Sometimes we need to view the issues and conditions that plague us here on Earth through a macro lens; one that can help us see the bigger picture. Space itself may grant us such a perspective.
The question of how to sustain human life on the delicate, resource-constrained closed systems of spacecraft, and the barren and hostile environments of extraterrestrial landscapes such as the Moon and Mars, is at the core of space research and exploration. While this research seeks to support a very select and rarefied group of people to live for long periods beyond the borders of Earth, the biotechnological experiments conducted on the International Space Station (ISS) and in laboratories at the furthest frontiers of research, such as those at the NASA funded Center for the Utilization of Biological Engineering in Space (CUBES), provide insights into human physiology, microbe and plant biology, materials science, and fundamental physics. All of which have direct and profound implications for those of us who remain grounded on Earth.
David Brady, an ISS Associate Program Scientist at NASA and Adam Arkin, a University of Berkeley Professor and the head of CUBES, believe that biotechnological research in space has immediate and pronounced relevance to challenges faced on Earth. These challenges include social justice issues relative to the accessibility to affordable pharmaceuticals, securing new technologies to fight climate change, combating new pathogens, and providing insights into the causes and treatment of common diseases.
The ISS has been operating for over 20 years, funded through collaborations by fifteen countries, including the United States, Russia, Japan and the UK. The ISS laboratory is the critical platform for space experimentation and innovation, providing a unique research environment to trial biotech innovations. Scientists, pharmaceutical companies, and biotech startups have undertaken over 3000 experiments since the ISS opened its low-orbit doors in 2000. According to Brady, “access to continuous microgravity [on the ISS] enables us to model real-world cellular structure much better than what can be achieved in terrestrial laboratories because microgravity allows a 3D development of cellular structures.” Biotechnological innovations achieved at the ISS are critical for developing and verifying the capacity and reliability of tools needed to go beyond low Earth orbit into deep space.
Advances in disease research and treatment
Extensive investigations into cancer, neurodegenerative diseases, heart disease and asthma have been undertaken on the ISS. Brady notes that the research into diseases has only really gathered pace in the last ten years, though the direct medical applications of this research are becoming clearer.
One key research area examines the formation of amyloids, which are protein clusters that can cause neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Researchers harness microgravity to explore their molecular foundations and the risks associated with the onset of amyloids. An ongoing experiment exploits microgravity's effects on liquids to examine the formation of amyloids without the requirement of a solid container which allows for more precise analysis than possible on Earth. By minimising the influence of gravity on the molecular formation of amyloids, researchers can understand the pathological formation of amyloids resulting in improved clinical strategies and drug treatments.
Perhaps the most exciting field or space research with direct medical applications for neurodegenerative diseases involves organ-on-chips aka tissue chips, which are human cells added to micro-engineered environments to recreate functional organs such as lungs, livers and brains. Chris Hinojosa, the Vice President of platform development at Emulate.Inc has been at the forefront of this research on the ISS, examining the blood-brain barrier via tissue chips. This research seeks knowledge about the role of the blood-brain barrier in preventing inflammation, likely to lead to more effective anti-inflammatory treatments and more precise and enduring brain protection to stressors. For astronauts, the research may counter the long-term effects of microgravity and other agitators, enabling technologies to counter some of the debilitating effects of long term space travel. While on Earth, it may lead to greater understanding of and targeted immunosuppression for neurodegenerative diseases.
Cancer research on the ISS is also promising. Cancer researchers have grown protein crystals, such as MicroQuin’s target protein, a group of IV membrane proteins, which cannot be crystallised or purified on Earth. These proteins are integral to cancer survival and pivotal in tumour development. Brady believes protein crystal growth experiments in microgravity have major potential in more general applications, stating that “they continue to improve our understanding of biological systems as well as generating new medical applications.” Medical applications may involve the development of novel pharmaceutical interventions, reduction of drug toxicity, and amplifying drug efficiency before clinical trials in humans.
Brady is particularly excited about experiments with protein crystals and the considerable implications they have for drug therapies. One study examined variables in crystal growth. The aim was to streamline and homogenise the production of monoclonal antibodies, which are essential for fighting a range of human diseases, including cancer. According to Brady, “Microgravity enables the growth of extremely high-quality crystals of uniform size, which allows scientists to improve drug delivery options. Many cancer therapies currently require intravenous infusion, which requires a patient to take time away from work or school and is expensive due to medical facility and personnel requirements. High concentration uniform crystalline suspensions are suitable for injectable formulations that a patient could receive at a doctor’s office or for delivery at home.”
Another fertile area of cancer research on the ISS involves growing endothelial cells. Endothelial cells supply blood in the body, which tumours use to form. Like the protein crystals, cells on the space station grow better than those on Earth. If the researchers can show that the cells produced on the space station model the growth of the cells on Earth, it would likely lead to a revolution in vascular biology research, initiating the advent of drugs that target cells that make blood vessels or lymphatic vessels before the development of tumours.
Degenerative conditions like osteoporosis are also finding hope in the challenges being tackled in space. Astronauts often face muscular atrophy and bone loss in space. Experiments currently being completed, examine how to mitigate the effects in partial gravity environments of the Moon and Mars. Brady notes that “the effects of long-term microgravity on the musculoskeletal system are very similar to the effects of bed rest or degenerative conditions like osteoporosis. Over 50% of all women over age 70 suffer from the latter, so there’s a large potential for helping people on Earth with what we learn in space.”
Another investigation in the musculoskeletal space is a tissue engineering experiment on the ISS that examines human muscle contraction in space as a means to study sarcopenia—age-related muscle decline—on Earth. The study uses tissues in a chip or 3D models of muscle fibres created from cells of younger and older adults. Electrodes cause tissue contractions that allow researchers to see how muscle function changes in space. Microgravity encourages rapid deterioration, allowing researchers to mimic the slow changes in muscular atrophy due to age on Earth in a short period. It is a challenge to study this on Earth and the area remains poorly understood because molecular changes accumulate in skeletal muscles over time.
A biomanufactory on Mars as a model for self-sufficient sustainability
CUBES research focuses explicitly on long-term space exploration, which changes requirements enormously compared to shorter missions. Lengthy missions demand sustainable resource utilisation and on-site material creation because it’s unfeasible to cart all the water, food, fuel and materials needed from Earth. For example, it’s estimated that a 900-day mission to Mars requires over 10,000kg of food mass to sustain six crew members. Quantities like these are massive, risky given unknowns, insanely expensive—just 1kg of food costs 10,000 US dollars—and always limited if provided via a linear pathway at launch. Shorter missions of 30 days to a year are generally manageable but longer trips introduce new complexities and demands; as Arkin states, “the logistics of getting stuff to Mars is just nuts, right, it takes too long. Jeff Bezos quips that he can do Amazon Prime to the Moon. It's a day trip, you know, but getting to Mars is not a day trip, and you're going to be waiting a long time.”
Arkin believes biotechnology will be at the core of all independent space communities. He argues biology itself is a manufacturing platform, “whether it be food, whether it be medicine or whether it be building materials, biology is a very flexible way of doing things, it uses resources very efficiently. It's regenerable, and it provides a set of autonomies that you might not get otherwise because of its programmability.”
CUBES has conceptually investigated a biomanufactory on Mars to support a small community of humans on Mars for an extended period. An integrated biomanufactory would enable the independent onsite production of food, nutrients and pharmaceuticals. It would also produce bioresources as physical components made of plastics, electronics, metals and ceramics as tools and infrastructure materials. Arkin admits that such a self-sustaining biomanufactory is still a long way off—at stage one of the nine-tier Technical Readiness Level (TRL)—but maintains that a Mars-based biomanufactory is viable within our lifetimes.
The biomanufactory would be the ultimate off-the-grid self-sufficient life support system—a kind of high-tech survivalist bunker. Arkin envisages it would look like a large shipping container, similar to those already in use for vertical farming. The Martian biomanufactory would contain plant growth chambers, bioreactors, 3D printers and related purification technologies. It would necessarily be completely closed-loop in the form of a circular system that maximises regenerable biomanufacturing in a way that is energy and mass efficient and low cost, overcoming obstacles of single supply chain resourcing from Earth. A key feature would be optimal water and waste recycling of organic biomass—human waste and inedible plants through microbial anaerobic digestion—as used in some biogas plants on Earth. The manufactory would also exploit resources available on Mars, such as sunlight, ice, atmospheric feedstock of carbon and nitrogen, and regolith (also knows as 'Martian soil'). Arkin remarks that “a Martian biomanufactory has implications for all sorts of disruptive distributed biomanufacture for things that give you autonomy for your food, autonomy for your medicine and autonomy for certain kinds of materials that you can build with.”
CUBES' research into a completely closed loop Martian biomanufactory is directly relevant to communities on Earth. A Martian biomanufactory requires the development and deployment of precision technologies capable of the maximal optimisation of renewable resources and the generation of necessary life support systems on demand. A lot of the resource challenges that astronauts face on inhospitable alien terra firma correspond to Earthbound investigation into sustainable technologies and waste valorisation in the face of climate change. This research could also benefit communities lacking certain resources and materials through developments in onsite continual regeneration and efficient, cost-effective technology to encourage resource sovereignty and localised control of the production of essential resources.
Fresh food on Mars and 3D steaks
Research at CUBES hopes to reduce the amount of food mass required at launch for deep space exploration because getting resources out of gravity and transporting them is prohibitively expensive: “Trying to move a mass from Earth to space and then from space all the way to Mars and then from Mars's orbit down to Mars, that's all very expensive,” Arkin says. He asserts that the focus should be on creating sustainable food on demand that can be grown in space. To lessen the launch mass radically, CUBES proposes launching seeds and small vials of bacteria that can be grown and reproduced in space laboratories such as a Martian biomanufactory. Crucially, these seed stocks would need to be bred or engineered to produce in low gravity situations and tolerate stress in hydroponic or Martian regolith.
CUBES examines how to produce food that offers astronauts variety, nutrition, taste, and the ability to produce biopharmaceuticals as needed. Variation in food and taste is essential to astronauts and their psychological wellbeing and performance. As Arkin states: “It turns out that food is very important as is its structure and how crunchy it is and what it tastes like. Autonomy is important; it’s very important you're able to choose what you eat and not have the same damn thing every day. All these maintain your ability to operate as an astronaut, and it's extremely important that people are respected in their ability to operate because they can't get pissed at each other; they have to be operating.”
Brady agrees that the appeal of food to astronauts is vital. NASA is actively researching menu fatigue and how the limited range of food choices available to astronauts may breed food aversion and decreased nutrient intake. NASA is looking at ways to complement supplied heavily processed foods with foods grown in space via in situ agriculture production and, once the technology becomes mature, 3D printing.
NASA’s Plant Biology Program examines how cultivated plants could supply nutrients that cannot be stored in the human body for long periods and are challenging to keep in a non-perishable form. Recent specialised biotechnology projects include veggie PONDS, a newly developed passive plant nutrient delivery system for cultivating and harvesting lettuce and Japanese mustard greens in low orbit. Space-focused food cultivation solutions can also be harnessed for densely populated areas on Earth where there is little room for growing vegetable gardens or the environmental conditions mean that essential crops struggle to grow. Veggie PONDS are part of the ISS’s Vegetable Production System (Veggie), which examines and experiments with agricultural production in low gravity to produce fresh food to sustain astronauts and as a source of recreation and relaxation. The therapeutic elements of gardens are profound in space. Arkin says, “People are pretty resilient, but if you go to the space station and you're hanging out on the space station - guess where everyone ends up? They end up in the room where the veggie producer is so they can see a green plant.”
Brady explains that research into plant growth in microgravity has applications on Earth, “especially in areas like water management, due to the need to understand how much water to supply in an environment where the effects of liquid surface tension and capillary flow can make the difference between food crop success or failure.”
While Israeli start-up Aleph Farms grabbed headlines by printing the first beef steak on the ISS in 2019, Brady notes that the ISS’s BioFabrication Facility is still developing its ability to print organic materials. Despite the sensationalist headlines, it is way off 3D printing of food for astronauts on demand or at scale. However, when possible, it will have a dramatic impact on long-term space travel and agricultural production on Earth.
Algae has also been explored as a source of food, dietary supplements, oxygen and even fuel. One research area involves genome sequencing of algae populations grown in tissue culture photobioreactors on the ISS, to see if and which genetic modifications are required for optimisation in microgravity so that astronauts can domesticate space algae at scale as a feedstock and means to remove Co2.
Researchers have also examined the effect of different lightwaves on algae, seeking the optimal lightwave lengths to grow algae in space, under the limited sunlight available. Algae are relatively easy to grow; one strain [Chlorella vulgaris] is high in protein, making it a potential food source for astronauts and for people on Earth. It also has a high oil content and can potentially be utilised as a biofuel to run cars or even power the ISS itself.
Red light promotes the presence of the antioxidant anthocyanin in algae. Algae with high levels of anthocyanin could combat some of the damaging effects of radiation which beyond low-orbit increases Astronaut's risk of neurodegenerative diseases, cancer and detrimental central nervous system effects. On Earth, algae enhanced with anthocyanin could counter the side-effects of radiation therapy and provide better UV protection in sun screens.
Biopharmaceuticals: lettuce as "drug factories"
Extended habitation in space requires new ways to produce pharmaceuticals. The drugs that are brought from Earth expire and run out, and unforeseen situations or reactions require novel interventions. Rather than transporting pharmaceuticals, astronauts could program plants and microbes based on the required DNA sequences to produce the needed drug, nutrients and vitamins.
The solution CUBES proposes can be made possible by bringing food and pharmaceutical production into synthesis. As plants and seeds are already a critical requirement—and seeds don’t decay over time—it makes sense to also use them to produce pharmaceuticals. A crucial component of the research is to produce drugs "just in time"—even within a 24-hour window—maximising the limited resources available on space missions. Arkin envisages a time when "in an emergency, NASA could beam a new DNA sequence from Earth to Mars to make a new thing which astronauts could put into the plants or the microbes and then create, on-demand, whatever they needed.”
As an exemplar of the synthesis of plants, food and pharmaceuticals, Arkin points to his colleague, Professor of Chemical Engineering Karen McDonald's research into plant-made pharmaceuticals. Her research with collaborator Dr. Somen Nandi, applies techniques in chemical engineering, plant sciences and molecular biology to produce plant ‘bioreactors'. These bioreactors introduce the genetic material of unrelated organisms into plants or cell cultures, which can be used at scale to produce novel recumbent proteins that have therapeutic potential as vaccines and antibodies.
At CUBES, Dr. McDonald is leading a study into the viability of using plants to make miniature "drug factories". Arkin notes plants already have the biosynthetic ability to produce proteins. Astronauts will just need to give them the instructions—as DNA sequences—to create what is required. One experiment examined how lettuce can be grown as a drug manufactory. The lettuce were infected with genetically modified bacteria carrying a DNA sequence to produce the parathyroid hormone (PTH), a peptide that works against bone atrophy in low gravity.
Similarly, BioNutrients experiments on the ISS seek to reduce the nutritional deterioration of stored food and supplements over time, as well as generate new food and supplements during space travel. For example, astronauts activated modified yeast in space over a five-year period to produce zeaxanthin, a beneficial carotenoid useful for eye health.
Arkin believes biopharmaceuticals could also overcome the current economic and environmental unsustainability of a lot of medicine production on Earth. He references work pioneered by Professor Jay Keasling at the Keasling Lab which produced yeast with synthetic genes to make a compound called artemisinin, effective in treating drug-resistant malaria. This innovation avoided the expensive and unsustainable harvesting of a Chinese wormwood shrub called Artemisia annua. Arkin believes that such synth-bio innovations such as these could “significantly lower costs and increase the accessibility for lots of different types of drugs.”
Climate change and pathogens
Space research and experimentation involving biopharmaceuticals has direct and immediate applications to issues on Earth. Innovation could lead to increased mobility, streamlined supply chains and adaptability to environmental extremes. CUBES research, in particular, may provide people with the tools to prevent the worst-case scenarios of climate change and allow people to operate in an increasingly hostile environment on Earth. Arkin contends that one of the biggest classes of pharmaceuticals urgently required is novel antibacterials and antivirals because of increased resistance by bacteria and fungi, and climate change driving emerging infection by viruses. While avoiding climate change and resultant desertification and mass migration would be the most obvious and necessary solution, Arkin is doubtful about our ability to do this. He believes we need to plan for the new environment we are in, especially because it will involve an increase in dangerous pathogens. He states:
"Climate changes biodiversity and that has a provable effect of increasing pathogens—an increased chance of zoonotic transmission. There's a series of ecological leaps that get us there. Climate-induced migration causes dispersal. Population density and population growth puts us in contact with more animals and that also drives it. Temperature change itself leads to the migration of animals and change in water bodies and things like that, leading to more niches in which pathogens can survive."
Arkin believes dealing with the emergence of novel pathogens requires an ability to engineer new organisms and to hit the new pathogens before they have a chance to get to us. Research is already examining the role of small molecule antibiotics on the ISS against resistant bacteria in space. Another critical research area involves engineering bacteriophage. Similar to McDonald's plant viruses, bacteriophage can only infect other bacteriophage and not humans. Arkin explains: “You can engineer them on-demand, in a sense, to kill an organism that you want, very specifically. There are some limits to that right now but there's no theoretical limit to it.”
Despite major advances in biopharmaceutical production, Arkin notes that it is still a complex process because “there's a shortage of new molecular types to use and these are often hard to synthesise.” Notwithstanding the scientific challenges, Arkin believes that careful consideration must also be given to the ethical deployment of biopharmaceuticals, because together with their clear benefits there are national security concerns related to the intentional deployment and containment of novel pathogens, and social harm concerns related to the disruption of ecological niches that people may depend on. Conspicuously, the production of biopharmaceuticals is not as economically remunerative for pharmaceutical companies as traditional production methods. However, Arkin urges that there is an acute need to shift from economically prohibitive and Big Pharma controlled biopharmaceuticals via animal cells to a focus on engineering new antibacterials and antivirals via alternative means. As referenced above, this perspective is foreshadowed in Dr. McDonald’s research, which proposes the large-scale manufacture of plant-based vaccines based on plant to plant viruses to build immunity for humans to COVID subsequent pandemics as a means to decentralise production away from pharmaceutical companies and to make vaccines more accessible, particularly in developing countries. Instead of importing vaccines, countries could grow and control the production of their own vaccines. The research correctly predicted that the global deployment of mammalian based genetic vaccines for SARS-CoV-2, such as Pfizer/BioNTech and Moderna/NIAID COVID vaccines would cause inequalities in the transport and deployment of the vaccine to developing countries. The paper notes: “Plants can be scaled-up to meet the demand for COVID-19 countermeasures without the need for extensive supply chains and/or complex and expensive infrastructure, thus ensuring low production costs.” At scale, vaccines derived from plant biomass could offer flexibility, rapid deployment once the DNA sequence of the pathogen is known and localised control of production and deployment. The Grill Laboratory at the Keck Graduate Institute has developed a low-cost plant-based vaccine for COVID-19 that is currently in trial stages and will soon be produced in Botswana.
The experimental work at CUBES aligns directly with the Earth-focused research at the Arkin Laboratory because both engage in predictable, designable, responsive bio-engineering. The Arkin laboratory examines how to engineer biology to solve problems for human beings and the Earth itself. It does this by blending bioengineering of organisms with wider systems analysis, which tracks plants and microbes within specific ecological niches. The foundational goal of the laboratory is to build "safe, sustainable biotechnologies for environmental stewardship, health, food, and materials based on well-informed systems-level bioengineering.” Essential to Arkin's system analysis is the development of good observatories and metrics so that when a new virus appears, the novel antibiotic can be deployed "ethically" in an environment. Ethical deployment involves what Arkin describes as a predictive ecologically informed design-test cycle and “‘measuring the environment, understanding that ecology, identifying the emerging infection or the emerging problem that changes the environment. And then to be able to intervene in predictable ways.”
Utilising biological systems and repurposing them to solve environmental, medical and social issues permeates space biotechnological innovation and experiments. It expands our focus beyond the Earth and utilises the environment, resources and materials of the much larger and older universe that surrounds us. By doing so it highlights both our interconnectedness and uniqueness. As our reach into space increases, there is clear hope that the Earth and its inhabitants will be better off in the future.
