Gravitational Biology - To understand how gravity determines the architecture and function of human cells

Gravity has been a constant force throughout evolutionary history on Earth. Thus, it is one of the fundamental biological questions, if and how life on Earth requires and responds to gravity at the functional cellular and molecular level. In history, Anatomical research elucidated in detail, how the human body is constructed to withstand and to live under the gravity conditions of Earth. Now, we try to understand how the architecture and function of human cells is related to the gravitational force and therefore adapted to live on Earth. Since the 80ties, a lot of evidence has been obtained that the function of mammalian cells and of small unicellular organisms is different under the conditions of microgravity. Consequently, the question arose how normal gravity may play a role in "normal" cellular function and if gravity may provide important signals for the cell. Due to the fact that cells of the immune system are obviously influenced by altered gravity, its gravi-sensitive nature render these cells also an ideal biological model in the search for general gravi-sensitive mechanisms in mammalian cells.

Ullrich O. Thiel C. (2011) Gravitational force – triggered stress in cells of the immune system. In: Stress Challenges and Immunity in Space, Springer, Heidelberg, Germany, 187-202)

Joint division together with the University of Magdeburg, Germany

Team

Introduction

Ground-Based-Studies

Parabolic Flight Missions

Space Missions

Team:

• Prof. Dr. Dr. Oliver Ullrich (UZH/University of Magdeburg)
  

ARES

• Dr. med. Katrin Paulsen, Teamleader Science (UZH/University of Magdeburg)
• Capt. Dr. Marc Studer, Swiss Air Force, MD/PhD student (UZH)
• Eva Hürlimann, MD student(UZH)
• Stephanie Engeli, MD student (UZH)
• Brice Mouttet, MD student (UZH)
• Svantje Tauber, PhD student (UZH)
• Dr. rer. nat. Cora Thiel

Immunolab

• Dr. med. Katrin Paulsen, Head Bioscience, Teamleader Science and Operations (UZH)

Shenzhou 8

• Dr. med. Katrin Paulsen (UZH)
• Dana Simmet, PhD student (UZH/University of Magdeburg)
• Svantje Tauber, PhD student (UZH/University of Magdeburg)

• Nadine Göltz, Diploma student (UZH)

• Josefine Biskup, MD student (UZH)
• Stephanie Engeli, MD student (UZH)
• Eva Hürlimann, MD student(UZH)
• Sandra Hunziker, MD student (UZH)

• Christoph Signer, MD student (UZH)

• Annisja Kramer, MD student (UZH)

• Laura Roose, MD student (UZH)
• Caroline Stern, MD student (UZH)

• Durie Suh, MD student (UZH)

• Anna Wang, MD student (UZH)

• Mirjam Christen, Technical Assistant (UZH)

TripleLux A

• Dr.rer.nat. Cora Thiel, PhD, Head Bioscience, Teamleader Science (UZH/University of Magdeburg)
  
• Dana Simmet, PhD student (UZH/University of Magdeburg
• Josefine Biskup, MD student (UZH)
• Sonja Krammer-Oswald, Technical Assistant (UZH)
• Annett Gutewort, B. Sc. student (University of Magdeburg)
• Mirjam Christen, Technical Assistant

Introduction

With the completion and utilization of the International Space Station and with mission plans to Earth, the Moon and Mars during the first half of our century, astronautics has entered the era of long term space missions. Such long term missions represent a challenge never experienced before: Small or even marginal medical problems could easily evolve to substantial challenges which could possibly endanger the entire mission, complicated by a significant number of severe health risks: Several limiting factors for human health and performance in microgravity have been clearly identified for the musculoskeletal system, the immune system, the cardiovascular system, nutrition and toxicology/pharmacology during spaceflight conditions [1].

Considering these constraints, it has been concluded that substantial research and development activities are required in order to provide the basic information for appropriate integrated risk management, including efficient countermeasures and tailored life support systems [2]. In particular, bone loss during long stays in weightlessness still remains an unacceptable risk for long-term and interplanetary flights [3]. Additionally, serious concerns arose whether spaceflight-associated immune system weakening ultimately precludes the expansion of human presence beyond Earth's orbit [4]. As crew performance is the crucial factor during space missions and since evacuation or exchange of the crew is impossible during interplanetary flights, there is an urgent need to elucidate the underlying mechanism of limiting factors for human health and performance in microgravity and to identify and test potential counteractive interventions. Therefore, understanding the ways gravity changes influence the human body and its cellular architecture and function is an indispensable subject for human space flight.

In this context, decades of research in space medicine and gravitational biology revealed clear evidence that the appropriate function of crucial bone and immune system cell types depend on gravity [5-10]. As a predominant example, cells of the immune system are exceptionally sensitive to microgravity. During the first Spacelab-Missions in 1983, a pioneering discovery by Cogoli et al., where isolated human lymphocytes failed to proliferate after several days in microgravity, provided the first strong evidence of the sensitivity of cells to long-term reduced gravity exposure [5]. Follow-up experiments clearly verified the depression of lymphocyte proliferation activation after mitogenic stimulation in long-term microgravity [6]. A recent study also demonstrated reactivity of lymphocytes to short-term microgravity provided by parabolic flight maneuvers [7]. Cells of the bone metabolism are also clearly extremely sensitive to microgravity: Osteoclastogenesis was stimulated in simulated weightlessness provided by a rotary cell culture system [8] and indirectly by secretion of crucial regulatory factors by osteoblasts [9]. Microgravity directly stimulates osteoclastogenesis and increases bone resorption in the absence of osteoblasts [10], identifying osteoclasts and their precursors as direct targets of gravitational forces. Recently, there is emerging evidence that the immune and skeletal system are tightly linked by cytokine and chemokine networks and direct cell-cell-interactions [11,12]. It has been demonstrated that the immune system influences metabolic, structural and functional changes in bones directly [12]. Both systems share common cellular players such as the osteoclasts, which are bone-resident macrophages and derivatives of monocytic cells. The balance of bone formation by osteoblasts and bone resorption by osteoclasts determines the structure and density of bone tissue.

Therefore, knowing the cellular and molecular mechanisms of how gravity influences bone and immune cells function is an valuable requirement to provide therapeutic or preventive targets for keeping the bone and immune systems of astronauts fully functional during long-term space missions. Having this knowledge or not will ultimately determine whether long-term and interplanetary space flights are an unacceptable risk or a challenging, but realistic option for mankind.

(Introduction in Studer et al. / Ullrich. Acta Astronautica 68 (11-12) : 1729-1741)

References

[1] B. Comet, Limiting factors for human health and performance: microgravity and reduced gravity. In: Study on the survivability and adaptation of humans to long-duration interplanetary and planetary environments; Technical Note 2: Critical assessments of the limiting factors for human health and performance and recommendation of countermeasures. HUMEX-TN-002 (2001).

[2] G. Horneck, R. Facius, M. Reichert, P. Rettberg, W. Seboldt, D. Manzey, B. Comet, A. Maillet, H. Preiss, L. Schauer, C.G. Dussap, L. Poughon, A. Belyavin, G. Reitz, C. Baumstark-Khan, R. Gerzer, HUMEX, a study on the survivability and adaptation of humans to long-duration exploratory missions, part II: Missions to Mars, Advances in Space Research, Mercury, Mars and Saturn 38 (2006) 752-759

[3] G. Horneck, B. Comet, General human health issues for Moon and Mars missions: Results from the HUMEX study, Advances in Space Research, 37 (2006) 100-108.

[4] N. Guéguinou, C. Huin-Schohn, M. Bascove, J.L. Bueb, E. Tschirhart, C. Legrand-Frossi, J.P. Frippiat, Could spaceflight-associated immune system weakening preclude the expansion of human presence beyond Earth's orbit? J Leukoc Biol. 86 (2009) 1027-1038.

[5] A. Cogoli, A. Tschopp, P. Fuchs-Bislin, Cell sensitivity to gravity, Science 225 (1984) 228-230.

[6] A. Cogoli, Gravitational physiology of human immune cells: a review of in vivo, ex vivo and in vitro studies, J Gravit Physiol 3 (1996) 1-9.

[7] K. Paulsen, C. Thiel ,J. Timm, P.M. Schmidt, K. Huber, S. Tauber, R. Hemmersbach, D. Seibt, H. Kroll, K.H. Grote, F. Zipp, R. Schneider-Stock,A. Cogoli, A. Hilliger, F. Engelmann, O. Ullrich, Microgravity-induced alterations in Signal Transduction in Cells of the Immune System, Acta Astronaut 67 (2010) 1116–1125.

[8] R. Saxena, G. Pan, J.M. McDonald, Osteoblast and osteoclast differentiation in modeled microgravity, Ann. NY Acad. Sci. 1116 (2007) 494-498.

[9] N. Rucci, A. Rufo, M. Alamanou, A. Teti, Modeled microgravity stimulates osteoclastogenesis and bone resorption by increasing osteoblast RANKL/OPG ratio, J. Cell Biochem 100 (2007) 464-473.

[10] R. Tamma, G. Colaianni, C. Camerino, A. Di Benedetto, G. Greco, M. Strippoli, R. Vergari, A. Grano, L. Mancini, G. Mori, S. Colucci, M. Grano, A. Zallone, Microgravity during spaceflight directly affects in vitro osteoclastogenesis and bone resorption, FASEB J 23 (2009) 2549-2554.

[11] H. Takayanagi, Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems, Nat Rev Immunol. 7 (2007) 292-304.

[12] J. Caetano-Lopes, J.E. Canhão H. Fonseca, Osteoimmunology--the hidden immune regulation of bone, Autoimmun Rev. 8 (2009) 250-5.

Special Equipment:

• 2D clinostat providing „functional weightlessness“ for cell incubators (developed by German Aerospace Center DLR)
• Hyper-g centrifuge for cell incubators
• Fully equipped cell culture and experiment laboratory for Airbus A300 ZERO-G
  (developed by University of Magdeburg)
  
• System for cell culture experiments on board of the F-5E military fighter jet

Parabolic Flight Missions

What is a Parabolic Flight ?

8th DLR Parabolic Flight Campaign (2006) PROCASIS "Effect of microgravity on membrane proximal and chromatin-associated signal transduction in cells of the immune system" PI: Prof Dr. Dr. Oliver Ullrich
45th ESA Parabolic Flight Campaign (2006) SEGRIS “Signal transduction in human T cells in microgravity: expression and function of chemokines, cytokines and their receptors, epigenetic alterations” PI: Prof. Dr. Dr. Oliver Ullrich, Dr. Augusto Cogoli (ETHZ) Funding: ESA/DLR
9th DLR Parabolic Flight Campaign (2006) PROCASIS-2 "Effect of microgravity on membrane proximal and chromatin-associated signal transduction in cells of the immune system" PI: Prof. Dr. Dr. Oliver Ullrich Funding: DLR
10th ESA Parabolic Flight Campaign (2007) MARS-1 „Effect of microgravity on migration- and adhesion-regulating signal pathways in cells of the immune system” PI: Prof. Dr. Dr. Oliver Ullrich, Prof. Dr. Fengyuan Zhuang (Beijing) Funding: DLR
10th DLR Parabolic Flight Campaign (2007) CEMIS (Cell Migration in Space): “Effect of microgravity on the cytoskeleton and calcium signalling of immune cells during cell migration” PI: PD Dr. Kerstin Lang (Witten/Herdecke), Prof. Dr. Dr. Oliver Ullrich Funding:DLR
13th DLR Parabolic Flight Campaign (2009) MICOS-1: “Molecular, cellular and functional effects of microgravity on immune control of the central nervous system, part 1” PI: Prof. Dr. Dr. Oliver Ullrich, Dr. Cora Thiel Funding: DLR
13th DLR Parabolic Flight Campaign (2009) PHOX: “Short-term influences of altered gravity on the kinetics of phagocyte’s oxidative burst using the TRIPLE-LUX A PMT-clinostat for reference experiments” PI: Dr. Kathrin Huber, Astrid Horn, Prof. Dr. Dr. Oliver Ullrich Funding: DLR
14th DLR Parabolic Flight Campaign (2009) CLARA (Osteoclasts in Space): “Effect of microgravity on osteoclast regulation and activation” PI: Dr. Meliha Karsak, Prof. Dr. Dr. Oliver Ullrich Funding: DLR
51st ESA Parabolic Flight Campaign (2009) PHOX-2: “Short-term influences of altered gravity on the kinetics of phagocyte’s oxidative burst using the TRIPLE-LUX A PMT-clinostat for reference experiments” PI: Dr. Kathrin Huber, Astrid Horn, Prof. Dr. Dr. Oliver Ullrich Funding: DLR
16th DLR Parabolic Flight Campaign (2010) MICOS-2: “Molecular, cellular and functional effects of microgravity on immune control of the central nervous system, part 2” and “Validation of microgravity experiments during parabolic manoeuvres of the military fighter jet Northrop F5-E (Aircraft-Based-Reduced-Gravity-Experimental System project, acronym: ARES)“ PI: Prof. Dr. Dr. Oliver Ullrich Co-I: Dr. Gesine Bradacs, Dr. Cora Thiel, Capt. Marc Studer (Swiss Air Force) Funding: DLR
ARES (Aircraft-Based-Reduced-Gravity-Experimental System) Parabolic Flights using Northrop F-5E military fighter jet Joint project between UZH, Swiss Air Force and RUAG Aviation PI: Prof. Dr. Dr. Oliver Ullrich Co-I: Dr. Gesine Bradacs, Capt. Marc Studer (Swiss Air Force)
19th DLR Parabolic Flight Campaign (2012) SITI-3: Signal transduction in cells of the immune system. PI: Prof. Dr. Dr. Oliver Ullrich Co-I: Dr. Cora Thiel, Liliana Layer, Dr. Katrin Paulsen Funding: DLR

Ground-Based-Studies

• ESA-AO-2005-005 “Effect of vector-averaged gravity on signal transduction and epigenetic gene regulation in cells of the immune system“, European Space Agency (ESA), 2007-2008,
  PI: Prof. Dr. Dr. Oliver Ullrichl
• Systematic Evaluation of the ground based (micro-) gravity simulation paradigms available in Europe. First Phase (SEGMGSPE Ph1), 2009-2010,
  WP Leader: Prof. Dr. Dr. Oliver Ullrich,Dr. Susanne Wolf, Dr. Gesine Bradacs
• “Cellular and molecular mechanisms of gravisensitivity in human cells”, Sino-Swiss Science and Technology Cooperation Program (SSSTC), IP04-092008, 2010-2012, PI: Prof. Dr. Dr. Oliver Ullrich und Prof. Dr. Chun Yang, Beijing University of Aeronautics and Astronautics and Tsinghua University, Beijing

Space Missions

Sounding Rockets: “Signal Transduction in Cells of the Immune System” (Acronym: SITI-1) PI: Prof. Dr. Dr. Oliver Ullrich, Dr. Cora Thiel Flight assignment: TEXUS-49 Launch: 29.03.2011, 06:01 a.m. Funding: DLR

http://www.promocell.com/rocket-launch http://www.mdr.de/mdr-um-zwoelf/8435410.html http://idw-online.de/pages/de/news415613 “Signal transduction in human T cells in microgravity: expression and function of chemokines, cytokines and their receptors, epigenetic alterations” (ESA-AO-2004-010) PI: Dr. Augusto Cogoli, WP Leader: Prof. Dr. Dr. Oliver Ullrich Flight assignment: MASER-12 Launch: 13.02.2012, 09:32 UTC Funding: ESA, DLR Funding: ESA, DLR

International Space Station (ISS)

• “Phagozytose als Biomarker für Immuntoxizität“ im Experiment “TRIPLE-LUX”,
  PI: Prof. Dr. Dr. Oliver Ullrich, Dana Simmet, Dr. Gesine Bradacs im ESA-Experiment “Gene, immune and cellular responses to single and combined Space flight conditions (Acronym: TRIPLE LUX, Prof. Dr. Bertold Hock),
  Experiment ID: 96-HEDS-04/05-101, German Aerospace Center DLR.
  Status: Flight Readines Review. Launch: tbd.
• „Function, Adaptation and Re-Adaptation to Altered Gravity in Cells of the Immune System”,
  Acronym: FARAGIS, (ESA, ILRSA-2009-1045),
  Coordinator: Prof. Dr. Dr. Oliver Ullrich, (University of Zurich, University of Magdeburg).
  Science Team Members: Dr. Isabelle Walther (ETH Zurich), Dr. Marcel Egli (ETH Zurich), Prof. Dr. Ludmila Buravkova (IMBP, Russian Academy of Sciences, Moscow), Prof. Dr. Millie Hughes-Fulford (University of California), Prof. Dr. Meliha Karsak (University of Ulm)

Shenzhou-8 Spaceship Mission:

• Project “Innate Immunity in microgravity” (Acronym: SITI-1), SHENZHOU-8 Space Ship Mission,
  PI: Prof. Dr. Dr. Oliver Ullrich. German Aerospace Center DLR and China Manned Space Engineering Office (CMSEO)
  Launch: 01.11.2011, 05:58 CT
  Landing: 17.11.2011, 20:38 CT

Immune surveillance of the central nervous system

Immune surveillance of the central nervous system

During the last decades of neurobiological research, it has become clear that inflammatory reactions in the CNS, which result from a loss of control and involve a network of non-neuronal and neuronal cells, contribute significantly to the onset and progress of several major neurodegenerative diseases. On the other hand, constant immune surveillance is indispensable for neuroprotection and neurorepair, in particular during pathological conditions. To avoid inflammatory escalation, the CNS harbours an impressive arsenal of cellular and molecular mechanisms enabling strict control of immune reactions – the so-called “immune privilege”. In the last years, several in vitro, in vivo and clinical studies suggested that the endocannabinoid system participate crucially in CNS immune control and neuroprotection, therefore playing an important role in the cellular network of communication in and between the nervous and immune system during neuroinflammation and neuronal damage. In our research projects, we aim to elucidate the cellular and molecular mechanisms, how the endocannabinoid system controls and modulates CNS immune systems and how it is related and involved in inflammation, neurodegeneration, neuroprotection and neurorepair.

Gravitational and Space Biology