A policy of anticipation as a strategic objective of space biology and medicine at the present stage

This article reflects the ongoing debates in Russia regarding paths of innovative development and the role that fundamental science has played in the development of technology critical for national security and for its breakthrough potential. Alternative routes of technical development include variations in priority support for those points of growth, in which Russia has attained and steadily held the leading position, occupying a prominent place in the international division of labor. Russia’s space program is a good example of the successful implementation of a national program and provides a demonstration of the country’s leadership role in this area of human activities. This article presents an analysis of the factors and circumstances in Russia that predetermined, in the early, “Gagarin” period of piloted space flights, its winning of the leading position. They also determined the vector of the development of manned space flight for many years to come. Even taking into account the host of issues with the implementation of the International Space Station (ISS) utilization program and the planning of manned flights to the Moon and Mars, the unique experience of preparations and the conducting of research and tests with humans in space—the enormous groundwork in fundamental biomedical research over the past 50 years of piloted flights—provides the basis for an optimistic prognosis for gaining headway with essentially new, ambitious space projects. The key question is whether the proactive strategy of prioritized development and the affirmation of the role of manned space flights as the most integrated and science-intensive sector of innovative achievement will be realized. The development of the space industry depends upon the answer, not only at the present stage but in the long-term as well, as does the fate of the national fundamental space sciences, an integral part of which is space biomedicine.     

Medical care for Russian cosmonauts on board the ISS

Established with the personal participation of O.G. Gazenko, the Russian system of medical care for cosmonauts has been largely preserved to this day. The system was fully functional on board the orbital complex Mir and, with appropriate modifications, has been adopted as the core of the medical care for Russian members of ISS crews. In 2000–2008, 22 cosmonauts were members of 17 ISS missions lasting from 140 to 216 days. The main functions of the medical care system were to control health, physical, and mental performance, and to support space research. Readaptation to normal gravity was, in most cases, similar to what has been typical on the return from Russian orbital stations; some deviations are accounted for by the use of in-flight countermeasures. The paper presents some aspects of the theoretical work of Academician Gazenko in the field of medical care in space flights. It outlines the principles of ISS medical management. The integrated medical support system combines medical equipment and items available in the Russian and U.S. segments; the integrated medical group consists of flight surgeons, medical experts, and biomedical engineers of international partners and coordinates the planning and implementation of medical operations. In addition, challenges of health care in the phase of ISS operation are defined.     

BIOPACK: the ground controlled late access biological research facility

Future Space Shuttle flights shall be characterized by activities necessary to further build the International Space Station, ISS. During these missions limited resources are available to conduct biological experiments in space. The Shuttles' Middeck is a very suitable place to conduct science during the ISS assembly missions or dedicated science missions. The BIOPACK, which flew its first mission during the STS-107, provides a versatile Middeck Locker based research tool for gravitational biology studies. The core facility occupies the space of only two Middeck Lockers. Experiment temperatures are controlled for bacteria, plant, invertebrate and mammalian cultures. Gravity levels and profiles can be set ranging from 0 to 2.0 x g on three independent centrifuges. This provides the experimenter with a 1.0 x g on-board reference and intermediate hypogravity and hypergravity data points to investigate e.g. threshold levels in biological responses. Temperature sensitive items can be stored in the facilities' -10 degrees C and +4 degrees C stowage areas. During STS-107 the facility also included a small glovebox (GBX) and passive temperature controlled units (PTCU). The GBX provides the experimenter with two extra levels of containment for safe sample handling. This biological research facility is a late access (L-10 hrs) laboratory, which, when reaching orbit, could automatically be starting up reducing important experiment lag-time and valuable crew time. The system is completely telecommanded when needed. During flight system parameters like temperatures, centrifuge speeds, experiment commanding or sensor readouts can be monitored and changed when needed. Although ISS provides a wide range of research facilities there is still need for an STS-based late access facility such as the BIOPACK providing experimenters with a very versatile research cabinet for biological experiments under microgravity and in-flight control conditions.     

Comparative efficiency of different regimens of locomotor training in prolonged space flights as estimated from the data on biomechanical and electromyographic parameters of walking

Biomechanical and electromyographic characteristics of locomotion were studied before and after a space flight on days 3, 7, and 10 after landing in 18 participants of prolonged space missions on board the International Space Station. It has been shown that microgravity causes significant changes in biomechanical and electromyographic characteristics of walking, such as a decrease in the amplitude of angular displacement in leg joints, a decrease in the double step length, and an increase in the electromyographic costs of locomotion. It has been also shown that interval locomotor physical training, such as alternation of running and walking, in prolonged space flights prevents an increase in the physiological costs of locomototions after a space flight and provides more efficient maintenance of the neuromuscular system’s performance after a flight. Cosmonauts who performed interval locomotor training had fewer changes in biomechanical and electromyographic characteristics of walking.     

Cytogenetic studies of blood lymphocytes of cosmonauts after long-ter, space flights

An analysis was performed of unstable chromosomal aberrations in peripheral blood of 36 cosmonauts after long-term space missions on "Mir" orbital station. 25 cosmonauts were examined before their flights to score spontaneous yields of cytogenetical damage. In all cases the doses absorbed by crews during space flights did not exceed permissible levels of irradiation, adopted for cosmonauts. The frequencies of chromosomal-type aberrations after space missions were found to increase significantly compared to the pre-flight levels. The yields of dicentrics and centric rings on the average were as high as 0.12 +/- 0.02 and 0.47 +/- 0.06% before and after the 1st flight, 0.18 +/- 0.05 and 0.71 +/- 0.11% before and after the 2nd flight respectively. During the inter-flight periods, usually lasted 1.5-2 years, the yields of chromosome damage lowered, but did not reach their spontaneous values. After each next flight the yields of chromosome aberrations increased again. The cytogenetical damage detected in cosmonauts' peripheral blood lymphocytes after chronic action of low doses of space radiation points out a possible increase in risks of stochastic effects in distant future for crews after long-term space missions.     

Parameters of the innate and adaptive immunity in cosmonauts after long-term space flight on board the international space station

The results of the study of the innate and adaptive immunity indicators in 12 cosmonauts who took part in long-term (128–215 days) expeditions on board the International Space Station (ISS) are presented. It was shown that the space flight may lead to deviations in the human immune system. A decrease in the functional activity of phagocytes, NK and T-cells, as well as in the ability of immunocompetent cells to synthesize cytokines were observed. Significant individual changes were observed in the immune system’s response to a long-term space flight, which indicated an individual’s predisposition to the development of immune reactivity disorders under varying gravitation conditions.     

Preparing normal tissue cells for space flight experiments

Deterioration of health is a problem in modern space flight business. In order to develop countermeasures, research has been done on human bodies and also on single cells. Relevant experiments on human cells in vitro are feasible when microgravity is simulated by devices such as the Random Positioning Machine or generated for a short time during parabolic flights. However, they become difficult in regard to performance and interpretation when long-term experiments are designed that need a prolonged stay on the International Space Station (ISS). One huge problem is the transport of living cells from a laboratory on Earth to the ISS. For this reason, mainly rapidly growing, rather robust human cells such as cancer cells, embryonic cells, or progenitor cells have been investigated on the ISS up to now. Moreover, better knowledge on the behavior of normal mature cells, which mimic the in vivo situation, is strongly desirable. One solution to the problem could be the use of redifferentiable cells, which grow rapidly and behave like cancer cells in plain medium, but are reprogrammed to normal cells when substances like retinoic acid are added. A list of cells capable of redifferentiation is provided, together with names of suitable drugs, in this review.     

Detection of Renal Tissue and Urinary Tract Proteins in the Human Urine after Space Flight

The urine protein composition samples of ten Russian cosmonauts (male, aged of 35 up to 51) performed long flight missions and varied from 169 up to 199 days on the International Space Station (ISS) were analyzed. As a control group, urine samples of six back-up cosmonauts were analyzed. We used proteomic techniques to obtain data and contemporary bioinformatics approaches to perform the analysis. From the total number of identified proteins (238) in our data set, 129 were associated with a known tissue origin. Preflight samples contained 92 tissue-specific proteins, samples obtained on Day 1 after landing had 90 such proteins, while Day 7 samples offered 95 tissue-specific proteins. Analysis showed that consistently present proteins in urine (under physiological conditions and after space flight) are cubilin, epidermal growth factor, kallikrein-1, kininogen-1, megalin, osteopontin, vitamin K-dependent protein Z, uromodulin. Variably present proteins consists of: Na(+)/K(+) ATPase subunit gamma, β-defensin-1, dipeptidyl peptidase 4, maltasa-glucoamilasa, cadherin-like protein, neutral endopeptidase and vascular cell adhesion protein 1. And only three renal proteins were related to the space flight factors. They were not found in the pre-flight samples and in the back-up cosmonaut urine, but were found in the urine samples after space flight: AFAM (afamin), AMPE (aminopeptidase A) and AQP2 (aquaporin-2). This data related with physiological readaptation of water-salt balance. The proteomic analysis of urine samples in different phases of space missions with bioinformation approach to protein identification provides new data relative to biomechemical mechanism of kidney functioning after space flight.     

Dynamics of the body liquids and composition in long-duration space flight (Bioimpedance Analysis)

Bioimpedance measurement was used to study dynamics of human hydration status and body composition on board the International space station (ISS). At different stages of 100- to 200-day flights of 12 cosmonauts, the volume of their body liquid was reduced: the overall, intra-, and extracellular volumes became on average 5.2 to 10.4% less per group as compared to the baseline level. The in-flight changes in the body composition of the cosmonauts were also consistent: while the lean mass loss determined by impedance measurement was insignificant (on average, from 1.9 to 4.0%), the gain of the fatty mass ranged from 4.6 to 8.2% during the first three months of the flight. Thus, hydration of a human body decreased during the long-term space flight, which was accompanied by reduction of the muscular mass and the gain in fatty mass.     

Effect of space flight factors on health of cosmonauts in the near and late term after space flights

Cytogenetical studies of cosmonauts' peripheral blood lymphocytes after space flights on MIR orbital station showed a statistically significant increase in the yields of radiation-induced chromosomal aberrations. However, similar studies with in vitro irradiation of biological objects with accelerated charged particles are of great importance for elucidation of the nature of cytogenetical damage induced in vivo. It is also important to investigate the structure of cosmonatus' diseases over their life, in particular, lens opacities and oncological diseases. Thus, the purpose of the investigations planned is to study cytogenetical damage in blood lymphocytes from cosmonauts after space flights on the ISS in vivo, as well as in donor blood lymphocytes after in vitro exposure to accelerated charged particles. The tasks of the project are as follows: determination of the yields and types of chromosomal aberrations in cosmonauts' blood lymphocytes before and after space flights, comparative studies of biological effects induced in vitro by different types of ionizing radiation in human blood lymphocytes in ground experiments, assessment of cytogenetical risks, analysis of the structure of cosmonatus' diseases comparing with that of whole population, study of the mortality and frequency of cataracts and oncological diseases in cosmonauts. The results to be obtained will be used for setting of health norms applied to the influence of radiations of different types, and for elaboration of measures to reduce health risks from space flight factors.     

Reflex response changes during hyper and microgravity

This paper reports the quantitative evaluation of the H-reflex exhibited by parabolic flight with exposure to micro and high-gravity. With respect to previous findings in parabolic flights and short-term space missions, the analysis focused on reflex activity in weightlessness. The aim of this study was to investigate the effect of gravity on H-reflex and motor evoked potentials (MEP) in soleus muscle (SOL) during parabolic flight.     

Current problems of space cardiology

The development of space cardiology is considered, from the first flights of animals and humans to the studies conducted on board International Space Station (ISS). The material is recounted in four sections in accordance with the theoretical statements presented in the book “Space Cardiology” (1967). The first section is analysis of rearrangement of blood circulation under the conditions of microgravity. Long-term microgravity has been demonstrated to require mobilization of additional functional reserves of the body. During the first six months of the flight, the cardiovascular homeostasis is supported by the regulatory mechanisms of the blood circulation system, whereas in the case of a more prolonged impact of microgravity, intersystem control is actively involved (suprasegmental divisions of autonomic regulation). In the second section dealing with the roles of the right and left divisions of the heart in adaptation to microgravity of the cardiovascular system, the important role of the right heart at the initial stage of a space flight (SF) is emphasized. The third section addresses the problem of reducing the orthostatic stability; this study has been initiated as early as the first manned space flights. The results obtained on board ISS testify to the importance of evaluating the functional reserves of the blood circulation system. The fourth section presents data on the new methods of myocardial examination that are to be soon introduced into SF medical provision. In conclusion, some new projects in space cardiology are discussed.     

Simulations of the MATROSHKA experiment at the international space station using PHITS

Concerns about the biological effects of space radiation are increasing rapidly due to the perspective of long-duration manned missions, both in relation to the International Space Station (ISS) and to manned interplanetary missions to Moon and Mars in the future. As a preparation for these long-duration space missions, it is important to ensure an excellent capability to evaluate the impact of space radiation on human health, in order to secure the safety of the astronauts/cosmonauts and minimize their risks. It is therefore necessary to measure the radiation load on the personnel both inside and outside the space vehicles and certify that organ- and tissue-equivalent doses can be simulated as accurate as possible. In this paper, simulations are presented using the three-dimensional Monte Carlo Particle and Heavy-Ion Transport code System (PHITS) (Iwase et al. in J Nucl Sci Tech 39(11):1142–1151, 2002) of long-term dose measurements performed with the European Space Agency–supported MATROSHKA (MTR) experiment (Reitz and Berger in Radiat Prot Dosim 120:442–445, 2006). MATROSHKA is an anthropomorphic phantom containing over 6,000 radiation detectors, mimicking a human head and torso. The MTR experiment, led by the German Aerospace Center (DLR), was launched in January 2004 and has measured the absorbed doses from space radiation both inside and outside the ISS. Comparisons of simulations with measurements outside the ISS are presented. The results indicate that PHITS is a suitable tool for estimation of doses received from cosmic radiation and for study of the shielding of spacecraft against cosmic radiation.     

Comparative analysis of preventive efficacy of different modes of locomotor training in space flight

According to the results of the experiment performed on board the International Space Station with participation of 15 Russian cosmonauts, comparative analysis of efficacy of two models of preventive measures used by the Russian members of long-term space missions is carried out: intense interval training in the aerobic–anaerobic power zone (recommended model) and continuous low-intensity exercises in the aerobic power zone of muscle activity energy supply. Interval training in space flight provided the maintenance of the level of physical performance close to the pre-flight level as indicated by the maximum running speed, physiological value of work, and the lactate level after performing the standard load. We describe putative mechanisms of counteraction to adaptive rearrangement of the propulsion system in zero gravity and expand understanding of the laws governing human body’s interaction with Earth’s gravitational field. The research results presented in this paper show the high preventive efficacy of interval training compared with regular aerobic training, which is very important now in the time of searching for means and methods of prevention of hypogravitational alterations during interplanetary missions.     

Historical aspects of the early Soviet/Russian manned space program.

Human spaceflight was one of the great physiological and engineering triumphs of the 20th century. Although the history of the United States manned space program is well known, the Soviet program was shrouded in secrecy until recently. Konstantin Edvardovich Tsiolkovsky (1857-1935) was an extraordinary Russian visionary who made remarkable predictions about space travel in the late 19th century. Sergei Pavlovich Korolev (1907-1966) was the brilliant "Chief Designer" who was responsible for many of the Soviet firsts, including the first artificial satellite and the first human being in space. The dramatic flight of Sputnik 1 was followed within a month by the launch of the dog Laika, the first living creature in space. Remarkably, the engineering work for this payload was all done in less than 4 wk. Korolev's greatest triumph was the flight of Yuri Alekseyevich Gagarin (1934-1968) on April 12, 1961. Another extraordinary feat was the first extravehicular activity by Aleksei Arkhipovich Leonov (1934-) using a flexible airlock that emphasized the entrepreneurial attitude of the Soviet engineers. By the mid-1960s, the Soviet program was overtaken by the United States program and attempts to launch a manned mission to the Moon failed. However, the early Soviet manned space program has a preeminent place in the history of space physiology.     

Bone Mineral Density and Molecular Genetic Markers of Bone Remodeling in Blood of Cosmonauts after Long-term Missions on Board the International Space Station

The results of the investigation of the bone system of 24 Russian cosmonauts after long-term (124–199 days) missions on board the International space station (ISS) are presented. Functional adaptation of the bone system involves some complex changes in the metabolic activity of osteoblasts and osteoclasts, such as alterations of the serum concentrations of osteocalcin, tartrate-resistant acid phosphatase (TRAP), osteoprotegerin, and the activator ligand of the receptor of nuclear factor kappa-B (RANKL); in addition, in peripheral blood leucocytes, there are changes in the expression of genes regulating the development of skeletal system and bone mineral metabolism. Significant variability in the mineral density of femoral neck and molecular genetic markers studied after long-term space flights indicates individual variability of the balance of the processes of bone remodeling, bone formation and resorption. Significant bone mass losses in the femoral bone of cosmonauts are associated with more pronounced changes in the markers of metabolic activity of osteoclasts.     

The biological effects of space radiation during long stays in space.

Many space experiments are scheduled for the International Space Station (ISS). Completion of the ISS will soon become a reality. Astronauts will be exposed to low-level background components from space radiation including heavy ions and other high-linear energy transfer (LET) radiation. For long-term stay in space, we have to protect human health from space radiation. At the same time, we should recognize the maximum permissible doses of space radiation. In recent years, physical monitoring of space radiation has detected about 1 mSv per day. This value is almost 150 times higher than that on the surface of the Earth. However, the direct effects of space radiation on human health are currently unknown. Therefore, it is important to measure biological dosimetry to calculate relative biological effectiveness (RBE) for human health during long-term flight. The RBE is possibly modified by microgravity. In order to understand the exact RBE and any interaction with microgravity, the ISS centrifugation system will be a critical tool, and it is hoped that this system will be in operation as soon as possible.     

Effects of long-term space flight on erythrocytes and oxidative stress of rodents

Erythrocyte and hemoglobin losses have been frequently observed in humans during space missions; these observations have been designated as "space anemia". Erythrocytes exposed to microgravity have a modified rheology and undergo hemolysis to a greater extent. Cell membrane composition plays an important role in determining erythrocyte resistance to mechanical stress and it is well known that membrane composition might be influenced by external events, such as hypothermia, hypoxia or gravitational strength variations. Moreover, an altered cell membrane composition, in particular in fatty acids, can cause a greater sensitivity to peroxidative stress, with increase in membrane fragility. Solar radiation or low wavelength electromagnetic radiations (such as gamma rays) from the Earth or the space environment can split water to generate the hydroxyl radical, very reactive at the site of its formation, which can initiate chain reactions leading to lipid peroxidation. These reactive free radicals can react with the non-radical molecules, leading to oxidative damage of lipids, proteins and DNA, etiologically associated with various diseases and morbidities such as cancer, cell degeneration, and inflammation. Indeed, radiation constitutes on of the most important hazard for humans during long-term space flights. With this background, we participated to the MDS tissue-sharing program performing analyses on mice erythrocytes flown on the ISS from August to November 2009. Our results indicate that space flight induced modifications in cell membrane composition and increase of lipid peroxidation products, in mouse erythrocytes. Moreover, antioxidant defenses in the flight erythrocytes were induced, with a significant increase of glutathione content as compared to both vivarium and ground control erythrocytes. Nonetheless, this induction was not sufficient to prevent damages caused by oxidative stress. Future experiments should provide information helpful to reduce the effects of oxidative stress exposure and space anemia, possibly by integrating appropriate dietary elements and natural compounds that could act as antioxidants.     

Animals and spaceflight: from survival to understanding

Animals have been a critical component of the spaceflight program since its inception. The Russians orbited a dog one month after the Sputnik satellite was launched. The dog mission spurred U.S. interest in animal flights. The animal missions proved that individuals aboard a spacecraft not only could survive, but also could carry out tasks during launch, near-weightlessness, and re-entry; humans were launched into space only after the early animal flights demonstrated that spaceflight was safe and survivable. After these humble beginnings when animals preceded humans in space as pioneers, a dynamic research program was begun using animals as human surrogates aboard manned and unmanned space platforms to understand how the unique environment of space alters life. In this review article, the following questions have been addressed: How did animal research in space evolve? What happened to animal development when gravity decreased? How have animal experiments in space contributed to our understanding of musculoskeletal changes and fracture repair during exposure to reduced gravity?     

Immune suppression of human lymphoid tissues and cells in rotating suspension culture and onboard the International Space Station

The immune responses of human lymphoid tissue explants or cells isolated from this tissue were studied quantitatively under normal gravity and microgravity. Microgravity was either modeled by solid body suspension in a rotating, oxygenated culture vessel or was actually achieved on the International Space Station (ISS). Our experiments demonstrate that tissues or cells challenged by recall antigen or by polyclonal activator in modeled microgravity lose all their ability to produce antibodies and cytokines and to increase their metabolic activity. In contrast, if the cells were challenged before being exposed to modeled microgravity suspension culture, they maintained their responses. Similarly, in microgravity in the ISS, lymphoid cells did not respond to antigenic or polyclonal challenge, whereas cells challenged prior to the space flight maintained their antibody and cytokine responses in space. Thus, immune activation of cells of lymphoid tissue is severely blunted both in modeled and true microgravity. This suggests that suspension culture via solid body rotation is sufficient to induce the changes in cellular physiology seen in true microgravity. This phenomenon may reflect immune dysfunction observed in astronauts during space flights. If so, the ex vivo system described above can be used to understand cellular and molecular mechanisms of this dysfunction.