Francis Harry Compton Crick OM FRS (8 June,
1916 – 28 July, 2004), (Ph.D.,
Gonville and Caius College, Cambridge, 1953) was an
English molecular biologist, physicist, and neuroscientist, who is most noted for being one of the
co-discoverers of the structure of the DNA molecule in 1953. He,
James D. Watson, and Maurice Wilkins were
jointly awarded the 1962 Nobel Prize for Physiology or Medicine
"for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material".[2]
His later work, until 1977, at the MRC Laboratory of Molecular Biology, has not received as much formal recognition. Crick is
widely known for use of the term “central dogma” to summarize an idea
that genetic information flow in cells is essentially
one-way, from DNA to RNA to protein. Crick was an important
theoretical molecular biologist and played an important role in research related to
revealing the genetic code.[3]
During the remainder of his career, he held the post of J.W. Kieckhefer Distinguished Research Professor at the
Salk Institute for Biological Studies in La Jolla, California. His later research centered on theoretical neurobiology and attempts to advance the scientific study of human consciousness. He remained in this post
until his death; "he was editing a manuscript on his death bed, a scientist until the bitter end" said his close associate
Christof Koch[4].
Biography, family and education
Stained glass window in the dining hall of
Caius College, in
Cambridge, commemorating Francis Crick and representing the structure of
DNA.
Francis Crick, the first son of Harry and Alex Elisabeth Crick (nee Wilkins), was born and raised in Weston Favell, a small village near the English town of Northampton in which Crick’s father and uncle ran the family’s boot and shoe factory. At an early age, he
was attracted to science and what he could learn about it from books. As a child, he was taken
to church (Congregationalist) by his parents, but by about age 12 he told his
mother that he no longer wanted to attend.[5] Crick preferred the scientific search for answers over belief in any dogma. He was educated at
Northampton Grammar School
(now Northampton School For Boys) and, after the age of 14, Mill Hill School in London (on scholarship), where he studied mathematics, physics, and chemistry. At
the age of 21, Crick earned a B.Sc. degree in physics from University College London (UCL) [5] after he had failed to gain his intended place at a Cambridge college, probably through
falling foul of their requirement for Latin; his contemporaries in British
DNA research Rosalind Franklin and Maurice Wilkins both went up to Cambridge colleges, to Newnham and St. John's
respectively.
Crick began a Ph.D. research project on measuring viscosity of water at high temperatures (what he later described as "the
dullest problem imaginable"[6]) in the
laboratory of physicist Edward Neville da Costa Andrade, but with the outbreak of
World War II - in particular, an incident during the Battle of Britain when a bomb fell through the roof of the laboratory and destroyed his experimental
apparatus [7] - Crick was deflected from a
possible career in physics.
During World War II, he worked for the Admiralty Research Laboratory,
from which emerged a group of many notable scientists; he worked on the design of magnetic and acoustic mines and was instrumental in designing a new
mine that was effective against German minesweepers.[8]
After World War II, in 1947, Crick began studying biology and became part of an important
migration of physical scientists into biology research. This migration was made possible by the newly won influence of physicists
such as John Randall, who had helped win the war with inventions such as
radar. Crick had to adjust from the "elegance and deep simplicity" of physics to the "elaborate
chemical mechanisms that natural selection had evolved over billions of years." He described this transition as, "almost as if
one had to be born again." According to Crick, the experience of learning physics had taught him something important—hubris—and
the conviction that since physics was already a success, great advances should also be possible in other sciences such as
biology. Crick felt that this attitude encouraged him to be more daring than typical biologists who tended to concern themselves
with the daunting problems of biology and not the past successes of physics.
For the better part of two years, Crick worked on the physical properties of cytoplasm at
Cambridge's Strangeways Laboratory, headed by Honor Bridget Fell,
with a Medical Research Council studentship, until he joined
Perutz and Kendrew at the Cavendish Laboratory. The Cavendish Laboratory at
Cambridge was under the general direction of Sir Lawrence Bragg, a
Nobel Prize winner in 1915 at the age of 25. Bragg was influential in the effort to beat a
leading American chemist, Linus Pauling, to the
discovery of DNA's structure (after having been stung by Pauling's success in determining the alpha
helix structure of proteins). At the same time Bragg's Cavendish Laboratory was
also effectively competing with King's College London, which was under
Sir John Randall. (Randall had turned down Francis Crick from working at
King's College London.) Francis Crick and Maurice Wilkins of King's College London were personal friends, which influenced subsequent scientific
events as much as the friendship between Crick and James Watson. Crick and Wilkins first
met at King's College London and not as reported at the Admiralty during World War II.
- Spouses: Ruth Doreen Crick, nee Dodd (m. 1940-1947); Odile Crick, nee Speed (b. 11 August 1920, m. 1949-2004, d. 5 July
2007)
- Children: Michael b. 1940 [by Doreen Crick]; Gabrielle b. 1951 and Jacqueline [later Nichols] b. 1954 [by Odile Crick];
- Grandchildren: Alex, Camberley, Francis, and Kindra (Michael and Barbara Crick's children] and Jacqueline Nichols' two
children.
Biology research
Crick was interested in two fundamental unsolved problems of biology. First, how
molecules make the transition from the non-living to the living, and second, how the brain makes a conscious mind.[9] He realized that
his background made him more qualified for research on the first topic and the field of biophysics. It was at this time of Crick’s transition from physics into
biology that he was influenced by both Linus Pauling and Erwin Schrödinger.[10] It was clear in theory that covalent bonds in
biological molecules could provide the structural stability needed to hold genetic information
in cells. It only remained as an exercise of experimental biology to discover exactly which molecule was the genetic molecule.[11][12]
In Crick’s view, Charles Darwin’s theory of evolution
by natural selection, Gregor Mendel’s genetics
and knowledge of the molecular basis of genetics, when combined, reveal the secret of life.[13]
It was clear that some macromolecule such as protein
was likely to be the genetic molecule.[14] However, it was well known that proteins are structural and functional macromolecules, some of which carry out enzymatic reactions of
cells.[14] In the 1940s, some evidence
had been found pointing to another macromolecule, DNA, the
other major component of chromosomes, as a candidate genetic
molecule. Oswald Avery and his collaborators showed that a phenotypic difference could be caused in bacteria by providing them with a
particular DNA molecule.[12]
However, other evidence was interpreted as suggesting that DNA was structurally uninteresting and possibly just a molecular
scaffold for the apparently more interesting protein molecules.[15] Crick was in the right place, in the right frame of mind, at the right time (1949), to join
Max Perutz’s project at Cambridge
University, and he began to work on the X-ray crystallography of
proteins.[16] X-ray crystallography
theoretically offered the opportunity to reveal the molecular structure of large molecules like proteins and DNA, but there were
serious technical problems then preventing X-ray crystallography from being applicable to such large molecules.[16]
X-ray crystallography 1949-1950
Crick taught himself the mathematical theory of X-ray crystallography. During the period of Crick's study of X-ray
diffraction, researchers in the Cambridge lab were attempting to determine the most stable
helical conformation of amino acid chains in proteins (the α
helix). Pauling was the first to identify the 3.6 amino acids per helix turn ratio of the α helix. Crick was witness to
the kinds of errors that his co-workers made in their failed attempts to make a correct molecular model of the α helix; these
turned out to be important lessons that could be applied to the helical structure of DNA. For
example, he learned the importance of the structural rigidity that double bonds
confer on molecular structures which is relevant both to peptide bonds in proteins and the
structure of nucleotides in DNA.
The double helix 1951-1953
In 1951, together with Cochran and V. Vand, Crick assisted in the development
of a mathematical theory of X-ray diffraction by a helical
molecule.[17] This theoretical result matched well with
X-ray data obtained for proteins that contain sequences of amino
acids in the Alpha helix conformation (published in Nature in 1952).[18] Helical
diffraction theory turned out to also be useful for understanding the structure of
DNA.
Late in 1951, Crick started working with James D. Watson at Cavendish Laboratory at the University of
Cambridge, England. Using the X-ray
diffraction results of Raymond Gosling and
Rosalind Franklin of King's College
London, given to them by Gosling and Franklin's colleague Maurice Wilkins, Watson
and Crick together developed a model for a helical structure of DNA, which they published in
1953.[19] For this and subsequent work they were awarded
the Nobel Prize in Physiology or Medicine in 1962, jointly with
Maurice Wilkins.[20]
When James D. Watson came to Cambridge, Crick was a 35 year old graduate student and
Watson was only 23, but he already had a Ph.D. They shared an interest in the
fundamental problem of learning how genetic information might be stored in molecular form.[21][22] Watson and Crick talked endlessly about DNA and the idea that it might be possible to
guess a good molecular model of its structure.[23] A key piece of experimentally-derived information came from X-ray diffraction images that had been obtained by Maurice
Wilkins and his research student, Raymond Gosling. In November 1951, Wilkins came
to Cambridge and shared his data with Watson and Crick. Alexander Stokes (another expert in
helical diffraction theory) and Wilkins (both at King's) had reached the
conclusion that X-ray diffraction data for DNA indicated that the molecule had a helical structure. Stimulated by Wilkins, and a
talk given by Rosalind Franklin about her work on DNA, Crick and Watson produced and
showed off an erroneous first model of DNA. Watson, in particular, thought they were competing against Pauling and feared that
Pauling might determine the structure of DNA.[24]
Many have speculated about what might have happened had Pauling been able to travel to
Britain as planned in May of 1952.[25] He might have seen some of the Wilkins/Gosling/Franklin X-ray diffraction data and such an event might
have led him to a double helix model. As it was, his political activities caused his travel to be restricted by the
U. S. government and he did not visit the UK until later, at which point he met none of the DNA researchers in
England.[26] Watson and Crick were not officially working
on DNA. Crick was writing his Ph.D. thesis. Watson also had other work such as
trying to obtain crystals of myoglobin for X-ray diffraction experiments. In 1952, Watson did
X-ray diffraction on tobacco mosaic
virus and found results indicating that it had helical structure. Having failed once, Watson and Crick were now somewhat
reluctant to try again and for a while they were forbidden to make further efforts to find a molecular model of DNA.
Digram that emphasizes the phosphate backbone of DNA. Watson and Crick first made helical models with the phosphates at the
center of the helices.
Of great importance to the model building effort of Watson and Crick was
Rosalind Franklin's understanding of basic chemistry, which indicated that the hydrophilic phosphate-containing backbones of the nucleotide chains of DNA should be
positioned so as to interact with water molecules on the outside of the
molecule while the hydrophobic bases should be packed into
the core. Franklin shared this chemical knowledge with Watson and Crick when she pointed out to them that their first model
(1951, with the phosphates inside) was obviously wrong.
Crick described what he saw as the failure of Maurice Wilkins and Rosalind Franklin to cooperate and work towards finding a molecular model of DNA as a major reason why he and Watson eventually made a second attempt to
make a molecular model of DNA. They asked for, and received, permission to do so from both Bragg and Wilkins. In order to construct their model of DNA, Watson and Crick made use of
information from unpublished X-ray diffraction images of Franklin's (shown at
meetings and shared by Wilkins), and preliminary accounts of Franklin's detailed analysis of the X-ray images that were included in a written progress report for the King's laboratory of John Randall from late 1952.
It is a matter of debate whether Watson and Crick should have had access to
Franklin's results without her knowledge or permission and before she had a chance to
formally publish the results of her detailed analysis of her X-ray diffraction data
that were included in the progress report. In an effort to clarify this issue, Perutz later
published[27]
what had been in the progress report, and suggested that nothing was in the report that Franklin herself had not said in her talk
(attended by Watson) in late 1951. Further, Perutz explained that the report was to a Medical Research Council (MRC) committee that had been created in order to "establish
contact between the different groups of people working for the Council". Randall's and Perutz's labs were both MRC funded laboratories.
It is also not clear how important Franklin's unpublished results from the progress report actually were for the model building done by
Watson and Crick. After the first crude X-ray
diffraction images of DNA were collected in the 1930s, William Astbury had talked about stacks of nucleotides spaced at 3.4 angstrom (0.34 nanometre) intervals
in DNA. A citation to Astbury's earlier X-ray diffraction
work was one of only 8 references in Franklin's first paper on DNA.[28] Analysis of Astbury's published DNA results and the better X-ray
diffraction images collected by Wilkins, Gosling and Franklin revealed the helical nature of DNA. It was possible to
predict the number of bases stacked within a single turn of the DNA helix (10 per turn; a full turn of the helix is 27 angstroms
[2.7 nm] in the compact A form, 34 angstroms [3.4 nm] in the wetter B form). Wilkins shared this information about the B form of
DNA with Crick and Watson. Crick did not see Franklin's B form X-ray images until after the DNA
double helix model was published[29].
One of the few references cited by Watson and Crick when they published their model of DNA, was to a published article that included Sven Furberg’s DNA model that had the bases on the inside. Thus, the
Watson and Crick model was not the first "bases in" model to be published. Furberg's results had also provided the correct
orientation of the DNA sugars with respect to the bases. During their model building, Crick and Watson learned that an
antiparallel orientation of the two nucleotide chain backbones worked best to orient the base pairs in the centre of a double
helix. Crick's access to Franklin's progress report of late 1952 is what made Crick
confident that DNA was a double helix with anti-parallel chains, but there were other chains of reasoning and sources of
information that also led to these conclusions.
As a result of leaving King's College for another institution, Franklin was asked by John Randall to give up her work on
DNA. When it became clear to Wilkins and the supervisors of
Watson and Crick that Franklin was going to the new job, and that Pauling was working on the structure of DNA, they were willing to share
Franklin's data with Watson and Crick, in the hope that they could find a good model of DNA before Pauling was able. Franklin's
X-ray diffraction data for DNA and her systematic analysis of DNA's structural
features was useful to Watson and Crick in guiding them towards a correct molecular model. The key problem for Watson and Crick,
which could not be resolved by the data from King's College, was to guess how the nucleotide bases pack into the core of the DNA
double helix.
Diagrammatic representation of some key structural features of DNA. The similar structures of guanine:cytosine and
adenine:thymine base pairs is illustrated. The base pairs are held together by hydrogen bonds. The phosphate backbones are
anti-parallel.
Another key to finding the correct structure of DNA was the so-called Chargaff ratios, experimentally determined ratios of the nucleotide subunits of DNA: the amount of
guanine is equal to cytosine and the amount of
adenine is equal to thymine. A visit by Erwin Chargaff to England in 1952 reinforced the salience of this
important fact for Watson and Crick. The significance of these ratios for the structure
of DNA were not recognized until Watson, persisting in building structural models, realized that A:T and C:G pairs are
structurally similar. In particular, the length of each base pair is the same. The base pairs
are held together by hydrogen bonds, the same non-covalent interaction that stabilizes the
protein α helix. Watson’s recognition of the A:T and C:G pairs was aided by information from Jerry Donohue[30] about the most
likely structures of the nucleobases. After the discovery of the hydrogen bonded A:T and C:G
pairs, Watson and Crick soon had their double helix model of DNA with the hydrogen bonds at the
core of the helix providing a way to unzip the two complementary strands for easy replication: the last key requirement for a likely model of the genetic molecule. As important as
Crick’s contributions to the discovery of the double helical DNA model were, he stated that without the chance to collaborate
with Watson, he would not have found the structure by himself.
Crick did tentatively attempt to perform some experiments on nucleotide base pairing, but he was more of a theoretical than an
experimental biologist. There was another close approach to discovery of the base pairing rules in early 1952. Crick had started
to think about interactions between the bases. He asked John Griffith to try to calculate attractive interactions between the DNA
bases from chemical principles and quantum
mechanics. Griffith's best guess was that A:T and G:C were attractive pairs. At that time, Crick was not aware of
Chargaff's rules and he made little of Griffith's calculations. It did start him thinking
about complementary replication. Identification of the correct base-pairing rules (A-T, G-C) was achieved by Watson "playing" with cardboard cut-out models of the nucleotide bases, much in the manner that
Pauling had discovered the protein alpha helix a few years earlier. The Watson and Crick
discovery of the DNA double helix structure was made possible by their correct interpretation of the significance of experimental
results that had been obtained by others.
Molecular biology
In 1954, at the age of 37, Crick completed his Ph.D. thesis: "X-Ray Diffraction:
Polypeptides and Proteins" and received his degree. Crick then worked in the laboratory of David Harker at Brooklyn Polytechnic Institute, where he continued to develop his skills in the
analysis of X-ray diffraction data for proteins, working primarily on
ribonuclease and the mechanisms of protein
synthesis.
After the discovery of the double helix model of DNA, Crick’s interests quickly turned to the
biological implications of the structure. In 1953, Watson and Crick published another article in Nature which stated: "it therefore seems likely that the precise
sequence of the bases is the code that carries the genetical information".[31]
In 1956, Crick and Watson speculated on the structure of small viruses. They
suggested that spherical viruses such as Tomato bushy stunt virus had icosahedral symmetry and were made from 60 identical
subunits.[32]
After his short time in New York, Crick returned to Cambridge where he worked until
1976, at which time he moved to California.
Crick engaged in several X-ray diffraction collaborations such as one with Alexander Rich
on the structure of collagen.[33] However, Crick was quickly drifting away from continued work related to his expertise in the
interpretation of X-ray diffraction patterns of proteins.
George Gamow established a group of scientists interested in the role of
RNA as an intermediary between DNA as the genetic storage molecule in
the nucleus of cells and the synthesis of proteins in the cytoplasm. It was clear to Crick that there had to be a code by which a short sequence of nucleotides would
specify a particular amino acid in a newly synthesized protein. In 1956, Crick wrote an informal paper about the genetic coding
problem for the small group of scientists in Gamow’s RNA group.[34] In this article, Crick reviewed the evidence supporting the idea that there was a common set of
about 20 amino acids used to synthesize proteins. Crick proposed that there was a corresponding set of small adaptor molecules
that would hydrogen bond to short sequences of a nucleic acid and also link to one of the amino acids. He also explored the many
theoretical possibilities by which short nucleic acid sequences might code for the 20 amino acids.
Molecular model of a
tRNA molecule. Crick predicted that such adaptor molecules might exist
as the links between
codons and amino acids.
During the mid-to-late 1950s Crick was very much intellectually engaged in sorting out the mystery of how proteins are
synthesized. By 1958, Crick’s thinking had matured and he could list in an orderly way all of the key features of the protein
synthesis process:[35]
- genetic information stored in the sequence of DNA molecules
- a “messenger” RNA molecule to carry the instructions for making one protein to the cytoplasm
- adaptor molecules (“they might contain nucleotides”) to match short sequences of nucleotides in the RNA messenger molecules
to specific amino acids
- ribonucleic-protein complexes that catalyse the assembly of amino acids into proteins according to the messenger RNA
The “adaptor molecules” were eventually shown to be tRNAs and the catalytic
“ribonucleic-protein complexes” became known as ribosomes. An important step was later (1960)
realization that the messenger RNA was not the same as the ribosomal RNA. None of this, however, answered the fundamental theoretical question of the exact nature of
the genetic code. In his 1958 article, Crick speculated, as had others, that a triplet of nucleotides could code for an
amino acid. Such a code might be “degenerate”, with 4x4x4=64 possible triplets of the four
nucleotide subunits while there were only 20 amino acids. Some amino acids might have multiple triplet codes. Crick also explored
other codes in which for various reasons only some of the triplets were used, “magically” producing just the 20 needed
combinations. Experimental results were needed; theory alone could not decide the nature of the code. Crick also used the term
“central dogma” to summarize an idea that implies that genetic
information flow between macromolecules would be essentially one-way:
DNA → RNA → Protein
Some critics thought that by using the word "dogma" Crick was implying that this was a rule that could not be questioned, but
all he really meant was that it was a compelling idea without much solid evidence to support it. In his thinking about the
biological processes linking DNA genes to proteins, Crick made explicit the distinction between the
materials involved, the energy required, and the information flow. Crick was focused on this third component (information) and it
became the organizing principle of what became known as molecular biology. Crick had
by this time become a dominant, if not the dominant, theoretical molecular biologist.
Proof that the genetic code is a degenerate triplet code finally came from genetics
experiments, some of which were performed by Crick.[36]
The details of the code came mostly from work by Marshall Nirenberg and others
who synthesized synthetic RNA molecules and used them as templates for in vitro protein synthesis[37].
Controversy about using King's College London's results
-
An enduring controversy has been generated by Watson and Crick's use of
DNA X-ray diffraction data
collected by Rosalind Franklin and Raymond
Gosling. The controversy arose from the fact that some of the data were shown to them, without her knowledge, by her
estranged colleague, Maurice Wilkins, and by Max Perutz.[38] Her experimental results provided estimates of the
water content of DNA crystals and these results were consistent with
the two sugar-phosphate backbones being on the outside of the molecule. Franklin personally told Crick and Watson that the
backbones had to be on the outside. Her identification of the space group for DNA crystals
revealed to Crick that the two DNA strands were antiparallel. The X-ray
diffraction images collected by Gosling and Franklin provided the best evidence for the helical nature of DNA. Franklin's superb
experimental work thus proved crucial in Watson and Crick's discovery.
Prior to publication of the double helix structure, Watson and Crick had little interaction with Franklin. Crick
and Watson felt that they had benefitted from collaborating with Maurice Wilkins. They
offered him a co-authorship on the article that first described the double helix structure of DNA.
Wilkins turned down the offer and was in part responsible for the terse character of the acknowledgement of experimental work
done at King's College. Rather than make any of the DNA researchers at King's
College co-authors on the Watson and Crick double helix article, the solution that was arrived at was to publish two additional
papers from King's College along with the helix paper. Brenda Maddox suggested that because of the importance of her work to Watson and Crick's model building,
Franklin should have had her name on the original Watson and Crick paper in Nature.[39] Watson and Crick offered joint authorship to Wilkins which he turned
down at the time, but which he may have subsequently regretted. (Franklin and Ray Gosling submitted their own joint 'second'
paper to Nature at the same time as Wilkins, Stokes and Wilson submitted theirs, i.e.,
the 'third' paper on DNA.)
Views on religion
Crick once joked, "Christianity may be OK between consenting adults in private but should not be taught to young
children."[40]
In his book Of Molecules and Men, Crick expressed his views on the relationship between science and religion.[41] After suggesting that it would become possible for people to wonder if a computer might be programmed so as to have a soul, he wondered: at what point
during biological evolution did the first organism have a
soul? At what moment does a baby get a soul? Crick stated his view that the idea of a non-material soul that could enter a body and then persist after death is just that, an imagined idea. For Crick, the
mind is a product of physical brain activity and the
brain had evolved by natural means over millions of years. Crick felt that it was important that
evolution by natural selection be taught in public schools and that it was regrettable
that English schools had compulsory religious instruction.
Crick felt that a new scientific world view was rapidly being established, and predicted that once the detailed workings of the
brain were eventually revealed, erroneous Christian concepts
about the nature of man and the world would no longer be tenable; traditional conceptions of the
"soul" would be replaced by a new understanding of the physical basis of mind. He was skeptical of
organized religion, referring to himself as a skeptic and an agnostic with "a strong
inclination towards atheism".[42]
In 1960, Crick accepted a fellowship at Churchill
College Cambridge, one factor being that the new college did not have a chapel. Sometime later a large donation was made
to establish a chapel and the fellowship elected to accept it. Crick resigned his fellowship in protest[43].
In October 1969, Crick participated in a celebration of the
100th year of the journal Nature. Crick attempted to make some predictions about
what the next 30 years would hold for molecular biology. His speculations were later published in Nature.[44] Near the end of the article, Crick briefly mentioned the
search for life on other planets, but he held little hope that extraterrestrial life would be found by the year 2000. He also
discussed what he described as a possible new direction for research, what he called
"biochemical theology". Crick wrote, "So many people pray that one finds it hard to believe that they do not get some
satisfaction from it...."
Crick suggested that it might be possible to find chemical changes in the brain
that were molecular correlates of the act of prayer. He speculated that there might be a
detectable change in the level of some neurotransmitter or neurohormone when people pray. Crick may have been imagining substances such as dopamine that are released by the brain under certain conditions and produce
rewarding sensations. Crick's suggestion that there might some day be a new science of
"biochemical theology" seems to have been realized under an alternative name: there is now the new field of Neurotheology.[45] Crick's view of
the relationship between science and religion continued to play a role in his work as he made the transition from
molecular biology research into theoretical
neuroscience.
Directed panspermia
During the 1960s, Crick became concerned with the origins of the genetic code. In 1966, Crick took the place of
Leslie Orgel at a meeting where Orgel was to talk about the origin of life. Crick speculated about possible stages by which an initially simple code with a few
amino acid types might have evolved into the more complex code used by existing
organisms.[46] At that
time, everyone thought of proteins as the only kind of
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