"Some papers are great, of course, because they establish, define, settle their issues. This great paper did something else: Avery opened a new space in biologists' minds--a space that his conclusions, so carefully hedged, could not at once fill up."
--Horace Freeland Judson
After Oswald T. Avery, Colin M. MacLeod, and Maclyn McCarty published the 1944 article, a number of their contemporaries immediately understood that transformation was the transfer of genetic material from one bacterium to another, and that the transforming substance, DNA, must be the genetic material. However, the team's somewhat tentatively stated conclusions were not met with complete acceptance. At the time, the belief that DNA was a monotonous chain of four repeating nucleotides--structurally important but of little physiological interest--was still difficult to overcome. The belief that only proteins possessed the structural complexity necessary to carry hereditary information was pervasive among geneticists. Many of the scientists who had previously thought that genetic material was protein still believed that the effects of the transforming principle were perhaps due to some undetected protein associated with the DNA.
Much of the opposition to any identification of DNA as genetic material was concentrated at the Rockefeller Institute. One of Avery's colleagues, Alfred E. Mirsky, himself a noted figure in biochemical genetics, was certain that the active component of the transforming substance was a protein associated with nucleic acids in the chromosomes of some higher organisms. For several years, Mirsky carried on a campaign within the institute and in public to show that some proteins were resistant to the purification process used by Avery's team, and thus suggested that the DNA could have been contaminated by traces of protein.
In two papers that followed in 1946, Avery and McCarty attempted to answer critics like Mirsky and provided details of their experimentation which described the inactivation of the transforming substance by DNase. In his biography of Avery, McCarty wrote that when one considered the combined data of the three papers, "there was not much room left for the skeptics to advance sensible alternatives to the view that DNA was the active substance in transformation." Yet for some, questions persisted. Biologist H. Bentley Glass, who attended the Cold Spring Harbor conference in 1946 at which McCarty presented one of these follow-up papers, later recalled that despite Avery, McCarty, and MacLeod's strong evidence that DNA was the transforming substance, the purification technique was "not so complete that everyone is convinced that some protein does not remain in the preparation."
Despite the reservations offered by some researchers, Avery, MacLeod, and McCarty's work prompted further research on nucleic acids. Avery's laboratory continued to work on transformation, and other researchers showed that the process was not unique to pneumococci but also occurred in other bacterial species. Upon reading the 1944 paper, biochemist Erwin Chargaff changed the focus of his laboratory work from lipoproteins to nucleic acids. By 1950, he had discovered that while DNA was similar from cell to cell within any particular species, the proportions of the four organic bases (adenine, cytosine, guanine, and thymine) differ widely from species to species. This indicated that DNA possessed more complexity than previously suspected. In 1952, Alfred Hershey and Martha Chase reported the results of their experiments on bacteriophages (viruses which infect bacteria). Phages consist of little more than DNA and protein, and Hershey and Chase showed that during the process of infection, only the phage's DNA enters the bacterial cell. While Hershey and Chase's experiment was not as carefully conceived and executed as Avery's had been, their demonstration that DNA was the material responsible for viral replication was seen by many as the final confirmation that DNA encoded hereditary information. The work which began with Avery's identification of DNA as the "transforming principle" thus led to research that overturned the old conception of DNA as a repetitive and simple molecule, confirmed DNA's role in genetic transmission, and, with James Watson and Francis Crick's 1953 paper, elucidated its structure with its genetic implications.
While the immense significance of Avery's discovery is unquestionable, the reception of the discovery by other scientists at the time is a much debated question. It is important to note that the paper was released in 1944, at the height of World War II, which impeded international exchange between scientists. Also, the readership of the Journal of Experimental Medicine, in which most of Avery's scientific papers were published, was limited and never widely read by the geneticists and general biologists who would have immediately grasped the article's implications. Nobel Prize winner Joshua Lederberg has written, "There has been considerable interest on the part of historians and social scientists in the way in which the revolutionary findings of the role of DNA were understood, skeptically questioned, and finally accepted by the scientific community." Lederberg added that, despite initial skepticism and the limited circulation of the journal, the 1944 article was widely read. By 1954, the original article had been cited over three hundred times, and the elaborative articles that McCarty and Avery produced between 1944 and 1946 enjoyed even greater circulation among geneticists.
When Avery and his colleagues identified DNA as the "transforming principle" in the early 1940s, they resolved one of the fundamental problems in biological science. At the same time, that discovery launched the field of molecular biology and marked the start of the contemporary era in genetics. Through his dedicated study of a single type of bacteria--the pneumococcus--Avery advanced biological and medical science, providing knowledge and insight that could be applied to the study of all living things.