Building on a previous article about transporting animals to Mars, I am following up with a - "what next" - We have transported animals to Mars, now what? Assume in this scenario, that an organisation has managed to bring humans successfully to Mars. These humans have the starter resources they have brought with them and also the makings of systems to enable sustainable propellant, food, water and oxygen/ air.
Here I'll shortly discuss why animals are used for testing and the practicalities of transporting animals in space. I'll also cover the parameters that a Martian crew and Earth-based scientists could hope to analyse and why these parameters specifically.
We will cover the limitations of animal testing as an activity, and the limitations of the experimental outcomes in animal models when transposed onto human subjects.
N.B. This article seeks to extrapolate out how previous animal testing in space may adapted and extended to test other factors for Martian colonisation.
Why use animals for testing?
Animal models have been a core part of the frontier of space exploration, from dozens of species, from fish to dogs, to chimpanzees. I covered the range and some brief on their endeavours in my previous article.
In most cases, these creatures were sent up to test aspects related to survivability and the impact of space travel on the processes of these animals. In some cases, the ability of animals to conduct tasks in space was tested. Later missions in the 1990s focused on the study of reproductive habits of reptiles in space. The outcome of the earlier survivability tests paved the way for human space flight, starting with Yugi Gagarin, the Russian cosmonaut hero back in Soviet era Russia, 1961.
Remember, the beginning of the original Space Race to put a man on the moon and demonstrate superiority in spacefaring technologies was seen against a backdrop of political posturing during the Cold War. There wasn't a platform for animal rights to get in the way. This battle was seen by many as a proxy battle between the Soviet Union, representing communism, against the USA, representing capitalist, or at least a champion of more democratic processes.
To help get some long-term understanding of the impact of long-duration Mars habitat exposure on physical systems, including reproduction, the new Martians can bring along some animal models. Let us consider this idea on its merits and limitations further below. Blindly following previous bouts of animal testing may not yield any value.
Why bother taking animals to Mars
It is generally held that animal models are a great way to observe the health impact of animal models, and Genetic Disease - Download Link. A great article from "Scitable" shows the value in evaluating genetic disease through animal models. This is the basis of medical trials with animal models.
Earlier in genetics, pioneered by Gregor Mendel the monk - the concept of genetic inheritance started to be observed. the higher turnover in animal generations was used for..... understanding genetic transfer. It enabled observation of changes which would take time in humans to observe.
| Common Name | Research Applications | |
| Saccharomyces cerevisiae | Yeast | Used for biological studies of cell processes (e.g., mitosis)and diseases (e.g., cancer) |
| Pisum sativum | Pea plant | Used by Gregor Mendel to describe patterns of inheritance |
| Drosophila melanogaster | Fruit fly | Employed in a wide variety of studies ranging from early gene mapping, via linkage and recombination studies, to large scale mutant screens to identify genes related to specific biological functions |
| Caenorhabditis elegans | Roundworm (nematode) | Valuable for studying the development of simple nervous systems and the aging process |
| Danio rerio | Zebra fish | Used for mapping and identifying genes involved in organ development |
| Mus musculus | House mouse | Commonly used to study genetic principles and human disease |
| Rattus norvegicus | Brown rat | Commonly used to study genetic principles and human disease |
Table detailing the Animal Models and their use to study genetic diseases. Some here are relevant to the disease concerns that may present during life on Mars. Namely cancer owing to the high radiation environment. Credit: Nature Journal.
What the practicalities of transporting animals
There are some key requirements to take care of rodents in space - if we follow the design of the RR apparatus - really a system of 3 interconnecting modules:
1) Habitat
2) Transporter unit
3) Animal Handling box
In the habitat, 10 mice or six rats are provided with all of the basics they need to live comfortably aboard the ISS. This covers their basic needs including water, food, lighting and fresh air. Rodents easily can move around the living space by grasping grids - equivalent to a grid of human handholds - that line the floor and walls. On Earth this would enable the rodents to exploit their Thigmotropsim - ability to generally hold on to vertical surfaces. However, on the ISS in zero gravity, it enables them to get a 'footing' wherever they find themselves.
Shot of Habitat 1 of the Rodent Research system from the ISS. Note the large grille on the outside for air handling and filtration, and inside, the movement grates that mice or rats can use to get around inside the habitat. Credit: NASA
To keep an eye on the rodent health, monitoring and recording data on animal health, the habitat is equipped with visible light and infrared video system. This data is downlinked to the scientists and veterinarians on the ground to monitor behavior and overall health of the rodents on a daily basis.
Consider that the rodent habitat is significantly more simple and compact than an equivalent environment which could be designed for a dog or some larger mammal. Consider also the larger amounts of waste coming from such animals would make keeping the animals in a cared-for, dignified state would be quite difficult in low gravity. Even humans wear adult diapers while conducting space-walks. Such would be difficult to transfer onto dogs. The Atlantic also covered this concept in a very light view, giving more colour to the history of fabricating space suits for animals undertaking short missions. Furthermore, larger animals require more space, which is already at a premium onboard the ISS and would similarly be scarce in a Martian colony in its infancy.
Another option to study the impact of background levels of Martian habitat radiation can be tested through the relatively simple genetics of the pea plant. Plant matter and bugs, insect meal flour may be the only food grown in a Martian colony because of the above complication in transporting relatively sophisticated food animals As a result, it also makes sense to not only grow the food, but to also study it, and understand how genes have been altered/ or not even while growing in the fairly shielded Martian colony covered in metres of dirt.
In the rest of the article, I will consider mouse / rodent models because those have been pursued on the ISS over the last 7 years and are the most recent indication of animal testing for space-exploration purposes.
What parameters the crew could hope to study?
The rodent research onboard the ISS was the initiated with the original Rodent Research 1 mission opening up in September 2014. The follow-on series of experiments have had some longevity, running from from Rodent Research mission 1 - through to mission RR-11 in 2019. These missions typically run on the order of 30 - 45 days. However, the animals euthanised in space, then frozen to preserve them for return and analysis.
The aims of these missions as a group were diverse but each mission was targeted. For instance, RR-1 aimed simply, specifically, to prove the viability of the concept of rodent transport in the self-contained habitat.
RR-4, launched aboard SpaceX CRS-10 mission, built on this foundation of a proven technology platform. On this mission, the Dragon capsules had not yet started their self-docking manoeuvres and it was caught by the ISS' own arm "Canadarm-2".
RR-4 mission was funded by the US DoD to study the impact on healing of bone tissue, and bone regeneration in microgravity. This study wanted to understand how microgravity interfered with bone health and healing. It also tested various agents on the mice, to determine their efficacy in promoting bone regeneration in that environment. An interesting footnote, the study exceeded the NASA guidance for for the Care and Use of Laboratory Animals - by cramming a higher density of mice into the environment than was normal in previous RR missions.
In these missions typically a cohort of mice were sent to the ISS, and a control group were left on Earth. Remembering back to your high school experiments, establishing a control group enables you to establish the baseline which helps contrast to the experimental group. In this case, the ISS microgravity environment mice.
A further mission RR-5 looked at bone density, injecting specimens with placebo and active agents to promote bone growth. Later RR missions investigated other therapeutic agent delivery systems (Novartis-sponsored) and studies of critical physiological processes which could be interrupted, disturbed by micro-gravity. RR-7 mission specifically observed the impact on the gut microbes - and consequent impact on body health, mental health.
It was not until RR-9 that NASA sponsored rodent research started to embark. This programme highlighted the need for close public-private collaboration on extended mission series, particularly on diversity of the mission priorities. NASA missions looked at:
- Impact of increased head blood pressures, on brain tissues, eye health - due to low gravity
- impact of mRNA on vascular health, due to function in low gravity
- Study of a specific protein CDKN1a/p21 and its own impact on bone regeneration
From these experiments on rodents already completed in the 5 year window from 2014, to 2019, we can infer some themes which are high priority for human missions in deep space, lower gravity environments:
- Blood pressure on sensitive brain and eye tissues (eyes swell and vision is impaired through higher fluid volumes in the eyes)
- Bone density, bone health and processes - it is well documented that astronauts returning to Earth had suffered atrophy of muscles and bones while in orbit. NASA highlighted this effect even on short missions of 6 - 11 days.
- Vascular health, and - we could consider a wider impact of vascular health throughout the cardio-vascular system.
While there is a clear benefit to knowing how space travel affects astronauts with the above conditions, there is also a benefit for us on earth. Insight on the processes around blood pressure, bone health and vascular health have a real benefit for informing medical practise on earth. As of 2016, more than 1800 studies had been conducted aboard the orbital lab.
In a later article in Nature journal, it was posited that artificial atmosphere and confinement in the habitat, could also have a bearing on space-traveller health outcomes. On this point, the study considers that being cooped up in an artificial environment breathing controlled, but not fresh air on Earth.
In the short term, any human crews arriving to Mars will likely want to return home because of the challenge of being isolated from home in a high hazard, high risk situation for multiple years. This reduces the exposure to the hazards that scientists would be worried about, limiting it to a maximum 3 years (For reference, a Hoffman transfer exploits the synodic pattern of Mars and the lower energy transit between Earth and Mars. However, this journey can take 9 months. This is followed by a 500 day stay on mars, approximately 1.3 Earth years, then another 9 month return journey).
The composition of the crew at first will likely not be host to husband and wife teams. There is no firm steer on what the composition of a Mars crew would look like. As a result,
Additionally, because the humans would not arrive in great numbers or stay long on Mars at first, it would not provide a meaningful base of data for human reproduction data on Mars as the sample size of humans born would be on the order of 1 or 2. This is a very small sample size and could be open to spurious results. This is particularly problematic if we use the data to try to derive insights on human physiology.
Why study these parameters?
It is good to question why the same research and discussion themes come up again and again on the topic of space exploration and human health. Why are vascular issues, muscle atrophy, mental acuity studied? Because these are the issues that are seen right now in astronauts aboard the ISS and the main issues catered to when they enter physiotherapy back on Earth.
This article from Musculoskeletal Science and Practise advises of some subtle health impacts directly related to a lack of gravity. Perhaps most interesting of these is that because there is no gravity on the ISS, the crew's gravity sensing organs - Graviceptors - stop contributing to the perception of gravity direction. As a result, astronauts have to use vision and peripheral senses to understand position of the body. This has a direct impact on posture: if you don't sense hunching shoulders because you don't notice your centre of gravity or the weight of your torso moving, you will start to adopt poor posture.
Furthermore, because the reduced gravity removes the force (mechanical unloading on intervertebral discs) which acts on the fluid within tissues comprising human, and rodent bodies, more fluid enters the spinal discs. This can lead to weakening of the discs which are no longer used to mechanical loading caused by gravity acting on the spinal column. This has a direct impact on the care required for astronauts returning to Earth to ensure back health is managed with this in mind, while the fluid is redistributed and discs lose turgidity.
Excellent graphic showing how fluid can enter and swell a cell. When extrapolated up to the level of tissues, it is easy to see how spinal discs can become swollen and uncomfortable in low gravity contexts. Credit: QS Study
In humans, most of the body is fluid - 50 - 60% water. Of that roughly 55% is intracellular, retained in cells. 20% interstitial fluid sitting in spaces between cells, and the remaining portion split between Blood Plasma and other fluids.
On Earth, gravity acts on the fluid and our tissues, helping draw fluid down, through our vascular tissues, into the distant extremities of the legs, toes, into the ends of the finger tips, etc. The heart pushes the blood along, but the impact of gravity cannot be neglected in overcoming the flow restriction of small vessels.
This effect is akin to a fire protection engineering problem of pumping fire-water through larger diameter pipes on a distribution main. These pipes reduce down in diameter along the length of the system as they branch off and flow through small diameter branches and into deluge systems used to protect buildings. These deluge systems carry great resistance The insight here being that lots of pumping energy is lost when he surface area to volume ratio is high. Water loses mechanical energy as friction as it touches the walls of the pipe.
The impact of fluid redistribution is underscored by research from 2020, which looked at a group of 11 astronauts before, immediately after, and 6-7 months after a mission aboard the ISS. This study led by Steven Jillings, at the Lab for Equilibrium Investigations and Aerospace (LEIA) at the University of Antwerp in Belgium, discovered through magnetic resonance imaging (MRI) scans, that the cerebrospinal fluid surrounding the brain tends to redistribute in low gravity conditions.
The study by Jillings highlighted that following a tour in space, the astronaut brain images tended to show a shorter span of fluid between the brain and the skull. This suggests that the brain, no longer held down by Earth's gravity, is more free to rise up within the skull.
The study found that this effect held no ill-effects despite this cerebrospinal fluid tending to pool under the brain due to this brain movement. The concern came from this fluid being the medium that takes away waste from the brain. However, the changed flow of cerebrospinal fluid can cause blurry vision.
This is highlighted when we remove the impact of gravity, such as when astronauts arrive in orbit. At this time, fluid, no longer drawn by gravity, starts to migrate around the body. It is well documented that after months aboard the ISS, the crew start to see significant atrophy of lower limbs and higher blood pressure, fluid pressure in their head and eyes. At the moment, astronauts from NASA are kept to 4-6 month rotations where possible. However, this coming week will be a busy time with multiple crew sets rotating at once. This is to enable greater control of the study of such effects.
In the above example with the Rodent Research, we did not approach the impact of cosmic radiation, radiation exposure to the genetic material and the consequent impact on reproduction of DNA of the rodents. As noted, the studies under the RR programme (full paper here) were very short (30-45 days) compared with the lifespan of rats (1 year) and mice (2 years) being considerably longer than the study period.
A stint on Mars (including the travelling time) will be a minimum of 3 years, because the alignment of Earth and Mars orbits co-incide only every 2 years. This mission proposal desktop study proposes a 1100 day Mars mission length. To expect significant data on reproduction and genetic inheritance effects from mouse models could be a challenge. This is because the animals would not have had the chance to produce many generations before the crew return to Earth.
However, mice typically live 2 years. There may only be 2-3 generations of mice produced within this time as mice quickly reach maturity - starting breeding at around 6 weeks and can produce multiple litters of pups each year (up to 80-90 offspring in one lifetime. This could still be enough time to observe generational changes. This study shows how implanted, edited genes can be passed on and expressed in grand-children animals. This could work in our favour because we already have information about how these mice cope on shorter duration missions aboard the ISS. Scientists can cross-check the animals against the previous data sets to determine how the feared physiological effects are being expressed in the animal models.
The hope from such an experiment would be that Martian rats and mice could adapt to the lower gravity, and not experience negative health effects from reduced gravity. What could escape researchers could be more subtle, unanticipated effects which were not observed in earlier experiments. Once seen in mice on Mars, it would already be too late to avoid human crews from experiencing these effects.
Furthermore, because reproduction of the Martian mice and the Earth-based mice groups cannot be aligned or controlled as other parameters, say food for instance, the experiment also loses the control to give objective results. I say this because the sets of animals are no longer aligned in their developmental and life stages, making objective comparisons more difficult. This would further undermine the reliability of experiments looking at these parameters. However, at this point, comparisons could be drawn around gestation cycles, in-vivo development, birthweights of mice (once landed on Mars and weigh scales become useful) and early development stages between Earth and Mars mice.
What would an experiment look like on Mars?
Once the human and rodent crews arrive on Mars, life changes from a micro/ no-gravity environment to a reduced-gravity context, relative to Earth. With 38% equivalent gravity on Mars, there is some gravity, this can reduce the effects of fluid re-distribution within the body.
Timing
As discussed above - the most recent experiments on board the ISS with mice models typically take up to 30 - 45 days. With some lasting 6 months. In all cases, the mice are euthanised, either on ISS for dissection, or on Earth, to study the impact on organs and tissues. In all cases, detailed analysis is conducted on Earth because the wide range of equipment to conduct detailed analysis is here. However, on a Mars, the Mice would not be returned to Earth. This begs the question again - the resolution of analytical instruments on Mars will be low relative to Earth, so the fine insights would not be picked up. So why try and analyse animals on Mars?
The second study focused on the effect of elevated intracranial pressure occurring in microgravity on the blood-brain barrier which may provide insight into neurological changes, such as impaired vision or reduced cognitive ability during long-duration missions.
Physical Studies
A 2009 study found that mouse test subjects created a 'race-track' game of running around the perimeter of their self-contained habitat once in zero-gravity aboard the ISS. This happened without inducement or use of any rewards but it evolved into a communal, coordinated group activity between younger (not older) mice. This is not too dissimilar to how the astronauts move around the wider ISS habitat.
It was estimated by researchers that this behaviour was born out of typical motor behaviour in mice- the need to run, and the benefits of physical exercise, the sensation of controlled motion.
Anecdotes such as these are some of the types of insights we can gain by simply observing the mice as they go about their 'work'.
Other physical studies can involve dissection. This routinely happened during the Rodent Research missions and would also happen on Mars. However, the problem comes with managing the rodent population as a viable experiment. Dissection of too many of the mice could result in the study prematurely ending as there are not enough viable subjects to continue.
Intellectual Acuity studies
Perhaps surprisingly, there are a great range of tests that can be conducted to evaluate the mental condition, mental acuity of mice. This great Stanford Medicine article shows a shortlist of no less than 11 categories of such tests. By running such tests, the crew can test how the animals are coping, and so what conditions the crew can expect as their time on Mars grows.
How accurate are the insights from such a study? How 'trusted' the output could be?
The above effort could lead to a spurious waste of resources because of genuine concerns around the applicability of animal models to human disease and physiology.
It has been documented that drugs which were developed using animal models, had failed during human trials. This could be owed to deviations in the biological pathways of the animals from those of the human body. Chief of these are trials which focused on Alzheimers, a neurological condition which could give insight for impaired astronauts on long-haul deep-space missions.
It is even hard to know the outcome of the RR missions aboard ISS because while the Rodent Research mission technical documents -offer a great many details, the sections on the pages themselves show a placeholder showing "Data is either unavailable, restricted or under review."
However, these pages do share the intent of the study, the design of the study - what will happen - how many rodents, control conditions, test descriptions, euthanisation method, preservation conditions, control group observations. This is rich data and shows a standardised approach to gathering data from animal models.
It is reassuring to know that NASA, as part of the Human Research Roadmap, to which Rodent Research is a complement, has a detailed job list for many of the parameters we have discussed above. Their website here shows a considered Neurobehavioural Conditions List for Exploration Missions. This is one of a catalogue of detailed NASA missions specifically conducted to challenge a limitation, a sub-optimal scenario or a perceived risk associated with human space travel within and beyond Earth orbit.
A glance across the roster shows multiple studies of stress, vascular analysis of the astronaut corps, circadian rhythm analysis. These are diverse themes but directly related to human physiology. A failure, or rather significant disruption of any of these could severely impact a human mission to Mars, or indeed anywhere else beyond Earth's gravity, and magnetic field.
Ultimately, animal models have been used throughout human spaceflight to help de-risk mankind's steps on its journey to the stars. However, for the many detailed health concerns, mental, physical, that could impact the crew, we see that animal models are limited in the scope, resolution and validity of the results. It looks like, as ever, humans themselves are the guinea pigs and will bring the trove of information by undergoing the experiment themselves.
You can reach me on Twitter: @Ronnie_Writes
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