Max Perutz, 87; Pioneer in Field of Molecular Biology
Max Perutz, the British chemist whose efforts to solve the riddle of life by unraveling protein structures led to the creation of the field of molecular biology, died Wednesday of cancer at his home in Cambridge. He was 87.
Perutz and his colleague John C. Kendrew were the first to determine the three-dimensional structure of proteins, the molecular machines that run cells. Their feat garnered them the 1962 Nobel Prize for chemistry. More important, it gave scientists their first insight into how chemical reactions within the cell are carried out.
Enzymes, in particular, are the movers and shakers of the cellular world, said molecular biologist Richard Dickerson of UCLA, “but we had no idea how they worked until we could get molecular structures.”
Perutz devised the technique known as “isomorphic replacement” that for the first time allowed scientists to convert the massive amounts of data obtained from shining X-rays on a protein into a precise picture of the arrangement of individual atoms. His discovery unleashed a flood on new data.
Perutz published the structure of hemoglobin--the complex protein that carries oxygen and carbon dioxide through the bloodstream--in 1959. By the end of the next decade, researchers were using his technique to publish an average of one new structure a day.
A check at an online protein structure database Friday showed that it contained 17,248 individual structures.
Perutz’s achievement was “absolutely monumental,” said molecular biologist Thomas Poulos of UC Irvine. “He put the ‘molecular’ in molecular biology.”
Perutz was also the founder and first director of the renowned Laboratory of Molecular Biology at Cambridge, which has produced nine Nobel laureates since the 1950s.
There are two major problems in doing X-ray crystallography of proteins: growing the proteins themselves and analyzing the data. Perutz chose hemoglobin as the subject of his research not only for its biological importance, but also because hemoglobin crystals could be grown readily. Nonetheless, he often was said to have a “glass thumb” because of his facility at producing protein crystals.
Analyzing Data Proved Tough Task
The more important problem was data analysis. When X-rays are passed through a crystal, their paths are bent by interactions with the individual atoms, producing a characteristic pattern of spots on photographic film. The accumulated data from the spots has two unique characteristics, called amplitude and phase.
When Perutz began his work at Cambridge’s Cavendish laboratory in the late 1930s, physicists William Bragg and Lawrence Bragg had learned how to calculate amplitudes, which made it possible to deduce the structures of simple molecules, such as inorganic salts. But phases had proved intractable.
Perutz’s inspiration was to add a single atom of a heavy metal, such as mercury, to each molecule of hemoglobin before exposing it to X-rays. Such metals diffract X-rays much more strongly, leaving a unique signature. Adding the mercury atoms at different locations on the molecule--isomorphous replacement--and comparing the resultant X-ray patterns caused by the change gave Perutz a baseline from which he was able to calculate the position of all the other 11,000 atoms in the hemoglobin molecule.
Kendrew, a postdoctoral fellow in Perutz’s laboratory and later the first staff member at the Laboratory of Molecular Biology, actually beat Perutz into print by two years, publishing the structure of myoglobin--a protein that stores oxygen in muscle--in 1957. But he used Perutz’s technique to do it.
Perutz found that hemoglobin was much more complicated, consisting of four subunits, each of which looked very similar to myoglobin. By 1970, he was able to show that when oxygen binds to one of the subunits, it changes the shape of the entire molecule, exposing sites on the other three subunits where oxygen would quickly bind.
Similarly, when a fully oxygenated hemoglobin molecule loses one oxygen molecule, its shape changes in such a manner that the other three oxygen molecules are quickly released as well. This feat marked the first time that biologists had completely understood how a protein functioned.
That was a major feat for a boy whose parents had wanted him to become a lawyer and take over their textile business.
Max Ferdinand Perutz was born in Vienna on May 19, 1914. He enrolled at the University of Vienna fully intending to honor his parents’ wishes, but was seduced by the mysteries of chemistry and biology and became a chemist instead. His university’s chemistry department still was mired in 19th century ideas, however, and, supported financially by his parents, he escaped to the more progressive confines of Cambridge in 1936.
His parents were forced to abandon their textile business and follow him a few years later when Adolf Hitler took over Austria.
Now classified as a refugee and with his parents homeless, Perutz had few financial resources. To finance a vacation in Switzerland in 1938, he snared a grant to apply his knowledge of crystallography to glaciers. He was the first to demonstrate how glaciers move, showing that ice on the surface flowed faster than ice near the glacier’s bed.
In 1940, the German invasion of Holland and Belgium prompted England to arrest all “enemy aliens,” including Perutz. “It was a very nice, very sunny day--a nasty day to be arrested,” he recalled in Horace Freeland Judson’s “The Eighth Day of Creation: Makers of the Revolution in Biology.”
Perutz spent nearly a year in various internment facilities, ending up at a camp in Quebec, where many other intellectuals and scientists were held. Perutz created a camp university, where the various residents lectured about their specialties. He taught a course of crystallography.
Helped Develop Ice ‘Aircraft Carriers’
By 1941, the British government had recognized its mistake and Perutz and his colleagues were returned to England, where most enlisted in the war effort. Because of his experience with glaciers, he was assigned the task of developing “aircraft carriers” made of ice that could be anchored in the Atlantic Ocean to provide refueling stations for planes being flown from the United States to Europe.
Perutz successfully devised a chemical process to harden ice so that it was resistant to bullets, but it became apparent that the cost of the way stations would be lower if they were made of steel. The advent of long-distance capabilities for planes rendered the entire enterprise superfluous.
After the war, he was able to turn his efforts toward deciphering proteins and eventually toward running the Laboratory of Molecular Biology. The great success of the lab has been attributed to his ability to recruit visionary scientists and then to leave them alone.
“Well-run laboratories can foster [creativity],” he wrote in an essay, “but hierarchical organization, inflexible, bureaucratic rules and mountains of futile paperwork can kill it.”
He handed off leadership of the institution to Sidney Brenner in 1979, but worked in his own laboratory until just before Christmas. Most recently, he had been studying the brain plaques and tangles that characterize diseases such as Alzheimer’s and Huntington’s. Publication is pending for several of his papers.
In his later years, Perutz wrote popular essays for the New York Review of Books. They were collected in two books, “I Wish I Had Made You Angry Earlier: Essays on Science, Scientists and Humanity” and “Is Science Necessary? Essays on Science and Scientists.”
He is survived by his wife, Gisela, whom he married in 1942, and children Robin and Vivien.
