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Space Synthetic Biology: A Paradigm

for Sustainability on Earth and Beyond

Tiffany J. Vora,1,2 Nils J. H. Averesch,3 Erika A. DeBenedictis,4

Keywords: synthetic biology, space biotechnology, human
and Lynn J. Rothschild5
spaceflight, sustainable space exploration, dual-use technol-
1
Explore Mars, Massachusetts, USA. ogies, circular bioeconomy
2
Singularity University, Mountain View, California, USA.
3
Center for the Utilization of Biological Engineering in Space
(CUBES), Berkeley, California, USA.
INTRODUCTION TO SPACE SYNTHETIC BIOLOGY:
4
Biodesign Laboratory, The Francis Crick Institute, London,
WHY NOW?

S
UK. ynthetic biology (SynBio) is the application of engi-
5
Space Science and Astrobiology, NASA Ames Research Center, neering principles to biology for the design and con-
Moffett Field, California, USA. struction of units or systems with new functions.
Propelled by the ever accelerating advances in inte-
grating life and computer science, from bioinformatics to deep
ABSTRACT learning to artificial intelligence, SynBio is poised to deliver
National space agencies and private entities aim to establish breakthrough technologies that play a pivotal role in the
emergence of a new bio-based economy. This bioeconomy is
outposts on the Moon and Mars before the second half of the
expected to redefine aspects of the energy, materials, food,
century. This goal requires new technology paradigms that must
and pharma sectors, related to but not limited to areas such as
be readied now for implementation in mission architecture. Here
safety, security, and sustainability.
we present the case that synthetic biology is one such enabling
Given a projected global annual impact of USD 2–4 trillion by
technology that will work in synergy with a growing bioeconomy
2040,1,2 the U.S. government has taken several actions to secure
to solve a broad array of challenges facing humans on- and off-
the position of the USA as a major stakeholder in bioindustrial
Earth, as they establish a foothold on the Moon in the post- manufacturing. Consortia of national laboratories such as Agile
Artemis years and continue to the exploration and eventual BioFoundry, funded by the U.S. Department of Energy, serve to
habitation of Mars. We propose a phased integration of synthetic “operate as a distributed biofoundry in collaboration with indus-
biology into Space missions over time and identify critical dual- try and academia.”3 Federally sponsored manufacturing innova-
use breakthroughs that will expand the impact of synthetic tion institutes such as the bioindustrial manufacturing and
biology on both Space missions and the Terrestrial bioeconomy. design ecosystem (BioMADE), which is sponsored by the U.S.
Finally, we highlight actions by national space agencies and the Department of Defense, have been formed to spawn a “sustain-
private sector that will be critical in the coming years to harness able, domestic end-to-end bioindustrial manufacturing eco-
the potential of synthetic biology for establishing a sustainable system.”4 White House Executive Order 140815 announced a
human presence off-Earth. “whole-of-government approach to advance biotechnology and

All authors contributed equally to this article.

DOI: 10.1089/space.2024.0002 ª MARY ANN LIEBERT, INC.
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biomanufacturing towards innovative solutions in health, cli- and manufacturing). SynBio is also relevant to recurring tenets
mate change, energy, food security, agriculture, supply chain of NASA’s Moon to Mars objectives, including: RT-1, Interna-
resilience, and national and economic security.” Given the wide tional Collaboration; RT-2, Industry Collaboration; RT-3, Crew
range of industry verticals that could be affected by an expand- Return; RT-5, Maintainability, and Reuse.19
ing bioeconomy, “Bold Goals” have been defined for U.S.-based
biotechnology and biomanufacturing,3 substantiating EO 14081. THE POWER OF BIOTECHNOLOGY TO
A sustainable biochemical industry is seen as a foundation OVERCOME UPMASS CONSTRAINTS
of an eventual circular economy, transforming the life cycle Imagine a manufacturing technology that is self-replicating
of commodities with regular demand and high turnover, both and self-repairing, modular, reprogrammable, and exceedingly
on Earth and in space.6 Hence, in addition to driving the bio- flexible in terms of the input. It can create fine chemicals and
economy, SynBio-based solutions are relevant to the current polymers with monomeric precision, is remarkably resilient,
United Nations Sustainable Development Goals,7,8 with poten- and can be stabilized simply by dewatering, with a shelf-life at
tially major economic and social benefits worldwide.9–12 room temperature on the order of years to centuries.20 That
The bioeconomy will also extend into the new Space Age13 technology is life.
as SynBio has several unique advantages with regard to Space Biotechnology has the power to solve many of the upmass
versus Terrestrial applications (examples are discussed below). constraints of Space travel by enabling the reuse of resources
First, SynBio has the potential to solve upmass constraints on and basic feedstocks that are available en route (through so-
missions, thus increasing mission capabilities.14 Second, there called “loop closure”) and/or at destination (through “in situ
are no indigenous manufacturing industries or jobs off-Earth resource utilization” (ISRU)). In the former case, the feedstock
that would be disrupted by designing systems and processes can be derived through the recycling of waste streams derived
that are inherently sustainable. Third, the potential for estab- from supplies that have been transported from Earth such as
lishing new jobs and new economies through SynBio in Space food and packaging. In contrast, ISRU takes advantage of feed-
is attractive for investing in the Space-specific education, func- stocks that are available in significant, accessible quantities on-
tionalities, and markets that tie back to the Terrestrial site, such as H2O, atmospheric CO2 and N2, and minerals, in the
bioeconomy.15 case of Mars.18,21–23 On Earth, advanced manufacturing
Perhaps most importantly, SynBio will also be key to approaches that leverage these resources usually require bulky
addressing the recommendations of the National Academies’ (heavy) and sophisticated hardware and infrastructure such as
2023 Decadal Survey on Biological and Physical Sciences chemical reactors, rectification columns, and cleanrooms, as well
(BPS) Research in Space that will empower humans to live and as costly and potentially environmentally damaging inputs such
travel in Space,16 as we argue below. as fossil fuels, rare earths, and noble metals. But there is no more
What are the major challenges to human long-duration precise nanotechnologist and molecular factory than a living
Space travel and settlement across the solar system? The 2020 cell.24 For example, several biochemical mechanisms exist for
NASA Space Technology Taxonomy identifies distinct chal- fixing CO2 and N2; metals are bound to various biomolecules
lenges,17 such as radiation and physiological adaptation to with precision, potentially paving the way for extraction and
lower gravity. Although SynBio conceivably could be applica- separation of ore as well as spent electronics.25,26
ble in nearly all of these areas, we must consider whether it Further, many supplies of regular use,18,27,28 such as food and
should. Although there are strong arguments for using existing pharmaceuticals but also materials, lack the long-term stability
systems that are proven to support humans off-planet, required for a nominal *2.5-year roundtrip Mars mission (con-
extended missions will need to address additional payload con- junction class).29 Thus, a “take” strategy must be supplemented
straints, particularly limits to the mass launched into Space with “make” strategies to enable sustainable exploration.18,27,28
(upmass) and the shelf-life of the cargo.18 Critically, reliability Examples of such supplies include food30 as well as pharma-
and resilience as well as redundancy and flexibility will be key ceuticals—especially peptide-based biologics that support crew
to mission success and crew safety, given the increasing fragil- health, such as human growth hormone (hGH)—and have shelf-
ity of supply chains when advancing into deep Space. These lives of much less than a year, even with refrigeration.31 An on-
considerations motivate our focus here on three NASA technol- site, on-demand “astropharmacy” based on the transgenic
ogy taxonomy areas in particular: TX06 (human health, life SynBio production of such pharmaceuticals may be part of the
support, and habitation systems), TX07 (exploration destination solution,32–34 supplementing abiotic approaches.35 Importantly,
systems), and TX12 (materials, structures, mechanical systems, such technologies have dual applications on Earth, particularly

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 SPACE SYNTHETIC BIOLOGY: A PARADIGM FOR SUSTAINABILITY

for austere locations with unreliable supply chains or when cases in low Earth orbit (LEO). Within 5 years of the first Arte-
needs are restricted to a small number of people, such as orphan mis astronauts setting foot on the Moon, “make it there” Syn-
drugs.36 Further, Space Biotechnology could include self- Bio approaches with the greatest potential to be transformative
renewing recycling and manufacturing systems (biorefineries) for space missions (e.g., by dramatically decreasing upmass)
for materials, as well as power plants, sensors, and diagnostics.14 should be prioritized to deliver reliable applications within the
The major challenge to harnessing the power of biology in 10–30 year horizon. Such prioritized SynBio approaches would
support of Space activities pertains to the fact that Terrestrial life include ones that tackle problems for which there are no abi-
evolved on Earth. Natural biological organisms and their otic approaches currently available, such as the shelf-life issue
underlying biochemistries have evolved for survival and com- of pharmaceuticals described above. Ideally, these approaches
petitive advantage on Earth, rather than being optimized for will be highly automated and resilient, minimizing burdens on
one specific task. Thus, most organisms taken out of their nat- crew training and active time during a mission. The specific ben-
ural ecological niche and possibly even off-planet should and efits of implementing such advanced support functions will
perhaps must be adapted (evolved or engineered) to the altered depend on many factors that determine the concept of operations
conditions (such as higher radiation and lower gravity). Syn- for a given mission scenario, which will be informed by explicit
Bio provides the means to tailor organisms or ecosystems for techno-economic analyses and backed by calculations of equiva-
specific off-planet needs.37,38 This strategy may reduce the lent systems mass to validate biotechnological approaches for in
engineering required for designing and operating bioprocesses situ manufacturing.41 Potentially pivotal “stretch goals” for Syn-
in Space, thus decreasing mass and power requirements while Bio in Space should be defined and researched as soon as possi-
delivering robust and potentially flexible mission capabilities. ble to enable proof-of-principle work and, if promising, the
For example, a microbial cell factory that has already been required DBTL cycles to raise their TRL to where they are robust
modified on Earth for a particular biomanufacturing task may and reliable solutions. Consistent with this latter approach, the
only require additional genetic engineering to withstand the 2023 Decadal Survey on BPS Research in Space recommended
higher radiation levels of Space.39 Alternatively, a species that NASA pursue a research campaign in Bioregenerative Life-
must be cultivated in a controlled environment closer to its Support Systems (BLiSS).16
Terrestrial environment, which has the benefit of relying on We believe that SynBio will be key for both of these recom-
well-studied systems that do not need significant further mod- mended research campaigns, which constitute science and
ifications. In either case, planetary protection concerns need engineering fundamental to life off-planet. When biological
to be considered to avoid contamination of potential research engineering at destinations like Mars becomes possible, an
targets for astrobiology.14,36,40,41 ecosystem of biomanufacturing facilities co-localized to space-
craft, -stations, or bases could underpin sustainable commun-
FROM EARTH TO SPACE: PHASED INTEGRATION ities of people, delivering the food, air, water, and waste
OF SYNTHETIC BIOLOGY processing that will enable long-duration or even permanent
Harnessing the power of SynBio in support of human human habitation off-Earth while protecting environments
exploration and settlement of the Moon and Mars requires the such as the surfaces of the Moon and Mars.
coordination of two rapidly moving fields: (1) the planning
and implementation of space-exploration programs, and (2) CRITICAL BREAKTHROUGHS WILL DELIVER
the advancement of SynBio and its applications.40 Replacing DUAL-USE TECHNOLOGIES
existing abiotic technologies with potentially superior but less All technologies, including SynBio, must become efficient,
flight-tested biological solutions introduces risk until proven reliable, and flexible before they can become critical pieces of
by design-build-test-learn (DBTL) cycles designed to increase infrastructure that drive circular economies on Earth or in
the technology readiness level (TRL) of the biotic solutions. Space. We have identified critical breakthroughs that will enable
Ideally, such technologies will drop into the existing mission the development of dual-use technologies, having the potential
architecture, minimizing the extent of changes required and to benefit both Earth and Space (Fig. 1). Specifically, the suc-
disruption to other systems, thus enabling rapid deployment. cessful application of SynBio in Space will require purposefully
Therefore, we envision a phased approach toward integra- created reagents, chassis organisms, methods, and hardware
tion of SynBio in which missions during the 10-year horizon with maximum fidelity for cross-platform application.
focus on “carry-along” and “drop-in” SynBio-based technolo- Molecular biology requires reagents that are manufactured
gies that have a track record of success on Earth or in some and formulated to exceedingly high standards, while key

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Fig. 1. Critical dual-use breakthroughs of SynBio for Space. Pursuing critical technologies to advance SynBio in Space will benefit basic
science, technology development, business, and ultimately daily life on and off Earth. These critical breakthroughs largely align with
overarching research and development needs to fulfill the Bold Goals for U.S. Biotechnology and Biomanufacturing, (2) as well as the
recommendations of the Decadal Survey on BPS Research in Space (9). LC, loop-closure; ISRU, in situ resource utilization; SynBio,
Synthetic Biology.

components require cold storage to deliver even limited shelf- A second critical breakthrough is the development of Space-
life. This limitation constrains the deployment of molecular worthy chassis organisms. Today, we know of extremophiles
biology on Space missions, where power for temperature con- that tolerate or thrive in many of the exotic conditions that are
trol is at a premium and fresh reagents cannot be readily more like places elsewhere in the solar system than the rest of
obtained (even “just” for resupply to LEO); holding times of Earth’s biosphere. Nevertheless, organisms that match the com-
payloads in anticipation of launch can be excessive. There is bined demands of a specific extraterrestrial environment are
already movement toward adapting more robust and func- lacking. Harnessing the natural diversity of life on Earth to find
tional molecular biology for rugged conditions, for example by or engineer microbes that are designed for use in specific
creating shelf-stable diagnostic tests that can be freeze-dried unusual environments is a breakthrough critical for effective
and rehydrated for use.33 Further investing in the development biomanufacturing—and not only in Space.37 This task will
of simple, robust reagents for molecular biology such as highly involve applying the entire modern toolkit of SynBio biopro-
stable dried cell-free transcription/translation systems will specting,23 adaptive evolution,38,39 and genetic manipulation
accelerate the field by opening up new application areas in toward new Space-focused applications. On Earth, advancing
Space and on Earth, for example in remote and resource- the engineering of extremophilic organisms will enable indus-
constrained locations. trial bioprocesses to operate under more extreme (non-natural)

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 SPACE SYNTHETIC BIOLOGY: A PARADIGM FOR SUSTAINABILITY

conditions—such as high pressure, temperature, or excess con- biomanufacturing a staple of life on Earth and in Space, driven
centrations of chemicals (e.g., solvents)—to optimize production by the private space sector and national (space) agencies alike.12
(rate, titer, yield) and thereby reduce process costs. Longer- Fundamental improvements to the resource requirements,
term, Space-worthy chassis organisms may one day be the reliability, and scale of biomanufacturing are best addressed
backbone of in situ biomanufacturing on Mars. To this end, the by the global bioeconomy.2 Today, biomanufacturing proc-
2023 Decadal Survey on BPS Research in Space16 recom- esses often require expensive (and often unsustainable) feed-
mended that NASA increase investigations into the impacts of stocks, are prone to variability in product quality, and are
the Space environment on biological growth, reproduction, and difficult to scale. Decreasing costs and improving the reliability
evolution, fundamental scientific knowledge that will be key to of biomanufacturing is therefore essential. The global bioecon-
sustainable SynBio with live organisms. omy is collectively tackling these fundamentals by experi-
The lack of hardware for biomanufacturing in Space, under menting with new low-cost feedstocks derived from waste
conditions of lower gravity and higher radiation than on streams, creating low-cost purification strategies, developing
Earth,42 is a crucial bottleneck that presently limits the speed of processes that are more scalable, and engineering pathways to
progress in the field. Most notably absent is flight-tested hard- produce new products. For example, the USA has substantial
ware for DNA synthesis and manipulation where low gravity renewable carbon resources that could support large-scale bio-
makes standard methods impossible. Bioprocessing in Space42 manufacturing efforts, which will likely incentivize invest-
is still in its infancy, with some basic techniques such as DNA ments into the development of the infrastructure required
sequencing, DNA amplification,43 and gel electrophoresis44 to leverage these resources.48,49 The result will be a thriving
performed in Space; facilities such as the Wet Lab RNA Smart- bioeconomy that creates jobs and is reliable, cost-effective,
Cycler45 and a bioreactor (Multiple Orbital Bioreactor with and sustainable. In this article, we call for the expansion of
Instrumentation and Automated Sampling (MOBIAS))46 are this vision to encompass humanity’s future off-Earth, posi-
already operational on the ISS. The ability to synthesize DNA tioning SynBio to address the recommendations of the
remotely, and thus program biological instructions on demand, National Academies as fundamental to human success in
unlocks the full utility of SynBio as a highly flexible and pro- Space.16
grammable technology platform for manufacturing and sens- Meanwhile, the private sector is well positioned to address
ing. A critical breakthrough for the field will be translating the many of the new hardware needs that come with the use of
existing capabilities of ground-based biofabs to Space,47 allow- SynBio off-planet. Several companies have developed and
ing the rapid prototyping and building of any molecule. The are flight-testing cell-culture devices to conduct bioengin-
existing infrastructure on the ISS has previously been sufficient eering and biomanufacturing in a microgravity environ-
to test SynBio capabilities, especially with an emphasis on mini- ment.12 Expanding this repertoire of devices, particularly
aturization and automation, while accounting for lower gravi- through open-access frameworks, will benefit these for-
tational forces (e.g., the use of microfluidic rather than “test- profit companies as well as national space agencies. This
tube” platforms42). As ISS is decommissioned, small satellites, public-private integration will be critical for expanding both
commercial platforms for LEO, Gateway, and other upcoming the pool of contributors to key advances in Space and the set
cis-Lunar operations must provide opportunities for extended of stakeholders in a sustainable human future.
testing and translation of biofoundry components. Due to the exceptional flexibility of this technology, it is
A suite of hardware for SynBio in Space may in the short challenging to isolate a single best first use case of SynBio in
term allow for rapid iteration on biomanufacturing protein- Space that extends further than technology demonstration;
based biomaterials in LEO, or deployment of similar devices the first use case will be determined based on mission needs
in low-resource environments, benefiting developing coun- and associated quantitative analyses such as equivalent sys-
tries in particular. In the long term, it will enable on- tems mass.41 For example, is it better to ignore drugs that
demand synthesis of chemicals that were not or could not have a short shelf-life or make them fresh on demand? Most
be brought along (for example to Mars), significantly importantly, the multitude of national space agencies (e.g.,
improving the resilience and feasibility of future missions. NASA, CSA, ESA, JAXA, CNSA, and ISRO) can uniquely and
in combination contribute to advancing the field by putting
HOW TO GET THERE—A CALL TO ACTION biomanufacturing solutions through the rigorous flight-
The bioeconomies of the USA and other countries will testing process, ensuring that these processes are ready for
contribute to making reliable, cost-effective, and sustainable human missions.

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CONCLUDING REMARKS AND VISIONARY encouraged the writing of this article. The authors are grate-
OUTLOOK ful to the following individuals for fruitful discussions dur-
The vast majority of humans are and likely will stay, on ing the inception of the article: David Bray, Daniela Billi,
planet Earth for the foreseeable future. So what is to gain from Jennifer Brophy, Christopher Hernandez, and Andrew Hessel.
advancing SynBio for Space applications? Simply put, SynBio
has the potential to revolutionize manufacturing, healthcare, AUTHORS’ CONTRIBUTIONS
environmental remediation, energy dependence, and other All authors contributed equally to the development, writ-
problem spaces. Critically, on Earth, solutions to these issues ing, and editing of the article.
are pursued through legacy approaches that may not meet the
needs of future generations. Game-changing solutions often do AUTHOR DISCLOSURE STATEMENT
not gain traction as there is no immediate economic advantage The authors declare no competing interest.
to replacing legacy solutions. Planning for Space empowers us
to reimagine solutions to Terrestrial problems by focusing on a FUNDING INFORMATION
use case that either does not currently have a solution, or N.J.H.A. acknowledges funding under award #80NSSC22
replacing the planned solution has little socioeconomic or geo- K1474, granted by the National Aeronautics and Space
political ramification. Further, these solutions must ultimately Administration (NASA). E.A.D. was supported by the Francis
be closed-loop—where all inputs and outputs as well as their Crick Institute, which receives its core funding from Cancer
dynamic fluctuations are known and accounted for—thus pro- Research UK (CC2096), the UK Medical Research Council
viding a template for a circular economy at a global scale. (CC2096), and the Welcome Trust (CC2096). L.J.R. is grateful for
Vulnerabilities in bioeconomy supply chains were exposed continued support by the NASA Science Technology Mission
during the COVID-19 pandemic. Off-planet, supply chains Directorate.
are limited and fragile. A Mars supply chain would be the
ultimate onshoring effort. Given the wide spacing of launch
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