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• W2079426513 abstract "HomeCirculationVol. 107, No. 13Donald Sharp Fredrickson, MD Free AccessObituaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessObituaryPDF/EPUBDonald Sharp Fredrickson, MD1924–2002 Antonio M. GottoJr, MD, DPhil Antonio M. GottoJrAntonio M. GottoJr Search for more papers by this author Originally published8 Apr 2003https://doi.org/10.1161/01.CIR.0000064600.16488.F8Circulation. 2003;107:1714–1716Dr Donald Sharp Fredrickson was one of the foremost physician scientists and medical leaders of our time. In 1953, as a young investigator, he joined the National Institutes of Health (NIH), where he held a series of increasingly important research and administrative positions in the National Heart Institute, later renamed the National Heart, Lung, and Blood Institute. In 1975, Don was asked to become NIH director. He served under 3 presidents until resigning in 1981.FigureDownload figureDownload PowerPointDuring his 2 decades as a clinical and basic research scientist at the National Heart Institute, Don Fredrickson was part of a remarkable team that helped transform our understanding of the pathophysiology of cardiovascular disease. The work of this team was instrumental in creating the field of lipidology and establishing the foundation for present-day approaches to the management of lipid disorders. Don also trained a generation of international basic and clinical research scientists, fostering their careers in immeasurable ways. These investigators are now among the world’s preeminent lipidologists.After his early work on sterol metabolism, Don studied the structure and metabolism of the plasma lipoproteins, their role in fat transport, and the genetic factors that regulate their metabolism and concentration in the blood (personal communication, NIH, July 23, 2002). He participated in research on apolipoproteins A, B, and C, including the separation of apolipoproteins A and C into their component parts and the characterization and sequencing of apolipoproteins A-II, C-I, C-II, and C-III.1–8 Don also discovered 2 genetic disorders: Tangier disease (TD), whose principal feature is a lack of high-density lipoprotein (HDL), and cholesteryl ester storage disease, a lysosomal enzyme deficiency.9–12 Research into the genetic abnormality that causes TD has provided us with a key to understanding the molecular mechanisms of lipoprotein metabolism.In the early 1960s, Don formed the National Heart Institute’s Section on Molecular Disease, which, to his knowledge, was the first use of this term in the organizational chart of the NIH.8 In addition to serving as head of the Molecular Disease Section, Don was Clinical Director, Director, and Scientific Director of the National Heart Institute over a 13-year period.13 During this time, his laboratory attracted international attention.Believing that scientific knowledge should benefit both the practices of professionals and the lives of as many people as possible, Don never viewed lipoproteins in a vacuum.14 He was also a great conceptualizer. Together with Robert I. Levy and Robert S. Lees, Don established a system for identifying 5 patterns of lipoprotein disorders and their clinical characteristics, including 3 phenotypes not previously recognized as discrete forms of dyslipidemia (personal communication, NIH, July 23, 2002).15 This system was intended to help clinicians find a rational approach to the treatment of patients with certain abnormalities of fat metabolism.15 In 1967, The New England Journal of Medicine published “Fat transport in lipoproteins-an integrated approach to mechanisms and disorders,” a 5-part description of the system that came to be known as the Fredrickson Classification of the Hyperlipidemias. Quickly adopted by the World Health Organization, the Fredrickson phenotypes brought lipid disorders to the world’s attention16 and remain useful today.In 1970, the work of Don and his colleagues resulted in creation of the nationwide Lipid Research Clinics Program (LRCP), led by Bob Levy under the auspices of the National Heart and Lung Institute. One objective of the LRCP was to study the relation between cholesterol and heart disease. The Lipid Research Clinics Coronary Primary-Prevention Trial (LRC-CPPT), which became a model for collaborative studies involving government, academic research centers, and the pharmaceutical industry, was the first clinical trial to show that cholesterol reduction can decrease the incidence of cardiovascular disease.8,17–20 This was a critical step in the sequence of events that led to formation of the National Cholesterol Education Program, whose guidelines for the diagnosis and treatment of high blood cholesterol have become the basis of therapeutic decision making in the United States.In 1975, Don became NIH director, a position that he held for 6 years during one of the most controversial periods in the agency’s history. Despite his many outstanding achievements in that capacity, Don remained a researcher and a clinician at heart. In his 1981 remarks to the NIH community announcing his resignation as director, Don explained that “[i]t’s time for me to shed those burdens [of administration] for a while, lest I forget completely how to be a scientist and a physician.”21Don and his colleagues first described TD in 1961 after discovering 2 siblings on Tangier Island in the Chesapeake Bay who had hypocholesterolemia and enlarged tonsils of unusual appearance.10 Tangier disease was later observed in another sibling pair elsewhere in the country. Further investigation revealed that many members of both families had low HDL levels; this appeared compatible with the hypothesis that plasma concentrations of HDL were regulated within a single pair of autosomal genes.10 Almost 40 years later, a mutation in the gene for the adenosine triphosphate binding cassette (ABC)-A1 transporter was identified as the abnormality linked to TD.22–26 The ABC-A1 transporter is responsible for the efflux of cellular cholesterol, the first step in reverse cholesterol transport.The story of the ABC-A1 mutation reminds us of Don’s admonition in his farewell remarks to the NIH community: “to keep up that faithful curatorship of invaluable collections of data and the tangible collections of objects, cells, mutants…which join us to preceding generations and will join us to the future.”14 In this case, the past includes the accomplishments of Don and his colleagues, while the future signifies hope for the development of novel therapies to prevent and treat cardiovascular disease. Disorders such as TD also remind us that the elemental past, encoded in our genes, can predetermine the future. As Don, Bob Levy, and Bob Lees noted in their 1967 series of articles, “[i]f a pedigree chart appeared on the clinical record of every patient with hyperlipidemia, the number of unanswered questions might be reduced by half.”15Occurring 4 decades after TD was first described, the discovery of the ABC-A1 mutation reaffirms Don’s belief in the long-term nature of scientific inquiry. In the 1980s, as president of the Howard Hughes Medical Institute, one of the world’s largest private institutions funding medical research, Don stressed the importance of making multi-year commitments to grant recipients.27Identification of the TD mutation also recalls Don’s achievements as NIH director. At the start of his tenure, recombinant DNA technology had recently been developed, and some prominent scientists, concerned about the social and ethical implications, were calling for self-imposed restrictions on genetic research. As a pioneer in the study of molecular biology and genetic disorders, Don fully grasped the tremendous potential of recombinant DNA technology to help scientists probe the intracellular errors that contribute to disease.15,28–30 In his role as NIH director, he supported genetic research through leadership in the formulation of public policy that achieves a balance between scientific freedom and responsibility.29,30 Current NIH director Elias Zerhouni has characterized him as a “true statesman of science” who “helped guide the world into the promising, yet uncharted, era of recombinant DNA technology.”31 Don was also instrumental in preserving the law that grants perpetual funding to the NIH, thereby protecting biomedical research from shifting political and ideological priorities. Some regard this as his most important contribution to the future of science.32Don was a superb author and editor whose numerous publications are models of intelligence, objectivity, and lucidity. It was a pleasure to sit with him and carefully go over the articles on which we collaborated. In 1960, just 7 years after Watson and Crick described the double helix, Don joined with John Stanbury and James Wyngaarden to produce the first edition of The Metabolic and Molecular Bases of Inherited Disease. Conceived as a “bold intention to take up from where Garrod had left his descriptions of inherited metabolic disorders in 1908,” this “bible of molecular medicine” is now in its eighth edition.8,33,34As both a realist and an idealist, Don pondered the philosophical bases of science and medicine. He wrote and spoke about the importance of remaining true to our highest principles, stating that we must “maintain a rigorous defense of scientific ethics and of scientific freedom, for they are inseparable.”14,35 These reflections are particularly pertinent today, when the conduct of research and the practice of medicine are under intense economic and social pressure and ethical scrutiny.Don’s other accomplishments and honors are too numerous to describe in full. They include serving as president of the Institute of Medicine of the National Academy of Sciences (NAS) from 1974 to 1975, and, after resigning as NIH director, returning to the NAS as a visiting scholar (personal communication, NIH, July 23, 2002). During the 1990s, Don was a Scholar-in-Residence at the National Library of Medicine (NLM), where he chaired the Long-Range Planning Panel on International Programs. He also played a crucial role in developing Profiles in Science, an Internet archive that contains collections donated to the NLM by prominent biomedical scientists. Don was one of the first to contribute his papers (personal communication, NLM Executive Officer, August 7, 2002). Now available online, his collection contains an invaluable array of primary and secondary source materials.36My personal memories of Don Fredrickson date back to 1965, when he first interviewed me for a research position in the Molecular Disease Branch of the NIH. The interview, which took place over a sandwich lunch in his office, resulted in an invitation to work with Don, Bob Levy, and the other remarkable investigators on their team. I shall always treasure this extraordinary time of intellectual excitement, absolute commitment to scientific integrity, and friendship. Don and his beloved wife also welcomed us into their home, where they were the warmest of hosts. Mrs. Fredrickson often befriended the young scholars whose careers Don nurtured, helping them meet the challenges of daily life.Don was a wonderful physician who exercised his calling with the utmost compassion. Patients with disorders of lipid metabolism were regularly referred to him, and his clinic at the NIH attracted international attention. Don’s patients ranged from humble citizens to the King of Morocco, to whom he became personal physician in 1975.13 Whether in the hospital corridor or the corridors of power, Don treated each colleague and patient with respect, kindness, and personal attention. His standards of performance and integrity, both personal and professional, were of the highest order. In all his relationships, whether brief or of long duration, Don was absolutely honest and trustworthy, and yet his candor was always tempered by kindness. He was devoted to family, friends, and profession.When Don retired from the NIH, he wrote a farewell poem to his colleagues.37 Entitled “A Fading King’s Bequest (on eve of metamorphosis to Guest Worker),” the poem truly represents Don both in content and in style. It is written in a manner that evokes his erudition and love of language and is modest, self-effacing, humorous, affectionate, and serious. Each stanza captures the essence of those whom he describes. The final lines are perhaps the best expression of our loss:Yes, a host come and goneGone, reaching way back in the past—What can I say butThank you, it’s been fun, my dears…Not very original, but all I can dare do,For the very next sounds will be tears.Correspondence to Antonio M. Gotto, MD, DPhil, Weill Medical College of Cornell University, c/o Paula Trushin, Olin Hall 205, 445 E 69th St, New York 10021. E-mail [email protected]References1 Gotto AM, Levy RI, Fredrickson DS. Observations on the conformation of human beta lipoprotein: evidence for the occurrence of beta structure. Biochemistry. 1968; 60: 1436–1441.Google Scholar2 Gotto AM, Levy RI, Rosenthal AS, et al. The structure and properties of human beta-lipoprotein and beta-apoprotein. Biochem Biophys Res Commun. 1968; 31: 699–705.CrossrefMedlineGoogle Scholar3 Brown WV, Levy RI, Fredrickson DS. Studies of the proteins in human plasma very low-density lipoproteins. J Biol Chem. 1969; 244: 5687–5604.CrossrefMedlineGoogle Scholar4 Brown WV, Levy RI, Fredrickson DS. Further characterization of apolipoproteins from the human plasma very low-density lipoproteins. J Biol Chem. 1970; 245: 6588–6594.CrossrefMedlineGoogle Scholar5 Brown WV, Levy RI, Fredrickson DS. Further separation of the apoproteins of the human plasma very low-density lipoproteins. Biochem Biophys Acta. 1970; 200: 573–575.CrossrefMedlineGoogle Scholar6 Brewer HB Jr, Shulman R, Herbert P, et al. The complete amino acid sequence of alanine apolipoprotein (apoC-3), an apolipoprotein from human plasma very low density lipoproteins. J Biol Chem. 1974; 249: 4975–4984.CrossrefMedlineGoogle Scholar7 Shulman RS, Herbert PN, Wehrly K, et al. The complete amino acid sequence of C-1 (apoLp-Ser), an apolipoprotein from human very low density lipoproteins. J Biol Chem. 1975; 250: 182–190.CrossrefMedlineGoogle Scholar8 Fredrickson DS. Phenotyping: on reaching base camp (1950–1975). Circulation. 1993; 87 (suppl III): III-1–III-15.CrossrefGoogle Scholar9 Fredrickson DS, Altrocchi PH, Avioli LV, et al. Tangier disease. Ann Intern Med. 1961; 55: 1061–1031.Google Scholar10 Hoffman HN, Fredrickson DS. Tangier disease (familial high density lipoprotein deficiency): clinical and genetic features in two adults. Am J Med. 1965; 39: 582–593.CrossrefMedlineGoogle Scholar11 Fredrickson DS. Newly recognized disorders of cholesterol metabolism. Ann Intern Med. 1963; 58: 718.Abstract.Google Scholar12 Fredrickson DS, Sloan HR, Ferrans VJ, et al. Cholesteryl ester storage disease: a most unusual manifestation of deficiency of two lysosomal enzyme activities. Trans Assoc Am Physicians. 1972; 85: 109–119.MedlineGoogle Scholar13 National Library of Medicine. Profiles in Science: The Donald Fredrickson Papers: Physician, Scientist, and Leader of Biomedical Research. Available at: http://profiles.nlm.nih.gov/FF/Views/Exhibit/narrative/biographical.html. Accessed March 4, 2003.Google Scholar14 National Library of Medicine. Profiles in Science. The Donald Fredrickson Papers: All Visuals. Remarks to the NIH Community [thinking of the future]. Excerpt. Speech. Video Recording. June 19, 1981; Available at: http://profiles.nlm.nih.gov/FF/B/B/N/J/_/ffbbnj_.mov. Accessed December 23, 2002.Google Scholar15 Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins: an integrated approach to mechanisms and disorders. N Engl J Med. 1967; 276: 34–43, 94–103, 148–156, 215–225, 273–281.CrossrefMedlineGoogle Scholar16 Beaumont JL, Carlson LA, Cooper GR, et al. Classification of hyperlipidaemias and hyperlipoproteinemias. Bull WHO. 1970; 43: 891–915.MedlineGoogle Scholar17 Wilson TE, Kimmel B. Managing collaborations among federal government, academia, and the biomedical industry. Research Management Review Online. National Council of University Research Administrators. Available at: http://www.ncura.edu/rmr/feature14.htm. Accessed July 25, 2002.Google Scholar18 Lipid Research Clinics Coronary Primary Prevention Trial results: I: reduction in incidence of coronary heart disease. Lipid Research Clinics Program. JAMA. 1984; 251: 351–364.CrossrefMedlineGoogle Scholar19 Lipid Research Clinics Coronary Primary Prevention Trial results: II: the relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984; 251: 365–374.CrossrefMedlineGoogle Scholar20 Lipid Research Clinics Coronary Primary Prevention Trial: results of 6 years of post-trial follow-up. Arch Intern Med. 1992; 152: 1399–1410.CrossrefMedlineGoogle Scholar21 National Library of Medicine. Profiles in Science. The Donald Fredrickson Papers: All Visuals. Remarks to the NIH community [resignation announcement]. Excerpt. Speech. Video Recording. June 19, 1981. Available at: http://profiles.nlm.nih.gov/FF/B/B/N/L/_/ffbbnl_.mov. Accessed December 23, 2002.Google Scholar22 Rust S, Rosier M, Funke H, et al. Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet. 1999; 22: 352–355.CrossrefMedlineGoogle Scholar23 Remaley AT, Rust S, Rosier M, et al. Human ATP-binding cassette transporter 1 (ABC1): genomic organization and identification of the genetic defect in the original Tangier disease kindred. Proc Natl Acad Sci U S A. 1999; 96: 12685–12690.CrossrefMedlineGoogle Scholar24 Brooks-Wilson A, Marcil M, Clee SM, et al. Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency. Nat Genet. 1999; 22: 336–345.CrossrefMedlineGoogle Scholar25 Marcil M, Brooks-Wilson A, Clee SM, et al. Mutations in the ABC1 gene in familial HDL deficiency with defective cholesterol efflux. Lancet. 1999; 354: 1341–1346.CrossrefMedlineGoogle Scholar26 Santamarina-Fojo S, Peterson K, Knapper C, et al. Complete genomic sequence of the human ABCA1 gene: analysis of the human and mouse ATP-binding cassette A promoter. Proc Natl Acad Sci U S A. 2000; 97: 7987–7992.CrossrefMedlineGoogle Scholar27 Fredrickson DS. Face to Face. Donald Fredrickson: spending Hughs’ [sic] legacy [interview]. Scientist. 1987;1:16. Available at http://www.the-scientist.com/yr1987/jan/features_870126.html. Accessed July 9, 2002.Google Scholar28 The National Health Museum. Milestones in DNA history. Available at: http://www.accessexcellence.org/AB/WYW/wkbooks/SFTS/sidebarmilestone.html. Accessed January 14, 2003.Google Scholar29 Murray TH. Recombinant DNA. Review of Fredrickson DS. The Recombinant DNA Controversy: A Memoir: Science, Politics, and the Public Interest 1974–1981. JAMA. 2001; 286: 2331–2332.Google Scholar30 Fredrickson DS. The Recombinant DNA Controversy: A Memoir. Science, Politics, and the Public Interest 1974–1981. Washington, DC: ASM Press; 2001.Google Scholar31 Weil M. Ex-NIH Director Donald Fredrickson dies. Washington Post. June 8, 2002:B7. Obituary.Google Scholar32 Metheny B. Donald Fredrickson “stood tall” for the National Institutes of Health. Washington Fax. June 17, 2002. Chevy Chase, Md: FDC Reports, Inc. Available at: http://www.washingtonfax.com.Google Scholar33 Nyhan WL. Molecular medicine. JAMA. 2001; 286: 2329.Review.Google Scholar34 Scriver CR, Beaudet AL, Sly WS, et al (eds). The Metabolic and Molecular Bases of Inherited Disease. vols 1–4. 8th ed. New York, NY: Mc Graw-Hill; 2001.Google Scholar35 Fredrickson DS. On the cultivation of virtue. Mayo Clin Proc. 1983; 58: 660–662.MedlineGoogle Scholar36 National Library of Medicine. Profiles in Science. The Donald Fredrickson papers. Available at: http://profiles.nlm.nih.gov/FF. Accessed December 16, 2002.Google Scholar37 National Library of Medicine. Profiles in Science: The Donald Fredrickson papers. A Fading king’s bequest. Fredrickson’s departing poem to NIH (1981). Available at: http://profiles.nlm.nih.gov/FF/Views/AlphaChron/alpha/10027./ Accessed December 23, 2002.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetails April 8, 2003Vol 107, Issue 13 Advertisement Article InformationMetrics https://doi.org/10.1161/01.CIR.0000064600.16488.F8 Originally publishedApril 8, 2003 PDF download Advertisement" @default.
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