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that interfering with tyrosine kinase signaling pathways will be an important anticancer therapeutic strategy. Thus, efforts
invested to optimize new classes of
inhibitors, such as that described by Parang
et al.5, should yield high dividends.
W. Todd Miller is in the Department of
Physiology and Biophysics, State University
of New York at Stony Brook, Stony Brook,
New York 11794-8661, USA. email:
[email protected]
1. Hunter, T. Cell 100, 113–127 (2000).
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(1998).
4. Druker, B.J. & Lydon, N.B. J. Clin. Invest. 105, 3–7
(2000).
5. Parang, K. et al. Nature Struct. Biol. 8, 37–41 (2001).
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345–355 (1994).
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Nature 372, 746–753 (1994).
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P.A. Biochemistry 37, 165–172 (1998).
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(1997).
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book review
Hershey heaven
Angela N. H. Creager
We can sleep later: Alfred D. Hershey and the origins of molecular biology, Edited by Franklin W. Stahl. Published
by Cold Spring Harbor Press, Cold Spring Harbor, New York, USA; 2000. 357 pages, US $39. ISBN 0-87969-567-6.
When Alan Garen asked Alfred Hershey
for his idea of scientific happiness,
Hershey replied, “To have one experiment
that works, and keep doing it all the
time”1. The first generation of molecular
biologists referred to this as “Hershey
heaven.” Both Hershey’s wit and his scientific achievements receive their due in
We can sleep later: Alfred D. Hershey and
the origins of molecular biology. This volume, edited by Franklin Stahl, pays tribute
to Hershey through essays and reminiscences by scientists who knew him and
includes a selection of his writings. The
recognition, as several contributors point
out, is long overdue.
Hershey, who died in 1997 at the age of
88, is best known as one of the three
founders of the ‘phage group’. He shared the
Nobel Prize in 1969 with Max Delbrück and
Salvador Luria for their pioneering work
establishing bacteriophage as the premier
model system for molecular genetics. Yet
Hershey’s reticence kept him out of the
public spotlight, and his research career at
Cold Spring Harbor meant that he taught
few students. The marvelous reflections on
science, which he often included in his yearly reports as director of the Carnegie
Institution’s Carnegie Research Unit,
reached a small audience. Consequently,
this engaging volume introduces us to a little-known Hershey, filling in the details
beyond his famous 1952 experiment and
his quip about experimental bliss.
18
Hershey’s versatility with genetic and
chemical methods was remarkable even
for the time. He and Raquel Rotman provided the first linkage map of a virus, bacteriophage T2, in 1949 (ref. 2). Three years
later, the ‘Hershey-Chase’ experiment
(performed with technician Martha
Chase) provided decisive biochemical evidence that nucleic acids are the hereditary
material3. Using a Waring blender to separate radiolabeled phage that had infected
bacteria from the phage ‘ghosts’ which
remained on the outside of the cells,
Hershey and Chase showed that
32P-labeled nucleic acids entered the cells
whereas 35S-labeled proteins largely
remained on the outside.
Hershey’s new evidence for the genetic
role of nucleic acids in virus reproduction
came as a surprise, despite the experiment
published by Avery, MacLeod and
McCarty in 1944 showing that DNA could
genetically alter bacteria4. According to
several contributors to the book, even
Hershey expected his experiment to confirm that genes were composed of proteins. James Watson credits Hershey’s
results with providing the impetus for him
to pursue the structure of DNA. The
experiment’s significance was reinforced
by its pedagogical value; the HersheyChase experiment became a staple of molecular biology textbooks.
The blender experiment exemplified
Hershey’s ingenuity but did not exhaust it.
In 1957 Hershey turned his attention to
nucleic acid structure, using chromatography and ultracentrifugation to ascertain the
size and shape of viral DNA. He demonstrated that the chromosome of phage
(using T2 and λ) consisted of a single double-stranded molecule. Hershey’s further
characterization of the λ chromosome
showed that it had “sticky ends” (in his apt
phrasing).
Hershey’s adeptness as an editor
matched his elegant experimentation. The
title of the volume is taken from a letter he
wrote to contributors to Bacteriophage λ,
published in 1971 (ref. 5). Urging the
authors of the 52 essays to complete and
return their manuscripts, he ended the letter: “We can sleep later”.
The subtitle of We can sleep later invokes
a longstanding historical debate with
respect to the origins of molecular biology.
nature structural biology • volume 8 number 1 • january 2001
© 2001 Nature Publishing Group http://structbio.nature.com
© 2001 Nature Publishing Group http://structbio.nature.com
book review
The 1966 Phage and the origins of molecular
biology6, edited by John Cairns, Gunther
Stent, and James Watson, offered a genealogy of molecular biology with Delbrück as
founding father. The book’s implicit message that molecular biology derived from
the phage group drew fire from some. John
Kendrew argued that structural biologists
(such as those in his unit at Cambridge)
had also played a crucial role in the founding of molecular biology7.
Gunther Stent subsequently offered a
conciliatory view of the origins of molecular biology that combined the ‘informational’ school of phage genetics with the
‘structural’ school of X-ray crystallographers, a meeting of the minds that was
conveniently personified by Watson and
Crick8. This enlarged family tree still did
not satisfy everyone; Origins of molecular
biology: A tribute to Jacques Monod9,
stressed the early importance of French
microbiologists. Nonetheless, historical
interpretations that emphasized these various ‘origins’ tended to demarcate molecular biology firmly from pre-existing
fields, especially biochemistry (Delbrück
famously disparaged biochemistry).
By all these accounts, Hershey makes an
odd revolutionary. He is described by
friends as a “biochemist’s biochemist” as
well as a pioneering molecular geneticist.
His research defied any dichotomy between
informational and structural approaches,
and he retained a skeptical attitude towards
the supremacy of nucleic acids. Attention to
Hershey as one of the original molecular
biologists complicates the story, showing
the limitations of views that emphasize a
single approach, dogma, or charismatic
leader. By portraying a trailblazing biologist
who combined structural, biochemical, and
genetic methods in his quest to understand
life at the molecular level, We can sleep later
cautions us to keep a broad view of molecular biology’s past — and its future.
Angela N. H. Creager is in the Department
of History and Program in History of
Science, Princeton University, Princeton,
New Jersey 08544, USA. email:
[email protected]
1. As quoted in Judson, H.F. The eighth day of
creation: The makers of the revolution in biology,
275 (Simon and Schuster, New York; 1979).
2. Hershey, A.D. & Rotman, R. Genetics 34, 44–71
(1949).
3. Hershey, A.D. & Chase, M. J. Gen. Physiol. 36, 39–56
(1952).
4. Avery, O.T., MacLeod, C.M. & McCarty, M. J. Exp.
Med. 79, 137–158 (1944).
5. Hershey, A.D., ed. The bacteriophage lambda. (Cold
Spring Harbor Laboratory Press, Cold Spring
Harbor, New York; 1971).
6. Cairns, J., Stent, G.S. & Watson, J.D. Phage and the
origins of molecular biology. (Cold Spring Harbor
Press, Cold Spring Harbor, New York; 1966).
7. Kendrew, J. Sci. Am. 216, 141–43 (1967).
8. Stent, G.S. Science 160, 390–395 (1968).
9. Lwoff, A. & Ullmann, A. Origins of molecular
biology: A tribute to Jacques Monod. (Academic
Press, New York; 1979).
history
Phage facts
Often the simplest experiments lead to
the most remarkable insights. So it was
with the famous fluctuation experiments
of Luria and Delbrück and the Waring
blender experiments of Hershey and
Chase for which they were awarded the
Nobel Prize in Physiology or Medicine in
1969. While the results of these experiments are permanently etched into every
first year biology student’s brain, it is
worth recalling what was known at the
time these experiments were conducted
and the conclusions the authors drew.
In the early 20th century, the role of
chance mutations in the genetic variation
of higher organisms was generally accepted. However, bacterial cultures seemed to
be plastic. Exposed to adverse conditions,
cultures of bacteria could give rise to resistant variants that remained resistant “to
the action of the virus even if subcultured
through many generations in the absence
of the virus”1. At the time, many scientists
believed that the “virus by direct action
induced the resistant variants”1. Others
believed that the “resistant bacterial variants are produced by mutation in the culture prior to the addition of virus. The
virus merely brings the variants into
prominence by eliminating all sensitive
bacteria”1. These two alternative theories
— induced immunity and selection of
spontaneous mutations — were rigorously tested both theoretically and experimentally by Max Delbrück and Salvadore
E. Luria, respectively, in 1943.
The two hypotheses lead to different predictions regarding the distribution of resistant bacteria in a series of parallel cultures.
The hypothesis of acquired or induced
immunity predicts that the number of
mutants in each culture would be clustered
around the mean with little variation
between cultures. According to the selection
hypothesis, resistant bacteria could arise at
any point in the life of the culture. This
would result in very different numbers of
mutants per culture and thus the variability
from culture to culture would be high.
Luria found that in every experiment the
“fluctuation of the numbers of resistant
bacteria is tremendously higher than could
be accounted for by the sampling errors, in
striking contrast to the results of plating
from the same culture and in conflict with
the expectations from the hypothesis of
acquired immunity”1. Luria and Delbrück
concluded that the “resistance to virus is
due to a heritable change of the bacterial cell
which occurs independently of the action of
the virus”1. In other words, the mutation
was there before the virus was added.
nature structural biology • volume 8 number 1 • january 2001
Later, when Alfred D. Hershey and
Martha Chase began their experiments,
little was known about the early steps of
phage infection. What was known was
that after the phage adsorbed to the bacteria there was a latent period of ∼10
minutes after which time infectious virus
particles were made, ultimately leading
to host cell lysis and phage release.
Hershey and Chase reasoned that if they
knew the fate of the viral protein and the
nucleic acid at the beginning of phage
infection they would understand more
about the nature of those early steps.
They labeled the phage with either 35S or
32P, allowed them to adsorb to the bacteria
and then the cells were separated from the
unadsorbed material by centrifugation.
The cells were resuspended and the suspension was spun in a Waring blender to
separate the phage from the infected bacteria. They found that ∼80% of the 35S label
was removed from the bacteria whereas
only ∼20% of the 32P label was removed.
They concluded that “most of the phage
DNA enters the cell, and a residue containing at least 80% of the sulfur-containing
protein of the phage remains at the cell
surface”2. Together with the 1944 experiments of Oswald Avery3 in which nucleic
acid, not protein, was shown to have
“transforming” properties, these findings
persuaded most scientists that DNA carried the genetic information. Curiously,
however, Hershey himself remained skep19