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At One Hundred: The Living Legacy of Francis Crick
SAHOTRA SARKAR
O
n 8 June 2016, we celebrate the birth centenary of Francis
H. C. Crick. Few biologists have had a
greater impact on the science of their
age. Of the many seminal contributors from the period that wrought the
molecular transformation of biology,
four stand out: Linus Pauling, Jacques
Monod, Francois Jacob, and Crick.
Pauling came earliest, in the 1940s,
when he showed how macromolecular
structures determined their functions.
Monod’s most important contributions came shortly after Crick’s entry
into the field, with the elaboration of
a physical model for the regulation
of genes—that is, the operon model
of 1961—and, later, with a structural
change model of allostery. Much of
Monod’s work was done in collaboration with Jacob (and others). However,
Jacob is perhaps even better known
for his later work from the 1970s,
emphasizing contingency and historicity in evolution. Meanwhile, in the late
1950s, Crick elaborated the dominant
conceptual framework for early molecular biology, one in which the concept
of information played a central role:
DNA carried the genetic information. This information was transcribed
into RNA and subsequently translated
into proteins at ribosomes. Arguably,
such informational thinking is what
set molecular biology apart from the
earlier traditions of biochemistry and
biophysics.
Crick first burst into prominence
in 1953 with the double-helix model
for DNA. Thanks to Watson’s (1968)
phenomenally popular account of
that episode, that story is well known
(although the accuracy of Watson’s
account has been questioned by others, including Crick). In 1953, Crick
was 37 years old and still working on
his doctoral dissertation. He was born
near Northampton during World War
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I and was educated at Northampton
High School and Mill Hill School, in
London. Subsequently, he earned an
undergraduate degree in physics from
the University College London and
began his doctoral research in physics
there with a project to measure the viscosity of water at high temperatures.
This work was interrupted by World
War II (and Crick’s equipment was
destroyed by a German bomb in 1942).
During the war, Crick worked with
distinction for the Admiralty Research
Laboratory on the design and detection of mines. After the war, partly
inspired by Schrödinger’s 1944 book
What Is Life?, Crick became part of an
intellectual migration of physicists to
biology that helped establish molecular
biology as a distinct field. He moved to
Cambridge (United Kingdom) to pursue his new career and remained there
until 1977. (All of the biographical
material is from Olby 2007.)
In 1949, when Crick began doctoral
research in biology at Cambridge, his
project was supposed to focus on the
structure of proteins. (Officially, he
did complete this work and received
a doctoral degree for it in 1954.) By
this time, it had become fairly clear
that genes were specified by the DNA
rather than by the protein components
of chromosomes—in contrast to what
had been generally accepted until 1944,
when Oswald Avery at the Rockefeller
Institute and his collaborators published experimental results showing
that DNA induced inherited transformations in bacteria. In 1951, Watson
arrived in Cambridge determined
to solve the structure of DNA using
model-building techniques introduced by Pauling. These techniques
were based on Pauling’s remarkable
insight that biological specificity relied
on very weak forces, such as hydrogen
bonds or van der Waals interactions
between atoms of macromolecules.
Consequently, what mattered were the
size and shape of molecular surfaces,
and these could then be approximated
by building space-filling models consisting of atoms represented as balls of
appropriate radii. This technique led
Pauling and Robert Corey to propose
(as it turned out, successfully) the
alpha-helix model for protein structure. Crick and Watson began collaborating and used these techniques
and experimental X-ray diffraction
data from Rosalind Franklin to solve
the structure of DNA. After an initial
failure (which was independently replicated by Pauling’s group), they produced a successful model in 1953: the
DNA double helix with two strands
running in opposite directions and the
bases stacked inside, showing basepair complementarity (A:T and C:G),
in concordance with experimental
results previously reported by Erwin
Chargaff.
What really matters about the
double helix is not its iconic helical shape but this complementarity.
It naturally suggests a mechanism
of semiconservative replication during gene duplication for reproduction
that was experimentally demonstrated
in 1958 by Matthew Meselson and
Franklin Stahl. The model also placed
no restriction on the order of bases
along one helix. Crick and Watson
immediately noticed that this feature
could account for the known diversity of genes. Moreover, because proteins were also linear molecules, the
relationship between DNA and proteins could be conceptualized as one
of “coding.” The same possibility had
been broached (in a much more speculative manner) by Schrödinger, and
the double-helix model provoked yet
another physicist, George Gamow, to
attempt to solve the problem largely
June 2016 / Vol. 66 No. 6 • BioScience 437
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through abstract arguments. Gamow’s
enthusiasm inspired Crick to focus on
the genetic code until it was finally
deciphered in the early 1960s. At that
point, the lack of any obvious functional interpretation of codon assignments led him to propose that the
code is a “frozen accident” (1968), a
view that continues to be generally—
although not universally—accepted
today.
A focus on the coding problem probably led Crick to elaborate in detail an
informational framework for molecular biology. This was laid out in a 1958
paper, “On Protein Synthesis,” which
can credibly be regarded as the single
most important publication in the history of molecular biology. In it, Crick
argued that the main role of proteins
was to act as enzymes (p. 138), viewed
genes as controllers of protein synthesis (p. 139), presented the canonical
list of 20 amino-acid residues in proteins (p. 140), argued that the aminoacid sequence constituted the “most
delicate expression” of the phenotype
of an organism, and envisioned a
molecular taxonomy (p. 142), as well
as arguing that this sequence probably determined the conformation of
a protein (p. 144). Most important,
Crick argued that protein synthesis
required “the flow of energy, the flow
of matter, and the flow of information”
(p. 144, emphasis added because this
is what Crick explicitly decided to
emphasize). Finally, he argued for the
sequence hypothesis—“the specificity
of a… nucleic acid is expressed solely
by the sequence of its bases, and this
sequence is a (simple) code for the
438 BioScience • June 2016 / Vol. 66 No. 6
amino acid sequence” (p. 152)—and
elaborated the central dogma: “once
‘information’ has passed into protein it
cannot get out again” (p. 153, emphasis
in the original). As Joshua Lederberg
had already noted in 1956, information
provided a new theory of specificity
different from Pauling’s theory based
on shape and size. The 1958 paper also
proposed the existence of an adaptor molecule (i.e., tRNA) that mediated protein synthesis. Crick made
many more contributions to molecular
biology subsequently, including establishing the triplet nature of the code
(with Sydney Brenner) and the wobble
hypothesis, but none of them surpassed the singular achievements of
the 1958 paper.
In 1976, Crick spent a sabbatical period at the Salk Institute for
Biological Studies, at La Jolla, and
moved there permanently in 1977.
That move was accompanied by a
shift of interest away from molecular
biology to neurobiology; he eventually focused on the neural correlates of
consciousness. With many collaborators—in particular, Graeme Mitchison
and Christof Koch—Crick continued
to pursue these studies until his death
on 28 July 2004. The results were not
as breathtaking as his achievements
in molecular biology. Perhaps he was
already too old when he embarked
on this new project—or, perhaps, the
problems are intrinsically more difficult, although that is a position that
Crick denied in his 1994 book, The
Astonishing Hypothesis.
Returning to the 1958 paper,
which was Crick’s most important
scientific contribution, over the last
two decades, the unexpected complexities of eukaryotic genetics and genomics have led some biologists (as well as
philosophers of science) to question
the continued utility of the informational picture of DNA. The presence
of large segments of apparently nonfunctional DNA in chromosomes and
even within loci (as introns), ubiquitous alternative splicing, exceptions to
the standard genetic code, and other
complications have shown that Crick’s
1958 framework for protein synthesis
is far too simple to be adequate (Sarkar
1996). This is an ongoing debate, but it
seems likely that parts of the informational interpretation of the molecular
gene will remain central to biology for
years to come.
References cited
Crick FHC. 1958. On protein synthesis.
Symposia of the Society for Experimental
Biology 12: 138–163.
———. 1968. The origin of the genetic code.
Journal of Molecular Biology 38: 367–379.
Olby R. 2009. Francis Crick: Hunter of Life’s
Secrets. Cold Spring Harbor Laboratory
Press.
Sarkar S. 1996. Biological information: A skeptical look at some central dogmas of molecular biology. Pages 187–231 in Sarkar S, ed.
The Philosophy and History of Molecular
Biology: New Perspectives. Kluwer.
Watson JD. 1968. The Double Helix: A Personal
Account of the Structure of DNA. Atheneum.
Sahotra Sarkar is a professor in the Department
of Integrative Biology and the Department of
Philosophy at the University of Texas at Austin
and is a member of the BioScience Editorial
Board.
doi:10.1093/biosci/biw065
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