Max Perutz

Max Perutz (born 1914) pioneered the use of X-ray crystallography to determine the atomic structure of proteins by combining two lines of scientific investigation--the physiology of hemoglobin and the physics of X-ray crystallography. His efforts resulted in his sharing the 1962 Nobel Prize in chemistry with his colleague, biochemist John Cowdery Kendrew.

Perutz's work in deciphering the diffraction patterns of protein crystals opened the door for molecular biologists to study the structure and function of enzymes--specific proteins that are the catalysts for biochemical reactions in cells. Known for his impeccable laboratory skills, Perutz produced the best early pictures of protein crystals and used this ability to determine the structure of hemoglobin and the molecular mechanism by which it transports oxygen from the lungs to tissue. A passionate mountaineer and skier, Perutz also applied his expertise in X-ray crystallography to the study of glacier structure and flow.

Perutz was born in Vienna, Austria, on May 19, 1914. His parents were Hugo Perutz, a textile manufacturer, and Adele Goldschmidt Perutz. In 1932, Perutz entered the University of Vienna, where he studied organic chemistry. However, he found the university's adherence to classical organic chemistry outdated and backward. By 1926 scientists had determined that enzymes were proteins and had begun to focus on the catalytic effects of enzymes on the chemistry of cells, but Perutz's professors paid scant attention to this new realm of research. In 1934, while searching for a subject for his dissertation, Perutz attended a lecture on organic compounds, including vitamins, under investigation at Cambridge University in England. Anxious to continue his studies in an environment more attuned to recent advances in biochemical research, Perutz decided he wanted to study at Cambridge. His wish to leave Austria and study elsewhere was relatively unique in that day and age, when graduate students seldom had the financial means to study abroad. But Hugo Perutz's textile business provided his son with the initial funds he would need to survive in England on a meager student stipend.

In 1936, Perutz landed a position as research student in the Cambridge laboratory of Desmond Bernal, who was pioneering the use of X-ray crystallography in the field of biology. Perutz, however, was disappointed again when he was assigned to research minerals while Bernal closely guarded his crystallography work, discussing it only with a few colleagues and never with students. Despite Perutz's disenchantment with his research assignments and the old, ill-lit, and dingy laboratories he worked in, he received excellent training in the promising field of X-ray crystallography, albeit in the classical mode of mineral crystallography. "Within a few weeks of arriving," Perutz states in Horace Freeland Judson's Eighth Day of Creation: Makers of the Revolution in Biology, "I realized that Cambridge was where I wanted to spend the rest of my life."

Begins Work with Hemoglobin

During his summer vacation in Vienna in 1937, Perutz met with Felix Haurowitz, a protein specialist married to Perutz's cousin, to seek advice on the future direction of his studies. Haurowitz, who had been studying hemoglobin since the 1920s, convinced Perutz that this was an important protein whose structure needed to be solved because of the integral role it played in physiology. In addition to making blood red, hemoglobin red corpuscles greatly increase the amount of oxygen that blood can transport through the body. Hemoglobin also transports carbon dioxide back to the lungs for disposal.

Although new to the physical chemistry and crystallography of hemoglobin, Perutz returned to Cambridge and soon obtained crystals of horse hemoglobin from Gilbert Adair, a leading authority on hemoglobin. Since the main goal of X-ray crystallography at that time was to determine the structure of any protein, regardless of its relative importance in biological activity, Perutz also began to study crystals of the digestive enzyme chymotrypsin. But chymotrypsin crystals proved to be unsuitable for study by X-ray, and Perutz turned his full attention to hemoglobin, which has large crystal structures uniquely suited to X-ray crystallography. At that time, microscopic protein crystal structures were "grown" primarily through placing the proteins in a solution which was then evaporated or cooled below the saturation point. The crystal structures, in effect, are repetitive groups of cells that fit together to fill each space, with the cells representing characteristic groups of the molecules and atoms of the compound crystallized.

In the early 1930s, crystallography had been successfully used only in determining the structures of simple crystals of metals, minerals, and salts. However, proteins such as hemoglobin are thousands of times more complex in atomic structure. Physicists William Bragg and Lawrence Bragg, the only father and son to share a Nobel Prize, were pioneers of X-ray crystallography. Focusing on minerals, the Braggs found that as X-rays pass through crystals, they are buffeted by atoms and emerge as groups of weaker beams which, when photographed, produce a discernible pattern of spots. The Braggs discovered that these spots were a manifestation of Fourier synthesis, a method developed in the nineteenth century by French physicist Jean Baptiste Fourier to represent regular signals as a series of sine waves. These waves reflect the distribution of atoms in the crystal.

The Braggs successfully determined the amplitude of the waves but were unable to determine their phases, which would provide more detailed information about crystal structure. Although amplitude was sufficient to guide scientists through a series of trial and error experiments for studying simple crystals, proteins were much too complex to be studied with such a haphazard and time consuming approach.

Initial attempts at applying X-ray crystallography to the study of proteins failed, and scientists soon began to wonder whether proteins in fact produce X-ray diffraction patterns. However, in 1934, Desmond Bernal and chemist Dorothy Crowfoot Hodgkin at the Cavendish laboratory in Cambridge discovered that by keeping protein crystals wet, specifically with the liquid from which they precipitated, they could be made to give sharply defined X-ray diffraction patterns. Still, it would take twenty-three years before scientists could construct the first model of a protein molecule.

Research Interrupted by War and Internment

Perutz and his family, like many other Europeans in the 1930s, tended to underestimate the seriousness of the growing Nazi regime in Germany. While Perutz himself was safe in England as Germany began to invade its neighboring countries, his parents fled from Vienna to Prague in 1938. That same summer, they again fled to Switzerland from Czechoslovakia, which would soon face the onslaught of the approaching German army. Perutz was shaken by his new classification as a refugee and the clear indication by some people that he might not be welcome in England any longer. He also realized that his father's financial support would certainly dwindle and die out.

As a result, in order to vacation in Switzerland in the summer of 1938, Perutz sought a travel grant to apply his expertise in crystallography to the study of glacier structures and flow. His research on glaciers involved crystallographic studies of snow transforming into ice, and he eventually became the first to measure the velocity distributions of a glacier, proving that glaciers flow faster at the surface and slower at the glacier's bed.

Finally, in 1940, the same year Perutz received his Ph.D., his work was put to an abrupt halt by the German invasions of Holland and Belgium. Growing increasingly wary of foreigners, the British government arrested all "enemy" aliens, including Perutz. "It was a very nice, very sunny day--a nasty day to be arrested," Perutz recalls in The Eighth Day of Creation. Transported from camp to camp, Perutz ended up near Quebec, Canada, where many other scientists and intellectuals were imprisoned, including physicists Herman Bondi and Tom Gold. Always active, Perutz began a camp university, employing the resident academicians to teach courses in their specialties. It didn't take the British government long, however, to realize that they were wasting valuable intellectual resources and, by 1941, Perutz followed many of his colleagues back to his home in England and resumed his work with crystals.

Perutz, however, wanted to contribute to the war effort. After repeated requests, he was assigned to work on the mysterious and improbable task of developing an aircraft carrier made of ice. The goal of this project was to tow the carrier to the middle of the Atlantic Ocean, where it would serve as a stopping post for aircrafts flying from the United States to Great Britain. Although supported both by then British Prime Minister Winston Churchill and the chief of the British Royal Navy, Lord Louis Mountbatten, the ill-fated project was terminated upon the discovery that the amount of steel needed to construct and support the ice carrier would cost more than constructing it entirely of steel.

Embarks on Nobel Prize-Winning Research

Perutz married Gisela Clara Peiser on March 28, 1942; the couple later had a son, Robin, and a daughter, Vivian. After the war, in 1945, Perutz was finally able to devote himself entirely to pondering the smeared spots that appeared on the X-ray film of hemoglobin crystals. He returned to Cambridge, and was soon joined by John Kendrew, then a doctoral student, who began to study myoglobin, an enzyme which stores oxygen in muscles. In 1946 Perutz and Kendrew founded the Medical Research Council Unit for Molecular Biology, and Perutz became its director. Many advances in molecular biology would take place there, including the discovery of the structure of deoxyribonucleic acid (DNA).

Over the next years, Perutz refined the X-ray crystallography technology and, in 1953, finally solved the difficult phase dilemma with a method known as isomorphous replacement. By adding atoms of mercury--which, like any heavy metal, is an excellent X-ray reflector--to each individual protein molecule, Perutz was able to change the light diffraction pattern. By comparing hemoglobin proteins with mercury attached at different places to hemoglobin without mercury, he found that he had reference points to measure phases of other hemoglobin spots. Although this discovery still required long and assiduous mathematical calculations, the development of computers hastened the process tremendously.

By 1957, Kendrew had delineated the first protein structure through crystallography, again working with myoglobin. Perutz followed two years later with a model of hemoglobin. Continuing to work on the model, Perutz and Hilary Muirhead showed that hemoglobin's reaction with oxygen involves a structural change among four subunits of the hemoglobin molecule. Specifically, the four polypeptide chains that form a tetrahedral structure of hemoglobin are rearranged in oxygenated hemoglobin. In addition to its importance to later research on the molecular mechanisms of respiratory transport by hemoglobin, this discovery led scientists to begin research on the structural changes enzymes may undergo in their interactions with various biological processes. In 1962, Perutz and Kendrew were awarded the Nobel Prize in chemistry for their codiscoveries in X-ray crystallography and the structures of hemoglobin and myoglobin, respectively. The same year, Perutz left his post as director of the Unit for Molecular Biology and became chair of its laboratory.

The work of Perutz and Kendrew was the basis for growing understanding over the following decades of the mechanism of action of enzymes and other proteins. Specifically, Perutz's discovery of hemoglobin's structure led to a better understanding of hemoglobin's vital attribute of absorbing oxygen where it is plentiful and releasing it where it is scarce. Perutz also conducted research on hemoglobin from the blood of people with sickle-cell anemia and found that a change in the molecule's shape initiates the distortion of venous red cells into a sickle shape that reduces the cells' oxygen-carrying capacity.

In The Eighth Day of Creation, Judson remarks that Perutz was known to have a "glass thumb" for the difficult task of growing good crystals, and it was widely acknowledged that for many years Perutz produced the best images of crystal structures. In the book, published in 1979, Perutz's long-time colleague Kendrew remarks that little changed over the years, explaining, "If I had come into the lab thirty years ago, on a Saturday evening, Max would have been in a white coat mounting a crystal--just the same." Although Perutz retired in 1979, he continued to work as a professor for the MRC Lab of Molecular Biology at Cambridge and also served as a patron for the Cambridge University Scientific Society.

Historical Context

• The Life and Times of Max Perutz (1914-)
• At the time of Perutz's birth:
• The Panama Canal opened
• Edward Kleinschmidt invented the teletype machine
• James Joyce's Dubliners was published
• Woodrow Wilson was president of the U.S.
• The times:
• 1914-1918: World War I
• 1936-1939: Spanish Civil War
• 1939-1945: World War II
• 1950-1953: Korean War
• 1957-1975: Vietnam War
• 1991: Persian Gulf War
• Perutz's contemporaries:
• Alexander Todd (1907-) British chemist
• Bette Davis (1908-1989) American actress
• Louis Jordan (1908-1975) American jazz musician
• Katharine Hepburn (1909-) American actress
• Artie Shaw (1910-) big band leader
• Ben Hogan (1912-) American golfer
• Konrad Bloch (1912-) German-born American biochemist
• James R. Hoffa (1913-c. 1975) American labor leader
• Elizabeth Shull Russell (1913) American geneticist
• Menachem Begin (1913-1992) Prime minister of Israeli
• Selected world events:
• 1916: Jeannette Rankin became the first U.S. Congresswoman
• 1926: Josef Stalin became dictator of the Soviet Union
• 1934: Clyde Barrow and Bonnie Parker were killed in a shootout with lawmen
• 1945: Adolf Hitlercommitted suicide in Berlin
• 1955: Rosa Parks refused to give up her seat on a bus in Montgomery, Alabama
• 1960: Harper Lee's To Kill a Mockingbird was published
• 1969: Neil Armstrong was the first person to walk on the moon
• 1978: Louise Brown, the first "test tube baby," was born
• 1986: The Iran-Contra scandal began in the U.S.
• 1992: Riots erupted in Los Angeles following the Rodney King court decision

Further Reading

• Cambridge University Scientific Society, 1997, "http://cygnus.csi.cam.ac.uk/CambUniv/Societies/cuss/patrons/patrons.htm," July 22, 1997.

• Judson, Horace Freeland, The Eighth Day of Creation: Makers of the Revolution in Biology, Simon & Schuster, 1979.

• "X-rays Mark the Spots," in The Economist, November 21, 1992, pp. 100-101.