Scientific contact lies at the heart of research and that between China and the U.K. is an important example of how it can come about. In 1911, when the Biochemical Society began, U.K. science was developing fast with profound discoveries in physics (the Rutherford atomic model) and biochemistry (the discovery of vitamins). In China, however, there was great social and political instability and a revolution. Since then, the turbulence of two world wars and a variety of deep global political tensions meant that the contacts between China and U.K. did not reflect the prodigious growth of biochemistry. There was, however, one particular and remarkable contact, that made by Joseph Needham, an outstanding biochemist. He visited China between 1943 and 1946, contacting many Chinese universities that were severely dislocated by war. Showing remarkable diplomatic abilities, Needham managed to arrange delivery of research and teaching equipment. His activities helped the universities to carry out their functions under near-impossible conditions and reminded them that they had friends abroad. Most remarkably, Joseph Needham developed an extraordinary grasp of Chinese culture, science and history and he opened the West to the extent and importance of Chinese science. Formal scientific and intellectual contacts between the scientific academic bodies in China and U.K., notably the Chinese Academy of Science and the Royal Society, resumed after British recognition of the Chinese Communist government in 1950. The delegations included outstanding scientists in biochemistry and related disciplines. Research activities, such as that concerning influenza, were soon established, whereas institutions, such as the Royal Society and the Wellcome Trust, acted a little later to support research. The outcomes have been long-term collaborations in such areas as insulin structure and function. There are now numerous joint activities in biochemistry and biomedicine supported by the MRC (Medical Research Council), BBSRC (Biotechnology and Biological Sciences Research Council), NERC (Natural Environment Research Council), EPSRC (Engineering and Physical Sciences Research Council) and UKRC (UK Research Councils). The present contacts and the associated research are very considerable and growing. It is clear that biochemistry in both countries has much to offer each other, and there is every reason to believe that these contacts will continue to expand in the future.
Centenaries are occasions that should prompt recollection, ideas for the future and, one hopes, a certain amount of satisfaction. The Biochemical Society, now in its centenary year, is experiencing exactly this. It was founded as the Biochemical Club in 1911, a time when the scientific scene in Europe and the Western hemisphere was alight; Rutherford's description of atomic structure, the basis of chemistry, was one major achievement among many. One particularly consequential biochemical discovery of the period was that of the vitamins by Eijkman and Gowland. Many recognized the potential of this physiological chemistry and responding to its growth, Benjamin Moore at Liverpool University and William Halliburton at Kings College, among others, founded the Biochemistry Club (Figure 1). The name was soon altered to the Biochemical Society, which included women in its membership. It is also worth noting in this context that it is 101 years since Dorothy Hodgkin, one of the critical figures in biochemistry and in Chinese–British biochemical collaboration, was born.
Two of the founders of the Biochemistry Club
It is difficult to do justice to all the people and institutions involved in the biochemical collaborations between China and the U.K. since 1911 and I have concentrated on what I best know. I am conscious that the collaborations, initially few, now extend across the whole academic field and I have had to cover these in rather general ways. The background to the biochemical research and development is relevant to the scientific history and is a reminder of the equations that link science and society. Colin Kleanthous, the Society's Chairman, has pointed out in his centenary article  that, at this time, there were a variety of divisive social issues in Britain. Some of these led to reforms, whereas others were resisted; for example, trade union power illustrated here by the 1911 transport strike at Liverpool (Figure 2) and votes for women. China, in contrast, was experiencing huge social and economic turbulence with the Nationalist Revolution in 1911. This removed the old Qing Dynasty and established a republic (Figure 3), under which scientific research became more formalized, and in 1926 in Beijing, Robert K.S. Lim and Hsien Wu founded the Chinese Biochemical Society. It prospered until war with Japan broke out in 1937. After this war was over and after the Communist victory in December 1949, the Chinese Biochemical Society was re-established, but its activities were suspended during the ‘Cultural Revolution’. By the 1970s, however, China was opening up; a delegation of crystallographers attended the International Union of Crystallography in Warsaw in 1978 (and visited the U.K.), while the Chinese Biochemical Society was reactivated in 1979 as the Chinese Society of Biochemistry and Molecular Biology in 1993.
Soldiers in Liverpool in response to the transport union strike, 1911
Establishment of the Republic of China
During the 1930s, the remarkable biochemist Joseph Needham at Cambridge and seen at the bench in Figure 4(A), became first fascinated and then passionately committed to understanding Chinese science and culture. He already had made an immense impact on biochemistry and biology with his researches into morphogenesis, embryology and their associated chemistry. Joseph Needham's passion for China and its culture, illustrated in Figure 4(C), was stimulated by three Chinese biochemists who came to work in Cambridge in 1937; Lu Gwei-djen (), Wang Ying Lai () and Chen Shi-zhang (). Lu, who taught Needham Chinese, is shown in Figure 4(B). At the same time, China was being brutally invaded by Japan and its universities and intellectual life were especially attacked. This caused particular concern in Britain, and Needham, with others, campaigned energetically on China's behalf. In 1943, the British Council and the Royal Society set up the Sino–British Science Co-operation Office and chose Needham to go to China to assess the situation and to take what actions he could to help. This was an extraordinary trip which lasted for 3 years. Needham achieved an enormous amount; he not only reported on the conditions in Chinese universities, but also organized the delivery of much desperately needed teaching and research equipment. He also set himself the task of describing the development of China's science and technology and comparing it with that of the West. This involved collecting a vast amount of ancient Chinese scientific records, manuscripts and material. Needham's experiences in China and his deep commitment to its science, culture and history is comprehensively described by Simon Winchester in his excellent biography .
Joseph Needham's passions: biochemistry and China
In China, Needham was hugely busy and much absorbed by what he saw (Figure 5). He visited, travelled exhaustively and observed, questioning and recording ceaselessly, following up every lead and detail. For example, a typical entry reads: ‘Li Yen, ancient old man, chemist at Chungshen Ta Agricultural College, pupil of Sir William Ramsay at University College in 1906’. In those 3 years, Joseph Needham assembled the materials for the monumental study that engaged him for the rest of his life. His scientific trips also led to many British–Chinese contacts. One such person, later important in the development of biochemistry in China, was Cao Tianqin (), a biochemist and staff member from the Sino–British Science Co-operation Office. Cao graduated from the Department of Chemistry, Yenching University, in 1944 and in 1951 took a Ph.D. in the Department of Biochemistry, University of Cambridge, U.K. In Figure 6, he is shown as part of Joseph Needham's Sino-British Science Co-operation Office. After World War II, there were still conflicts within China between the Communists and Nationalists, finally resolved in 1949 by the victory of the Communist Army. This put China in the Communist bloc and regrettably led to its isolation from the West. Following recognition of the Communist government by the U.K. in 1950, there were some formal contacts between the Royal Society and the Chinese Academy of Sciences. The contacts on the British side were obviously informed by Joseph Needham's knowledge of China's science and research laboratories, and he was active in furthering Chinese research interests. One of the very earliest Chinese–British research contacts began when Zhu Jiming (Chu Chi Ming), the Director of the World Influenza Centre at the NIMR (National Institute for Medical Research), returned to Beijing in 1950 to manage the Virology and Influenza Centre. Jiming Zhu's appointment meant that the Chinese influenza group had continuing contacts with the World Centre at the NIMR.
Needham was able to attend occasional scientific meetings
Cao Tianqin and other members of staff standing by the SBSCO (Sino–British Science Co-operation Office) truck at the ferry crossing at Chungking (Chongqing) in 1946
In the early 1950s, Fred Sanger and colleagues determined the amino acid sequences of the cow, human and sheep insulin A- and B-chains  (Figure 7). This research, published in the Biochemical Journal, was a fundamental landmark in the understanding of proteins and had a major impact on biochemistry and medicine. It also gave the biochemists an immensely important goal: the chemical synthesis of insulin and research groups in Germany and in the U.S.A. began experiments to synthesize the hormone. It was decided in China that the scientific and technical demands in this goal would bring strategic benefits, especially if the chemicals and materials needed were made locally and forcing the development of a local chemical–pharmaceutical industry. Influential figures in this exercise (all with a Cambridge Ph.D.) were Zou Chenglu, Wang Ying Lai and Cao Tianquin . The work was divided so that Beijing the A-chain and Shanghai studied the B-chain and the combination of the A- and B-chains. The programme began in 1958 and was completed in 1965, a stunning achievement and accomplished at about the same time as the German and American projects. The Chinese synthetic product was, moreover, pure enough to produce crystals, the classical definitive stage in organic synthesis.
Dorothy Hodgkin and Fred Sanger, Cambridge, 1984, at the 50th anniversary of the first X-ray diffraction
In 1959, Dorothy Hodgkin visited China in a delegation, invited by the Chinese government, to mark the tenth anniversary of the revolution. On this occasion, she met (again) Tang Youqui and other Beijing crystallographers. She was already working towards the crystal structure of insulin in Oxford, but progress was slow. After the successful synthesis of insulin, there were proposals that Chinese crystallographers should, because of the successful synthesis, undertake insulin's crystal structure . In 1965, Tang Youqui, after some anxiety, undertook to set up this project with Liang Dong Cai. There was, after all, the potential to use chemical methods to insert heavy atoms into crystals of synthesized insulin, a possibility Dorothy Hodgkin had noted herself. The Chinese crystallographic research was given impetus by Liang Dong Cai's visit in 1965, first to work with Charles Bunn in London and then with Dorothy Hodgkin on the insulin project. When Liang returned to China after the Cultural Revolution began, he left in Oxford a balsa wood model of the two zinc–insulin hexamer, based on a promising set of data and phases extending to 6 Å (1 Å=0.1 nm) spacing (Figure 8). Liang Dong Cai's visit to Oxford was very important in establishing scientific contact and friendships with Dorothy Hodgkin and the younger crystallographers, Tom Blundell, Eleanor Dodson and myself. There was crystallographic progress in both countries and in the summer of 1969, the two zinc–insulin hexameric structure was solved in Oxford using data to 2.8 Å spacing  and in 1971 in Beijing with 2.5 Å spacing data [6,7]. Both laboratories reached the same conclusions in their descriptions of the surfaces involved in the hormone's assembly from monomer to hexamer and the zinc co-ordination that stabilized the hexameric species, illustrated in Figure 9.
Balsa wood representation of the electron density corresponding to the two zinc–insulin hexamer calculated at 6 Å resolution
The assembly of the insulin monomers into dimers and then, in the presence of zinc, to three different hexameric structures
The duplication of a protein crystal X-ray analysis had not happened before. It led to detailed comparisons that showed the processes used in the two studies gave essentially identical results and gave further confidence in crystallographic methods and brought benefits to both laboratories. Both groups traced out the surfaces involved in the hormone's assembly from monomer to hexamer and characterized the zinc co-ordination that stabilized the hexameric species. The comparisons of the maps also showed that the poorly defined solvent regions differed; this was likely to be caused by phasing and experimental errors, but was possibly due to some variation in the water positions. Both laboratories went on in the analyses to higher resolution, partly to understand better the atomic interactions and solvent structure, and partly to develop new refinement methods. In Japan and in China, the resolution was pushed to 1.2 Å [8,9], and in the U.K., to 1.5 Å [10,11]. The Chinese studies showed that their research potential was now realized, and that their future was bright.
Dorothy Hodgkin and I went to China in December 1977 and were able to meet the crystallographers in Beijing, particularly Liang Dong Cai, Gu Xiaocheng, Tang Youqui and the research team (Figure 10). This was an extraordinarily stimulating meeting; it was clear that the research skills and the enthusiasm that led to the determination of the crystal structure were still very present. The comparisons then, and those later based on the further extensions of the insulin diffraction data in both centres, showed that the two independent structures were identical at a detailed level. There was a trip to Shanghai where the synthetic programmes on insulin and on the tRNA were discussed. A year later, a Chinese crystallographic delegation came to the U.K. after attending the 1978 International Congress in Warsaw. The delegation visited various centres: London, Oxford, Cambridge and York, where contact was made again with those we had met in China (Figure 11). Further visits between the Chinese and U.K. crystallographers have taken place, in particular Olga Kennard, Neil Isaacs, David Blow and David Stuart have been hosts and visitors have included Zihe Rao, Bi Ruchang, Wang Da Cheng and Wan Zhu Li, and there have been a growing number of collaborations and contacts between British and Chinese laboratories generally.
Dorothy Hodgkin, Guy Dodson, Gu Xiaocheng and Wan Zhu Li in Beijing 1977 comparing electron density maps
Some visits to England in the summer of 1978
Neither the Chinese nor the British laboratories, nor other laboratories, have been able to obtain a receptor–insulin complex, so the question of how insulin structure responds to receptor binding cannot be answered directly. However, there are clues about the hormone's active structure that can be deduced from its conformational behaviour and from the biological potency of various vertebrate and invertebrate insulins and from mutated and chemically modified insulins. Both groups have studied truncated insulins, focused on shortening the B-chain C-terminus; one example is the highly active monomeric desB26–B30 insulin [9,12] (Figure 12). In China, the crystallographic and receptor-binding studies have extended to the inactive desB24–B30 (Figure 13A) and desB23–B30 insulins, sometimes to very high resolutions [13–15]. The high potency of the desB26–B30 insulin indicated that the B26–B30 segment masks the active surface below and is not involved in receptor binding. The loss of the B-bend at B20–B23 in the truncation beyond B24 shows this element is associated with binding and activity. In Britain, there was also research on the monomeric desB26–B30 insulin as well as the medically important mutated ‘monomeric’ insulins [16,17], the single-chain insulins , insulin's structural variation and the different hexameric structures obtained under different conditions [19,20]. In addition, joint research was also carried out on some mutant insulins prepared in Shanghai . More recently, the structure of a super-active insulin has been determined, illustrated in Figure 13(B); the conformation of the B-chain C-terminal residues has been designed after many experiments and fixed by chemical modifications in York and Prague [22,23].
Crystal structures of active insulin monomers
Crystal structures of two modified insulin monomers
The contacts with Shanghai and York continue to address the question of insulin's structural behaviour, including the structural changes caused by pH and its ready capacity to form fibrils. There are experiments being pursued by Shanghai (Zhang Youshang) and York (Jean Whittingham) to capture the unfolding of the molecule by studying the structures of native, monomeric and single-chain insulins in crystals grown at very low pH (, and Y. Zhang, E. Dodson, G. Dodson and J. Whittingham, unpublished work). There have also been longstanding collaborations on crystal structure determination methods between Michael Woolfson in York and the crystallographers in Beijing, in particular Fan Hai Fu. These began in the early 1980s and continued until very recently, the longest running collaboration the Royal Society has ever sponsored.
On 14–16 July 1982, a joint Biochemical Society–Chinese Biochemical Society meeting was held in Oxford (Figure 14), reflecting the awakened interest and increased activities between the two countries . In 1987, the Royal Society and the Chinese Academies selected 25 Chinese scientists to visit the U.K. for 1 year of research. The scheme was very successful, with an emphasis on the physical sciences and engineering. Survey of the extent of current Chinese and U.K. collaborations and contacts shows that they are a very significant component in biochemical and biomedical research. At the same time, the research environment in China began to expand: over the last decade, it has burgeoned and its standards are now much on a par with those of Western laboratories , and it now includes an advanced synchrotron source. At the same time, the U.K. Research Councils have become increasingly engaged in developing contacts and collaborations with China. The BBSRC (Biotechnology and Biological Sciences Research Council) now has several programmes, the largest of which is the China Partnering Award. It was started in 2003 and aims to link laboratories in the two countries. The topics cover the whole range of biology and, with the numbers of laboratories involved, the programme has had, and will have, considerable impact. The China–U.K. HUST–RRes Crop Genetic Engineering and Genomics Joint Laboratory in Wuhan was established in 2000. It involves the Huazhong University of Science and Technology (HUST), under the MoE (Ministry of Education) of China, and Rothamsted Research (RRes), sponsored by the BBSRC. The Joint Laboratory's goal is to improve crop quality and yield through biotechnology, to investigate and exploit functional genomics, and to establish an international training centre in plant science and biotechnology. A further Rothamsted collaboration, with the China Agricultural University in Beijing, aims to reduce fertilizer usage, a significant ingredient in the Chinese government's long-term energy strategy.
British and Chinese biochemists at the joint Biochemical Society–Chinese Biochemical Society Meeting held in Oxford, 14–16 July 1982
The Wellcome Trust has, since 1977, supported a number of Chinese collaborations, usually with a strong biomedical character. Three major collaborative ventures stand out. The first, begun in 2010, is with the Beijing Genomics Institute where high-throughput sequencing has been established; the commitment here is to determine the chicken genome that has both evolutionary interest and agricultural relevance. The second, begun in 2004, is between, in China, the Kadoorie Biobank Study and the Centre for Disease Control and Prevention and, in the U.K., the Biobank and the University of Oxford. It is a ‘large-scale’ medical study on a cohort of 500000 people that will address and compare the patterns of disease across China and the U.K. The third, referred to as CONVEX, started in 2008 and involves laboratories in the U.K., U.S.A. and China. The object in this programme is to study the genetics of major depression in Chinese women. Finally, and not biochemistry, there is the initiative between the Wellcome Trust's Collection and the Chinese Arts Centre to tackle the idea of identity in contemporary China. A very recent development is the ICUK (Innovation China UK) scheme; it is another indication of the commitments to collaborations. It involves five British and more than ten Chinese higher education institutions with some government support. Biochemistry is the third highest category in its academic projects.
In her Nobel lecture, Dorothy Hodgkin said, “our scientific world ceased to know any boundaries…”. This simple statement says it all. Shared interests and complementary expertise are the natural basis for collaboration, although there is no doubt that individuals can make a difference. Collaboration is intrinsic to science and research and this is just as much the case now as it was in the early days. In the 1930s, crystallography, by revealing the structural basis of chemistry, physics, mineralogy and biochemical sciences, was linked to them all, but it took the intellectual breadth and energy of J.D. Bernal and Dorothy Hodgkin to set the example so powerfully. Collaboration has been recognized as a vital component in the development and acceleration of national research capacities by governments; the EU (European Union), for example, has pursued these policies to great effect. The striking growth in scale and scope of the biochemical sciences and the huge expansion of the Chinese economy and its science is increasing the opportunities for collaborations . In this context, two quotes from this Royal Society report on the state of global science  are relevant: (i) the Chinese Ministry of Science and Technology has now signed science and technology co-operation agreements with more than 100 countries; and (ii) emerging nations are transforming the [scientific] scene, although traditional powers remain. Equally, there has been a striking increase in international collaborative research involving every nation.
The future increase in the U.K. biochemical research interactions will include those with China; these for me have a special value and I hope that this is true for the Chinese biochemists as well. One positive factor is our history of scientific contact going back to the 1940s, and another is the large presence of Chinese students in the U.K.; these are people who will help to build the basis for increasingly varied and effective collaborations. Additionally, although collaborations are one proven means of enhancing our research, full benefit demands equal partnership. Thus this engagement requires that the U.K. matches scientific growth in China and elsewhere; here is another spur for the U.K. scientific community and the government to ensure the expansion of our scientific investment.
Joint Sino–U.K. Protein Symposium: a Meeting to Celebrate the Centenary of the Biochemical Society: A Biochemical Society Focused Meeting held at Shanghai University, Shanghai, China, 5–7 May 2011. Organized by Tom Blundell (Cambridge, U.K.), Zengyi Chang (Peking University, China), Ian Dransfield (Edinburgh, U.K.), Neil Isaacs (Glasgow, U.K.), Glenn King (University of Queensland, Australia), Sheena Radford (Leeds, U.K.), Zihe Rao (Nankai University, China), Yi-Gong Shi (Tsinghua University, China), Chihchen (Zhizhen) Wang (Institute of Biophysics, Chinese Academy of Sciences, China), Jiarui Wu (Shanghai Institute of Biological Sciences, China) and Xian-En Zhang (Ministry of Science and Technology, China). Edited by Zengyi Chang and Neil Isaacs.
I am grateful to the Needham Foundation for generous advice, help with photographs and background material, and also to the Biochemical Society and staff, in particular John Lagnado, for their interest and support. I am indebted to Marek Brzozowski and Jiri Jirácek for their discussions on insulin modifications and active structure, to Eleanor Dodson for crystallography, memories and perspectives. We have had many discussions and ideas together with Chinese colleagues; I especially remember those with Zhang Youshang, Liang Dong Cai, Feng You Min, Bi Ruchang, Wan Zhu Li and Wang Da Cheng. Finally, I acknowledge the profound role of Dorothy Hodgkin in insulin research and the way in which she led us into these, and many other, collaborations.