Non-exhaustive list of research fields in microgravity.
\r\n\tDNA is responsible for carrying all the information an organism needs to survive, grow and reproduce. However, during its lifetime an each organism experiences a wide range of cases with DNA damages; therefore the DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Mutagenesis is known as an important factor which may lead to different disorders, disabilities and diseases. Any defect in DNA repair system may lead to the death of the organism.
\r\n\r\n\t
\r\n\tRecognition of these items in different organisms drives us to know more about the characteristics of DNA repair systems in different types of organisms. Hopefully, this book will offer an interesting read by introducing, explaining and comparing these diversities.
Locating at the outermost layer of the skin, the epidermis plays a critical role protecting our body against environmental pathogens and insults by forming a physical and immunological barrier. This protective role of skin epidermis is manifested by extensive cytoskeletal architecture, and keratins represent its principle structural protein, contributing to 30–80% of the total protein and forming the major intermediate filament cytoskeleton of the epidermis. Since keratin family proteins were initially characterized based on their mobility on 2D SDS-PAGE back in 1980s, more than 50 mammalian keratins have been identified and characterized. Keratins can be sub-classified into two distinct classes: Type I keratins, including K9–K40, are relative acidic (pKi = 4.5–5.5) and small (40–56.5 kDa) whereas type II keratins, including K1–K8 and K71–86), are more basic (pKi = 5.5–7.5) and larger (53–67 kDa) [1, 2, 3]. The active keratin genes are clustered into two dense region of the chromosome: all type II keratins plus one type I keratin (K18) are located on chromosome 12q, and the remaining type I keratins are all on chromosome 17q. Despite the fact that type I and type II keratins are located at distinct region of the chromosome, they show beautifully specific patterns of gene expression within adjacent epidermal cell layers and a specific pair of keratins are usually co-expressed as a heterodimer between one acidic (type I) and one basic (type II) keratin [4]. These keratin heterodimers self-assemble into antiparallel, staggered tetramers, yielding intermediate filament through lateral and longitudinal interactions [4].
The primary function of the keratin intermediate filament cytoskeleton is to provide cells with structural resilience against mechanical trauma, and this is especially important for epidermal cells because as the outermost barrier tissue the epidermis has to have the ability to resist some of the most severe physical stress levels experienced by any human tissue. The basic structural organization of keratin intermediate filaments contains four helical or coiled-coil segments flanked by N- and C-terminal glycine rich sequence. And most disease-causing mutations occur in the well-conserved coiled-coil domains of keratins, leading to disruption of secondary structure formation between the heterodimer and the subsequent aggregation of the keratin filaments. In addition to structural and mechanical support, cell-specific keratin expression also modulates growth, adhesion, migration and invasion of epithelial cells. Thus, dysfunction or mutations of keratin proteins are associated with a remarkable variety of skin disorders, such as skin blistering, inflammatory disorders and skin tumors. So far more than 100 different disorders (termed as keratinopathies) have been linked to inherited keratin changes (
In this chapter we will first describe how keratins are normally expressed and regulated during epidermal development and in adult homeostasis, then we will describe how mutation or abnormal expression or modification of keratin proteins are associated with various skin diseases, and their function and regulatory mechanisms during disease pathogenesis. Keratin mutations and related diseases in skin appendages, including hair and nail, will not be reviewed here.
The barrier function of epidermis is mainly provided by keratinocytes (KC), the predominant cell type in the epidermis, and it is maintained by a tightly controlled balance between proliferation and differentiation of KC [5, 6]. As shown in Figure 1, the murine epidermal development begins at embryonic day (E) 8.5 from a single layer of progenitor cells that express keratin pair K8–K18, and around E 9.5 these progenitor cells are specified to an epidermal cell fate and switch to express a different pair of keratins, K5–K14 [7, 8, 9, 10]. Between E 10.5–E15.5, the committed KC begin a process of upward stratification and differentiation leading to the generation of suprabasal cells, in which cell cycle is arrested and early differentiation program is initiated and K5/K14 are substituted by K1 and K10. Studies have suggested that the ectopic expression of K10 inhibits cell cycle progression and proliferation and thus promotes terminal differentiation of keratinocytes [11, 12]. At E 16.5, the suprabasal KC commit to terminal differentiation and continue to migrate upward forming the granular layer, and these granular KCs express late differentiation markers, such as Filaggrin (FLG), Loricrin (LOR) and Involucrin (INV). By E 18.5, epidermis becomes fully mature, and terminally differentiated KCs become enucleated corneocytes forming the outer most cornified layer with complete barrier function.
Overview of keratin expressions during different stage of mouse epidermal development. Murine epidermis develops from a single layer ectodermal keratinocyte (KC) progenitor cells which commit to an epidermal fat around embryonic day 8–9 (E 8–9). These KC progenitors express simple epithelia cell marker keratin pair of K18-K8. Around E 10.5 and the expression of K18/K8 starts to be substituted by K14/K5 in the committed KC, and stratification process starts leading to the formation of suprabasal cells. Around E15.5, early differentiation starts in the spinous/suprabasal layer (SL) and K10/K1 are expressed in the differentiated suprabasal cells while the expression of K14/K5 is restricted to basal layer (BL). At E16.5, suprabasal cells committed to terminal differentiation move upwards to form granular layer (GL) and K10/K1 expression are replaced by late differentiation markers. Finally cornification starts around E 16.5–17.5 and by E 18.5 epidermis becomes fully mature with intact cornified layer and complete barrier function.
Note that K15 is an additional type I keratin protein co-expressed with K5/K14 in the basal keratinocytes of stratified epithelia and in the bulge in hair follicles [13], and K2 is an additional type II keratin protein co-expressed with K1/K10 in the differentiated keratinocytes [14]. Although K15 or K2 are generally considered as minor keratins, but the ratio of K15 to K14 or K2 to K1 can vary dramatically during development or upon disease condition at different skin sites [15]. In adult skin, K15 expression is restricted to hair follicle stem cells [16, 17]. This cell-stage specific expression pattern of keratins is precisely maintained through postnatal development and adulthood under homeostatic condition in both human and mouse skin epidermis. Therefore K5 and/or K14 are highly specific markers for basal proliferative KC, K15 is generally used as a marker for epithelial stem cells in the hair follicle bulge, and K1 and/or K10 have been robustly used to mark KC in the early differentiation stage (Figure 2).
Expression of K14 and K10 in adult human skin epidermis. (A). H&E staining of adult human skin epidermis showing distinct epidermal layers including basal layer (BL), spinous (suprabasal) layer (SL), granular layer (GL) and cornified layer (CL). The dashed line marks the epidermal-dermal junction. Boxes on the right panel indicate the location of K14 and K10 expression in distinct epidermal layers. While K14 is restricted to cells in the basal layer, K10 is induced in early differentiated cells at the spinous layer and is maintained through all differentiated layers. Scale bar = 20 μm. (B-C). Adult human skin epidermis was immunostained by antibody specific for K14 (green in B) or K10 (red in C). Zoom-in pictures highlighted in white box are shown to illustrate distinct localization of K14 and K10 in skin epidermis. Scale bars = 100 μm.
Keratin synthesis is regulated at the level of transcription by a characteristic constellation of transcription factors. Regulatory mechanisms for the expression of K5 and K14, the key keratins forming the cytoskeletal IF network in mitotically active basal cells, have been extensive studied. Studies have shown that the promoter activities of K5 and K14 genes are collaboratively regulated by several transcription factors, including AP1, AP2, NFκB, Skn-1a, Tst-1, RAR (nuclear receptor for retinoic acid), T3R (receptor for thyroid hormone), GR (glucocorticoid receptor) and coactivator CBP/p300 in response to many extracellular signals, such as growth factor, vitamins (retinoic acid/VitA), thyroid hormone, or glucocorticoids [18, 19, 20, 21, 22] .
The expression of K1 and K10 is upregulated during early differentiation process. Forced expression of transcription factor C/EBPβ in keratinocytes arrested growth and induced the expression of K1 and K10 but had a minimal effect on the expression of late differentiation markers [23]. In consistent, Cebpb-deficient mice had reduced levels of K1 and K10 but not of Lor or Inv, suggesting that C/EBPβ modulates K1 and K10 expression during early events of keratinocyte differentiation. Other transcription factors, such as C/EBPα and AP2 are also required for K10 expression during differentiation [24]. Therefore, C/EBPβ, C/EBPα and AP2 are considered the differentiation-associated transcription factors controlling early differentiation process of keratinocytes. We have shown previously that in cultured primary mouse basal keratinocytes, while elevating extracellular calcium robustly triggers stratification and the expression of late differentiation markers, K10 expression is only moderately increased by high calcium [6, 25]. In contrast, growth factor depletion/starvation strongly induced K10 expression [6, 25], suggesting that growth arrest but not high calcium is the key signal to turn on K10 expression. Indeed, studies have shown that C/EBPβ expression localizes in the upper differentiated layers of human skin epidermis [26] and C/EBP family of transcription factors inhibit proliferation by blocking cell cycle progression [27, 28]. Therefore it is possible that growth factor depletion condition in culture induces and activates C/EBPs which in turn trigger cell cycle arrest and induction of K10 gene.
K8 and K18 are the keratin pair that is expressed earliest during embryonic development of the epidermis and their expressions are suppressed upon epidermal progenitor cells commitment to keratinocyte lineage [8, 29]. Several transcription factors, such as p63, Ovol2 and Ctip2, have been shown to suppress K8 expression during epidermal development [6, 9, 30]. It has been shown that developing murine p63−/− epidermis expressed high level of K8 and failed to develop a fully mature stratified epidermis [9], suggesting that p63 may regulate epidermal development through suppressing K8 transcription. We have also shown that in wild-type mouse keratinocytes K8 promoter was repressed by transcription factor Ctip2, and upon Ctip2 depletion K8 expression became strongly upregulated in both developing epidermis and in primary mouse keratinocytes at both transcript and protein levels, demonstrating that Ctip2 functions as a transcription suppressor of K8 gene [6].
Epidermolysis bullosa simplex (EBS) is an autosomal dominant skin disorder, manifests itself upon trauma in the form of epidermal basal cell death leading to skin blisters [31]. The primary cause of EBS is dominant mutations in either of the genes encoding keratins K5 or K14 [32]. This pair of type I (K14) and type II (K5) is specifically expressed in the basal cell layer of the skin epidermis, which is in direct contact with the basement membrane of the underlying dermis. Therefore, loss of function or mutation of K5 or K14 leads to defects in keratin filament formation in basal keratinocytes and thus triggers skin blistering due to fragility of the basal cell compartment in either human or mouse skin epithelium [33, 34, 35] (Figure 3). Additionally, it has been shown that overexpression of transcription factor Ovol2 in mouse basal keratinocytes caused reduced K5 and K14 expression, leading to a severe blistering phenotype that resembles the clinical features of EBS [30].
Keratins and skin diseases. Autosomal dominant mutations of basal cell keratins K14 or K5 are associated with skin blistering disease “Epidermolysis Bullosa simplex” and are caused by an increase in basal cell fragility/death, epidermal inflammation and epidermal blistering. Autosomal mutations of the suprabasal KC markers K10 and K1 are associated with hyperkeratosis skin disease “Epidermolytic/Bullous ichthyosis” and are caused by an increase in suprabasal cell fragility/blistering, inflammation, proliferation of basal cells and hyperkeratosis of epithelium. In skin wounds, inflammatory skin diseases such as psoriasis, or squamous cell carcinomas (SCCs), suprabasal cells express high levels of K6, K16 and K17 (keratins associated with activated KC), and these keratins decrease KC adhesion and differentiation and promote immune cell activation and KC proliferation. K8/K18 expression is found in poorly differentiated SCCs with increased invasiveness. K8 or K18 expression in KC leads to decreased cell–cell contact and an increase protection against apoptosis, as well as invasiveness and malignant transformation potential of KC.
Although K5/K14 mutations are associated with the majority of EBS population, about a quarter of patients with EBS do not have genomic mutations nor abnormal transcript expressions of K5 or K14 [36], suggesting that alternative pathways may be involved in the pathogenesis of these patients. Indeed, recent studies have suggested that in addition to genetic mutation, abnormal K5/K14 functions in basal keratinocytes can also be regulated at post-transcriptional level through post-translational modifications, such as phosphorylation and disulfide bonding. Abnormal phosphorylation of keratins contributes to the pathogenesis and progression of EBS [37]. For example, threonine 150 (T150) in the head domain of K5 was found to be phosphorylated in human EBS keratinocytes. Expression of phosphomimetic T150D K5 mutant in keratinocytes arrested keratin heterodimer assembly leading to impaired keratin filament formations and reduced cell viability and elevated response to stressors [38], suggesting a possible role of K5 T150 phosphorylation in EBS pathogenesis. In addition to phosphorylation, it has been shown that proper disulfide bonding between K14-K5 heterodimers is required to maintain keratin intermediate filament organization and dynamics in primary mouse skin keratinocytes, and disruption of this K14-dependent disulfide linkages may lead to keratinopathies, such as EBS [39].
When basal keratinocytes migrate to suprabasal layer of the epidermis, supra basal cells cease transcription of K5 and K14 but instead express K1 and K10. Mutations in either K1 or K10 cause several human skin diseases, such as Epidermolytic ichthyosis (EI), Bullous ichthyosis (BI), palmar-plantar keratoderma and Epidermolytic nevus (EN). BI/EI are caused by rare autosomal dominant mutations of either of K1 or K10 that manifest at birth with fragile blisters and erosions that develop into hyperkeratotic lesions. X-ray crystal structure analysis of K1-K10 heterodimer suggested that point mutation of these keratins may disrupt the disulfide linkage and secondary structure formation between the heterodimer leading to aggregation of the keratin filaments [40]. In contrast to EBI, only the K1 or K10 expressing suprabasal cells are affected in EI/BI patients, and the basal proliferative compartment are not affected. However, these unaffected basal proliferating cells are bathed beneath the rupturing suprabasal cells with inflammatory cytokines, leading to over-proliferation of the basal cells and epithelium – known as hyperkeratosis (Figure 3). Therefore, BI skin contains a highly thicken epidermis made up of fragile cells and it is highly susceptible to bacterial and fungal colonization and is highly disfiguring and debilitating for the patient.
In contrast to EI or BI, Epidermolytic nevus (EN) is caused by somatic mutation of either K1 or K10, and the skin blistering phenotype is only affecting part of the body [41, 42]. Because germ line cells are not affected in EN patient, EN parents usually do not transmit the mutations and disease to next generation. However, it has been reported that under rare conditions EN can produce EI in the next generation through transmission from mosaic to germ line. And the risk of disease transmission to the next generation can be evaluated by next generation sequencing of mutation rate in sperm, leukocytes and lesional skin of the EN patients who wish to bear children [43].
Superficial epidermolytic ichthyosis (SEI), previously known as ichthyosis bullosa of Siemens (IBS), is an autosomal dominant skin disorder linked to K2 mutations and it is characterized by superficial epidermal fragility and desquamation that lead to characteristic denuded areas. In SEI, aggregates of KF bundles and cytolysis are confined to the upper spinous and granular layers of the epidermis where K2 is expressed [44, 45]. In human, K2 is expressed later in differentiation in the upper spinous and granular layers of skin collected from different body sites [14], but SEI patients usually develop more severe symptoms in palms and soles compared to other body sites suggesting that K2 may play a major role to support tissue integrity in these areas. The tissue specific expression pattern of K2 has been better characterized in mouse skin: in regions of the soles (except foodpad which expresses K2-K9/K10), ears and tail of the mouse, K2 instead of K1 is the major type II keratin that pairs with K10. K2−/-K10−/− double knockout mice or K2−/−mice developed epidermal acanthosis and hyperkeratosis in the tail epidermis, ear epidermis and inter-footpad epidermis of the soles [46, 47], demonstrating that K2-K10 keratin pairs are essential for the epidermal integrity of plantar skin.
Epidermal palmoplantar keratoderma (PPK) is an autosomal dominant skin disorder that develops shortly after birth, and manifests as diffuse hyperkeratosis of the palms and soles and showing sharp demarcations with erythematous margin. Mutations of K9, which is expressed specifically in the suprabasal keratinocytes of the glabrous skin epidermis (palms and soles), are the major cause for EPPK [48, 49]. In human plantar and palmar epidermis, K9 functions as the additional type I keratin, besides K10, to partner with type II keratin K1 [50]. Therefore, mutations of K9 cause pathological epidermal thickening on palms and soles, manifesting as different forms of palmoplantar keratodermas [49]. In mice, K9 expression is restricted to skin epidermis of the footpad, and K9 deficient mice developed calluses marked by hyperpigmentation that are exclusively localized to the stress-bearing footpad. Additionally, hyperproliferation, impaired terminal differentiation, and abnormal expression of K5, K14 and K2 were found in the lesions of K9 deficient mice [51]. Together, these evidence demonstrate that K9 is required for the structural integrity and terminal differentiation of the palmoplantar epidermis.
In mammals, the skin of the palm is uniquely adapted to withstand remarkable physical stress, and the palmoplantar epidermis contains a more complex pattern of keratins than thin skin and it is characterized by the constitutive expression of K6, 16, 17 and K9 [52, 53]. Mutations in K6, K16 and K17 genes cause pachyonychia congenita (thick nails, plantar keratoderma) [49].
Distinct from the palmoplantar epidermis, the interfollicular epidermis normally does not express K6, 16 or K17 under homeostatic conditions but these genes can be induced in interfollicular keratinocytes upon activation and reflects a hyper-proliferative state of keratinocytes under wounding or inflammatory conditions [54, 55, 56] (Figure 3). Upon injury, keratinocytes at the wound edge quickly downregulate K1/K10 and markedly induce K6 (type II)-K16 (type I) keratin heterodimer along with cytoplasmic K17 within 2–6 h of wounding [57], and therefore K6/K16/K17 have been widely used as markers for wound-activated keratinocytes in both human and mouse skin (Figure 4). The expressions of K6, 16 and 17 are also elevated in the hyperproliferative epithelium of inflammatory skin diseases such as psoriasis (Figures 3 and 4), which shares many inflammatory features with normal skin wounding, including elevated proinflammatory cytokines such as interleukin 1(IL1), tumor necrosis factor α (TNFα), type 1 interferons, interferon γ (IFNγ), IL17 and IL22 [58, 59, 60].
The expression of K6 is elevated in both wounded and psoriatic human skin epidermis. Human skin sections from (A) psoriasis lesional (PSOL), (B) in vivo wounded skin (by punch biopsy and collected at day3), or (C) ex vivo wounded skin were stained with K6 antibody in green or red as indicated. Non-wounded nuclei were counterstained with DAPI (blue). Scale bar, 100 μm. In A, non-lesional skin (NL) from the same patient was used as control for PSO. In B, skin biopsy collected at day 0 was used as non-wounded control. Note that while K6 expression was not detected in all control skin epidermis, strong K6 staining was detected in the suprabasal layers of both wounded and psoriatic skin epidermis in similar patterns. Also K6 was strongly elevated in the migrating tongue of ex vivo wounded human skin at the wound edge. Details of these samples can be found in our previous published work [58].
Hallmarks of activated keratinocytes include cell hypertrophy, altered cell adhesion and juxtanuclear reorganization of the keratin intermediate filament network, allowing activated keratinocytes to quickly migrate into the wound site, repopulate the skin and restore the epithelial lining and barrier function. In vitro study of mouse keratinocyte overexpressing K16 revealed that while forced expression of K16 did not alter cell proliferation, it caused a reduction in cell adhesion and K10 expression (early differentiation) [61]. K10 expression inhibits cell proliferation, but ectopic expression of K16 promotes cell proliferation and diminishes the inhibitory function of K10 on cell proliferation when K6 and K10 are co-expressed [11] . K6−/− mouse keratinocytes migrated faster than control wild-type cells [56], and K6 negatively regulates the migratory potential of skin keratinocytes by inhibiting Src kinase [62], suggesting that the migratory feature of activated keratinocytes may be regulated by an K6/K16 independent pathway or by a non-cell autonomous manner. In contrast to K6−/− keratinocytes, K17−/− mouse keratinocytes show a delay in the closure of wounds [63], and protein translation, AKT activity and cell proliferation are suppressed in K17−/− keratinocytes [64]. These results suggest that in activated keratinocytes while the cell adhesion and differentiation maybe regulated by K6, cell hyper-proliferation and migration in response to wound maybe controlled by K17.
Our group has shown that damage-associated molecular patterns “DAMPs”, such as double-stranded RNA, are the first signals released from necrotic cells to rapidly initiate the inflammatory cytokine production from surrounding undamaged human keratinocyte upon injury [58, 65]. Inflammatory cytokines released either from activated keratinocytes or from recruited immune cells initiate expression of hyperproliferative keratins and keratinocyte hyperproliferation. It has been shown that cytokines interleukin 1(IL1) and tumor necrosis factor α (TNFα) can synergistically induce the transcription of K6 through transcription factor C/EBPβ and NFκB [66]. Transcription factor AP1 (c-Fos + c-Jun) can also activate K6 promoter synergistically with NFκB under inflammatory conditions [19]. Additionally, transcription factor NRF2 translocated from cytoplasm to nucleus upon stimulation with proinflammatory cytokines such as IL 17 or IL 22, and upregulated the expression of K6, K16 and K17 genes via the antioxidant responsive element (ARE)-binding region, promoting proliferation of keratinocytes in psoriasis [67]. K17 expression could also be induced by IFNγ in skin epidermis, and the K17 in turn function as an auto-antigen to stimulate proliferation of T cells and IFN expression, contributing to the amplification of the autoimmune response and immunopathogenesis of psoriasis [68, 69]. Accumulating recent evidences have suggested that microRNAs also play important roles in modulating keratinocyte activation and skin inflammation [70, 71]. Keratin expression can be regulated by microRNA in the contact of psoriasis. For example, miR-486-3p targeted K17 mRNA for degradation and it was identified as the top downregulated microRNAs in psoriasis, leading to K17 overproduction and hyperproliferation in psoriatic keratinocytes [72].
Cutaneous squamous cell carcinoma (SCC) is the second most common skin cancers and represents about 20% of all skin cancer, with up to 700,000 new cases annually diagnosed in the USA, and it is associated with a substantial risk of metastasis [73]. SCC is characterized by extensive expression of K5/K14 through the epidermis and the expression of hyperproliferative keratin K6, K16 and K17 [50], which are not only upregulated in inflammatory skin, but often upregulated in many tumors originating in stratified and pseudostratified epithelia. K1/K10 may also be focally expressed in SCCs, and K8/K18 is often detected in poorly differentiated SCCs, and the role of K8/K18 will be discussed in more details next.
As we have described in chapter 2, the simple epithelia-specific keratin pair, K8/K18, are expressed in keratinocyte progenitors, early on during embryonic skin development, and upon vertical epidermal stratification K8/K18 expression is then substituted by K5/K14, and becomes eventually lost in fully mature skin epidermis [9, 10, 74]. Overexpressing human K8 in mouse epidermis (TGHK8 mice) lead to severe epidermal phenotypes including epidermal hyperplasia associated with orthokeratotic hyperkeratosis, dysplastic hair follicles and altered expression terminal differentiation markers [75]. The severity of these skin phenotypes increased during aging, and the aged TGHK8 mice developed spontaneous premalignant skin tumors, and TGHK8 mice showed a drastic increase in the malignant progression of skin tumors in mouse model of chemical skin carcinogenesis. Previously, we have shown that Ctip2−/− mouse keratinocytes that overexpressed K8 exhibited loss of cell–cell contact and contain much thicker central stress fibers [6], indicating that aberrant K8 expression may decrease cell–cell adhesion and trigger an EMT (epithelial–mesenchymal transition) phenotype in epidermal keratinocytes. These results suggest that expression of K8 in adult epidermis impairs the normal epidermal differentiation program and may be responsible for the invasive behavior of transformed epidermal keratinocytes. Indeed, in adult skin epidermis, aberrant K8/K18 expression is broadly correlated with increased invasiveness and poor prognosis of squamous cell carcinomas [76]. In addition, K8/K18 protect epithelial cells against apoptosis mediated by proapoptotic signals, such as TNFα [77] released by macrophages and T lymphocytes and Fas [78], and may enable cancer cells to resist immune cell-mediated cell death and escape immune surveillance.
Phosphorylation is the key post-translational modification that regulates keratin functions, and phosphorylation of K8 is among the most well studied in keratin family [79]. More than a dozen phosphorylation sites have been identified on serine residues of K8 [79], and phosphorylation of K8 enhances the migratory, proliferative and invasive potential of epithelial cells, therefore promoting the malignant transformation of cancer cells [80]. Keratin expression can be altered through epigenetic modification during malignant transformation. A recent study investigating genome-wide DNA methylation changes in the progression from healthy human epidermis to cSCC reveals that DNA methylation profiles of cSCC epidermis display classical features of cancer methylomes compared to normal epidermis samples [81]. Further analyses of DNA methylation patterns of keratin gene clusters (including basal cell keratins K5 and K14 which are ectopically expressed throughout cSCC epidermis) identified major DNA methylation differences between healthy donors and cSCC patients, suggesting that abnormal keratin expression in SCCs may be regulated through epigenetic mechanism such as DNA methylation.
Tissue and cell differentiation specific expression of pair between type I and type II Keratins play essential roles in forming the intermediate filaments and providing cytoskeletal and structural support and mechanical resilience for epithelia tissues. In addition to these structural roles, keratins also control cell migration, cell adhesion, proliferation and differentiation processes in keratinocytes and modulate immune system in various settings. The transcriptions of keratins are tightly controlled by a series of transcription factors, and keratin functions are also regulated by post-translational modifications such as phosphorylation and intermolecular disulfide bond formation. Mutation or dysfunction of basal keratins K14/K5 or suprabasal keratins K1/K10 lead to severe skin blistering diseases, whereas K6, K16 and K17 are rapidly induced in activated keratinocytes upon skin wounding and are also expressed in inflammatory skin diseases, such as psoriasis. Understanding keratin functions and related regulatory mechanisms will help to design new therapeutic interventions for keratin-related skin diseases.
This work was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases grant (R01AR069653).
The author has nothing to disclose.
Space orbital environment is characterized by several factors that affect experiments in physical sciences and influence the good functioning of all living systems, from cells to humans. The main factors are weightlessness, high-energy radiations, vacuum and temperature differences. These last two factors are generally mitigated by the vehicle yielding the necessary life support to the systems under study. The first two factors on the contrary cannot be completely compensated.
The concept of weightlessness will be developed further.
Perfect protection against high-energy radiations cannot be completely achieved, unless thick shielding walls are installed all around the spacecraft, which is presently excluded in view of launch costs per kg. Nevertheless, a vehicle in low Earth orbit (a few hundred kilometers altitude) stays relatively protected by Earth’s Van Allen radiation belts (inner energetic proton belt at 1,000–6,000 km altitude and outer energetic electron belt at 13,000–60,000 km altitude).
To these orbital factors, one should add the conditions at launch and during atmospheric reentry and landing of a spacecraft, i.e. important accelerations and vibrations, that can affect the quality of physiological samples or configurations obtained in microgravity (e.g. for crystals).
The state of microgravity, or more correctly micro-weightiness, exists in an orbital vehicle in a state of free fall, i.e. without any force acting on it except for gravitational forces [1]. This means that the vehicle must not be propelled or submitted to any other nongravitational force. Perfect weightlessness is an ideal state practically impossible to achieve. However, microgravity of an excellent quality (typically 10−5 g, where g is the acceleration of weightiness, commonly and erroneously mistaken for gravity1, with an average value of 9.81 m/s2) can be achieved in orbit.
Gravity (weightiness) disturbs certain experiments and reduces the field of investigation of some scientific domains. Gravity (weightiness) effects hide other effects pertaining to materials or fluids under study, and that depends often on intrinsic properties of matter or of its state. Convection in fluids, so evident that it is called “natural,” is caused by gravity (weightiness) acting on local differences of density caused by differences of temperature or concentration. The resulting Archimedes or buoyancy force induces an ascending motion of fluid zones of lesser density and a descending motion of fluid zones of larger density, creating convection cells in gases, liquids and solids in fusion, yielding disruptive phenomena in separation processes.
Although physical and biological processes are often investigated in hypergravity, e.g. in centrifuge, one knows less what happens in reduced gravity. However, in most cases, one cannot extrapolate from results obtained in hypergravity to microgravity, most of the phenomena being nonlinear in function of the gravity level. One observes many more differences while passing from 1 g to 0 g than between 5 g and 4 g, for example.
Many scientific fields profit from the peculiarities of weightlessness to enlarge their field of investigations. Material sciences, fluid physics and life sciences (biology and physiology) were the first to use microgravity, followed later by many other disciplines (combustion physico-chemistry, crystallography, fundamental physics, critical point phenomena, etc.) in view of varying a new experimental parameter: gravity. Microgravity allows to deepen scientific knowledge in domains that are hardly accessible on Earth.
Table 1 shows some of the scientific fields in which experiments were conducted in microgravity.
Physical sciences | Life sciences |
---|---|
Fundamental physics | Human research |
Complex plasmas and dust particle physics Aerosol particle motion Frictional interaction of dust and gas Plasma physics Aggregation phenomena | Integrated physiology Cardiovascular function Respiratory function Body fluid shift Central venous pressure system Digestive system Muscle and bone physiology Skeletal system Blood lactate studies Body mass tests Human locomotion Posture Bone models Neuroscience Neurobiology Vestibular functions Spatial orientation Motion sickness Motor skills |
Materials science | |
Thermophysical properties Thermophysical properties of melts New materials, products and processes Morphological stability and microstructures Physical chemistry Aggregation phenomena Granular matter | |
Fluid and combustion physics | |
Structure and dynamics of multiphase systems Pool boiling Heat and mass transfer Dynamics of drops and bubbles Thermophysical properties Interfacial phenomena Dynamics and stability of fluids Evaporation Complex dynamic systems Diffusion Foams Chemo-hydrodynamic pattern formation Combustion Droplet and spray combustion Soot concentration Combustion synthesis Laminar diffusion flames Fuel droplet evaporation Ignition behaviour | |
Biology | |
Plant physiology Statolith movement Gravitropism Gravireceptors Cell and developmental biology Animal physiology Aging processes Electrophysiological and morphological properties of human cells Osteoblast cells | |
Technology | |
ISS experiment validation Phase separation technologies for biological fluids Crew foot restraint Crew exercise devices Urine monitoring system | |
Technology | |
ISS experiment validation Metal halide lamps Micro-acceleration measurement |
Non-exhaustive list of research fields in microgravity.
Microgravity research allows to study the gravity effects on these different phenomena and the effects of other forces normally masked by gravity on Earth. Weightlessness became an experimental research tool that allows to transpose in microgravity the investigation of phenomena known on Earth but sometimes insufficiently understood, in order to investigate the fundamental processes and to understand their functioning without gravity.
Modifications appear when one studies matter behaviour in weightlessness. One observes on the one hand the disappearance of “natural” phenomena caused by gravity and, on the other hand, the preponderance in microgravity of phenomena that can hardly be observed in normal conditions of gravity. These modifications are particularly important for certain physical, chemical and metallurgical processes having at least one fluid phase: crystal growth, alloy solidification, separation of biological substances, etc.
The main differences that are observed for fluid phases in weightlessness are as follows.
Separation phenomena observed on Earth in multiphase systems that include a fluid phase disappear in microgravity. Sedimentation (precipitation of dissolved or suspended matter) and Archimedean buoyant force (or buoyancy, i.e. the force due to a liquid pressure on a body-immersed volume) disappear. The advantage of the absence of separation in weightlessness is the possibility of obtaining mixtures that are unstable on Earth and material alloys impossible to obtain on Earth or with great difficulty. A disadvantage of the absence of separation in weightlessness is the difficulty of eliminating the gaseous inclusions while, on Earth, degassing is done “naturally” (gaseous zones in liquid matrices go up to the free surface).
“Natural” convection disappears in fluids in microgravity. There is no more natural upward displacement of hot zones and downward displacement of cold zones. In fact, there is no up and no down. Other forces become dominant for movements in liquids in microgravity. These forces are linked to superficial or interfacial tension between two liquids. Indeed, such an interface behaves as an elastic “membrane” whose tension is a thermodynamic function of temperature (or concentration for solutions), as shown in Figure 1.
Liquid/gas interface submitted to a superficial tension gradient, yielding a Marangoni convection cell caused by the physical displacement of the interface membrane from the hot side (point 2) to the cold side (point 1) [1].
For an interface subjected to a temperature difference, superficial tension for most liquids is generally smaller for the hot side than for the cold side. The interface, i.e. the common layer formed by molecules of both fluids, physically moves parallelly to itself from the hot side to the cold side; this membrane deforms itself and slides from the hot side to the cold side. The liquid layers on both sides of the interface are dragged along by viscosity, and a new convection appears, called Marangoni convection, after the name of the Italian physicist who studied this phenomenon at the end of the nineteenth century. This phenomenon exists obviously also on Earth, but as its effect is much smaller than those caused by gravity, it is in general negligible and much more difficult to observe. Its study in microgravity allows thus to better understand the fundamental characteristics of liquid behaviour.
It is also because of the absence of “natural” convection that the shape of a combustion flame is different in weightlessness. On Earth, gases produced by the chemical reaction of combustion (e.g. of a candle wick), much hotter, rise, and fresh air oxygen migrate to the combustion centre to feed the combustion process. In microgravity, hot gases have no reason to rise anymore, and the flame is surrounded by a hemispherical ball formed by combustion gases (Figure 2), limiting the amount of fresh oxygen transfer.
Flames on ground in 1 g (left) and in microgravity in near 0 g (right). Notice the near-hemispherical shape of the flame in microgravity with the reddish-purple part on top due to some convection caused by small perturbations in the microgravity environment (photo credit: NASA).
In microgravity, hydrostatic pressure disappears. On Earth, it is responsible for the tendency of fluids to deform under the effect of their own weight, a liquid zone supporting the weight of zones on top. The same phenomenon exists for solids. Structures can be built that would collapse under their own weight on Earth, e.g. crystalline networks (Figure 3).
Protein crystals obtained with ESA’s Advanced Protein Crystallization Facility during the Life and Microgravity Spacelab mission on NASA Space Shuttle STS-98 in May 1995 (credit: Prof. Martial, University of Liege, Belgium).
Liquids in weightlessness, abandoned to themselves without any contact with a solid surface, form spherical drops (Figure 4), which is the minimal surface enclosing a given volume when subjected to the only forces of superficial tension.
Water drop in free float on ISS (credit: NASA).
On Earth, crucibles are used to melt alloys, which may contaminate the melt liquid phase. In weightlessness, the liquid phase can be maintained in a contactless levitation, without touching any solid walls, using an electrostatic, magnetic or acoustic confining (Figure 5). Many parameters of materials at high temperatures are still unknown and cannot be measured on Earth due to difficulties and limitations caused by crucible contamination and gravity effects.
Core element of an electromagnetic levitator (photo credit: DLR).
The list of the advantages and applications of microgravity to scientific research could be continued at length but is outside of the aim of this publication. The interested reader will find other examples and more details in Refs. [2, 3, 4, 5].
Initially developed in the 1950s and 1960s to support US and USSR space programs, space microgravity medical research quickly evolved. Manned spaceflights very quickly showed physiological changes in astronauts and cosmonauts. The duration of spaceflights has increased throughout the years, from a few hours at the beginning of the 1960s to several months (or even more than a year) today on board the International Space Station (ISS, Figure 13). The ISS allows to conduct and to repeat experiments during several years.
New phenomena have been observed on astronauts, some of these effects appearing only after several weeks or months in space. Despite the large number of hours spent in orbit around the Earth by astronauts and cosmonauts from all countries involved in space research and exploration, some problems are still far from being fully understood, and the necessary solutions have not yet been found.
Although physiological systems of human organism function interdependently, one can classify physiological effects of microgravity in four categories:
Perturbations of sensorial systems related to balance, orientation and the vestibular system
Modifications of bodily fluid distribution and their impact on the cardiovascular system
Effects on metabolism and bodily functions
The adaptive processes of muscular and skeletal systems and their pathological consequences
Relevant knowledge and research on human physiology are presented below, and more details can also be found in Refs. [6, 7, 8, 9, 10, 11].
On Earth, in a normal gravity environment, the human body has three means to obtain the information of the reference vertical direction and of the top-bottom orientation, characteristic of the gravitational environment on our planet.
The main system is the vestibular system, which is double, located in the inner ear. In one of these organs, small crystals of calcium carbonate called otoliths weigh on a membrane with nervous endings. The semicircular canals form another sensor. Formed by the three canals in planes approximatively orthogonal to each other, a physiological liquid moves by inertia in these canals during a head movement, stimulating nervous endings in the canals. The combination of the information coming from the otoliths and semicircular canals allows the brain to interpret the movement and the position of the head.
The second source of information is the visual system. The visual information allows the brain to recognize the body position with respect to external references (floor, ceiling, walls).
The third information source is the proprioceptive system, constituted of the whole of skin tactile perceptions, articulations and muscle tension. The neck proprioceptive system is the most developed and informs the brain on the position of the head with respect to the rest of the body.
In weightlessness and in absence of accelerated motion, there is no stimulation of the vestibular system. Otoliths are no longer attracted downward by gravity, and the semicircular canals are no longer stimulated. However, the visual and proprioceptive systems continue to function normally. Information sent by these different systems to the brain are incoherent for an organism used to normal gravity and create confusion in the brain zone that normally treats the information on position and orientation. This confusion often yields dizzy spells and nausea and sometime triggers the reflex of emptying the stomach. In short, the subject is sick. This sickness, called space adaptation syndrome, affects most astronauts. On average, one out of two astronauts suffers from nausea during the first few days of spaceflight. After a day or two, the human organism adapts to the new environment, and astronauts can continue to function and work “normally.” After the flight, the balance and orientation systems readapt quickly to the Earth’s environment.
On Earth, while standing in normal gravity, arterial blood pressure is normally distributed such that, if intracardiac pressure is taken as unity, it is approximately double in feet arteries and two third at head level. While lying down, the distribution of blood pressure is more uniform. Passing from the lying to the standing position yields a blood flow toward the lower part of the body, and blood pressure diminishes in the head. Known as orthostatic postural intolerance, the change of blood pressure is detected by baroreceptors in the vascular system and close to the heart. These receptors send signals that yield, firstly, an increase of cardiac rhythm to compensate the blood volume decrease in head arteries and, secondly, a contraction of arteries in the lower body to diminish the blood flow toward the legs.
In microgravity, gravity does not attract liquids downward anymore, and a redistribution of body fluids takes place. A volume of approximately two liters of body fluids is displaced from the lower extremities to the upper part of the body, increasing the blood volume and pressure in the heart. The volume and blood flow receptors are alerted, and this new situation is interpreted as an overload of the blood system. The reaction of body liquid elimination starts and yields a complex hormonal game, which results in a natural elimination by urine of body liquids. The organism adapts to this new environment, and a new balance is established after 4–5 days.
On the other hand, liquid transfer from lower members toward the upper body has other secondary effects: face swelling due to blood rush in the head, the increase of intraocular pressure, and sinus congestion. These secondary effects disappear up to a certain point after a few days in microgravity. Back on Earth, the organism readapts to a 1 g environment.
The results of experiments performed with ultrasound echocardiography show a diminution of the left ventricle and auricle volumes during a spaceflight of several weeks. However, after the flight, the cardiac muscle comes back to a normal state.
In microgravity, a decrease of cardiac rhythm and of arterial tension is observed, the heart not needing to pump blood against gravity’s downward pull (Figure 6).
Experiments during aircraft parabolic flights (left) showed (right) a decrease in heart rate, seen at the beginning of microgravity (arrows), i.e. an increase of duration between successive peaks, corresponding to increased vagal modulation of the heart rate. A sudden increase is also seen in pulse blood pressure (difference between maximum and minimum pressures), indicating an increase in stroke volume (ECG, electrocardiogram; BP, blood pressure) (credit: Left, ESA; right, Prof. A. Aubert, Katholieke Universiteit Leuven, Belgium).
A high tachycardia (increase of the cardiac rhythm) is observed also at launch, due to psychological stress, but also necessary to compensate the effects of accelerations, in the order of 3–4 g, with a maximum of 8 g.
Visual impairment and intracranial pressure are another consequence of the upward body fluid shifts, the head filling with blood and other bodily fluids. The various consequences are an increase in intracranial pressure that can cause headache of varying levels of severity and an increase of the intraocular pressure that affects the visual performance and other more minor effects such as congestion of the sinuses. These effects, although observed and investigated for several years, are thought to be temporary as they tend to disappear after return to Earth.
However, intracranial pressure and visual impairment were only recently recognized as more serious as they could impair the performance of astronauts during long-duration 0 g travels in space.
In microgravity, the main physiological functions are practically unchanged. Astronauts can eat and drink without major constraints. Digestion and intestinal transit are accomplished also nearly normally, except that gravity action is no longer present.
Breathing is also made without too important problems. However, the breathing mechanism is altered: the distribution of inspired and expired gases in the lungs and oxygen exchanges in blood hemoglobin at the level of pulmonary alveoli are modified. The way to breathe is also modified: statistically, in weightlessness, the forced movement of the abdomen contributes more to the breathing mechanism.
Astronauts can also sleep in space. However, daily and sleep rhythms are disturbed. Indeed, on board the ISS in low Earth orbit at 400 km altitude, day and night alternation repeats approximately every 90 min. Astronauts see a sunrise and sunset 16 times per terrestrial 24 h a “day.” Psychological and emotional factors and travel excitement intervene also. To remedy it, one imposes a strict and well-established schedule taking into account human natural rhythms. On board the ISS, a three times 8-h schedule is applied: 8 h for sleep, 8 h for work depending on missions and 8 h for personal time, meals, rests, etc. This schedule is purely theoretical as astronauts on board the ISS spend much more of their time to work, although for long-duration stays on ISS, schedules are loose, and longer rest periods are foreseen some days, generally used by astronauts to watch Earth through windows, mainly the cupola (Figure 7).
NASA astronaut Karen Nyberg, Expedition 37 flight engineer in 2013, enjoys the view of earth from the windows in the ESA-built cupola of the International Space Station. A blue and white part of earth is visible through some of the seven windows of the cupola (photo credit: NASA).
After long stays in weightlessness, changes are observed in blood composition that can be problematic. Firstly, the number of red blood cells and the hemoglobin level decrease. Secondly, red blood cells of unequal sizes and of abnormal shapes have been also discovered. After 6 months in microgravity in orbit, up to 2% of ovalized red blood cells have been observed in Russian cosmonauts. Thirdly, the immune defense system of astronauts diminishes in microgravity after approximatively 7 days of flight. One observes a reduction of production of lymphocyte T cells (the white blood cells) that intervene in the immune responses and in antibody production. This observation did not find so far a satisfactory fundamental explanation, and this problem could be the one that would impede mankind to adapt to long-duration space travels in microgravity. Astronauts are more prone to infections in space, and they need more time to recover after an infection on ground after their return. The immune system is back to its normal preflight level after a period of 5–10 days after return to Earth.
In microgravity, the first effect that is noticed is the spine extension up to a point that astronauts can gain a few centimeters in height. This is due to the partial decompression of intervertebral discs that do not have to support the weight of the upper body anymore. Back on Earth, after the flight, this effect disappears, and height becomes normal again but with, sometime, the risk of having a nerve blocked between discs and vertebrae. Furthermore, some astronauts complained of back pains during or after a spaceflight, probably caused by this phenomenon of spine extension.
The muscular system atrophy is a second consequence, observed after some days in weightlessness. In particular, the most affected muscles are those that control posture and that contribute to support the body weight on Earth. In microgravity, the natural position that astronauts take is a curved position with the legs slightly bent. One floats freely and moves by pushing oneself against a wall, using the action-reaction principle. One notices thus a muscle atrophy, a loss of mass of muscles and the elimination of muscular proteins (Figure 8).
British ESA astronaut Tim Peake operates the muscle atrophy research and exercise system (MARES) equipment inside the Columbus module. MARES is an ESA facility used for research on musculoskeletal, biomechanical and neuromuscular human physiology to better understand the effects of microgravity on the muscular system (photo credit: NASA/ESA).
By practicing regularly (more than 2 h per day!) and by applying sometime treatments of muscular fiber electrostimulation, astronauts and cosmonauts have no difficulties to readapt upon return to Earth after a more than 6-month mission.
Bone demineralization, and mainly decalcification, is the most important and serious physiological phenomenon observed in microgravity. Appearing only after 1–2 months in orbit, this could be the second problem that could thwart the hopes of mankind to adapt to space travels in weightlessness.
The loss of calcium is still not completely understood. One knows that decalcification is related to an atrophy of bone fibrous cells containing calcium, corresponding to the part of the bone that allows the marrow to pass. This effect seems to be irreversible once it has started. The rate of calcium loss varies from an astronaut to another and varies also from a type of bone to another. Numerous experiments yield sometime diverging results. On one side, one observes an increase of activity of osteoclastic cells, whose role is to eliminate and resorb elements of bone tissues. On the other side, some results show that bone demineralization would be due to a decrease of activity of osteoblastic cells, responsible for regenerating bone tissues.
This problem of bone decalcification resembles by certain aspects osteoporosis, an illness known on Earth affecting mainly elderly people. This sickness yields a change in the structure (demineralization) of bones, but the composition stays globally the same. The bone loses in thickness, fragilizes and fractures more easily. This shows the importance of conducting research in microgravity on astronauts to better understand this sickness and to contribute in finding a cure for it.
All the means to generate microgravity are based on the principle of free fall; any other method will not result in a real microgravity environment but in a simulated microgravity environment. Microgravity is created in a non-inertial reference frame attached to a vehicle in free fall, in which the resultant of forces other than gravity is null or negligible.
Figure 9 summarizes the different platforms used for microgravity research in an increasing order of microgravity duration.
Reduced gravity platforms accessible to microgravity researchers (vertical axis, duration of microgravity; horizontal axis, quality of microgravity) (credit: DLR).
Drop tubes and drop towers provide a few seconds (up to 5 s) in the vertical drop mode, where an experimental payload is literally dropped in vacuum or behind a shield to reduce the perturbing effect of air friction.
The level of microgravity obtained in the drop tube of NASA Marshall Centre of 105 m high and 25 cm diameter is in the order of 10−6 g during 4.6 s in a vacuum. In Europe, the ZARM drop tower in Bremen, Germany (Figure 10), is 110 m high with a diameter of 3.5 m. Experiment capsules fall during 4.7 s in vacuum, yielding microgravity levels of 10−5 g. The microgravity duration can be doubled up to 9.5 s by launching the experiment capsule in a catapult mode from the bottom of the tower upward, falling freely first upward and then downward [12, 13].
The ZARM drop tower in Bremen, Germany. The 146 m high building protects the free fall facility from atmospheric perturbation and wind (photo credit: ZARM).
Aircraft parabolic flights provide a reduced gravity environment of approximately 20 s, with the major advantage of having human operators and subjects on board. The level of microgravity is typically in 10−2 g when attached to the floor structure that can be improved down to 10−3 g for a few seconds when left free-floating (Figure 11). This important microgravity platform is addressed in the next chapter.
During a parabolic flight on board the Airbus A300 ZERO-G during an ESA campaign, several experimental racks are visible to the left and the back, while one of the authors floats freely “upside down.” There is no “up” and “down” in weightlessness (photo credit: ESA).
Sounding rocket flights, for which microgravity levels are in the order of 10−4–10−5 g, are used for automated or remotely operated experiments with relatively reduced volumes. Depending on the size of the rocket and the engine used, the duration of microgravity during the ballistic phase of the flights varies between 3 and 14 min [14].
In the near future, suborbital flights will provide microgravity duration in the order of 3–4 min for paying customers but also for microgravity experiments. There are typically two US companies that are working on suborbital vehicles (Figure 12): Blue Origin with the New Shephard capsule and a reusable rocket and Virgin Galactic and the SpaceShipTwo spaceplane carried by the WhiteKnightTwo airplane carrier. These two systems would carry passengers and experiments up to an altitude of 100 km or more in a propelled mode and continue in a ballistic mode for approximately 3–4 min after propulsion has stopped.
Two suborbital facilities in development: (left) the New Shephard capsule with a reusable rocket (credit: Blue origin) and (right) the WhiteKnightTwo airplane carrying the SpaceShipTwo spaceplane (photo credit: Virgin galactic).
Manned orbital platforms provide microgravity periods of several years for the International Space Station (ISS, Figure 13) [15, 16, 17], and the future Chinese Space Station is foreseen to be assembled in orbit in 2022 (Figure 14). Residual accelerations are in the order of 10−2–10−4 g, depending on internal perturbations (e.g. crew movements) and external ones.
The International Space Station (ISS) is the first major international project that includes 14 countries in its realization: The USA, Russia, Canada, Japan and 10 European countries (France, Germany, Italy, Belgium, the Netherlands, Spain, Sweden, Switzerland, Denmark and Norway). With a total mass of 440 tons (but weighing 0 kg ...), the ISS is in low earth orbit between 400 and 450 km altitude at 51.6° inclination. Since November 2000, the station is inhabited by permanent international crews (photo: NASA).
The Chinese Space Station foreseen to be launched and assembled in the coming years with an assembly completed for 2022. From left, the Tianzhou (meaning “heavenly vessel” in Chinese Mandarin) cargo freighter docked to the Tianhe (“harmony of the heavens”) core module in the Centre; a piloted Shenzhou (“divine vessel”) vehicle is connected to a node in front of Tianhe, which are connected to two scientific modules: Wentian (“quest for the heavens,” at right) and Mengtian (“dreaming of the heavens,” left) (credit: CMSA).
Space missions of orbital platforms and of sounding rockets require a long preparation, typically of several years, and should be considered for experiments that need a long exposition duration to microgravity. The relatively short preparation time for the use of drop tubes and towers and of aircraft parabolic flights (typically of few days to few months) renders them particularly attractive for short-duration experiments of a few seconds. The utilization of these experimental platforms of earthbound microgravity must be considered as preparatory and complementary to space missions.
Let us insist on the fact that the platforms described in this section do not simulate microgravity but that they really create microgravity, even if it is not always perfect, as all these means are in free fall.
To the contrary of the means creating microgravity, simulation methods do not allow to really create microgravity. The simulation means allow to obtain experimental configurations in which certain aspects of phenomena can be studied in a way similar to what could be observed in microgravity but without being in weightlessness.
Therefore, these methods have important limitations that reduce their scientific interest to the investigations of some very specific cases. The results obtained by these simulation methods generally complete those obtained in real microgravity. In none of the three following configurations, microgravity is really created as there is no free fall.
The first simulation method was used at the end of the nineteenth century by a Belgian physicist, Joseph Plateau, who gave his name to this method. The principle is simple: it consists in immersing a liquid in another immiscible liquid matrix having the same volumetric mass. By Archimedes principle, the buoyancy exerted by the liquid matrix of volumetric mass ρ1 on a volume V of a liquid of volumetric mass ρ2 is directed along the gravity acceleration vector and reads
This force becomes null for ρ1 = ρ2, yielding results similar to what could be obtained in weightlessness when g = 0. In the Plateau configuration, the gravity force is not balanced by inertia forces but by a buoyancy force.
Only static configurations are truly well simulated with this method, e.g. configurations of static equilibrium of liquid zones.
The second simulation method is less known. It consists in balancing locally the force of gravity acting on a body by a magnetic or electrostatic force acting in the other direction. The effects of two fields, the gravitational field and a magnetic or electrostatic field, have to be locally balanced. One sees immediately the limitation of this configuration that would work only for bodies sensitive to magnetic induction or electrically charged. Furthermore, the power needed to maintain these fields is quite important and limits the size of observed configurations. Nevertheless, this method is used sometime to investigate magnetohydrodynamic problems in the absence of gravity effects.
The third simulation method is what is called the dimensionless reduction. This method mainly applies to fluid research for which scientists use a series of dimensionless numbers describing the ratios of different forces acting on fluids. Reducing physical dimensions of an experimental liquid zone greatly diminishes effects caused by gravity in comparison to other forces acting on fluids, e.g. superficial tension force or capillarity forces. One manages to build floating liquid zone of a few millimeters size that allow to study certain phenomena. The main limitations of this method are linked to reduced sizes: firstly, they make it difficult to install precise means of observation and measurement; secondly, they reduce the field of investigation to limited ranges of values of other effects specific to fluids.
Space medical and physiological research does not limit itself to conducting medical experiments in orbit or during parabolic flights but relies also on results obtained by earthbound means. For research on adaptation of the human body to weightlessness, scientists use two simulation techniques that allow within certain limits to recreate the effects of microgravity on the human body. It consists firstly of immobilization (or hypokinesia, Figure 15) in a horizontal position or slightly inclined (head-down) that simulates the shift of body fluids, mainly blood, toward the upper part of the body like in weightlessness.
Head-down bed rest simulates microgravity effects on human physiology. Subjects stay in slightly tilted head-down (typically 6°) beds for weeks or months at a time (photo credit: CNES/ESA).
The second technique is water immersion. As the human body is mainly made of water, buoyancy induces conditions partially similar to microgravity acting on the human body, somewhat akin to Plateau’s configuration. A variant of water immersion, called dry immersion, is also used sometime where the subject is placed in an elastic or plastic sheet in a liquid matrix, such that the subject is immersed in the liquid but without direct contact with the liquid.
A better understanding of the effects of microgravity on physics and the human body, from cells to body systems, is essential if the human exploration of outer space is to continue. The capacity to conduct research in the microgravity environment provided by spaceflight is fundamental, especially given current plans to expand long-term missions in low Earth orbit and to establish the commercial use of space, together with the ultimate goals of creating a human colony on the Moon and sending a first crewed mission to Mars. Nonetheless, there are many limiting factors that restrict the performance of experiments in space, such as the high costs involved in sending resources and equipment up into space, the safety requirements to which experimental devices must adhere and the small number of astronauts per flight. These constraining factors have motivated the establishment of ground-based research facilities and parabolic flights. The latter presents some limitations in terms of the short period of time of exposure to microgravity given and the hypergravity condition that precedes and succeeds each parabola. However, it is the only provider of microgravity, in which experiments in physics, biology, physiology and medicine can be conducted by human operators and volunteers. Parabolic flights are not a perfect analogue of spaceflight, but they remain a valuable research tool that enables research and testing to take place and a better understanding of the effects of microgravity, assisting academia, the private sector and governments to better design future plans for the human exploration of outer space.
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