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Methane-based industrial biomanufacturing for fuel and chemical production. Exploiting biological processes can enable the conversion of
single-carbon feedstocks, like methane, to the array of chemical products currently produced through industrial chemical manufacturing with con-
siderable economic, environmental, and societal advantages.
Industrial biomanufacturing: The per day (Fig. 1C). These large-scale facilities,
spanning upwards of 1375 ha (3500 acres) (Fig. 1A),
are located close to high-volume feedstock sources
future of chemical production (e.g., tight oil/shale gas) or transportation hubs
(e.g., Gulf coast) (Fig. 1B), ensuring high-volume
feedstock availability.
James M. Clomburg,1 Anna M. Crumbley,1 Ramon Gonzalez1,2*
The traditional model of economies of unit
scale described above for industrial chemical
The current model for industrial chemical manufacturing employs large-scale
manufacturing has long held that the only way
megafacilities that benefit from economies of unit scale. However, this strategy faces
to reduce capital costs per unit is by scale
environmental, geographical, political, and economic challenges associated with energy
essentially, bigger is better. Although this model
and manufacturing demands. We review how exploiting biological processes for
has been extremely successful, the inherent high
manufacturing (i.e., industrial biomanufacturing) addresses these concerns while also
C
may also restrain the suitability of the current
hemical manufacturing firms currently pro- for the commercial-scale production of both med- model to address the many interconnected eco-
duce more than 70,000 products as part of ical and industrial compounds (7). Despite these nomic, environmental, geographical, and political
a worldwide industry projected to grow advancements, the earlier adoption, better un- factors that are shifting the way we view global
beyond US$5 trillion by 2020 (1, 2). The derstanding, and suitability of chemical tech- energy and manufacturing demands in the 21st
roots of chemical manufacturing are inher- niques for large-scale manufacturing of industrial century. For example, the requirement of direct
ently tied to the Industrial Revolution, a time chemicals have made this industry essential for access to high-volume feedstocks inherently ties
period in which a predominantly agrarian society our current way of life. However, the recent spot- industrial chemical manufacturing to large-scale
was transformed into one reliant on manufactur- light on sustainability challenges inherent to in- petroleum resources and limits feedstock diver-
ing for domestic and worldwide markets. The dustrial chemical manufacturing, coupled with sification. This not only limits access to fossil
development and use of chemical processes was rapid advances in biotechnology, have brought resources such as remote natural gas but also
a major part of this shift, as chemical techniques a renewed interest in industrial biomanufac- restricts the ability to shift to more sustainable
for the large-scale production of compounds such turing. Here, we review recent advances related resources such as biomass, which are distributed
as sulfuric acid, bleaching powder, and soda ash to harnessing the power of biology for industrial and smaller volume by nature (9). The large-scale
in the 18th century helped transform and shape manufacturing, with a focus on applications pres- and energy-intensive nature of these facilities also
the production of glass, textiles, soaps, and paper enting major challenges for traditional chemical greatly contributes to their environmental impact
(35). These chemical processes laid the ground- techniques. through wasted fossil resources during feedstock
work for continued expansion in the 19th and extraction and chemical processing (10).
early 20th centuries, which would see the devel- What are the limits to industrial The cost, size, and scale characteristic of chem-
opment of manufactured fertilizers and petro- chemical manufacturing? ical processing facilities mandated by the econo-
chemicals that continue to be central to industrial Current chemical manufacturing techniques, mies of unit scale model impose substantial
chemical manufacturing. which dominate fuel and chemical production, barriers to diversifying the players in chemical
Advancing knowledge and understanding in employ processes incurring numerous heat and manufacturing. This represents a concern for the
the field of biology in the 20th century enabled pressure changes, with multiple unit operations globalization of resources and the progression
the use of biological processes for the production and heat integration schemes. Given that capital of developing countries toward self-reliance for
of important industrial compounds, such as ace- infrastructure expenditures (CapEx) are largely chemical production. For example, the cost of
tone and ethanol, in addition to many important correlated to process complexity (i.e., amount building a large-scale ammonia production plant,
compounds in medicine, including penicillin and of energy and material transferred), the chem- oil refinery, or GTL facility (Fig. 1A) is on par with
other antibiotics. However, it was not until the ical manufacturing industry has leveraged an the gross domestic product of countries like
1970s, with the development of recombinant DNA economies of unit scale model to reduce CapEx Equatorial Guinea, Congo, and Gabon (US$8 to
technologies, that the true potential of biological per unit scale. This is reflected in both the large 15 billion) (11), countries that possess large oil
processes for the industrial production of an array CapEx and the immense scale and size of faci- and natural gas reserves. This places an econo-
of compounds was envisioned (6). From there, lities such as oil refineries, ethylene crackers, mic barrier on access to chemical manufacturing
developments in discovery, use, optimization, and ammonia plants, and gas-to-liquid (GTL) plants facilities needed to use local resources for do-
engineering of biological techniques, organisms, (Fig. 1A). The economies of unit scale enabling mestic fertilizer or energy production, products
and processes have led to a quickly evolving field these megafacilities require large amounts of ag- essential for progressive development. As such,
gregated feedstock(s)typically fossil-based, such the characteristics of the economies of unit scale
1
as petroleum and natural gasto support large- model not only impose an access barrier to both
Department of Chemical and Biomolecular Engineering, Rice
University, Houston, TX, USA. 2Department of Bioengineering,
scale production. These factors have led to a mod- countries and companies but also limit the poten-
Rice University, Houston, TX, USA. el in which a small number of large-scale facilities tial for rapid and innovative solutions to tackle
*Corresponding author. Email: ramon.gonzalez@rice.edu rely on access to high-volume feedstocks and/or these challenges.
Can industrial biological manufacturing cost reductions as total production volume (i.e., available chemical technologies have not been
make the case for economies of number of facilities times facility production able to operate efficiently in such a fashion, the
unit number? rate) increases. development of technologies with lower overall
Contrary to the traditional model of economies To exploit this economic model in the context complexity that operate efficiently at a smaller
of scale used in industrial chemical manufactur- of chemical manufacturing, one can envision the scale can help support mass-produced, modular,
ing, a model based on economies of unit number custom-built, high-CapEx, large-scale operations small-unit-scale design.
uses facility-level mass production and improve- being replaced with a large number of mass- In this context, exploiting the diversity and
ments to process design resulting from repeti- produced, modular, small-unit-scale technology. strengths of biological processes for fuel and chem-
tion, a learning by doing approach, to reduce This can enable an economies of unit number ical production provides the opportunity for CapEx
capital costs per unit capacity (12). Here, eco- approach that can use automation principles, and process-efficient technology development,
nomies of unit number can be defined as a shift advances in engineering, and streamlining of enabling an economies of unit number model.
from a small number of high-capacity units or efficient technologies to reduce capital costs Industrial biomanufacturing employs biological
facilities to a large number of units or facilities per unit capacity. By efficiently scaling down, catalysts for the conversion of various feedstocks
operating at a smaller scale. Through increasing this type of approach can support small-scale, to fuels and chemicals analogous to those cur-
the number of units produced, this model can CapEx- and process-efficient flexible technolo- rently produced via chemical manufacturing means
leverage cost reduction through mass production gies. The smaller-scale and CapEx efficiency (Fig. 2). Biological processes, such as microbial
in which costs decline as cumulative output reduces both the time and cost required for com- fermentation, efficiently operate at mild temper-
increases because of specialization in the pro- mercial facilities, enabling rapid, mobile, and atures (20 to 100C) and pressures (atmospheric)
duction process and improved process and pro- widespread deployment. This model could address and can achieve high carbon- and energy-
duct design (12). Furthermore, by increasing the many of the aforementioned limitations of in- conversion efficiencies in a single unit operation,
number of operating units and facilities, cumu- dustrial chemical manufacturing by enabling a which in turn leads to more streamlined and less
lative experience on the process is gained that greater number of companies to access distributed technologically complex processes (13, 14). Indus-
can uncover a myriad of improvements in design, and sustainable resources and new markets and trial biocatalysts afford the ability to produce a
materials, and production methods (12). These allowing quick adaptation to both local and single product with an easily adjustable output
continuous improvements can offer substantial global market conditions. Although historically, at high selectivity without dramatically altering
process conditions (15). As such, the process ities comparable to large-scale chemical oper- ing the scale of facilities per se, but rather in-
equipment for the conversion step is largely ations (Fig. 1A). This system-level productivity creasing the number of facilities built (Fig. 3).
similar regardless of the desired output, which comparison further demonstrates how industrial Although modest cost gains have been achieved
can enable mass production of modular units biomanufacturing facilities can effectively oper- by optimizing the scale of the facilities, techno-
as opposed to custom-built equipment, both re- ate at a small scale, with process intensification logical learning has had a dramatic effect on
ducing equipment cost and fabrication time. enabling further size reduction at comparable CapEx reduction by both reducing costs related
These traits are ideally suited for a shift in chem- magnitudes to that of chemical facilities. to production and energy and driving process
ical production to a model based on economies The ability of these biomanufacturing facilities optimization and integration. As a result of learn-
of unit number. for rapid, small-scale, and widespread deploy- ing by doing, the CapEx per unit capacity of corn-
The potential for industrial biomanufacturing ment has supported a more than 10-fold increase ethanol production facilities of the same scale
to support economies of unit number can be in U.S. ethanol production from 1995 to 2015 has dramatically decreased over the past 30 years,
quantitatively established through the analysis (16). Although one cannot overlook the role that affording industrial biomanufacturing processes
of corn-grain ethanol fermentation, which rep- government incentives had in influencing the the ability to operate at a small scale in a CapEx-
resents the most widely developed current ex- ethanol market and demand, the intrinsic char- efficient manner (Fig. 3). This analysis suggests
ample of a bioconversion process adopted for acteristics (small-scale, CapEx efficiency) of these that not only do industrial biomanufacturing pro-
the production of chemicals and fuels at com- bioconversion facilities enabled their rapid and cesses require lower capital investment and oper-
mercial scale. Comparison of bioethanol plants widespread deployment to capitalize on these ate in a CapEx-efficient manner at a smaller scale
(industrial biomanufacturing) to oil refineries, incentives and outpace the deployment of other (Fig. 1A) but also these processes support and
ethylene crackers, ammonia plants, and GTL technologies. Furthermore, while corn-ethanol benefit from an abundance of small-scale facili-
plants (industrial chemical manufacturing) on a represents the only current process with an es- ties according to the economies of unit number
CapEx and barrels of oil equivalents (BOE) basis tablished network of facilities, other demonstrated model rather than the established paradigm of
demonstrates the extent to which industrial bio- commercial-scale bioprocesses have CapEx per economies of unit scale for industrial chemical
manufacturing can support smaller-scale, CapEx- unit capacities comparable to those of chemical manufacturing (Fig. 3).
efficient facilities (Fig. 1A). This has resulted in manufacturing facilities (Fig. 1A). DuPonts first- The lower investment and financial risk asso-
U.S.-based bioethanol production developing as of-their-kind bio-1,3-propanediol and cellulosic eth- ciated with smaller-scale industrial biomanufac-
a network of distributed plants (Fig. 1B) that anol facilities operate at similar CapEx/capacity turing facilities allows a larger number and more
operate on a substantially smaller scale than metrics to that of many recently constructed re- diverse group of technology players to be involved,
chemical manufacturing facilities. The 195 opera- fineries and ethylene crackers, with the Novamont in turn enabling faster innovation and novel tech-
tional bioethanol plants in the United States in 1,4-butanediol plant, using Genomatica engineered nology adoption as well as a faster response to
2016 have a total production capacity of 0.53 million strains for bioconversion, displaying slightly higher market drivers. The ability for rapid and distrib-
BOE/day, with the majority producing between CapEx/capacity than would be expected of a first- uted deployment enables feedstock diversifica-
1000 and 5000 BOE/day (Fig. 1C). In contrast, of-its-kind process. tion by enabling access to remote, smaller-scale
135 operating U.S. refineries produce more than Central to the rapid adoption of these bio- resources. This can not only help reduce envi-
19.1 million barrels of oil per calendar day, about manufacturing technologies is the fact that the ronmental impact by capitalizing on sustain-
35 times the total BOE produced by ethanol CapEx entry-level cost of ethanol production via able feedstocks such as biomass but also help
plants, and operate with a production capacity fermentation has markedly decreased over the reduce greenhouse gas emissions through tar-
greater than 75,000 barrels per day (Fig. 1C), past few decades. Focusing on capital expend- geting smaller-scale methane resources like flared
which is 15 to 75 times the average production iture costs, which are representative of stan- and vented natural gas and biogas. The smaller-
capacity of ethanol plants. Despite differences dard biological production processes, rather than scale, lower-CapEx facilities can also promote
in production capacities, the reduced land usage process-specific operational costs, the decreasing equitable resource globalization by lowering
of bioethanol facilities enables aerial productiv- CapEx cost has been the result not of increas- the economic barrier to chemical manufacturing.
stocks; however, the amounts produced are on mass production of facilities and the benefits of
par with ethanol plants on a BOE basis (compare manufacturing automation to reduce CapEx per
Fig. 1C and Fig. 4B). For example, gas-generation unit scale. Additionally, distributed feedstocks
rates from 1233 U.S. Environmental Protection can be coupled to localized markets by tailor-
Agency (EPA)reporting landfill projects range ing product synthesis to regional market needs.
between 2 and 300 BOE/day (Fig. 4B), whereas The aforementioned characteristics of indus-
gas production from 239 EPA-reporting agricul- trial biomanufacturing (e.g., small-scale, flexible,
tural sites operate at a narrower range centered CapEx-efficient processes) supports this approach
around 2 to 20 BOE/day (Fig. 4B). Flaring from and can provide the needed process and econo-
490 petroleum operations visible through the mic characteristics to recover methane resources
National Oceanic and Atmospheric Administra- through rapid, mobile, and widespread technol-
tions Visible Infrared Imaging Radiometer Suite ogy deployment directly at the feedstock source.
(VIIRS) Nightfire (17) indicates the smaller scale Recovering these distributed gas feedstocks al-
of flare-associated gas as well, with the majority lows capitalization on otherwise wasted or in-
of sites generating 2 to 40 BOE/day (Fig. 4B). accessible resources, which if left to current
Despite the small scale of individual-site meth- technologies will continue to result in consider-
ane generation, the large number of sites results able greenhouse gas emissions.
in substantial total resources, with more than Although the demonstrated abilities of bio-
Fig. 3. Reduction in capital costs of U.S. etha-
which a CH bond in methane is converted to a Efforts to identify methanotrophic organisms Methanotrophic bacteria have also been used
COH group. Two variations of MMO exist: par- for industrial fermentation have revealed sev- for the production of a number of compounds
ticulate, membrane-bound MMO (pMMO), and eral promising directions, despite historical li- from methane, including BioProtein (2931), poly-
cytoplasmic, soluble MMO (sMMO) and, given mitations due to low organism productivity and hydroxybutyrate (32, 33), carotenoids (34), vita-
their role and novel function in methanotrophs, a lack of genetic tools for manipulation. Re- mins (35), and methanol (36) (Table 1). Recently,
these enzymes have been extensively studied cent efforts have focused on Methylomicrobium the identification of an active Embden-Meyerhof-
(19). Obligate methanotrophs metabolize meth- buryatense, a Group I methanotroph with a faster Parnas (EMP) pathway in novel gammaproteo-
ane as their sole carbon and cellular energy doubling time compared with traditional meth- bacterial methanotrophs, notable for resistance
[adenosine triphosphate (ATP)] source, oxidizing anotrophs (24, 25). Genetic tools have recently to the toxic components of natural gas and bio-
methane to CO2 via the intermediates metha- been developed for M. buryatense (26, 27) and gas, has redefined carbon efficiency calculations
nol (CH3OH), formaldehyde (CH2O), and formate the ability for transient gene expression opens and ATP availability in certain methanotrophic
(CHO2 ). Methane-derived carbon is assimilated the door for the development of powerful gen- organisms, most notably indicating the opportu-
at the level of formaldehyde via the ribulose- etic tools such as clustered regulatory interspaced nity for organic acid production via fermentation
monophosphate (RuMP) cycle or serine cycle, short palindromic repeats (CRISPR)/CRISPR- (37, 38). EMP pathway presence provides the po-
formate via the serine cycle, or CO2 via the Calvin- associated protein Cas9based genome editing. tential to couple methanotrophic use with con-
Benson-Bassham (CBB), depending on the specific Recently, application of rational metabolic engi- ventional industrial strain-engineering routes
metabolism (Fig. 5) (20, 21). The majority of neering strategies employing these genetic engi- from sugars to biochemical intermediates and
methanotrophs are organized into two groups, neering tools enabled the development of a strain products due to the conserved downstream meta-
designated Gammaproteobacteria or Group I, which of M. buryatense engineered for the production of bolic machinery (Fig. 5). Continued pathway dis-
use the RuMP pathway for carbon assimilation, lactate from methane. Heterologous overexpres- covery, advancements in genetic tools, and focused
and Alphaproteobacteria or Group II, which use sion of a Lactobacillus helveticus L-lactate de- metabolic engineering efforts in the methano-
the serine cycle (22). More recently, thermoacido- hydrogenase in M. buryatense enabled L-lactate trophic space stand well-placed to further ex-
philic aerobic methanotrophs (Verrucomicrobia) production from methane, with cultivation in a pand the number of chemicals produced and
have been identified, which can assimilate car- continuous bioprocess resulting in the produc- improve carbon conversion efficiency. Improv-
bon through the CBB cycle at the level of CO2 (23). tion of 0.8 g/L L-lactate (28). ing both the range of products and the efficiency
can also be exploited to use other single-carbon processes. As the most oxidized C1 feedstock, CO2 of such organisms (5860). Further efforts have
feedstocks, including methanol, formaldehyde, represents a single-carbon substrate that requires enabled the conversion of syngas feedstocks to
formate, and carbon dioxide. C1 feedstocks not very different mechanisms for use. The high level an array of products, including potential fuels,
only hold great promise for a number of appli- of oxidation requires energy input to produce more biopolymers and precursors, specialty plastics,
cations (31) but also demonstrate the flexibility of reduced carbon forms, and as a result the biological nylon precursors, solvents, and pharmaceutical
biocatalysts and bioconversion processes to tar- fixation of CO2 proceeds through a number of precursors, among others (5964). Benefits of
get various feedstocks. As an intermediate of different enzymes independent of those discussed bioconversion syngas fermentation include bio-
aerobic methane activation, the use of methanol above. Pathways for CO2 fixation include the catalyst tolerance to gas impurities and flexibility
as a carbon source requires similar pathways to Calvin-Benson-Bassham cycle, the reductive tri- regarding gas feedstock composition, whereas
that of methane, and many microorganisms carbocylic acid cycle, the Wood-Ljungdahl pathway, challenges include gas-liquid mass transfer li-
capable of using methane are also able to use the 3-hydroxypropionate:4-hydroxybutyrate cycle, mitations and the availability of genetic tools
methanol. Accordingly, organisms have been and the dicarboxylate:4-hydroxybutyrate cycle (55, 56). Despite these challenges, the potential
engineered to produce compounds from meth- (50). Each uses different key CO2 fixation enzymes, for syngas fermentation through combinatorial
anol (Table 1). Furthermore, identification and and these pathways are found across a wide scope metabolic engineering and process development
characterization of enzymes involved in meth- of various microorganisms. Microalgal species and has recently been demonstrated by the large-
anol use have enabled the construction of path- cyanobacteria are candidates for the conversion of scale production of ethanol (64), also demon-
ways for methanol conversion both in vitro (47) CO2 to various products, and the availability of strating that the challenges of gas-intensive
and heterologously in vivo (48). Notably, a unique genetic tools has enabled the metabolic engineer- fermentations can be overcome.
approach for the fixation of general C1 units ing of cyanobacteria, including Synechococcus Unique approaches for providing the required
has recently demonstrated a computationally elongatus PCC 7942 and Synechocystis sp. PCC reducing power for CO2 use have also been ex-
designed enzyme, formolase (FLS), which cat- 6803, to produce a number of compounds di- plored. One such approach is the use of microbial
alyzes the carboligation of three one-carbon rectly from CO2 (51). Despite this success, a major biofilms that directly accept electrons from elec-
formaldehyde molecules into one three-carbon challenge with the use of photosynthetic or- trodes for the reduction of CO2 to organic products
dihydroxyacetone molecule (49). This approach ganisms is providing large light-exposing sur- (65), a process referred to as microbial electro-
enabled the conversion of formate to the central faces, which requires extensive process design synthesis. Clostridium ljungdahlii has been shown
carbon metabolite dihydroxyacetone phosphate and optimization. to be highly effective in electrosynthesis for
in vitro, providing a proof-of-principle demon- An alternative to light-energy, fixation of the acetate production (65), with a newly developed
stration for the potential of a FLS pathway to oxidized carbon in CO2 can also be accom- genetic toolbox making it feasible to expand
convert C1 feedstocks such as formate or for- plished through the input of reducing power in product synthesis from CO2 (66). Another in-
maldehyde into chemical products. In addition the form of electrons from shuttles such as H2 novative method for direct electron input to
to providing routes to product synthesis from and formic acid. Systems in which H2, either the Wood-Ljungdahl pathway of an acetogen
these C1 feedstocks, these reports also represent externally added or produced via electrocata- has recently been reported in which the microbes
important steps in transferring methanotrophic lytic water splitting, or electrochemically pro- are photosensitized (67). Self-photosensitization
ability because these pathways can be combined duced formate, from water and CO2, are coupled of a nonphotosynthetic bacterium, Moorella
with continued efforts for heterologous MMO to the growth of lithoautotrophic organisms, thermoacetica, was demonstrated in which bio-
expression to enable various routes to metabolic have been demonstrated as a means of convert- logically generated cadmium sulfide semicon-
intermediates and product synthesis from methane. ing CO2 to useful chemical products (5254). Sim- ducting nanoparticles absorb light and use the
Developing and improving pathways for the ilarly, anaerobic fermentation of syngas, a fuel energy to carry out photosynthesis for the pro-
use of the above C1 compounds can aid in the gas mixture of CO2, H2, and CO, by acetogenic duction of acetate from CO2.
development of efficient biocatalysts for tar- bacteria via the Wood-Ljungdahl pathway, has Given the challenge of reducing the highly
geting distributed methane feedstocks. In addition, been demonstrated for the production of fuels oxidized carbon in CO2, continued insight into
given the gaseous nature of CO2, bioconversion and chemicals from C1 feedstocks (5557). A num- the characterization and mechanism of enzymes
processes targeting this feedstock offer the po- ber of acetogens have been used for this pur- for CO2 reduction is another critical area of re-
tential to both contribute to and leverage from pose, with the recent development of genetic tools search. Despite being a widely distributed reaction
knowledge gains for gas-intensive fermentation a key step in enabling the metabolic engineering in nature, relatively little is known about enzymes
catalyzing CO2 reduction activity. Recently, a can potentially target applications challenging scale without the loss of performance. Typical
novel, hydrogen-dependent CO2 reductase, pur- for a single engineered organism (75). These bioprocess development takes 5 to 10 years and
ified from the model acetogenic organism Ace- include engineering naturally occurring micro- can be considerably more expensive than chem-
tobacterium woodii, was identified that fixes CO2 bial consortia while also developing synthetic ical technologies owing to the relative infancy of
to formate via the electron shuttle H2 (68, 69). consortia to improve efficiency, stability, and the process (87). The holistic consideration of
Furthermore, the ability for enzymes such as control. Beyond the traditional single-cell bio- process parameters, including product purity
formate dehydrogenase to catalyze the reduc- catalyst, another approach uses synthetic cell- and waste-stream management, at an early stage
tion of CO2 has also been discovered (70), and free systems, which convert a substrate to a is desirable to develop small-scale testing pro-
further characterization and discovery can be ex- product using a mixture of enzymes and co- tocols mimicking required larger-scale process
ploited to better understand and improve CO2 factors for the cascade of reactions (76, 77). These parameters. Modeling and designing novel bio-
utilization processes. Of special interest is the in vitro systems provide the potential for greater reactors, especially those for gas-intensive fer-
form of the electron donor, which can potentially control and flexibility by uncoupling product mentations, will be critical to improving the
be coupled to other biological reactions to max- synthesis from cellular viability, complexity, and reproducibility and predictability of bioconver-
imize overall efficiency. physiology and enabling high catalyst loading sion processes at the commercial scale. Process
to support high product titer and productivity. intensification can build on initial success in
What is the future of Advancements in material design and three- commercial-scale gas fermentation, with the
industrial biomanufacturing? dimensional printing have the potential to im- flexibility and modularity of biocatalyst devel-
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