The Molecular Revolution: How We Learned to See the Machinery of Life
The story of how scientists cracked the code of life's molecular structures, transforming biology forever
The Invisible Blueprint
Imagine trying to assemble a complex piece of furniture without the instructions, relying only on shaking the box and listening to the rattles inside. For the first half of the 20th century, this was essentially the state of biology. Scientists knew that proteins and DNA were the fundamental molecules of life, but their precise shapes and structures were a complete mystery. They were like formless, functionless chemicals in a cellular soup 3 .
The idea that these biological molecules had defined, three-dimensional architectures—structures that directly determined their function—was a radical concept. The story of how this mystery was unraveled, a 30-year revolution between 1933 and 1963, is masterfully told by Richard E. Dickerson in Present at the Flood: How Structural Biology Came About.
Dickerson was not just a historian; he was a pioneer who was famously "present at the flood" of discovery, helping to solve the first protein structure and later the first atomic-resolution structure of B-DNA 1 . This is the tale of how scientists learned to see the very machinery of life, transforming biology from a science of observation into one of atomic-level understanding.
From Formless Blobs to Precise Machines
Demolishing the Colloid Theory
Before the structural revolution, the prevailing theory was that proteins were colloids—formless, gelatinous globules or micelles with no specific sequence or structure 3 . Think of them as biological glue or amorphous slime. This idea was profoundly limiting; if a protein had no fixed shape, how could it perform specific tasks like catalysis or information sensing?
Colloid Theory
Proteins as formless, gelatinous globules with no specific structure.
Polypeptide Chains
Proteins as linear chains of amino acids in specific, unique order.
The first major breakthrough was the decisive demolition of this colloid theory. Through meticulous chemical experiments, researchers demonstrated that proteins were not colloids but were instead composed of long, linear chains of amino acids linked in a specific, unique order 3 . This was a paradigm shift. It meant that each protein had a precise chemical identity, a sequence that could, in theory, dictate a specific three-dimensional form. This set the stage for the next, even bigger question: if proteins are chains, how do they fold?
The Alpha-Helix: A Flash of Structural Insight
With the concept of polypeptide chains established, a race began to discover their natural conformation. The winner was Linus Pauling, one of the greatest chemists of the 20th century. While sick in bed, Pauling began playing with paper and a ruler to model how a polypeptide chain might fold 1 .
Through model-building and brilliant chemical intuition—rather than complex experimental data—he proposed the alpha-helix, a elegant, coiled structure held together by hydrogen bonds 1 3 .
This was a monumental achievement. It was the first time anyone had accurately predicted a protein's secondary structure. Pauling and his colleague Robert Corey also described the beta-sheet, another fundamental building block of proteins 3 . These discoveries showed that the complex folding of proteins obeyed the well-understood rules of structural chemistry. The formless blob was rapidly giving way to an architecture of stunning elegance.
The Race for the Double Helix
A Tale of Two Approaches
Perhaps the most famous story in this molecular revolution is the discovery of DNA's structure. Dickerson's account provides a nuanced historical analysis, capturing both the moments of critical insight and the stumbles of erroneous ideas 1 . The race pitted several top scientists against one another, primarily Linus Pauling in the United States and James Watson and Francis Crick in the UK.
Watson & Crick's Approach
Leveraged high-quality X-ray data from Franklin and Wilkins to build the correct double helix model.
Pauling, fresh from his success with the alpha-helix, initially stumbled. He proposed a three-stranded DNA model with the phosphate groups on the inside, a structure that was chemically implausible 1 3 . This error was partly due to his lack of access to high-quality experimental data. Meanwhile, at the University of Cambridge, Watson and Crick were working in the same institution as Maurice Wilkins and Rosalind Franklin, who were producing the world's best X-ray diffraction images of DNA.
The Moment of Discovery
The final breakthrough came when Watson and Crick combined key pieces of information:
Chargaff's Rules
The observation that in DNA, the amount of adenine equals thymine, and guanine equals cytosine.
Franklin's Photo 51
This critical X-ray diffraction image revealed an unmistakable helical pattern with phosphate groups on the outside.
Model Building
With these clues, they built the now-iconic double helix model with specific base pairing.
With these clues, they built the now-iconic double helix model in 1953—two chains winding around a common axis, with the bases pairing specifically (A with T, G with C) on the inside 1 3 . This structure was not just beautiful; it was functionally profound. It immediately suggested how genetic information could be stored and replicated. The discovery was synergistic, born from the interplay of chemistry, physics, biology, and not least, the complex personalities of the scientists involved 1 .
Cracking the Myoglobin Code: A Landmark Experiment
The Methodology: From Crystal to Map
While the DNA story was unfolding, another monumental challenge was underway: determining the first atomic-level structure of a protein. The target was myoglobin, an oxygen-storing protein in muscle. The team, led by John C. Kendrew at Cambridge, used X-ray crystallography, a powerful but painstaking technique. Richard E. Dickerson himself was a key part of this effort, developing the mathematical basis to refine the "phases" critical to solving the structure in 1957 1 .
The Experimental Procedure
- Crystallization: Growing high-quality crystals of sperm whale myoglobin
- Data Collection: Shooting X-rays at the crystal to create diffraction patterns
- The Phase Problem: Solving the missing phase information
- Isomorphous Replacement: Introducing heavy atoms to solve phases
- Electron Density Map: Computing 3D electron density
- Model Building: Interpreting the density with atomic models
Results and Analysis: Seeing a Protein for the First Time
When the structure was finally solved in 1958, the result was breathtaking. For the first time in history, scientists could see the detailed atomic architecture of a protein. The structure revealed:
Dense, Asymmetric Core
The myoglobin molecule was a compact, intricately folded chain.
Mostly Helical
Structure dominated by alpha-helices folded at odd angles.
Heme Group
Flat heme group with iron atom for oxygen binding.
The scientific importance was immense. It proved that a protein's specific function was a direct consequence of its unique, complex, and evolutionarily shaped three-dimensional structure. It validated the entire field of structural biology and paved the way for understanding how enzymes work, how drugs interact with their targets, and ultimately, how life's molecular machines operate.
Key Discoveries in Structural Biology
~1935
Demise of the Colloid Theory - Established proteins as unique, ordered polypeptide chains.
1951
Alpha-Helix & Beta-Sheet - Pauling & Corey's first prediction of protein secondary structure.
1953
DNA Double Helix - Watson & Crick revealed the structure of genetic material.
1958
First Protein Structure (Myoglobin) - Kendrew & Dickerson's atomic-resolution view of a protein.
1960
Hemoglobin Structure - Perutz showed how a multi-subunit protein functions.
- Linus Pauling - Predicted alpha-helix; proposed incorrect DNA triple-helix
- Francis Crick - Co-discovered DNA double helix; theoretical thinker
- Rosalind Franklin - Produced critical X-ray diffraction data for DNA
- Richard Dickerson - Solved phases for myoglobin; first atomic structure of B-DNA
- X-Ray Crystallography - Primary technique for determining 3D atomic structure
- Isomorphous Replacement - Method to solve the "phase problem"
- Molecular Model Building - Physical models to interpret electron density
- Protein Crystals - Regular arrays needed to diffract X-rays
The Legacy of the Flood
The 30-year revolution chronicled in Present at the Flood did more than just win Nobel Prizes. It created the foundation for modern molecular biology, genetics, and proteomics 1 . The ability to see biological molecules transformed medicine, enabling the rational design of drugs that fit into the specific pockets of their target proteins like a key in a lock.
Dickerson's book is unique because it captures this history not as a dry sequence of events, but as a vibrant, human story. He recounts the "slight remark that triggered a cascade of thought," the collaborative synergy, and the sometimes "sarcastic or even mean-spirited responses to competitors" 1 .
It is a story of brilliant minds, fierce competition, and occasional blunders, all culminating in a new way of seeing life itself. As Dickerson recounts, when Francis Crick first saw Dickerson's atomic-resolution structure of B-DNA decades after his own seminal discovery, he could only exclaim with delight: "So that's what it looks like!" 1 . After the flood of discovery receded, the landscape of biology was forever changed.
