Explorer of the Bloodstream

The tangled mass of tubing, disks and light bulbs unveiled before a packed meeting of the Royal Society of scientists in London looked for all the world like an outsize example of abstract sculpture. In fact, it was a precise piece of technical art. It was a model of the hemoglobin molecule, the vital constituent of blood corpuscles, and it was the result of nearly 30 years of effort by Cambridge University Molecular Biologist Max Perutz.

In those three decades, Perutz discovered much of what is now known about the hemoglobin molecule, which he rightly calls "an incredible apparatus." Scientists have long known that hemoglobin in the bloodstream carries oxygen from the lungs to the body tissues and returns waste products from the tissues to be exhaled from the lungs. But not until Perutz learned how to put the pieces of his intricate puzzle together did anyone begin to understand just how hemoglobin does its job.

Each hemoglobin molecule, Perutz found, consists of 10,000 atoms, of which four are iron atoms that have an affinity for oxygen. In the lungs, in the presence of oxygen, the hemoglobin molecule changes shape, moving each of the four iron atoms, which are located in separate "pockets" on its surface, to different positions. This change increases by 300 times the molecule's attraction for oxygen atoms, pulling four of them into combination with the iron atoms. It is only because there are 280 million hemoglobin molecules in each red corpuscle that the blood has sufficient oxygen-carrying capacity for human respiration.

As the molecule delivers its oxygen to the body's tissues, it reverts to its original shape and attracts charged hydrogen atoms. The blood thus becomes alkaline, forms a temporary chemical bond with carbon dioxide and water from the tissues in the form of bicarbonate and carries it to the lungs, where it changes back into water and carbon dioxide before being exhaled. The change of molecular shape is important, says Perutz, "because it is the most elementary manifestation of the property of a living system that can turn chemical energy into movement."

Bizarre Scheme. Perutz studied molecular structure by analyzing X-ray photographs of crystallized hemoglobin. Scattered and deflected by the atoms within, the X-rays form a pattern of light and dark spots on a film behind the crystal. By patient mathematical analysis of thousands of variations of this pattern (each produced by a Perutz technique of substituting mercury "tag" atoms for different atoms within the hemoglobin molecule), the structure of the complex molecule was carefully pieced together.

Shy and diffident, Perutz began to probe the hemoglobin structure in 1937, after he came to Cambridge as a refugee graduate student. His work was interrupted during the war because he was interned as an enemy alien; then he was released to work on a bizarre and impractical scheme to tow Arctic ice islands into the North Atlantic to serve as airbases.

Back in his laboratory, Perutz returned to hemoglobin and worked until 1953 "just finding a way (the mercury technique) to attack the problem." But there were important byproducts along the way. Working under Perutz at Cambridge in 1953, James Watson and Francis Crick discovered the structure of dioxyribonucleic acid (DNA), the heredity-determining master molecule of life. By 1959, Perutz himself had partially solved the more complicated structure of hemoglobin, locating the sites where iron atoms pick up oxygen. That feat won him a Nobel Prize in 1962.

Atomic Anatomy. Despite his elegant display before the Royal Society, Perutz has far from completed his work on hemoglobin. The model, he points out, shows the structure of hemoglobin only while it is carrying oxygen. To better understand the variable nature of the molecule, he must now build another model that shows its deoxygenated state. Perhaps then Perutz will be able to explain just how the very presence of oxygen causes the molecule to change shape. "What we have done," he says, "is merely the anatomy at the atomic level. Now it is necessary to advance to the physiology."

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