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81 sarett

N A T I O N A L A C A D E M Y O F S C I E N C E S Any opinions expressed in this memoir are those of the author and do not necessarily reflect the views of the T H E N A T I O N AL A C A D E MY P R E S S Courtesy of Merck & Co., Inc., Whitehouse Station, New Jersey.
December 22, 1917–November 29, 1999 LEWIS H. SARETT WAS the first chemist to synthesize corti- sone. It was a feat of remarkable complexity involving nearly 40 chemical steps from desoxycholic acid and wasachieved during World War II as a chemist in the MerckResearch Laboratories. This synthesis and subsequent im-provements of it ultimately led to cortisone’s use in treat-ing rheumatoid arthritis and was the first of Sarett’s manycontributions to medicine during a 40-year career at Merck.
When he retired in 1982 he was senior vice-president forscience and technology. He had been a key contributor toMerck’s growth, and in later years Sarett was an influentialindustry spokesman for U.S. science policy.
Lew Sarett was born in Champaign, Illinois, on Decem- ber 22, 1917. His father was a professor of speech at North-western University, a poet, and an outdoorsman. The latterinterest led him to locate his family in Laona in northernWisconsin while he lived in Evanston, Illinois, for one se-mester of the school year. Lew enjoyed rural life, but thecommuting ultimately became too much for his father, andthe family moved back to Illinois, where Sarett attendedhigh school in Highland Park. A beginner’s chemistry setintroduced him to science, and with the encouragement of one of his relatives, Charles Osgood, later to become a cu-rator of the Peabody Museum at Yale, he acquired an inter-est in fossils. Apparently on his own, Lew became an avidchess player and even in retirement he continued to playchess using a computer as his opponent. One of his charac-teristics as a chemist and manager was his love of chal-lenges and an ability to devise detailed strategies. Thesetraits were evident in his lifelong enjoyment of chess.
In 1935 Lew enrolled in Northwestern University where he originally thought he might major in mathematics, butthe chemistry department, which included Charles Hurdand Ward Evans, was a good one. Sarett had a natural tal-ent for chemistry, more so than for advanced mathematics,so he became a chemistry major. He continued playing chessand, with the encouragement of his father who was an ath-lete in college, he also took up wrestling. He did well in hischemistry courses and graduated from Northwestern Uni-versity in 1939 with Phi Beta Kappa honors.
To continue his studies after Northwestern Sarett ap- plied to four graduate schools. Princeton offered him ateaching assistantship, which he accepted on the recom-mendation of Professor Hurd. Princeton’s department wasstrong in physical chemistry (Henry Eyring, Hugh Taylorand John Turkevich), but Sarett wanted to do synthesis.
The choices were Greg Dougherty and Everett Wallis, andthe latter’s work in steroid chemistry held great appeal.
Some of the best chemists of the day were working on ste-roids. Sarett was caught up in that cutting-edge research,which intensified when the United States entered WorldWar II in December 1941. Sarett’s assignment with Walliswas to explore bromination reactions of steroidal ketoneswith the long-range objective of converting steroids like cho-lesterol into the female sex hormone estradiol.
Princeton granted Sarett a Ph.D. degree after only two and one-half years so he could begin working in early 1942at Merck on the synthesis of cortisone. Syntheses of it andpenicillin were given high priority in the war effort andconsortiums of industrial and academic scientists were cre-ated to expedite their production. The cortisone consor-tium included a group at the Mayo Clinic under E. C. Kendall,and Sarett spent a short time there before working full-time at Merck. Great importance was attached to a corti-sone synthesis since supplies from bovine adrenal glandswere extremely limited and it was believed (although erro-neously) that the hormone increased the endurance of Ger-man pilots at high altitudes.
Sarett’s synthesis of cortisone from desoxycholic acid required moving the 12-ketone to the 11-position, intro-duction of an unsaturated ketone in the A-ring and replace-ment of the bile acid side chain by dihydroxyacetone func-tionality. Relocating the ketone was achieved usingmethodology pioneered by Tadeus Reichstein’s group inBasel, Switzerland. Sarett degraded the bile acid side chainto a 17-ketone, from which he fashioned a protected dihy-droxyacetone side chain in a multi-step process. Bromina-tion and dehydrobromination afforded the unsaturated ke-tone functionality required in ring A. The Merck processresearch group led by Max Tishler supplied some of theintermediates required in this synthesis; however, withoutan assistant, Sarett had gone through nearly 40 steps toproduce 18 milligrams of cortisone.
On March 1, 1944, Sarett married Mary Adams Barrie.
They lived in Princeton and had two daughters: Mary NicoleSarett of Skillman, New Jersey, and Katharine Wendy Youngof Devon, Pennsylvania. Sarett frequently entertained Merckcolleagues at his home and in later years he became a low-handicap golfer.
Shortly after the war ended, Merck management decided to make cortisone available to clinical investigators to see ifa use could be found for it. Sarett’s partial synthesis hadbeen improved and scaled up by Max Tishler’s chemistsand by April 1948 almost 100 grams of cortisone were onhand.
When later that year Philip Hench tried cortisone in a female patient with rheumatoid arthritis, her improvementwas spectacular, and cortisone was hailed as a wonder drug.
Knowledge of its efficacy led to urgent clinical requests forthe compound. With justifiable confidence in Merck chem-istry, George Merck convinced U.S. government officialsthat Merck could in reasonable time supply all that wasneeded. While Tishler’s group improved the bile acid pro-cess still further and established its commercial viability,Lew Sarett and his group accomplished a total synthesis ofcortisone, which he announced in 1952. Although it didnot go into production, Sarett was very proud of that achieve-ment, which the Annual Reports of the Chemical Societysaid was the best synthetic chemistry contribution of thatyear. Sarett’s cortisone achievements brought him acclaimin the academic community. He was offered a faculty posi-tion at MIT, but he turned it down to accept expandedresponsibilities at Merck as head of medicinal chemistry.
Cortisone’s leadership position in the treatment of ar- thritis was overtaken by prednisolone following its discov-ery in 1955 by scientists at the Schering Corporation. Theyhad been working on alternative methods of making corti-sone; instead, they discovered that an additional doublebond in the A-ring of cortisol modestly increased its po-tency, and more importantly, this change markedly reducedthe sodium retention properties of cortisol. The realizationthat a natural hormone’s efficacy and therapeutic indexcould be improved by chemical manipulation had profoundconsequences in the steroid field and in drug design more generally. Josef Fried and his group at Squibb enhancedcortisone’s potency by introducing a 9α-fluorine group.
Sarett’s group showed 16α-methyl steroids had advantagesin both potency and sodium retention. Putting all of thesestructural features together, Sarett’s group produced Decadron,which to this day is the high-potency clinical standard amonganti-inflammatory steroids.
As head of medicinal chemistry at Merck, Sarett became an industry leader in drug design. He evolved rules for theminimum systematic development of screening leads andelaborated receptor concepts to rationalize the anti-inflam-matory activities of cortisone analogs. His department inRahway, New Jersey, also had responsibility for Merck’s ani-mal health products. That business had begun several yearsearlier with Tishler’s development of sulfaquinoxaline forcoccidiosis. Sarett and his group led by Ed Rogers and HoraceBrown produced the coccidiostats Amprol and Nicarbazin andthe anthelmintic Thibenzole. They were market leaders formany years.
Most importantly, Sarett continued to innovate therapy for arthritis. When manipulations of the steroid nucleusfailed to improve the therapeutic index of Decadron, he andRalph Hirschmann devised steroidal conjugates that wereselectively activated in the inflamed joint. These compoundsunfortunately lacked oral activity and so were not devel-oped, but this work was a dramatic early example of druglatentiation that is still a viable way to maximize safety.
Ultimately, addressing the shortcomings of steroids re- quired a fundamental change in strategy. Aspirin had beenin use for many years, so there was precedent for nonsteroi-dal arthritic drugs. The problem was how to discover newtherapeutic mechanisms or improve the potency of aspirin.
Under Sarett’s leadership Merck scientists took up that chal-lenge. A reliable animal assay for anti-inflammatory activity was developed by Charles A. Winter, and T. Y. Shen headedthe chemistry effort. Together with their colleagues thisteam and Sarett in a remarkable burst of creativity pro-duced Indocin, Clinoril, and Dolobid. With Decadron these drugsbecame mainstays of therapy and have been used to allevi-ate the pain and disabilities of millions of rheumatoid andosteoarthritis patients.
In 1969 Sarett was made president of the Merck Sharp and Dohme Research Laboratories, a position that he helduntil 1976. During that time Merck became a leader invaccine research. Maurice Hilleman’s group in its West Pointlaboratories produced a triple vaccine for measles, mumps,and rubella, and Pneumovax was introduced, affording pro-tection against 14 strains of pneumonia.
Sarett had a longstanding interest in natural products and one of his legacies was to strengthen Merck capabilitiesin fermentation product research. An early achievementwas the identification of a methoxycephalosporin in 1972from which Burton Christensen and his associates producedMefoxin. This injectable antibiotic had excellent activity againsta group of organisms resistant to existing antibiotics. Forseveral years it became one of the leading antibiotics inhospital use.
Most importantly, in 1976, the year of his retirement as president of the Merck Research Laboratories, the broad-spectrum antibiotic thienamycin and the antiparasitic drugavermectin were discovered. Their development in subse-quent years led to Imipenem and Ivermectin. The former isone of the antibiotics of last resort in hospital use today.
The latter is widely used to treat roundworms in cattle andsheep and prevent heartworm infections in dogs and riverblindness in humans.
Sarett also organized the New Lead Discovery Depart- ment first under Ralph Hirschmann and then under Arthur Patchett in 1972. Sarett was ahead of his time in recogniz-ing a need to generate compounds in large numbers forbiological testing. That department, whose structure andmission were established by Sarett, produced several ofMerck’s biggest products in the 1980s and 1990s, includingVasotec, Prinivil, and Mevacor.
When Sarett was promoted to corporate management in 1976, he was the inventor or coinventor of 178 U.S. pat-ents. His scientific honors were numerous and included: Northwestern Alumni Associate Award of MeritMerck Board of Directors Scientific AwardLeo Hendrik Baekeland Award of theAmerican Chemical Society (North JerseySection) William Scheele Lecture Award, Stockholm,SwedenAmerican Chemical Society Award for CreativeResearch in Synthetic Organic ChemistrySynthetic Organic Chemical ManufacturersAssociation Medal for Creative Research inSynthetic Organic Chemistry New Jersey Patent Award, New Jersey Councilfor Research and Development Chemical Pioneer Award of the AmericanInstitute of Chemists Perkin Medal Award of the Society ofChemical Industry From 1976 to 1982 Sarett was Merck senior vice-presi- dent for science and technology and directed the strategicplanning activities of all the company’s divisions worldwide.
He had corporate responsibility for licensing new productsand technologies and built relationships with companiesand academic groups. He also became a leading spokesmanfor Merck and the industry on national science policy, in-cluding service on the General Accounting Office’s advi-sory group regarding the Food and Drug Administration(1978), a Commerce Department subcommittee on researchsupport and industrial innovation (1978-79), and a U.N.
advisory group on science and technology development (1978-82). He was also a member of the Task Force on Scienceand Technology for President-elect Reagan and served onthe Science and Technology Panel of the Reagan transitionteam. Sarett testified seven times during 1980-82 before com-mittees of the U.S. Senate and House of Representativesabout the interrelationships of governmental policy and in-novation in the pharmaceutical industry.
During his tenure as senior vice-president for science and technology, Sarett was asked if he would like to bedirector of the National Institutes of Health, but MerckPresident Henry Gadsden asked him to remain at Merck,and somewhat reluctantly Sarett turned down the NIH pos-sibility.
He became a member of the National Academy of Sci- ences in 1977 and a member of the Institute of Medicine in1978. Other honors included: Honorary doctor of science, BucknellUniversity Election to the National Inventors Hall of FameIndustrial Research Institute Medal Gold Medal Award of the American Instituteof Chemists Proctor Medal of the Philadelphia DrugExchange Throughout his career Sarett was an active participant and advisor to numerous professional organizations. Amongthese activities were the following: Chair, Basic Science Advisory Committee,National Cystic Fibrosis Research Foundation Consultant, Department of Defense,Chemotherapy of Malaria and Schistosomiasis Member, Board of Trustees, Cold SpringHarbor Laboratory for Quantitative Biology Member, Advisory Council, Department ofChemistry, Princeton UniversityMember, Editorial Advisory Board, Chemicaland Engineering News Representative, Pharmaceutical ManufacturersAssociation Member, Governing Board, Association ofPrinceton Graduate Alumni He also became a member of the Industrial Advisory Committee of the University of California, San Diego, in1971; a member of the Center for Public Resources TaskForce on Developing Countries’ Health in 1979; and a mem-ber of the Pharmaceutical Manufacturers Association’s Com-mission on Drugs for Rare Diseases in 1981.
Sarett retired from Merck in 1982 several months ahead of his sixty-fifth birthday and mandatory retirement as acorporate officer. An overflow crowd of admirers packedthe Baltusrol Country Club in Springfield, New Jersey, onJuly 23, 1982, to express their gratitude and to wish himwell. Among the speakers was his long-time mentor andcolleague Max Tishler. With great pride he described Sarett’scontributions to chemistry, to the growth and welfare of Merck, and to the shaping of public science policy. It was amemorable night and a breadth of achievements unequaledin Merck chemistry was honored.
Sarett’s first marriage ended in divorce and he remar- ried on June 28, 1969. His second wife was Merck microbi-ologist Pamela Thorp, and they were together for the re-maining 30 years of his life. They had two children: Will H.
Sarett of Bonney Lake, Washington, and Renee M. Sarett ofNorwich, Vermont. Like Sarett, Pamela Thorp had grownup in Wisconsin and when he retired from Merck, theydecided to relocate from Skillman, New Jersey, to a ruralarea. Their choice was to build a home in Viola, Idaho,where they could have fruit trees, tend garden, and Sarettwould be well located for occasional hunting trips. The sur-rounding countryside was beautiful and the University ofIdaho was nearby. He was offered a position in its chemis-try department, but he declined feeling that he had beenaway from the laboratory for too many years. Instead, hejoined the advisory committee of a venture capital com-pany, New Enterprise Associates, and became active in theWest Coast biotech industry. With years of experience heknew how to develop drugs and this knowledge was an im-portant asset for biotech companies to draw upon; follow-ing his retirement from Merck he served on the boards ofdirectors of more than 15 of them, including Affymax, Amylin,Immunex, and Genentech Development Corporation. He en-joyed working with innovators, and the entrepreneurial spiritof these smaller organizations brought back pleasant memo-ries of his early days at Merck.
Lew Sarett died in Viola at age 81 of complications from advanced colitis. In addition to his wife and four childrenhe was survived by five grandchildren. As Max Tishler saidof him at his retirement dinner “both by words and by his accomplishments he added a sense of excitement to inven-tion in industrial laboratories.” THE AUTHOR IS most grateful to Joseph M. Ciccone for providingbiographical data from the Merck archives, including the transcriptof an interview with Lew Sarett conducted by Leon Gortler on Sep-tember 6, 1990. Review of this manuscript by Pamela Sarett Presoland information supplied by Renee Sarett and Charles W. Newhallof New Enterprise Associates are also gratefully acknowledged.
With P. N. Chakravorty and E. S. Wallis. Studies on the bromination of steroid ketones. J. Org. Chem. 8:405-16.
Partial synthesis of pregnene-4-triol-17(β), 20(β), 21-dione-3, 11 and pregnene-4-diol-17(β),21-trione-3,11,20 monoacetate. J. Biol. Chem.
Partial synthesis of dehydrocorticosterone acetate. J. Am. Chem.
With E. S. Wallis. The chemistry of steroids. Annu. Rev. Biochem.
A new method for the preparation of 17(α)-hydroxy-20-ketopregnanes.
With G. E. Arth, R. E. Beyler, and others. Stereospecific total syn- thesis of cortisone. J. Am. Chem. Soc. 74:4974-76.
With G. E. Arth, D. B .R. Johnston, J. Fried, and others. 16-Methy- lated steroids. I. 16-Methylated analogs of cortisone, a new groupof antiinflammatory steroids. J. Am. Chem. Soc. 80:3160-61.
With G. E. Arth, J. Fried, D. B. R. Johnston, and others. 16-Methy- lated steroids. II. 16α-Methyl analogs of cortisone, a new groupof anti-inflammatory steroids, 9α-halo derivatives. J. Am. Chem.
Soc. 80:3161-63.
With R. Hirschmann, J. M. Chemerda, K. Pfister, and others. Syn- thesis of cortisone 21-phosphate. J. Am. Chem. Soc. 80:6300-6303.
With J. H. Fried and G. E. Arth. Alkylated adrenal hormones. Syn- thesis of 6α-methyl cortical steroids. J. Am. Chem. Soc. 81:1235-39.
With E. F. Rogers, R. L. Clark, A. C. Cuckler, and others. Antipara- sitic drugs. III. Thiamine-reversible coccidiostats. J. Am. Chem.
Soc. 82:2974-75.
With H. D. Brown, W. C. Campbell, A. C. Cuckler, and others.
Antiparasitic drugs. IV. 2-(4-Thiazolyl)benzimidazole, a newantihelmintic. J. Am. Chem. Soc. 83:1764-65.
With R. E. Beyler and others. Bis(methylenedioxy) steroids. V. Gen- eral method for protecting the dihydroxyacetone side chain. J.
Org. Chem. 26:2421-25.
With A. A. Patchett and S. Steelman. The effects of structural alter- ation on the antiinflammatory properties of hydrocortisone. Prog.
Drug Res. 5:11-154.
With G. E. Arth and others. Aldosterone antagonists. 2′,3′-Tetrahy- drofuran-2′-spiro-17-(4-androsten-3-one) and related compounds.
J. Med. Chem. 6:617-18.
With R. Hirschmann, S. L. Steelman, R. Silber, and others. Ap- proach to an improved anti-inflammatory steroid. Synthesis of11β,17-dihydroxy-3,20-dioxo-1,4-pregnadien-21-yl 2-acetamido-2-deoxy-β-D-glucopyranoside. J. Am. Chem. Soc. 86:3903-3904.
Progress in chemotherapy of inflammation. Farm. Revy. 64:525-43.
With T. Y. Shen. Indolyl aliphatic acids. U.S. Patents 3,242,162; International symposium on inflammation and its therapy—experi- ences with indomethacin. Florence, April 1-4, 1971. Introduc-tion. Arzneimittelforsch. 21:1759-61.
Impact of regulations on industrial R and D—FDA regulations and their influence on future R and D. Res. Manage. 17:18-20.
Private research in the public eye. Perkin Medal address, Feb. 28, With J. Hannah, W. V. Ruyle, T. Y. Shen, and others. Discovery of diflunisal. Br. J. Clin. Pharmacol. 4(Suppl. 1):7-13.
With J. Hannah, W. V. Ruyle, T. Y. Shen, and others. Novel analge- sic-antiinflammatory salicylates J. Med. Chem. 21:1093-1100.
The impact of natural product research on drug discovery. Prog.
Research and invention. Proc. Natl. Acad. Sci. U. S. A. 80:4572-74.



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