Effects of spaceflight detected in blood
Effects of spaceflight detected in blood
January 25, 2017
January 25, 2017
As researchers have long known, the punishing conditions associated with human spaceflight present profound challenges for the mental and physical health of astronauts. Acceleration during launch
, (which must rapidly propel the craft to some 18,000 mph), acute conﬁnement, hazardous levels of radiation, sleep deprivation, and reduced gravity (or microgravity) can produce a range of physiological effects, from suppressed immune function, bone and muscle loss, eyesight problems, and viral reactivation to anxiety and depression.
In a first of its kind study, Cheryl Nickerson and her colleagues at the Biodesign Institute have demonstrated that the spaceflight environment can also produce alterations in gene expression in human blood that may leave space travelers more susceptible to a range of diseases. These changes were detected in blood samples taken from astronauts before and after spaceflight missions.
The unique pilot study of spaceflight-induced changes in gene expression involved the examination of 234 well-known genes associated with stress responses, which were measured in the whole blood of 6 astronauts (four men and two women). The samples had been carefully preserved before and immediately after spaceflight.
As the study’s lead author Jennifer Barrila notes, the research paves the way for improved methods for protecting future astronauts during critical space missions and also advances fundamental knowledge of cellular processes in both space bound and earthbound environments: “As astronauts continue to live and work in space, it is important that we gather as much evidence as we can about how this unique environment may induce changes in human physiology, even down to the most basic molecular level. Although no major conclusions regarding health or disease status of the crew can be drawn from this small pilot study, the data indicate the need to follow up and expand on these findings to gain a better understanding of the molecular changes that are occurring in humans during both short term and long-term spaceflight.”
Nickerson and Barrila are with the Biodesign Center for Immunotherapy, Vaccines and Virotherapy. They are joined by ASU colleague Phillip Stafford, from the Biodesign Center for Innovations in Medicine as well as by C. Mark Ott (co-first author) and Duane L. Pierson of the NASA Johnson Space Center, Carly LeBlanc from Tulane University Health Sciences Center, Satish K. Mehta from EASI/Wyle laboratories and Aurélie Crabbé, from Ghent University.
Their research findings recently appeared in the journal npj Microgravity.
The first stage in the expression of genes is known as transcription, during which a segment of DNA is copied into RNA. This process takes place with the aid of a polymerase, an enzyme that reads the DNA sequence and helps generate the nucleotides for the RNA copy or transcript. Not all genes are expressed at any given time. Rather, those that are needed for a specific task are called into play at the appropriate time and first transcribed into RNA, then translated into protein.
The new study examined a suite of genes known to play a role in biological stress responses, noting any alterations occurring in the regulation of RNA transcripts of these genes following spaceflight. Among the 234 stress-related genes examined, regulatory alterations were seen in genes responsible for DNA repair, oxidative stress, and proper folding of proteins.
“In addition to providing important insight for astronaut health, such studies also have implications for the growing space tourism industry and the public sector,” says Nickerson. “In the near future, as space travel becomes a practical option for the general public, it is important to recognize how this environment impacts the transition between health and disease.”
Until now, there have been no studies profiling spaceflight-induced changes in gene expression in astronaut blood, including the activation of critical genes linked with stress. The new research examined total RNA isolated from samples of whole blood extracted 10 days prior to launch aboard the space shuttle and again 2-3 hours after return to earth.
The male astronauts examined in the study were between 38 and 47 years of age while the two female subjects were between 38 and 44. Each astronaut flew aboard one of four shuttle missions ranging from 10-13 days, which occurred over a two-year period – with some astronauts flying multiple missions. Earlier studies of these same astronauts had shown a marked increase in Epstein-Barr virus reactivation during and immediately following spaceflight, a phenomenon suggesting the astronauts were indeed under spaceflight-induced stress.
To capture and evaluate RNA transcripts and their variability, the group used microarray technology. Microarrays contain a set of short probes composed of DNA that are immobilized on a solid surface (like a glass slide) and are complementary to the cellular RNA transcripts of interest.
Probes that correspond to transcribed RNA bind with their complementary target. Transcripts may be extracted from samples to be investigated, labeled with fluorescent dyes and scanned using a laser. Light intensity may be used to measure levels of gene expression.
Microarray results have produced a wealth of knowledge about the universe of RNA transcripts (known as the transcriptome), helping researchers better understand how transcripts are managed in different cell types and tissues, how gene expression changes across development states, disease types, and in response to stress, and how it varies within and between species. The technology has also offered fascinating insights into foundational questions in biology, for example, how much of the genome is transcribed into RNAs that do not code for proteins.
Tracking spaceflight effects
In the present study, six transcripts in particular showed statistically relevant changes due to spaceflight in all subjects tested. The alterations seen were not gender-specific nor did they appear to be related to the number of missions flown. Of the six gene transcripts studied, two are recognized for encoding proteins involved in DNA repair, one related to oxidative stress, and two transcripts involved in the proper folding of proteins.
The observed down-regulation of DNA repair proteins coincides with earlier research showing that astronauts experience chromosomal aberrations in white blood cells—a critical immune system component—following long duration spaceflight. Increased DNA damage has also been described in such cases. Further, when genes were subjected to simulated conditions of microgravity over a period of 7 days, which can be accomplished in earthbound studies using a device known as a rotating wall vessel bioreactor, DNA damage also resulted, leading to decreased expression of DNA repair mechanisms. The authors believe these changes could lead to increased damage and mutation resulting from spaceflight.
The study draws particular attention to the downregulation of a gene that codes for glutathione peroxidase. This critical enzyme serves a variety of functions, including protecting cells from oxidative damage and modulating an immune response that typically arises 24 to 72 hours after infection. Known as DTH (for delayed-type hypersensitivity), this inflammatory response occurs when T cells encounter a disease antigen. Spaceflight has the effect of depressing the DTH response as well as altering the delicate balance of reactive oxygen species in cells (also known as free radicals) and increasing reactivation of herpes virus.
The authors note that one of the challenges in this type of study is accurate interpretation based on the available small sample size of spaceflight subjects and the differences inherent in human versus animal studies of cellular stress responses. Nevertheless, the current study points to altered stress responses detectable in RNA transcripts as a consequence of spaceflight and therefore holds important clues for assessing and mitigating risk to space travelers. The integrity of cellular machinery involved in DNA repair, oxidative stress response and accurate protein folding are essential for safeguarding cells from environmental and physiological stressors that have been linked with a wide variety of diseases. This data will also be relevant for future comparison to the NASA Twins Study, which is focused on long-term spaceflight effects on the blood of astronauts Scott and Mark Kelly, and faces similar challenges with gene expression data interpretation, as there is only one individual for each condition (spaceflight and ground).
Future studies will be aimed at solidifying the links between specific cellular adaptations to the microgravity environment and observed alterations in gene expression. Such research will help to provide a necessary foundation for evaluating disease risk in flight crews, particularly in the case of extended periods in space. Further, advances in understanding of stress-related cellular responses may lead to improved diagnostics and therapeutics for the general public.
In addition to her appointment at the Biodesign Center for Immunotherapy, Vaccines and Virotherapy, Cheryl Nickerson is a professor in ASU’s School of Life Sciences.
Written by: richard harth