Available via license: CC BY 4.0
Content may be subject to copyright.
Space Bioprocess Engineering on the Horizon1
Aaron J. Berliner1,2,*, Isaac Lipsky1,2, Davian Ho1,2, Jacob M. Hilzinger1,2, Gretchen2
Vengerova1,2, George Makrygiorgos1,3, Matthew J. McNulty1,4, Kevin Yates1,4, Nils J.H.3
Averesch1,5, Charles S. Cockell1,6, Tyler Wallentine1,7, Lance C. Seefeldt1,7, Craig S.4
Criddle1,5, Somen Nandi1,4,8, Karen A. McDonald1,4, Amor A. Menezes1,9 , Ali Mesbah1,3,5
and Adam P. Arkin1,2,*
6
1Center for the Utilization of Biological Engineering in Space (CUBES), http://cubes.space/7
2Department of Bioengineering, University of California Berkeley, Berkeley, CA8
3Department of Chemical and Biomolecular Engineering, University of California Berkeley, Berkeley, CA9
4Department of Chemical Engineering, University of California, Davis, Davis, CA10
5Department of Civil and Environmental Engineering, Stanford University, Stanford, CA11
6UK Centre for Astrobiology, School of Physics and Astronomy, University of Edinburgh, Edinburgh, UK12
7Department of Chemistry and Biochemistry, Utah State University, Logan, UT13
8Global HealthShare Initiative, Davis, CA14
9Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL15
*Corresponding authors e-mail: aaron.berliner@berkeley.edu and aparkin@lbl.gov16
Reinvigorated public interest in human space exploration has led to the need to address the science and engineering
challenges described by NASA’s Space Technology Grand Challenges (STGCs) for expanding the human presence in space.
Here we define Space Bioprocess Engineering (SBE) as a multi-disciplinary approach to design, realize, and manage a
biologically-driven space mission as it relates to addressing the STGCs for advancing technologies to support the nutritional,
medical, and incidental material requirements that will sustain astronauts against the harsh conditions of interplanetary transit
and habitation offworld. SBE combines synthetic biology and bioprocess engineering under extreme constraints to enable
and sustain a biological presence in space. Here we argue that SBE is a critical strategic area enabling long-term human
space exploration; specify the metrics and methods that guide SBE technology life-cycle and development; map an approach
by which SBE technologies are matured on offworld testing platforms; and suggest a means to train the next generation
spacefaring workforce on the SBE advantages and capabilities. In doing so, we outline aspects of the upcoming technical and
policy hurdles to support space biomanufacturing and biotechnology. We outline a perspective marriage between space-based
performance metrics and the synthetic biology Design-Build-Test-Learn cycle as they relate to advancing the readiness of SBE
technologies. We call for a concerted effort to ensure the timely development of SBE to support long-term crewed missions
using mission plans that are currently on the horizon.
Keywords:
space systems bioengineering, biomanufacturing, space bioprocess engineering, biotransformation human
exploration, in situ resource utilization, life support systems, biomanufacturing, space policy
17
Biotechnologies may have mass, power and volume advantages compared to abiotic approaches for critical mission elements
18
for long-term crewed space exploration
1,2
. While there has been point progress in demonstration and evaluation of these
19
benefits for specific examples in this field such as for food production, waste recycling, etc., there is only just emerging possible
20
consensus on the scope of the application of biosynthetic and biotransformative technologies to space exploration and there
21
is almost no formal definition of the scope, performance needs and metrics, and technology development cycle for these
22
systems. It is time to formally establish the field of Space Bioprocess Engineering (SBE) to build this nascent community,
23
train the workforce and develop the critical technologies for planned deep-space missions. The inter-sectional nature of SBE
24
(Fig. 1a) implies that the field borrows many elements from a number of related fields such as the synthetic biology design
25
process from Bioengineering, astronaut sustainability
3,4
and mission design from Astronautics
5,6
, environmental-context
26
and constraints from the Space Sciences, and living systems habitability and distribution concepts from Astrobiology
7
. SBE
27
represents an extension of the standard astronautics paradigm in meeting NASA’s Space Technology Grand Challenges (STGCs)
28
for expanding the human presence in space, managing resources in space, and enabling transformative space exploration and
29
scientific discovery
8,9
(Fig. 1b). Aspirational realizations of SBE would feature prominently in establishment of in-orbit
30
test-facilities, interplanetary waystations, lunar habitats, and a biomanufactory on the surface of Mars
10
. Differentiated from
31
traditional efforts in space systems engineering, these systems would encapsulate elements from in situ resource utilization
32
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 December 2021
© 2021 by the author(s). Distributed under a Creative Commons CC BY license.
Figure 1. (a) Venn Diagram-based definition of Space Bioprocess Engineering (SBE) as an interdisciplinary field. (b)
NASA’s space technology grand challenges8key by shape and colored by group. (c) Possible SBE components separated by
colors for in situ resource utilization (ISRU), food and pharmaceutical synthesis (FPS), in situ manufacturing (ISM), and loop
closure (LC), with the biological processes inherent to each represented below in circles.
(d)
Platform evolution for biological
experiments starting with Earth-orbit CubeSats and proceeding through the ISS, Mars-and-Luna-based rovers, to Lunar and
cis-Lunar based human and autonomous systems via the Artemis program.
(ISRU) for the production of biological feedstocks such as fixed carbon and nitrogen for use as inputs for plant and microbial
33
production systems
11,12
, fertilizers for downstream use by plants
13
;in situ (bio)manufacturing (ISM) to produce materials
34
requisite to forge useful tools and replacement parts
14
, food and pharmaceutical synthesis (FPS) via plant and microbial
35
engineering for increased productivity and resilience in space conditions, production of nutrients and protective/therapeutic
36
agents for sustaining healthy astronauts
15,16
; and life-support loop closure (LC) for minimizing waste and regenerating
37
life-support functions and biomanufacturing. Maximizing the productivity of the biomanufacturing elements increases the
38
delivery-independent operating time of a biofoundry in space while minimizing cost and risk.
17
(Fig. 1c). Ultimately, efforts
39
must be mounted to update the mandate to include SBE as a tool for enabling human exploration; specialize the metrics
40
and methods that guide SBE technology life-cycle and development; further develop means by which SBE technologies are
41
designed for ground testing and matured on offworld testing platforms (Fig. 1d); and train the minds that enter the spacefaring
42
workforce on the SBE advantages and capabilities.43
An Inclusive Mandate To Leverage SBE44
While previous strategic surveys such as NASA’s Journey to Mars program
18
the 2018 Biological and Physical Sciences (BPS)
45
Decadal Survey
19
have acknowledged that plants and microbes may be integral parts of life support and recycling systems
46
but can present challenges to the environmental operation of engineering systems in space due to contamination and other
47
inherent drawbacks. However, none of these have coherently called for the development of the science and technology to
48
engineer these organisms and their biotransformative processes in support of space exploration. The SBE community requires
49
a mandate that identifies mission designs and elements for which engineering biosystems would be most appropriate, and
50
defines the productivity, risk and efficiency targets for these systems in integrated context with other mission elements and
51
in fair comparison to abiotic approaches. This will require integration of SBE resources and knowledge across government,
52
industry, and academia. Previous biological strategies should now specifically call for (1) definition of the physical engineering
53
constraints on the production systems and development of optimized reactor/processing systems for these elements; (2)
54
quantitative assessment of the bioengineering required to meet performance goals in space given the special physiology required
55
in an offworld environment; and (3) development of efficient tooling for offworld genetic engineering along with the proper
56
2/10
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 December 2021
containment and clean-up protocols.57
Such a mandate would result in: (1) a deeper, more mechanistic understanding of the growth and phenotypic characteristics
58
of organisms operating in space-based bioprocesses taking into account issues of differences in gravity, radiation, light,
59
water quality, etc.; new applications of these organisms off-planet; (3) new reactors, bioprocess control designs and product
60
processing/delivery technologies accounting for these conditions and the specific constraints of scaling and operational
61
simplicity in space. The development of open, publicly accessible data and tools would enable rigorous comparison among
62
biotechnologies and with abiotic (physical and chemical) approaches within better defined mission-scenarios. Ideally, this
63
should create interative sub-communities that may collaborate and compete on different approaches to meet bioengineering
64
goals and metricize results against the mission specifications.65
SBE is an emerging engineering discipline and there are long but feasible routes from discovery, through invention to
66
application. Furthermore, SBE is multidisciplinary and its utility within the larger space community demands specialized
67
cross-training of diverse teams. It in such situations agencies like the Department of Energy (DOE) have found it effective to
68
ensure there is specific funding to support longer term team science to accomplish ambitious scientific and technical goals. The
69
Industrial Assessment Centers (IACs) program is one longest-running DOE programs (started in 1976) and has provided nearly
70
20,000 no-cost assessments for small- and medium-sized manufacturers and more than 147,000 recommendations in an effort
71
to reduce greenhouse gas emissions without compromising U.S. manufacturing’s competitive edge globally
20
. Conversely,
72
successful examples for demonstrating the effect of fostering multidisciplinary centers for space-based biotechnology can
73
be found in NASA’s Center for the Utilization of Biological Engineering in Space (CUBES,
https://cubes.space/
),
74
or ESA’s Micro-Ecological Life Support System Alternative (MELiSSA, https://www.melissafoundation.org/)75
program – with the capabilities to design, prototype, and ultimately translate biological technologies to space while training the
76
necessary workforce. Such centers are tasked with the development of initial concept trade studies; defining requirements;
77
managing life-support interfaces; evaluating ground integration, operations, and maintenance; coordinating mission operations;
78
and supporting and sustaining engineering and logistics
21,22
. However, these programs are generally restricted to shorter
79
operation timelines – and would benefit from a longer horizon. This is especially true for SBE as biological developments
80
generally require a longer timeframe for integration in industrial endeavors.81
Specialization of SBE Metrics and Methods82
Response to the proposed expanded mandate above requires careful consideration of the space-specific performance metrics
83
that SBE must fulfill. Payload volume, mass, and power requirements are made as small as possible and are limited in
84
envelope by their carrier system. One of the most compelling aspects of biotechnology is the ability of such systems to adapt
85
to these constraints relative to certain industrial alternatives. To efficiently evaluate and deploy novel biotechnologies, SBE
86
experiments should begin with standardized unit operations that clearly define the desired biological function. This allows for a
87
standardized experimental framework to test modular biotechnologies not only within the system to be engineered, but also
88
within and between research groups. To define the minimal basis set of unit operations for a given mission, test and optimize
89
the biotechnologies for each unit operation, and integrate each unit operation into a stable system, we adopt the methods from
90
standard bioengineering in the form of a Design-Build-Test-Learn (DBTL) cycle23 (Fig. 2).91
Performance Metrics92
The design phase of the DBTL cycle begins with the establishment of core constraints and engineering targets that can
93
be explored by standardizing the high-priority performance metrics ({Modularity, Recyclability, Supportability, Autonomy,
94
Sustainability})- which we argue gain special weight in space- from which downstream technoeconomic and life-cycle analysis
95
decisions can be explored (Fig. 2a). The space-specific constraints on performance include: (1) an exceptionally strong
96
weighting on a low mass/volume/power footprint for the integrated bioprocess; (2) limited logistic supply of materials and a
97
narrow band of specifically chosen feedstocks; (3) added emphasis on simplicity of set-up, operation and autonomous function
98
to free up astronaut time; (4) mission-context de-risking against cascading failure; (5) strong requirements for efficiency and
99
closed-loop function to maximize efficient resource use and minimize waste products; (5) a critical need for modularity and
100
’maintainability’ so that parts can be swapped easily, new functions added easily, and repairs can be done without logistical
101
support beyond the crew; (6) an increased dependence on other mission elements such as provision of water, gases, astronaut
102
wastes, power, and other raw materials such a regolith which may vary in abundance, quality, and composition in unpredictable
103
ways; (7) the need to design sustainable and supportable operation across long time horizons without logistical support beyond
104
the bounds of the local mission; (8) increased ability to operate in more extreme environments including low gravity, high
105
radiation, low nutrient input, and other stressors; and (9) and process compatibility among common media and operational
106
modes to allow for easy process integration and risk-reduction through redundancy of systems.107
Ideally, this combination of performance metrics provides informative constraints on biology and technology choicesd.
108
Feedstock, loop-closure, environmental parameters and product needs will constrain the minimal set of organisms to develop
109
3/10
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 December 2021
Figure 2. Overview of (a) space systems bioengineering (SBE) performance metrics as core constraints and engineering
targets within the (b) diagram of SBE-specific Design, Build, Test, Learn (DBTL) cycle.
and test for growth rate, optimal cultivation, robustness and resilience to space conditions and shelf-life, safety and genetic
110
tractability, product yield, titer and rate, feedstock utilization and waste streams
24
. Once suitable chassis organisms have been
111
evaluated and selected, the DBTL cycle can integrate staged co-design of the optimal process hardware (e.g. molecular biological
112
set-ups, genetic engineering tools, bioreactors, and product post-processing systems) configuration, operating parameters, and
113
process controllers. Operation of the cycle over increasing scale and ever more realistic deployment environments permits
114
controlled traversal of the technology readiness levels for each technology and mission.115
Design-Build-Test-Learn116
In the design phase, we argue that efforts must be made to (1) create a database of engineering targets (products, production
117
rates, production yields, production titers, risk factors, waste/recyclability factors, material costs, operational costs, weight,
118
power demand/generation) that set the core constraints for workflow and mission optimization; (2) leverage emerging pathway
119
design software and knowledge bases
25
to identify the key types of biological production workflows (i.e. metabolic engineering
120
strategies
26
) that need to be modified for different space-based scenarios; (3) identify the supporting biomanufactory design
121
elements within which these production workflows could be implemented
27–29
; and (4) identify the chassis organisms and
122
other biological components
30–32
that will be required to compose the complete set for downstream engineering specifications.
123
Systems designed from a minimal set of reliable parts, standard interconnects, and common controller languages also offer the
124
best possible chance of characterized reliability under changing environmental conditions. Therefore, control of hardware and
125
wetware should be augmented through the design and operation of software support. We see a fundamental effort in SBE as the
126
amalgamation of space-driven hardware, software, and wetware that follows a synthetic biology DBTL cycle33.127
The foundation of new SBE performance metrics that guide the design phase of the DBTL cycle must be augmented with
128
additional downstream efforts in the build and test phases to (1) develop a process design framework that takes in specific
129
production needs in amounts/time over acceptable ranges under the constraints expected across different offworld scenarios;
130
(2) create the biological, process, and mission design software platforms to allow sophisticated DBTL, risk assessment, and
131
mission choice support; (3) create the sensor/controller sets that will allow real-time optimization of biological production
132
workflows; and (4) develop the online process controller framework that coordinates reactor conditions and inter-reactor flows
133
to optimize reliable production across all units within acceptable ranges with minimal power and risk. The realization of this
134
SBE DBTL cycle depends on the integration of such benchmark models and modeling standards. These benchmarks describe
135
the dynamics of all SBE processes and relate to the SBE metrics in the design phase from which optimization can be carried
136
out in the learn phase.137
DBTL cycles within the scope of SBE must prepare for both ground- and flight-based system operations. Ground-based
138
developments must prioritize designs that meet the requirements for flight-based testing, during which system behaviors may
139
be better characterized in unique environments such as those offered in micro- and zero-gravity. For instance, a biological
140
nitrogen-fixing system on earth must at least be designed to meet the mass and volumetric constraints required for validated
141
4/10
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 December 2021
ground-based simulators of microgravity, GCR, other physical stressors. Meeting certain requirements for time, power, and
142
substrate usage is essential for any degree of long-term operation. This allows for the in-flight testing of bioreactors test-bedded
143
on-earth that can more directly measure the effects micro-gravity, radiation and other stressors on the bioprocessing system. A
144
combination of ground- and flight- based tests are required for the development of functional and robust space biosystems.145
Development of Means for SBE Flight146
Deployment of SBE platforms as mission critical elements will likely be reserved for longer duration human exploration
147
missions such as those in the Artemis or Mars programs
10
. These future programs are still in the concept and planning
148
stage in development, but will certainly be composed of a myriad of technologies that range in degree of flight-readiness as
149
standardized by NASA’s Technology Readiness Level
34
(TRL, used to rate the maturity of a given technology during the
150
acquisition phase of a program). Recent updates in NASA’s definitions of and best-practices for applying the TRL paradigm led
151
Platform Volume Power Op. Lifetime Temperature Air Comp.
CubeSat 0.0187 m320-45 W ∼20 years
PocketQube 0.000125 m3Variable ∼5 years
Requires heating unit
within constraints Self-contained
Bioculture System Not stated 140W ∼60 days
37-45°C in main
chamber, ambient to
5°C in cooling chamber
Self-contained
medical grade gas
WetLab-2
(SmartCycler) 235.97 m3350W Extractions <3hrs,
no lifetime stated 50-95°C
Rodent Habitat
Hardware System 0.019 m3Not stated ∼30 day experiments
Compact Science
Experiment Module 0.0015 m33.2W >1 month experiments
Vegetable
Production
System (Veggie)
0.48 m3
growth area
>12 day experiments,
can replace crops
Ambient temp, no
heating module
None, reliant on
cabin air system
Advanced Plant
Habitat (APH)
889.44 m3
growth area
∼1 year 18-30°C Self-contained
gas supply
Spectrum 10 x 12.7 cm
internal area
Not stated
12 day experiments 18-37°C None, reliant on
cabin air comp
BRIC-60 11.03 m3
60M variant can
draw from an external
gas tank
BRIC-100 38.78 m3>12 day experiments
BRIC-100VC 16.33 m34.5 months
Self-contained gas
canister of designated
compositionKSC Fixation
Tubes (KFTs) 0.2387 m3
Unpowered
67 days
Ambient temp,
no heating module Airtight, reliant on
cabin air comp
miniPCR 0.00066 m365W ∼2 year <120°C
Group Activation
Pack-Fluid Processing
Apparatus (GAP-FPA)
Eight 6.5 cm3
test tubes
Unpowered
for manual 4-37°C
Multi-use Variable-g
Platform (MVP)
Twelve 800 cm3
modules Not stated Not stated 14-40°C
MinION 0.0796 m35W ∼1 year Ambient temp, no
heating module
Airtight, reliant on
cabin air comp
Perseverance
(MOXIE) 0.017 m3300W ∼2 years 800°C operational
-60°C ambient
CO2input
CH4output
Gateway
(HALO)
>125 m3planned
internal volume
∼60kW >2 years ∼18°C Pressurized cabin air
Mars Hab
(6 Crew) 300 m3∼100kW 600 day nominal,
619 day maximum ∼18°C Pressurized cabin air
Table 1. Constraints on past and current experimental platforms including Small Satellites (light blue), Space Stations
(medium blue), Rovers (dark blue), planned Lunar Habitation (light red), and Martian Habitation (red). The shade of color
darkens with increasing complexity and cost. The specific sources can be found in the SI.
5/10
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 December 2021
to the standardization and merging of exit criteria between hardware and software systems
35
. However, the TRL concept as it
152
relates to SBE must be further expanded to include definitions and exit criteria for ’wetware’ in addition and in relationship to
153
hardware and software elements.154
Deployment of SBE is space requires a level of rigor in technology acceptance that is of a different order than most
155
earth-based systems because mission failures are exceptionally costly and difficult to recover from. The missions into which
156
SBE processes will integrate are hugely complicated and as noted above will be interdependent in complex ways. Thus while
157
low levels TRLs can be reach through unit testing in modest formats both on earth and limited flight chasses, the integrated
158
nature of the bioprocess control and engineering will require integration testing even at the TRL 4 and 5 levels
35
. To meet
159
acceptance at TRL 6 and beyond will require long term planning realistic integration and deployment testing with actual
160
sophisticated space missions and their logistics.161
Even at low TRLs, research on the timescales needed to validate extended-use systems as would be leveraged on extended-
162
stay forward deployment such as Martian or lunar missions are not possible given the current ISS capabilities and constraints.163
Constraints in astronaut time and limitations in hardware designed for shorter experiments prevent testing times comparable
164
to long duration missions. Table 1outlines a number of constraints on past and current experimental platforms and provides
165
some basis for constraints of future systems (Fig. 1d). Here we note that extended multigenerational studies, especially in
166
microbiology, can be difficult with some of the operational lifetimes.
36
. Volume is also constrained, and available space is
167
broken up into segmented rack testbeds and independent machines, which can prevent aspects of a system from interacting
168
with each other (Table 1). Much of the testing hardware on the ISS is designed for front-end processing and basic science, and
169
many experiments in microbial observation
37,38
, hybrid life support
39
, antibiotic response
40
, and more all require returning
170
samples to Earth for efficient processing, limiting the end-product downstream analysis and use as feedstocks for other
171
integrated processes, as is needed to advance TRL beyond 6. This also cuts down on the ability to run DBTL diagnostics
172
and SBE performance metrics on the system in toto as recyclability and sustainability are reliant on those end-products, and
173
supportability if the processing is often reliant on Earth resources. Though much of the potential testing: PCR
41
, imaging
42
,
174
and DNA sequencing
43,44
is possible with current miniaturized ISS modules, it may not all be at the scale needed for future
175
experiments, and there may be gaps in capability as the field matures. Improved in situ data analysis through development of
176
new, high-throughput instruments could help suture those gaps
45
and allow better metricization of whole systems under these
177
new performance paradigms.178
Lunar and Martian gravity can potentially have distinct biological effects compared to Earth gravity, resource composition,
179
and radiation profile – and the ISS has only a limited volume in which to simulate them
46
. Additionally, both ambient
180
environmental and target temperature windows span an extensive range across extraterrestrial environments, as do gas
181
compositions, making representative testing more difficult in growth and testing chambers (plant, animal, and microbial)
182
without full environmental control (Table 1). ECLSS systems for large-scale plant science requisite for advancing TRL for
183
downstream lunar and Martian missions also require larger volume bounding boxes than is currently provided on the ISS
47
. Here
184
we note the trade-offs with the tight volume and power stores on board. Smaller satellite modules can get technologies off the
185
ground to advance TRL
48–50
, but feature even greater size handicaps, and may prevent testing at the integrated, factory level in
186
the DBTL cycle
51,52
. Scientific instruments and modules on rovers have been geared primarily for exploration and observation,
187
not technology validation. Dedicated rovers or simply landing SBE payloads onto extraterrestrial sites, SBE-ready orbiters,
188
and Artemis operations as a stepping-stone to Mars can all demonstrate technology within a representative context and stand
189
as some of the premier testbeds to “flight qualify” SBE prototypes
34
.In situ testing is key to the proposed SBE performance
190
metrics: it forces technology and bioprocesses into accurate, integrated environments, and provides better confidence under
191
radiation, microgravity, and isolation.192
Training of SBE Minds193
Maturation of space bioprocess engineering requires specialization of the training needed to produce the next generation of
194
spacefaring scientists, engineers, astronauts, policy makers, and support staff
53
. Lessons learned from the Space Transportation
195
System (STS) era led to calls for an increase in Science-Technology-Engineering-Mathematics (STEM) educational programs
54
196
beginning in secondary schools
55
and propagating to novel astronautics-based undergraduate
56
and graduate programs
57
, and to
197
the establishment of specialty space research centers
58
focused on technology transfer
59
. The calls for workforce development
198
were repeated just prior to the collapse of the STS program, noting the dangers likely to arise from the lack of educational
199
and training resources for those entering the space industry.
60
. Such a risk as described is especially poignant in the case
200
of space-based biotechnologies given that mature technologies are far fewer, the new applications more futuristic, and the
201
disciplines are not well represented in the traditional physics and engineering curricula. The Universities Space Research
202
Association (USRA) lists 114 institutions with Space Technologies/Science academic programs while recent accounting
203
of bioastronautics programs numbers 36
61
. However, the intersection between these lists yields only 22 schools. Given
204
that US News names 250 world schools that have tagged themselves with Space Science programs, only
∼
8% of these are
205
6/10
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 December 2021
Figure 3. Conceptual undergraduate SBE program.
currently offering bioastronautics specialization – demonstrating that efforts that integrate human performance, life support and
206
bioengineering are under-served. Furthermore, the bioastronautics programs such as those offered by schools like Harvard-MIT,
207
University of Colorado Boulder, and Baylor University are not focused on biomanufacturing aspects that underlie SBE62.208
Academia must be prepared to capitalize on the opportunities of future SBE applications starting with either the creation
209
of new and interdisciplinary programs or by assembling those from related disciplines (Fig. 1a). Because scientific and
210
mathematical core courses are relatively standard across SBE-related disciplines, an effective foundation of technical skills
211
could be easily constructed from the shared curriculum (Fig. 3). From there, specific SBE-driven training can be offered in
212
(1) effects of space on plant and microbes; (2) process design for low gravity/high radiation; (3) management and storage of
213
biological materials in space based operations; (4) low energy/low mass bioreactor/bioprocessor design; (5) integrated biological
214
systems engineering; (6) biological mission planning and logistics; (7) risk and uncertainty management; (8) containment
215
and environmental impact of biological escape, films, corrosion and cleanup; and (9) ethics of cultivation and deployment.
216
While the logistics for organizing such pathways for formal SBE training are non-trivial within the academic machine, we
217
note that nearly all schools listed by USRA offer the component programs in bioengineering, planetary science or astronomy,
218
and electrical or systems engineering. Since the courses for such engineering programs are standardized
63
, it stands to reason
219
that establishing focused SBE programs can begin by collecting and highlighting course combinations. As programs grow,
220
additional faculty with SBE-driven research can be sourced. Such openings offer a much needed opportunity to address systemic
221
issues of diversity, equity, and inclusion both within SBE-based academia and the industrial space community at large64.222
Moving Forward223
Making progress on the program above requires scientists, engineers, and policy experts to work together to verify, open, and224
update campaign specifications. The science requires scientists from multiple disciplines spanning biological and space systems
225
engineering that require a degree of modularity, small footprints, and robustness not found elsewhere. Additionally, bioprocess
226
and biological engineering must be applied to the building of cross-compatible and scalable processing systems and optimized
227
organisms within the confines of space reactor and product. Finally, coordination mission specialists are critical to deploy tests
228
into space during the run-up and through crewed missions. We argue that such groundwork requires multidisciplinary centers
229
that can build long term partnerships and understanding; train the workforce in this unique application space; and perform the
230
large-scale, long-term science necessary to succeed.231
7/10
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 December 2021
Acknowledgements232
This material is based upon work supported by NASA under grant or cooperative agreement award number NNX17AJ31G.233
Authorship Contributions234
AJB, AM, JMH, APA conceived the concept based on the Center for the Utilization of Biological Engineering in Space
235
(CUBES). DH led the graphics effort with assistance from AJB. GM, IL, NJHA, AAM, AM, and APA contributed to research
236
and analyses. All authors wrote and edited the manuscript.237
Competing Interests238
The authors declare that they have no conflicts of interest.239
References240
1.
Menezes, A. A., Cumbers, J., Hogan, J. A. & Arkin, A. P. Towards synthetic biological approaches to resource utilization
241
on space missions, vol. 12 (The Royal Society, 2015).242
2. Nangle, S. N. et al. The case for biotech on Mars. Nat. Biotechnol. 38, 401–407 (2020).243
3. Young, L. R. & Sutton, J. P. Handbook of Bioastronautics (Springer, 2020).244
4.
Whitmore, M., Boyer, J. & Holubec, K. NASA-STD-3001, Space Flight Human-System Standard and the Human
245
Integration Design Handbook. In Industrial and Systems Engineering Research Conference (2012).246
5.
Hoffman, S. J. & Kaplan, D. I. Human exploration of Mars: the reference mission of the NASA Mars exploration study
247
team, vol. 6107 (National Aeronautics and Space Administration, Lyndon B. Johnson Space Center, 1997).248
6.
Drake, B. G., Hoffman, S. J. & Beaty, D. W. Human exploration of Mars, design reference architecture 5.0. In Aerospace
249
Conference, 2010 IEEE, 1–24 (IEEE, 2010).250
7. Fridlund, M. & Lammer, H. The astrobiology habitability primer. Astrobiology 10, 1–4 (2010).251
8. Talbert, T. & Green, M. Space Technology Grand Challenges (2010).252
9.
Menezes, A. A., Montague, M. G., Cumbers, J., Hogan, J. A. & Arkin, A. P. Grand challenges in space synthetic biology.
253
J. The Royal Soc. Interface 12, 20150803, DOI: 10.1098/rsif.2015.0803 (2015).254
10.
Berliner, A. J. et al. Towards a Biomanufactory on Mars. Front. Astron. Space Sci.
8
, 120, DOI: 10.3389/fspas.2021.711550
255
(2021).256
11.
Cestellos-Blanco, S. et al. Production of PHB From CO2-Derived Acetate With Minimal Processing Assessed for Space
257
Biomanufacturing. Front. Microbiol. 12, 2126, DOI: 10.3389/fmicb.2021.700010 (2021).258
12.
Langenfeld, N. J. et al. Optimizing Nitrogen Fixation and Recycling for Food Production in Regenerative Life Support
259
Systems. Front. Astron. Space Sci. 8, 105, DOI: 10.3389/fspas.2021.699688 (2021).260
13.
Rapp, D. Mars ISRU technology. In Use of Extraterrestrial Resources for Human Space Missions to Moon or Mars, 31–90
261
(Springer, 2013).262
14. Werkheiser, N. In-space manufacturing: pioneering a sustainable path to Mars. (2015).263
15. Cannon, K. M. & Britt, D. T. Feeding one million people on Mars. New Space 7, 245–254 (2019).264
16.
McNulty, M. J. et al. Molecular Pharming to Support Human Life on the Moon, Mars, and Beyond. Critical Rev.
265
Biotechnol. 0, 1–16, DOI: 10.20944/PREPRINTS202009.0086.V1 (2020).266
17.
Poughon, L., Farges, B., Dussap, C. G., Godia, F. & Lasseur, C. Simulation of the MELiSSA closed loop system as a tool
267
to define its integration strategy. Adv. Space Res. 44, 1392–1403, DOI: https://doi.org/10.1016/j.asr.2009.07.021 (2009).268
18.
NASA. NASA’s Journey to Mars: Pioneering Next Steps in Space Exploration. Tech. Rep. (2015). DOI:
269
NP-2015-08-2018-HQ.270
19.
A Midterm Assessment of Implementation of the Decadal Survey on Life and Physical Sciences Research at NASA. Tech.
271
Rep., National Academy of Sciences (2018).272
20. DOE Announces New $60 Million Investment to Increase Energy Efficiency in Manufacturing (2021).273
21.
Marshall Space Flight Center Space Systems. Tech. Rep., National Aeronautics and Space Administration, Marshall Space
274
Flight Center, Huntsville, AL (2011). DOI: NP- 2011-05-051-MSFC8\T1\textendash477491b.275
8/10
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 December 2021
22. Chapline, G. & Sullivan, S. Systems engineering for Lifecycle of Complex Systems. Eng. Innov. (NASA) (2010).276
23. Cohen, J. The crucial role of CS in systems and synthetic biology. Commun. ACM 51, 15–18 (2008).277
24.
Averesch, N. J. H. Choice of Microbial System for In-Situ Resource Utilization on Mars. Front. Astron. Space Sci.
8
, 116,
278
DOI: 10.3389/fspas.2021.700370 (2021).279
25.
Arkin, A. P. et al. KBase: the United States department of energy systems biology knowledgebase. Nat. biotechnology
36
,
280
566–569 (2018).281
26.
Lucks, J. B., Qi, L., Whitaker, W. R. & Arkin, A. P. Toward scalable parts families for predictable design of biological
282
circuits. Curr. opinion microbiology 11, 567–573 (2008).283
27. Carbonell, P. Getting on the Path to Engineering Biology. In Metabolic Pathway Design, 3–10 (Springer, 2019).284
28.
Appleton, E., Madsen, C., Roehner, N. & Densmore, D. Design automation in synthetic biology. Cold Spring Harb.
285
perspectives biology 9, a023978 (2017).286
29.
Goñi-Moreno, A. et al. An implementation-focused bio/algorithmic workflow for synthetic biology. ACS synthetic biology
287
5, 1127–1135 (2016).288
30.
Shetty, R. P., Endy, D. & Knight, T. F. Engineering BioBrick vectors from BioBrick parts. J. biological engineering
2
,
289
1–12 (2008).290
31.
Canton, B., Labno, A. & Endy, D. Refinement and standardization of synthetic biological parts and devices. Nat.
291
biotechnology 26, 787–793 (2008).292
32. Cox, R. S. et al. Synthetic biology open language (SBOL) version 2.2. 0. J. integrative bioinformatics 15 (2018).293
33.
Cheng, A. A. & Lu, T. K. Synthetic biology: an emerging engineering discipline. Annu. review biomedical engineering
14
,
294
155–178 (2012).295
34. Mankins, J. C. Technology readiness levels. White Pap. April 6, 1995 (1995).296
35. Hirshorn, S. & Jefferies, S. Final report of the NASA Technology Readiness Assessment (TRA) study team. (2016).297
36.
Castro, S. L., Smith, D. J. & Ott, M. Researcher’s Guide to: International Space Station Microbial Research. Tech. Rep.,
298
National Aeronautics and Space Administration, Johnson Space Center, Houston, TX (2014).299
37.
Khodadad, C. L. M. et al. Microbiological and Nutritional Analysis of Lettuce Crops Grown on the International Space
300
Station. Front. Plant Sci. 11, 199 (2020).301
38.
Burton, A. S. et al. Off Earth Identification of Bacterial Populations Using 16S rDNA Nanopore Sequencing. Genes
11
,
302
DOI: 10.3390/genes11010076 (2020).303
39.
Keppler, J. et al. The final configuration of the algae-based ISS experiment PBR@ LSR. In 48th International Conference
304
on Environmental Systems (ICES, Albuquerque, NM, 2018).305
40.
Aunins, T. R. et al. Spaceflight Modifies Escherichia coli Gene Expression in Response to Antibiotic Exposure and Reveals
306
Role of Oxidative Stress Response. Front. Microbiol. 9, 310, DOI: 10.3389/fmicb.2018.00310 (2018).307
41.
Boguraev, A.-S. et al. Successful amplification of DNA aboard the International Space Station. npj Microgravity
3
, 26,
308
DOI: 10.1038/s41526-017-0033-9 (2017).309
42.
Levine, H. G. & Flowers, D. A. Spectrum. Tech. Rep., NASA Ames Research Center, Kennedy Space Center, Merritt
310
Island, Florida (2019).311
43. McIntyre, A. B. R. et al. Nanopore sequencing in microgravity. npj Microgravity 2, 1–9 (2016).312
44. Joannès, J. Feasibility Study of a DNA-Sequencing Cubesat Satellite. J. Br. Interplanet. Soc. 70, 287–299 (2017).313
45.
Karouia, F., Peyvan, K. & Pohorille, A. Toward biotechnology in space: High-throughput instruments for in situ biological
314
research beyond Earth. Biotechnol. advances 35, 905–932 (2017).315
46.
Zavaleta, J., Iyer, J., Mhatre, S., Dolling-Boreham, R. & Bhattacharya, S. An Automated Behavioral Analysis of Drosophila
316
Melanogaster. In Annual Meeting of the American Society for Gravitational and Space Research (2019).317
47.
Suffredini, M. T. Reference guide to the international space station. Tech. Rep., National Aeronautics and Space
318
Administration, Johnson Space Center, Houston, TX (2014). DOI: NP- 2015-05-022-JSC.319
48.
Marzioli, P. et al. CultCube: Experiments in autonomous in-orbit cultivation on-board a 12-Units CubeSat platform. Life
320
Sci. Space Res. 25, 42–52, DOI: https://doi.org/10.1016/j.lssr.2020.02.005 (2020).321
9/10
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 December 2021
49.
Luna, A., Meisel, J., Hsu, K., Russi, S. & Fernandez, D. Protein structural changes on a CubeSat under rocket acceleration
322
profile. npj Microgravity 6, 12, DOI: 10.1038/s41526-020-0102-3 (2020).323
50.
Santoni, F. et al. GreenCube: microgreens cultivation and growth monitoring on-board a 3U CubeSat. In 2020 IEEE 7th
324
International Workshop on Metrology for AeroSpace (MetroAeroSpace), 130–135, DOI: 10.1109/MetroAeroSpace48742.
325
2020.9160063 (2020).326
51. Cubesat 101: basic concepts and processes for first-time CubeSat developers. Tech. Rep. (2017).327
52.
Johnstone, A. CubeSat design specification (1U-12U) rev 14 CP-CDS-R14. Tech. Rep., California Polytechnic State
328
University, San Luis Obispo, CA (2020). DOI: CP-CDS-R14.329
53.
Hurlbert, K. et al. Human Health, Life Support and Habitation Systems Technology Area 06. NASA Sp. Technol. Roadmaps
330
(2012).331
54. Farmer, T. A STEM Brainstorm at NASA. Tech. Connect. Educ. Careers (J1) 84, 42–43 (2009).332
55.
Engle, H. A. & Christensen, D. L. Identification and evaluation of educational uses and users for the STS. Educational
333
planning for utilization of space shuttle ED-PLUSS. (1974).334
56. Brodsky, R. F. The Time Has Come for the BS in Astronautical Engineering. Eng. Educ. 76, 149–152 (1985).335
57. Sonnenfeld, G. NASA Space Biology Research Associate Program for the 21st Century. (1999).336
58.
Mclntire, L. V. & Rudolph, F. B. NASA Specialized Center of Research and Training (NSCORT) in Gravitational Biology.
337
(1996).338
59.
Fletcher, L. S. & Page, R. H. Technology transfer: The key to successful space engineering education. Acta Astronaut.
29
,
339
141–146, DOI: https://doi.org/10.1016/0094-5765(93)90032-R (1993).340
60.
Gruntman, M. The Time for Academic Departments in Astronautical Engineering. In AIAA SPACE 2007 Conference &
341
Exposition, DOI: 10.2514/6.2007-6042 (2007).342
61.
Young, L. R. & Natapoff, A. The Harvard-MIT PHD Program in Bioastronautics. Life Space for Life on Earth
553
, 90
343
(2008).344
62.
Klaus, D. M. Incorporating Bioastronautics into an Engineering Curriculum (44th International Conference on Environ-
345
mental Systems, 2014).346
63. Criteria for Accrediting Engineering Programs, 2020 – 2021 | ABET (2021).347
64.
National Aeronautics And Space Administration (NASA) Model Equal Employment Opportunity Program Status Report:
348
FY 2019 . Tech. Rep., NASA (2020).349
10/10
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 24 December 2021