Can Humanity Thrive Beyond the Galaxy?

Abstract

In the future, human beings will surely expand into space. But given its unique risks, will humanity thrive in space environments? For example, when humans begin living and reproducing in space habitats or on other planets in the solar system, are there risks that future generations may suffer from adverse mutations induced by space radiation, or that embryos and fetuses will develop abnormally in gravitational environments that differ from that of Earth? Moreover, human expansion to other stellar systems requires that for each breed of animal, thousands of individuals must be transported to destination planets to prevent populations from experiencing inbreeding-related degeneration. In even more distant future, when humans have spread throughout the galaxy, all genetic resources on Earth, the planet where humans originated, must be permanently and safely stored— but is this even possible? Such issues with future space colonization may not be an urgent research priority, but research and technological development accompanying advancements in spaceflight will excite many people and contribute to technological improvements that can improve living standards in the present day (e.g., more effective treatments for infertility, etc.). This review will therefore focus primarily on issues related to mammalian reproduction in space environments.

Introduction

In science fiction films and other media, many stories describe humans colonizing planets beyond the solar system. They are often depicted as living on planets circling other stars or in self-contained space habitats, giving birth and raising children as normal— but is such a thing really possible? In the early space age, humans were expected to live in large bases at various locations in the solar system, such as in near-Earth space habitats, on the Moon, Mars, or on moons of outer planets such as Ganymede or Titan [1]. However, it remains unknown whether mammals that evolved in the 1-G gravity of the Earth can reproduce normally in the microgravity of the space environment or on other planets with different gravitational forces [2, 3]. Furthermore, unlike the Earth, which is protected by a thick atmosphere and a relatively strong magnetic field, space environments are much harsher, and contain powerful deep-space radiation from the sun and galaxies (Fig. 1) [4]. Gametes— i.e., oocytes and sperm— sourced from parents who lived in space for long periods of time, and were therefore exposed to large quantities of space radiation, may have been containing several damaged DNA. If so, the offspring of space dwelling parents may show different phenotypes due to the presence of these mutations [5, 6]. Even if only a few mutations occur in each generation, mutational load can accumulate over generations of exposure to space radiation, and the descendants of the original spacefaring humans may eventually become a different species. If such a risk occurs when human space colonists remain inside the solar system, colonists may be required to periodically return to Earth to heal and have children, thereby remaining “Earthlings”. However, in a far-distant galactic age, when humans have outgrown the solar system and have expanded to stars thousands of light years away, accepting human mutation may be inevitable. In that age, humans will have evolved into a “New type”, and the term “Earthling” may come to mean something like “Neanderthal”.

Fig. 1.

Three stages of reproductive issues arising during human space exploration. In the early phase of space exploration, which will take place within our solar system, the effects of microgravity and space radiation on reproduction must be further studied. Later, human expansion beyond our solar system into the rest of the galaxy will require study of each animal species that will be transported. This will involve movement of hundreds or thousands of individuals or their germ cells to avoid inbreeding. Finally, if humans move beyond our galaxy further into space, Earth’s genetic resources must be permanently preserved in a safe place. Each of illustrations was created by Copilot, and then modified to create this figure.

Moreover, human life in space will require an accompanying emigration of domesticated animals, pets, and other Earth animals. However, to the maintenance of emigrated animal species on new planets will require hundreds to thousands of individuals of each breed (e.g., St. Bernard and Chihuahua dog breeds, and Angus and Wagyu beef cattle) to avoid inbreeding [7]. It may be possible to transport thousands of small animals by spaceship, but it would be difficult to transport thousands of pigs, cows, or other large animals (e.g., elephants and giraffes), even if huge spaceships become easy to build. Therefore, it is likely that genetic resources, such as frozen sperm and oocytes/embryos, instead of live animals, will be transported to other planets (Fig. 1). However, while liquid nitrogen is generally used for the cryopreservation of sperm and oocytes/embryos [8, 9], it cannot be used to transport genetic resources to another planet because liquid nitrogen cannot be used inside spacecraft environments [10]. This is because while the spaceship itself can get very cold during interstellar flight (~3K), at such temperatures liquid nitrogen is not needed. However, heating during flight near stars raises the temperature to approximately ~6000K [11], and temperatures nearly as high are reached during planetary launch and landing. Therefore, methods of preserving genetic resources that can withstand exposure to both extremely low and extremely high temperatures as well as space radiation are needed. Furthermore, given that it can take decades to hundreds of years for a spaceship to reach another star, bulky containers cannot be used since the spaceship must be loaded with as large a genetic resource cargo as possible.

By the time humans have expanded into other galaxies, Earth’s genetic resources are likely to be enormously valuable. These must be preserved as much as possible, but with global warming and frequent major earthquakes on the Earth, there may be no absolutely safe place for the storage of genetic resources on the Earth itself (Fig. 1). Therefore, in addition to preserving genetic resources here, humans may have to consider safely and permanently storing copies of Earth’s genetic resources on another planet to act as a backup [12]. In addition, animal sperm and oocytes are not only more difficult to preserve than microorganisms or plant seeds, but can also be more difficult to collect from adult specimens. With respect to plants, for many seeds can be collected easily and in large quantities, and when seeds cannot be collected, some plants can reproduce by grafting or nutrient propagation (e.g., potatoes). However, animal oocytes must not only be surgically retrieved from a female body, but only a small number can be retrieved from each individual. Moreover, it is not possible to recover both sperm and oocytes from immature, elderly, or infertile individuals. Finally, many rare and endangered species are protected by law, and it is practically impossible to collect oocytes or sperm from such species without damaging their bodies. So could we feasibly collect the genetic resources of thousands of individuals from each animal species?

The challenges listed here represent only some of the problems related to mammalian reproduction that must be solved in order for humans to enter the spacefaring age, but most of which we know nothing about [13]. In this review, we present the problems related to mammalian reproduction in space and the experiments being conducted to solve them.

Issues for mankind’s expansion into the solar system

When considering human expansion further into the solar system, gravity and space radiation are two challenges thought to have the greatest impact on reproduction [13]. If these two effects negatively affect mammalian reproduction, then humans may not be able to explore and colonize the solar system.

Gravity

Biologists have interested in how gravity affects fertilization, early embryo development, cell differentiation, fate determination, and sexual differentiation. As soon as it was possible to conduct experiments in space, studies of development and fertilization using sea urchin, fish, and amphibian model systems were conducted, and it became clear that although space microgravity may cause some developmental delays and morphological abnormalities, in general it does not seriously affect individual development [14,15,16,17,18]. However, since mammals have a unique reproductive method, which involves implantation in the maternal uterus, forming a placenta, and developing a fetus until term, the relevance of studies using the above model species may be lower. To determine whether mammalian space reproduction is possible, it is necessary to actually transport mammals to space and conduct experiments there. However, keeping rodents on the International Space Station (ISS) is difficult, and a recent breeding equipment developed by Japan Aerospace Exploration Agency involved keeping each animal in a separate cage for up to one month [19]. Interestingly, it has been reported that even after only one month of rearing male mice on the ISS, their sperm were found to have undergone epigenomic changes that were transmitted to offspring born using these sperm [20]. If experiments to study mice from fertilization to birth were conducted on the ISS, they would have to be bred for longer periods of time, but would also have to be mate in space. However, another experiment in which male and female rats lived together in space during an orbital flight failed because they did not mate, even in ground control experiments [21]. Taken together, these results indicate that it is not only difficult to raise animals in space, but also that it is extremely difficult to conduct experiments exploring how this may be done, since results depend on animal behavior in novel environments [22].

Attempts have also been made to conduct similar experiments on early-stage embryos in space instead of adult animals [23]. However, it usually takes at least one week from the time a sample is loaded onto a spaceship to the time it arrives at the ISS for the experiment to be conducted, resulting in degeneration of embryo before start experiment. Several ground experiments have therefore also been conducted to investigate the effects of microgravity on the early development of embryos. Many of these have involved a clinostat, which uses centrifugal force to cancel out Earth’s gravity, thereby producing pseudomicrogravity conditions. Such experiments have shown that fertilization and early development are in principle possible under microgravity, but the development of the trophectoderm (TE; i.e., cells of the placental lineage) in the blastocyst was poor, resulting in low birth rates [24,25,26]. If this result is correct, then humans and mammals would be functionally unable to produce offspring in space due to placental dysplasia. However, since the pseudomicrogravity environment created by the clinostat differs from true microgravity, it remains unknown whether the same result would occur in space.

Recently, Lei et al. [27] performed an experiment in which live embryos were placed on a spacecraft and were cultured in low earth orbit. The results of this experiment showed that while the embryos were at the 2-cell stage at launch, they were able to develop into blastocysts under microgravity conditions. However, the same study observed a slow developmental rate due to DNA damage caused by space radiation. Importantly, no control experiments were conducted at 1G in a spacecraft, and it may be that lower developmental rates are linked to intense vibrations that occur at spacecraft launch or to the sealed container used for embryo culture.

Next, we launched frozen embryos to the ISS to rigorously study the effects of microgravity and radiation on the human body [28]. This involved avoiding all factors that may affect these results, such as the launch vibrations and the fact that embryos can develop even while being prepared for launch. The astronauts then thawed the frozen embryos on the ISS and conducted an experiment in which embryos were cultured simultaneously in a pseudo-1G environment by centrifugation as well as in a true microgravity environment. The development of the “Embryo Thawing Culture device”, which allows astronauts to thaw and culture frozen mouse embryos on the ISS, was difficult and took more than 10 years to complete [10, 29, 30]. Overall, this project was a success. We observed that mouse embryos at the two-cell stage that were cultured in microgravity were able to develop into blastocysts just as well as embryos cultured in a pseudo-1G environment on the ISS. This result indicated that gravity had no effect on embryo development or on first cell fate determination—i.e., differentiation into to the inner cell mass (ICM) and TE [28]. Next, we turn to radiation. The amount of space radiation the embryos were exposed to during this experiment was 4.29 mGy, which was 10 times higher than the amount that embryos were exposed to in the Lei et al. experiment. Although a direct comparison cannot be made since there are differences between our experiments and those of Lei et al. [27] in terms of the location (i.e., ISS orbiting at a height of 400 km versus other spacecraft orbiting at a height of 252 km) and embryo condition (i.e., frozen versus non-frozen), our results show that space radiation probably does not affect embryo development during the four-day window studied.

However, we did identify a few specific differences. For example, in the pseudo-1G environment conducted on the ISS, we observed that the ICM was clustered in a single region of the blastocyst, as was observed in a control experiment conducted simultaneously on the ground; in contrast, 25% of blastocysts cultured in microgravity had two separated ICMs [28]. Usually, ICM separation increases the likelihood of the birth of identical twins, but poses a risk to both the mother and fetus [31]. These results indicate that gravity may be necessary to collect the ICM in one location within the blastocyst. Unfortunately, since during these experiments embryos were chemically fixed and brought back from the ISS to Earth, it was not possible to determine whether they were capable of developing into healthy offspring. In addition, since this experiment involved space culturing from the two-cell embryo stage, it remains unknown whether oocytes can be fertilized under microgravity or whether they can develop from the one-cell stage to a blastocyst.

Space radiation

Previous studies using cultured somatic cells have shown that space radiation can severely damage cellular DNA [32, 33]. However, to date it has been impossible to study the effects of space radiation on later generations since it is impossible to study future generations using somatic cells. Therefore, we conducted an experiment to investigate how space radiation affects mouse sperm as well as the offspring they generate; this was done by storing mouse sperm on the ISS for up to six years using freeze-drying technology (see next chapter) (Fig. 2) [12, 34]. We found that the level of DNA damage in freeze-dried (FD) sperm stored on the ISS for 1–6 years that was continuously exposed to space radiation tended to increase in proportion to the duration of storage in space, but fertilization and birth rates did not significantly differ from those of ground-based controls. Moreover, offspring born from space preserved sperm were normal in appearance, and a comprehensive analysis of gene expression revealed no abnormalities. Moreover, mating after sexual maturity produced healthy offspring and grandchildren, thereby confirming that the effects of space radiation do not persist for generations. Overall, we estimate that sperm stored on the ISS for six years were exposed to a total radiation dose of 0.87 Gy (0.145 Gy/year), which is more than 100 times the amount that humans are naturally exposed to on Earth [34]. Finally, calculations based on experiments in which FD sperm were irradiated with X-rays on the ground showed that—at least theoretically—FD sperm could be stored on the ISS for more than 200 years.

Fig. 2.

Interstellar transport of animal genetic resources at scale. It may be impractical to transport large numbers of living individuals to other planets. Instead, it may be more feasible to transport genetic resources. Of these, sperm and somatic cells will be the most suitable genetic resource for transport to other planets since it can be collected easily and in large quantities. Freeze-drying protocols would not only eliminate the need for liquid nitrogen to preserve those cells but would also make it possible to transport a large quantity of genetic resources over great interstellar distances due to the greater tolerance of cells to temperature and radiation damage and its ability to be stored at room temperature for long periods of time. This method would avoid inbreeding degeneracy of animals on the destination planets and allow humans to thrive beyond galaxy. Each of illustrations was created by Copilot, and then modified to create this figure.

Issues at the time when mankind entered the galaxy

In the future, humans may spread beyond the solar system and colonize other stellar systems. The problem then will be the enormous quantity of genetic resources that must be transported to avoid inbreeding in nonhuman species accompany human colonization (e.g., farm animals and pets), as well as the need for preservation technologies that can enable these resources to withstand exposure to radiation and high temperatures during transport (Fig. 2).

Development of safe long-term preservation methods for genetic resources

Although technologies for preserving genetic resources using liquid nitrogen have already been established, since liquid nitrogen cannot be used in enclosed spacecraft, a new preservation method that does not use liquid nitrogen is required for transport of genetic resources to newly colonized planets. On the ground, research on how to preserve genetic resources for very long periods of time without using liquid nitrogen is already underway. These studies are motivated by a need to develop a strategy in case liquid nitrogen cannot be supplied due to natural disasters or supply chain disruption, as well as to reduce maintenance costs. Studies have therefore examined preservation of sperm by salting [35] or chemically fixation [36], but only FD or several related methods of drying sperm have been successful in producing offspring following long-term storage at room temperature [37,38,39]. This was first successfully performed using mouse sperm [39] and has since been repeated in other mammals, including rabbits, rats, hamsters, and horses [40,41,42,43]. At present, freeze-drying sperm causes the cell membrane to break down and the sperm themselves to die—however, if the sperm’s DNA remains undamaged, healthy offspring can be obtained by injecting sperm into the oocyte (intracytoplasmic sperm injection: ICSI) using a micromanipulator [44]. Initially, FD sperm could only be stored for a long time at low temperatures. However, improved storage methods have been developed [38, 45, 46] that are capable of achieving storage in a desk drawer at room temperature for over six years, with no observable reduction in offspring birthrates [47]. It remains unknown whether this method can preserve sperm for hundreds of years, and such an experiment will be difficult to prove. Nonetheless, perhaps a method like this can be used to preserve genetic resources during interstellar transport.

During such transport, genetic resources will also be exposed to more intense deep-space radiation than on the ISS, which stays in low earth orbit, where it remains partially protected by the Earth’s magnetic field [48]. Thus, if FD sperm can be preserved for only 200 years on the ISS [34], they would not be able to be preserved for longer periods of time in harsher deep space environments that are subjected to more intense and varied space radiation. In the aforementioned experiment, we simply stored FD sperm in a freezer on the ISS and did nothing to protect them from space radiation. Thus at present we are also conducting research on how to protect FD sperm from deep space radiation. So far, we have found that when FD sperm are covered with 10 cm thick polyethylene before being irradiated with iron heavy particle beams that mimic deep-space radiation, FD sperm can theoretically produce offspring even after 2000 years of continuous radiation exposure (manuscript in preparation). Overall, by optimizing protective materials and preservation methods, we will enable longer-term protection of FD sperm from deep space radiation, and therefore we are currently conducting experiments on which protocols best protect FD sperm from space radiation on the ISS.

In addition, since spacecraft are cooled to near absolute zero in deep space but are intensively heated when passing by stars [11], any genetic resources loaded onto a spacecraft must be able to withstand temperature changes (Fig. 2). We therefore conducted an experiment to determine how tolerant FD sperm were to temperature [49]. To do so, we first exposed FD sperm to room temperature and −196°C (i.e., liquid nitrogen) temperatures ten times in succession, an observed that the birth rates from these sperm were only slightly lower than those of FD sperm exposed only once. Next, we examined sperm resistance to high temperatures and found that FD sperm were able to produce offspring even when heated to 95°C for up to 6 h. Over shorter periods of time, it was possible to produce offspring from FD sperm even after exposure to 150°C. Thus, we initially developed a sperm freeze-drying method capable of preserving sperm at room temperature, but it is clear that this treatment not only increases the sperm’s radiation tolerance but also helps them tolerate extreme temperatures.

Transport of genetic resources to other planets

To transport genetic resources to other planets, it is important that long-term storage containers be light, small, and robust to external damage. In general, FD sperm do not require liquid nitrogen for storage, which greatly reduced overall weight. However, these sperm are stored in glass ampoules, which may break. We and others therefore developed a more convenient storage container as an alternative to the glass ampoule. For example, a protocol was developed to preserve FD sperm in low-cost microtubes [50], in stainless steel minicapsules [51], and even between laminated sheets [52, 53]. Using these methods, FD sperm can be pasted onto a postcard and sent through the air mail or “space mail,” and a single album would be able to store FD sperm from several hundred individuals/strains, thereby eliminating the need to consider physical space requirements when loading them into a spaceship.

Collection of genetic resources from all animals

To transport genetic resources to other planets in quantities that are sufficient to maintain adequate population sizes for all species/strains, large numbers of sperm and oocytes must be collected from a large number of animal individuals [7]. However, sperm and oocytes may not be harvestable from some individuals due to youth/old age or infertility. In general, if there are still immature germ cells in the testes or ovaries, they can be retrieved and used to make offspring, but what if no germ cells remain or if the testes or ovaries are lost in an accident? In this case, large quantities of somatic cells can be easily collected from both male and female specimens, of any age, as well as from infertile animals. It has therefore been proposed that such animals may be produced via cloning from somatic cells [54, 55]. In addition, there are reports of successful cloning from very old individuals [56, 57] or from endangered species [58, 59], as well as cloning from somatic cells collected from urine (i.e., noninvasively) [60]. It may also be possible to establish induced Pluripotent Stem (iPS) cells from the somatic cells of animals and/or to produce oocytes and sperm from iPS cells in vitro [61]. Further development of this technology may permit creation of cloned individuals from the cells of extinct animals, such as mammoths excavated from permafrost [62]. To this end, cloned mice have been created from the bodies of dead mice frozen at –20°C for 16 years [63].

If somatic cells are to be loaded onto a spacecraft, it may be essential that somatic cells can be stored at room temperature as well as FD sperm. However, nearly a quarter of a century after offspring were born from FD sperm in 1998 [39], no cells other than sperm have been successfully used for the creation of a new generation after freeze-drying, despite several attempts of nuclear transplantation of FD somatic cells [64, 65]. In general, sperm are very different from somatic cells not only because they have half the amount of DNA, due to meiosis, but also because their DNA is bound to protamine instead of histones. Therefore, it has been proposed that the only mammalian cells capable of withstanding the freeze-drying procedure were sperm, since their DNA is hardened by protamine [66, 67]. However, in one recent experiment we attempted to freeze-dry sperm progenitor cells (i.e., round spermatids; haploid cells but not yet protaminated) and showed that offspring could be produced from FD spermatids, although their birth rate was worse than that of mature sperm [68]. This result indicates that some cells or nuclei can withstand freeze-drying even if nuclei are not yet protaminated. Additionally, there have been reports of successful generation of early cloned embryos from FD somatic cells [69] and the establishment of ES cells from these cloned embryos [65]. Given these results, we tried freeze-drying somatic cells and succeeded in cloning mice, albeit at an extremely low success rate (0.03%) [70]. Interestingly, in some cases, we found that the Y chromosome was missing from the male somatic cells during nuclear transfer, and female clones were born despite the use of male donor cells. If this technique could be further refined, it may be possible to create females from endangered species in which only males survive, thus avoiding extinction [70]. Finally, we speculate that somatic cells may also be useful as a genetic resources during the transport of large quantities of animal genetic resources to other planets, [71].

Beyond the galaxy

In the distant future, when humanity has expanded beyond our galaxy, Earth’s “original” genetic resources will become increasingly precious, and must be preserved as safely and permanently as possible. But is there any absolutely safe place on Earth to store them (Fig. 1)? A permafrost underground storage facility would maintain low temperatures even in the event of a power outage [72], but if global warming continues, few such places will be able to store large amounts of genetic material. Moreover, during the 2011 earthquake in Japan, an unexpectedly high (i.e., ~40 m) tsunami caused a nuclear reactor explosion, and the surrounding area was exposed to high levels of radiation [73]. Thus, the imposition of serious disasters will occur more than is currently expected, thereby making it difficult to find a permanently safe place on Earth [74].

Also, in the far distant future during which humans begin to colonize throughout the galaxy, Earth may someday be a landmark or legendary planet, making access to the Earth difficult. If this occurs, it may make it more difficult to relocate genetic resources from the Earth to other planets. Therefore, we advocate that almost all genetic resources be stored outside the Earth, where they can act as a backup for Earth as well as to facilitate colonization more effectively and conveniently. For example, the underground of the moon, with its very low temperatures, protection from space radiation by a thick layer of bedrock [75], and complete isolation from earthquakes and weather-related disasters that occur on Earth, may be an ideal location for the permanent preservation of genetic resources. Interestingly, shortly after we published this idea [12], a huge underground cavity was discovered on the moon [76]. Such a cavity should make the preservation of genetic resources easier since it means that there would be no need to dig an equivalent hole on the surface of the moon. Moreover, this idea has attracted research interest [77], although it remains unknown when it would be acted upon.

Perspectives

Many people may feel that human advancement into space is so far in the future that there is no need to conduct research on how reproduction can occur in space at present. However, the advancement of mankind into space represents both a dream and a hope, as evidenced by the many science fiction movies that depict human spacefaring. The possibility of mammalian space reproduction is an important topic that can determine the success or failure of human space exploration, although at present it remains understudied since many technical difficulties exist. To conduct reproductive research in space, further development of assisted reproductive technologies, which may also be useful for other reasons, such as new embryo culture devices, gamete and embryo preservation at room temperature, and even artificial wombs, is required. Such new technologies will not only contribute to human infertility treatment but may also serve as a new tools that we can use to study the developmental mechanisms of early mammalian embryos and the gravity response of cell differentiation. Finally, we hope that this review can contribute to the promotion of human space exploration in the future, even if it takes a hundred or a thousand years.

Conflict of interests

The authors declare that they have no conflict of interests.