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The FASEB Journal  • FASEB Milestones

50 years ago protein synthesis met molecular biology:the discoveries of amino acid activation

and transfer RNA Thoru Pederson1

Department of Biochemistry and Molecular Pharmacology, University of MassachusettsMedical School, Worcester, Massachusetts, USA 

Two key biochemical insights emerged nearly 50 yearsago with the discoveries, by Mahlon Hoagland and PaulZamecnik, of the two initial steps in the synthesis of protein: the activation of amino acids and their subse-quent linkage to a hitherto unidentified cellular RNA 

fraction—tRNA (1–3). These laboratory events coin-cided with Francis Crick’s brilliant prediction that such“adaptor” RNAs must exist (i.e., before amino acidscould be ordered as prescribed by DNA they must begiven an identity that could be recognized by a nucle-otide sequence) (4).

Hoagland had intended to become a surgeon but had contracted tuberculosis while a medical student at Harvard. Two years later, recovered, he completed hisMD training but, finding himself still not up to thephysical demands of surgery, he turned to biochemis-try. He spent three years as a post-doc at the Massachu-setts General Hospital (MGH) in cancer research, a

 year with Kaj Linderstrøm-Lang at the Carlsberg Labo-ratory in Copenhagen and a year in Fritz Lipmann’s labat the MGH—all seminal experiences (5). He then joined the group headed by Paul Zamecnik at theMGH.

Using a technique involving amino acid-dependent exchange of radioactive pyrophosphate with ATP, cat-alyzed by enzymes in cell-free fractions of rat liver,Hoagland found that amino acid activation involvedthe formation of a mixed anhydride bond between the␣-phosphorous of ATP and the carboxyl group of theamino acid (2). Importantly, the activated amino acidadenylate remained bound to the enzyme that cata-

lyzed its formation. Hoagland then turned his attentionto a curious earlier finding of Zamecnik, viz. that 14C-amino acids became covalently linked to a non-sedimentable RNA species. Hoagland followed up thislead and found that the attachment of amino acids tothis “soluble RNA” (soon renamed tRNA) seemed to becatalyzed by the same enzymes that had activated themand that, once linked to the RNA, the amino acids wererapidly transferred to peptide linkage in protein- clearly indicating that this special RNA was behaving as anintermediate in protein synthesis (3). Hoagland hasengagingly written (6) about how, in 1956, Jim Watson

had visited his lab at the MGH and told him of FrancisCrick’s earlier astonishingly prescient prediction of theexistence of “adaptor” RNA (which Crick had not yet published, see ref. 4). Thus, the two seemingly dispar-ate schools, biochemistry and molecular biology, which

had managed to slide past one another as two ships inthe night, now henceforth sailed on in tandem.

Following a faculty position at Harvard MedicalSchool, Hoagland went on to become Chairman of theDepartment of Biochemistry at Dartmouth MedicalSchool and in 1970 became President and ScientificDirector of the Worcester Foundation for BiomedicalResearch, retiring in 1985. Now 84, he remains in-tensely active, with a passionate interest and extraordi-nary skill in educating the lay public (e.g., 7–11) andalso deeply absorbed in the joy of wood sculpture(perhaps a “surgeon” after all). Paul Zamecnik contin-

ued a productive and highly creative research career at MGH through the 1960s and 70s. In 1979, he moved tothe Worcester Foundation, bringing Hoagland andZamecnik together once again, but now in the positionsof institute director and active investigator, respectively (Fig. 1). In 1997, Zamecnik returned to MGH asPhysician Emeritus, thus closing a career circle. Now 92, he continues an active research program on anti-sense DNA (e.g., 12), a field that he single-handedly opened (13).

The careers of Mahlon Hoagland and Paul Zamecnik(5, 14) are extraordinary in both scientific significanceand longevity. As the 50th anniversary of their break-

throughs in protein synthesis approaches, The FASEB  Journal  warmly salutes them.

The author is supported by NIH grant GM-60551, NSFgrant MCB-0445841, and the Vitold Arnett Professorship.

1 Correspondence: E-mail: thoru.pederson@umassmed.edudoi: 10.1096/fj.05-1002ufm

15830892-6638/05/0019-1583 © FASEB

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REFERENCES:

1. Hoagland, M. B. (1955) An enzymatic mechanism for aminoacid activation in animal tissues. Biochim. Biophys. Acta  16,288–289

2. Hoagland, M. B., Keller, E. B., and Zamecnik, P. C. (1956)Enzymatic activation of amino acids. J. Biol. Chem. 218, 345–358

3. Hoagland, M. B., Stephenson, M. L., Scott, J. F., Hecht, L. I., andZamecnik, P. C. (1958) A soluble ribonucleic acid and interme-diate in protein synthesis. J. Biol. Chem. 231, 241–256

4. Crick, F. H. C. (1957) On protein synthesis. Symp. Soc. Exp. Biol.12, 138–163

5. Hoagland, M. (1990) Toward the Habit of Truth: A Life in

Science. W.W. Norton & Co.6. Hoagland, M. (2004) Enter transfer RNA. Nature  431, 2497. Hoagland, M. (1978) The Roots of Life. A Layman’s Guide to

Genes, Evolution and the Ways of Cells. Houghton Mifflin Co.8. Hoagland, M. (1981) Discovery. In Search of DNA’s Secrets.

Houghton Mifflin Co.

9. Hoagland, M., and Dodson, B. (1995) The Way Life Works.Random House.

10. Hoagland, M., McPherson, K., Dodson, B., and Needham, C.(2000) Intimate Strangers: Unseen Life on Earth. AmericanSociety of Microbiology Press.

11. Hoagland, M., Dodson, B., and Hauck, J. (2001) Exploring the Way Life Works: The Science of Biology. Jones and Bartlett Publishers.

12. Zamecnik, P. C., Raychowdhury, M. K., Tabdatze, D. R., andCentiello, H. F. (2004) Reversal of cystic fibrosis phenotype in acultured Delta508 cystic fibrosis transmembrane conductanceregulator cell line by oligonucleotide insertion. Proc. Natl. Acad.Sci. USA  101, 8150–8155

13. Zamecnik, P. C., and Stephenson, M. L. (1978) Inhibition of Rous sarcoma virus replication and cell transformation by aspecific oligodeoxynucleotide. Proc. Natl. Acad. Sci. USA  75,260–264

14. Zamecnik, P. C. (2005) From protein synthesis to geneticinsertion. Annu. Rev. Biochem. 73, 1–28

Figure 1. Mahlon Hoagland (left), then President and Scientific Director of the Worcester Foundation for Biomedical Research,

and Paul Zamecnik, then a Principal Scientist at the Foundation, ca. 1984.

1584 Vol. 19 October 2005 PEDERSONThe FASEB Journal