Vol 8. Issue 6 / February 25, 2008
Diamonds & Pearls
By Eric Sauter
This year marks the 30th anniversary of Ernest Beutler as chair of the Department of Molecular and Experimental Medicine at The Scripps Research Institute. Traditional 30th anniversary gifts have a pearl theme, while diamonds are more contemporary. Thinking about Beutler's years at Scripps Research and beyond, the temptation is to argue for both.
How else does one acknowledge 800-plus scientific papers, numerous monographs and book chapters, editing of the widely used textbook William's Hematology, the invention of the computerized Reference Manager, plus a host of discoveries, including X-inactivation, and novel treatments for Gaucher disease and several forms of leukemia?
And the discoveries continue. Recently, Beutler ventured into a collaborative effort with his son, Bruce Beutler, a distinguished Scripps Research professor and department chair himself, an effort that is resulting in new insights into iron absorption.
As Bruce Beutler described it, "In our lab, we look for strange mice that have immunological oddities. The Mask phenotype—the mouse retains facial hair while shedding the rest—has very high levels of hepcidin, which reduces body iron content. As a result, it has an abnormally low rate of iron absorption. When we found this, I thought, this falls right into my father's lifetime interest. Without sounding like I'm bragging about my father, he's the world's expert on iron metabolism."
Bruce obviously forgot the aphorism, usually attributed to Muhammad Ali—it ain't bragging if it's true.
Ernest Beutler was born in Berlin in 1928 and left seven years later when the terrible agenda of the Third Reich became visible. His family settled in Milwaukee
"We had a distant cousin who owned a knitting mill in Milwaukee, so we had an affidavit of support—that was essential in enabling us to come to the United States," he said.
"Although the change in scenery didn't have an impact on a conscious level", he said, "it did have an impact. There were challenges in coming to a new country when you're seven years old," Beutler said. "Even though I knew English—I learned to speak it with a British accent in Germany—I had to apply myself to succeed. But as children do, I learned fast."
In a counterintuitive way, that abrupt shift may speak to the utter stability of his life, both in and out of the laboratory. He and his wife recently celebrated their 57th wedding anniversary; three of his four children are involved in either science or medicine; and several of the people who work in his Scripps Research laboratory have been with him from the day he moved in.
But he has embraced change when he has needed to. As a young man, he picked up and went to the University of Chicago, where he earned his medical degree in 1950.
In 1953, as a lieutenant in the Army Medical Corps, assigned to a research project at the Illinois state penitentiary, Beutler was the first to link a specific enzyme deficiency with hemolytic anemia (a form of anemia in which red blood cells are destroyed and removed from the bloodstream before their usual lifespan is over). It was a somewhat sensational start to his career.
Following his stint in the Army, Beutler returned to the University of Chicago, joined the faculty, and expanded his work on iron. In 1959, he moved to the City of Hope, a medical center in Duarte, California, founded in 1913 as a place to treat tuberculosis patients; it later blossomed into a research facility focused on cancer, diabetes, HIV/AIDS, and other life-threatening diseases.
In Duarte, the scope of Beutler's research ambitions broadened. He had been recruited to serve as chair of the Department of Medicine, and during the next 19 years, he published more than 300 papers and originated the concept of X chromosome inactivation in females, which eventually was applied to the understanding of the clonal origin of neoplasia, the abnormal growth of cells in a tissue or organ, which had been a long-standing goal of cancer researchers.
Beutler also expanded into the area of genetics and genetic diseases, including galactosemia, a rare hereditary enzyme deficiency, which leaves individuals unable to metabolize a sugar commonly found in milk. Beutler developed a test for potential carriers and for newborns for the disease. He discovered a prevalent enzyme variant that did not cause galactosemia, but that could confuse the diagnosis, and named it the Duarte variant. At the City of Hope, he also established one of the nation's first bone marrow transplant programs, eventually publishing a paper with Karl Blume and other members of his team that was the first to advocate the use of marrow transplantation as a primary treatment for acute leukemia.
Technology Catches Up
In 1978, Beutler moved to what was then the Scripps Clinic and Research Foundation (now The Scripps Research Institute) as chair of the Department of Basic and Clinical Research (now the Department of Molecular and Experimental Medicine). In La Jolla, his research and his reputation as a molecular and clinical geneticist continued to grow.
By then, technology had finally caught up with his ambitions.
"What has made a major change in hematology and the biological sciences," Beutler said, "is DNA sequencing. This has been the key to solving problems that were basically unapproachable before. My laboratory is again devoted to iron just as it was in the 1950s. But there was a hiatus of a great number of years because there were no tools to approach some of the fundamental questions I wanted to answer. When they finally arrived, I thought we could address some of these problems."
Beutler's interrupted interest in iron, now in force once again, is consistent with his interest in creating the tools that provide the ability to move things along faster in the laboratory. It was one of the reasons that he joined with his son on the Mask study—senior Beutler's lab had in place the tools to answer questions about iron metabolism more quickly.
"I enjoy developing methods," he said. "When a method works, you can quantify how well it works, you can improve it, and others can use it, too. Overall, what drives me in my work is scientific curiosity on the one hand and doing the kind of things I enjoy. I tend to do the things I enjoy. No one has ever really told me what to do in the laboratory. I've always been fortunate to be able to decide what to work on."
At Scripps Research, that enjoyment has ranged from his work with Dennis Carson in the development of a treatment for hairy cell leukemia, his investigation of the causes and treatment of Gaucher's disease (a rare inherited metabolic disorder), and his semi-legendary tinkering with software development. When one of his sons, a software developer, proclaimed that he was too busy to help update his father's electronic reference files, Beutler—who was already an accomplished programmer himself—did the job. This was the first version of the program now known as Reference Manager.
Then there was Beutler's 2002 study of hemochromatosis—the buildup of iron in the body caused by a specific genetic defect—a study that caused a certain amount of skepticism when published. Beutler had found that only about one percent of those who inherited two mutated genes developed the disease. His conclusion was in sharp contrast to the conventional wisdom, which put that figure closer to 95 percent. As other centers confirmed his studies, Beutler's view has become generally accepted, and this had a profound effect on the perception of the value of screening the general population for this disease.
In addition, his hemochromatosis studies produced an invaluable collection of more than 40,000 DNA samples that made possible future research into the relationship between genetic polymorphisms and a variety of diseases. The samples have enabled studies of genetic factors, including those that may affect aging, hypertension, drug addiction, obesity, arthritis, atherosclerosis, amyloidosis, and lung infection.
Speaking His Mind
Beutler never felt constrained about speaking his mind on controversial subjects. In Gaucher's disease, for example, Beutler wrote in a September issue of the Journal of the American Medical Association that screening for Gaucher's disease was not only impractical but perhaps even harmful.
"Not until clinicians and researchers better understand the factors that determine whether a patient homozygous for the N370S mutation will develop severe disease or none at all will screening for Gaucher's disease become useful," Beutler wrote. "Until then, screening for Gaucher's disease will likely do more harm than good."
He has been studying the disease and its treatment for more than three decades. In 1996, in an article for Nature Medicine, he talked about the cost of treating rare diseases, and the general lack of a workable solution, something that he finds is even truer today.
"Science keeps moving ahead but the health care system is collapsing," he said. "One of the things we worked on was to bring the cost of treating Gaucher's disease down because even if you use small doses of enzymes, the cost is still $80,000 a year. Our health care system doesn't accommodate this well, and I don't see anything that will solve the problem because the fundamental problem is not being addressed—and that is the concept that everybody can have everything they want in health care. This is just not compatible with our GDP [gross domestic product]."
He is also wary of the discoveries that frequently make headlines but just as often make little scientific sense.
"There tends to be more of this these days," he said. "Someone will show me a discovery in the paper and I have to respond that it's been known for 30 years. Now, having said that, promoting findings as breakthroughs when in fact they are far from that has always happened to some extent, but it seems that this unfortunate trend has accelerated."
Beutler's breakthroughs have been the real thing, and will continue to be as long as he has a say.
Send comments to: mikaono[at]scripps.edu