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.
Locks are the key
The team concluded that the so-called Muller, Bermann, Halm-Thayer, Moscheles, and Stumpf locks—all dating from the last seven years of Beethoven's life— "almost certainly derive from Beethoven." The Halm-Thayer and Stumpf locks also had perfect chains of custody, and the latter is still attached to a document signed by the original owner, Johann Andreas Stumpf.
There's even a detailed firsthand account of how the Holm-Thayer lock was acquired. The wife of pianist and composer Anton Halm greatly admired Beethoven and desired a lock of his hair. A mutual acquaintance named Karl Holz delivered such a lock, and the wife was initially delighted—except it turned out to be the hair of a nanny goat. As atonement, Beethoven cut off a lock of his hair for Halm's wife ("That is my hair!").
There wasn't sufficient preserved DNA to definitively determine the authenticity of the Keller lock. As for the Hiller lock—allegedly cut from the composer's head shortly after his death by a 15-year-old musician named Ferdinand Hiller—it wasn't Beethoven's, but rather that of a woman belonging to a haplogroup that is prevalent among Ashkenazi Jews. The Carmolini-Brown lock belonged to a male of European ancestry, but it had the most dubious provenance, with the earliest confirmed information only dating back to 2012. So, the authors concluded, "It is most certainly inauthentic."
Of the five authenticated locks of hair, the authors determined that the Stumpf lock was the best preserved, so it was chosen for sequencing, drawing on recent improvements in ancient DNA analysis that make it possible to do whole-genome sequencing from even small quantities of human hair. The locks were decontaminated one hair at a time using tweezers and a light bleach concentration; they were then rinsed in water and put into a test tube. The hairs were chemically digested to extract the DNA, and that DNA was then purified so it was ready for sequencing.
Unlocking genetic secrets
Could Beethoven's cirrhosis of the liver have been caused by excessive drinking? The composer's contemporaries thought his alcohol consumption was moderate, although standards were different in the early 19th century, and his own "conversation books" show he was a regular drinker. He may have been drinking as much as a liter a day around 1825–1826, and there does seem to be a family history of alcohol dependence and liver disease.
Begg et al.'s analysis revealed a high genetic predisposition for liver disease. There was also evidence of a hepatitis B infection in the months preceding Beethoven's final illness that might have caused the liver damage, which was exacerbated by his drinking and genetic risks. The authors caution that this cannot be conclusively determined at this time since we don't know the exact nature and timing of the hepatitis B infection, nor how much alcohol the composer actually consumed.
The authors found no genetic explanation for the composer's chronic gastric problems, but they determined celiac disease and lactose intolerance were highly unlikely. Ditto for irritable bowel syndrome since Beethoven's genetic profile showed a lowered risk for IBS.
As for Beethoven's hearing loss, past scholars have attributed it to otosclerosis, or possibly lead poisoning from the wines Beethoven preferred, or perhaps complications from when he contracted murine typhus in 1796. But the lead poisoning argument rested largely on toxicological analysis of the Hiller lock, which we now know is inauthentic. Testing the authenticated locks for lead poisoning, mercury, or opiates would be more conclusive. The authors of this latest study found no clear genetic underpinning for the hearing loss, including otosclerosis, although they could not rule out a genetic basis entirely.
Finally, sequencing DNA inevitably brings a few surprises—in this case, evidence that someone in Beethoven's paternal line had an extramarital affair that resulted in offspring. This finding is based on an analysis of DNA from Beethoven's modern relatives carrying the same name and recorded in genealogical records. Beethoven's Y chromosome doesn't match any of them. The authors think the affair likely occurred sometime between the conception of Hendrik van Beethoven around 1572 and when Ludwig was conceived seven generations later in 1770.
In fact, "You cannot rule out that Beethoven himself may have been illegitimate," Begg said during a press conference. "I'm not advocating that; I'm simply saying it's a possibility."
Krause added, "It could also be anywhere in the seven generations before."
DOI: Current Biology, 2023. 10.1016/j.cub.2023.02.041 (About DOIs).
