Dr. Ernest Beutler, a Scripps Research Institute physician and researcher who was one of the country’s leading experts on diseases of the blood and iron metabolism, died Sunday of lymphoma at Scripps Green Hospital in La Jolla. He was 80.
Beutler was a pioneer in bone marrow transplantation for fighting cancer; made key discoveries about the role of the X-chromosome in women; helped discover G6PD deficiency, the most common clinically significant enzyme deficiency of humans; improved the diagnosis and treatment of Gaucher disease; and developed cladribine, a treatment for both leukemia and multiple sclerosis.
In his spare time, he also wrote the original programming for the widely used software Reference Manager.
“Ernie always had a sparkle in his eye, the energy of a man half his age and a bottomless treasury of new ideas,” said Dr. Richard A. Lerner, president of Scripps. He “was a truly extraordinary man who led an exceptional life, full of kindness, wisdom, strength and knowledge.”
Beutler developed his interest in blood as a newly commissioned lieutenant in the U.S. Army after he finished his residency in 1953. The Korean War had illustrated the military’s need for improved treatments for malaria, and Beutler was sent to Joliet Prison in Illinois to study the severe anemia produced in some people by the malaria drug primaquine.
With his colleagues Ray Dern and Alf Alving, Beutler determined that patients who developed anemia suffered a genetic deficiency of the enzyme glucose-6-phosphate dehydrogenase or G6PD. When stressed by the drug, their red cells were destroyed, producing anemia.
An estimated 400 million people worldwide are now thought to carry this genetic defect. Beutler later developed tests for the condition.
After becoming chairman of the department of medicine at the City of Hope National Medical Center in Duarte in 1959, Beutler built on a chance observation by his lifelong friend Susumu Ohno by exploring the workings of the X chromosome in females.
While males carry both X and Y sex chromosomes, females carry two X chromosomes, one from each parent. Because the two chromosomes carry different genetic information, Beutler deduced that one chromosome must be inactivated in each cell of the body.
He demonstrated that some African American women who inherited the defective gene for G6PD deficiency from only one parent had some blood cells that did not display the deficiency and others that did, indicating that different X chromosomes were being randomly inactivated in the two groups of cells.
The principle was soon demonstrated for other genes on the X chromosome as well. Independently, the English geneticist Mary F. Lyon demonstrated the same phenomenon in mice.
The concept ultimately had a more widely applied application in explaining the origin of tumor cells.
Beutler also studied genetic diseases, especially those that manifested in blood cells. One such disorder is galactosemia, a rare hereditary enzyme deficiency in which individuals are unable to metabolize galactose, a sugar found in milk.
He developed a test for the disease in carriers and newborns and identified a variant of the disease gene that was harmless but could be confused with the genuine item. He named it the Duarte variant.
He also purified the enzyme that is dysfunctional in Tay-Sachs disease, a fatal lipid storage disorder.
In 1970, he recognized the potential importance of bone marrow transplants and recruited Dr. Karl Blume to head the program at City of Hope. He and Blume published the first paper supporting the use of marrow transplants from a relative or volunteer donor to treat acute leukemia.
In 1978, Beutler moved to what was then called the Scripps Clinic and Research Foundation, where he established another bone marrow transplant program and continued his work on genetic disorders.
He isolated the gene that is defective in Gaucher disease -- a severe disorder marked by the accumulation of a fatty substance called glucocerebroside in the bone marrow, spleen and liver -- devised a diagnostic test and developed treatments for it.
He also attempted to isolate the gene for hereditary hemochromatosis, in which iron accumulates at high levels throughout the body, but was beaten to it by other researchers.
Hemochromatosis was once thought to be the most common genetic disorder among Europeans because about five out of every 1,000 carry the mutant gene that causes it. But in his studies on 43,000 subjects, Beutler found that only about 2% of those with the gene actually develop symptoms. He argued forcefully that proposed screening programs for the disorder should be abandoned because they would produce a very high number of false positives.
Throughout his career, Beutler had accumulated a very large number of scientific references that he had originally kept on index cards. While he was at City of Hope, he had a programmer develop a program that would allow him to recover references by keyword or author on a primitive PDP-1140 computer.
The program was so valuable that he bought the computer and took it with him when he moved to Scripps. But the programmer ultimately left and the program was in what is known as assembly language, which is hard to use.
After learning some basics about programming from his son Earl, Beutler wrote the new program himself. Reference Manager is now widely used in the scientific community.
Ernest Beutler was born in Berlin, Germany, on Sept. 30, 1928, the son of two physicians. The family moved to America in 1935, settling in Milwaukee.
After only two years in high school, he enrolled in a special program at the University of Chicago, receiving his bachelor’s degree in 1948 and his medical degree in 1950.
He wrote more than 800 scientific papers as well as many book chapters and monographs. He also served as editor of the widely used textbook, “Williams Hematology,” and received numerous awards and prizes.
Beutler is survived by his wife of 58 years, the former Brondelle Fleisher; a daughter, Dr. Debbie Beutler Guzner of Pasadena; three sons, Earl Beutler of Encinitas, Dr. Steven Beutler of Redlands and Dr. Bruce Beutler of San Diego, who was his colleague at Scripps; eight grandchildren; and a brother, Frederick Beutler of Ann Arbor, Mich.