Development, growth, and future of the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College: 65 years tackling medical research paradigms

The Institute of Basic Medical Sciences (IBMS) is a global leader in biomedical research and advanced medical education. This year (2023) marks the 65^th anniversary of its foundation at the Chinese Academy of Medical Sciences (CAMS) and School of Basic Medicine (SBM) of the Peking Union Medical College (PUMC). In the beginning, the IBMS and SBM incorporated the premedical departments of the PUMC, which was established by the Rockefeller Foundation in 1917. Since then, these departments have been committed to undertaking first-rate medical science research in China.

Today, the IBMS consists of 13 academic departments, 3 National Science and Technology Infrastructure (NSTI) platforms, and a National Demonstration Center for Experimental Basic Medical Education, and supports and provides leadership to four state key laboratories. Two professors of the IBMS are members of the Chinese Academy of Sciences (CAS), five are members of the Chinese Academy of Engineering (CAE). Alongside, the IBMS hosts a few dozens of young to middle age investigators in national talent programs.

The IBMS proudly sets the pace of the sci-tech revolution, founding several modern medical disciplines in China. Moreover, the IBMS leads in combining basic research with clinical practice, establishing new research methods, and integrating research with the major national strategic needs. Here, we outline the historical innovations made and the research paradigms tackled by members of the IBMS.

Rise of premedical disciplines in China: discipline integration and experimental innovation. In the early 20^th century, advances in the traditional sciences such as chemistry, physics, and mathematics started to infiltrate the field of biomedicine. The result was the rise of the more modern disciplines of biochemistry, physiology, anatomy, pharmacology, immunology, epidemiology, biophysics, and medical bioengineering. Research objectives shifted in parallel to understanding human disease mechanisms and developing new drug targets. These new objectives required innovative models, technologies, and experimental designs. The field of “experimental medicine” gradually emerged as the principal basis of medical research and accelerated the transition from empirical to modern medicine.

Prof. Hsien Wu and Prof. Robert Kho-Seng Lim are highly regarded founders of modern medical disciplines in China. Both established world class research teams and launched the careers of several outstanding researchers in the life sciences. Prof. Wu, founded the Department of Biochemistry at PUMC, and received great accolades in the fields of biochemistry and nutrition science in China.^[1] Prof. Wu proposed that protein denaturation is caused by unfolding rather than chemical alteration, and also developed the Folin-Wu method of blood-glucose detection that may be the first scientific method named after China. Moreover, Prof. Wu conducted a comprehensive analysis of food composition, on which nutritional guidelines were established to solve the problem of malnutrition in China.^[1] Prof. Lim achieved remarkable progress in the fields of digestive and circulatory physiology.^[2] Using his skills in experimental animal model techniques, Prof. Lim successfully conducted various impactful studies on gastric secretion and in the 1930s, coined the term “enterogastrone” to describe the hormones that inhibit gastric secretion and mobility. Notably, the enterogastrone hormone was the first hormone discovered by a Chinese scientist. Prof. Xijun Zhang and Prof. Depei Feng, both students of Dr. Lim, are now leading authorities on neurotransmitter function and neuromuscular junctions, respectively.

The PUMC soon became regarded as “the cradle of modern medicine in China” due to such significant contributions to early premedical disciplines. The founder of the Chinese public health industry, Prof. John B. Grant, launched the first community health institution in the world and promoted the three-tier healthcare network model that is now implemented in modern cities.^[3] Professor of the Pharmacology Department, Ko Kuei Chen, not only discovered the pharmacological action of ephedrine, but also successfully translated the drug into the clinic. Prof. Chen also made several critical discoveries in natural product chemistry and drove the advent of pharmacology-based concepts of drug action.^[4] The first director of the IBMS, Prof. Jun Zhang, is known as the pioneer of modern human anatomy in China. Prof. Zhang made substantial contributions to the fields of histology and embryology. Prof. Samnel Zia helped to found modern microbiology and immunology in China. By cultivating Rickettsia in live cells using chicken embryos, he revealed the pathogenic mechanism of infectious disease, which in turn contributed to the fight against biological warfare. Finally, Prof. Jiasi Huang is considered a founder of biomedical engineering as a medical science discipline in China, and advocated research efforts that yielded outstanding advances in the field. Key examples include the foundation of Chinese Society of Biomedical Engineering and active academic exchanges at home and abroad.

The period 1917–1978 saw massive integration of disciplines and new research directions leading to the formation of IBMS research system. The legacy left by the aforementioned researchers remains today, as evidenced by the establishment and reformation of several state key laboratories.

Understanding of critical clinical problems by fundamental research. As discussed, the founding members of the PUMC kept developing new methods to address clinical issues. From the 1930s, we saw an explosion in mechanistic studies addressing fundamental research questions.

Prof. Shih-Hao Liu, the founder of Chinese Endocrinology and the former head of the Biochemistry Department at PUMC, is renowned for his early work on calcium and phosphorus metabolism.^[5] Together with his team, Prof. Liu conducted a detailed metabolic analysis of patients with osteomalacia to understand the pathophysiological mechanisms of the disease and optimize the therapeutic regimen. These studies led to the identification of vitamin D deficiency as the disease driver.

Others were inspired to leverage epidemiological data to investigate links between certain diseases and potential causes. For example, Prof. Jian Yang investigated the etiology of esophageal cancer in Lin County (Henan Province), due to its high prevalence in this region. Findings from a comparative investigation of the living environment, lifestyle, diet, and hygiene status of farmers in rural areas implicated food contaminated with mold as the cause of this cancer. These findings contributed to the development of new strategies for disease prevention and treatment.

The famous parasitologist Prof. Lan-chou Feng discovered that Anopheles sinensis and Anopheles minimus are the vectors for malaria and filariasis transmission in China. This breakthrough provided a reliable theoretical basis for the large-scale prevention and control of five major parasitic diseases. Later, based on an analysis of data from more than 100 infant cases of visceral leishmaniasis, Prof. Guanqing He elucidated the pathogenic characteristics of visceral leishmaniasis by identifying Phlebotomus chinensis as the vehicle.

Transition from life sciences research to translational studies. The fundamental research conducted at the PUMC helped to fuel efforts to translate findings made in the laboratory to the clinic. Indeed, a major emphasis of the IBMS upon its construction was to bridge the gap between life sciences and the successful development of various therapeutics for numerous human diseases. Key examples of such successes are described below.

Molecular explorations of etiological mechanisms. The second half of the 20^th century saw the molecular biology, genetics, and cell biology fields take center stage, with subsequent technological advances in the life sciences to study life at the submicroscopic level. Research at the newly established IBMS took full advantage of this golden age in the life sciences. To exemplify, during his early years at the IBMS, Prof. Shepu Xue derived critical theoretical support for the principle of cell differentiation and its regulation. Notably, his molecular biology studies on the genes encoding the family of erythroid differentiation denucleation factors (EDDF) solved the mystery of natural enucleation of mammalian erythrocytes, which led to potential cancer treatment that is based on reversing the malignant proliferation of cancer cells.^[6]

Prof. Linfang Wang, a pioneer of Chinese reproductive biology research, conducted a systematic study to elucidate the structure, gene expression and function of sperm membrane proteins. Some 50 novel genes directing spermatogenesis were identified in humans and mice and their relationships with reproductive disorders were clarified, leading to great insight and subsequent improvements in human reproductive health.^[7]

As the founder of the medical genetics department, Prof. Wilson H. Y. Lo set up the first domestic genetic counseling clinic for patients with genetic diseases and diagnosed many rare genetic diseases that were previously unreported in China. After identifying the genetic mutation responsible for classic phenylketonuria (PKU) in China, Prof. Lo developed methodological innovations that increased the success rate of prenatal diagnosis of the condition from 30% to 85%.^[8]

Finally, Prof. Xuetao Cao made outstanding contributions to the analysis of signaling pathways in innate immunity and inflammation, the identification of regulatory immune cell subsets (e.g., dendritic cells and macrophages) and discovered new regulators of immune responses.^[9] In addition, his basic research together with clinical trials led to the adoption of new approaches to cancer immunotherapy.

Inauguration of a new era of gene and cell therapeutics. Continuous progress in cell engineering, immunology and stem cell biology gradually propelled contemporary molecular therapy to more advanced gene and cell therapy. The result was innovative approaches to the treatment of certain cancers, infectious diseases, and autoimmune diseases. Prof. Denian Ba took the lead in this area in China by conducting research on lymphokine-activated killer (LAK) cells. The understanding of the mechanism of cytotoxicity as well as methods to induce these cells facilitated the application of LAK cell therapy in clinical practice, which has proved effective in preventing cancer metastasis.^[10]

In extensive studies on human γδ T cells and their functional plasticity in the tumor microenvironment, Prof. Wei He^[11] identified the DNA mismatch repair protein MutS homologue 2 as ligands for γδ T cells. As a result of his work conducted at the IBMS, preclinical and clinical evaluation of γδ T cell therapy is well underway and stands to impact on the development and test of various therapeutic concepts and strategies in multiple cancer settings.

Exploratory research driven by big data and systematic methodology. The 21^st century has seen a gradual shift from analytical and reductive ideology to more holistic and systematic principles. Integrated approaches are now required to address complex medical issues. Indeed, the completion of the Human Genome Project and advances of multi-omics technology, including transcriptomics, proteomics and metabolomics, have promoted the “data-driven” paradigm we currently face in the research lab. In recent 25 years, the IBMS has hosted numerous leading researchers who are specialized in gene diagnosis and gene therapy.

Prof. Yan Shen focused on identifying the human genes related to inherited diseases, including childhood absence epilepsy, primary erythromelalgia, and cortical cataract and applied to developing DNA diagnostic methods. Notably, he succeeded in identifying a mutation in the gene encoding dentin sialophosphoprotein in a Chinese family with dentinogenesis imperfacta type II.^[12] Such discoveries have formed the basis of a novel, powerful, and high-throughput technologies that have improved the diagnostic efficiency of rare genetic diseases. Similarly, Prof. Xue Zhang identified the gene mutations underlying several monogenic disorders, including familial acne inversa,^[13] Marie Unna hereditary hypotrichosis,^[14] familial idiopathic basal ganglia calcification^[15] and syndactyly type V. He also identified the pathogenic genomic rearrangements responsible for congenital generalized hypertrichosis terminalis, X-linked congenital hypertrichosis syndrome and syndactyly type IV. Together with developments in the genomic sciences, these discoveries have increased opportunities for precision medicine designed to treat patients with rare diseases.

Prof. Depei Liu now leads the National Population Health Data Center (NPHDC), which undertakes the tasks of collection, review, processing, storage, mining, certification, and sharing service of scientific data in the field of population health to ensure the long-term preservation and continuous management of population health scientific data. Aside from this work, and based on his research on regulatory mechanisms in aging and his expertise in traditional Chinese medicine,^[16-18] Dr. Liu proposed the novel Systems Medicine model for comprehensive, and multidimensional investigations of the whole process of life and disease. This approach requires interdisciplinary integration, including a combination of omics and bioinformatics technologies, to help fully elucidate the mechanisms of human physiology and pathology.^[19]

Mission-oriented research to solve significant challenges. Since the founding of the People’s Republic of China, the IBMS has consistently focused on tackling pertinent health challenges to benefit the nation. Indeed, by adhering to the national strategic requirements of developing China, the IBMS was included in the state science and technology plan.

In the 1950s, Prof. Chih-chuan Liang proposed the idea of developing animal substitute plasma to treat volunteer soldiers who suffered injuries. His team successfully developed two types of plasma substitutes: Shiyan No.2 and Shiyan No.3. These substitutes exhibited safety characteristics that were superior to equivalent products available in China and abroad. Prof. Fangzhou Gu, known as the father of “sugar pills”, devoted his whole life to the eradication of polio.^[20] He took the lead in using attenuated virus strains to develop safe and effective vaccines that successfully impacted the spread and prevalence of the disease.

By the 1990s, experts at the IBMS had made substantial contributions to genome research project. The first official national-state program designed as part of the Human Genome Project in China was co-hosted by Prof. Boqin Qiang.^[21] As one of the chief coordinators of the mission and the principal of the Chinese National Human Genome Center, Beijing, Dr. Qiang and colleagues successfully completed the “1% Sequencing Project”, which engraved the name of “China” in the milestone of human science and technology development. The results of this project laid a solid foundation for further developments in the life sciences and biotechnology in China.

Most recently, Prof. Chen Wang, the president of CAMS and PUMC, proposed the use of epidemic prevention mobile cabin hospitals in Wuhan when the coronavirus disease 2019 (COVID-19) pandemic emerged.^[22] This approach avoided the risk of transmission within families and communities, contributing to the success of COVID-19 control in China. He also initiated the Chinese Life-Course Cohort Study of Multimorbidity project. This project integrated with the promotion, prevention, diagnosis, control, treatment, and rehabilitation initiative to explore the concept that disease prevention and control should be conducted from the perspective of population medicine, with the focus on the individual and community.

Since their inception, the premedical departments of the PUMC and IBMS have made great contributions to the development of Chinese medical sciences. These advances are more and more bolstered by important scientific and technological breakthroughs, such as robust quantitative prediction, multi-disciplinary integration, and artificial intelligence.

The development of medical research now extends beyond the scope of the life sciences: it must develop not only together with science, engineering, and other natural sciences, but also integrate the social sciences and humanities. Our research model is now transitioning both from molecular biomedicine to systems biomedicine and from evidence-based medicine to precision medicine.

Nowadays, the IBMS has provided novel strategies for early detection, prevention, and intervention of major diseases, including cancer, respiratory, cardiovascular, blood and neurological disorders. The IBMS is proud to host numerous distinguished scholars who are conducting pioneering cutting-edge research across various medical fields, and have outstanding potential as the next leading figures in scientific research. The institute houses four State Key Laboratories and three National platform programs which are entrusted by the Ministry of Science and Technology of China to produce research of international quality and carry out important national research tasks. The education experience in IBMS is distinguished by the support of China’s Double First-Class University Plan, offering a wide array of excellent undergraduate and postgraduate programmes.

Transition of IBMS to a new level of development will demand new resources. While such change might seem challenging, the IBMS is committed to optimizing the layout of core research areas to promote interdisciplinary integration and research, train a large number of basic medicine research talents urgently needed for China’s innovation-driven development, and form a state-level laboratory and resource network, so as to build a high-quality, comprehensive biomedical discipline. Meanwhile, future expansion opportunities are coordinated with the completion of a new research building in North Beijing and estabilshement of translantional medicine center in South Beijing.

The next 65 years of research at the IBMS promises great things. Based on its strategy of “advocating the innovative spirits and making concerted efforts”, the IBMS aspires to be known for its innovations in medical technology systems and its double first-class medical education. In turn, the IBMS will ensure continual advances in basic research are made while consolidating the country’s self-reliance and strength in medical science and technology.

Acknowledgments

The author would like to thank Jinyu Zhou for collecting relevant supporting information and Chao Ma for his valuable suggestions.

Funding

This work was supported by a grant from the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2022-I2M-2-001).

Conflicts of interest

None.