“Man is an artifact designed for space travel. He is not designed to remain in his present biologic state any more than a tadpole is designed to remain a tadpole.”
William S. Burroughs, The Adding Machine: Selected Essays (1993)
We humans are an exploratory species. We have charted the great expanses amongst the stars while recording events so small and so fast that they hardly could have been said to have occurred at all. For all our advances, there is still so much more in the universe that we have yet to discover. Space exploration will be the next chapter in humankind’s voyage of discovery of the natural world, and our inevitable dissemination from planet Earth will redefine what it means to be human. This will also be a challenge, and one we must meet with our best tools and capabilities.
All organisms are the products of their environment. The sum collection of our genes reflect the environment we inhabit, a product of genetic variations shaped and nurtured by selection pressures acting on population level mutations over long periods of time. When migrating to new environments, we find ourselves undergoing significant cultural, genetic, and social changes, an old canon of the history of our species; but perhaps the most drastic change is yet to come. Unforeseen perturbations to the pace of technological progress over the next several decades aside, we will open this grand chapter by building outposts on the planets of our solar system, such as Mars or Venus. These environments will be unlike we have inhabited, and the journeys to reach them more difficult than any we have endeavoured to undertake.
Humanity’s capability for feats of peerless ingenuity under nigh-impossible pressures is historical fact; the moon was famously reached using less computer processing power than an iPhone. We are meeting this new challenge with our latest and best in aerospace engineering, and there’s no reason why we shouldn’t do the same in regards to our own biologies, to better equip ourselves for this new task that lays ahead of us and the many generations of humans ahead. The question: how can we optimise our biologies to be better equipped for thriving away from Earth, using modern tools at our disposal? Space is likely the most hostile environment ever encountered by humankind, or any other species that exists on the planet, and is uniquely dangerous in ways that even the inhospitable areas we find on the planet are not. Moving through space is necessary prerequisite to arriving at our next interplanetary home, the climate of which will also be far from forgiving, and we need every advantage we can get in navigating such perilous environs.
The effects of radiation, variation in gravity, and the response of our physiology to such changes is well documented. As of the 29th of June this year, humans have left the planet 372 times since Yuri Gagarin’s first flight in 1961, and the data we’ve gathered paints an unfavourable picture of the human body’s response to off-planet environments. Our bodies and minds must change to meet this new challenge head on. As humans, enhancing our abilities through technology is the modus operandi that’s taken us to our position of species-level dominance; fire and flint knives begetting phones and planes for global travel and communication. Recently, advances in biotechnology may give us the option of improving ourselves on a more invasive level, which I will examine here. Gene editing with the aim of human enhancement would allow us to select genes that can be modified to confer particular benefits, and maximise the safety and capabilities of human space explorers. Many genetic loci of interest have already been catalogued in Harvard professor George Church’s legendary transhumanist wishlist, which details causal links between genes and desirable traits, from less pain sensitivity to greater memory. The question is which traits would be most valuable for space exploration, and how could we attain them?
“But as always in my strange and roving existence, wonder soon drove out fear; for the luminous abyss and what it might contain presented a problem worthy of the greatest explorer.”
H.P. Lovecraft, The Nameless City (1921)
The first noticeable difference between being on Earth and in space is the microgravity, the absence of an atmosphere to push down on you. Data from decades of astronaut experience and flight follow-ups have conclusively shown that the human musculoskeletal system is far from optimised for functioning outside the confines of our pale blue dot. NASA prescribes two hours of working out a day in order to maintain a healthy level of musculature, though this barely helps; on spaceflights lasting five to eleven days, astronauts see up to 20% muscle atrophy or loss. Besides directly reducing physical performance, full-body atrophy can be outright pathological, leading to breathing problems, bone fractures, spinal curvature, and in the absence of treatment, death.
We have somewhat of a head-start here, as different congenital muscular atrophies have been on gene therapy hit-lists for a long time. MSTN is a gene coding for growth diffraction factor 8 (GDF8), also known as myostatin, a protein that inhibits synthesis of other proteins while also negatively regulating stem cell proliferation into muscle cells. It’s been shown that too much myostatin leads to muscle wasting. Mice that have had this gene knocked out (KO) exhibit a 200 - 300% increase in muscle mass, due to an increase in both muscle cells and fibres.
Inhibition of this gene’s function has been a target of therapy for muscle dystrophy disorders, but so far, the results have shown mixed success. Researchers attempted to regulate muscle growth by knocking out the MSTN gene. How was this different to just inhibiting myostatin with a drug? Well, traditional, drug-based inhibition only affects post-natal muscle growth. Knocking out MSTN in mouse embryos has a greater impact on global muscle mass, but there was skepticism that greater muscle growth and regeneration rates in mice leads to poor replicability in human muscle, which could be less amenable to drugs. But these are engineering problems, so to say, and MSTN is still a highly lucrative gene to target. For example, this phenomenon has been observed in a human subject, who was already capable of lifting 3 kilogram weights in each hand as a four year old. Trialled inhibitors such as stamulumab have suffered from poor coverage and weak pharmacokinetics in humans, while another trial inhibitor lead to nonspecific inhibition and unacceptable side-effects. Recent advances in gene editing technology, however, could allow us to re-examine MSTN as a target for downregulation.
Myostatin mutations leading to increased strength and mass are what we call de novo mutations, arising due to genetic errors at random, and can certainly be useful. But why not copy existing traits, selected over many generations by evolutionary pressures? Biomimicry is an approach which looks to the natural world for inspiration in human engineering and design, but perhaps we could also look at the desirable characteristics of other organisms to apply to our own phenotypes. At least for spaceflight, we can look to how certain species conserve their body mass and function over long periods of reduced activity; hibernation. One of the most notable features of many hibernating species, such as bears, is the lack of muscle loss that one would expect from the complete lack of movement and neural stimulus over a period of six months or more.
Recent research compared the response of human muscle cells cultured in a dish to those grown in nutrient media that had been treated with serum taken from the blood of Japanese black bears. The idea was to divulge what metabolic factors, if any, allow bears to undergo their legendary month long periods of inactivity without losing significant amounts of muscle mass. The researchers noticed that while protein content increased, the protein synthesis pathways weren’t apparently affected; more protein wasn’t being made. The secret likely lay in less degradation of existing proteins. Specifically, it was the expression of muscle RING-finger protein-1 (MuRF1), a skeletal muscle-specific ubiquitin ligase and biomarker of muscle atrophy which was significantly decreased following treatment with hibernating blood serum. The essence of ubiquitin ligases is in degradation of proteins to control their levels by tagging them with a molecule called ubiquitin, because it is ubiquitous, and because creatively naming your discovery isn’t necessary to win the Nobel Prize. Hibernation in bears is also noted by an increase in protein synthesis in both liver and muscle tissue, as well as deregulation in the ubiquitin-proteasome (basically, protein digesting) pathways, essentially signalling that there was less degradation of proteins. The take home lesson here is that if we want a lot of something, we can either make more, or simply get rid of less. We can surmise that a modality for replicating the same in humans would involve downregulating these exact pathways, and could be applied intermittently during long periods of space travel, conserving precious resources that may be scarce, such as freeze-dried ice cream or contraband corn beef.
Muscle atrophy aside, humans that are in space for significant periods of time will find themselves challenged by the aptly named spaceflight osteopenia, the loss of bone mineral density as a result of microgravity. In his 2017 memoir, Endurance, astronaut Scott Kelly described the bone loss he experienced, framing this process as his body’s way of minimising unnecessary expenditure. NASA observed that astronauts in flight can lose up to 1.5% of bone mass per month; compare this to the elderly on Earth, who lose that much per year. Loss of bone mineral density leads to an increased risk of fracture and general premature osteoporosis. Modalities to combat this degeneration have thus far revolved around physical exercise and calcium supplements, which as evidence shows, simply doesn’t cut it.
If I don't exercise six days a week for at least a couple of hours a day, my bones will lose significant mass - 1 percent each month ... Our bodies are smart about getting rid of what's not needed, and my body has started to notice that my bones are not needed in zero gravity.
Scott Kelly (2017)
In 1994, a man involved in a serious car accident reported to the clinic with a curious outcome; he sustained no injuries, and X-rays of his spine showed no fractures. In fact, they showed that his bones were unusually dense; approximately 8x the density of the bones of an average human being; this was due to a gain-of-function mutation in his LRP5 gene.
The low-density lipoprotein receptor-related proteins (LRP) are a family of proteins that regulate bone development during growth. Loss of function mutations of LRP5 often preclude osteoporosis, but other mutations often reveal interesting things. In transgenic mice exhibiting a mutation (G171V), resulting the single change of a nucleotide from a guanine to a thymine, changing the codon sequence from GGX to GTX and the coded amino acids from glycine to valine. This seemed to reduce the cell death, or apoptosis, seen in osteoblasts (cells a few steps down from stem cells that form bone tissue) and allowed for more growth than in the wild type mice.
Above, we can see a marked difference between the vertebral bone volume fractions of normal mice compared to mice with over expressed LRP5 (gain of +25%) and the G171V mutation in LRP5 (gain of +109%). Bone remodelling in microgravity may be inevitable, the surplus density can allow an enhanced level of function and stability, even in such adverse conditions. SOST is a gene coding for sclerostin, a bone-morphogenic protein antagonist that has anti-anabolic (anti-growth) effects on bone formation. Mice with a mutation knocking-out the SOST gene were completely immune to bone loss following injury to the spinal cord which saw wild type mice suffer a 64% reduction in bone volume. As we saw with MSTN, promoting the growth of a certain kind of tissue can be achieved by removing the negative regulator of growth from play. Targeted protein degradation, for example, has emerged as a modality of getting rid of proteins (say, disease causing ones) without necessarily disrupting an organism’s ability to produce them wholesale. The advantages of this approach are that it’s reversible and tuneable. This could allow for treatments timed to coincide with long-haul space trips, to help preserve muscle and bone mass in microgravity environments, or as a permanent therapeutic supplement “package” for humans who live on a planet with weaker gravity than Earth’s, such as Mars.
Greater strength and general hardiness, while crucial, pale in comparison to one of the most important traits spacefaring humans must possess. This is resistance against a very specific kind of damage not often encountered on Earth; radiation. In addition to the general increase in mutation leading to cancer, ionising radiation damages the central nervous system and impairs motor and cognitive functions, neither of which you’re well to do without on a long haul space flight. Even more worrying is the radiation bystander effect, where cells unaffected by radiation yet proximal to those that are will activate their own DNA damage response pathways.
Mars lacks a global magnetic field like that of Earth’s. Consider a flight time of several years to Mars, and an initial stay of just over a year. The estimated total radiation dose for a round trip mission, based on current calculations and measurements for conjunction-class missions, is approximately 1.01 Sv, the point at which reduction in white blood count is observed. While dependent on the specific details of the mission and the solar conditions, this is twenty times the yearly dose permitted by the U.S. Nuclear Regulatory Commission for workers exposed to radiation at their job. On Mars, the conditions may be more promising; 240 - 300 mSV per year which, while considerably higher than Earth’s average of 6.2 mSV per year, may actually not be past the range which humans can thrive in. Inhabitants of Ramsar, Iran, reportedly enjoy a yearly dose of 260 mSv, 13x what the rest of the planet experiences. Natives still live for many generations in the area with no apparent ill effects, so it’s possible that the secret of human biological radiation resistance may be in closer reach than previously thought. Some preliminary research hints at the role of MLH1, a gene coding DNA repair proteins, being expressed at higher levels than normal in the local population. However, the authors only selected this protein and one other, so other more prominent ones could remain to be found.
While mitigating radiation exposure will be a mechanical engineering problem, there is no need for us to limit ourselves and only thinking of it as one; we must take a multidimensional approach involving bioengineering. Indeed, work in this direction has been progressing. An international consortium comprised of participants from NASA, Oxford University, Boston University and more met in 2018 to develop a roadmap for engineering radioresistance in humans. Likewise, the Consortium for Space Genetics at Harvard aims to investigate the best approaches to maintain and optimise human health for space travel.
This roadmap sets the stage for enhancing human biology beyond our natural limits in ways that will confer not only longevity and disease resistance but will be essential for future space exploration.
João Pedro de Magalhães (2018)
Tardigrades, also known as water bears, are microscopic, four-legged aquatic animals that are known for both their funny shape and an uncanny ability to survive conditions that would hang even the most hardy of extremophiles out to dry. From resistance to temperatures of -196 to 100° C, to high pressure, organic solvents, radiation and even the vacuum of outer space, these microfauna can survive practically anything. In part this is due to their intrinsically disordered proteins, proteins which don’t have a set shape or form allowing them great adaptability. Boothby et al. treated human blood clotting factors with protein and sugar-based mediators of anhydrobiosis (extreme drying-induced suspended animation), observing that the factor was stabilized under repeated cycles of thermal stress and desiccation. Interestingly enough, the preservative functions were controlled by different proteins entirely; the nematode worm’s AavLEA1 did best at protecting from desiccation (vacuum for an hour), while the tardigrade’s CAHS D protected against thermal shock (95° C for a whopping 48 hours). The cytoplasmic abundant heat soluble (CAHS) protein family is joined by secreted (SAHS) and mitochondrial (MAHS) proteins which work to protect the cells of the organism in adverse conditions.
Researchers sequenced a section of the genome of R. varieornatus, one of the most stress-tolerant tardigrade species. One protein, Dsup (damage suppression), particularly stood out - highly produced at an early embryonic stage, and localised with nuclear DNA, suggesting a role in protecting the DNA from external stress. To test their hypothesis, the researchers established a cell line expressing Dsup in the growing cells, and exposed them to 10 Gy of X-ray radiation. When compared with cells that weren’t expressing Dsup, the researchers saw about two times less structural changes evidencing DNA damage. Previously, the radiation resistance of tardigrades was attributed to their dehydrated state; however, it’s been show that hydrated tardigrades are more radioresistant. Human HEK293 cells engineered to produce the Dsup protein were 40% more resistant to X-ray radiation, and if further research shows no negative side effects from producing this protein in human cells, then we have another excellent candidate for radiation resistance in humans.
Concerns regarding germline and somatic gene editing in humans with the sole purpose of enhancing existing traits or generating advantageous characteristics is the lack of supposed necessity, even assuming safety and efficacy standards are met. Nevertheless, despite a brutal false start in 1999, advances in genetic technologies have heralded our age of safe and reliable gene therapies. As of 2021, over 2,400 gene therapy drugs are in development; most still at the preclinical (animal models, in vivo cell cultures) stage, with a small percentage in phase 3 of clinical trials. Recently developed prime editing showing promise due to its far greater precision in causing small nicks in the DNA, rather than breaking open large swaths, as in traditional CRSIPR Cas9 gene editing. Just last month the Zhang lab characterised Fanzor, a human-derived analogue to bacterial Cas9, potentially promising more effective editing in human cells. The gene targets discussed above and more are often involved in metabolic pathways critical to healthy functioning of the body, so perturbations would have to be carefully overseen so as not to induce excessively detrimental side effects. Nevertheless, to increase our capability and competence at modelling our own biologies, we must take a proactive stance, and take prophylactic steps today to solve the problems of the future.
In looking towards the stars, a clear usecase emerges; a future where humankind, or our descendants, freely traverse the cosmos as we freely traverse the skies and the seas. Our ever-deepening understanding of our own biologies and gradual mastery over our capacity to manipulate them would only leave it to our tastes and conventions to prevent rapid adoption of this technology. The high costs of current gene therapies are mostly due to the great expenses of pharmaceutical R&D programs relative to the few patients these therapies have. Simple therapies to increase strength, resistance to radiation, and other traits later down the line would be available and desirable by many more, greatly increasing their affordability and practical availability. And if we prepare our astronauts with the latest, next-generation spacesuits - then why not the latest, next-generation genomes?
