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Stem cell translational medicine: The Tianjin model revisited

Abstract Stem cells hold great promise for cell therapy to treat a wide spectrum of intractable diseases. Despite enthusiasm for stem cell therapy, the clinical and translational research of stem cells overall has been a slow and cumbersome process. This article uses the “technological system” as a framework to analyze the Tianjin model of stem cell translational medicine. It shows how heterogeneous elements interact with one another and relate to scientific, technological, social, economic, and political variables in order to fulfill the system goal of producing cell therapy in China. Then the strengths and weaknesses of the Tianjin model are compared with translational programs in other countries and the implications for the cell therapy industry are discussed.


| INTRODUCTION
Stem cells hold great promise for cell therapy to treat a wide spectrum of intractable diseases and to improve human health. Many countries have invested heavily in the stem cell field to translate basic and clinical research to stem cell therapies and clinical practice. In the past decade, stem cell clinical trials have been rapidly evolving and carried out worldwide using various stem cell types, such as mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and human embryonic stem cells. 1 As of February 2021, more than 8000 clinical trials on stem cells have been registered at ClinicalTrials.gov; most of these are in phase 1 or 2, with only approximately 10% in phase 3.
MSCs have generated interest among scientists and have become popular cell types for stem cell clinical trials. More than 900 of the registered clinical trials used MSCs on a wide range of diseases and injuries. MSCs are also debated in the scientific literature with regard to their meaning and so their defining biomarkers. [2][3][4] Despite enthusiasm in stem cell therapy, the clinical and translational research of stem cells overall has been slow and cumbersome due to translational gaps and innovation challenges. 5,6 Only a small number of stem cell-based products have demonstrated sufficient scientific evidence and clinical benefits to be approved for the market worldwide. Most of these products are based on MSCs and are mainly produced in North America and Europe; none are from China. 7 Early on, China made stem cell research a priority in its science and technology policies. It launched various programs to fund stem cell research and attract talent back home from overseas. 8 In recent years, both local and national stem cell policies and programs have advocated for stem cell translational research and industry. 9 Tianjin, a city in North China, has expended considerable effort in building a "stem-cell city" based on its local advantages in hematology, stem cell research, and applications at the Institute of Hematology and Blood Diseases Hospital (IH) of the Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC). 10 12,13 as an analytical framework, it shows that stem cell translational medicine is a technological system that contains complicated and problem-solving components: various organizations (such as research institutes, hospitals, enterprises), physical artifacts (such as laboratory equipment, raw materials, storage infrastructure), and nonphysical artifacts (such as industry standards and specifications, business model, regulatory strategy, workforce development). These disparate elements interact with one another and relate to scientific, technological, social, economic, and political variables. Thus, fulfilling the common system goals of producing innovative, safe, effective, and affordable regenerative medicine products requires no less than reordering the material world.
System builders play a crucial role as "heterogeneous engineers" 14 in the invention, development, and consolidation of technological systems. To build a successful technological system, system builders need a systematic approach to relate everything to a single central vision. They use organizing principles to integrate heterogeneous factors and components, and they coordinate a team of diverse professional backgrounds. These are people who are consistently committed to solving a blend of scientific, technological, financial, business, political problems that hinder the growth of the technological system. 13 The next sections show how Zhongchao Han and Tao Cheng, two such system builders, constructed the technological system of stem cell translational medicine in Tianjin.  Han had the vision to transform the results of good scientific research to technological products and social benefits. He devoted his career to translating stem cell knowledge gained from laboratories to stem cell products and industrialization. Han and his team have conducted innovative research in this field, winning several local and national science and technology progress awards. 16 In the early days, they worked on blood stem cells and tried autologous transplantation of peripheral blood stem cells in the treatment of patients with severe lower-limb ischemia. [17][18][19] Han proposed that perinatal tissues, including cord blood, umbilical cord, and placentas, are important natural sources of MSCs. 20 In 2002, under Han's leadership, IH and the investors built one of the largest stem cell bank in the world, the Tianjin cord blood stem cell bank, and established a standardized process for banking human umbilical cord-derived mesenchymal stromal cells for therapeutic uses. 21 Following MSC safety studies for clinical applications, they conducted clinical studies on umbilical cord-derived MSCs to treat diseases, such as mild graft vs host disease (GVHD) 22 and refractory hematologic malignancy. 23

| Heterogeneous and interacting variables
Bridging translational gaps between bench and bedside is difficult and has been likened to crossing the "valley of death". 27 Four key aspects-active program leadership; substantive and productive interdisciplinary collaborations; innovative research resources; and training, education, and community engagement-were identified as crucial in advancing clinical and translational research. 28  consolidate the Tianjin stem cell technological system to produce cell therapy, system builders need to function as "heterogeneous engineers." They can then take the lead in associating entities ranging from professions with a variety of expertise and related organizations, to physical and nonphysical artifacts, and assemble them in appropriate ways, in order to tackle scientific, technological, social, economic, and political problems.
On the whole, the global field of stem cells has been subject to the institutionalization of commercialization pressure. 41 The main purpose of establishing the translational programs in each country is to promote the commercialization of cell therapy. Nevertheless, these translational programs have pros and cons. They could facilitate collaborations across diversified disciplines, expertise, institutions, and artifacts to foster knowledge translation, generate value, and speed product development. At the same time, they could also create conflicts of interest among various stakeholders, such as researchers, industry partners, patients, and the public. Therefore, the issues of commercialization need to be addressed in a timely and constructive manner to realize the maximum benefits of translational programs.

| CONCLUSION
This article presents a case study of the Tianjin model of stem cell translational medicine from the perspective of a technological system.
The system builders have implemented a variety of initiatives to invent and develop the technological system, and they have gathered momentum for its growth and consolidation. As a large, novel, and