In Chennai, not far from the banks of river Adyar, there’s an auditorium in the heart of a national research centre that appears wholly unremarkable – except for its name, Triple Helix. This holds the key to a David and Goliath story from the rarified realms of research. The plot, set in the early 1950s, involves a puzzle in structural biology. The cast spans continents.
A young scientist in Madras, now Chennai, is pitted against celebrated researchers from labs at the University of Cambridge, the King’s College in London, and Caltech. This elite group of Goliaths included the co-discoverer of the DNA double helix, and the proposer of the single helix structure of proteins.
The David in this story is Gopalasamudram Narayana Ramachandran, or simply, GNR.
The year is 1952. Barely 30, GNR had just been made head of the Department of Physics at the University of Madras. As a graduate student, he worked in the field of optics under CV Raman at the Indian Institute of Science, Bangalore, and received the equivalent of a doctorate degree. Later, he received a PhD from Cambridge University in 1949, where he worked for two years in the laboratory directed by Sir Lawrence Bragg, co-discoverer of X-Ray diffraction. Diffraction was the technique being used to decipher the structures of biomolecules such as DNA and proteins.
The structure of DNA was decoded and published in 1953 – revealing the double-helical shape – but the structures of complex and even common proteins had remained puzzling.
Like a string of pearls, proteins are made of repeating units or monomers of amino acids (there are 20 essential amino acids in the human body). What links the monomer units is a peptide bond – formed by removing a water molecule from a pair of amino acids – so what you have is a polypeptide chain. These chains pleat or intertwine, to yield two dimensional structures – helices or sheets – which then fold into 3D shapes.
This molecule’s architecture is important because it decides what the protein will do in the body. We know today, that incorrect folding of peptide chains causes proteins to function incorrectly, and folding errors manifest as diseases. But the foundation for this understanding was being laid in the 1950s when first-rate scientists worked to discover the architecture of biomolecules.
In 1952, GNR got a laboratory of his own. Studying biomolecules would be the lab’s theme, the crystal physicist had decided, but he didn’t know where to begin. Right around then, a former colleague from England, the renowned crystallographer JD Bernal, who was on a visit to Madras, informed GNR that many research groups were grappling with the structure of collagen – the most abundant protein in animals – and no one had hit the mark yet.
Collagen, present in the connective tissue of animals, gives strength and form to all creatures, humans included. Structure-wise, collagen seemed knottier than the DNA. This, GNR decided, would be the problem he would work on.
First, he needed to find a source of collagen. The shark fin collagen from the biochemistry department on campus didn’t yield great images. Good quality pictures were essential to cracking the collagen puzzle, he knew. Leather, it occurred to GNR, was largely collagen.
Not far from the university campus was a new institute – the Central Leather Research Institute. GNR decided to pay his neighbours a visit. As he made his way there, the leather choices in GNR’s mind were Kangaroo Tail Tendon or Beef Achilles Tendon. The deputy director of CLRI turned out to be a kindred soul, happy to help a fellow scientist. The beef sample was easy to obtain locally. But if kangaroo collagen was going to yield the best diffraction images – as the scientific literature said – the deputy director promised to get GNR samples from Australia.
Thus, GNR found himself some purified marsupial collagen to work with.
The only information available on the fibrous protein collagen was this: one-third of its total amino acid content was glycine. Using this fact, looking at the pictures he had taken, GNR made an intuitive leap. Every third monomer in the polypeptide chain is glycine, and so collagen must be a triple helix. He saw it as three separate helical chains stacked in a hexagonal array. GNR and his group published this prototype structure in the August 7, 1954 issue of the journal Nature.
Suddenly, top-notch molecular biologists in Cambridge, California, and elsewhere, began paying attention to the work of the “Madras group”. Between themselves, they began to refer to the model GNR proposed as the Madras triple helix.
A year later, GNR and his first post-doc refined the prototype and came up with the “coiled-coil” structure, which could explain all available experimental data on collagen.
In this new model, the three helical chains – originally thought of as separate – intertwined to form a second helix. Their results appeared in the September 1955 issue of Nature.
Referring to his seminal discovery, the “coiled-coil” model, GNR said that he was inspired by astronomy. Think of the night sky: the rotating moon which revolves around the earth, always presents the same side to earth. In collagen, the smallest of amino acids, glycine, always faces the center of the triple helix.
There is a simpler way to think of this structure, as described by D Balasubramanian, The Hindu’s inimitable science columnist: the three helices were “braided in the manner of the pigtail of a long-haired maiden from Madras”. Maybe, GNR’s collagen model was subliminally inspired by his beloved wife Rajam’s everyday coiffure as well.The “coiled coil” model was a fundamental advance in understanding protein structure. Francis Crick (who cracked the structure of the DNA with James Watson) acknowledged this in the November 1955 issue of Nature: “Very recently Ramachandran and Kartha have made an important contribution by proposing a coiled-coil structure of collagen. We believe this idea to be basically correct but the actual structure suggested by them to be wrong.” Crick and his post-doc offered minor modifications. So did another group, based in King’s College, London.
In the end, the big names received the lion’s share of the credit for deciphering the structure of collagen. GNR seemed doomed to be a mere footnote in collagen literature – but he wasn’t ready to give up. GNR took the criticism aimed at the Madras triple helix and worked to find the underlying principles which determined what forms polypeptides chains could and could not take in a protein. By doing this, in 1963, he came up with the very grammar of protein folding. To this day, researchers use the Ramachandran Plot (or map, even diagram) to validate protein structures.
Like the Raman Effect, Heisenberg’s Uncertainty Principle, or Einstein’s Theory of Relativity, the Ramachandran Plot has rendered the scientist behind it immortal. You’ll find Ramachandran’s name in standard biochemistry text books, and in the latest papers on protein structure in prestigious journals.
GNR organised two international symposia in Madras, one in the winter of 1963 and another in the winter of 1967. The symposia acknowledged the high scientific standard of research done by the Madras group. Nobel laureates attended the events.
Addressing the second symposium as the president, two-time Nobel winner Linus Pauling, discoverer of the alpha helix structure of proteins, recalled how GNR’s team had pipped his group to the post in a race for the collagen structure.
After close to two decades in Madras, in 1971, GNR returned to the Indian Institute of Science to set up the Molecular Biophysics Unit. An excellent teacher, GNR spawned a dynasty of scientists who address biological questions in structural terms.
Within a decade, however, the field became computationally intensive. In the 1980s, computational biologists in India were handicapped by a lack of access to computers – so we may have squandered a precious lead. But with cloud computing, the playing field is now level for scientists worldwide. In a tribute to GNR, who died in 2001, and as a token of their collaboration, the folks at CLRI named their lecture theatre the Triple Helix Auditorium.
The name signifies what was, and what could be, in Indian science.
A version of this appeared in Madras Musings.