After almost 700 years, a black legend has been debunked: it was a rare genetic disease, more precisely the late-onset Glycogenosis type II, that led to the death, in just three days, Cangrande della Scala, Lord of Verona and protector of Dante Alighieri during the exile and which the poet recalls in the Divine Comedy. No murder, therefore, as a certain tradition has maintained for centuries, assuming a poisoning with a herbal tea of chamomile and digitalis. On 22 July 1329, Cangrande died in Treviso, just 38, as a result of a rare genetic disease.
This was revealed by the scientific analyzes conducted on DNA by the Functional Genomics Laboratory of the Department of Biotechnology of the University of Verona, directed by Professor Massimo Delledonne. The results of the research were presented as part of the project “Verona, Dante and his legacy 1321-2021”, with a conference entitled “The genome of Cangrande della Scala. The DNA as a historical source” at the Natural History Museum of Verona held by Massimo Delledonne, David Caramelli e Alessandro Salviati, professors of the Department of Biotechnology of the University of Verona.
Cangrande’s DNA was collected in 2004 in collaboration with the Laboratory of Molecular and Paleogenetic Anthropology of the University of Florence, coordinated by Professor David Caramelli and by the professor Martina Larry, experts in ancient DNA extraction.
A first extraction, performed on liver fragments, did not make clinical sequencing possible. A second extraction was then carried out, from a small fragment of a phalanx. Also in this case the quantity of extracted DNA presented contaminating DNA. However, a higher percentage of human DNA made it possible to carry out a process of analysis. The Functional Genomics Laboratory of the University of Verona has therefore decided to apply a laboratory technique currently used for the clinical diagnosis of patients suffering from genetic diseases, which has made it possible to specifically capture the approximately 35 million DNA bases they contain. human genes, thus eliminating contaminating DNA.
DNA sequencing
Cangrande’s DNA was then “sequenced” as if it were a patient of our day, and the bioinformatic analysis of the 83 million sequences produced led to the reconstruction of 93.4% of its genes, a very high value.
Subsequent analyzes identified 249 disease-associated variants from which it was possible to recognize two different mutations in the lysosomal enzyme alpha-acid glucosidase gene. The disease resulting from the dysfunction of this enzyme is a glycogenosis, in this case the type II glycogenosis.
In late-onset cases, such as that attributable to Cangrande, the clinical picture shows poor resistance to physical fatigue, with breathing difficulties, muscle weakness and cramps, spontaneous bone fractures and heart disease. The death of adult patients is often almost sudden from a rapid onset of strength deficiency of the diaphragm and other respiratory muscles.
Some historical works have brought to light small clues compatible with this pathology, relating to forced stops during fairly short journeys on horseback, sudden illness and, perhaps, also the preference for the use of the bow instead of the sword (which involved less vigorous and more controllable muscle engagement).
The clinical picture of Cangrande’s death in Treviso is therefore compatible with late-onset type II glycogenosis disease. The doctor from Cangrande, in an attempt to counter this weakness, administered excessive doses of digitalis (a substance used as a cardio tonic) and this led to think of poisoning, so much so that the doctor was hanged shortly thereafter. Today we know that this administration was far from the intent of poisoning the Prince.
The end of a centuries-long mystery
“This is how the word ends – says the Councilor for Culture of the Municipality of Verona, Francesca Briani – to one of the mysteries that still surround Signora Scaligera, the family that welcomed the exiled Dante into the city and that the poet recalls in the Divina Comedy. An exciting scientific process that, for the first time, led to an in-depth observation of Cagrande’s DNA. A second study step which, after the acquisition of the samples carried out in 2004, completes the analysis on the prince’s mummy Scaligero, giving us the opportunity to identify new and interesting historical information about his life and, in particular, death. This scientific project represents one of the main appointments scheduled during this year on the occasion of Dante’s celebrations “.
“The decision to entrust the remains of Cangrande della Scala to the Natural History Museum – underlines the director of the Civic Museums of Verona, Francesca Rossi – was dictated by the fact that the conservation of biological materials requires special precautions, already foreseen for the Museum’s collections. , in particular the zoological ones. Through this extraordinary project it was finally possible to complete the analysis process on the finds preserved since 2004 and to reach certain scientific results, which reveal the causes of Cangrande della Scala’s death “.
This joint effort between the experts of the Museum of Natural History and the Universities of Verona and Florence has allowed us to demonstrate how it is possible to analyze the genes of such an ancient DNA with very high precision, using cutting-edge diagnostic procedures, to arrive at a certain clinical diagnosis, even when historical sources are scarce. Using the new diagnostic sequencing technologies applied in the most advanced research centers to sick people to improve the diagnosis, prognosis and treatment of genetic-based diseases, it has been possible not only to reconstruct the information stored in the DNA of Cangrande della Scala, but also to recognize the pathological conditions that led to his death.
The first investigations in 2004
The investigation started from afar, exactly from 12 February 2004 when, by decision of the Municipality and the civic Art Museums, the reconnaissance and opening of the funeral ark of Cangrande della Scala was organized, which led to the identification of the body mummified by the Scaliger, more or less in the same conditions in which it had already been found inside the chest at the opening of 1921 (on the occasion of the sixth centenary of Dante Alighieri’s death). The prince’s body was subjected to a series of scientific and autopsy investigations before being returned to the ark that had preserved them for centuries.
Part of the biological materials, in particular the liver and some phalanges of the foot, were sent to the University of Pisa for further biomedical investigations. In early 2007, the finds were returned and deposited at the Natural History Museum to be preserved and made available for future further study.