Death by Parasite!
Scientists Solve the Mystery of the Death of the Medici Brothers, Clearing Centuries of Speculation About Poisoning
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Cosimo Gamberucci, Michelangelo and Francesco I de Médici. Credit: Dominio público / Wikimedia Commons
An international team of researchers has successfully sequenced the DNA of the skeletal remains of brothers Giovanni and Francesco de’ Medici, discovering a previously unknown strain of the parasite Plasmodium falciparum and confirming malaria as the cause of their deaths.
In 1562, Cardinal Giovanni de’ Medici, scion of the dynasty that dominated the politics and banking of Tuscany during the Renaissance, died of malaria. Twenty-five years later, in 1587, his older brother, Grand Duke Francesco I de’ Medici, succumbed to the same disease.
What had been accepted by historians for centuries, but in the case of the ruler was always tinged with suspicion of poisoning at the hands of his own brother, has now been corroborated with the certainty that only genetic analysis can provide.
A new study published in iScience and led by researchers from Yale University in collaboration with paleopathologists from the University of Pisa conducted a genetic analysis of the brothers’ skeletal remains, searching for several species of Plasmodium, the protozoan parasites that cause malaria.
The results confirm the diagnoses of the era and have allowed the identification of a novel strain of Plasmodium falciparum in the cardinal’s bones, the species responsible for the deadliest form of human malaria, as well as molecular traces of this same species and a second one, P. malariae, in the remains of Grand Duke Francesco.
The discovery, which is part of an ongoing effort to trace the spread and evolution of malaria in central Italy during the Renaissance and beyond, provides valuable insights into the genetic diversity of P. falciparum and the evolution of different malaria species.
Our study is a great example of how we can use advanced ancient DNA laboratory methods to trace the history of this deadly pathogen, said Serena Tucci, assistant professor of anthropology in Yale’s Faculty of Arts and Sciences and lead author of the study.
The work, added Adalgisa Caccone, senior research scientist in the Department of Ecology and Evolutionary Biology at Yale and co-author of the study, not only helps illuminate events of the past but also generates data that can inform current and future research on malaria, which remains a deadly disease affecting millions of people worldwide.
Alexander Ochoa, associate researcher in the Department of Ecology and Evolutionary Biology and in the Department of Anthropology at Yale, is the first author of the paper. To carry out the research, the team extracted DNA from four rib samples, three belonging to the grand duke and one to the cardinal.
The brothers rest in the Medici Chapels, mausoleums located in the Basilica of San Lorenzo in Florence, where the main members of the family are buried. The finding that Francesco de’ Medici carried traces of two species of malaria aligns with previous analyses conducted on Belgian samples from the same historical period that showed the coexistence of multiple malaria species in a single individual. However, Ochoa noted that deeper genetic sequencing is needed to confirm that both species coexisted in central Italy during the 16th century.
The P. falciparum strain recovered from Giovanni de’ Medici presents two unique genetic mutations that, according to the study, likely resulted from a demographic expansion of the parasite as it spread across Europe. The study of ancient DNA gives us the opportunity not only to diagnose malaria in the remains of individuals from the past, but also provides a window to understand the evolution of malaria species, in this case Plasmodium falciparum, which can help scientists better understand how the pathogen adapts over time, explained Ochoa.
Historical archives already described in detail the symptoms suffered by the brothers, as well as the treatments they underwent. Cardinal Giovanni contracted malaria along with his mother, Eleonora of Toledo, and his younger brother, Garzia, during a trip to the Tuscan coast in 1562, where the marshes were known as a breeding ground for the disease-carrying mosquitoes.
The three suffered recurrent fevers that ended their lives within the span of a month. The cardinal was 19 years old at the time. In 1587, Francesco de’ Medici and his wife, Bianca Cappello, visited the family villa in Poggio, located among marshy rice fields where mosquitoes thrived.
The couple died on consecutive days after suffering intermittent fevers consistent with malaria. The swiftness of their deaths fueled rumors that Francesco’s brother and rival, Cardinal Ferdinando de’ Medici, had poisoned them with arsenic.
Contemporary reports from court physicians described the symptoms suffered by the brothers as consistent with malaria, which the inhabitants of central Italy at the time called terzana fever. The accounts also describe the treatments the sick were subjected to, including bloodletting, a common practice that likely caused more harm than benefit to the patients.
Previous immunological analyses carried out by the University of Pisa team had already indicated that both Giovanni and Francesco were carriers of P. falciparum, but until now no genetic evaluation had been conducted on their skeletal remains to confirm those findings.
At the time, both were diagnosed with symptoms, such as intermittent fevers, consistent with malaria, said Valentina Giuffra, professor of the history of medicine at the University of Pisa and co-author of the study. This genetic analysis confirms the historical accounts, as well as the previous research. We can now state with scientific certainty that it was malaria, and not poisoning, that killed Grand Duke Francesco de’ Medici, Giuffra concluded.
Malaria was endemic in central Italy from antiquity until the 20th century, when eradication campaigns eliminated the disease from the region. Nevertheless, in other parts of the world, the disease remains a serious public health threat.
According to the World Health Organization, around 282 million cases of malaria were recorded worldwide in 2024, causing 610,000 deaths. The discovery of this ancient strain and its specific mutations opens a unique window to understand the evolution of this pathogen over the centuries.
SOURCES
Alexander Ochoa, Samantha L. Miller, et al., Ancient DNA analyses of remains of the Medici family (16th century) provide insights into the genetic variation of Plasmodium falciparum, iScience (2026). DOI: 10.1016/j.isci.2026.116371
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