17th Century Variola Virus Reveals the Recent History of Smallpox
Why this work is in the frame
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Bibliographic record
Abstract
Smallpox holds a unique position in the history of medicine. It was the first disease for which a vaccine was developed and remains the only human disease eradicated by vaccination. Although there have been claims of smallpox in Egypt, India, and China dating back millennia [1Fenner F. Henderson D. Arita I. Jezek Z. Ladnyi I. Smallpox and Its Eradication. World Health Organization, 1988Google Scholar, 2Hopkins D. The Greatest Killer: Smallpox in History. University of Chicago Press, 2002Crossref Google Scholar, 3McNeill W. Plagues and Peoples. Anchor, 2010Google Scholar, 4Li Y. Carroll D.S. Gardner S.N. Walsh M.C. Vitalis E.A. Damon I.K. On the origin of smallpox: correlating variola phylogenics with historical smallpox records.Proc. Natl. Acad. Sci. USA. 2007; 104: 15787-15792Crossref PubMed Scopus (128) Google Scholar], the timescale of emergence of the causative agent, variola virus (VARV), and how it evolved in the context of increasingly widespread immunization, have proven controversial [4Li Y. Carroll D.S. Gardner S.N. Walsh M.C. Vitalis E.A. Damon I.K. On the origin of smallpox: correlating variola phylogenics with historical smallpox records.Proc. Natl. Acad. Sci. USA. 2007; 104: 15787-15792Crossref PubMed Scopus (128) Google Scholar, 5Babkin I.V. Babkina I.N. A retrospective study of the orthopoxvirus molecular evolution.Infect. Genet. Evol. 2012; 12: 1597-1604Crossref PubMed Scopus (26) Google Scholar, 6Babkin I.V. Babkina I.N. The origin of the variola virus.Viruses. 2015; 7: 1100-1112Crossref PubMed Scopus (44) Google Scholar, 7Esposito J.J. Sammons S.A. Frace A.M. Osborne J.D. Olsen-Rasmussen M. Zhang M. Govil D. Damon I.K. Kline R. Laker M. et al.Genome sequence diversity and clues to the evolution of variola (smallpox) virus.Science. 2006; 313: 807-812Crossref PubMed Scopus (142) Google Scholar, 8Hughes A.L. Irausquin S. Friedman R. The evolutionary biology of poxviruses.Infect. Genet. Evol. 2010; 10: 50-59Crossref PubMed Scopus (95) Google Scholar, 9Shchelkunov S.N. How long ago did smallpox virus emerge?.Arch. Virol. 2009; 154: 1865-1871Crossref PubMed Scopus (29) Google Scholar]. In particular, some molecular-clock-based studies have suggested that key events in VARV evolution only occurred during the last two centuries [4Li Y. Carroll D.S. Gardner S.N. Walsh M.C. Vitalis E.A. Damon I.K. On the origin of smallpox: correlating variola phylogenics with historical smallpox records.Proc. Natl. Acad. Sci. USA. 2007; 104: 15787-15792Crossref PubMed Scopus (128) Google Scholar, 5Babkin I.V. Babkina I.N. A retrospective study of the orthopoxvirus molecular evolution.Infect. Genet. Evol. 2012; 12: 1597-1604Crossref PubMed Scopus (26) Google Scholar, 6Babkin I.V. Babkina I.N. The origin of the variola virus.Viruses. 2015; 7: 1100-1112Crossref PubMed Scopus (44) Google Scholar] and hence in apparent conflict with anecdotal historical reports, although it is difficult to distinguish smallpox from other pustular rashes by description alone. To address these issues, we captured, sequenced, and reconstructed a draft genome of an ancient strain of VARV, sampled from a Lithuanian child mummy dating between 1643 and 1665 and close to the time of several documented European epidemics [1Fenner F. Henderson D. Arita I. Jezek Z. Ladnyi I. Smallpox and Its Eradication. World Health Organization, 1988Google Scholar, 2Hopkins D. The Greatest Killer: Smallpox in History. University of Chicago Press, 2002Crossref Google Scholar, 10Paulet J.J. Histoire de la Petite Vérole: Avec les Moyens d'en Préserver les Enfans et d'en Arrêter la Contagion en France. Volume 1. Ganeau, 1768Google Scholar]. When compared to vaccinia virus, this archival strain contained the same pattern of gene degradation as 20th century VARVs, indicating that such loss of gene function had occurred before ca. 1650. Strikingly, the mummy sequence fell basal to all currently sequenced strains of VARV on phylogenetic trees. Molecular-clock analyses revealed a strong clock-like structure and that the timescale of smallpox evolution is more recent than often supposed, with the diversification of major viral lineages only occurring within the 18th and 19th centuries, concomitant with the development of modern vaccination.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it