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Crystals and Chains: The work of Frederick Sanger & Dorothy Hodgkin in understanding the structure of Insulin

By August 9, 2021August 12th, 2021Insulin Centennial, The Log Book

This blog about the Structure of Insulin is part of a series celebrating the 100th anniversary of the discovery of insulin. You can check out previous blogs in this series, written by CIM Intern Eleanor Medley, here!

Insulin is a protein hormone. Two people instrumental in the advancement of protein structure determination, Frederick Sanger and Dorothy Hodgkin, conducted their revolutionary work on insulin. Both greatly increased the scientific community’s understanding of insulin, and proteins at large. Here are their stories:

Frederick Sanger

Sanger was born in England in 1918.[1] When he studied biochemistry, very little was known about the structure of proteins. In 1943, Sanger started working with a scientist named Albert Chibnall at Cambridge who believed that proteins were distinct chemical compounds. He was tasked with identifying the composition of insulin.[2] Because of its medical use, pure insulin was available in high quantities.[3]

Using a new separation technique, Sanger determined that insulin was composed of 2 amino acid chains held together with disulfide bridges (linkages between sulfur atoms). Using another new separation method, he determined the sequence of the chains.[4] This was groundbreaking! Sanger was the first to show that proteins were made up of specific amino acids at specific sites.

Primary Structure of Insulin

Primary Structure of Insulin

For this accomplishment, Sanger was awarded the Nobel prize for Chemistry in 1958.[5] This breakthrough transformed the field of biochemistry. Now, it is common practice to sequence all proteins. 

Sanger later went on to develop a method for sequencing DNA, receiving another Nobel prize in 1980.[6] His work helped explain the genetic code and paved the way for the modern genomics era. 

Genetic Code, Central Dogma 

Now, insulin is made by expressing the insulin gene in E. coli. Insulin analogs are genetically modified to change how fast the body uses them. None of this would be possible without Sanger’s initial work on the structure of insulin. 

Dorothy Hodgkin

Dorothy Hodgkin was born in Cairo, Egypt to English parents in 1910. She became fascinated with crystals as a young child and when she was 16, she read a book about x-ray crystallography: a method for using x-rays to analyze the structure of crystals. She pursued her interest in crystallography during her undergraduate studies at Oxford University and then her doctoral studies in J.D. Bernal’s lab at Cambridge. Bernal’s lab took the first x-ray image of a protein crystal, showing that organic molecules could be crystallized and studied that way.[7]

While Sanger was interested in the sequence of the building blocks of proteins, Hodgkin was interested in the three-dimensional shape that proteins took on. At age 24, Hodgkin began studying the 3D structure of insulin, but it was too complex to get a good image. She took a break from insulin to map the structures of penicillin (part of a war effort to refine antibiotics) and Vitamin B12.[8] They were considerably smaller molecules than insulin, but getting their structures still took 4 and 8 years respectively. She received the 1964 Nobel prize for Chemistry for her work.[9]

In 1969, after sufficient evolution of crystallography and computing methods, she and a team of researchers finally mapped the structure of insulin.[10] It had been 34 years since she first began the endeavor![11] The advancement helped insulin be mass-produced for people with diabetes around the world.[12]

Fig. 2 Photograph of a model of the insulin dimer. From “Structure of Rhombohedral 2 Zinc Insulin Crystals” Published in Nature Vol. 224 November 1969. 

Though not diabetes, Hodgkin lived with chronic illness herself. In her twenties, she developed rheumatoid arthritis. She said, “I found I had great difficulty and pain in getting up and dressing. Every joint in my body seemed to be affected.”[13] Continuing her research, she found ways to make her lab more accessible, like adding a long lever to the x-ray switch so her hands could use it better.[14]

In addition to being an accomplished scientist, Hodgkin was also a prominent activist. She was a big proponent of peaceful international scientific cooperation. Serving as the president of the Pugwash Conferences on Science and World Affairs from 1975 to 1988, she campaigned against weapons of mass destruction.[15]

As a woman in STEM living with a disability and advocating for what she believed in, Hodgkin contributed greatly to both diabetes treatment and biological knowledge in general through her amazing protein structures. 

  1. “Frederick Sanger.” Nature Education, Nature Publishing Group, www.nature.com/scitable/topicpage/frederick-sanger-method-man-problem-solver-6537485/.
  2.  Jeffers, Joe Stewart. “Frederick Sanger.” Encyclopædia Britannica, Encyclopædia Britannica Inc., www.britannica.com/biography/Frederick-Sanger.
  3. Stretton, A. O. W. (2002). The First Sequence: Fred Sanger and Insulin. Genetics, 162(2), 527 LP – 532. Retrieved from http://www.genetics.org/content/162/2/527.abstract
  4. Jeffers, “Frederick Sanger.”
  5. Jeffers, “Frederick Sanger.”
  6. Jeffers, “Frederick Sanger.”
  7. “Women Who Changed Science: Dorothy Crowfoot Hodgkin.” The Official Website of the Nobel Prize – NobelPrize.org, www.nobelprize.org/womenwhochangedscience/stories/dorothy-hodgkin.
  8. “Dorothy Hodgkin – Scientists with Disabilities: Royal Society.” Scientists with Disabilities | Royal Society, royalsociety.org/topics-policy/diversity-in-science/scientists-with-disabilities/dorothy-hodgkin/.
  9. NobelPrize.org, “Women Who Changed Science: Dorothy Crowfoot Hodgkin.”
  10. Ferry, Georgina. “Dorothy Hodgkin.” Encyclopædia Britannica, Encyclopædia Britannica Inc., https://www.britannica.com/biography/Dorothy-Hodgkin
  11. NobelPrize.org, “Women Who Changed Science: Dorothy Crowfoot Hodgkin.”
  12. Weidman, Chelsea. “Meet Dorothy Hodgkin, the Biochemist Who Pieced Together Penicillin, Insulin, and Vitamin B12.” Massive Science, 12 May 2019, massivesci.com/articles/dorothy-hodgkin-facts-penicillin-insulin-vitamin-b12-folate-cobalamin-antibiotic/.
  13. Royal Society, “Dorothy Hodgkin – Scientists with Disabilities: Royal Society.”
  14. Royal Society, “Dorothy Hodgkin – Scientists with Disabilities: Royal Society.”
  15. NobelPrize.org, “Women Who Changed Science: Dorothy Crowfoot Hodgkin.”, Weidman, “Meet Dorothy Hodgkin, the Biochemist Who Pieced Together Penicillin, Insulin, and Vitamin B12.”
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