John Howard Northrop: Crystallising the Machinery of Digestion

John Howard Northrop (1891-1987) was an American biochemist who worked for most of his career at the Rockefeller Institute for Medical Research in New York. He crystallised the digestive enzymes pepsin, trypsin and chymotrypsin and showed that enzymes are proteins. In 1946 he shared the Nobel Prize in Chemistry with Wendell Stanley, and James Sumner received the other half. He lived to the age of 95, and his life spans the journey of biochemistry from a young field to molecular biology.

Early Life & Family

Northrop was born on 5 July 1891 in Yonkers, New York. His father, John Isaiah Northrop, was a zoologist and teacher at Columbia University, who died in a laboratory explosion shortly before the son was born. His mother, Alice Rich Northrop, was a botanist and a teacher, and she raised him in a scientific atmosphere. Growing up with parents who were both scientists made a career in science natural for him. As a boy he attended school in Yonkers and later went to Columbia University in New York City.

He married Louise Walker in 1917, and the couple had a son and a daughter. Later in life he moved to the west coast of the United States, where he lived in California and, in his old age, in Arizona.

Education & Mentors

Northrop studied chemistry at Columbia University, where he obtained his Bachelor's degree in 1912 and a Master's degree in 1913. He stayed on to do his doctorate in chemistry, completing it in 1915 on a problem in physical chemistry. He also studied zoology, which gave him a broad base. After his doctorate he worked at the Rockefeller Institute for Medical Research with Jacques Loeb, a biologist who studied the physical chemistry of living things, including the way proteins behave in solution. Loeb's quantitative approach was a strong influence on Northrop.

Career Timeline

Major Scientific Contributions

Northrop's major work was the crystallisation of enzymes and the proof of their protein nature. The steps are described in our discovery post on crystalline pepsin and zymogens. Here is a summary:

• Pepsin, trypsin, chymotrypsin. He crystallised these digestive enzymes and showed that their activity is constant per unit protein, and thereby proved that the enzyme is the protein.
• Zymogens. He demonstrated that inactive precursors such as pepsinogen and trypsinogen are converted to active enzymes by partial proteolysis, and that trypsin activation is autocatalytic.
• Solubility method. He used the phase rule and constant solubility as a criterion of purity of proteins.
• Bacteriophage. In his later career, he studied bacteriophages as chemical substances, and the growth of phage in bacteria.
• Fermentation. Before his enzyme work, he developed a process for the production of acetone and ethanol by fermentation that was useful during the First World War, and he worked on the kinetics of enzyme action.

Awards, Honours & Nobel Prize

The Nobel Prize in Chemistry for 1946 was divided. One half went to James Batcheller Sumner "for his discovery that enzymes can be crystallized". The other half was shared by John Howard Northrop and Wendell Meredith Stanley "for their preparation of enzymes and virus proteins in a pure form". Northrop was a member of the National Academy of Sciences of the United States, and he received honorary degrees and other scientific honours.

Personality, Struggles & Lesser-Known Facts

• Born into science, born after tragedy. His father died in a laboratory explosion before Northrop was born, yet he chose a career in the laboratory.
• Applied science in war. In both world wars he put his skills to use for national defence, which is documented in the history of the Rockefeller Institute. During the First World War he worked in chemical warfare and fermentation, and in the Second World War he worked on defence chemistry.
• Hobbies. He liked outdoor life, and was known for his hunting, fishing and love of the countryside. He also learned to fly an aircraft, which was unusual for a laboratory scientist of his generation.
• Quantitative mind. His strength was in careful measurement. The proof of purity, through constant solubility and activity, convinced the sceptics where claims alone had not.
• Long life. He lived to be 95, and saw the rise of X-ray crystallography of proteins and DNA, which grew from the work he and his contemporaries began.

Legacy & Influence on Modern Chemistry

The crystals of pepsin, trypsin and chymotrypsin that Northrop obtained were soon used for X-ray diffraction work. Chymotrypsin and trypsin became model enzymes. Their mechanism, with a catalytic triad and an oxyanion hole, is described in every biochemistry course. The concept of the zymogen is the first example of regulation of enzyme activity by proteolytic cleavage, and it is relevant to clotting, digestion, complement and cell death. At a time when the nature of enzymes and viruses was uncertain, his methods of purification and proof of purity showed how to study large biological molecules as chemical substances. In India, students meet his name in biochemistry and enzymology: digestive enzymes, zymogens and the serine protease mechanism are all topics for JAM, NET and GATE.

Lessons for Students

• Test purity in more than one way. Northrop used activity and solubility together.
• Confirm findings from others. Northrop supported Sumner's result with new examples, and this is how science becomes accepted.
• Build the team. His co-worker Moses Kunitz made major contributions to crystallisation methods.
• Keep a balance in life. Outdoor interests helped him to sustain a long career.

FAQ

Where did Northrop work?

Mostly at the Rockefeller Institute for Medical Research in New York, and later at the University of California, Berkeley.

Which enzymes did Northrop crystallise?

Pepsin first (1930), and then trypsin and chymotrypsin along with their inactive precursors.

How is Northrop different from Sumner?

Sumner crystallised the first enzyme, urease (1926). Northrop crystallised several more and gave strong proof that enzymes are proteins.

Who shared the 1946 Nobel Prize in Chemistry?

Sumner (one half), and Northrop with Stanley (the other half).

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