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In 1965, Chinese scientists first synthesized crystalline bovine insulin (Chinese: 人工合成结晶牛胰岛素), which was the first functional crystalline protein being fully synthesized in the world. Research on synthesizing bovine insulin started on 1958. Members in the research group were from the Chemistry Department of Beijing University (Chinese: 北京大学化学系), Shanghai Institute of Biochemistry, CAS (Chinese: 中科院上海生物化学研究所) and Shanghai Institute of Organic Chemistry, CAS (Chinese: 中科院上海有机化学研究所).

Insulin is a protein (peptide) consisting of two chain, A and B. Chain A consists of 21 amino acid residues while chain consists of 30 amino acid residues. The main function of insulin is to regulate the concentrate of sugar in blood. Type 1 diabetes are caused by dysfunction on the synthesis or secretory of insulin while injecting insulin can treat type 1 diabetes.

A member in the group, Jingyi Niu (Chinese: 钮经义) who had made significant contribution to the research project, was once selected as a nominator to Nobel Chemistry Prize in 1979. However, he failed to get the Nobel Chemistry in that year ultimately. Rumours about the nomination are widely distributed on the websites and BBS in Mainland China.

Background

Insulin is a protein hormone secreted by beta cells in pancreatic islets. Frederick Grant Banting and John James Rickard Macleod won the Nobel Prize in Physiology or Medicine in 1923 for discovery of insulin. It consists of two peptide chain, A and B. Chain A consists of 21 amino acid residues and chain B consists of 30. Chain A and B are connected by several disulfides. Insulin plays an important role in the regulation of sugar concentration in blood in human body. Dysfunction on the synthesis or secretory can cause Type 1 diabetes, while injecting insulin can treat this disease. However, for a long time, insulin can only be isolated from the animal pancreas, which is a costly and inefficient process. Structure of Bovine or swine insulin is similar with that of human insulin in spite of differences in several amino acid residues. Side effects like allergic reaction may occur in some people's body after injecting bovine or swine insulin.

Insulin was the first sequenced protein. This work is done by Frederick Sanger in 1955 and it helped him won the Nobel Chemistry Prize in 1958. The first peptide synthesized was oxytocin made by 8 amino acid residues. For this work, Vincent du Vigneaud won the Nobel Chemistry Prize in 1955.

History

In 1958, China started a political campaign called "Great Leap Forward" (simplified Chinese: 大跃进; traditional Chinese: 大躍進). At that time, Beijing University and Shanghai Institute of Biochemistry, CAS decided to start a research project about protein synthesis, aiming at making China become the first country to fully synthesize a protein. This research was backed by the central government in Beijing.

At the time, industrial development in China was limited. To meet the research group's requirement for biochemical reagent, Shanghai Institute of Biochemistry, CAS opened a plant called "East Wind"(Chinese: 东风厂) to manufacture biochemical reagent like amino acids in 1959.

However, after this research started, the project was quickly politicized. In 1960, hundreds of people were once involved in this research. By the second half of 1960, the project had cost a lot of money, but poor progress had been made. Then the research group was re-organized, partly forced by the economic crisis of China in 1960. After that only about 20 to 30 researchers from the Chemistry Department of Beijing University, Shanghai Institute of Biochemistry, CAS and Shanghai Institute of Organic Chemistry, CAS stayed in the research group. The group leaded by Jingyi Niu (Chinese: 钮经义) was responsible for the synthesis of the chain B of insulin while some researchers from Beijing University and Shanghai Institute of Organic Chemistry were working on synthesizing the chain A. Another Group leaded by Chenglu Zou (Chinese: 邹承鲁) was focus on the combination pattern of chain A and chain B.

In 1963, Helmut Zahn from RWTH Aachen, West Germany and Panayotis Katsoyannis from University of Pittsburgh, USA independently reported synthesis of insulin in vitro. However, the insulin they synthesized showed weak activity. The work of Helmut Zahn and RWTH Aachen made the researchers focusing on synthesizing crystalline bovine insulin in China burden huge pressure.

The group leaded by Chenglu Zou found out a method to recombine chain A and chain B in 1959. However, researchers are not permitted to report this method for political reasons. The group was not permitted to report their work until Dixon and Wardlaw reported their work of recombining chain A and chain B of insulin on Nature in 1960. Ultimately, their work was reported on the SCIENTIA SINICA in 1961. They showed that their recombination efficiency was higher than Dixon and Wardlaw. Then they further improved their method to make the recombination efficiency higher. The method to be used in recombining synthesized chain A and chain B was introduced in 1963. In 1964, the group leaded by Jingyi Niu synthesized the chain B. Then researchers used method introduced by Chenglu Zou successfully recombined synthesized chain B with natural chain B and got recombined insulin. However, the synthesis of chain A was once frustrated and it A was not synthesized by Mar 1965. In Mar 1965 researchers decided to change the synthesis pathway of the last 12 amino acid residues section. Using the improved methods, the chain A was synthesized in May 1965.

Then three researchers, Yucang Du (Chinese: 杜雨苍), Weijun Zhang (Chinese: 张伟君) and Putao Shi (Chinese: 施溥涛) commence to recombine synthesized chain A and chain B, expecting to get crystalline insulin. However, their first try failed. The recombined molecules only showed 0.7% of activity compared with natural insulin molecules. Additionally, experiment in mice showed that convulsion didn't happen after injecting the recombined molecules into mice's body. Such results suggested that the recombined molecules didn't work in vivo. Then Yucang Du modified the recombination method. On Sep 17th, 1965, after freezing the recombined molecules for 14 days, researchers found that crystal of insulin was formed in the tube and this time the mice convulsed after being injected water solution of recombined insulin molecules.

An appraisal to the synthesis of crystalline bovine insulin was called in Nov 1965 led by Youxun Wu (Chinese: 吴有训), the vice president of CAS at the time. After the appraisal, because some scientists thought that further experiments are needed to identify the crystalline bovine insulin, only a brief report was published on the English version of SCIENTIA SINICA. Then researchers unfolded a series of experiment such as chromatography, electrophoresis and enzyme digestion to further identify the crystalline bovine insulin. After these experiments finished, an article was published on he English version of SCIENTIA SINICA in Apr 1966.

The successful synthesis of crystalline bovine insulin shocked the whole world at that time. BBC reported this news in prime time. In Apr 1966, Chenglu Zou, Yinglai Wang (Chinese: 王应睐) and Yueting Gong (Chinese: 龚跃亭) reported this work on the 3rd Federation of European Biochemical Societies (FEBS) meeting in Warsaw in 1966. Frederick Sanger attended this report and praise the synthesis work. In August 1966, the work was reported by Science journal.

Arne Tiselius visited Shanghai Institute of Biochemistry on Apr 30th, 1966. He was quite interested in the synthesis of crystalline bovine insulin. He remarked "the making of an atom bomb you can learn from the textbooks but not the synthesis of insulin". In the later part of 1966, John Kendrew visited Beijing. During the trip, he said synthesis of crystalline bovine insulin was the most famous Chinese science achievement in UK.

Mechanism

Synthesis of crystalline bovine insulin was divided into 3 parts: the chemical synthesis of chain A and chain B, and recombining chain A and chain B. To synthesize chain A and B, researchers first synthesized fragments of chain A and chain B. Protective groups were added to the fragments to prevent them from oxidation. Then, researchers combined these fragment to chain A and B. Finally, synthesized chain A and chain B was combined using method introduced by Chenglu Zou and his colleagues (Yucang Du modified this method in 1965).

Nomination for the Nobel Prize and related rumours

In 1972, Chen-Ning Yang said he was willing to nominate the synthesis of crystalline bovine insulin for the Nobel Prize in Chemistry when he talked with Enlai Zhou on his trip in China, but the suggestion was rejected by Zhou. In 1973, Yang offered a nomination again in a letter to Moruo Guo, President of CAS. But the authorities rejected again. It's believed that the authorities reject the nomination for political reasons, since at the time China is in the Cultural Revolution.

The Cultural Revolution was ended in 1976. In 1977, when Sanqiang Qian visited Australia, an Australia scientist suggested him to nominate the synthesis of crystalline bovine insulin for the Nobel Prize. In Sep 1978 Chen-Ning Yang talked with Xiaoping Deng and said he was still willing to nominate the synthesis of crystalline bovine insulin for the Nobel Prize in Chemistry of 1979. At the same time, a letter from Nobel Committee for Chemistry was sent to Yinglai Wang, the president of Shanghai Institute of Biochemistry, asking him to recommend the nominators of the Nobel Prize in Chemistry of 1979. In Dec 1978 a conference was called in Shanghai to determine the nominators. At first four scientists, including Jingyi Niu, Chenglu Zou, You Wang (Chinese: 汪猷) and Aixue Ji (Chinese: 季爱雪) were selected as nominators. Nevertheless after considering the unwritten rules of Nobel Prize in Chemistry that only up to 3 persons can win the prize in a year, only Jingyi Niu was selected as the nominator. Niu was then nominated by Yinglai Wang, Chen-Ning Yang and Hao Wang, a Chinese American scientist. However, Niu didn't win the Nobel Prize in Chemistry of 1979.

Many rumours about the nomination of the synthesis of crystalline bovine insulin are widely distributed on the websites and BBS in Mainland China. Some rumours are listed as followed: the authorities rejected the nominated in 1966 for political reasons; the nomination was rejected by the Nobel Prize Committee because all members of the research groups including staff was nominated; four scientists were nominated but only up to 3 persons can win the Nobel Prize of Chemistry in a year; the Nobel Prize Committee discriminate Chinese scientists.

See Also

• Helmut Zahn
• Panayotis Katsoyannis
• Cell-free protein synthesis