Beethoven’s genome, sequenced for first time, yields clues on cause of death

Ludwig van Beethoven is one of the greatest composers of all time, but he was plagued throughout his life by myriad health problems, most notably going mostly deaf by 1818. These issues certainly affected his career and emotional state, so much so that Beethoven requested—via a letter addressed to his brothers—that his favorite physician examine his body after his death to determine the cause of all his suffering.

 

Nearly two centuries after the composer's demise, scientists say they have sequenced his genome based on preserved locks of hair. While the analysis of that genome failed to pinpoint a definitive cause of Beethoven's hearing loss or chronic digestive problems, he did have numerous risk factors for liver disease and was infected with hepatitis B, according to a new paper published in the journal Current Biology. The researchers also found genetic evidence that somewhere in the Beethoven paternal line, an ancestor had an extramarital affair.

 

“We cannot say definitely what killed Beethoven, but we can now at least confirm the presence of significant heritable risk and an infection with hepatitis B virus,” said co-author Johannes Krause, an expert in ancient DNA at the Max Planck Institute of Evolutionary Anthropology. “We can also eliminate several other less plausible genetic causes.” The fully sequenced genome will be made publicly available so other researchers can have access to conduct future studies.

 

Beethoven began losing his hearing in his mid- to late 20s, experiencing tinnitus and the loss of high-tone frequencies in particular. He claimed the onset began with a fit in 1798 induced by a quarrel with a singer. By his mid-40s, he was functionally deaf and unable to perform public concerts, although he could still compose music. He also had lifelong chronic gastric ailments, including persistent abdominal pains and prolonged stretches of diarrhea. By 1821, the composer showed signs of liver disease, marked by the first of two severe attacks of jaundice.

 

By December 1826, Beethoven was quite ill, suffering from a second bout of jaundice and swollen limbs, fever, dropsy, and labored breathing. His doctor performed several operations to remove excess fluid from the composer's abdomen. Beethoven was mostly bedridden for the next few months, receiving visitors and being showered with gifts and tributes as news of his illness spread. On March 24, 1827, he purportedly said to visitors, "Plaudite, amici, comoedia finita est" ("Applaud, friends, the comedy is over"). Two days later, he died. According to his good friend Anselm Hüttenbrenner, who was present, lightning and a loud clap of thunder briefly woke Beethoven, who "opened his eyes, lifted his right hand and looked up for several seconds with his fist clenched ... not another breath, not a heartbeat more."

 

 

An autopsy identified severe liver damage (evidence of cirrhosis) as the likely cause of death and significant dilation of the auditory nerve. But what caused that liver damage or his hearing loss—or his chronic stomach complaints, for that matter? Medical detectives have been debating possible causes for nearly two centuries, drawing on the composer's letters, diaries, and physicians' notes for evidence, as well as reports on skeletal remains from when his body was exhumed in 1863 and 1888. But no general consensus has yet emerged.

 

That's where Tristan Begg and his co-authors come in. Begg studies genomic analysis as a graduate student at the University of Cambridge, and he became intrigued by Beethoven's letter requesting that his physician determine the cause of his illness. In what is now known as the Heiligenstadt Testament, Beethoven wrote to his brothers of his distress at being "hopelessly afflicted" by his hearing loss. He wrote that the only reason he hadn't committed suicide was that he didn't want to die "before I had produced all the works that I felt the urge to compose." Beethoven ended with the request that his favorite physician, Dr. Johann Adam Schmidt, determine the cause of his ailments and make that information public. The testament was written in 1802, and Schmidt died 18 years before Beethoven.

 

Toxicological analysis of hair samples claimed to be those of Beethoven had been done in the past, along with an examination of skull fragments. For Begg et al., the first order of business was to authenticate 34 locks of hair traditionally attributed to Beethoven by tracking the provenance and conducting DNA analysis. They focused on eight locks from public and private collections, which ultimately took eight years.