Progress of Space Medicine Research in China

DING Bai LIU Zhaoxia Lü Ke LING Shukuan LIU Yue XU Zi LI Yinghui

Progress of Space Medicine Research in China

DING Bai LIU Zhaoxia Lü Ke LING Shukuan LIU Yue XU Zi LI Yinghui

(100094)

With the approaching of the Chinese Space Station (CSS) era, the focus of space medicine applications and related research has shifted to addressing the astronauts’ health support in long-duration spaceflights, including nutrition, countermeasure against the physiological effects of weightlessness, medical monitoring and support, psychology status,., and accordingly the human experiments to simulate long-duration weightlessness have been carried out. Increasingly, basic research has been put forward in the key areas, such as space bone loss, cardiovascular dysfunction and the molecular mechanisms underlying radiobiological effects. Moreover, specific novel research fields, such as hypometabolism technology, were explored. The research projects in the field of space medicine experiment, as an important aspect of the Chinese Space Station’s application, have been officially approved and launched.

Space medicine, Chinese Space Station, Health risk

1 Introduction

On 19 July 2019, the Tiangong-2 space laboratory was de-orbited in a controlled demolition, a milestone marking the successful completion of all missions of the space laboratory mission phase of China’s manned space project and officially ushering the era of the space station in China.

Aiming at the completion of China’s space station, the construction of the national space laboratory and the long-term in-orbit stay of astronauts, a slew of health measures has been developed to ensure the health of astronauts and their safety during a long- term stay in orbit. A bunch of space medical experiments research projects have been systematically laid out, achieving a number of ground-based research results in space medicine and laying solid theoretical and technical foundations for the sustainable deve- lopment of China’s manned space project.

This report provides a brief introduction to the recent progress of space medicine research in China from 2018 to 2020.

2 Application and Research in Space Medicine for Long-term Spaceflights

2.1 Astronaut Health Support

The Chinese astronauts’ stay in orbit will be gradual- ly extended to 180 days during the upcoming routine flight missions, posing greater challenges to their health support as follows. The physiological effects of weightlessness will become more prominent, such as bone loss, muscular atrophy, decreased muscular strength and cardiovascular dysfunction. The systematic and comprehensive accommodation is increasingly required for the nutritional supply of space food during long-term spaceflight. Furthermore, the health risks become greater, such as clinical disorders/illness, accidental injury and psychological problems. Focusing on the goal of ensuring astronauts’ health and their efficient work in orbit, the Astronaut Center of China established the astronauts’ health support technology system for long-term spaceflight, including four aspects: the countermeasure against physiological effects of weightlessness, nutritional supply, medical monitoring and support, and psychological support.

2.1.1 Countermeasure Against Physiological Effects of Weightlessness

To tackle the adverse physiological effects of long-term weightlessness on human body and consequently effectively protect against the decline in aerobic exercise capacity, muscular atrophy and bone loss, a number of experimental studies on human body have been carried out. These studies include the vertical treadmill exercise and long-term head-down bed rest (HDBR) weightlessness simulation experiments. Other in-orbit countermeasure technologies have been developed,space bicycle, space treadmill, resis- tance exercise device, gradient compression garments, respiratory muscle exercisers,In addition, targeted exercise prescriptions/recommendations have been developed and, based on different flight duration, different episodes and in-orbit tasks, a comprehensive countermeasure protocol has been accomplished, which integrates exercise, physics and medicine, and also combines duration-specificity, mission-orientation and individualization. The protocol has been verified by ground-based experiments and is expected to effectively play important roles in the aerobic exercise capacity, muscle dimension and strength, bone density, and orthostatic tolerance.

2.1.2 Nutritional Supply

Research has been conducted to form the nutrition supply standards for long-term in-orbit flights, and to establish a dietary structure framework and flight menu. Safe and reliable, comprehensively nutritional and sensory acceptable space food products have been developed. To tackle the potential problems during the long-term flight, such as decreased immune function, fatigue, oxidative damage and intestinal dysbacteriosis, special functional food products have been developed to ensure that astronauts are in good nutritional condition and to reduce their body mass loss, consequently to maintain astronauts’ normal physical work capability. Additionally, multi- ple protocols are coordinated to maintain the homeo- stasis of the astronauts.

To address the risk of a possible decline in food sensory acceptability, which is prominent in long-term missions, the food diversity has been further enriched in staple and subsidiary-foods, fast foods, beverages and condiments. The menu cycle has been extended to no less than 7 days, achieving both the reasonable combination of long-term and short-term expiration period and cold and hot foods, and the consideration for the individualized requirements.

2.1.3 Medical Monitoring and Support

Integrated medical monitoring and support technology has been established, which contains diagnosis, prevention, treatment and recovery, for the astronauts during long-term spaceflight.

In health condition assessment and disorder diagnosis, the spectrum of spaceflight disorders has been established, and an integrated diagnosis system of traditional and western medicine has been con-structed. It combines physiological functions, biochemical indicators, medical imaging and the “Four Diagnostic methods” of Traditional Chinese Medicine. Integrated mode of both regular and individualized durations for medical monitoring and support has been established, which makes it precisely to assess the major physiological functions and the health status of “core” tissues and organs in human body.

In terms of disorder prevention and treatment, based on the core concept of “preventive treatment of disease” from Traditional Chinese Medicine, electrical stimulation and regulation technology in neuromuscular tissues has been developed to solve the problems that commonly happen during long-term spaceflights, such as muscle tension, back pain, sleep disturbances,. In addition, the research and development of the Chinese patent medicines for bone-strengthening and anti-atrophy are supportive in enhancing the countermeasure against muscular atrophy and bone loss. Integration of the methods from both physical interference and Chinese-western medicines could regulate and maintain astronauts’ health in multi-dimensional ways.

In order to ensure sound body recovery after long-term spaceflight, integrated recovery measures, including exercise, physiotherapy, medication and traditional medicine, have been formulated. Accordingly, the comprehensive recovery protocol has been formed, which adopts the principle of “dynamic assessment, gradual progress, continuous rehabilitation and individualization”.

2.1.4 Psychological Support

With regard to the mental health risks during long- term spaceflights in space station missions, the astronauts’ mental health support program has been developed,the utilization of the 4-person 180-day controlled ecological life support system (CELSS) experiment, astronauts’ in field training, science experiment during Antarctic expedition and long- term integrated manned simulation and verification experiment. The psychological evaluation protocols and technical standards suitable for long-term spaceflight have been set up, and a combination of both social and professional psychological support has been established. Effective measures for self- adjustment and self-relaxation has been developed. All these measures are expected to reduce and control the negative psychological factors during long- term flights and consequently maintain the well psychological state of astronauts.

2.2 Space Experiments in Space Medicine and Biology

Venturing into the “deep blue” to expand the space for human survival is the goal of human space exploration. To tackle the major medical problems and the human factor-related engineering problems that restrict long-term space flight, and to provide theoretical and technical support for the enhancement of astronauts’ ability to remain healthy in orbit, the space medicine experiment research focuses on the “human-system-risks” during long-term spaceflight, and the space medicine experiments during the construction and operation phases of the Chinese Space Station have been evaluated and planned. In addition, aiming at the future manned lunar exploration, considerations have also been taken into the future research program.

The Phase I research platform for space medical experiments has been constructed which has developed human systems research cabinets and medical sample analysis payloads and boasts in-orbit human research capabilities,. brain function research, vascular function research, muscle structure function research, medical sample preparation and observation, metabolomics research, biomechanics testing of human movement, basic cognitive testing, biological rhythm testing, and visual function testing,

The project guidance of space medicine experi- ments has been drafted and announced. The first batch of research projects have been selected and 81 research institutes involved in the projects will conduct research in five directions, including the impact of long-term weightlessness on astronauts’ health and related countermeasure technology, the impact of space radiation on astronauts’ health and related countermeasure technology, astronauts’ behavior and ability, advanced in-orbit monitoring and medical treatment technology, and space application technology of traditional medicine. These research will systematically analyze the dynamic evolution of the effect of weightlessness on human body, explore the mechanism of multi-system mutual adjustment network, and develop new protection technology and methods; it will also study the main hazards of space radiation on human body and establish space radiation assessment model; it will study the changes of the human’s basic ability during long-term weightlessness, human adaptiveness in the space station, the influence of space environment on biological rhythm and the effective entrainment technology, and human-computer interaction; it will aim at the R&D of advanced in-orbit monitoring and medical treatment technologies, such as microchip laboratory and wearable biosensors. In addition, the research projects will develop diagnostic technologies featuring traditional Chinese medicine (TCM), and health support and adjustment technologies based on the TCM and traditional medical therapies.

In the Tianzhou-1 cargo spacecraft mission, an application project, Professor Shang Peng in Nor-th- western Polytechnical University and Professor Chen Guoqiang of Tsinghua University conducted a 7–21 day space flight study of bone tissue cells using an in-orbit system of automated cell cultivation and real-time microscopic recording, which revealed that morphological changes in murine osteocyte -MLO-Y4 and the reduced cell mineralization capacity are caused by space microgravity, and 3-hydroxybutyric (3-HB) plays an antagonistic effect against microgravity-induced slowing of osteoblast MC3T3-E1 proliferation. The research also found that in microgravity environment casein kinase 2 interacting protein 1 (CKIP-1) is involved in regulating osteoblast differentiation process.

2.3 Basic Research in Space Medicine

The basic theory with regard to the effects of weightlessness has been enriched by the research advances in cellular and molecular mechanisms underlying bone loss in space, degradation of cardiovascular function, muscular atrophy, neurocognition, and the frontier explorations in the fields of space pathogenic microbes, and radiation biology effects. Furthermore, hypometabolism regulation techniques have provided new perspectives and new approaches to long-term in-orbit health support.

2.3.1 Bone Loss and Muscular Atrophy in Space

Bone dynamic homeostasis under force stimulation involves a very complex regulatory network. Using tail-suspended transgenic rats, Shang Peng. showed that blocking glucocortical signaling pathways in osteoblasts and osteocytes can prevent cortical bone loss due to weightlessness, suggesting an important role of stress response and elevated glucocorticoid levels in the process of bone loss induced by space flight[1]. Li Yingxian. found that the endoplasmic reticulum protein TMCO1-mediated Ca2+leak provides local Ca2+signals to activate the CaMKII-HDAC4-RUNX2 signaling axis. The establishment of TMCO1 as a pivotal player in osteogenesis uncovers a novel potential therapeutic target for ameliorating osteoporosis and bone loss[2]. Sun Weijia. revealed that the mechanosensitive channel-Piezo1 functions as a key mechanotransducer for conferring mechanosensitivity to osteoblasts and determining mechanical load-dependent bone formation, and represents a novel therapeutic target for treating osteoporosis or mechanical unloading-induced severe bone loss[3]. Sun Lianwen. showed that the simulated weightlessness may inhibit and restrain early osteogenic differentiation of bone marrow- derived mesenchymal stem cells through negative regulating Transcriptional co-Activator (TAZ)[4]. Qian Airong. found that the cytoskeletal key regulator-microtubule Microfilament Crosslinking Factor (MACF1), affects osteoblast differentiation through the β-catenin signaling pathway[5]. Chen Xiaoping. found that Hemojuvelin is a novel suppressor for Duchenne muscular dystrophy and age-related muscle wasting[6]. Wang Linjie. found that 2~4 weeks’ high-intensity intermittent exercise can rapidly increase oxygen uptake and maintain lower limb muscle strength, and that continuous endurance exercise can steadily increase aerobic endurance and improve bone density through 8-week-1-weight-loss endurance exercise[7].

2.3.2 Cardiovascular Function in Space

Cardiac remodeling is closely related to hemodynamic loading. Li Yingxian. demonstrated that CKIP-1 protein exerts an inhibitory effect on pressure overload-induced cardiac remodeling by regulating the dephosphorylation process of HDAC4. Moreover, myocardial CKIP-1 overexpression inhi- bited cardiac remodeling and functional decline induced by simulated weightlessness[8]. Peng Tianqing. suggested that blocking angiotensin II receptor can inhibit myocardial atrophy and cardiac dysfunction induced by Hindlimb Unloading, which may be related to reactive oxygen species (ROS) production, Calpain activation and ERK1/2 inhibition[9]. Sun Xiqing. elucidated that under the effect of simulated weightlessness, autophagy of human umbilical vein endothelial cells is enhanced, and that phagocytosis of ubiquitinated proteins further inhibits unfolded protein responses so as to inhibit apoptosis. Furthermore, the differential analysis of microRNA expression suggests that, under simulated weightlessness, miR-27b-5p may affect apoptosis of vascular endothelial cells by regulating ZHX1[10].

2.3.3 Neuro-immuno-endocrine Functions and Sleep Medicine

Qu Lina. investigated the mechanism of neurocognitive decline due to simulated weightlessness which found that the MGF-NRF2-HO-1 signaling pathway and the hypoxia-inducible factor HIF-1a correlated with the regulation of learning and memory function, revealing the important regulatory role of oxygen stress triggered by oxygen metabolic imbalance in spatial cognitive dysfunction[11, 12]. Adop-ting combined analysis of cycle RNA sequencing and serum metabolomics, Dai Zhongquan and Zhang Hongyu found that simulated microgravity enhances circulating miR-383-5p expression which is involved in the process of weightlessness headward distribution of body fluids on learning and memory through the brain tissue water channel protein APQ4[13]. By analyzing changes in the proportions and functions of HSC differentiated immune cells, hematopoietic cells, and HSC in a simulated weightlessness mouse model, the research shows that weightlessness can alter the proportions of B cells, T cells, and NK cells and that weightlessness leads to an increase in the number of HSC while a decrease in HSC function, and these changes can be restored after the removal of weig-htlessness[14]. The Cooperative research by Wang Liping and Li Yinghui found that the neural circuit of the nucleus stria terminalis (BNST)-ventromedial hypothalamus (VMH)-nucleus tractus solitarius (NTS) regulates the bone loss induced by chronic pressure stress by regulating the activity of the peripheral sympathetic nervous system process[15]. Wu Bin. reviewed the on-orbit sleep problems, which is crucial to health and performance and is commonly caused by the space risk factors (. microgravity, isolation, insufficient light exposure,.), could be interfered with or regulated by seven kinds of potentially efficacious countermeasures, including pharmacologic interventions, light treatment, crew selection and training, and so on[16]. Wu Xiaorui. testified the negative effects of 72 h isolation and confinement (IC) and sleep deprivation on the attention of network functions and operational performance via fMRI and manual controlled rendezvous and docking simulation task, respectively[17].

2.3.4 Space Microbes

Changes in the characteristics of microorganisms in the space environment, including pathogenic changes, are important risk factors for long-term spaceflight activities. Onboard Shenzhou-8, Shenzhou-10, and Tiangong-2, a series studies on space microbes were conducted, and some of the results are as follows: the changes in the biological phenotype, genome and transcriptome of Klebsiella pneumoniae carbape- nemase (KPC-2) after space flight mainly concentrate on the transport and metabolism of inorganic ions, amino acids and carbohydrates; the second space flight changed the biological traits such as growth rate and biofilm-forming ability of Immobilis shenensis; the cell wall ofshowed prominent changes such as increased physical resistance, increased sensitivity to antibiotics and biofilm thickening after the space flight; the biofilm- forming ability of Immobilis baumanensis was enhanced after 64 days of flight. Systematic ground- based studies were performed by Li Yongzhi. about the effects of simulated weightlessness on Fungi, Staphylocollcu aureus, E. col, Candida albicans and so on[18]. Wang Jiaping. revealed the accumulation of cysteine and methionine inafter 12-day spaceflight on the SJ-10 satellite and provides an important basis for the assessment of the risk that the opportunistic pathogenic yeast could cause[19].

2.3.5 Radiobiological Effects

Space radiation may induce tumors, cause neurological damage and cognitive ability decline, degene- rative lesions, and immunosuppression. Zhou Guangming and his team establish a quantitative relationship for radiation-induced carcinogenesis and obtained lung cancer cell models at different develop- mental stages by irradiating human lung epithelial cells with long-term low-dose-rate alpha particles. The afore-mentioned research found that the risk of low-dose-rate radiation-induced carcinogenesis was positively correlated with radiation dose without any dose threshold, and there is no difference in tumor formation between long-term low-dose rate irradiation and equal-dose single irradiation, but long-term irradiation leads to increased malignancy of tumors; there is a synergistic effect between microgravity and radiation to reinforce radiation-induced epithelial mesenchymal transformation. The study suggests that non-coding RNAs play an important regulatory role in the space radiation effect, and that high LET ions can specifically induce the expression of the long-non-coding RNA-LNC-CRYBG3, which directly binds G-actin to inhibit microfilament skeleton assembly and constrict loop formation, leading to M-phase cell block[20]; LNC-CRYBG3 can also bind the LDHA, which alters cellular metabolism and promotes glycolysis[21]. The research also reveals that the low dose rate and high LET radiation environment in space makes the paracrine effect more prominent[22]. It is noteworthy that resting cells are more radiation resistant than dividing cells, and data from studies on cells that are at the phase of exponentially growing tend to overestimate the risk of space radiation. The expression level of the NADPH oxidase subunit RAC2 is significantly lower in resting cells than in dividing cells, resulting in lower radiation-induced endogenous reactive oxygen species (ROS) than in dividing cells; In addition, radiation- generated ROS tends to lead to Dephosphorylation of P38 MAPK, which can mutually regulate with RAC2 through feedback and negative feedback, resulting in increased radiation resistance of G0 cells[23].

2.3.6 Hypometabolic Technology

Technologies and methods for long-term manned spaceflight health support remain to be the frontier of space exploration and Li Yinghui and her team have conducted research to explore hypometabolism regulation technology. In 2018, a 12-person 24-day human hypometabolism regulation technology experiment was performed and successfully completed, which was designed to analyze the tendency of psychological and cognitive changes in hypometabolism conditions and their correlation with energy metabolism substrates. A hibernation model of chipmunk was established and researchers completed the samples collection at consecutive time points of chipmunk hibernation and the analysis of the transcriptome data of brain tissue, as well as sorted out the possible molecular mechanisms underlying the rhythmic changes in the formation of hibernation bouts. Researchers also investigated the hypometabolic state induction techniques on non-hibernating rats, such as fasting, hypothermia, and drugs, and successfully induced golden gophers and rats into a hypome-tabolic state in spring and summer, respectively.

3 Large-scale Experiments and Major Projects

3.1 Long-term Head-down Bed Rest Weightlessness Simulation Experiment

The 90-day long-term head-down bed rest experiment (HDBR) is China’s first large-scale long-term mission simulation experiment to study the effects of weightlessness and the countermeasures on human body. In 2019, the experiment was led by Li Yinghui, Wang Linjie, Qu Lina. from Astronaut Center of China with more than 20 domestic scientific research institutes involved. 36 male volunteers were recruited to participate in the experiment, who were divided into the bed rest control group, the comprehensive countermeasure-I group, the comprehensive countermeasure-II group, space treadmill exercise group and the resistance exercise group.

During the 90-day head-down bed rest experiment, temporal change data of 9830 times were obtained regarding the participants’ basic physiology. It includes the indicators from cardiovascular system, musculoskeletal system, psychological assessment, nutritional status and other systems. It is the first time in China that the experiment accumulated the objective data on the physiological and psychological changes and adaptive characteristics of the human body under long-term simulation conditions of weightlessness. It improves the understanding of the main physiological characteristics of the human body changes in long-term simulated weightlessness. The experiment promotes China’s capability of mastering the countermeasure efficacy of the single resistance exercise and space treadmill exercise, which verifies the rationality and effectiveness of the two comprehensive countermeasure protocols against weightlessness, the weightlessness countermeasure evaluation index system and evaluation protocol, and the post-flight recovery protocol that is mainly based on exercise therapy, therefore, providing important data support for countermeasure against physiological effects of weightlessness in long-term spaceflight missions and other astronauts’ health counter-measure technology development.

3.2 Long-term Confinement and IsolationEnvironment Experiment (“Space-180” Experiment)

The 4-person 180-day controlled ecological life support system (“Space-180” experiment) based medical research projects continue to yield scientific findings and publications. Analysis of blood cell DNA methylation, metabolic and biochemical group data revealed the correlation between human DNA methylation and biochemical and psych-physiological phenotypes, including perturbations in glucose metabolism and emotional states. Feng Qiang. showed that in the simulated space environment, human microecology is affected by circadian rhythm and other factors under the overall stable state, the correlation analysis between microecology and plasma metabonomics shows that the ratio of phosphatidylcholine (PC): phosphatidylamide (PE) plays an important role in the regulation of intestinal inflammation[24]. Dong Haisheng. showed that the unique isolation process could lead to a loss of alpha diversity and a transition of enterotypes between Bacteroides and Prevotella[25]. The study from Yuan Ming and the colleagues in ACC and CNES suggests the need for countermeasures to prevent increased carotid intima-media thickness (IMT) and endothelial deconditioning[26]. Chen Hailong. found that serum protein levels were changed,total protein, globulin and bilirubin exhibited chronic acclimatization[27]. Psychological study by Wu Ruilin. and the colleagues in ACC identified that leadership had a positive effect on the group climate by clarifying tasks and reducing aggression and the various functions of perceived leadership roles could be explained by crew composition and occupational features[28, 29].

3.3 National Instrumentation Program of China

The real-time, dynamic, comprehensive and in-orbit analysis of space medical body fluid sample is of crucial importance to the in-flight monitoring and assessment of health risks and the acquirement of new knowledge in space medicine. The project “development and application of space medical body fluid research equipment” in the framework of the national instrumentation program of China was successfully completed by Li Yinghui and her colleagues. The project integrated microfluidics, MEMS, nano technology and other advanced technologies to overcome a series of key technologies for space-based application, and a body fluid sample pre-processing and multi-indicator real-time testing equipment has been developed to further accommodate the space environment application. The equipment integrates six independent functional modules, including sample pre-processing module, protein detection module, semi-antigen detection module, virus nucleic acid detection module, nucleic acid epigenetic information detection module and blood cell characterization analysis module. It can automatically, in a fully enclosed way, achieving the multi-target cell typing tests of the protein, small molecule semi-antigen, virus nucleic acid, microRNA, DNA methylation and so on, in blood, urine, saliva and other body fluid samples, which will provide core equipment support for the Chinese Space Station.

4 Conclusion

The Chinese Space Station provides a broader platform for space medicine research and its discipline development. The implementation of research projects in the field of space medical experiments and the increasing advancement of ground-based basic research will continue to improve the understanding of the impact of the space environment on human health. Noteworthily, the progress of relevant theories and related technologies will not only pave the way for mankind to march into deep space, but also facilitate the development of medicine to serve the public health, make contributions to the economy and society, and be beneficial to the future.

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DING Bai, LIU Zhaoxia, Lü Ke, LING Shukuan, LIU Yue, XU Zi, LI Yinghui. Progress of Space Medicine Research in China., 2020, 40(5): 920-927. DOI:10.11728/cjss2020.05.920

September 8, 2020

E-mail: yinghuidd@vip.sina.com