Paul C. Zamecnik (1912–2009)

Paul Zamecnik's scientific curiosity was tweaked when the fat lady died. As a young medical resident in Cleveland, Ohio, a morbidly obese woman under his care died within a week of hospitalization. At autopsy, he was struck by the excessive amount of fat in her tissue but only minimal protein, and began to wonder how proteins were actually synthesized. It was 1936, and Zamecnik's effort to answer that question proved to occupy his thinking and research for much of his scientific career. After working on toxic shock syndrome during World War II at Harvard's Collis P. Huntington Memorial Hospital for Cancer Research, Zamecnik established a laboratory at the Massachusetts General Hospital (MGH), focusing on the mechanisms of protein synthesis. Fortunately, in the late 1940s, the carbon-14 (14C) isotope was available as a tracer, and he enlisted Robert Loftfield to synthesize 14C-labeled amino acids. Zamecnik promptly showed that 14–Camino acids were incorporated into proteins in rat liver, but realized that to dissect the intermediary events, a cell-free system was needed. He achieved that with colleague Nancy Bucher, who was working on hepatic cholesterol biosynthesis. With this system in hand in 1956, his laboratory had a succession of major achievements. Together with Mahlon Hoagland and Mary Stephenson, he showed that adenosine 5′-triphosphate was required for protein synthesis, and that ribosomes were the site of protein assembly. Zamecnik further discovered that a soluble small molecular RNA—later called transfer RNA (tRNA)—was essential. tRNA proved to be the adaptor molecule proposed by Francis Crick as to how DNA might be translated into an amino acid sequence. James Watson remarked at the time that if a cell-free system could be developed in the model bacterium Escherichia coli , the field could take off. Again, the Zamecnik group accomplished this in short order, and it attracted the prompt attention of scientists including Marshall Nirenberg, Heinrich Matthaei, Har Gorbind Khorana, and Robert Holley. Deciphering the genetic code quickly followed. Years later, Zamecnik, in somewhat lamenting tones, told me, “Our cell-free bacterial protein synthesizing system opened a floodgate of exciting research. We felt as if we were left standing on Mt. St. Michel while the incoming tide roared past us.” In 1978, while working on the structure of Rous sarcoma virus (RSV), Zamecnik showed that a short chain of nucleotides—a synthetic antisense chain—could bind to the complementary sequence of messenger RNA (mRNA). He successfully used antisense oligonucleotides to block the replication, transcription, and translation of RSV in chicken fibroblasts. Thus, a new concept for drug development was born and later, Zamecnik and co-workers used antisense inhibition to interfere with the growth of influenza virus, HIV, malaria parasites, and Mycobacterium tuberculosis in vitro. The recently discovered mechanisms by which small interfering RNA and microRNA control gene expression depend on the hybridization of single-strand oligomers of ∼22 nucleotides with target mRNAs. In fact, in 1987, Zamecnik published the first evidence for the existence of microRNAs and suggested presciently that they might function as metabolic regulators. ![Figure][1] CREDIT: ZAMECNIK ARCHIVE Paul C. Zamecnik was born in 1912 and grew up in Cleveland. He received a bachelor's degree from Dartmouth College in 1933 and medical degree from Harvard Medical School in 1936. He applied for a surgical internship at MGH but was put on a waiting list. After a year back in Cleveland at Lakeside Hospital, he became an intern at the Collis P. Huntington Hospital of Harvard University where he cared for cancer patients. However, he found clinical medicine wanting and felt there was nothing one could really do for patients. He was told that if he was interested in protein synthesis he should work with Max Bergmann at the Rockefeller Institute for Medical Research. After being told by Bergmann that “I want a chemist, not a medical man,” Zamecnik obtained a fellowship to work with Kaj Linderstrom-Lang at the Carlsberg Laboratory in Denmark. However, the Nazi invasion of Denmark cut his stay short and on returning home, Bergmann accepted him in his lab. Bergmann believed that protein synthesis was the reverse of proteolysis, but Zamecnik had his doubts. In the mid-1940s, Fritz Lipmann came to the MGH from Denmark and at lunch with him one day, Zamecnik said, “You don't really think these Bergmann enzymes have anything to do with protein synthesis, do you?” Lipmann thought there was a whole new pathway in which amino acids were energized. That led to Zamecnik's quest to find out whether Bergmann or Lipmann was correct. It was obviously Lipmann. In 1956, Zamecnik be came the Collis P. Huntington Professor of Oncologic Medicine at Harvard Medical School and continued research at MGH until reaching mandatory retirement in 1979. He moved his lab to the Worcester Foundation for Medical Research in Massachusetts and in 1997 returned to MGH as a senior scientist affiliated with its Cancer Center. He continued to be remarkably productive, showing that the insertion of oligonucleotides by transhybridization could correct the cystic fibrosis gene mutation, and using antisense oligonucleotides to inhibit M. tuberculosis cell wall synthesis. He was at work on these and other projects until 4 weeks before his death on 27 October. Zamecnik received many prestigious awards including the National Medal of Science in 1991 and the Albert Lasker Award for Special Achievement in Medical Science in 1996. In making the presentation, Joseph Goldstein, Chair of the Lasker Jury, noted that “Zamecnik's identification of transfer RNA is a landmark in the history of science. In this one experiment biochemistry and genetics became fused into the new science of molecular biology and the door was opened for creating the genetic code.” Paul Zamecnik was admired by his peers and colleagues for his integrity, generosity, originality, and wisdom. He was reserved and modest and viewed his accomplishments with a quiet and dignified humility. [1]: pending:yes