The dawning of molecular genetics

tling between service as a hospi-

tal corpsman at a US Naval
Hospital and the completion of my
pre-medical studies at Columbia
College in New York. I was just
short of 19, and in uniform in the
Navy V-12 officers’ training pro-
gram. At Columbia, as an under-
graduate I had already worked
for two years in the laboratory of
Francis J. Ryan, among the first of
the league of students and follow-
ers of George Beadle and Edward

I: February 1944, 1 was shut-

L. Tatum, the pioneers of the bio- .

chemical genetics of Neurospora.

0966-842X/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.

Joshua Lederberg

Our main preoccupation at that
moment was probably the falter-
ing beachhead at Anzio, the inva-
sion of Italy and the breathless
anticipation of the Normandy
invasion, the D-Day that was to
come on June 6, 1944: the hinge of
history that would tell the out-
come of the war against Hitler.

 

J. Lederberg is at The Rockefeller
University, 1230 York Avenue, New York,
NY 10021-6399, USA.
tel: +1 212 327 7809,
fax: +1 212 327 8651,
e-mail: jsI@rockvax.rockefeller.edu

However, February 1, 1944 was
the date of publication of the paper
identifying DNA as the genetic
material, a scientific revolution
with consequences that can be
viewed, in a historical perspective,
as having comparable import.

At Columbia, we had heard of
this research even before its publi-
cation, largely through the herald-
ing of Alfred Mirsky from the
Rockefeller Institute for Medical
Research. There, Mirsky was a
colleague of Oswald Avery, and
embroiled in some sibling rivalry
that sparked ongoing skepticism

PII: $0966-842X({00)01753-4

TRENDS IN MICROBIOLOGY 194 VoL. 8 No. 5 May 2000
 

as to the finality of the proof that
DNA, and DNA alone, was the
operative molecule. Mirsky collabo-
rated with Arthur Pollister at
Columbia on studies of chroma-
tin, a ‘nucleoprotein’ complex.
Throughout 1944, there was some
buzz about these findings, tem-
pered by the ongoing skepticism.
After all, in 1935, Wendell Stanley
had proclaimed the isolation of the
tobacco mosaic virus as a pure
crystalline protein, an announce-
ment that was soon to be compli-
cated by further analyses demon-
strating the presence of an RNA
moiety. Not until January 20,
1945 did I actually read the text of
Avery’s paper', having borrowed a
copy from Harriett Taylor - a
graduate student who was about
to join Avery’s lab, and who was
also later to meet and wed Boris
Ephrussi. My reaction can only be
described as a deflagration.

From my diary, Saturday
January 20, 1945, 21.00h:

‘... [had the evening all to myself,
and particularly the excruciating plea-
sure of reading Avery ‘43 (sic) on the
deoxyribose nucleic acid responsible
for type transformation in Pneumo-
coccus. Terrific and unlimited in its
implications. Viruses are gene-type
compounds, but they cannot grow on
synthetic or even dead media, and
their capacity for production is limited
to reproduction. The TF of Pneumo-
coccus has every characteristic of a
mutation (should read gene)... I can see
real cause for excitement in this stuff
though.’

Noted in the margin:

‘Direct demonstration of the multi-
plication of TF as well as its polysac-
charide products! or the synthetic
enzyme for it which may be TF itself.
Dual function - reproduction — pro-
duction.’

This has some garbled thinking,
but there is no doubting the enthu-
siasm generated by Avery’s publi-
cation. As recounted elsewhere’,
it set me on the path of looking
for DNA transformation in Neuro-
spora, and eventually to my studies
of genetic recombination in Escher-
ichia coli. What was important for

me, and how the article changed
my life, was the demonstration
that genetic information could
be reduced to chemical analysis.
That is to say, that we were seeing
the dawn of molecular genetics.
Whether the agent responsible was
pure DNA would be resolvable in
due course; the important icono-
clasm was that it could be. Once
that was settled, the power of phys-
ical and chemical analysis would
be brought to bear, and such fur-
ther triumphs as the double-helical
structure? were inevitable. Mean-
while, the biological interpretation
of the pneumococcal transforma-
tion was somewhat foggy. Avery
himself was quite reserved', doubt-
less dominated by Dobzhansky’s
authority in calling it an ‘induced
mutation’, which hardly encapsu-
lates the spirit of having captured
the genes in the test tube. He was
more expansive in a letter to his
brother Roy on May 26, 1943
(Ref. 4):

‘,.. are thereafter reduplicated in the
daughter cells and after innumerable
transfers and without further addition
of the inducing agent, the same active
and specific transforming substance
can be recovered far in excess of the
amount originally used to induce the
reaction. Sounds like a virus - may be
a gene. But with mechanisms I am not
now concerned — one step at a time —
and the first is: what is the chemical
nature of the transforming principle?
Someone else can work out the rest.’

It was to be many years before
this letter would come to light, and
it did so in parallel with universal
recognition that its underlying in-
tuitions were correct. For my part,
a critical challenge was what did
the pneumococcal transformation
have to do with genetics, in the ab-
sence of any concrete evidence for
‘genes’ in bacteria. This led me to
re-examine the prospects for ‘play-
ing Mendel’ to E. coli, and the
surprising realization that this
venture had scarcely been tried in
the 80 years since the abbot’s work
on garden peas. My experiments
began in Ryan’s lab at Columbia,
and reached consummation in
June, 1946, after a few months
work with Ed Tatum at Yale, and

COMMENT

the results were presented at Cold
Spring Harbor in July, 1946
(Ref. 2). These results uncovered
the conjugal cell-to-cell interaction
in E. coli strain K-12. We would
have been delighted if we could
have promptly matched this with a
DNA transformation in the same
bacterium, We did get problematic
inspirations from Andre Boivin,
who reported exactly that at the
1947 Cold Spring Harbor sym-
posium’, but alas he died soon
thereafter. We had no inkling of
electroporation; the floodgates to
direct DNA transfer in E. coli were
only opened in 1970 with tricks no
more complicated than the use of
calcium phosphate gels®. Today,
the very terminology of ‘gene’ is
being supplanted by ‘DNA se-
quence’, and ‘genetics’ by ‘gen-
omics’ as we are indeed moving
into an undistracted, reductionist,
molecular genetics.

Further bibliographic resources,
and detailed documentation includ-
ing many primary sources such as
letters, reviews and interviews, can
be found at the archival website of
the National Library of Medicine
athttp://profiles.NLM.nih.
gov/

Acknowledgement
J.-L. is a Raymond and Beverly Sackler
Foundation Scholar.

References

1 Avery, O.T. et al. (1944) Studies on
the chemical nature of the substance
inducing transformation of
pneumococcal types. J. Exp. Med. 79,
137-158

2 Lederberg, J. (1987) Genetic
recombination in bacteria: a discovery
account. Annu. Rev. Genet. 21, 23-46

3 Watson, J.D. and Crick, F.H.C. (1953)
Molecular structure of nucleic acid. A
structure for deoxyribose nucleic acid.
Nature 171, 737-738

4 Dubos, R.J. (1976) The Professor, The
Institute and DNA: Oswald T. Avery,
His Life and Scientific Achievements,
Rockefeller University Press, New York

5 Boivin, A. (1947) Directed mutation in
colon bacilli, by an inducing principle of
deoxyribonucleic nature: its meaning for
the general biochemistry of heredity. .
Cold Spring Harbor Symp. Quant. Biol.
12, 7-17

6 Mandel, M. and Higa, A. (1970)
Calcium-dependent bacteriophage DNA
infection. J. Mol. Biol. 53, 159-162

TRENDS IN MICROBIOLOGY 195 VoL. 8 No. S May 2000