Scientists decode Beethoven’s genome, do we know what really killed him?

Deafness, liver problems, alcoholism, lead poisoning: the list of known and rumoured afflictions plaguing the life of celebrated composer Ludwig van Beethoven has fascinated historians and scientists alike.

Now, researchers have decoded his genome in an effort to learn what really killed him.

Beethoven suffered from progressive hearing loss over two decades. By his mid-forties he was functionally deaf.

But while the trope of the famous composer who couldn’t hear his own music has been a regular prompt for pub quiz nights, he was equally afflicted with gastrointestinal and respiratory issues, rheumatism and alcohol-related liver disorders, which the researchers say, probably led to his death in 1827.

But probably not lead poisoning, as Austrian researchers once suggested contributed to his death.

Much knowledge of Beethoven’s illnesses have been assembled from historic accounts, such as his diaries and letters, but now an international team can say what did – and didn’t – play a role in his death.

For those hoping for a hitherto unknown explanation, they’ll be sadly disappointed, with multiple indicators of liver disease now unscrambled from his DNA.

And while an explanation for his deafness remains sadly, elusive, the researchers behind the investigation are hopeful that more genetic markers in modern-day humans will emerge over time that might point to a culprit in Beethoven’s genome.

“Although a clear genetic underpinning for Beethoven’s hearing loss could not be identified [we] caution that such a scenario cannot be strictly ruled out,” says Cambridge PhD student Tristan Begg, who led the study.

“Reference data, which are mandatory to interpret individual genomes, are steadily improving. It is therefore possible that Beethoven’s genome will reveal hints for the cause of his hearing loss in the future.”

Beethoven’s hair. Or is it?

Hair samples are generally well-preserved sources of DNA that can be used to analyse genetic information.

But before rushing into decoding sections of the classical composer’s locks, geneticists first had to perform some quality control: splitting the hairs into the authentic and bogus.

To do this, they cross-referenced eight samples obtained from Beethoven collections across Europe, the UK and US.

Five were found to be authentic.

On the other hand, the scientists ruled out three as being derived from the composer. One of these was the so-called ‘Hiller lock’ purported to have been cut from the deceased Beethoven’s head by then 15-year-old composer, Ferdinand Hiller.

That sample was one used to prescribe lead poisoning – plumbism – as a cause of Beethoven’s death and afflictions.

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However, the research team has now dismissed the explanation that the Hiller Lock came from the head of the great composer, instead finding it was from a woman with close ancestral ties to modern North African, Middle Eastern and Jewish populations.

From this, the scientists dismiss suggestions that Beethoven had lead poisoning.

“Since we now know that the ‘Hiller lock’ came from a woman and not Beethoven, none of the earlier analyses based solely on that lock apply to Beethoven,” says Begg.

“Future studies to test for lead, opiates, and mercury must be based on authenticated samples.”

Another sample, known as the ‘Cramolini-Brown Lock’, was found to be from a European male, but failed to match the other five samples.

From the five authentic samples one known as the ‘Stumpff Lock’ was found to be the best preserved and used to provide the genetic sequence for analysis.

Risk inherent in Beethoven’s genetic symphony

Screening for genetic risk is part and parcel of modern medicine, and identifying potentially problematic genes can help tailor interventions to manage health problems for many people.

If Beethoven were born today, some of the issues that plagued him in the 19^th century may have been detected earlier.

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The analysis of the Stumpff Lock found Beethoven had gene variants potentially heightening his risk of liver cirrhosis.

Variations to the PNPLA3 gene are “consistently implicated” in genome-wide association studies for the disease, and when combined with prodigious alcohol intake, may have substantially raised his risk of the disease. He was also found to possess two mutations to the HFE gene known to cause hereditary haemochromatosis, which can trigger liver disease.

Digging further, they found evidence of the hepatitis B virus in the hair sample. Hepatitis B is a viral form of liver disease, and one which they believe was likely to have infected the composer in the year leading up to his death.

While conclusive findings on the true cause of Beethoven’s death remain elusive, Professor Johannes Krause from Max Planck Institute of Evolutionary Anthropology says the study at least zeroes in on liver complications.

“We cannot say definitely what killed Beethoven,” says Krause.

“But we can now at least confirm the presence of significant heritable risk, and an infection with hepatitis B virus. We can also eliminate several other less plausible genetic causes.”

Ancestry questions suggest possible infidelity

DNA sequenced from the Stumpff lock shows a connection to people who today live in the North Rhine-Westphalia region of Germany, which includes the city of Bonn, where Beethoven was born.

But when comparing the Beethoven genome to modern-day Belgian relatives, the scientists were unable to find a paternal connection.

That can be explained by an ‘extra pair paternity’ occurring in Beethoven’s ancestry – creating a biological split in the family somewhere between his birth and that of his ancestor Aert van Beethoven in Kampenhout, Belgium around two hundred years earlier.

Digitally deconstructing Beethoven

Basically, there was an extramarital relationship in Beethoven’s paternal line. But while geneticists involved in the study can conclude this to be the case, they can’t pinpoint where exactly this deviation in the composer’s ancestry occurred.

To help find out, they plan to release information to other researchers to connect the dots in the Beethoven family tree.

“We hope that by making Beethoven’s genome publicly available for researchers, and perhaps adding further authenticated locks to the initial chronological series, remaining questions about his health and genealogy can someday be answered,” Begg says.