Open access, freely available online Obituary A Path to Discovery: The Career of Maclyn McCarty Joshua Lederberg*, Emil C. Gotschlich aclyn McCarty, who devoted his life as a physician-scientist Mto studying infectious disease organisms, was best known for his part in the monumental discovery that DNA, rather than protein, constituted the chemical nature of a gene. Uncovering the molecular secret of the gene in question—that for the capsular polysaccharide of pneumococcal bacteria—led the way to studying heredity not only through genetics but also through chemistry, and initiated the dawn of the age of molecular biology. McCarty was the youngest and longest surviving member of the research team responsible for this feat, which also included Oswald T. Avery and Colin MacLeod; he died on January 2, 2005, from congestive heart failure. McCarty was born in 1911 in South Bend, Indiana, the second of four sons of a branch manager for the Studebaker Corporation while it was DOI: 10.1371/journal.pbio.0030341.g001 still a fi rm for horse-drawn carriages. Maclyn McCarty (June 9, 1911, to January 2, 2005) with Francis Crick and James D. In his teens, McCarty set himself the Watson goal of becoming a physician-scientist, (Photo: Marjorie McCarty) and he pursued a successful strategy to prepare for admission to, and early pneumococcal transformation, the However, in 1928, Fred Griffi th, success in, Johns Hopkins University heritable alteration of a pneumococcal a leader in public-health research Medical School. As an undergraduate strain from a nonvirulent rough form in Britain, demonstrated that the at Stanford University, he presciently to a virulent smooth encapsulated conversion of one strain to another began his studies in the nascent fi eld form. McCarty’s arrival at the could happen in vivo in mice. Shortly of biochemistry, working with James Rockefeller Institute in September after the publication of his results, Murray Luck on protein turnover 1941 marked 13 years since this they were confi rmed in several in the liver. In 1937, he began his discovery, also known as the Griffi th quarters, including Avery’s lab. The clinical training in pediatrics at the phenomenon. Prior to this discovery, Harriet Lane Service at Johns Hopkins the 1920s had been marked by a University. There McCarty developed medley of disparate observations on Citation: Lederberg J, Gotschlich EC (2005) A path a special interest in infectious that seemed to discovery: The career of Maclyn McCarty. PLoS Biol Streptococcus pneumoniae 3(10): e341. diseases—in particular, antibacterial to involve an exchange of receptors sulfonamide drug treatments that among diverse bacteria either grown Copyright: © 2005 Lederberg and Gotschlich. This is an open-access article distributed under the were just entering medicine—which together in liquid media or exposed terms of the Creative Commons Attribution License, he subsequently pursued by moving to various kinds of extracts and which permits unrestricted use, distribution, and to New York University to work with supernatants. With rare exception, reproduction in any medium, provided the original work and source are properly cited. William Tillett. A National Research the early researchers in this area were Council Fellowship in the medical utterly confused about the distinction Joshua Lederberg and Emil C. Gotschlich are at the sciences and an opening in Oswald T. between genotype and phenotype. No Rockefeller University, New York, New York, United States of America. Avery’s laboratory spurred his move to single experiment was carried forward Rockefeller University in 1941. to confi rmation by other observers, so *To whom correspondence should be addressed. At that time, research in the the entire fi eld of “para agglutination” E-mail: [email protected] Avery laboratory was focused on the was in some disrepute. DOI: 10.1371/journal.pbio.0030341 PLoS Biology | www.plosbiology.org 1690 October 2005 | Volume 3 | Issue 10 | e341 analysis relied on serotyping: it was positively correlate DNA with biological most commentators had accepted the known that phenotypic differentiation activity. It gradually became evident untrammeled heuristic value of the of pneumoccocal groups could be that the active material in purifi ed proposition that, indeed, genes were diagnosed by their reactions with extracts had astonishingly high made of DNA. specifi c antisera, already recognized potency in micrograms of DNA that Meanwhile, a physician-scientist to refl ect chemically distinct capsular could consummate the pneumococcal through and through, McCarty turned polysaccharides. Griffi th had neither transformation in vitro. his attention to diseases promoted the resources nor the inclination to McCarty, MacLeod, and Avery by streptococci. So it happened that purify and identify the responsible wrestled with the standard of on the retirement of Homer Swift agent in pneumococcal extracts that proof required to claim that they in 1946, McCarty was asked to head induced the changes of serotype. But had accomplished pneumococcal the laboratory established in 1922 to the phenomenon of transformation was transformation with highly purifi ed work on streptococci and rheumatic at least vaguely understood to comprise DNA from extracts. After much self- fever. This was the scientifi c home of an alteration of what we would now call inquiry, in 1944, they published in the Rebecca Lancefi eld, who developed the genetic factors. Journal of Experimental Medicine that the still powerful serological classifi cation Though interrupted, sometimes active material was, indeed, DNA [2], of streptococci. From innumerable for years at a time, these studies bereft of protein or any other known clinical observations, combined with were from 1928 onwards the polymer [3,4]. Lancefi eld’s classifi cation, it was centerpiece of Avery’s lab agenda. The vicissitudes of the acceptance clear that acute rheumatic fever, a Around 1940, they were activated of the concept that “genes are DNA” severe sterile infl ammatory condition by Colin MacLeod’s efforts to purify deserve the scholarly praise they affecting particularly the joints and the the chemical agent responsible for have received [5,6]. The claim was, heart, was a complication of group A changes of serotype—whether protein, indeed, subject to a formidable, but streptococcal pharyngitis, following the nucleic acid, or some other class of predictable, round of organized infection by several weeks. The causal molecule—and demonstrate that it skepticism. Some would say, even chain of events still eludes us. McCarty was necessary and suffi cient to cause worse, that it was simply ignored, but attacked this problem by studying both the Griffi th phenomenon. Studies that is manifestly untrue, at least in the biology of group A streptococci on pneumococcal transformation the case of the New York research and patients with acute rheumatic fever were grossly burdened by a wide institutions. The scientifi c community admitted to the Rockefeller Hospital. variety of variables, which needed to does not accept major scientifi c claims Together with his students and be controlled to allow quantitative with ease, and in this case, there were collaborators, over the next 20 estimation of transforming activity challenges associated with research on years, McCarty’s work changed the in extracts undergoing various stages S. pneumoniae, which made it especially understanding of the organism from of purifi cation. MacLeod, over a diffi cult to attract other investigators a gram-positive streptococcus with a number of years of research, had to pursue this research. To begin with, particular serological characteristic resolved several thorny technical issues few people had the necessary expertise to one of the best characterized to render the experimental system with this pathogen from a biological bacterial species. Work on bacterial somewhat more reliable as an assay perspective—it was dangerous to work cell-wall anatomy and chemistry was just for biological activity. By the time with, and at the same time, it was beginning. His work led to the isolation McCarty arrived at the Rockefeller fi nicky to grow. In order to assay its of the streptococcal cell wall as a University, Avery’s team had just about virulence, one needed to use mice as a structural entity suitable for anatomic decided that the active reagent was selective fi lter. Most critically lacking as inspection by electronmicroscopy. not a protein. But what was it then? corroboration was the examination of Chemical dissection led to Could it be a soluble saccharide, RNA, other phenotypic markers, besides the characterization of the group or, least likely, DNA? The progress of capsular polysaccharide, to determine A–specifi c polysaccharide and the this research over the next three years the extent that the fi ndings on the peptidoglycan, and the identifi cation of is beautifully described in McCarty’s gene for one pneumococcal antigen its serological specifi city in the terminal memoir The Transforming Principle, would apply to other metabolic markers hexosamine. In order to prove this written in the early 1980s [1]. of S. pneumoniae. specifi city, he fi rst had to identify and As purifi cation progressed, exposure However, by 1953, infl uenced by purify a specifi c enzyme that cleaved of extracts to crystalline RNase and to the enormous impact of Watson and hexosamine (a hexosaminidase) proteinase preparations helped Avery’s Crick’s bihelical structure of DNA, from a soil organism. Treating the team determine that the biological the majority of researchers had fully polysaccharide with this enzyme activity of extracts was not dependent accepted the 1944 paper. In fact, abrogated its serological reactivity. on RNA or protein. Crystalline one might say, formal proof that McCarty further demonstrated DNase was not available until 1948, DNA encoded genetic material was the precise confi guration of the but biological activity was rapidly approximated only much later by the hexosamine linkage by synthesizing reduced by tissue extracts rich in laboratory synthesis of oligonucleotides, both α- and β-N-acetyl-glucosamine DNase.