Sixty Years of DNA as the Genetic Material
William A. Wells
News Editor, The Rockefeller University Press
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| Maclyn
McCarty in 1942. |
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DNA stands today so firmly at the center of biology that
it is hard to imagine a time when it was regarded as merely a pedestrian polymer. DNA muscled its way into the spotlight beginning with a paper in the JEM sixty years ago—a
paper that established DNA as a carrier of genetic information (1).
According to one participant's 1993 recollection, "we felt this was the answer" (2). And yet the wording used at the
time was more circumspect. Sixty years ago,
Oswald Avery, Colin MacLeod, and Maclyn McCarty made no sweeping statements about all
of biology, but restricted themselves to
the evidence at hand: that "a nucleic acid of
the desoxyribose type is the fundamental unit of the
transforming principle of Pneumococcus Type III."
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| Diagram
of the transforming system. |
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Pneumococcus was the study system of choice based on Fred Griffith's 1928 observation of a "transformation" seen in vivo between bacterial forms. Live attenuated bacteria (type
II, non-encapsulated [R]) were coinjected with heat-killed but previously virulent bacteria (type III, encapsulated [S]) resulting in isolation of live, virulent type III (S) bacteria (see diagram). The change was sustained and heritable.
Avery worked with first MacLeod and then McCarty to reproduce this II (R) to III (S)
transformation with extracts in vitro, and to reduce its "exasperating variability" (3). The latter was problematic until heat inactivation of the extract was found to neutralize
most inhibitory activity (i.e., DNase).
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| Colin
MacLeod in 1936. |
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The first sign of DNA was noted by
MacLeod in his 1941 notes: "Thus it would appear as though these transforming extracts contain a little desoxyribosenucleic acid in addition to the large amount of ribosenucleic
acid present" (3). It was McCarty who continued the purification. Transforming
activity was conserved during purification despite
the removal of virtually all proteins, lipids, and polysaccharides,
and its behavior during electrophoresis and ultracentrifugation was consistent with
it being DNA.
Avery et al. noted that pneumococcus transformation could be "interpreted from
a genetic point of view." But DNA was an unlikely contender for carrying genetic information. It was a simple polymer with only four subunits, in contrast to proteins, whose complexities were revealed by
crystallization in the 1930s.
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| Oswald
Avery in the mid-1930s. |
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Avery et al. searched for a source of DNA's information content in their paper,
noting the "possible effect that subtle differences in molecular configuration may exert on the biological specificity of these substances [DNA]," but it took many more years to determine how DNA might code for complex biological traits. Indeed, Joshua Lederberg
has noted that "a certain leap
of faith was required to relate the transformation—and therefore, in turn, DNA—to mendelizing genes, like
those of fruitflies and garden peas" (4).
Doubts remained long after 1944. The transforming
agent may have been contaminated with adsorbed molecules, and may have been acting as a
specific mutagen, polysaccharide autocatalyst (S vs. R differed in their polysaccharide coat), or bacterial
virus. Transformations of other bacterial species with DNA encoding other traits later helped defuse
some of these arguments.
In 1946, McCarty published his purification of DNase and its inactivation of the
transforming agent (5), and other work
soon followed. Edwin Chargaff found that different organisms had different proportions of DNA bases, but matched amounts of A and T, and G and C. Alfred Hershey and Martha Chase saw that only phage DNA,
but not protein, entered the cell upon infection. And in 1953 James Watson and Francis Crick published the structure
of DNA, whose elegance made the possibility of DNA as information
store immediately apparent. After its genetic debut in pneumococcus, DNA was here to stay.
Further Reading
