Santa Monica Community College Science Essay

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Leading Edge
BenchMarks
Rosalind Franklin and the Advent
of Molecular Biology
Patrick Cramer1,*
1Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Göttingen, Germany
*Correspondence: patrick.cramer@mpibpc.mpg.de
https://doi.org/10.1016/j.cell.2020.07.028
Rosalind Franklin provided the key data for deriving the double helix structure of DNA. The English chemist
also pioneered structural studies of colloids, viruses, and RNA. To celebrate the 100th anniversary of
Franklin’s birth, I summarize her work, which shaped the emerging discipline of molecular biology.
In November 1951, Rosalind Franklin
presented her latest research at King’s
College London (Watson, 1968; Klug,
2004). Her results would soon change
the course of science, but this could
not be envisaged by the few attendees
at the time, including James Watson.
In her talk, the 31-year old crystallographer showed X-ray diffraction photographs that indicated that DNA has
a helical structure. To obtain these
images, Franklin and her graduate
student Raymond Gosling humidified
DNA fibers and exposed them to an
X-ray beam. The resulting cross-shaped
pattern was certainly enigmatic to most
listeners, but Franklin was able to interpret it.
One-and-a-half years later, on April 25,
1953, James Watson and Francis Crick
from the Cavendish Laboratory at
Cambridge published a double helix
model for DNA (Watson and Crick,
1953). In the same issue of the journal,
Franklin and Gosling reported and
analyzed their key X-ray photograph of
B-DNA (Figure 1) (Franklin and Gosling,
1953a). Another accompanying paper by
Franklin’s colleague Maurice Wilkins and
his coworkers also presented a diffraction
photograph of DNA, which showed
fewer features than the one from Franklin
(Wilkins et al., 1953).
These publications marked one of the
most important scientific advances of
the 20th century and, more broadly, in
the history of science: the mystery of genetic inheritance was unveiled. The discovery of the DNA double helix structure
was recognized with the 1962 Nobel Prize
in Physiology or Medicine, shared by Watson, Crick, and Wilkins. Franklin was
mentioned in passing during the
ceremony.
Rosalind Franklin could obtain the key
X-ray photograph because of her training
in sample preparation and X-ray analysis.
She studied Natural Sciences at Cambridge and earned a PhD degree in
1945. In her thesis work, she characterized organic colloids such as coal.
Franklin went to Paris in 1947 and was
trained by Jacques Méring, who studied
rayon and carbonaceous materials with
the use of X-ray diffraction. In January
1951, Franklin moved to London and
joined the MRC Biophysics Research
Unit headed by John Randall.
At King’s College, Wilkins and Gosling
had previously collected X-ray photographs of DNA fibers that they had obtained from Rudolf Signer at the University
of Berne. In fact, the first experiments of
this kind had already been reported
before the war (Astbury and Bell, 1938).
However, Franklin obtained improved
diffraction patterns of DNA by drawing
thinner fibers and controlling humidity.
She also used a more focused X-ray
beam, produced with a microfocus generator that she assembled with the help of
Gosling (Klug, 2004). The images obtained by Franklin were later described
by John Bernal as being among the
most beautiful X-ray photographs ever
taken of any substance.
Based on her X-ray analysis, Rosalind
Franklin came very close to solving the
double helix structure independently
(Klug, 1968). From her data, she
concluded that the B-DNA structure was
probably a helix of two co-axial strands,
offset along the helical axis, with their
phosphate groups on the outside
(Franklin and Gosling, 1953a). Franklin
had already prepared the manuscript by
March 17, 1953 and only later inserted
by hand a sentence acknowledging that
her results were ‘‘not inconsistent’’ with
the Watson-Crick double helix model
(Klug, 1974).
The year before, Watson and Crick had
built an initial, very different DNA model.
This model was a triple helix, with the
phosphates located on the inside and
the bases pointing outward. Franklin rejected this first model as being inconsistent with her experimental data when
she visited Cambridge together with
Wilkins (Klug, 2004). A similar, incorrect
model was published by Linus Pauling
and Robert Corey in February 1953.
Around this time, Watson and Crick
resumed active model building, stimulated by Franklin’s unpublished results
(Klug, 2004).
Before
the
double
helix
was
announced, Franklin had prepared two
other manuscripts that were received by
the journal on March 6, 1953 (Franklin
and Gosling, 1953b, c). In the first of
these, she described two forms of DNA,
the previously known A-DNA and the
novel B-DNA, which she obtained at
higher humidity (Franklin and Gosling,
1953b). For some time, Franklin was uncertain whether the structure of A-DNA
would be helical. However, on her 33rd
birthday, July 25, 1953, Franklin published that A-DNA, like B-DNA, also has
a helical structure (Franklin and Gosling,
1953d). More specifically, she reported
crystallographic evidence for inter-molecular vectors between phosphate groups in
a two-chain helix (Franklin and Gosling,
1953c, d, 1955).
Cell 182, August 20, 2020 ª 2020 Elsevier Inc. 787
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Figure 1. Rosalind Franklin’s X-Ray Diffraction Photograph of B-DNA (‘‘Photo 51’’)
This X-ray diffraction image was recorded on photographic film by Franklin and Gosling in May 1952
(Franklin and Gosling, 1953a). It shows a specific cross-shaped pattern of X-ray reflections at the center
that revealed the overall geometry of the DNA double helix, including its dimensions, pitch, and a period of
34 Å (Franklin and Gosling, 1953a). It also uncovered the offset between the two strands that gives rise to
the major and minor grooves of DNA. To derive the strand offset, the absence of the fourth reflections from
the center needed to be detected (Franklin and Gosling, 1953a), which was not possible in an unambiguous manner from the image published by Wilkins (Wilkins et al., 1953). The strong black streaks on the
top and bottom provided the distance between base pairs of 3.4 Å, implying that one helical repeat of
DNA contains ten base pairs. The secondary fans extending from the two outer 3.4 Å reflections toward the
equator are characteristic for a discontinuous helix that is expected from the chemical nature of the DNA
backbone (Klug, 2004). Picture courtesy of Ava Helen and Linus Pauling Papers, Oregon State University
Libraries. Reproduced with permission.
Franklin’s unpublished results also
provided a clue to the antiparallel
arrangement of the two DNA chains in
the double helix. Her critical data were
contained in a report to the MRC that
was shown to Watson and Crick by Max
Perutz in February 1953 (Perutz et al.,
1969). The report mentioned that crystalline DNA has face-centered monoclinic
symmetry with the c-axis along the fiber
(Perutz et al., 1969). As pointed out by
Watson, this information implied to Crick
that a two-fold symmetry axis exists
perpendicular to the helix axis. To be
related by two-fold symmetry, the two
DNA strands had to be arranged in an
antiparallel fashion. Franklin later said
she could have kicked herself for missing
this (Klug, 2004).
Although Franklin had uncovered the
critical features of the DNA structure,
she did not envision that the DNA bases
would be paired (Klug, 1968). Base pairing
is a key feature of the Watson-Crick
model and immediately led to the pro-
788 Cell 182, August 20, 2020
posal of a semiconservative mechanism
for copying the genetic material (Watson
and Crick, 1953). To discover base pairing, Watson used the correct tautomeric
forms of the nucleobases that were
pointed out to him by Jerry Donohue
(Klug, 2004).
In summary, Franklin’s unpublished results prevented Watson and Crick from
pursuing their incorrect modeling and
enabled them to arrive at the correct
DNA structure. Watson and Crick
acknowledged that they had been stimulated by knowledge of the general results
and ideas of Wilkins and Franklin (Watson
and Crick, 1953). This acknowledgment,
however, was too muted and coupled to
the name of Wilkins.Fifteen years later,
Watson admitted that on January 30,
1953, Wilkins showed him Franklin’s
X-ray photograph, without her knowledge, and that his ‘‘mouth fell open’’ (Watson, 1968). Wilkins admitted in 1969 that
the best and most helical looking B-DNA
pattern was obtained by Franklin (Perutz
et al., 1969). Erwin Chargaff, whose results supported the base pairing model,
wrote in 1969 that Franklin made crucial
contributions. Thus, Franklin’s essential
contributions to the discovery of DNA
structure were not appropriately recognized and instead ascribed to her
male colleagues, constituting an evident
gender discrimination case.
In March 1953, Rosalind Franklin
moved to Birkbeck College because she
felt unhappy at King’s. Her departure
was mainly because of conflict with Wilkins, who continued to work on DNA after
she had left. At Birkbeck, Franklin shifted
her research focus to the three-dimensional structure of viruses. She soon obtained very clear X-ray diffraction patterns
of tobacco mosaic virus (TMV) that revealed great structural detail.
As the sole author, Franklin published a
model of the arrangement of protein units
in TMV that was once more based on
insightful X-ray analysis (Franklin, 1955).
The TMV structure was the first threedimensional model of any virus. Soon
thereafter, Franklin also reported on the
location of RNA inside the virus (Franklin,
1956). The RNA chain formed a spiral
within a hollow tube made of viral proteins. Through these studies, Franklin
also pioneered the analysis of RNA structure, in addition to her ground-breaking
work on DNA.
Franklin continued her studies on TMV
until her untimely death. She published
another dozen papers and was proud of
her reputation in the field of virus structure
research. Her team also assembled a sixfoot-high model of TMV for the 1958
World’s Fair, the same event for which
the Atomium building was constructed in
Brussels. Unfortunately, Franklin did not
see the model at the exhibition. She died
of ovarian cancer on April 16, 1958, at
the age of only 37.
Rosalind Franklin’s work was continued
and extended by her coworkers, including
Aaron Klug, who later solved the structure
of tRNA and was awarded the 1982 Nobel
Prize in Chemistry. Klug once said that
what Franklin touched, she adorned.
Franklin was also joined by Ken Holmes,
who later pioneered structural studies of
other viruses and muscle fibers. Holmes
also developed the use of synchrotron radiation for X-ray diffraction experiments.
As is often the case with great scientists,
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Franklin not only left fundamental knowledge but also outstanding scholars who
continued her legacy. Indeed, John Bernal said that she inspired those who
worked with her to reach the same high
standard.
During the last five years of her life,
Rosalind Franklin actively corresponded
with Watson and Crick and formed a
friendship with Crick’s wife Odile. There
is no reason to believe that she felt bitter
about the achievements of her colleagues
who arrived at the DNA structure. Instead,
Franklin had instantly accepted the double helix model (Watson, 1968). In retrospect, this is not surprising because the
model was based to a large extent on
her X-ray data. The double helix was
soon adopted by the scientific community
and attained iconic status after Crick assigned the function of instructing protein
synthesis to DNA in his central dogma
in 1958.
In conclusion, Rosalind Franklin’s contributions demonstrate how high-quality
X-ray experiments and diffraction analysis
can provide structural insights into complex biological samples. Combining such
results with chemical knowledge enabled
modeling of the DNA double helix by Watson and Crick. In the same decade, a
similar approach allowed Pauling to
derive the a-helix structure and also
enabled Max Perutz and John Kendrew
to obtain the first protein structures.
Thus, Franklin’s work helped to establish
a path to unveil the inner workings of life.
The last years of Rosalind Franklin’s short
life marked the advent of molecular
biology.
ACKNOWLEDGMENTS
I am grateful to Elena Conti, Elspeth Garman, Herbert Jäckle, Tom Jovin, Mary Osborn, and ErnstLudwig Winnacker for insightful comments. I regret
that, due to space limitations, many references had
to be excluded. For readers interested in learning
more, I recommend Rosalind Franklin and D.N.A.
by Anne Sayre (W. W. Norton & Co, 1975), Rosalind
Franklin: The Dark Lady of DNA by Barbara Maddox (Harper Collins, 2002), and Francis Crick Discoverer of the Genetic Code by Matt Ridley
(Harper Perennial, 2006). I am supported by the
Max Planck Society, the Deutsche Forschungsgemeinschaft (SFB860, SPP1935, EXC 2067/1390729940), and the Advanced Investigator Grant
CHROMATRANS from the European Research
Council, grant agreement 882357.
REFERENCES
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Thymonucleic Acid. Nature 141, 747–748.
Franklin, R.E. (1955). Structure of tobacco mosaic
virus. Nature 175, 379–381.
Franklin, R.E., and Gosling, R.G. (1953b). The
structure of sodium thymonucleate fibres. I. The influence of water content. Acta Crystallogr. 6,
673–677.
Franklin, R.E., and Gosling, R.G. (1953c). The
structure of sodium thymonucleate fibres. II. The
cylindrically symmetrical Patterson function. Acta
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Franklin, R.E., and Gosling, R.G. (1953d). Evidence
for 2-chain helix in crystalline structure of sodium
deoxyribonucleate. Nature 172, 156–157.
Franklin, R.E., and Gosling, R.G. (1955). The structure of sodium thymonucleate fibres. III. The threedimensional Patterson function. Acta Crystallogr.
8, 151–156.
Klug, A. (1968). Rosalind Franklin and the discovery of the structure of DNA. Nature 219, 808–810,
passim.
Klug, A. (1974). Rosalind Franklin and the double
helix. Nature 248, 787–788.
Klug, A. (2004). The discovery of the DNA double
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Watson, J.D. (1968). The Double Helix: A Personal
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