Ernest Beutler

Ernest Beutler (September 30, 1928 – October 5, 2008), a hematologist and biomedical scientist, was born in Berlin, Germany, the son of Jewish parents (Alfred and Kaethe, née Italiener). Both of his parents were also physicians, and his mother, a pediatrician, was in pre-war times the physician to the children of Magda Quandt née Rietschel, later Magda Goebbels, wife of the German propaganda minister.

Early life

His family home was located on Reichskanzlerplatz, renamed “Adolf Hitler Platz” after Hitler’s ascent to power, and then Theodor Heuss Platz after the Second World War. The second of three children, he was preceded by an older brother, Frederick (b. October 3, 1926, later a professor of mathematics at the University of Michigan), and followed by a younger sister, Ruth (b. November 23, 1932, later a clinical psychologist; d. July 14, 1993). In 1935, when Beutler was seven years of age, the family emigrated to the United States to escape Nazi persecution. Beutler was raised in Milwaukee, Wisconsin.

Education

At 15, Beutler enrolled in a special program at the University of Chicago, founded by Robert Hutchins, then President of the University. He completed his undergraduate, medical school and residency training at the University of Chicago, receiving his doctorate in medicine in 1950 at the age of 21. He was the valedictorian of his graduating class.

Academic Career and Principal Scientific Contributions

Beutler pursued a remarkably eclectic research career, and made fundamental contributions in many different areas of science over 56 years of active publication. His first scientific paper was published in 1952, and concerned the effect of X-irradiation on susceptibility to influenza virus in mice [Beutler, E. and Gezon, H.M. The effect of total body x irradiation on the susceptibility of mice to influenza A virus infection. J Immunol. 68(3):227-42, 1952] . This was an attempt to determine whether irradiated mice might offer a better experimental model in which to detect human viral infections. Not long afterward, he published a paper on the lag phase of "E. coli", which is also influenced by X-irradiation [ Beutler E et al. Prolongation of the lag phase of irradiated Escherichia coli. Proc Soc Exp Biol Med 85: 682-685, 1954 ] . This work, carried out during his residency in the laboratory of Leon O. Jacobson, was aimed at the development of an assay for a humoral radioprotective factor, and reflected a chance observation. Beutler also developed an early interest in iron metabolism, prompted by his clinical observation of the rapid symptomatic improvement of iron deficient patients treated with iron: an improvement that preceded any major hematologic change, and showed that numerous enzymes were sensitive to iron deficiency [Beutler,E., Tissue effects of iron deficiency. In: Gross,F.; Naegeli,S.R.; Philps,H.D., eds. Iron Metabolism Berlin: Springer-Verlag; 1963: 256-262.] .

After completing his residency (1953), Beutler applied for a commission as a Lieutenant in the U.S. Army, and was assigned to the Army Malaria Research Program. During this period, he worked at Joliet Prison in Illinois (1953-1954), investigating anemia produced by antimalarial drugs. In the course of his work, he identified glucose-6-phosphate dehydrogenase (G-6-PD) deficiency as a genetic defect that leads to the lysis of red blood cells under conditions of oxidative stress [ Beutler, E. The hemolytic effect of primaquine and related compounds. A review. Blood 14: 103-139, 1959] . This work hinged on his demonstration that red blood cell glutathione was unstable to oxidative stress [Beutler, E: The glutathione instability of drug-sensitive red cells. A new method for the in vitro detection of drug-sensitivity. J Lab Clin Med 49: 84-95, 1957 ] . Later, he was to develop an assay for glutathione that was widely used in studies of red cell oxidative metabolism [Beutler E, et al. Improved method for the determination of blood glutathione. J Lab Clin Med 61: 882-890, 1963] .

He was later transferred to Camp Detrick (later Fort Detrick) in Frederick, Maryland (1954-1955), where he studied Q fever. He was honorably discharged from the Army with the rank of Captain.

Beutler then joined the faculty of the Department of Medicine at the University of Chicago, where he studied iron metabolism [Beutler, E. Hematology: Iron metabolism. Annu Rev Med 12: 195-210, 1961] and red blood cell metabolism [Beutler,E. Erythrocyte carbohydrate metabolism. In: Weinstein,I.M.; Beutler,E., eds. Mechanisms of Anemia in Man New York: McGraw-Hill, Inc.; 1962: 101-115 ] . In 1959, he became chairman of the Department of Medicine of the City of Hope National Medical Center in Duarte, CA, and in 1979 assumed the chairmanship of the Department of Clinical Research at the Scripps Clinic and Research Foundation. Three years later, he was asked to become Chairman of a merged department (the Department of Molecular and Experimental Medicine) at Scripps, which later became The Scripps Research Institute in La Jolla, CA. He maintained his position as Chairman until his 80th birthday, only a few days before his death.

Not long after moving to California, Beutler made one of his most important contributions. A new colleague at the City of Hope and ultimately a life-long friend, Susumu Ohno had recently demonstrated that the histologically observable Barr body present in the nuclei of mammalian female cells was a hyperchromatic X chromosome. Beutler immediately recognized that this might account for the variable expression of X-linked genes in females heterozygous for X-linked mutations. He soon determined that random X chromosome inactivation causes tissue mosaicism in female mammals, in that each somatic cell expresses one (but not both) of the alleles of X-linked genes with which it is endowed. This he accomplished by showing that two populations of erythrocytes exist in the blood of African American women who are heterozygous for G6PD deficiency [Beutler, E. et al. The normal human female as a mosaic of X-chromosome activity: Studies using the gene for G-6-PD deficiency as a marker. Proc Natl Acad Sci USA 48: 9-16, 1962] . Mary F. Lyon independently hypothesized that variegated coat colors in mice might arise from random X chromosome inactivation. This, too, flowed from Ohno’s observations.

Beutler’s seminal work on G6PD deficiency led him to further explore hemolytic anemias caused by various enzyme deficiencies. The systematic methodology that he developed became the standard approach to study of patients with these disorders [ Beutler,E. Red Cell Metabolism: A Manual of Biochemical Methods, 3 edition. New York, NY: Grune & Stratton, Inc.; 1984] .

Beutler made major contributions to the understanding of Tay-Sachs disease. He purified the enzyme that is aberrant in this disease and demonstrated its multimeric structure [Srivastava, SK et al. Studies on human beta-D-N-acetylhexosaminidases. III. Biochemical genetics of Tay-Sachs and Sandhoff's diseases. J Biol Chem 249: 2054-2057, 1974] . His group cloned the gene responsible for Gaucher disease [ Sorge J, et al. Molecular cloning and nucleotide sequence of the human glucocerebrosidase gene. Proc Natl Acad Sci USA 82: 7289-7293, 1985 ] and developed treatments for this disease [Beutler E. Enzyme replacement therapy. TIBS Rev. 6: 95-97, 1981] , [Sawkar AR, et al. Chemical chaperones increase the cellular activity of N370S b-glucosidase: A therapeutic strategy for Gaucher's disease. Proc Natl Acad Sci USA 99: 15428-15433, 2002] as well as diagnostic tests [Beutler E, et al. The diagnosis of the adult type of Gaucher's disease and its carrier state by demonstration of deficiency of beta-glucosidase activity in peripheral blood leukocytes. J Lab Clin Med 76: 747-755, 1970] . Beutler also developed a screening test for galactosemia, which is used to this day to detect the disease in neonates, and prevent its severe consequences [Beutler E, et al. A simple spot screening test for galactosemia. J Lab Clin Med 68: 137-141, 1966] .

Beutler was the first to attempt pharmacologic intervention in sickle cell disease by increasing methemoglobin levels [Beutler E. The effect of methemoglobin formation in sickle cell disease. J Clin Invest 40: 1856-1871, 1961] , carboxyhemoglobin levels [Beutler E. The effect of carbon monoxide on red cell life span in sickle cell disease. Blood 46: 253-259, 1975] , and fetal hemoglobin levels [ Beutler E. The effect of methemoglobin formation in sickle cell disease. J Clin Invest 40: 1856-1871, 1961] . The latter approach depended on administration of estrogen, progesterone and human chorionic gonadotropin. These attempts were unsuccessful, but set the stage for presaged the use of hydroxyurea as a treatment modality.

In addition, Beutler designed the first artificial storage media for red blood cells, introduced the use of mannitol (still a mainstay in red cell preservation), and devised a variety of approaches to maintaining red cell ATP and 2,3-DPG levels and determined the viability of the cells in human volunteers [ Beutler,E. Preservation of liquid red cells. In: Rossi,E.C.; Simon,T.L.; Moss,G.S., eds. Principles of Transfusion Medicine Baltimore: Williams & Wilkins; 1990: 47-56] .

He also played a major role in pioneering new therapies for leukemia: bone marrow transplantation in acute leukemia [ Beutler E, et al. Bone marrow transplantation as the treatment of choice for "good risk" adult patients with acute leukemia. Trans Assoc Am Phys 92: 189-195, 1979] , and 2-chorodeoxyadenosine in chonic leukemias and lymphomas [ Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet 340: 952-956, 1992] .

Beginning in the mid 1990s, Beutler attempted to positionally clone the mutation responsible for the common adult-onset form of hereditary hemochromatosis. He failed to identify the mutation before it was found by others to affect HFE, a member of the major histocompatibility complex family of proteins [ Feder JN, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13: 399-408, 1996] . However, in contrast to the reports of others, he found that only about 2% of males and no females homozygous for the mutation showed severe clinical manifestations of the disease. This study depended upon genotypic and phenotypic analysis of more than 43,000 subjects [Beutler E, et al. Penetrance of the 845G->A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 359: 211-218, 2002] .

Beutler served as an editor of Williams Hematology, a widely used text in this medical specialty, for more than 20 years: from its inception until the last year of his life. In keeping with his editorial interests and his requirements as a publishing scientist, Beutler also wrote the software for the first comprehensive bibliographic retrieval system used by publishing scientists [Beutler E. Reference Manager: A powerful microcomputer-based bibliographic retrieval system. Informatics in Pathol 1: 83-93, 1986] . Later commercialized as Reference Manager, it is still in wide use today.

Awards and Recognition

Beutler was elected to various prestigious professional societies, including the United States National Academy of Sciences, the Institute of Medicine, and the American Academy of Arts and Sciences. He was a president of both the American Society of Hematology and the Western Association of Physicians. He also received numerous awards for his outstanding contributions to biology and medicine. Among these was the Gairdner Foundation International Award (1975) and a Doctor Philosophiae Honoris Causa, Tel Aviv University.

Family

Married to Brondelle May Fleisher in 1950, Beutler had four children (Steven Merrill Beutler, Earl Bryan Beutler, Bruce Alan Beutler, and Deborah Ann Beutler). Bruce A. Beutler, also a biomedical scientist, occasionally collaborated with Ernest Beutler scientifically [Beutler E, et al. Electrophoretic polymorphism of glutathione peroxidase. Ann Hum Genet 38: 163-169, 1974] , [Beutler E, et al. Glutathione peroxidase activity of inorganic selenium and seleno-DL-cysteine. Experientia 31: 769-770, 1975] , [Beutler E, et al. Evolution of the genome and the genetic code: Selection at the dinucleotide level by methylation and polyribonucleotide cleavage. Proc Natl Acad Sci USA 86: 192-196, 1989] , [Du X, et al. The serine protease TMPRSS6 is required to sense iron deficiency. Science 320: 1088-1092, 2008] over a period spanning more than 30 years.

References

External links

* [http://www.gairdnerfoundation.org The Gairdner Foundation] - Official site
* [http://www.scripps.edu/mem/ The Scripps Research Institute Department of Molecular and Experimental Medicine] – Departmental website
* [http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&orig_db=pubmed&term=beutler%20e%20OR%20beutler%20e&cmd=&cmd_current= Scientific Publications] – All publications of articles by Ernest Beutler listed in PubMed.