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Book Reviews

The Origins of Molecular Biology

The Path to the Double Helix. Robert
Oxrsy. University of Washington Press,
Seattle, 1975. xxiv, 510 pp. + plates.
$23.50.

Robert Olby is a lecturer in the de-
partment of philosophy at the Univer-
sity of Leeds, specializing in the history
of science. He has previously written
The Origins of Mendelism (Schocken,
1966) and Charles Darwin (Oxford
University Press, 1967), as well as
articles on the origins of molecular
biology with particular emphasis on the
chemical and physical nature of genetic
material, One of these articles, pub-
lished in Daedalus (fall 1970), contains
a short biography of Francis Crick,
who has now contributed a brief fore-
word to the present volume. Praising
Olby’s work as a professional historian,
Crick has described this book as “the
first full scholarly account of how the
structure of DNA was discovered, set
against its proper historical back-
ground.” But Olby, who knows some-
thing more of the problems of histo-
rians attempting to sort out even rela-
tively recent events from the “vantage”
point of accepted contemporary view-
points, is less confident in his own in-
troduction, and refers to his work “not
as a definitive account but as a first
attempt which will stimulate others to
do better.” In qualifying the extent of
his considerable efforts to provide a
guide to the source material in this
area, Olby refers to various omissions
of relevant materials and notes defi-
ciencies in his treatment of such im-
portant topics as the history of the
chemistry of the nucleic acids.

Historians of science are greatly
concerned with the question of how
science advances. A serious and exten-
sive discussion of this topic has devel-
oped in recent years as a result of the
work of T. S. Kuhn, who has consid-
ered mainly the nature of theoretical
revolutions in physics and cosmology.
Kuhn conceived of science as moving

7 MARCH 1975

from paradigm to paradigm, “para-
digm” being a term devised to denote
the definite theoretical framework or
model within which scientists develop
their ideas. In a scientific revolution
such a framework is rejected or re-
placed in significant measure or in foto,
and scientists plan their experiments
within the new conceptual structure.
It is clear that in the two decades since
the proposal of the double helix as a
model for the nature, synthesis, and
behavior of genetic material biologists
have found it to provide the core of a
new and useful theoretical framework,
within which they have been able to
develop many significant experiments.
The recognition of the physical reality
of this structure has indeed helped to
initiate a revolution in biological
thought. Although both the term “para-
digm” and the enterprise of clarifying
the process of scientific revolutions
have become popular, littl has been
done to analyze the development of
biology in these terms. As a_profes-
sional historian, then, Olby has both
the opportunity and the responsibility
to clarify the nature of a crucial ad-

vance in a science relatively unex- _

plored bs other historians. For exam-
ple, we can ask whether this scientific
revolution is also characterizable as
moving from one paradigm which de-
termined .he quality of past biological
experimen-ation to another representing
the theoretical structure in which we
now operite.

In approaching the problems of re-
cent scientific history, Olby has been
able to interview some of the individ-
uals who contributed to the solution
of the structure of DNA. The profes-
sional historian working on contempo-
tary problems has devised “oral his-
tory,” in addition to the gathering,
sifting, and evaluation of written rec-
ords and other materials. He interviews
the individuals who have participated
in the events under investigation and

records their versions of the remem-
bered past. However, as Saul Benison
describes in his classic oral history
memoir Tom Rivers: Reflections on a
Life in Medicine and Science (MIT
Press, 1967), the process of extracting
reliable and useful accounts from such
survivors is complicated and arduous.
The historian must be prepared to see
and define the problems and to remind
and even spur as well as to check and
supplement the forgetful subject. In
short, a tape recorder does not of itself
make an “oral historian.” Olby learned
some of these problems in his years of
work on this book. For example, he
has discovered that the date reported
for the correct pairing of cut-out model
bases by Watson in February 1953 was
not quite as described in 1968 (and in
the 1970 Daedalus article). The book
contains evidence of such advances in
his technique, as well as a profusion
of quotations from the interviews, let-
ters, and other documents.

The book is organized in five sec-
tions, the first, fourth, and fifth of
which trace what constitutes a central
theme. This may be described as the
development of the work and ideas of
the polymer chemists and physicists .
who forged our knowledge of the struc-
ture of long-chain macromvlecuies, ad-
vancing slowly with insights concerning
certain natural polymers, polysaccha-
rides, proteins, and eventually DNA.
I will discuss separately the other two
sections, which are on more biological
and chemical themes, because I believe
they are less well done and dilute the
quality of the work. Although Olby
suggests that the central theme of the
book is the development of the molecu-
lar theory of the gene, the contribu-
tions of genetic experiments to the
analysis of gene structure receive little
discussion. Nineteen of 26 illustrative
plates show diffraction patterns and, of
about a hundred figures and tables,
fewer than ten, relate to genetics as
such whereas some 75 are concerned
with the physical chemistry of polymer
structure, The emphasis in the distribu-
tion of explanatory material defines
Olby’s most consistent efforts, if not
his stated intent.

The first section, From Colloidal
Particles to Long-Chain Molecules,
describes the evolution of the recogni-
tion of the existence of very large
molecules from the beginning of the
20th century until the beginning of
World War IL In this portion Olby
presents the achicvements and debates
of the German organic chemists and

827
physicists on this problem. Here also
we find the contributions of the physi-
cal chemists, such as Svedberg and
Staudinger, who affirmed the existence
of such molecules. A description of the
early development of x-ray analysis in
determining the size and shape of such
substances is also presented. The rise
of the school of Astbury in Leeds is
‘described in great detail, from Ast-
bury’s studies on keratin and rubber
to the surprising detection of regular-
ity in the stretched fibers of DNA. The
weaknesses in Astbury’s interpretations
of his x-ray analyses are characterized
very sharply. At the very end of the
book Astbury’s role in coining the
term “molecular biology” is set straight
‘by reference to the earlier contribution
of Warren Weaver, then of the Rocke-
feller Foundation, who in 1938 used
this term to describe the newly emerg-
ing dynamic and structural biology.

In the fourth section, Intellectual
Migrations, the now familiar story of
the growing interest of the physicists
and physical chemists in biology and
in natural polymers is told in perhaps
too great detail. In an introductory
chapter which Olby calls “The infor-
mational school,” the path of the
physicist Delbriick is traced from pre-
war Europe to an intellectual haven in
the United States where he and an early
segment of the phage group could con-
centrate on the biology of phage. In
my opinion, Schrédinger’s book on
biology did not contribute greatly even
to the early development of work on
phage and does not warrant the space
Olby gives it. Two vivid chapters de-
scribe the development of a “structural
school” concerned with the biophysics
of proteins, in England including Bragg,
Needham, Bernal, and Perutz and in
the United States Pauling, Corey, and
Huggins. This section also summarizes
the early careers of Watson and Crick
and indicates how these two elements,
mildly radioactive in isolation, began
to implode when brought together at
the Cavendish Laboratory in Cam-
bridge.

In an attempt to define the intellec-
’ tual milieu from which Watson had
emerged in the United States, this sec-
tion presents an inadequate and oc-
casionally inaccurate discussion of the
development of the biochemistry of
phage until 1950-51. If it is true, as I
believe, that the development of phage
biochemistry not only prepared Watson
and a large number of other biologists
and biochemists for acceptance of the
role of DNA as the genetic material but

828

also pointed to phage as a model system
for work on the nucleic acids, that his-
tory might have been given a bit more
space, time, and work than are Wat-
son’s efforts to obtain and retain a
fellowship in Europe, which are de-

scribed at length. The section con- -

cludes with an analysis of the Hershey-
Chase experiment. Watson’s apparently
ready acceptance of that experiment as
showing that phage DNA alone is the
genetic material contrasted with the
hesitancy of most phage workers in
this regard.

The fifth section, Hunting for the
Helix, is an instructive treatment of
the tortuous path to the solution of the
structure of DNA. There were three
laboratories competing actively on this
problem, one at King’s College in
London, that of Crick and Watson in
Cambridge, and Pauling’s in California.
The research unit at King’s College
was split internally and was self-de-
feating, whereas the approach and
model of the California group were
simply wrong. Watson and Crick not
only were fired by insights into both
the biological significance of DNA and
the potentialities of x-ray analysis and
model building but were also the cen-
ter of an active communications net-
work which assured knowledge of
almost all the data and thoughts of
their competitors in London and Pasa-
dena. Further, they pumped key col-
leagues and numerous visitors, such as
Chargaff and Donohue, who supplied
them with crucial knowledge. Never-
theless, after two years of work and
travel, Watson and Crick had not
solved the DNA problem. It is demon-
strated unequivocally in three long
chapters that they had made all the
possible incorrect choices for the struc-
ture of DNA and had eliminated these
from consideration. In ; ding off on
these wrong tracks, all three of the
laboratories had not heard of or had
actively repressed the ‘wo-year-old
crucial analytical data of C iargaff con-
cerning the equivalence o: purines to
pyrimidines, adenine to thymine and
guanine to cytosine. Only when these
rules had been recognized and an ele-
mentary knowledge of the chemistry
of the bases obtained were Watson and
Crick able to build a reasonable ap-
proximation of the double helix. This
event took about three weeks after the
structure was conceived to be of this
form.

Despite their settings in major uni-
versities with excellent libraries and the
presence of groups and occasional

visitors familiar with the chemistry and
biochemistry of the nucleic acids, all
these laboratories had worked on a
crucial polymer without any effort to
learn of the “recent” developments per-
taining to its composition and _ bio-
chemistry. [t may be noted that as early
as 1943 Mirsky had reported that
purine deoxyribose was half the total
deoxyribose in DNA. This reviewer
had confirmed this in 1945 and in
1946 had reported an equivalence of
purine and pyrimidine deoxyribose in
phage DNA. It appears that after the
paper on the “double helix” had been
sent to Nature Watson accidentally met
Wyatt in Paris and even then wished
to be reassured of the equivalence of
a number of bases, as obtained by
Chargaff for DNA in 1950 and in
1953 by Wyatt and the reviewer for.
phage DNA. What is the significance
of such specialization and intellectual
isolation, which led to fumbling for
two years in our best laboratories? Is
the question trivial, since a reasonable
structural model was eventually devised
by one of the few groups that were
capable of solving such structural prob-
lems? Or does the fact that Watson and
Crick now surround themselves with
numerous biochemists and specialists
in many other disciplines in their pro-
ductive laboratories at Harvard and
Cambridge reflect conclusions they
themselves have drawn? Olby has not
considered such questions, which clearly
fall within his province.

Nor has he asked if the process by
which the structure of DNA was gen-
erated and the derived new paradigm
fit the concepts of Kuhn, particularly
that relating the performance of “nor-
mal science” to the old paradigm and
of “extraordinary science” to the in-
ception of the new. Watson and Crick
used classical techniques to attempt to
solve their puzzle; to borrow a phrase
from Kuhn, they were in difficulty, not
current theory. These workers had been
moved to work and to continue work-
ing on DNA by the conviction that
this substance had been neglected in
the old fuzzy “paradigm” of the pro-
tein or nucleoprotein nature of the
gene, and they hoped their solution
would also say something about hered-
ity and gene replication. Nevertheless
they had set themselves no more of a
problem than had their predecessors
and contemporaries interested in pro-
tein structure. Solutions to protein
structure have stated little or nothing.
about the mechanism of protein syn-
thesis. In short, in Kuhn’s terms Wat-

SCIENCE, VOL. 187
son and Crick were engaged in normal
science, “the activity which practition-
ers are trained to carry on,” as had
been Chargaff, Mirsky, and everyone
else. It appears that several limited
lines of normal science converged in
the Cambridge laboratory to help solve
the structure. However, the solution
did contain elements that permitted
its virtually immediate acceptance both
as an event of extraordinary science
and as the core of a new paradigm.
Certainly Avery's discovery of bacterial
transformation by DNA was every bit
as epoch-making as the discovery of
the DNA structure. Would Kuhn and
Olby conclude that recognition as well
as discovery is required to constitute
“extraordinary science”?

I have no doubt that these three
sections of Olby’s book, introduced by
the chapter on “the nature of pro-
teins” in J. S. Eruton’s Molecules and
Life (Wiley-Interscience, 1972), would
form the basis for a useful course on
the history and organization of science
for students of biophysics and bio-
chemistry. After discussions of the im-
portant question posed by Olby’s case
history of the complexities of a path
to discovery, one can imagine another,
approximately equal period of inquiry

into the validation of the ingenious —

construct of the double helix as the
genetic material. The verification of
the structure, which is not discussed
in this book, has involved such matters
as the x-ray analysis of model com-
pounds, proof of the postulated anti-
parallel separate chains, the clarifica-
tion of some mechanisms of mutagene-
sis, the discovery of messenger RNA,
and the determination of the genetic
code, This process has taken two dec-
ades already, and understanding of the
structures and mechanisms developed
by cells to effect the synthesis of DNA
is still far from clear. I suspect that
it would be instructive to both students
and investigators to attempt to define
the nature of the laboratory or the in-
teractions of laboratories necessary to
develop extensive knowledge of the
biological synthesis of DNA.

The two large intervening sections
of the book, those on the nature of
hereditary material and on bacterial
transformation, need a thorough over-
hauling or, even better, should have
been reserved for a separate study. In
contrast with the extensive discussions
of the methodoldgy and concepts that
were involved in approaching problems
of polymer structure, here a reader
becomes familiar with the battles of

7 MARCH 1975

P. A. Levene and Simon Flexner over
administrative matters but does not
learn the structure of the bases or see
a clear representation of a nucleoside
or nucleotide until almost the end of
the book. We do not discover the re-
lation of alkaline extraction to the size
of the RNA isolated by early workers,
nor do we learn when and how RNA
joins DNA as a species of macromole-
cule. Olby delivers such uninformed
judgments as a reference to “the hall-
mark of biochemistry before the
1950’s—a limitation to metabolic path-
ways” and the comment, referring to
December 1949, “Now one could use
the techniques of biochemistry.”

Even worse, Olby finds it necessary
to assign blame to such creative work-
ers as Levene, Muller, and Stanley for
the lack of progress in defining the
genetic role of nucleic acid. Having
suggested that Stanley is particularly
responsible for the failure to identify
nucleic acid as the genetic material of
tobacco mosaic virus, he fails to credit
him and his laboratory with the dis-
coveries that the RNA of this virus is
far larger than a tetranucleotide and
eventually that this RNA is infectious
in its own right.

Olby has found it convenient to ex-
plain the limitations of many investi-

gators as a consequence of their belief

in “the protein version of the central
dogma.” This superficial explanation is
only a beginning. Olby indicates neither
the strength of convictions derived
from traditional learning and habits of
practice nor the overwhelming evi-
dence required to shake and shatter
the old comfortable habits of thought
and to replace these with a new uti-
lizable framework. Why did Mirsky
(and others) resist a straightforward
interpretation of Avery's experiment,
why did the laboratories of Stanley,
and of Schramm, and of Bawden, Pirie,
Markham, et al. fail to test the infectiv-
ity of the polymeric RNA of tobacco
mosaic virus before 1956, and why did
Luria, and even Hershey, hesitate in
interpreting the Hershey-Chase experi-
ment correctly? Can all these instances
be explained merely as “normal sci-
ence,” which Kuhn has described as
“a strenuous and devoted attempt to
force nature into the conceptual boxes
supplied by professional education”?
These questions seem worthy of Erik
Erikson, as well as of historians of
science. Obviously we must attempt to
understand these hindrances to prog-
ress, and Olby’s practice of awarding
demerits to certain scientists appears

quite inappropriate to such an effort.

These sections also close with a dis-
cussion of the discovery of the analyti-
cal foundations of base pairing, that is,
the crucial chromatographic work of
Chargaff and Wyatt. Olby then asks
why these men, who. knew the pairing
rules, did not themselves came up with
the structure of DNA. Does he really
expect that bond angles and helices will
fall out of classical analytical data on
base composition? Having composed
an entire book to tell us why x-ray
analysis and model building were es-
sential to determining the structure of
DNA, Olby appears to be taunting and
deprecating those less glorious scholars
who were untrained in those undeni-
ably essential techniques. He would do
better to ask why, when Chargaff,
Wyatt, or any other biochemist did
publish crucial data, their papers did
not reach the biophysicists concerned
with problems of macromolecular
structure. Nor do I doubt that the bio-
physicists can on occasion find similar
reasons for complaint concerning their
own data, lost in the wilderness.

In addition to the historical labors,
the preparation of a book such as this
is a formidable technical task. After
submitting a final manuscript, one is
usually so busy checking and correcting
in the course of various stages of
proofreading that it is virtually impos-
sible to read the book again. In the
case of this book, there are so many
minor errors that it seems impossible
that it was proofread at all by the
author, an editor, or technically
knowledgeable colleagues. I have found
at least two dozen misspellings of
words and names in the text. Incor-
rectly spelled names can be found in
the bibliography as well, and numer-
ous references are inappropriate to the
text. The index is far from thorough,
and Delbriick, a major figure in the
book, is not listed at ail. Among the
minor errors in the text, we can find
phenylmaltosazone described as a poly-
peptide derivative and biotin as a hor-
mone, Stanley’s group placed in Cali-
fornia in 1942, and many others. .

To sum up, a considerable quantity
of valuable material is collected in this
volume. Indeed, the central theme of
the book on the advance of our knowl-
edge of the structure of proteins and
DNA is well presented and provides
an important case history of the diffi-
culties in merging several paths of in-
vestigation to form this knowledge.
Unfortunately the author has chosen
to enlarge the central theme by less

“829
valuable discussions of relevant chemi-
cal and biological topics. Some of his
interpretations in these sections are un-
reasonably harsh, personal, and inju-
dicious. The book is marred also by
numerous minor errors of presentation
and technical substance.

SEYMOUR S, CoHEN
Department of Microbiology,
University af Colorado Medical Center,
Denver