Genomics of Ancient Pathogens: First Advances and Prospects.

Paleogenomics is one of the urgent and promising areas of interdisciplinary research in the today's world science. New genomic methods of ancient DNA (aDNA) analysis, such as next generation sequencing (NGS) technologies, make it possible not only to obtain detailed genetic information about historical and prehistoric human populations, but also to study individual microbial and viral pathogens and microbiomes from different ancient and historical objects. Studies of aDNA of pathogens by reconstructing their genomes have so far yielded complete sequences of the ancient pathogens that played significant role in the history of the world: Yersinia pestis (plague), Variola virus (smallpox), Vibrio cholerae (cholera), HBV (hepatitis B virus), as well as the equally important endemic human infectious agents: Mycobacterium tuberculosis (tuberculosis), Mycobacterium leprae (leprosy), and Treponema pallidum (syphilis). Genomic data from these pathogens complemented the information previously obtained by paleopathologists and allowed not only to identify pathogens from the past pandemics, but also to recognize the pathogen lineages that are now extinct, to refine chronology of the pathogen appearance in human populations, and to reconstruct evolutionary history of the pathogens that are still relevant to public health today. In this review, we describe state-of-the-art genomic research of the origins and evolution of many ancient pathogens and viruses and examine mechanisms of the emergence and spread of the ancient infections in the mankind history.

Ancient and modern pathologies and therapies: St. Gallicanus Hospital in Rome between the 18th and 20th centuries.

St. Gallicanus Hospital in Rome, Italy, created by the will of Pope Benedict XIII (1649-1730) in 1725, was the first dermatologic hospital in the world. The strong bond between science and faith, humanitarian spirit and scientific research, and the profoundness and legacy of its entire history have all contributed to its legacy. We have traced its development by examining archival documents to understand the life of the institute and the diseases that were diagnosed and treated from the 18th century to the first half of the 20th century. Some of the main diseases were leprosy, mange, scabies, ringworm, and syphilis, which were widespread in Rome during the 18th and 19th centuries and were creating a mortal threat for much of the population. St. Gallicanus Hospital was dedicated to the diagnosis, treatment, and prevention of these diseases where possible. Special attention has been directed to syphilis and the use of penicillin therapy after its introduction in 1943, especially for curbing the extensive problems created by prostitution.

Ancient genomes reveal structural shifts after the arrival of Steppe-related ancestry in the Italian Peninsula.

Across Europe, the genetics of the Chalcolithic/Bronze Age transition is increasingly characterized in terms of an influx of Steppe-related ancestry. The effect of this major shift on the genetic structure of populations in the Italian Peninsula remains underexplored. Here, genome-wide shotgun data for 22 individuals from commingled cave and single burials in Northeastern and Central Italy dated between 3200 and 1500 BCE provide the first genomic characterization of Bronze Age individuals (n = 8; 0.001-1.2× coverage) from the central Italian Peninsula, filling a gap in the literature between 1950 and 1500 BCE. Our study confirms a diversity of ancestry components during the Chalcolithic and the arrival of Steppe-related ancestry in the central Italian Peninsula as early as 1600 BCE, with this ancestry component increasing through time. We detect close patrilineal kinship in the burial patterns of Chalcolithic commingled cave burials and a shift away from this in the Bronze Age (2200-900 BCE) along with lowered runs of homozygosity, which may reflect larger changes in population structure. Finally, we find no evidence that the arrival of Steppe-related ancestry in Central Italy directly led to changes in frequency of 115 phenotypes present in the dataset, rather that the post-Roman Imperial period had a stronger influence, particularly on the frequency of variants associated with protection against Hansen's disease (leprosy). Our study provides a closer look at local dynamics of demography and phenotypic shifts as they occurred as part of a broader phenomenon of widespread admixture during the Chalcolithic/Bronze Age transition.

Human major infections: Tuberculosis, treponematoses, leprosy-A paleopathological perspective of their evolution.

The key to evolution is reproduction. Pathogens can either kill the human host or can invade the host without causing death, thus ensuring their own survival, reproduction and spread. Tuberculosis, treponematoses and leprosy are widespread chronic infectious diseases whereby the host is not immediately killed. These diseases are examples of the co-evolution of host and pathogen. They can be well studied as the paleopathological record is extensive, spanning over 200 human generations. The paleopathology of each disease has been well documented in the form of published synthetic analyses recording each known case and case frequencies in the samples they were derived from. Here the data from these synthetic analyses were re-analysed to show changes in the prevalence of each disease over time. A total of 69,379 skeletons are included in this study. There was ultimately a decline in the prevalence of each disease over time, this decline was statistically significant (Chi-squared, p<0.001). A trend may start with the increase in the disease's prevalence before the prevalence declines, in tuberculosis the decline is monotonic. Increase in skeletal changes resulting from the respective diseases appears in the initial period of host-disease contact, followed by a decline resulting from co-adaptation that is mutually beneficial for the disease (spread and maintenance of pathogen) and host (less pathological reactions to the infection). Eventually either the host may become immune or tolerant, or the pathogen tends to be commensalic rather than parasitic.

Insights from ancient DNA analysis of Egyptian human mummies: clues to disease and kinship.

The molecular Egyptology field started in the mid-eighties with the first publication on the ancient DNA (aDNA) analysis of an Egyptian mummy. Egypt has been a major interest for historians, archeologists, laymen as well as scientists. The aDNA research on Egyptian biological remains has been fueled by their abundance and relatively well-preserved states through artificial mummification and by the advanced analytical techniques. Early doubts of aDNA integrity within the Egyptian mummies and data authenticity were later abated with studies proving successfully authenticated aDNA retrieval. The current review tries to recapitulate the published studies presenting paleogenomic evidence of disease diagnosis and kinship establishment for the Egyptian human remains. Regarding disease diagnosis, the prevailing literature was on paleogenomic evidence of infectious diseases in the human remains. A series of reports presented evidence for the presence of tuberculosis and/or malaria. In addition, there were solitary reports of the presence of leprosy, diphtheria, bacteremia, toxoplasmosis, schistosomiasis and leishmaniasis. On the contrary, paleogenomic evidence of the presence of rare diseases was quite scarce and mentioned only in two articles. On the other hand, kinship analysis of Egyptian human remains, including that of Tutankhamen, was done using both mitochondrial DNA sequences and nuclear DNA markers, to establish family relationships in four studies. It is clear that the field of molecular Egyptology is still a largely unexplored territory. Nevertheless, the paleogenomic investigation of Egyptian remains could make significant contributions to biomedical sciences (e.g. elucidation of coevolution of human host-microbe interrelationship) as well as to evidence-based archeology.

Learning from the past in the COVID-19 era: rediscovery of quarantine, previous pandemics, origin of hospitals and national healthcare systems, and ethics in medicine.

After the dramatic coronavirus outbreak at the end of 2019 in Wuhan, Hubei province, China, on 11 March 2020, a pandemic was declared by the WHO. Most countries worldwide imposed a quarantine or lockdown to their citizens, in an attempt to prevent uncontrolled infection from spreading. Historically, quarantine is the 40-day period of forced isolation to prevent the spread of an infectious disease. In this educational paper, a historical overview from the sacred temples of ancient Greece-the cradle of medicine-to modern hospitals, along with the conceive of healthcare systems, is provided. A few foods for thought as to the conflict between ethics in medicine and shortage of personnel and financial resources in the coronavirus disease 2019 era are offered as well.

Commingled crypts: Comparative health among Byzantine monastics in the Levant.

OBJECTIVES: Early Byzantine (A.D. 330-842) monastic rules stipulated that entrants relinquished familial connections, personal belongings and secular relationships to become part of the ascetic collective that continued in death, resulting in bioarchaeological marginalization, as was the case of the monastics excavated from the Chapel of Robebus at Mount Nebo, Jordan (ca. A.D. 491-640). It was hypothesized that compared to contemporary monastic groups, the Mount Nebo monastics experienced poorer health and gravitated to Mount Nebo, owing to its association with the Prophet Moses and proximity to the Dead Sea, Livias baths and Jordan River, all associated with curative benefits, especially for those suffering from leprosy. MATERIALS AND METHODS: The commingled remains of 73 adult males from Mount Nebo and the articulated skeletons (n = 27) from the Sanctuary of Agios Lot at Deir 'Ain 'Abata (Jordan) were assessed for paleopathology, then compared with a contemporary commingled group from the Monastery of Saint Euthymius at Khan-el-Ahmar (Judean Desert) (n = 117). RESULTS: No skeletal evidence of leprosy was observed among the groups. Most Mount Nebo individuals did not reach an older age, yet injuries, severe osteoarthritis, lower leg osteoperiostitis and antemortem tooth loss were common. The paleopathological profile was similar at Deir 'Ain 'Abata, but paleopathology was negligible at Khan-el-Ahmar. CONCLUSIONS: The similar paleopathological profiles of the Jordanian monastic groups suggest that the proximity to the Dead Sea may have attracted monastics to both sites, in addition to spirituality, but leprosy was not a factor based on the skeletal evidence.

Paleomicrobiology: Diagnosis and Evolution of Ancient Pathogens.

The last century has witnessed progress in the study of ancient infectious disease from purely medical descriptions of past ailments to dynamic interpretations of past population health that draw upon multiple perspectives. The recent adoption of high-throughput DNA sequencing has led to an expanded understanding of pathogen presence, evolution, and ecology across the globe. This genomic revolution has led to the identification of disease-causing microbes in both expected and unexpected contexts, while also providing for the genomic characterization of ancient pathogens previously believed to be unattainable by available methods. In this review we explore the development of DNA-based ancient pathogen research, the specialized methods and tools that have emerged to authenticate and explore infectious disease of the past, and the unique challenges that persist in molecular paleopathology. We offer guidelines to mitigate the impact of these challenges, which will allow for more reliable interpretations of data in this rapidly evolving field of investigation.

Possible cases of leprosy from the Late Copper Age (3780-3650 cal BC) in Hungary.

At the Abony-Turjányos dulo site, located in Central Hungary, a rescue excavation was carried out. More than 400 features were excavated and dated to the Protoboleráz horizon, at the beginning of the Late Copper Age in the Carpathian Basin, between 3780-3650 cal BC. Besides the domestic and economic units, there were two special areas, with nine-nine pits that differed from the other archaeological features of the site. In the northern pit group seven pits contained human remains belonging to 48 individuals. Some of them were buried carefully, while others were thrown into the pits. The aim of this study is to present the results of the paleopathological and molecular analysis of human remains from this Late Copper Age site. The ratio of neonates to adults was high, 33.3%. Examination of the skeletons revealed a large number of pathological cases, enabling reconstruction of the health profile of the buried individuals. Based on the appearance and frequency of healed ante- and peri mortem trauma, inter-personal (intra-group) violence was characteristic in the Abony Late Copper Age population. However other traces of paleopathology were observed on the bones that appear not to have been caused by warfare or inter-group violence. The remains of one individual demonstrated a rare set of bone lesions that indicate the possible presence of leprosy (Hansen's disease). The most characteristic lesions occurred on the bones of the face, including erosion of the nasal aperture, atrophy of the anterior nasal spine, inflammation of the nasal bone and porosity on both the maxilla and the bones of the lower legs. In a further four cases, leprosy infection is suspected but other infections cannot be excluded. The morphologically diagnosed possible leprosy case significantly modifies our knowledge about the timescale and geographic spread of this specific infectious disease. However, it is not possible to determine the potential connections between the cases of possible leprosy and the special burial circumstances.

A synopsis of the history of Hansen's disease.

Leprosy is a contagious infectious disease caused by the bacillus Mycobacterium leprae. This microorganism was discovered by Dr. Gerhard Hansen, and the illness was then baptized as Hansen's disease. For a long time, Hansen's disease was thought to be hereditary-a curse or a punishment from God. The disease affects skin and nerves and can cause severe damage. Due to its destructive effects, leprosy has caused fear, segregation, and prejudice in all societies since Biblical times. Patients with Hansen's disease have not been treated humanely around the world throughout the ages. This article is a summary of curious and interesting facts about the history and cultural aspects of Hansen's disease, which has chastised humanity for centuries. These facts are about the discovery of the disease, its propagation, the evolution of treatments, and the prejudice of society towards patients.

[Notes for a History of Hygiene taken from the Bible]. / Notas para una Historia de la Higiene tomadas de la Biblia.

Reading once more the Gospels, we found a discussion between Jesus and the Pharisee about the hand washing, this golden rule of medicine, and then, with the help of Thomas Mann, we began a search for other notes on hygiene in the Bible. For the return from Egypt to the Promised Land, Moses established several rules for his people, some of them disguised as religious principles, concerning elimination of excreta, healthy and poisonous foods, isolation in case of contagious diseases (leprosy, gonorrhea), decontamination of clothes and houses, and many others that now seem to us ahead his time.

Paleomicrobiology of Leprosy.

The use of paleomicrobiological techniques in leprosy has the potential to assist paleopathologists in many important aspects of their studies on the bones of victims, solving at times diagnostic problems. With Mycobacterium leprae, because of the unique nature of the organism, these techniques can help solve problems of differential diagnosis. In cases of co-infection with Mycobacterium tuberculosis, they can also suggest a cause of death and possibly even trace the migratory patterns of people in antiquity, as well as explain changes in the rates and level of infection within populations in antiquity.

Microbial Genomics of Ancient Plagues and Outbreaks.

The recent use of next-generation sequencing methods to investigate historical disease outbreaks has provided us with an unprecedented ability to address important and long-standing questions in epidemiology, pathogen evolution, and human history. In this review, we present major findings that illustrate how microbial genomics has provided new insights into the nature and etiology of infectious diseases of historical importance, such as plague, tuberculosis, and leprosy. Sequenced isolates collected from archaeological remains also provide evidence for the timing of historical evolutionary events as well as geographic spread of these pathogens. Elucidating the genomic basis of virulence in historical diseases can provide relevant information on how we can effectively understand the emergence and re-emergence of infectious diseases today and in the future.