Painter of modern biology

THE understatement in the opening and the concluding sentences of that 1,000-word communication entitled "Molecular Structure of Nucleic Acids", to the April 25, 1953, issue of the journal Nature, which changed the face of biology and our perception of life in the years that followed, was contrary to the assertive tone in which the British biologist Francis Crick announced to the general public at the Eagle Pub on February 28, 1953 that he and James D. Watson, his collaborator, had discovered the "secret of life". Far from claiming any finality in the elucidation of the deoxyribonucleic acid (DNA) structure - which today stands validated as the true carrier of the genetic code and the template or "blueprint of life" - the historic paper merely said: "We wish to suggest a structure for the salt of deoxyribonucleic acid (DNA). This structure has novel features which are of considerable biological interest... . It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material."

These words also do not convey the image of the immodest person that Watson portrayed in his bestselling book The Double Helix, which describes the colourful tale of the race to decode the basic genetic material that all life is made of - the Holy Grail of biology, which Crick and Watson won over great biologists such as Linus Pauling. The tempered tone of the letter, the result of Watson's apprehensions, seemed to match the lukewarm reception that the paper got from the scientific community on publication.

Crick wrote in his 1988 book, What Mad Pursuit: "(I)t was a compromise, reflecting a difference of opinion. I was keen that the paper should discuss genetic implications. Jim was against it. He suffered from periodic fears that the structure might be wrong and that he had made an ass of himself. I yielded to his point of view but insisted that something be put in the paper, otherwise someone else would certainly write to make the suggestion, assuming we had been too blind to see it. In short, it was a claim to priority."

Thus, at the same time, the paper did not fail to convey the undercurrent of confidence that the authors had in the proposed DNA structure and its far-reaching implications. That confidence in his scientific perception and insight was typical of Crick, who passed away on July 28 in San Diego, United States, at the age of 88. His discovery of the DNA structure, which laid the foundations for molecular biology, is perhaps the most important discovery of the 20th Century after Einstein's theory of gravitation. In life sciences, it is bound to have the same lasting value as did Darwin's theory of evolution and Mendel's principles of heredity in the 19th Century. Five decades later, the world is witness to a rapid revolution in biosciences and technology that Crick's discovery unleashed, with the double helical structure of DNA itself becoming the icon for modern biology.

FRANCIS HARRY COMPTON CRICK was born on June 8, 1916, at Northampton, England, to Harrie Crick and Annie Elizabeth Wilkins. He studied physics at University College, London and obtained his BSc degree in 1937. He then started research under Professor E.N. da C. Andrade for his PhD. The subject was "measurement of viscosity of water at high temperatures and pressures", which he later described as "the dullest problem imaginable". But this work was interrupted by the outbreak of the Second World War in 1939. During the War, Crick worked as a scientist for the British Admiralty, chiefly in techniques for sweeping German magnetic mines and devising circuits for magnetic and acoustic mines for the Navy. He stayed on two years after the War, when he read the physicist Erwin Schroedinger's What is Life? The Physical Aspects of the Living Cell.

Schroedinger's exciting idea of applying physics to investigate genes at the molecular level fascinated Crick, provoking him to switch his career plans from particle physics to biology. Biochemistry and molecular biology were growing fields after the War. He quit his tenured job at the Admiralty in 1947, joined the Strangeways Laboratory, Cambridge, with Arthur Hughes and studied the physical properties of cytoplasm in the cultured fibroblast cells. Already revealing an extraordinary gift for biochemistry, he moved to the Medical Research Council (MRC) at the Cavendish Laboratory in 1949 and joined Max Perutz and John Kendrew, pioneers in applying x-ray diffraction techniques to studies in structural biology. The question posed by Schroedinger was: "How can the events of space and time which take place within... the living organism be accounted for by physics and chemistry?" This actually drove him to investigate the mysteries of the genetic code. Crick did not even have a PhD when he decoded the structure of DNA with Watson. He received it a year later on the subject of x-ray diffraction of proteins. His work on diffraction by helical structures is a very important piece of research.

Watson, a young 23-year-old American biologist with a fresh PhD from Indiana University, joined him in 1951, and this association was to grow into a close working relationship as well as a lasting friendship. The two were convinced that if the three-dimensional structure of DNA - already believed, from the work of Oswald Avery in 1944 on a pneumococcus strain, to be playing a critical role in passing genetic information - could be determined, then the way genes are passed on might also be revealed. Crick said that their collaboration worked mainly because they were never afraid of rigorously questioning each other's ideas.

Five weeks after their restrained note, the suggestion about DNA serving as a template for copying the genetic information was given a firmer ground in an equally important paper titled "Genetic Implications of the Structure of Deoxyribonucleic acid" that was published in Nature, on May 30, 1953. It is here that the two made the suggestion that the genetic code is imprinted as words made up of four letters, A, T, C and G (which stood for different nucleotide bases), and proposed the mechanism for duplication: "If the actual order of the bases on one of the pairs of chains were given, one could write down the exact order of the bases on the other one, because of the specific pairing. Thus one chain is, as it were, the complement of the other, and it is this feature which suggests how the deoxyribonucleic acid molecule might duplicate itself."

This breakthrough, which forms the foundation of modern molecular biology, won them the Nobel Prize in 1962, along with Maurice Wilkins of King's College, London, who provided Watson and Crick the x-ray diffraction image of DNA taken by his colleague Rosalind Franklin and helped with the analysis of the data and its interpretation through model building. Apparently, once the x-ray data was obtained, Crick was so sure of the structure that he did not even complete the building of the model, he left it to his wife, a painter, to do that. The Nobel citation read: "for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material".

WHAT was the relationship between the sequence of bases in DNA and the sequence of amino acids in proteins? In 1957, Crick became excited about his theory that DNA passed its information to Ribonucleic Acid (RNA), and this was then used in the synthesis of specific proteins. It seems Watson too had similar ideas, as is evident from his notebooks, but Crick "went around preaching it as certainty". This question - the genetic code - was the subject of a collaboration between Francis Crick, Sydney Brenner, Leslie Barnett and Watts-Tobin, which resulted in a famous paper in Nature in 1961.

In a long series of complex experiments, they induced mutations in the DNA of bacteriophage T4, a virus that infects bacteria. The mutations changed individual bases in the DNA. When two or four mutations were together, the gene was still inactive, but when three mutations were put together in the same gene, the gene started to work again. They concluded that the genetic code is a triplet code (three bases code for one amino-acid).

In the 1960s, Marshall Nirenberg and others "cracked" the code, working out which triplets of nucleotides coded for which amino acids. The concept of the triplet codon is now part and parcel of the language of molecular biology.

Crick wrote in Mad Pursuit: "Although Sydney [Brenner] and I clearly realised that the genetic code was a biochemical problem, we still had hopes that genetic methods could contribute to the solution, especially as genetic methods, using the right material, can be very fast..." And it is to the credit of Crick's insight that this worked. Indeed, Crick was not even fully familiar with the terminology being used for mutants, so he called it FC0, being sure that no one would have used his initials to name a mutant.

This was then followed by Crick's investigations into how long sequences of base pairs are isolated from the huge mass of information in the nucleus, and then read, with very few errors, during their rapid transcription in the living cell. With Brenner, he correctly proposed, with remarkable insight, the existence of small chemicals known as "adapters" that recognise the triplets of bases and assemble one amino acid at a time to synthesise proteins from the code. This work also led to his "wobble hypothesis", which postulated that while the first two bases in the triplet codon were always stringently complemented during (transcription) RNA's binding with (messenger) RNA, the third one was only less so - there was a "wobble", so to speak, in the way the code was translated into the protein. Crick thus not only established the basis of the genetic code but also elucidated the mechanism for protein synthesis.

Crick proposed several far-reaching theories, not all by experimentation, but simply through theoretical reasoning and insight. These have stood the test of time. His central dogma was that the genetic code was universal to all life and that once genetic information is passed on to a protein, it could not get out again. The dogma implied that the genetic message could not be broken by information from outside the cell. That is, it excluded the hypothesis that acquired characteristics could be inherited.

Crick is perhaps the greatest theoretical biologist that the world has witnessed, truly a giant in the field. "It is fair to say Crick defined the discipline of theoretical biology and so far no other practitioner of that art has come up to that standard," remarked Francis Collins, director of the U.S. National Human Genome Research Institute. "No one created molecular biology. But one dominates intellectually the whole field because he knows and understands the most - Francis Crick," said Jacques Monod to Horace Freeland Judson, a historian and the author of the book Eighth Day of Creation.

CRICK spent most of his research in genetics at the MRC at the Cavendish Laboratory, under the great Max Perutz, with brief stints at the Salk Institute, La Jolla, San Diego, at Harvard and elsewhere in the U.S. In 1962, he became the director of Cambridge University's Molecular Biology Laboratory. In 1966, he wrote the book Of Molecules and Men, describing the implications of the ongoing biomedical revolution. Crick was elected a Fellow of the Royal Society in 1959, primarily for his work on DNA and for his study on the structure of proteins and viruses. He was awarded the Royal Medal in 1972 and in 1975 he received the Copley Medal, the Royal Society's premier scientific award.

After 30 years of wide-ranging and revolutionary work in biology at the molecular level, and 87 papers bearing his name, in 1977 Crick went on to attack the toughest problems in biology - the mind and the brain. During this period, with Alex Rich and others, he also postulated the structures of polyglycine II and collagen and polyadenylic acid. The case of collagen is well-known in India; the original triple helical structure, on which Rich and Crick built a modified structure, came from the University of Madras. It is called the Madras Triple Helix.

On the persuasion of Leslie Orgel, a long-standing colleague, Crick moved to the Salk Institute and began studying neurobiology. With Graeme Mitchison, he investigated dreams. Overturning the Freudian hypothesis, he suggested that dreams were mechanisms for clearing out the debris of unwanted information and experiences. With Orgel, he developed in 1981 his ideas of panspermia, which formed the thesis of his book Life Itself. According to this idea, life developed in a far-away planet and arrived on earth aboard a spaceship of an advanced civilisation. The hypothesis, Crick has stated, makes a strong prediction that the "earliest organisms should appear suddenly, without any sign of any precursors here on earth". This is an idea that Fred Hoyle and Chandra Wickramasinghe had already been expounding in the context of unknown viruses and diseases.

BUT it was Crick's interest in the neural basis of consciousness that occupied his research work in the following three decades. He was a big influence in building up the neuroscience programme at the Salk Institute. Consciousness was a subject no neuroscientist went near because of its complexity, but Crick's foray has now led the practioners of the discipline to ask scientific questions - and not merely make philosophic and metaphysical speculations - and conduct experiments. Starting in 1984, Crick began his extensive collaboration with Christof Koch and together they authored most of Crick's papers on neuroscience. In his book The Astonishing Hypothesis (1994) Crick stated that "human soul" was explicable entirely in terms of brain activity.

The basis of the Crick-Koch theory is that consciousness involves the firing of specific neurons in a specific way in a specific part of the brain. Their work focussed on the visual system, and their hypothesis is that while vision is controlled by the primary visual cortex, it does not generate the eventual conscious perception and the neuronal correlates of consciousness lie elsewhere in the brain. In 1998, the two wrote a seminal paper setting out his rationale for tackling the issue of consciousness and defining a few critical questions. The paper also listed areas that were not worth approaching at that point of time, as science was not yet ready to formulate related questions.

CRICK disliked the limelight that the Nobel award brought upon him. In fact, he rarely gave lecture tours and was reluctant to give interviews, attend award functions or accept honorary degrees. As regards his manner of doing research, he rarely took graduate students under him, preferring to work with a single colleague on specific problems. "Francis essentially works alone but likes to have a colleague to play against, so to speak," Brenner said recently. Though he lived in California, he continued to be a British Citizen, thus enabling the Queen to bestow on him the rare and prestigious Order of Merit in 1999.

"Francis Crick," said Richard Murphy, Director of the Salk Institute, "will be remembered as one of the most brilliant and influential scientists of all time." Watson, his long-time colleague, friend and collaborator in the decoding of DNA, said in a statement after Crick's death: "I will always remember Francis for his extraordinary focused intelligence and for the many ways he showed me kindness and developed my self-confidence... Until his death, Francis was the person with whom I could most easily talk about ideas."

"I cannot do better," Crick once said in response to being asked whether he enjoyed his life, "than to quote from a lecture by the painter John Minton... "The important thing is to be there when the picture is painted". And this, it seems to me, is purely a matter of luck and partly good judgement, inspiration and persistent application." The genius of Crick was that he was the one who painted the picture of modern biology and the rest of this and future generations are lucky to witness the power of that picture.