeletal remains.
The possibility remains, however, that instead of describing M. leprae, as previous studies assumed, the ancient texts describe M. lepromatosis. A condition similar to diffuse lepromatous leprosy has been reported in India, but not M. lepromatosis itself, though it has been found to the east in Myanmar, as has M. lepraesnp type 3 (subtype unknown). Moreover, no publication appears to mention testing for M. lepromatosis in India; both modern and ancient samples should be tested for both species of leprosy. Finally, these divergence dates may be inaccurate. If M. leprae is the strain mentioned in ancient texts, and if a representative sample of snp types exists in India, then snp subtype 1A or 1D must date before 800 b.c., allowing subtype 2H in East Africa to be the oldest snp.19
If M. leprae originated in East Africa as subtype 2H, it must have existed there centuries prior to 800 b.c. to allow it time to spread to Iran, where it diverged into 2F before spreading to India, where it diverged into 1A or 1D to become common enough for mention in the Charak Samhita (Figure 1). Major problems include a lack of historical, archaeological, and skeletal evidence for leprosy in East Africa or Iran so early, and no evidence exists for migrations or trade between East Africa and either Iran or India at that time. The Dutch exported Indian slaves to Africa, as well as other regions during the seventeenth century, and labor was still needed even after the abolition of slavery in the British colonies (1824). More than 1 million people from India, Pakistan, and Bangladesh immigrated to British East Africa in the final quarter of the nineteenth century alone. Thus, the snp subtypes found in East Africa may have arrived quite late. Furthermore, if subtype 2H is the most ancient subtype, it should have spread to Egypt (Figure 1). The ancient Egyptians made direct, possibly annual, trading voyages to East Africa as early as c. 3000 b.c. and no later than c. 2487 b.c. These voyages continued, with a few breaks, until sometime during the reign of Ramses III (1187 to 1156 b.c.). Furthermore, their ships carried human cargo, consisting of men, women, and children, back to Egypt. All of them would have provided an excellent opportunity to spread leprosy to Egypt throughout the centuries. If subtype 2H was the most ancient, it should have spread to Egypt, but no evidence exists for it. More sampling is necessary.20
The Middle East and Europe
None of the exhaustive studies of ancient Middle Eastern texts has discovered a condition consistent with leprosy before 300 b.c. The earliest proposed skeletal evidence is Individual 416 Ka (c. 2700 to 2300 b.c.), from Karataş, Turkey, which continues to be cited as a possible case of leprosy. According to Angel, Individual 416 Ka had injuries that were “the healed result of gangrene after a crush injury (as from a wooden disk cart wheel) or might be leprosy.” Besides the feet, the only other lesions on this skeleton are arthritis in the right hand and spine. As previously noted, extensive lesions in both feet but none consistent with leprosy anywhere else on a skeleton, especially the face, disqualifies a diagnosis of leprosy. Finally, since no lesions in the feet are unique to leprosy, these pathologies should carry the primary diagnosis of a crushing injury.21
Two skeletons from Europe are the next-earliest proposed leprosy cases. Individual 257 S20 from Hungary (c. 3780 to 3650 b.c.) was an eighteen-to-twenty-two-year-old male with osseous lesions consistent with facies leprosa. Additional pathologies include porosity of the occipital bone near the lambdoid suture; pitting on the mandible below the incisors; porotic vertebral bodies; periostitis and hypervascularization on the ribs; periostitis on the right tibia and fibula; periostitis on the diaphysis of both humeri and on the medial surface of both radii, affecting both ulnae at the distal end and both femurs; and a deep cavity on the plantar surface of the os metacarpal on the right side. The left orbital roof had cribra orbitalia. Four other individuals also had osseous lesions, but none was specific to a particular condition. Köhler et al. tested for both M. tuberculosis and M. leprae, but the results were negative. They preferred a diagnosis of leprosy because of the facial lesions and the periostitis on the right tibia and fibula. They rejected tuberculosis because of a lack of classic tubercular lesions in the postcranial skeleton and because tuberculosis rarely affects the cranium, except in childhood.22
The main obstacle to a diagnosis of leprosy in this case is a lack of any lesion in the postcranial skeleton unique to leprosy, and despite periostitis in the right tibia and fibula (there is no mention of the left elements), no vascular grooving is in evidence. As such, the condition that caused this periostitis was probably the same condition that caused the extensive periostitis on the other postcranial elements, which does not indicate leprosy. Although the authors are correct that tubercular facial lesions are rarer in this age group, by their own admission they sometimes occur. Furthermore, the age at which this individual first contracted this condition and the osseous facial lesions began to develop is unknown; this individual could have died as young as eighteen years old. Ortner notes a fifteen-year-old with similar tubercular facial lesions. Furthermore, the date of this skeleton (3780 to 3650 b.c.) is too early for both divergence dates—that of M. leprae at 1592 b.c. or 1114 b.c.—or even for either date range of 3508 to 187 b.c. or 2545 b.c. to a.d. 42.23
Moreover, leprosy is a condition that afflicts populations, but the next earliest evidence for leprosy is more than three millennia later. If this dating system is inaccurate, and this individual was infected with either leprosy species, he must have been infected by a local animal vector. No such evidence for an animal vector, however, exists in this region. Yet, given that M. tuberculosis is found in West Asia as early as 7000 b.c. and in Scotland by 2000 b.c., it could also have been in Hungary at this time. Furthermore, as Köhler et al. noted, Individual 257 S20 had cribra orbitalia on the left orbital roof, indicating a “susceptibility for infections, a weakened immune system or haematological disorders.” Such an individual would be prone to tuberculosis, which could cause the osseous facial lesions as well as periostitis on the ribs. Tuberculosis can also lead to hypertrophic osteoarthropathy, which, though rare, can cause extensive periostitis on postcranial elements. One possible reason for this individual testing negative for both leprosy and tuberculosis is that he had neither condition. Instead, all osseous lesions could have derived from a single extensive infection or hematological disorder. Periostitis can involve multiple bones if an infection is widespread; it is not fatal unless the infection spreads to organs. Thus, based on the above data, leprosy is improbable.24
The second case is an adult male from tomb 74, Casalecchio di Reno in Bologna, Italy (henceforth, Individual T74) (c. 400 to 300 b.c.), whose osseous lesions were diagnosed as leprous. With regard to facial pathologies, the authors state that Individual T74 had only endonasal inflammatory changes, without facies leprosa; his additional facial lesions lacked parallels for leprosy. Both feet showed conical and blade-shape resorption at the distal ends of the metatarsals and a cup-shaped at the proximal end of one metatarsal, but, as the authors note, on at least three of the metatarsals, resorption began at the tarsometatarsal joint, which lacks a parallel for leprosy. Periostitis is present in both the tibiae and fibulae bilateral but apparently without vascular grooving, and the bilateral periostitis on both femora also lacks a parallel for leprosy. Only two distal phalanges survived from the hands; one of them exhibits the beginning of resorption, which can be caused by a secondary infection. Thus, Individual T74 lacks any classical patterns of osseous leprous lesions, exhibiting numerous lesions inconsistent with leprosy.25
The next earliest evidence comes from Egypt, which has excellent preservation of both texts and human remains, as well as a rich medical tradition dating back as early as c. 2686 b.c. The evidence strongly suggests that leprosy did not exist in Egypt before the Ptolemaic period (323–330 b.c.), though two challenges to this notion have recently emerged. First, in 2002, Lechat stated, “In Egypt, Huspati (Horus-Den), a quasi-mythical Thinite king of the First Dynasty (c. 3500 b.c.), is reported in a papyrus dating from ±1500–1200 b.c. as having suffered from a disease whose signs are evocative of leprosy.” Lechat did not cite the primary evidence himself. Instead, he referred to a work by Scott in 1943, which cited an 1879 English version of Brugsch’s 1859 translation of Berlin papyrus 3038. Brugsch’s only mention of leprosy, however, comes in the sentence, “This is the beginning of the collection of receipts for curing leprosy.” Apparently, he translated one word to mean leprosy without any supporting evidence. Although Wreszinski’s translation of Berlin papyrus 3038 in 1909 describes a number of conditions, it describes neither leprosy nor any other condition that resembles it. No other Egyptian papyri mentions leprosy.26
Second, Ibrahim and Abdul-Kadir stated, “There are Egyptian records from 1350 b.c. of leprosy among Negro slaves from Sudan and Dafur.” This idea originated with Munro in 1879, based on Brugsch’s work, which maintained, without any additional evidence, that as early as Husapti’s reign, “negroes were already carriers of wood to the people of Egypt. They were already slaves to them, and this communication between the Egyptians and the negro races has always been kept up.” Munro’s conclusion—that “as the immigration of negroes from Northern Central Africa to Egypt would be infinitely more likely to cause the propagation of a chronic disease to the Egyptians than the mere inroads of the latter to carry such disease to that centre, …Egypt first received leprosy from the Soudan and Darfur”—is fallacious, leaving the earliest evidence for leprosy in Egypt to remain in the Ptolemaic period (323–330 b.c.).27
The search for the earliest evidence for leprosy there has been extensive, revealing a clear pattern. Direct sea trade between Egypt and both East Africa and India was well developed no later than the reign of Ptolemy Philadelphus (308–246 b.c.) with the earliest harbor at Myos Hormos (Figure 2). The earliest description of lepromatous leprosy is attributable to Straton of Alexandria, Egypt (c. 300 b.c.). West of Myos Hormos, the earliest Egyptian lesions consistent with leprosy belong to four crania and some disassociated phalanges from the Dakhleh Oasis, c. 200 b.c. These skeletons have yet to be tested molecularly, but another one (a.d. 300 to 450) with similar lesions from the Dakhleh Oasis, had M. lepraesnp type 3. Its skeletal variation, hair structure, mtdna markers, and isotopic analysis are consistent with Egyptians living near the Nile. According to Dzierzykray-Rogalski, the number of remains suggest that leprosy was either endemic in this part of Egypt or that this oasis had become a leper colony by 200 b.c. Molecular testing of the earliest skeletons for both M. leprae and M. lepromatosis, however, is still needed.28
Lucretius (c. 99–55 b.c.) stated that leprosy was found only along the Nile River in Middle Egypt, suggesting that it spread northward along the Nile. A generation later, Plutarch (a.d. 45–120) posited leprosy as originating in Greece during the time of Asclepiades of Bithynia (c. 40 b.c.). Pliny the elder (a.d. 23/4–79)—a military officer stationed in Europe and later an official in Gaul, Spain, and Africa—put leprosy’s origin in Italy within the lifetime of Pompeius Magnus (106–48 b.c.) after coming from Egypt. The earliest molecularly confirmed case of leprosy (type unknown) in the Mediterranean region is an individual, also infected with tuberculosis, from the first century a.d. in what is now Israel.29
Rufus of Ephesus (c. a.d. 98–117), who lived in present-day Turkey and spent time in Egypt, also described lepromatous leprosy. Patients had the symptomatic leontiasis or lion’s face, sunken cheeks, thickened lips, and a bad odor, as well as “livid and black raised areas, especially resembling bruises; some … located on the face, others on the arms, and still others on the legs. It also spreads to the back, chest, and stomach. At first these raised areas are not ulcerated, but later they ulcerate in the most hideous manner. This ulceration is accompanied by the swelling of the lips, by a decay so extensive that sometimes the ends of the fingers fall off, and the ulcers never completely heal.” Part of this description, such as the leontiasis, facial collapse, and missing finger tips, could only be lepromatous leprosy. But the livid (cyanotic) areas without ulcers and the black (necrotic) areas with ulcers are inconsistent with lepromatous leprosy, though they are consistent with diffuse lepromatous leprosy, which is most commonly caused by M. lepromatosis. Since these symptoms are prominent, at least in Egypt and possibly Turkey, diffuse lepromatous leprosy must have been a relatively common form of leprosy that has since disappeared there.30
Galen (a.d. 130–200), who was one of the most knowledgeable and cosmopolitan physicians of ancient times, grew up in Pergamon and studied in Smyrna, both in western Turkey, and served as personal physician to a number of emperors in Rome. He spent extended periods in Corinth, Greece, and Alexandria, Egypt, and traveled to Cilicia, Palestine, Crete, Cyprus, Lemnos, and Syria. He proclaimed leprosy to be rare in true Germany, which was east of the Roman border, as well as among the Mysians (northwestern Turkey), but endemic to Alexandria.31
Not long after Galen’s death, leprosy became more common. An individual from Devkesken 6 on the Ustyurt plateau of Uzbekistan (Figure 2) (a.d. 80 to 240) had snp subtype 3L, placing it chronologically between 3K (782 b.c., 2157 b.c. to a.d. 389) and 3I (a.d. 516, 35 b.c. to a.d. 908). Leprosy was endemic to the west, in Armenia, by a.d. 400; a small leprosarium had emerged there as early as a.d. 260. It was also endemic as far north as Constantinople during the reign of Consantius II (a.d. 337–361).32
Notwithstanding the generally accepted view that once leprosy spread to Italy, it spread throughout Roman Europe, no evidence confirms it. Donoghue et al., who reviewed the earliest proposed skeletal evidence for leprosy in Roman Europe, cited only one case outside Italy from the fourth century. A skeleton from Poundbury Camp, Dorchester, England, with only the lower ends of both tibiae and fibulae and both feet surviving, does not permit a definitive diagnosis of leprosy, especially since the foot lesions are not bilateral and bilateral vascular grooving does not appear to be present. A number of conditions could have caused these lesions. The earliest confirmed evidence for M. leprae in northern Europe comes from Essex, England. Individual GC96, with subtype 3I (a.d. 515, 35 b.c. to a.d. 908), dates between a.d. 415 and 545. However, Sr-isotope analysis suggests that Individual GC96 was originally from Denmark, although Germany and France are also possible.33
The earliest texts also indicate a late date for the spread of leprosy in Europe. In France, the Fifth Council of Orleans (a.d. 549) set out guidelines for the care of those with leprosy, using church funds; the Third Council of Lyon (a.d. 583) issued similar guidelines and restricted the movement of those afflicted.34
This lack of evidence for leprosy even pertains to Italy. Donoghue et al. note that only one possible case of leprosy is in evidence prior to the sack of Rome by the Visigoths in a.d. 410 —from Martellona, dating from the second to third centuries a.d., consisting of only the cranium of a four-to-five-year-old with facies leprosa. Based on its similarity in age and in the pattern of its facial lesions with the child from Scotland, the Martellona child probably had another condition, possibly tuberculosis.35
Leprosy first appeared in Italy around 106 to 48 b.c., but a century later, during the reign of Tiberius (a.d. 14–37), Celsus reported that leprosy was almost unknown in Italy. Furthermore, Galen (a.d. 130–200) makes no mention of leprosy in Italy. At its peak, Rome’s population was between 450,000 and 1,000,000 people. The large number of poor residents who lived in the city, in buildings as high as six stories and without plumbing, would have created a permanent reservoir for any infectious condition. These people were also most likely to have been malnourished, making them even less resistant to infectious pathogens. Nonetheless, not a single case of leprosy was ever reported in Rome. Furthermore, Rome had laws to protect slave owners who unknowingly purchased a slave with a pre-existing condition—whether it be a fever, tuberculosis, eyesores, or mental disorders—but leprosy receives no mention. In contrast, leprosy does receive explicit legal mention in countries where we know that the disease existed.36
Kjellström purports to offer evidence for leprosy in Rome. Citing Browne’s work of 1975, she wrote that leprosy “must have been considered a serious health problem since leprosaria were founded in Rome already in the 4th century.” Browne’s only evidence, however, was a citation by Mercier in 1915 claiming only that the first hospital in Rome, established in the fourth century, was sufficiently large to suggest the existence of earlier hospitals. But Browne says nothing about leprosy itself. This first hospital in Rome, constructed and run by Fabiola, provided the poor with free treatment for any condition. In spite of assumptions that lepers also received treatment there, no evidence for the presence of leprosy in Rome or anywhere else in Italy at this time is available. Not until Rothari, king of Lombardy (a.d. 643), enacted laws to expel lepers and seize their property is there any indication that leprosy was in Italy. Leprosy was either extremely rare in, or altogether absent from, Roman Europe, at least until the end of its run.37
Based on molecular and archaeological data, Donoghue et al. proposed that the Avars, a nomadic people from north of the Black Sea, either first brought leprosy, or re-transmitted it, to eastern and central Europe (including Hungary), eastern Austria, and Italy in the sixth century a.d. Since leprosy had spread as far as northwest Turkey before a.d. 200 and infected an individual in Uzbekistan between a.d. 80 and 240, it could have already spread to populations north of these locations and east of the Roman border. If Galen was right that leprosy (as subtype 3M) had spread so far north as the present Czech Republic, even if the disease was not endemic to Rome, it could have been brought across the Rhine with the first Germanic groups in a.d. 376, as well as by groups like the Alans farther south, when they crossed the Rhine in a.d. 406. If so, these continued invasions from the East, which were also migrations, may have also been waves of vectors, spreading subtype 3M to central and Western Europe, thereby explaining why the earliest evidence of endemic leprosy in Roman Europe roughly coincides with its end.38
snp subtypes 3I, 2F, and 2G are found in northern Europe. According to Economou et al., the distribution of these subtypes is consistent with direct trade between northern European countries and Constantinople via rivers in western Russia as well as the Black Sea. By the sixth century a.d., trade was vigorous at sites like Helgö, Sweden, where archaeologists uncovered exotic goods—a bronze Buddha from India along with eastern and western coins from the fifth and sixth centuries. Also, Individual GC96 in England, who was most likely from Denmark, had the earliest known example of subtype 3I (a.d. 415 and 545) with a likely divergence date of a.d. 515, diverging either in Denmark or along these trade routes. Furthermore, Eurasian red squirrels on Brownsea Island in the English Channel, in Scotland, and in Ireland are also infected with both M. leprae subtype 3I and M. lepromatosis, and probably have been for centuries. These data, and Rufus of Ephesus’ possible description of diffuse lepromatous leprosy, allow for the possibility that both species spread contemporaneously via these trade routes to England. Since M. leprae concealed M. lepromatosis, we need to test for both species.39
The earliest known examples of subtype 2F are from England, Denmark, and Sweden; the earliest of them dates between a.d. 1010 and 1160. Subtype 2F has a likely divergence date of a.d. 735 and a date range of a.d. 466 to 964, suggesting that it either diverged in Turkey, spreading northward and southward, or it diverged in Iran, spreading northward through Turkey to northern Europe. One case of subtype 2G in Sweden from a cemetery (c. a.d. 1130 to 1300) is the earliest known example, but no divergence date or date range is available. Since 2G has been found only in Sweden and Nepal, the most likely scenario is that it diverged between them, but this wide distribution of just two cases emphasizes the need for more sampling from and between these regions to determine which strain is the earliest.40
Apparent inconsistencies exist. The first is that since southern England and northern France received similar migrations of Scandinavians during the early medieval era, both subtypes 3I and 2F should be in northern provinces of France like Normandy, but 3M is the lone subtype reported in France. Monot et al.’s “Comparative Genomic and Phylogeographic Analysis” (2009), the sole repository of subtypes in France, allots them by country. If samples were listed by province within countries, patterns would become clearer. Based on the scenarios above, we would expect subtype 3I to have been restricted to northern Europe, but the close proximity of subtypes 3I and 4N in Morocco (Figure 2) suggests that 4N diverged from 3I in this region before spreading southward to western Africa, and then 4O diverged from 4N. Moreover, the distribution of subtypes in the Americas indicates that the Portuguese and Spanish brought subtype 3I and African slaves brought subtypes 4N and 4O. Subtype 4P diverged either in Brazil or Venezuela since it is absent from Africa (Figure 3). This is the first indication of a major flaw in the snp dating system because 4O and 4P were stated to have diverged at the same time (4O, 4P=a.d. 1246, a.d. 842 to 1610). If 4P diverged in the Americas, it did so approximately three centuries later than predicted; these dates need to be reviewed. The divergence dates may well be correct, however, meaning that 4O and 4P diverged concurrently somewhere else, like Spain or Portugal, and 4P migrated to the Americas but never to Africa or that 4P exists in Africa but inadequate sampling has yet to find it.
Sharma et al., discovered two strains of subtype 3I in the armadillos and humans of the southeastern United States, the 3I-2-v15 strain diverging from the 3I-2-v1 strain. Furthermore, red squirrels on Brownsea Island are infected with subtype 3I of virtually the same strain as that from medieval skeletons in both Denmark (Jorgen 625, a.d. 1293 to 1383) and England (SK2, a.d. 1268 to 1263), which is closely related to the strain of 3I in the United States. Even so, no evidence demonstrates that either Scandinavians or the English brought leprosy to the southern United States. However, leprosy in Canada may have arrived either with immigrants from Brittany or sailors from Normandy; it then traveled to Louisiana, probably with Acadian French settlers after their expulsion from Canada in 1755. Because northern France and southern England accepted Scandinavian migrants in the early medieval era, both countries should have a similar strain of subtype 3I. Furthermore, since the Portuguese imported French marines to Brazil between 1555 and 1700, some of them from Normandy when leprosy was still prevalent there, the subtype 3I strain in Brazil may also have come from France. Thus, the historical data not only allows for a different interpretation for the spread of subtype 3I to the Americas; it also illustrates another major hole in our molecular data. The people of Portugal and Spain were vectors for the spread of leprosy to many regions during their ages of discovery and colonization, but the snp subtypes in either country as well as their changes over time are still something of a mystery. The same is true for most of Asia.41
The earliest Chinese texts are problematical. The most ancient medical text is the Nei Ching. Because it was continually updated throughout the centuries, we do not know when leprosy entered into it. The earliest surviving text dates to a.d. 762, but Bodde dates the passage describing leprosy to the second or first century b.c. Skinsenes contends that leprosy is the reason why Po-Niu is described in the Lun Yu (c. 600 b.c.) as behind a screen when Confucius comes to visit, touching his hand through a window. The assumption is that Po-Niu was disfigured from chi; in later times, O chi was a name for leprosy, though it can refer to any “evil disease.” Numerous diagnoses are possible, including tuberculosis or nasopharyngeal carcinoma (a facial cancer relatively common in some Chinese groups). If Po-Niu’s face was disfigured from leprosy, his hands would also have been disfigured. Since the two men touched hands, Po-Niu probably was not afflicted with leprosy.42
A bamboo book taken from the tomb of Magistrate Hsi is widely considered to describe a case of leprosy, often dated to the latter half of the third century b.c. Leung, however, proposes that the passage in question could date as early as the fourth century b.c.: “The headman A of X village has brought in villager B, a rank-and-file commoner. His denunciation reads: ‘I suspect li (leprosy), and I have come along with him (to the Judicial Office).’ We interrogated B. His statement reads: ‘At the age of three, I suffered from sores on my head, and my eyebrows fell out; but the nature of the illness could not be determined. There is no other offence of which I am culpable.’ Then we ordered the physician C to examine him. His statement says: ‘B has no eyebrows. The bridge of his nose is gone, his nostrils are rotted, and when I lanced what is left of his nose, he did not sneeze. His elbows and knees down to the soles of both feet are defective and suppurating at one place. His hands have no hair (on the back). When I asked him to shout, his voice and breath were both feeble. It is leprosy.’”43
As previously noted, Monot et al. proposed that leprosy spread to China from the west via the Silk Road, which began at the city of Xi’an in Shaanxi Province and continued through Gansu Province (Figures 2 and 4). If so, early evidence for leprosy should exist in these provinces, but none does. Also, if the Silk Road was such an efficient conduit for leprosy, subtypes 2F, 3K, and 3L should be in northwestern China, especially since the western end of the Silk Road was at Samarkand in present-day Uzbekistan, where the only confirmed case is subtype 3L (a.d. 80 to 240), which is not found in China. Moreover, the Silk Road was not a road per se but a collection of unmarked and shifting paths roughly 3,600 km long, some of which passed through deserts and mountains. Travel by this route was so treacherous that merchants rarely took it all the way, preferring to trade goods with the nearest village or oasis, passing goods down the line. Hence, instead of a conduit, the Silk Road would have been more of a barrier for a slow-spreading condition like leprosy. Furthermore, the Silk Road’s peak period of use was between a.d. 500 and 800; the earliest evidence of trade on it between the west and China are Byzantine coins from Chinese graves dating to the sixth century a.d. Finally, leprosy appeared in the West centuries after it emerged in China.44
Much later, the medical text Lingnan weisheng fang (a.d. 1264) confined leprosy to only the southern provinces of Fujian, Guangdong, and Guangxi. The sixteenth-century physician Zhiwen stated that Fujian and Guangdong suffered from it the worst, and in the mid-seventeenth century, leprosy was still primarily associated with the provinces of Fujian, Jiangxi, Guangdong, and Guangxi. Houses for lepers arose primarily in Fujian, Jiangxi, and Guangdong provinces from the fourteenth through the nineteenth century.45
In 1894, Cantlie sent out questionnaires to physicians about the prevalence of leprosy and other diseases throughout China’s provinces and then traveled to the affected regions to treat those with the disease. He discovered leprosy to be clustered along the southern coast, especially in Guangdong and Fujian Provinces and among ethnic Chinese on Taiwan and the Hainan Islands. It was less prevalent in Guangxi, Jiangxi, and Zhejiang; it was so rare in the northern provinces that people there believed themselves to be immune to it. Northern Shandong Province was an exception. Leprosy existed there but not profusely (Figure 4). In 1906, Hutchinson noted a greater presence of leprosy in southern China but still not in northern China. He and Cantlie also noted leprosy at a few locations along the Yangtze River, but it must not have been widespread because in 1929, the Ministry of Public Health stated that leprosy had just begun to penetrate the Yangtze River basin and the northern banks of the Yellow River (Figure 4).46
The evidence indicates that leprosy first spread to southern China in the fourth or third century b.c. Molecular data show that 3K was most common in both coastal and inland provinces. The appearance of subtypes 1D (seventeen cases) and 1A (one case) only in the coastal provinces of Guangdong, Fujian, and Guangxi indicates that subtype 3K arrived first. These data are consistent with the proposed snp dating system.47
The earliest evidence of leprosy in Japan emerged during the Nara period (a.d. 710–784). The earliest known homes for lepers date to the Kamakura period (a.d. 1185–1333). From Japan, leprosy spread northward to Korea. A possible description of it dates to 1251 and the earliest detailed description to 1433. In 1445, it was endemic only to Jeju Island between South Korea and Japan. In 1897, Cantlie noted that the incidence of leprosy was low in the south and diminished to the north of Korea. Hence, the evidence is consistent with M. leprae spreading to southern China (3K, 1A, 1D) before moving to Japan (3K, 1A, 1D, 2) and then Korea (3K, 1A, 2).48
The historical, molecular, and skeletal data indicate that determining a place of origin for M. leprae is far more complex than suggested by the molecular data alone. Both historical texts and molecular data suggest that M. leprae spread to both China and Egypt probably via maritime routes at roughly the same time between the fourth and third centuries b.c. The earliest diagnosed skeleton with leprosy between India and China is from Noen U-Loke, Thailand (c. 300 b.c.), though without molecular confirmation. Historically and geographically, India best fits as a point of origin for M. leprae, but, as noted above, the recorded snp subtypes are all too late. The molecular data, however, may be incomplete as in China where only subtype 3K was originally reported until more extensive sampling by province discovered subtypes 1D and 1A in some of the maritime provinces. Thus, a similar method of geographically mapping samples in India by province and molecularly testing modern and ancient samples for both species of leprosy could clarify whether India was the point of origin for one or both of them. Testing for both species extensively could also reveal a point of origin for M. lepromatosis and determine whether M. leprae and M. lepromatosis spread together within certain ancient populations, such as from Egypt to northern Europe.
Additional modern and ancient sampling would also confirm or refine the snp dating system. A comparison of these data with historical records and the earliest dated molecular data from ancient and medieval skeletons seems to support the present dating system—especially when mapping the spread of leprosy from southern Egypt to northern Europe. But additional data, even in these regions, could confirm, modify, or refute this interpretation, as well as shed light on whether leprosy began spreading to Western Europe from Italy in the first century b.c. or whether it first arrived with eastern invasions and migrations when the Roman Empire began to crumble. Skeletal cases from India, dating as early as 2000 b.c., that tested positive for M. leprae and permitted subtypes to be determined, would confirm or refute the snp dating system and possibly determine a place of origin for M. leprae. Without such confirmation, none of the current evidence can confirm that either species of leprosy invaded India before 800 b.c.
In contrast to the case of India, no evidence suggests that East Africa was a point of origin for M. leprae. If East Africa were to have been the point of origin, the present snp dating system would have to be incorrect, or all recorded snp subtypes would have to be late arrivals from slavery and migration, requiring additional sampling in East Africa and along trade and migration routes both through Arabia (no cases recorded), Iran to the east, and Egypt to the north (presently one case of M. leprae [snp type 3]).
Typically, a place of origin is genetically diverse. The only country between China and Egypt that fits this description is Myanmar where snp types 1, 2, and 3 and M. lepromatosis have been found but no subtypes determined. Even if all of the subtypes were to be found in Myanmar, some of them could turn out to have been relatively recent arrivals. Because Chinese laborers carried leprosy to various countries in Southeast Asia during the nineteenth century, including Myanmar, we have to differentiate earlier from later subtypes in each country—for instance, the 3K that spread to China c. 400–300 b.c. from the 3K re-introduced there in the nineteenth century. Additionally, the direct voyages to the region that the Europeans had begun to undertake by the late fifteenth century could have introduced, or re-introduced, snp subtypes, possibly 2G, to the region. Although data that locate a point of origin for either leprosy species are lacking, dated skeletons with snp subtypes and current molecular data illustrate areas where critical information remains to be collected. Such research could ultimately lead to a definite point of origin or possibly two separate points of origin, as well as more accurate mapping of the initial migration of both species. Considering the impressive number of snp subtypes that have been mapped since 2009, most of these gaps in our knowledge could be filled in a relatively short period.49
World Health Organization, “Global Leprosy Update, 2016: Accelerating Reduction of Disease Burden,” Weekly Epidemiological Record, XXXV (2017), 501, 505 (Table 2); Joshua Lane et al., “Borderline Tuberculoid Leprosy in a Woman from the State of Georgia with Armadillo Exposure,” Journal of the American Academy of Dermatology, LV (2006), 714–716; Rahul Sharma et al., “Zoonotic Leprosy in the Southeastern United States,” Emerging Infectious Diseases, XXI (2015), 2127–2134.
For works that propose leprosy as originating in India, see Dharmendra, “Leprosy in Ancient Indian Medicine,” International Journal of Leprosy, XV (1947), 424–430; Johs Andersen, Studies in the Medieval Diagnosis of Leprosy in Denmark: An Osteoarchaeological, Historical and Clinical Study (Copenhagen, 1969), 10–45, 123; Mark, “Alexander the Great, Seafaring, and the Spread of Leprosy,” Journal of the History of Medicine and Allied Sciences, LVII (2002), 286–311; Marc Monot et al., “On the Origin of Leprosy,” Science, CCCVIII (2005), 1040–1042; idem et al., “Comparative Genomic and Phylogeographic Analysis of Mycobacterium leprae,” Nature Genetics, XLI (2009), 1282–1289.
Xiaoman Weng et al., “Molecular, Ethno-Spatial Epidemiology of Leprosy in China: Novel Insights for Tracing Leprosy in Endemic and Non Endemic Provinces,” Infection, Genetics and Evolution, XIV (2013), 361–368; Lincoln Paine, The Sea and Civilization: A Maritime History of the World (New York, 2015), 171–173.
Verena Schuenemann et al., “Genome-wide Comparison of Medieval and Modern Mycobacterium leprae,” Science, CCCXLI (2013), 179–183. In genetic divergence, bacteria, which are asexual, reproduce by dividing into two clones. When a mutation occurs, a single base pair in a dna sequence, known as a single nucleotide polymorphism, can be either neutral or adaptive. Both the ancestral strain (before mutation) and the divergent strain (with mutation) can still exchange genes by horizontal gene transfer—the movement of genetic material between two adjacent bacteria. As these strains become more and more isolated, gene flow between them correspondingly lessens and can cease altogether.
Pushpendra Singh et al., “Insight into the Evolution and Origin of Leprosy Bacilli from the Genome Sequence of Mycobacterium lepromatosis,” Proceedings of the National Academy of Sciences of the United States of America, CXII (2015), 4459–4464.
Mark, “Early Human Migrations (c. 13,000 years ago) or Post-Contact Europeans for the Earliest Spread of Mycobacterium leprae and Mycobacterium lepromatosis to the Americas,” Interdisciplinary Perspectives on Infectious Diseases, MMXVII (2017), 1–8; Xiang Han and Francisco J. Silva, “On the Age of Leprosy,” PLoS Neglected Tropical Diseases, VIII (2014), 1–8 [earlier interpretations for both species].
For an example of vntr typing see, Sharma et al., “Zoonotic Leprosy,” 2127–2134.
Mark, “Early Human Migrations,” 2 [both species produce all forms of leprosy].
Lalit Bhutani et al., “Leprosy,” Lancet, CCCXLV (1995), 697–703, 698–699; Arthur Aufderheide and Conrado Rodriguez-Martin, The Cambridge Encyclopedia of Human Paleopathology (New York, 1998), 149 [Nauru Island]; Xiang Y. Han et al., “A New Mycobacterium Species Causing Diffuse Lepromatous Leprosy,” American Journal of Clinical Pathology, CXXX (2008), 856–864 [virulence of M. lepromatosis].
Bhutani et al., “Leprosy,” 698–699; Mark, “Alexander the Great,” 288.
For a description and discussion of diffuse lepromatous leprosy and early theories about the evolution of M. lepromatosis, see, Han et al., “Analysis of the Leprosy Agents Mycobacterium leprae and Mycobacterium lepromatosis in Four Countries,” American Journal of Clinical Pathology, CXLII (2014), 524–532; Singh et al., “Insight into the Evolution,” 4463; for a revised interpretation, Mark, “Early Human Migrations,” 2–3, 6.
Vilhelm Møller-Christensen, “Evidence of Leprosy in Earlier Peoples,” in Don Brothwell and A.T. Sandison (eds.), Diseases in Antiquity (Springfield, Ill., 1967), 295–306, 300; Donald Ortner, Identification of Pathological Conditions in Human Skeletal Remains (San Diego, 2003; orig. pub. 1981), 268 [conditions that mimic facies leprosa].
Møller-Christensen, “Evidence of Leprosy,” 298–300.
Ortner, Pathological Conditions, 580 [psoriatic arthritis]; R. Ted Steinbock, Paleopathological Diagnosis and Interpretation (Springfield, Ill., 1976), 208–209 [other conditions]; Andrew Dunwell, “Cist Burials and an Iron Age Settlement at Dryburn Bridge, Innerwick, East Lothian,” Scottish Archaeological Internet Report, 24 (2007), 10, 18, 22–23, available at http://archaeologydataservice.ac.uk/archives/view/sair/contents.cfm?vol=24; Mauro Rubini and Paola Zaio, “Lepromatous Leprosy in an Early Medieval Cemetery in Central Italy (Morrione, Campochiaro, Molise, 6th–8th century AD),” Journal of Archaeological Science, XXXVI (2009), 2777 [cited as a case of leprosy]; Mary Lewis, “Infant and Childhood Leprosy,” in Charlotte Roberts et al. (eds), The Past and Present of Leprosy: Archaeological, Historical, Palaeopathological and Clinical Approaches (Oxford, 2002), 163–170, 163–164 [osseous lesions and endemic populations], 165 [bone absorption and incisors]; Surendra Mohan Tuli, Tuberculosis of the Skeletal System (New Delhi, 2010; orig. pub. 1991), 193.
For the continued relevance of Møller-Christensen’s observations, see Aufderheide and Rodriguez-Martin, Cambridge Encyclopedia of Human Paleopathology, 150–154; Ortner, Pathological Conditions, 265–271; Helen Donoghue et al., “A Migration-Driven Model for the Historical Spread of Leprosy in Medieval Eastern and Central Europe,” Infection Genetics and Evolution, XXXI (2015), 250–256, 251.
Gwen Robbins et al., “Ancient Skeletal Evidence for Leprosy in India (2000 B.C.),” PLoS ONE, Vol. 4, No. 5 (2009), 1–8, 1 [the Atharva Veda]; Michael Witzel, “Autochthonous Aryans? The Evidence from Old Indian and Iranian Texts,” Electronic Journal of Vedic Studies, VII (2001), 1–115, 5–6 [dating the Vedas]. For the Charak Samhita and history of leprosy in India, see Dharmendra, “Leprosy Indian Medicine,” 424–430; Mark, “Alexander the Great,” 301–302; Kaviraj Kunja Lal Bhishagratna (ed. and trans.), The Sushruta Samhita (Varanasi, India, 1963), II, 36–40.
For a description of osseous lesions for Individual 1997-1, see Robbins et al., “Ancient Skeletal Evidence,” 4–6; for anterior wedging, S. Ansari et al., “Pott’s Spine: Diagnostic Imaging Modalities and Technology Advancements,” North American Journal of Medical Sciences, V (2013), 404–411, 405.
Gwen Robbins Schug et al., “Infection, Disease, and Biosocial Processes at the End of the Indus Civilization,” PLoS ONE, Vol. 8, No. 12 (2013), 1–20.
For diffuse lepromatous leprosy in India, see, Singh et al., “Insight into the Evolution,” 4460; for snp type 3 in Myanmar, Matsuoka et al., “Genotypic Analysis,” 150, 152.
Markus Vink, “The World’s Oldest Trade: Dutch Slavery and Slave Trade in the Indian Ocean in the Seventeenth Century,” Journal of World History, XIV (2003), 131–177 [Dutch slavery]; Andrew Godley, “Migration of Entrepreneurs,” in Anuradha Basu et al. (eds), The Oxford Handbook of Entrepreneurship (New York, 2006), 601–610 [1,000,000 immigrants]; Mark, “The Earliest Sailboats in Egypt and Their Influence on the Development of Trade, Seafaring in the Red Sea, and State Development,” Journal of Ancient Egyptian Interconnections, V (2013), 28–37, 35–36 [3100 b.c.]; idem, “Notes on Mediterranean and Red Sea Ships and Ship Construction from Sahure to Hatshepsut,” Journal of Ancient Egyptian Interconnections, VI (2014), 34–49 [2487 b.c. and later trade].
Mark, “Alexander the Great,” 294–295 [review of ancient texts]; J. Lawrence Angel, “Appendix: Human Skeletal Remains at Karataş in Mellink,” in Machteld Mellink and idem (eds.), “Excavations at Karataş-Semayük and Elmali, Lycia, 1969,” American Journal of Archaeology, LXXIV (1970), 245–259, 256; Anne Stone et al., “Tuberculosis and Leprosy in Perspective,” American Journal of Physical Anthropology: Supplement, CXL (2009), 66–94, 81 [cited as possible case of leprosy].
Kitti Köhler et al., “Possible Cases of Leprosy from the Late Copper Age (3780–3650 cal b.c.) in Hungary,” PloS ONE, XII (2017), 1–25, 10–12.
Ortner, Pathological Conditions, 253, Figure 10-42.
Robbins Schug et al., “Infection, Disease, and Biosocial,” 3 [M. tuberculosis 7000 b.c.]; Köhler et al., “Leprosy from the Late Copper Age,” 6, 12 [cribra orbitalia]; Daniel Wilner, Radiology of Bone Tumors and Allied Disorders (Philadelphia, 1982), II, 1809 [hypertropic osteoarthropathy].
Valentina Mariotti et al., “Probable Early Presence of Leprosy in Europe in a Celtic Skeleton of the 4th-3rd Century BC (Casalecchio di Reno, Bologna, Italy),” International Journal of Osteoarchaeology, XV (2005), 311–325, 313 [date], 315–319 [description of lesions]; Donoghue et al., “Migration-Driven Model,” 251 [cited as possible leprosy].
Mark, “Alexander the Great,” 294–295 [no evidence for leprosy before the Ptolemaic period]; Michel Lechat, “The Palaeoepidemiology of Leprosy: An Overview,” in Charlotte Roberts et al., (eds.), The Past and Present of Leprosy: Archaeological, Historical, Palaeopathological and Clinical Approaches (Oxford, 2002), 158; Harold Scott, “The Influence of the Slave-Trade in the Spread of Tropical Disease,” Transactions of the Royal Society of Tropical Medicine and Hygiene, XXXVII (1943), 181; Heinrich Brugsch, A History of Egypt under the Pharaohs (London, 1879; orig. pub. in French 1859), I, 58; Walter Wreszinski, Der grosse medizinische papyrus des Berliner museums (Pap. Berl. 3038) (Leipzig, 1909); Bayard Holmes and Peter Kitterman, Medicine in Ancient Egypt: The Hieratic Material (Cincinnati, 1914) [no mention of leprosy in any cited papyrus]; John F. Nunn and Eddie Tapp, “Tropical Diseases in Ancient Egypt,” Transactions of the Royal Society of Tropical Medicine and Hygiene, XCIV (2000), 147–153 [no mention of leprosy].
Sharaf Ibrahim and Abdul-Hamid Abdul-Kadir, “Childrens Orthopaedics in the Tropics,” in Michael Benson et al. (eds.), Children’s Orthopaedics and Fractures (New York, 2010; orig. pub. 1994), 185; William Munro, Leprosy (Manchester, 1879), 8.
Mark, “Alexander the Great,” 285–311 [Egyptian medicine, Ptolemaic trade, and earliest evidence of Egyptian leprosy]; Tadeusz Dzierzykray-Rogalski, “Paleopathology of the Ptolemaic Inhabitants of Dakleh Oasis (Egypt),” Journal of Human Evolution, IX (1980) 71–74 [skeletons c. 200 b.c.]; Joseph Molto, “Leprosy in Roman Period Skeletons from Kellis 2, Dakhleh, Egypt,” in Roberts et al., (eds.), Past and Present of Leprosy, 179–192 [skeleton a.d. 300–450].
Titus Lucretius Carus (ed. Adolphus Brieger), De rerum natura (Lipsiae, 1894), 201 [6.1114-15]; Plutarch (ed. Eric Warmington; trans. Edwin Minar, Jr.), Plutarch’s Moralia (Cambridge, Mass., 1969), 187 [8.9.731.1B]; Pliny (ed. George Goold; trans. William Jones), Natural History (Cambridge, Mass., 1980), VII, 270–271 [26.5.7-8]. For Pliny’s life, see M. C. Howatson and Ian Chilvers, The Oxford Companion to Classical Literature (New York, 1993), 431–432. Carney Matheson et al., “Molecular Exploration of the First-Century Tomb of the Shroud in Akeldama, Jerusalem,” PloS ONE, IV (2009) 1–13.
Mark, “Alexander the Great,” 304–305 [discussion of this passage]; Oribasius (ed. and trans. Ulco Cats Bussemaker and Charles Daremberg), Collectio medica (Paris, 1862), VI, 63–64 [Greek translation into English by author].
Howatson and Chilvers, Oxford Companion, 233–234 [Galen’s life]; Galen, “Ad Glauconem or a Method of Medicine to Glaucon,” in Ian Johnston (ed. and trans.), Galen: On the Constitution of the Art of Medicine; The Art of Medicine; A Method of medicine to Glaucon (Cambridge, Mass., 2016), 321–559, 555.
Alexandra Buzhilova, “The Geography of Leprosy in the Russian Empire: Historical Evidence for the Dissemination of the Disease,” in Roberts et al., (eds.), Past and Present of Leprosy, 123–133, 127 [Armenia]; Soren Blau and Yagodin Vadim, “Osteoarchaeological Evidence for Leprosy from Western Central Asia,” American Journal of Physical Anthropology, CXXVI (2005), 150–158, 153 [date]; G. Michael Taylor et al., “Mycobacterium leprae Genotype Amplified from an Archaeological Case of Lepromatous Leprosy in Central Asia,” Journal of Archaeological Science, XXXVI (2009), 2408–2414, 2413 [subtype 3L]; Timothy Miller and John Nesbitt, Walking Corpses: Leprosy in Byzantium and the Medieval West (London, 2014), 27 [Constantinople]. See also Susan Holman, “Healing the Social Leper in Gregory of Nyssa’s and Gregory of Nazianzus’s ‘περὶ φιλοπτωχίας,’” Harvard Theological Review, XCII (1999), 283–309.
Roberts and Keith Manchester, The Archaeology of Disease (Ithaca, 1997; orig. pub. 1983), 147 [leprosy in Roman Europe]; Donoghue et al., “Migration Driven Model,” 251; Rachel Reader, “New Evidence for the Antiquity of Leprosy in Early Britain,” Journal of Archaeological Science, I (1974), 205–207 [Poundbury skeleton]; Sarah Inskip et al., “Osteological, Biomolecular and Geochemical Examination of an Early Anglo-Saxon Case of Lepromatous Leprosy,” PloS ONE, X (2015), 1–22.
Agnes Lambert, “Leprosy: Past and Present II,” Nineteenth Century: A Monthly Review, XVI (1884), 467–489, 468–469.
Donoghue et al., “Migration Driven Model,” 251; Mauro Rubini et al., “Paleopathological and Molecular Study on Two Cases of Ancient Childhood Leprosy from the Roman and Byzantine Empires,” International Journal of Osteoarchaeology, XXIV (2014), 570–582, 573.
Aulus Cornelius Celsus (ed. T. Page; trans. Walter Spencer), De medicina (Cambridge, 1935), I, 342–343 (3.25.1–3); Glenn Storey, “The Population of Ancient Rome,” Antiquity, LXXI (1997), 966–978; Mortimer Wheeler, Roman Art and Architecture (New York, 1996), 129 [apartment buildings]; Lechat, “Palaeoepidemiology of Leprosy,” 157–162, 158 [Roman law]; Mark, “Alexander the Great,” 308–309 [laws in India and Egypt].
Anna Kjelleström, “Possible Cases of Leprosy and Tuberculosis in Medieval Sigtuna, Sweden,” International Journal of Osteoarchaeology, XXII (2012), 261–283, 262; Stanley Browne, “Some Aspects of the History of Leprosy: The Leprosie of Yesterday,” Proceedings of the Royal Society of Medicine, LXVIII (1975), 485–493, 486; Charles Mercier, Leper Houses and Mediaeval Hospitals: Being the Fitzpatrick Lectures, Delivered Before the Royal College of Physicians, London, 5th and 10th November, 1914 (London, 1915), 4; Timothy Miller, “From Poorhouse to Hospital,” Christian History Magazine, CI (2011), 16–23 [Fabiola]; Lambert, “Leprosy: Past and Present II,” 468 [Rothari].
Donoghue et al., “Migration Driven Model,” 262 [Avars], Table 1 [Czech Republic]; Barry Cunliffe, Europe Between the Oceans, 9000 BC–AD 1000 (New Haven, 2008), 413–421 [invasions and population migrations].
Christos Economou et al., “Ancient-DNA Reveals an Asian Type of Mycobacterium leprae in Medieval Scandinavia,” Journal of Archaeological Science, XL (2013), 465–470, Figure 2 [trade routes]; Cunliffe, Europe Between, 435 [Helgö]; Charlotte Avanzi et al., “Red Squirrels in the British Isles are Infected with Leprosy Bacilli,” Science, CCCLIV (2016), 744–747; Mark, “Early Human Migrations,” 3, 5–6 [discussion of both species of leprosy in red squirrels].
Schuenemann et al., “Genome-Wide Comparison,” 179–183 [2F data]; Economou, “Ancient-DNA Reveals,” Table 1 [2G data].
Sharma et al., “Zoonotic Leprosy,” 2127–2134; Avanzi et al., “Red Squirrels,” 744–747; Scott, “Influence of the Slave-Trade,” 169–188, 182 [Normandy]; Jonathan Hutchinson, On Leprosy and Fish-Eating: A Statement of Facts and Explanations (London, 1906), 68 [Portugal and Spain], 235 [Brittany].
Olaf Skinsenes, “Understanding of Leprosy in Ancient China,” International Journal of Leprosy and Other Mycobacterial Diseases, LIII (1985), 289–307, 289–290 [a.d. 762 and Lun Yu citations]; Derk Bodde, “Medicine in Pre-Imperial China,” Journal of the American Oriental Society, CII (1982), 1–15, 10 [date of passage in Nei Ching]; Lu Gwei-Djen and Joseph Needham, “A History of Forensic Medicine in China,” Medical History Journal, XXXII (1988), 357–400, 367 n. 37 [O chi definition]; Mark, “Nasopharyngeal Carcinoma: A Review of Its Causes and Its Diagnosis in Skeletal Material,” International Journal of Osteoarchaeology, XVII (2007), 547–562, 550–551.
Skinsenes, “Understanding of Leprosy,” 291; Bodde, “Medicine in Pre-Imperial China,” 9; Gwei-Djen and Needham, “A History of Forensic Medicine in China,” 364 [third century date]; Angela Leung, Leprosy in China: A History (New York, 2009), 22; Gwei-Djen and Needham, “A History of Forensic Medicine in China,” published the excerpt, translated by Donald Harper (367).
Valerie Hansen, The Silk Road: A New History (New York, 2012), 8–10.
Leung, Leprosy in China, 32–33 [Zhiwen and southern China], 98–100 [houses].
James Cantlie, “Report on the Conditions under which Leprosy Occurs in China, Indo-China, Malaya, the Archipelago, and Oceania. Compiled Chiefly in 1894,” in Prize Essays on Leprosy (London, 1897), 239–413; Hutchinson, Leprosy and Fish-Eating, xi; Leung, Leprosy in China, 139 [Yangtze River Basin 1929].
Weng et al., “Molecular, Ethno-Spatial Epidemiology,” 361–368 [molecular subtypes and locations in China].
Kathryn M. Tanaka, “Contested Histories and Happiness: Leprosy Literature in Japan,” Health, Culture and Society, V (2013), 99–118; Joon Lew, A Korean Model for the Healing of Leprosy: The Resettlement Village Movement by Spiritual, Physical Socio-economic Rehabilitation for Persons with Leprosy (Seoul, 1993), 27–41; Cantlie, “Conditions under Which Leprosy Occurs,” 319.
Cantlie, “Conditions under Which Leprosy Occurs,” 323–358 [Chinese laborers].
The author thanks the anonymous referees for suggestions and comments that greatly improved this article.