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Mayo Clinic Scientists Use Chemical Analysis of Beethoven’s Hair to Determine Lead Poisoning May Have Contributed to Composer’s Hearing Loss and Other Health Ailments

Results of an earlier study in which locks of Beethoven’s hair underwent genetic analysis showed the composer ‘had a predisposition for liver disease and became infected with hepatitis B’

Here is an example of modern technologies being used with “historical biospecimens” to solve long-standing mysteries or questions about the illnesses of famous historical figures. Clinical laboratory scientists at the Mayo Clinic have used modern-day chemical analysis techniques to answer a 200-year-old question: What caused Ludwig van Beethoven’s deafness and other health problems?

In a letter published in Clinical Chemistry, a journal of the Association for Diagnostics and Laboratory Medicine (ADLM) titled, “High Lead Levels in 2 Independent and Authenticated Locks of Beethoven’s Hair,” researchers with the metals laboratory within Mayo’s Division of Clinical Biochemistry and Immunology revealed analysis performed on authenticated locks of the composer’s hair. The results indicated extremely high concentrations of lead—64 to 95 times the expected level.

“Such lead levels are commonly associated with gastrointestinal and renal ailments and decreased hearing but are not considered high enough to be the sole cause of death,” the authors wrote.

Beethoven’s death at age 56 has been attributed to kidney and liver disease, CNN reported. Even if the lead concentrations were not the sole cause, they would nevertheless be regarded as lead poisoning, lead study author Nader Rifai, PhD, told CNN.

“If you walk into any emergency room in the United States with these levels, you will be admitted immediately and you will undergo chelation therapy,” he said.

Rifai is a professor of pathology at Harvard Medical School and director of clinical chemistry at Boston Children’s Hospital.

“It is believed that Beethoven died from liver and kidney disease at age 56. But the process of understanding what caused his many health problems has been a much more complicated puzzle, one that even Beethoven himself hoped doctors could eventually solve,” CNN reported, adding, “The composer expressed his wish that his ailments be studied and shared so ‘as far as possible at least the world will be reconciled to me after my death.’” Mayo clinical laboratory scientists are using chemical analysis on authenticated locks of Beethoven’s hair to do just that. (Photo copyright: Joseph Karl Stieler/Public Domain.)

Mass Spectrometry Analysis

Mayo Clinic’s metals laboratory, led by chemist Paul Jannetto, PhD, an associate professor in the Department of Laboratory Medicine and Pathology and Laboratory Director at the Mayo Clinic, performed the analysis on two authenticated locks of Beethoven’s hair, using inductively coupled plasma mass spectrometers.

The researchers found that one lock had 258 micrograms of lead/gram and the other had 380 micrograms. Normally they would expect to find less than four micrograms.

“These are the highest values in hair I’ve ever seen,” Jannetto told The New York Times. “We get samples from around the world and these values are an order of magnitude higher.”

The researchers also found that the composer’s hair had four times the normal level of mercury and 13 times the normal amount of arsenic.

Rifai and other researchers noted that Beethoven drank large amounts of plumbed wine, and at the time it was common to sweeten wine with lead acetate, CNN reported.

The composer also could have been exposed to lead in glassware. He likely absorbed high levels of arsenic and mercury by eating fish caught from the Danube River in Vienna.

David Eaton, PhD, a toxicologist, pharmacologist, and Professor Emeritus, Department of Environmental and Occupational Health Sciences at the University of Washington, told The New York Times that high levels of lead could have impaired Beethoven’s hearing through their effect on the nervous system. Additionally, he said the composer’s gastrointestinal ailments “are completely consistent with lead poisoning.”

Rifai told CNN that he’d like to study locks of hair from other 19th century Vienna residents to see how their lead levels compared with Beethoven’s.

Beethoven’s Genome and Genetic Predisposition for Liver Disease

Additional research published in May built on an earlier genomic analysis of Beethoven’s hair, which appeared in March 2023 in the journal Current Biology.

The international team included geneticists, archeologists, and immunologists who analyzed eight locks of hair attributed to the composer. They determined that five were authentic. One, known as the Stumpff Lock, appeared to be the best preserved. They used this lock to sequence Beethoven’s DNA.

“Although we could not identify a genetic explanation for Beethoven’s hearing disorder or gastrointestinal problems, we found that Beethoven had a genetic predisposition for liver disease,” the authors wrote. “Metagenomic analyses revealed furthermore that Beethoven had a hepatitis B infection during at least the months prior to his death. Together with the genetic predisposition and his broadly accepted alcohol consumption, these present plausible explanations for Beethoven’s severe liver disease, which culminated in his death.”

One surprising discovery was the likelihood of an extramarital affair on the composer’s father’s side, CNN reported. The researchers learned this in part by comparing his genetic profile with those of living relatives.

“Through the combination of DNA data and archival documents, we were able to observe a discrepancy between Ludwig van Beethoven’s legal and biological genealogy,” study coauthor Maarten Larmuseau, PhD, told CNN. Larmuseau is assistant professor, Faculty of Medicine, and head of the Laboratory of Human Genetic Genealogy at KU Leuven in Belgium.

The Mayo Clinic team used two locks authenticated in the 2023 study—the Bermann Lock and Halm-Thayer Lock—to perform their chemical analysis, CNN reported.

Beethoven’s Wishes

The earlier study noted that Beethoven wanted his health problems to be made public. In 1802, he wrote a document known as the Heiligenstadt Testament in which he asked that his physician, surgeon/ophthalmologist Johann Adam Schmidt, MD, discuss his disease after he died.

“For almost two years I have ceased to attend any social functions, just because I find it impossible to say to people: I am deaf,” Beethoven wrote at age 30, The New York Times reported. “If I had any other profession, I might be able to cope with my infirmity, but in my profession, it is a terrible handicap. And if my enemies, of whom I have a fair number, were to hear about it, what would they say?”

The authors of the Current Biology paper wrote, “Genomic sequence data from authenticated locks of Beethoven’s hair provide Beethoven studies with a novel primary source, already revealing several significant findings relating to Beethoven’s health and genealogy, including substantial heritable risk for liver disease, infection with HBV [Hepatitis B], and EPP [extra pair paternity]. This dataset additionally permits numerous future lines of scientific inquiry.

“The further development of bioinformatics methods for risk stratification and continued progress in medical genetic research will allow more precise assessments both for Beethoven’s disease risk and for the genetic inference of additional phenotypes of interest.

“This study illustrates the contribution and further potential of genomic data as a novel primary source in historical biography,” the scientists concluded.

The work of the clinical laboratory professionals at Mayo Clinic also demonstrates how advances in various diagnostic technologies can enable pathologists and lab scientists to participate in solving long-standing health questions about historical figures, especially if their hair or other types of specimens survived and can be used in the analysis.  

—Stephen Beale

Related Information:

High Lead Levels in 2 Independent and Authenticated Locks of Beethoven’s Hair

Locks of Beethoven’s Hair Offer New Clues to the Mystery of His Deafness

New Analysis of Beethoven’s Hair Reveals Possible Cause of Mysterious Ailments, Scientists Say

Beethoven May Have Had Lead Poisoning

Paul Jannetto, PhD, Contributes to Landmark Discovery of Beethoven’s Hair Lead Concentration

Beethoven Really Did Have Lead Poisoning, But That Didn’t Cause His Death

Genomic Analyses of Hair from Ludwig Van Beethoven

DNA from Beethoven’s Hair Unlocks Medical and Family Secrets

DNA Analysis of Beethoven’s Hair Reveals Health Issues—and a Family Secret

Collaborative Global Study Casts New Light on Breast Cancer’s Genetic Roots; Will Soon Provide Anatomic Pathologists and Clinical Laboratories with New Tools to Diagnose and Treat Cancer

In the same way that BRCA1 and BRCA2 mutations helped pathologists identify women with increased breast cancer risks in the late 1990s, this new study isolates an additional 72 mutations medical laboratories may soon use to diagnose breast cancer and assess risk factors

For 20 years genetic scientists, anatomic pathologists, and medical laboratories have employed the BRCA1/BRCA2 genes to identify women at higher risk for breast cancer. And, because pathologists receive a high number of breast biopsies to diagnose, physicians and clinical laboratories already have collaborative experience working with genetic mutations supported by ample published evidence outlining their relationship with cancer.

Now, a global research study is adding 72 more mutations to the list of mutations already known to be associated with breast cancer.

In coming years, physicians and anatomic pathologists can expect to use the knowledge of these 72 genetic mutations when diagnosing breast cancer and possibly other types of cancers in which these mutations may be involved.

New Precision Medicine Tools to Improve Breast Cancer Survival

Combining the efforts of more than 550 researchers across 300 institutions and six continents, the OncoArray Consortium analyzed the DNA of nearly 300,000 blood samples. The analysis included samples of both estrogen receptor (ER-positive and ER-negative) cases.

Taken from a study published in the British Journal of Cancer, the graph above illustrates “proportions of familial risk of breast cancer explained by hereditary variants.” It is expected that anatomic pathologists will eventually incorporate these genetic variants into diagnostic test for breast and other cancers. (Graphic copyright: British Journal of Cancer.)

The results of their research were published in two separate studies: one in the scientific journal Nature and the other in Nature Genetics. The studies outlined 72 newly isolated genetic mutations that might help quantify the risk of a woman developing breast cancer in her lifetime.

Among the 72 mutations, seven genes were specifically associated with ER-negative cases. ER-negative breast cancer often fails to respond to hormone therapy. Thus, this discovery could be crucial to developing and administering precision medicine therapies tailored to specific patients’ physiologies and conditions. Treatments that improve patient outcomes and overall survival rates in ER-negative and ER-positive breast cancers.

Genetics Could Help Clinical Laboratories Wage War on All Cancers

According to data published by the Centers for Disease Control and Prevention (CDC), breast cancer is the most common form of cancer among women of all races. It’s the second-leading cause of all cancer deaths among most races and first among Hispanic women.

In the past, it was estimated that 5-10% of breast cancers were inherited through the passing of abnormal genes. However, Lisa Schlager, Vice President of community affairs and public policy for FORCE (Facing Our Risk of Cancer Empowered), told CNN, “This new information may mean that that estimate is low.” FORCE is a national nonprofit organization dedicated to fighting hereditary breast, ovarian, and related cancers.

Schlager calls upon health systems to “embrace the ability to use genetic information to tailor healthcare by providing affordable access to the needed screening and preventive interventions.” As precision therapy and genetic analysis continue to shape the way patients are treated, medical laboratories will play a significant role in providing the information powering these innovative approaches.

Furthermore, medical laboratories might leverage the same methods used by researchers to assess risk factors and identify genetic mutations and markers associated with other cancers. Douglas Easton, PhD, Director of the Centre for Cancer Genetic Epidemiology within the Department of Public Health and Primary Care at the University of Cambridge, and leader of the OncoArray Consortium investigation, explained to CNN that Illumina’s Infinium OncoArray is not limited to breast cancer, but is designed to work with other cancers, including:

·       colorectal;

·       ovarian; and,

·       prostate cancers.

Identifying Women at Increased Risk for Breast Cancer

Peter Kraft, PhD, Professor of Epidemiology at Harvard’s T.H. Chan School of Public Health, and a study author, told CNN, “Taken together, these risk variants may identify a small proportion of women who are at three-times increased risk of breast cancer.”

Kraft notes that samples were sourced from women of primarily European ancestry. Further study of other ethnic populations could lead to yet more mutations and indicators for cancers more common outside of the European region.

Research authors also highlight the importance of continued standard screening, such as mammograms. However, they suggest that genetic mutations, such as those found in the OncoArray study, might be used to highlight high-risk individuals and screen sooner, or conduct more in-depth genetic analyses, to catch potential cancer cases earlier and improve outcomes.

“Many women are offered mammogram screening when they are middle-aged,” Georgia Chenevix-Trench, PhD, co-author of the Nature Genetics study and researcher at the QIMR Berghofer Medical Research Institute in Australia, told LabRoots. “But if we know a woman has genetic markers that place her at higher risk of breast cancer, we can recommend more intensive screening at a younger age.”

Anatomic pathologists and clinical laboratories can use these new insights to offer increased options for oncologists and physicians on the front lines of the battle against cancer. While the list of genetic mutations related to cancer is far from complete, each added mutation holds the potential to power a new treatment, improve early detection rates, and improve survival rates of this global killer.

—Jon Stone

Related Information:

Major Study of Genetics of Breast Cancer Provides Clues to Mechanisms Behind the Disease

Breast Cancer Genetics Revealed: 72 New Mutations Discovered in Global Study

Identification of Ten Variants Associated with Risk of Estrogen-Receptor-Negative Breast Cancer

Association Analysis Identifies 65 New Breast Cancer Risk Loci

An Unprecedented Study Has Revealed 72 New Breast Cancer Gene Variants

Study Finds 72 New Genetic Mutations Linked to Breast Cancer

Major Study Identifies 72 New Genetic Risk Factors for Breast Cancer

Breast Cancer: 72 New Gene Mutations Uncovered

 

New High-Tech Mobile Medical Laboratories Deployed by the U.S. Navy and a European Consortium Use Genetic Analysis to Get Rapid Diagnosis of Ebola

These genetic tests cut time to answer from days to a few hours, reducing the risk of exposing non-infected patients and improving outcomes for Ebola patients

In response to the continuing outbreak of Ebola in the West African countries of Guinea, Liberia, and Sierra Leone, more attention has been given to medical laboratory testing in these countries, along with a rush to develop diagnostic tests that can detect Ebola faster and more accurately without the need for state-of-the art clinical laboratories that are uncommon in those nations.The lack of even limited basic services in the region, such as electricity, hinders any attempt to install modern diagnostic facilities and clinical laboratories essential to controlling and preventing further spread of the disease. Another issue is the lack of trained pathologists, Ph.Ds., and clinical laboratory scientists to staff such labs in those nations.

One solution to this challenge, however, is for developed nations to provide mobile medical laboratories and hospital facilities. Such resources have been contributed by the United States, Canada, and several European countries. (more…)

New Medical Laboratory-in-a-Suitcase Detects Ebola in 15 Minutes or Less

Demand for a rapid, accurate diagnostic solution to combat Ebola is motivating research teams in many countries to develop solutions that can be put to immediate use

In West Africa, the outbreak of Ebola in several countries motivated researchers in Germany to develop a fast, accurate, and inexpensive test that could be performed in patient care settings without the need for a centralized medical laboratory.

In these West African countries, lack of electricity and reliable cold storage or diagnostic equipment handicaps clinical laboratory technicians who are testing patients for the Ebola virus. A new test developed by researchers at the German Primate Center (DPZ) in Göttingen, Germany, cuts the time to answer an Ebola diagnosis to just 15 minutes. It requires no electricity and is portable. Previously, the fastest Ebola diagnostics test took three hours to get results and required transporting samples to often-distant medical laboratories. (more…)

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