The different aspects of stranded resources and assets.
\r\n\t
\r\n\tRecently in 2019, International Council on Systems Engineering (INCOSE) has released the latest version of the “Guidelines for the Utilization of ISO/IEC/IEEE 15288 in the Context of System of Systems (SoS) Engineering” to industry for review and comments. The document was developed under the Partner Standards Development Organization cooperation agreement between ISO and IEEE, as it was approved by Council Resolution 49/2007. This document provides guidance for the utilization of ISO/IEC/IEEE 15288 in the context of SoS in many domains, including healthcare, transportation, energy, defense, corporations, cities, and governments. This document treats an SoS as a system whose elements are managerially and/or operationally independent systems, and which together usually produce results that cannot be achieved by the individual systems alone. This INCOSE guide book perceives that SoS engineering demands a balance between linear procedural procedures for systematic activity and holistic nonlinear procedures due to additional complexity from SoS perspectives.
\r\n\tThe objective of this book is to provide a comprehensive reference on Systems-of-Systems Engineering, Modeling, Simulation and Analysis (MS&A) for engineers and researchers in both system engineering and advanced mathematical modeling fields.
\r\n\tThe book is organized in two parts, namely Part I and Part II. Part I presents an overview of SOS, SOS Engineering, SOS Enterprise Architecture (SOSEA) and SOS Enterprise (SOSE) Concept of Operations (CONOPS). Part II discusses SOSE MS&A approaches for assessing SOS Enterprise CONOPS (SOSE-CONOPS) and characterizing SOSE performance behavior. Part II focuses on advanced mathematical application concepts to address future complex space SOS challenges that require interdisciplinary research involving game theory, probability and statistics, non-linear programming and mathematical modeling components.
\r\n\tPart I should include topics related to the following areas:
\r\n\t- SOS and SOS Engineering Introduction
\r\n\t- Taxonomy of SOS
\r\n\t- SOS Enterprise (SOSE), SOSE CONOPS, Architecture Frameworks and Decision Support Tools
\r\n\tPart II should address the following research areas:
\r\n\t- SOS Modeling, Simulation & Analysis (SOS M&SA) Methods
\r\n\t- SOS Enterprise Architecture Design Frameworks and Decision Support Tools
\r\n\t- SOS Enterprise CONOPS Assessment Frameworks and Decision Support Tools.
The power industry is in transition, and energy management systems are adapting to it. Recently, the rapid proliferation of distributed energy resources (DERs) (e.g., distributed generation such as residential solar photovoltaics (PV) and wind electricity, controllable loads, and energy storage), have transformed operational, planning, and regulatory dynamics. Low-cost natural gas in the US, Europe, and elsewhere continues to push gas-fired electricity generation to the top of the generation mix. To this end, governments continue to promote low-carbon technologies through ever-stringent energy policies, like renewable portfolio standards (RPS), net metering, feed-in tariffs, and carbon pricing initiatives and emission trading schemes like the European Union Emission Trading System (EU ETS), Switzerland Emissions Trading Scheme, emissions trading schemes in China and Australia, the Regional Greenhouse Gas Initiative (RGGI) in the nine U.S. states in the Northeast and Mid-Atlantic region, the Transportation and Climate Initiative (TCI) under consideration for transportation emissions in the Northeast and Mid-Atlantic, the California and Quebec’s Western Climate Initiative, among others. Furthermore, this growth in renewable electricity generation has been motivated by customers’ preference for distributed energy as a means to fostering grid reliability and system efficiency, cost reduction, and improved customer choice over their power supplies [1, 2, 3].
\nThese efforts are in line with the 2015 Paris Agreement on climate change and its nationally determined contributions’ (NDCs) long-term goal of keeping the rise in global mean temperature to “well below [two degrees Celsius (2°C)] above pre-industrial levels and pursuing efforts to limit the temperature increase to 1.5°C above pre-industrial levels” [4]. Moreover, limiting these temperature targets requires reaching net-zero global carbon dioxide (CO2) emissions “between 2060 and 2070,” with full decarbonization or “net negative CO2 emissions” realized before the end of the century [5]. From a policy perspective, this transition from carbon-intensive sources to low and non-carbon-emitting sources is continuing as high penetrations of distributed electricity, energy storage and management devices, and investment in new forms of flexible demand resources become connected to the power grid network. Such significant shifts threaten the fossil energy business model and could, in turn, result in the “stranding” of the carbon-intensive assets through retirement or devaluation [6, 7, 8]. In other words, meeting the Paris temperature targets necessitates turning existing fossil fuel investments into stranded assets and fossil fuel reserves into stranded resources. The concept of “stranding” or “stranded assets” has been explored broadly in extant literature, from environment-related risk exposure of coal assets [9] to “unburnable fossil fuel deposits” such as oil, gas, and coal and the risk of stranded assets [10, 11].
\nBos and Gupta [12] define stranded assets as “assets that lose economic value well ahead of their anticipated useful life, whether that is a result of changes in legislation, market forces, disruptive innovation, societal norms, or environmental shocks” p. 1 and stranded resources as “resources which are considered uneconomic or cannot be developed or extracted as a result of technological, spatial, regulatory, political or market limitations, or changes in social and environmental norms” p. 2. On the other hand, Caldecott et al. [13] define stranded assets as those assets which “suffer from unanticipated or premature write-offs, downward revaluations or [conversion] to liabilities” p. 11. Policymakers and experts concur that this transition should be managed proactively and pragmatically because if done haphazardly, it could perpetuate the techno-institutional complex of “carbon lock-in” and path dependency, thus making future transitions difficult [14, 15, 16, 17, 18, 19, 20, 21]. On the other hand, if variable renewable energy resources like solar and wind electricity is introduced in significant quantities and not correlated exactly with peak load, it may create a unique challenge like the infamous California ISO’s “duck curve” shown in Figure 1. How should the energy sector respond?
\nCalifornia ISO’s “duck curve.” Source: CAISO (2014).
This chapter is structured as follows. Section 2 discusses digitalization solutions and business model innovations and presents moral arguments for supply- and demand-side energy solutions, including sensors, meters, higher efficiency devices, and energy auditing, including measurement and verification strategies that can be utilized to improve energy management. Specifically, using ML (machine learning- and (AI) artificial intelligence solutions to support (a) tackling stranded assets in the transition to a low-carbon economy (b) real-time measurement of energy data, (c) manage data gathering and monitoring, (d) and proactively and accurately analyze the data gathered to detect changes in supply-demand imbalances and improve the situation promptly. Section 3 reviews the risks of stranding and identifies distinct opportunities for ML and AI applications in the energy sector. Section 4 emphasizes the impact of stranding risk factors on oil, gas, and coal resources and how this translates into the concept of “unburnable fossil fuel deposits.” Section 5 discusses how advances in ML and AI techniques might help tackle the risks of stranded carbon assets, and Section 6 concludes.
\nToday’s modern cities are sprouting with new industrial buildings and residential complexes. The consensus is emerging that dramatic growth in distributed renewable energy, and digitalization in economy and innovations, two megatrends of the twenty-first century, are critical strategies for climate change mitigation and changing the greenhouse gas (GHG) emission trajectories. Yet, while the electric power system is in transition, many of the vital power system challenges which confront governments and businesses, like access to a cleaner, more resilient, reliable, and affordable electricity, remain underfunded and unresolved. The increased deployments of energy management applications across the transportation, buildings, and industrial sectors, for example, reduce the cost of operation and consumption, lower energy losses, increase grid reliability, improve electric power production from carbon-free sources, and alleviate investment inefficiencies that could cause an energy-efficiency gap [22, 23, 24]. The continued growth of the fluctuated distributed generations (such as solar photovoltaics, wind turbines, electric vehicles, and energy storage systems) may perturb the network and create voltage drop/rise problems and in severe conditions, blackouts.
\nIn a highly electrified economy with high shares of variable solar and wind electricity systems, reducing systemic mismatches between the generation and energy demand assets in an efficient manner requires investments in smart energy management systems. Energy management systems consist of two main categories: (a) supply-side devices from the electric utility-side used to manage the fluctuation of the load demand such as substations, and (b) the demand-side management devices used to manage energy consumption and meet the available power from the generation side [25, 26, 27, 28]. Substations encompass transformers, switchgear, and protection, control and automation systems, and connect parts of the electric grid that operate at different voltage levels and managing these multidirectional power flows while ensuring reliability and security is critical as the share of decentralized and renewable energy increases. The rise of smart energy management systems, including ML, AI, big data, smart sensors, and the Internet of Things, is a boon not only to the electric power industry—especially in reducing operational costs and carbon emissions—but also the energy transition. For example, opportunities for leveraging digitalization for business model innovation in smart energy management and the corresponding implications for the power sector are substantial and untapped [29, 30].
\nEnergy management is subject to barriers and limitations, which can delay its full market integration. These barriers include high cost of system implementation, inflexible fixed-price electricity tariff system and rate design, aging network’s infrastructure, and the need for bidirectional power flow, which is ideal for an intelligent grid network. As a result, energy management continues to have a prominent role in decarbonization. Using ML algorithms and AI optimization models, utilities and system operators can apply optimal dynamic pricing and energy storage resource to improve the management of the “duck curve” phenomenon. For example, Sheha et al. [31] applied game-theoretic models to show that leveraging a combined effect of dynamic pricing profiles and distributed electrical energy storage can help flatten the duck curve, thus solar energy can be increasingly added on the grid without resulting in grid failure. The duck curve problem arises when increasing solar penetration on the grid creates a dip in net load in the middle of the day as solar generation peaks and wind electricity is low, followed by a significant rise in peak in residential demand at sunset as, without any form of energy storage, solar electricity rapidly subsides, and customer consumption increases as citizens get home from work/school thus necessitating significant ramping of thermal generators [24]. Figure 1 shows California Independent System Operator’s (CAISO) widely known “duck curve” (Figure 1) [32]. Besides California, the “duck curve” phenomenon also occurs in energy markets with high solar electricity penetrations such as Italy, Germany, Hawaii, and others.
\nTo eliminate the risk of over-generation and possibly, alleviate the “duck curve” problem, implementation of long-term solutions focusing on distinct opportunities for ML techniques, including distributed solar coupled with storage technologies and smart energy management, are emerging in various energy markets. At stake, according to Guidehouse Insights (formerly Navigant Research), is $278 billion in annual global market for the deployment of commercial and industrial (C&I) energy as a service (EaaS) solutions by 2028 [33].
\nThe intergenerational issues associated with climate change identifies it as an externality associated with carbon dioxide and other GHG emissions because it involves costs that are borne by future generations who have not created the emissions [34, 35, 36, 37, 38]. Climate change economists have introduced the concept of “social costs of carbon,” which externalizes the externalities of these emissions by denoting the damages caused by them with a monetary value [35, 39, 40, 41]. It is for this reason that climate policy experts have advocated for a carbon price to achieve the “right price” as well as incentivize the investments in low-carbon technologies. Furthermore, from a policy, equity and regulatory point of view, scaling the deployment of low-carbon energy technologies inspires innovation in technological development, diffusion, transfer, and discourages the holding of dirty exhaustible assets (fossil fuel reserves) [42, 43], which are prone to becoming stranded due to perfect substitution, and disproportionately impact low- and moderate-income communities.
\nThe risks of stranding of assets are likely to occur during the transition to a green economy. As van der Ploeg and Rezai [17] suggest two conditions are necessary for this transition to occur: (1), the unexpected future changes in the conditions likely to affect the economics of fossil fuel assets, such as customer demand, the social cost of carbon that values the climate externalities, and equity and efficiency considerations, must be present; (2) the cost of shifting around “the underlying capital stocks in the carbon-intensive industries to productive use elsewhere after the energy transition” must be too prohibitive or impossible to meet. Expectations about stranding carbon-intensive assets can occur due to sudden policy change, a breakthrough innovation in renewable energy technology such as energy storage batteries, which can lead to the stranding of fossil fuel-based financial assets since they directly pose a threat to the sustainability of the coal, oil, and gas-based business model.
\nWith ML and AI techniques, energy operators can foster better short-term and long-term forecasting to improve electricity scheduling and integrated system planning, respectively. This would enable the utility operators and system managers to reduce their reliance on polluting, exhaustible fossil assets as well as proactively manage increasing amounts of distributed, low-carbon, variable energy sources like solar and wind energy. Additionally, the ML-AI-driven energy forecasts can provide accurate and optimal management of power grid fluxes to help operators proactively match demand-supply imbalances, manage uncertainties, as well as understand where, when and how many solar power systems [44, 45] and wind generation plants [46] should be built.
\nHowever, much of these forecasts employ domain-agnostic techniques, in which domain-specific scenarios are often less applied. For this reason, ML and AI algorithms of the future must incorporate weather-related innovations in climate science and weather modeling techniques in order to improve parametric and nonparametric estimates of both short- and long-term forecast uncertainty, for example, of variable generation and electricity demand [44, 46, 47, 48, 49]. For example, using a novel deep learning framework that combines wavelet transforms, stacked autoencoders, and long-short term memory, Bao et al. [50] produced stock price forecasts that outperform other similar models in both predictive accuracy and profitability performance. This notion can be extended to aid electricity demand forecasts that optimize intraday and day-ahead levelized cost and levelized avoided cost of electricity generation resources that minimize GHG emissions. More broadly, in the transition from the incumbent centralized electricity network to a distributed model that is underway, driven by the rapid growth of DERs, understanding the domain value of improved forecasts (e.g., to model electricity load in rural microgrids) across the quartiles of electricity market operation, matching of supply-demand imbalances, network control, and governance and administrative networks [2, 51] is an exciting challenge for ML and the debate on stranded assets.
\nGoing by Bos and Gupta [12] and Caldecott et al. [9]’s definition, stranded assets and stranded resources manifest in two main ways (1) devaluation through the unburnable fossil fuel resources, which must be kept in the ground to keep the long-term global temperature target to below 2°C above pre-industrial levels [4], and (2) premature retirement of exhaustible fossil capital assets due to climate policies, including the optimal social cost of carbon in the form of a carbon price [40]. Figure 2 shows the US annual electricity generating capacity additions and retirements from oil, gas, and coal power plants.
\nAnnual oil, gas, and coal electricity generating capacity additions and retirements. Source: EIA (2020).
In the US Energy Information Administration (EIA) Annual Energy Outlook’s Reference case, natural gas-fired combined-cycle generation capacity will continue to be added steadily through 2050. Significant retirements of electric generation capacity, mostly from coal, occur by 2025, while approximately 117 GW of new wind and solar capacity additions could occur between 2020 and 2023 [52]. This means that without investing in heat rate improvement technologies by 2025 to increase their efficiency, coal-fired generation systems must retire to comply with the affordable clean energy (ACE) rule or become stranded assets. The AEO2020 Reference case also shows that the low cost of natural gas prices significantly contributes to the retirements of coal-fired and nuclear power plants by 2025. Diverse policy efforts, notably increasing state RPS targets, net metering policies, and declining capital cost profile of solar, are expected to incentivize and accelerated its growth through 2050 by making the investment case for widespread solar energy deployment attractive to investors, particularly when utility-scale and small-scale applications are considered. Table 1 summarizes the seven main drivers of stranding and the different aspects of stranded resources and assets.
\nType of stranding | \nNature of asset | \nCause of stranded asset | \nStranded resource | \nLiability | \nReferences | \n
---|---|---|---|---|---|
Economic | \nViable projects receive investment (e.g., growing biofuels in deforested lands)\na\n\n | \nIncreased market competition affects investment in the asset (e.g., falling oil prices leads to cuts in oil exploration investments) | \nWhen it becomes uneconomical to extract/convert the resource due to low demand | \nPremature stranding costs (e.g., decommissioning and phase-outs costs) | \n[10, 53, 54, 55, 56] | \n
Technological | \nNew technological breakthroughs (e.g., hydraulic fracturing, CCUS, and solar geoengineering like injecting sulfate aerosols into the stratosphere)\nb\n\n | \nNew technologies and disruptive innovations render old technologies obsolete | \nSlow technological learning to access the resource (e.g., deep-sea exploitation and exploration) | \nLiability when technology becomes obsolete or dangerous | \n[57, 58, 59, 60, 61] | \n
Political | \nThe political climate is conducive for resource exploitation | \nGeopolitical changes like sanctions may affect assets (e.g., The Trump administration sanctions against Huawei affected Chinese oil/gas contracts) | \nPolitical strife or civil war inhibits resource exploitation | \nLiabilities levied against governments or organizations for (short-term) policies (e.g., aid agencies for export credits on polluting industries) | \n[9, 12, 62, 63] | \n
Policy/legal | \nPolicies and laws allow consumption, contracts, leases, and intellectual property rights/patents | \nNew legal regime leads to asset retirement or phasing out (e.g., nuclear phase-out) | \nPolicies or laws may restrict resource extraction or conversion (e.g., moratoria) | \nPareto improvement; Liabilities for the premature stranding of investments due to policy changes (e.g., trade agreements) | \n[15, 64] | \n
Spatial | \nThe asset can be exploited | \nResource depletion; water scarcity | \nThe resource is remote (e.g., inaccessible gas or solar resource) | \nLiabilities for clean-up costs (e.g., Superfund clean-up costs for contaminated pollutants) | \n[65, 66, 67] | \n
Social | \nCommunities or consumers prevent the use of the asset (e.g., NIMBY (“not in my backyard”) protests) | \nA community or consumer protests lead to its ban (e.g., Keystone Pipeline XL protests) | \nA community or consumers prevent the use of a resource (e.g., local fracking bans) | \nCompensation for resource damage (e.g., US Deepwater Horizon BP oil spill environmental damages, Nigeria’s Niger Delta oil spills accidents) | \n[68, 69, 70] | \n
Ecological | \nEconomic benefits are greater than the ecological impacts. | \nEcological considerations (e.g., climate change) outweigh economic arguments. | \nEcological effects inform non-use decisions of resource (e.g., large hydro dams) | \nInsurance or costs of adaptation borne by an investor Punitive damages incurred as injunctive relief | \n[56, 71, 72, 73] | \n
The different aspects of stranded resources and assets.
Increased efficiency could create higher overall demand referred to as the Jevons paradox. For example, a shift to electric vehicle model may lead to the rebound effect, resulting in increased vehicle miles travelled, and overall rise in GHG emissions [54, 56].
New technological breakthroughs like carbon capture, utilization and storage (CCUS) innovations can be used to extract CO2 from power plant exhaust and industrial processes.
According to the Potsdam Climate Institute, to meet the Paris Agreement of a temperature target below 2°C of global warming with the aim to limit it to 1.5°C, the global carbon budget of the total volume of CO2 emissions permitted by 2050 is 886 GtCO2 [74]. However, more than a third of this carbon budget has already been used up from burning fossil fuels, leaving a budget of around 565 GtCO2. In the case of a 1.5°C temperature limit or even lower, this budget would be drastically contracted. It is for this reason that national, state and local governments must prioritize low-carbon transformations; for instance, (i) ramping up renewable energy over the next two decades, (2) switching from oil to less carbon-intensive gas [5, 15, 25, 42, 48, 55, 75, 76, 77], and (3) keeping large global deposits of coal, oil, and gas reserves “in the ground” (Table 2) [11, 13, 79]. This call has led to the “keep fossil fuels in the ground” initiative, “fossil fuel divestment” campaign, and “unburnable carbon” resistance movement, as a way to compel companies which are active in hydrocarbons or with high coal, oil, and gas reserves in their portfolios to reinvest elsewhere [17, 63, 79, 80, 81, 82, 83, 84].
\nTotal proved coal reserves at the end of 2019 | \nTotal proved oil reserves at the end of 2019 | \nTotal proved gas reserves at the end of 2019 | \n||||||
---|---|---|---|---|---|---|---|---|
Country | \nReserves (million tons) | \n% World | \nCountry | \nReserves (billion barrels) | \n% World | \nCountry | \nReserves (trillion cubic meters) | \n% World | \n
The United States | \n249,537 | \n23.3% | \nCanada | \n170.8 | \n9.8% | \nThe Russian Federation | \n38.0 | \n19.1% | \n
The Russian Federation | \n162,166 | \n15.2% | \nVenezuela | \n303.8 | \n17.5% | \nIran | \n32.0 | \n16.1% | \n
Australia | \n149,079 | \n13.9% | \nKazakhstan | \n30.0 | \n1.7% | \nQatar | \n24.7 | \n12.4% | \n
China | \n141,595 | \n13.2% | \nThe Russian Federation | \n107.2 | \n6.2% | \nTurkmenistan | \n19.5 | \n9.8% | \n
India | \n105,931 | \n9.9% | \nIran | \n155.6 | \n9.0% | \nThe United States | \n12.9 | \n6.5% | \n
Indonesia | \n39,891 | \n3.7% | \nIraq | \n145.0 | \n8.4% | \nChina | \n8.4 | \n4.2% | \n
Germany | \n35,900 | \n3.4% | \nKuwait | \n101.5 | \n5.8% | \nVenezuela | \n6.3 | \n3.2% | \n
Ukraine | \n34,375 | \n3.2% | \nSaudi Arabia | \n297.7 | \n17.1% | \nSaudi Arabia | \n6.0 | \n3.0% | \n
Poland | \n26,932 | \n2.5% | \nThe United Arab Emirates | \n97.8 | \n5.6% | \nThe United Arab Emirates | \n5.9 | \n3.0% | \n
Kazakhstan | \n25,605 | \n2.4% | \nThe United States | \n68.9 | \n4.0% | \nNigeria | \n5.4 | \n2.7% | \n
Turkey | \n11,525 | \n1.1% | \nLibya | \n48.4 | \n2.8% | \nAlgeria | \n4.3 | \n2.2% | \n
South Africa | \n9,893 | \n0.9% | \nNigeria | \n37.0 | \n2.1% | \nIraq | \n3.5 | \n1.8% | \n
\n | 92.8% | \n\n | 90.1% | \n\n | 84.0% | \n
Global reserves of coal, oil, and gas.
Source: BP Statistical Review of World Energy 2020 [78].
Notes: The total world proved coal, oil, and gas reserves at the end of 2019 were 1,069,636 million tons, 1735.9 billion barrels, and 198.8 trillion cubic meters, respectively. The total proved coal reserves include both anthracite and bituminous reserves and sub-bituminous and lignite reserves.
\nTable 2 shows the top 12 countries for each of the three fossil fuels. These coal, oil, and gas reserves represent 92.8%, 90.1%, and 84%, respectively, of the total global, proved reserves at the end of 2019 [78]. McGlade and Ekins [11] have computed a breakdown of the socially optimal distribution of stranded carbon assets that must be kept in the ground to meet the Paris Agreement temperature targets. They find that to have “a better-than-even chance of avoiding more than a 2°C temperature rise, the carbon budget between 2011 and 2050” must be kept at “around 870–1240 GtCO2” p. 187. This translates to approximately one-third of global oil reserves, half of the global gas reserves, and over 80% of global coal reserves of unburnable fossil fuels. Figure 3 summarizes the regional distribution of these unburnable reserves. These figures are in line with other estimates of the stranded coal, oil, and gas assets by other experts and organizations, that must be kept in the ground, to meet the 2°C Paris commitments [5, 10, 74, 85, 86]. However, while in the end, all carbon must be phased out, less-carbon intensive energy carriers like gas might continue to operate as a “bridging fuel” to the carbon-free economy, in tandem with renewable energy. When considering short- and long-term nature of technology rebound effects, path dependency in policymaking, and carbon lock-in in different markets [16, 20, 87, 88, 89, 90, 91, 92], adopting adaptive strategies, incorporating technology transfer, and incentivizing international collaboration in energy research, are vital stratagems for managing the distributional impact of this energy transition process as well as upstream value chain requirements (such as future nuclear baseload supply and renewables-based hydrogen generation).
\nPercent of regional distribution of unburnable fossil reserves before 2050 for the 2°C scenario—data from McGlade and Ekins [
Returning to physical and financial carbon assets at risk of being stranded, ML and AI techniques can provide appealingly pragmatic Pareto-optimal solutions for mitigating stranding risks among different policy aspects instead of using scalarization, thereby creating a balanced transition to lower-carbon technology [93, 94, 95]. What causes assets to strand? As discussed in Section 2, multiple factors, including economic, technological like disruptive innovation, political, regulation, spatial, and societal norms, or environmental shocks, can lead to asset stranding. Stranding is not just a loss in economic value but also an irreversibility of the investments. This means that if the investments wiped out is reversible and can be adjusted for other purposes such as retooling an obsolete coal power plant to be used as a hydro generation facility; then the assets have not stranded since they can be put to different profitable use [63, 80, 86].
\nWith respect to the unburnable carbon, stranding occurs when coal, oil, and gas companies, who have already committed heavy capital investment in related infrastructures such as exploitation, exploration, and pipelines, become hit by a sudden drop in commodity prices, leading to the stranding of their capital stocks. This could also happen when a government establishes an unanticipated Pigouvian fee, promoted by Pigou in a seminal article [96], on GHG emissions to correct for the unpriced environmental externality, either via a carbon price [97, 98] or a market-based emissions cap-and-trade mechanism [99]. This can have negative consequences for the market valuation of the upstream and downstream fossil fuel-based businesses and producers of electricity, leading to forced write-offs of their carbon assets [21] or their capital stocks getting stranded. For example, following the passage of the Powerplant and Industrial Fuel Use Act (FUA) in 1978 in response to the Arab oil embargo of 1973, a significant shortage of natural gas occurred, leading to a drop in natural gas-fired generation capacity additions. The unintended consequence of this policy-driven change in the national electricity generation mix was a shift to coal-fired generation capacity in the intervening years, leading to a rise in energy-related long-term carbon emissions.
\nIn recent years, research shows that ML and AI are broadly powerful tools for technological progress that can be applied with a high impact in mitigating the transition to low-carbon technologies, especially in tackling the problem of stranded assets in the electricity sector. Power generation and demand forecasting is one area in which ML and AI techniques can improve policy vagaries and uncertainty about future demand, thereby mitigating the risk of stranding [17]. Below are the 10 distinct opportunities for ML and AI applications in the energy sector that include:
Electricity scheduling and dispatch: Improving electricity scheduling and dispatch mechanisms using ML and AI tools amidst increasing variable DER generation, storage, and flexible demand.
Energy data analytics and informatics: Using ML supervised models, e.g., that employ regression-based techniques on cellular network data, to generate information about low-data settings and determine where electricity power lines can be placed in regions unmapped, and help improve energy access [100].
Energy materials research: Applying ML, AI, optimization techniques, and physics to better understand the science of energy material’s crystal structure, to accelerate materials discovery for solar fuels that improves harnessing of energy from variable natural resources [101].
Natural gas methane detection and prevention: Employing ML and AI techniques to detect and prevent the leakage of methane from natural gas pipelines and compressor stations.
Nuclear fission and fusion: Application of ML and deep networks to speed up inspection of nuclear power plants and help design next-generation smart, modular nuclear reactors [102, 103].
Solar PV design and innovations: Using ML techniques to design controllable movable solar panels that maximize electricity production, for example, in bifacial solar modules and dual-orientation racking techniques [53, 104, 105, 106, 107].
Solar PV technical and economic potential estimation: Using ML to help estimate technical and economic potential of rooftop solar PV, e.g., by optimizing Light Detection and Ranging (LIDAR)-Geographic Information Systems (GIS) imagery-rendering of size and location data for rooftop solar panels [108, 109] .
Wind power management and monitoring: ML-driven condition monitoring (such as dimensionality reduction algorithm like Principal Component Analysis—PCA) of wind turbine blades, including optimization of blade fault detection, power curve monitoring, and temperature monitoring [110, 111].
Integrated transportation planning: Using AI and ML to improve vehicle engineering, shared mobility, and shift to lower-carbon options, like rail. In the long-term, ML and AI applications can support integrated intelligent infrastructure through planning, maintenance, and operations to make transportation more efficient though the GHG reduction, provide better demand forecasts, and support smart transit policy efforts such as autonomous vehicles, alternative fuels and electrification (e.g., electric vehicles, and vehicle-to-grid algorithms), and predicting battery state and degradation rate using supervised learning techniques [112, 113, 114, 115, 116].
Urban energy planning: With ML and AI applications, available building1 energy use data can be extrapolated to predict energy use at the city level. Furthermore, ML is uniquely capable of supporting improvements in “smart energy frameworks for smart cities” [25], including building codes, informing policymakers about utilizing urban rooftops for solar PV electricity generation [55, 108], retrofitting strategies using automated performance control [117], public-private partnerships to improve low-and moderate-income (LMI) stipulations and equitable electricity access [15, 64].
The above list is by no means exhaustive. The transformation to a low-carbon economy is occurring at an expanding rate. The technical innovations accompanying these carbon-free energy sources such as solar, wind, hydro, and geothermal energy is driving down the cost of these technologies as production increases and knowledge accumulation results from learning by doing. As a result, they are yielding substitutes for coal, oil, and progressively rendering coal, oil, and gas capital stock obsolete. It is expected that as this shift continues, new opportunities for ML and AI applications will become available, including in modeling consumer behavior and facilitating sustainable behavior change energy consumption action [3, 65, 118, 119], estimating and predicting the marginal emissions of residential energy utilization and thermal comfort in buildings in real time, on a scale of hours [57, 118], and game-theoretic modeling and design of socially beneficial energy policies like social norms, public opinions, stakeholder engagement, and education efforts [120, 121, 122]. Other breakthrough innovations might displace fossil fuels leading to stranding, and creating opportunities for ML-based electricity pricing techniques and rate design to set dynamic pricing of carbon, electricity, and consumer choice [1, 123, 124, 125, 126, 127], and multi-objective optimization to compute Pareto-optimal solutions for climate engineering, climate informatics, and solar geoengineering [58, 128, 129, 130]. There is a possibility that these technological innovations could create a sudden improvement in market evaluation of the renewable energy industries, while some assets of related carbon-intensive industries become stranded due to obsolescence, write-offs, or retirements.
\nFollowing the passing of the Paris Agreement on climate change, nations committed to keeping the global temperature below 2°C. Achieving this temperature target means coal, oil, and gas producers face stranding more than 80% of all these proven fossil fuel reserves and existing investments becoming stranded assets. These threats lead policymakers and market analysts to conclude that market evaluation and capital investments of some of these carbon-intensive firms risk being stranded, unless they fundamentally change their business models per the risk of asset stranding, to cushion themselves from unanticipated economic, technological, political, regulatory, spatial, social, and environmental changes, resulting in cheap renewable substitutes for coal, oil, and gas. A pragmatic and proactive response by governments is urgently required in the form of NDCs and climate policies to guide this transition, and that puts nations on a sustained path to the 1.5 or 2°C “carbon budget.” Such a process should avoid a disruptive and unorderly energy transition and macro shocks. Using ML and AI techniques to tackle the risks of stranded carbon assets and related infrastructure can enrich and inform this praxis. Stranded assets are not new in the energy sector; the physical impacts of climate change and the transition to a low-carbon economy have generally rendered redundant or obsolete electricity generation and storage assets. Low-carbon electricity systems, which come in variable and controllable forms, are essential to mitigating climate change. These systems present distinct opportunities for machine learning and artificial intelligence-powered techniques, making their applications prominent.
\nSen and von Schickfus [62] calculate that €1.61 billion of security reserve or €13.38/MWh subsidy, is required to compensate coal energy assets in Germany at the risk of becoming stranded. Given the threats of sudden changes in the stringency of carbon policies and related abrupt repricing or retirement of fossil fuel assets, they also find that investors generally do care about stranded asset risk, but that they also expect to be financially compensated for stranded assets. This analysis highlights the threat of stranded asset risk in the coal industry and the need for understanding the interaction between policymaking and investors’ expectations. For example, the International Renewable Energy Agency (IRENA) [131] estimates that to meet the Paris Agreement’s 2°C temperature target, $1.9 trillion in electricity generation assets would be stranded after 2030. The report concludes that stranding will disproportionately affect $7 trillion in upstream energy infrastructure, of which three-quarters are in oil production. Institutional investors must tap ML and AI techniques ML to improve energy planning and system efficiency (e.g., detect and prevent the leakage of methane from natural gas pipelines, speed up inspection of nuclear power plants, and improve electricity scheduling and dispatch mechanisms). Given the vital role of the energy sector and its interrelation with the rest of the economy, using ML and AI to tackle stranded electricity assets is emerging as a cost-effective derisking strategy. Stranding and the risk of stranded carbon assets is a growing challenge requiring an interdisciplinary approach that brings together ideas from engineering, economics, and policy fields, as well as quantitative opportunities of ML, AI, optimization, and dynamical systems, to address interpretability, uncertainty quantification, and integration questions.
\nTo maintain hemostasis, new blood cells must be constantly generated to replace those lost through injury, disease, or age. Hematopoiesis, is the process where hematopoietic stem cells (HSC) differentiate into mature blood cells and is tightly regulated by the bone marrow (BM) micro-environment (or stem cell niche; reviewed in [1]), signal transduction pathways (reviewed in [2]), cytokines (reviewed in [3]), transcription factors (reviewed in [4]), epigenetics, (reviewed in [5]) and metabolic pathways (reviewed in [6]). HSCs are rare, constituting only 0.001% of peripheral blood (PB) and 0.05% of BM cells, but are responsible for producing a lifetime supply of blood cells. HSCs are cells that able to durably self-renew whilst also being multipotent. This differentiation is generally considered to occur via several intermediate progenitor cells, ultimately terminating in the specific mature blood cell through a process termed fate restriction or lineage commitment.
The compartmentalization of HSC, their progenitors and terminally differentiated blood cells, into different stages of differentiation, is traditionally based on the expression of cell surface proteins (Figure 1). The recent emergence of single cell technologies such as fluorescent in situ hybridization, high-throughput single-cell quantitative PCR, single cell mass spectrometry and mass cytometry however, have led to re-analysis of these models of hematopoietic differentiation [7]. Discrete progenitor cell populations, as determined by cell surface markers, have been shown to consist of heterogenous populations with different fates [8]. Recently, a study by Velten
Human hematopoiesis. Schematic diagram showing classical model of hematopoietic lineage commitment, with phenotypical cell surface markers (red), transcription factors determining differentiation (green box) and growth factors involved in myelopoiesis (blue). Hematopoietic stem cell (HSC), cluster of differentiation (CD), hematopoietic progenitor cell (HPC), common myeloid progenitor (CMP), common lymphoid progenitor (CLP), interleukin (IL), granulocyte macrophage (GM) colony-stimulating-factor (CSF), stem cell factor (SCF), thrombopoietin (TPO), erythropoietin (EPO), granulocyte myeloid progenitor (GMP), runt-related transcription factor 1 (RUNX1), transcription factor stem cell leukemia (SCL), ccaat enhancer binding proteins (C/EBP), friend of GATA protein 1 (FOG-1).
Regardless of provenance, leukemogenesis is characterized by a block in differentiation and an accumulation of immature white blood cell blasts with a rapid increase in these blasts, characteristic of the acute leukemias. Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are heterogenous diseases with a block in lymphoid or myeloid differentiation, respectively. They occur due to one or more genetic insults. Whilst ALL is predominantly a disease of children (80%), with a greater than 90% 5 y survival rate [10], in adults long term survival stands at only 30–40% [11]. AML in contrast is primarily a disease of the elderly, and like adult ALL it’s 5 y survival rate is around 30%, however this falls in the over 60’s to a particularly bleak 10% [12]. In ALL, recent advances for example in the use of tyrosine kinase inhibitors and CAR-T cell therapy, have started to suggest improvements to overall survival [10]. However, in patients fit enough to tolerate chemotherapy, the standard treatment for AML since 1973 has been a seven-day continuous intravenous infusion of cytarabine (Ara-C) (100–200 mg/m2) and 3 daily doses of daunorubicin (45–90 mg/m2), sometimes followed by allogeneic or autologous stem cell transplantation, and despite some recent advances (reviewed in [13, 14]), current treatments appear to have reached their efficacious limits and new therapies are required.
One potential therapeutic opportunity involves exploiting the metabolic differences that exist between malignant and non-malignant cells [15]. Differences that, in AML at least, appear exacerbated by cellular levels of reactive oxygen species (ROS) [16].
ROS is the collective term for several oxygen containing free radicals and other reactive molecules, such as hydrogen peroxide (H2O2). Physiologically, ROS are initially generated via the univalent reduction of molecular oxygen which generates superoxide (O2•−). Superoxide (t1/2 = 1 μs) subsequently dismutates to H2O2 (t1/2 = 1 ms) [17], either spontaneously or via the catalytic action of the enzyme superoxide dismutase (SOD), or reacts with other ROS molecules, forming a variety of other ROS (Figure 2). Functionally, ROS is important in innate immunity, protein folding in the endoplasmic reticulum and as a cell signalling molecule involved in cellular proliferation, survival, differentiation and gene expression [18].
Formation of reactive oxygen species (ROS). Diatomic oxygen (O2) is univalently reduced by peroxisomes (PO), xanthine oxidase (XO), the electron transport chain (ETC), or NADPH oxidase (NOX) to generate superoxide (O2•−). PO may also reduce O2 directly to form H2O2. O2•− may then dismutate to H2O2 either spontaneously or through the enzymatic action of superoxide dismutase (SOD). Hydroxyl radicals (OH•) may then be formed from H2O2 via the formation of hypochlorous radical (HOCl) in the PO, or via Fenton chemistry. Reactive nitrogen species (RNS) may also be formed through the reaction of nitric oxide radical (NO•) with O2•−.
There are several sources of cellular ROS, including the mitochondria, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes (NOX), the cytochrome P450 enzymes, peroxisomes and the metabolic enzyme xanthine oxidase (XO).
Generation of ROS by the mitochondria is primarily a function of ‘electron leakage’ from the electron transport chain (ETC), however, mitochondrial ROS may also be generated as a result of numerous enzymes including monoamine oxidase, cytochrome b5 reductase, glycerol-3-phosphate dehydrogenase, aconitase, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase (reviewed in [19]). Mitochondrial ROS production resulting from the ETC generates O2•−, and is thought to occur as result of one of three mechanisms. The first mechanism is a consequence of a high NADH/NAD+ ratio, and results from oxygen interacting with fully reduced FMN. Mitochondrial ROS generated by this mechanism has been observed due to mitochondrial mutation, physiological damage such as ischemia or aging, and only small amounts of ROS are thought to be generated via these mechanisms in normally respiring cells [20]. The second mechanism occurs when there is a high level of reduced co-enzyme Q (CoQH2) in complex II, which in the presence of a high proton motive force generated by the proton pump, force electrons back into complex I in a process known as reverse electron transport (RET). Whilst RET generated ROS has also been implicated in diseases such as ischemia, it is now also thought to be involved as a cell signalling molecule in metabolic adaptation, myeloid differentiation and response to bacterial infection [21]. The third mechanism of ROS generation by the ETC occurs at complex III and has also been implicated in ROS signalling. The formation of O2•− occurs at the ubiquinol oxidation centre (Qo) site of the cytochrome bc1 complex, in which fully oxidized CoQ supports formation of O2•−, through the transfer of electrons from reduced heme b1 to molecular oxygen [22]. Generation of O2•− by complex I and II occurs exclusively in the mitochondrial matrix, whereas O2•− generated by complex III also occurs in the intermembrane space. O2•− generated in the mitochondrial matrix is rapidly converted to H2O2 by mitochondrial SOD (Mn-SOD), whereas O2•− generated in the intermembrane space travels through the outer mitochondrial membrane prior to conversion to H2O2 by cytosolic SOD (Cu/Zn-SOD).
Whilst mitochondrial oxidative phosphorylation is a major source of intracellular ROS, the main source of extracellular ROS involves the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes (NOX). The NOX family of enzymes comprise of seven members, NOX1–5 and dual oxidase (DUOX) 1 and 2. NOX enzymes are transmembrane proteins that transfer electrons from NADPH to molecular oxygen, generating O2•− (or H2O2), which can then be converted to other forms of ROS. Different NOX isoforms share conserved structural features comprising of six helical transmembrane domains (TM) (with helix III and helix V containing two heme-binding histidines), and a C-terminus cytosolic domain (DH), which allows binding of FAD and NADPH (Figure 3). Difficulties in obtaining suitable levels of NOX proteins mean that to date relatively little crystal structure data is available. However, a recently published report [23], has elucidated the structure of the TM and DH domains (common to all NOX isoforms) of
Generation of superoxide (O2•−) by NADPH Oxidase (NOX). Schematic diagram showing the major structural features of NOX2, it’s activation by phosphorylation (P) of p67phoxand p47phox and the assembly of the major subunits of the NOX complex, and the generation of superoxide via electron transfer from NADPH to flavin adenine dinucleotide (FAD) to heme groups to diatomic oxygen. Guanosine triphosphate (GTP), guanosine diphosphate (GDP), homology domain (DH), RAS-related C3 botulinum toxin substrate 2 (Rac2).
From a metabolic perspective, one source of NOX2 activation results when cells experience intermittent hypoxia. Under this condition activation of the metabolic enzyme XO, an enzyme important in the catabolism of purines and a major source of cellular ROS, occurs [24]. XO activation leads to increased ROS, which induces Ca2+ activation of protein kinase C, an enzyme important in cell signalling, migration of p47phox and p67phox to the cell membrane, resulting in activation of the NOX2 complex (Figure 3). Finally it is important to note, from a cell signalling perspective, that extracellular H2O2 (which is rapidly formed from O2•−) is readily transported across the cell membrane via the transmembrane water permeable channel protein family of aquaporins [25, 26].
ROS has been implicated in both HSC quiescence and hematopoietic differentiation. HSC reside in the bone marrow and their quiescence is known to be negatively regulated by ROS. Forkhead box O (FOXO) transcription factors are involved in cell-cycle arrest and apoptosis and are activated in response to oxidative stress whereupon they translocate to the nucleus [27]. Translocation of FOXO4 to the nucleus has been shown to be a function of redox signalling, where oxidation of cys-239 by ROS mediates the formation of disulphide bonds with nuclear import receptor transportin-1, which in turn allows nuclear localization [28]. FOXO deactivation occurs as a result of phosphorylation in response to activation of the regulatory cell cycle PI3K/AKT/mTOR pathway, resulting in their export from the nucleus and subsequent degradation in the cytoplasm [29]. Studies in murine HSC have shown that deletion of FOXO3a, which upregulates transcription of Mn-SOD [30], results in decreased HSC renewal [31] which is mediated by the tumor suppressor protein ataxia-telangiectasia mutated (ATM) and is accompanied by elevated ROS levels and myeloid lineage expansion [32]. Deletion of ATM in mice resulted in BM failure which was restored following treatment with antioxidants [33]. In a different study, isolation of murine HSC into ROS high and ROS low populations showed that the ROS low population maintained self-renewal capacity following serial transplantations, whilst the self-renewal capacity of the ROS high population was exhausted following the third serial transplantation. Treatment of the ROS high HSC with the antioxidant N-acetyl cysteine (NAC), the p38 inhibitor SB203508 or rapamycin (a mTOR inhibitor), restored self-renewal activity [34]. Interestingly, the ROS high population in this study also exhibited a decreased ability to adhere to cells containing calcium sensing receptors, whilst NOX generated ROS has additionally been implicated in osteoclast differentiation in human mesenchymal cells, further emphasizing a potential regulatory role of ROS, in the BM niche [35].
Whilst these increased ROS levels are associated with HSC losing quiescence, it has also been shown, in the human megakaryocytic cell line MO7e, that hematopoietic cytokines, such as granulocyte macrophage-colony stimulating factor, interleukin-3, stem cell factor and thrombopoietin all increase ROS levels [36]. In megakaryopoiesis, ROS has been shown to increase platelet production and maturation in the chronic myeloid leukemia (CML) cell line MEG-01 and primary human megakaryocytes [37], which in murine models is mediated by the transcription factor NF-E2 [38]. Following lineage commitment, megakaryocyte progenitors undergo endomitosis (chromosomal replication in the absence of cell division), which in murine cells is potentially mediated by NOX1-derived ROS [39]. In human HSC, NOX-derived ROS has also been shown to be crucial for megakaryocyte differentiation via activation of ERK, AKT and JAK2 signalling pathways [40], whilst another study revealed the importance of cytochrome P450 2E1-generated ROS in megakaryocyte differentiation in human HSC [41]. As noted above, increased ROS in HSC has been associated with expanded myelopoiesis. Interestingly, a recent study using murine CMP, showed that higher levels of ROS impeded megakaryopoiesis, instead directing differentiation of CMP into GMP [42]. Finally, ROS has also been shown to induce differentiation of the promonocytic cell line, U937, into macrophages [43], and the differentiation of primary human monocytes into dendritic cells [44].
One of the first studies implicating ROS in carcinogenesis was performed in mice subcutaneously injected with C3H mouse fibroblasts, that had been previously cultured
In leukemia, a study which collected blood samples from ALL and CML patients samples and compared them with normal blood samples showed elevated levels of ROS in both ALL and CML patients [52], whilst elevated levels of NOX generated ROS, are observed, alongside increased proliferation in both AML models and AML patient samples when compared with healthy controls [53]. Reactions of ROS with DNA can generate numerous oxidised bases, including 8-hydroxy-2-deoxyguanosine (8-OHdG) which causes G:C to T:A DNA transversions (reviewed in [54]). Increased levels of 8-OHdG have been observed in patients with breast cancer [55], gastric carcinomas [56], lung cancer [57] and colorectal cancer [58]. In leukemia, a study of 116 Chinese children with either ALL or AML revealed significantly elevated levels of 8-OHdG, whilst 8-OHdG levels were also significantly elevated in relapsed AML adult patients [59].
As a signalling molecule, ROS can lead to hyperactivation of the PI3K pathway, a common feature of many cancers, resulting in increased cell survival, VEGF production, secretion of MMP (reviewed in [60]) and inactivation of FOXO [32]. In AML, constitutive activation of the PI3K/AKT pathway is frequently observed [61, 62], however the role of FOXO is less clear. A recent study revealed that FOXO1 expression in osteoblasts mediated β-catenin initiated AML [63], whilst a study of AML patient samples showed that 40% exhibited FOXO activation, that upon inhibition resulted in myeloid differentiation and AML cell death [64]. Additionally, in both CML and AML the BCR-ABL fusion protein and FMS-like tyrosine kinase receptor 3 internal tandem duplications (FLT3-ITD) have been shown to lead to phosphorylation of AKT resulting in increased activation of NOX, and increased ROS production (reviewed in [65]), which may in turn reinforce PI3K/AKT activation.
Broadly defined, cellular metabolism involves a series of catabolic or anabolic chemical reactions which generate or use energy as part of this process. In chemotrophs this energy is obtained through the oxidation of nutrients, with the energy typically stored in the form of ATP. Whilst in higher organisms a plethora of enzymatically catalyzed metabolic reactions occur, which are all part of different interconnecting metabolic pathways with multitudinous feedback mechanisms. These pathways are evolutionarily highly conserved with the citric acid cycle, for example, essentially a feature in all terrestrial life. There are three main classes of molecules involved in metabolism; carbohydrates, proteins and lipids that are either catabolized to generate energy or energy stores or used by anabolic pathways in the synthesis of, for example, nucleotides and structural molecules such as cell membranes. In mammals, a triumvirate of glycolysis, citric acid cycle and the ETC are central to the generation of ATP, with glycolysis and the citric acid cycle contributing 2 ATP molecules each and the ETC generating up to 34 ATP molecules in a process collectively termed aerobic respiration (reviewed in [66]).
Given the skew towards ATP production in the ETC, Otto Warburg’s observation in 1956 that aerobic glycolysis was a hallmark feature of cancer cells [15], was initially attributed to being the result of defective mitochondria in malignant cells, and initially raised little interest. However, this hypothesis is now known in most cases to be incorrect (reviewed in [67]) and instead, it has been shown that mitochondrial respiration is often necessary in tumorigenesis [68]. However, given its ubiquity and despite its inefficiency when compared with ETC, it is clear that the phenomenon of increased aerobic glycolysis (eponymously titled ‘The Warburg Effect’), must offer cancer cells some competitive advantage, although its exact ontology remains unclear. One hypothesis contends that whilst inefficient, aerobic glycolysis generates ATP at a rate 10–100 times faster than oxidative phosphorylation, therefore supplying cancer cells with energy at a faster rate. This increased glycolytic flux could then, potentially generate more nucleotides, amino acids and lipids for biosynthesis as well as generating the reducing agent NADPH, to deal with the increased levels of ROS common in many cancer cells [69]. Alternatively, increases in excreted lactate as a result of aerobic glycolysis would likely generate a more acidic microenvironment, breaking down stromal membrane structures and potentially increasing cancer cell motility and metastasis [70].
It has been shown that activation of the tumor suppressor protein ATM by ROS promotes glucose-6-phosphate dehydrogenase (G-6-PD) activity, the first step of the pentose phosphate pathway (PPP), which in turn generates NADPH [71]. Given that major cellular antioxidant systems, ultimately rely on NADPH to provide their reducing power, it is perhaps not surprising that ROS in both normal and aberrant cellular processes is inextricably linked with metabolism. In the cytosol, NADPH is primarily generated through the PPP, whilst a number of mechanisms exist for mitochondrial NADPH generation [72], which include the serine synthesis pathway (SSP) (via the folate cycle) [73] and the action of the citric acid cycle enzyme isocitrate dehydrogenase (IDH). IDH1 and IDH2 are commonly mutated in AML [74], although in this context NADPH is consumed, and the D-2-hydroxyglutarate generated leads to stabilization of the hypoxia regulator, hypoxia inducible factor alpha (HIF-1α) [75].
HIF-1α as a target of ROS is controversial [76], however it is overexpressed in many cancers where it induces expression of numerous glycolytic genes. The ROS regulated transcription factor nuclear-related factor 2 (NRF2) has also been shown to modulate metabolism in lung cancer cell lines, through the upregulation of enzymes involved in the NADPH production, notably G-6-PD, IDH1 and malic enzyme 1 [77] and high NRF2 levels have previously been reported in AML [78]. Furthermore, the tumor suppressor protein TP53 is also important in regulating metabolism. Homozygous deletion of TP53 in mice results in decreased oxygen consumption arising from decreased mitochondrial respiration [79]. TP53 expression has been shown to inhibit, both glucose transporter (GLUT) 1 and 4 and the glycolytic enzyme phosphoglycerate mutase (PGAM) (reviewed in [80]) leading to decreased glycolysis and potentially increased metabolism via the PPP and SSP. Finally, TP53 also upregulates the apoptosis regulator (TIGAR) an enzyme which has an active domain similar to 6-Phosphofructo-2-kinase/fructoste-2,6-bisphosphatase (PFKFB). TIGAR catalyzes the reaction of fructose-2,6-bisphosphate (F-2,6-BP) to fructose-6-phosphate (F-6-P), which inhibits glycolysis, redirects metabolites into the PPP, generating NADPH [81].
Changes of cellular ROS levels in both normal signalling as well cell signalling following cellular transformation result in changes in numerous signalling pathways controlling multiple cellular functions including growth, proliferation and differentiation. A number of these signalling pathways, exercise regulatory control over various metabolic pathways, which in turn modulate ROS levels via several feedback mechanisms (Figure 4). In leukemia, mutations in the
Regulation of metabolic pathways. Schematic illustration outlining some of the regulatory mechanism involved in glycolysis and other key metabolic pathways. Transcription factors are in pink and signalling pathways in blue. Reactive oxygen species (ROS), forkhead box O (FOXO), pyruvate kinase muscle 2 (PKM2), signal transducer and activator of transcription (STAT), nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB), glucose transporter (GLUT) hypoxia inducible factor-1 alpha (HIF-1α), tumour suppressor protein 53 (TP53), glycogen synthase kinase 3β (GSK-3β), isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), fumarate hydratase (FH), protein kinase B (AKT), mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K), synthesis of cytochrome c oxidase 2 (SCO2) and prolyl-hydroxylase domain (PHD).
Nuclear localization of the glycolytic enzyme pyruvate kinase muscle 2 (PKM2) is also ROS mediated, where it acts as a co-factor in the activation of the transcription factor, c-MYC. RAS also activates c-MYC which is overexpressed in greater than 50% of human cancers and c-MYC has been shown to activate glycolysis via the upregulation of GLUT, the glycolytic enzymes hexokinase (HK), phosphoglucose isomerase (PGI), phosphofructokinase (PFK), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK), PKM2, as well as lactate dehydrogenase A (LDHA), pyruvate dehydrogenase kinase 1 (PDK1) and PFKFB3 (reviewed in [87]). Increased glutaminolysis is also a target of c-MYC, which upregulates the glutamine transporter ASCT2 and a key enzyme glutaminase. Additionally, c-MYC was shown to upregulate both phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first step of the SSP, serine hydroxymethyltransferase, part of the folate cycle as well as several genes involved in fatty acid metabolism and the citric acid cycle (reviewed in [67]). In contrast TP53 is known to inhibit glycolysis through inhibition of GLUT1, GLUT4 and PGAM and through activation of TIGAR and synthesis of cytochrome c oxidase 2 (SCO2). Inhibition of glycolysis also occurs due to the regulatory role of miRNA. For example, miR-195-5p inhibits GLUT3, miR-143 inhibits HK2 and miR-155 inhibits HIF-1α. Furthermore, TP53 induces miR-34a which suppresses HK1, HK2, GPI and PDK1, as well as sirtuin 1, which activates FOXO1, NF-κB and in a positive feedback loop TP53 (reviewed in [80]).
Given the role that ROS plays in regulating metabolism, it is not surprising that expression of nearly all enzymes associated with glycolysis have been shown to be altered in solid tumors, a pattern also observed in leukemia. In ALL, micro-array analysis showed significant upregulation of PFK as well as the glucose transporters GLUT1 and GLUT4 in pediatric B-ALL samples [88], whilst deletion of GLUT1 in primary human B-ALL cells suppressed leukemic progression
The citric acid cycle is a series of metabolic reactions involving oxidation/reduction reactions, which generate nicotinamide adenine dinucleotide (NAD)H and flavin adenine dinucleotide (FAD)H via the transfer of hydride ions, thus providing electrons for the ETC which is a major source of cellular ROS (reviewed in [106]). Mutations of IDH, which catalyzes the decarboxylation of isocitrate to alpha-ketoglutarate are frequently reported in AML (reviewed in [107]). Characterization of the inhibitor AG-221, which has been shown to inhibit mutant IDH2 in AML cells
The SSP branches from the glycolytic pathway at the glycolytic intermediate 3-PG, where it is converted into 3-phosphohydroxypyruvate by the enzyme PHGDH, followed by conversion to phosphoserine by phosphoserine aminotransferase 1 and finally to serine by the action of the enzyme phosphoserine phosphatase (reviewed in [73]). Regulation of the SSP is achieved through 2-phosphoglycerate (2-PG) which activates PHGDH whilst serine activates the tetrameric form of PKM2 leading to increased glycolysis and decreased levels of 2-PG. Importantly serine can enter the folate cycle, which provides another route for the generation of NADPH, which has been shown to contribute to tumor growth
The PPP generate nucleotides for biosynthesis and is a major source of cellular NADPH, an important cellular antioxidant. The first step involves the dehydrogenation of G-6-P to 6-phosphogluconolactone (6-PG) catalyzed by G-6-PD and the conversion of NADP+ to [115]. Gluconolactonase catalyzes the hydrolysis of 6-PG to 6-phosphogluconate, which is then catalyzed by 6-phosphogluconate dehydrogenase (6-PGD) to ribulose-5-phosphate (Ru-5-P) alongside the generation of a second NADPH. Ru-5-P can then be converted into ribose-5-phosphate (R-5-P) by the enzymatic action of ribulose-5-phosphate isomerase. R-5-P can then be used in the synthesis of nucleotides. Alternatively, where redox homeostasis and not nucleotide synthesis is the major requirement of the cell Ru-5-P can be catalyzed by ribulose-5-phosphate epimerase, into xyulose-5-phosphate (X-5-P) and via a series of further metabolic reactions back into the glycolytic intermediates F-6-P and glyceraldehyde-3-phosphate. G-6-PD is the rate limiting step of the PPP and is regulated by the NADP+/NADPH ratio, RAS/PI3K signalling and phosphorylation by Src, whilst 6-PGD is inhibited by 3-PG [99]. In cancer, aberrant RAS signalling or activation of Src can promote activation of the PPP. In AML, a recent study showed upregulation of
Lipid metabolism has also been shown to be dysregulated in both solid tumors and hematological malignancies (reviewed in [120]). Increased fatty acid oxidation (FAO) allows cancer cells to overcome metabolic and oxidative stress through the generation of ATP and NADPH. Significant changes to lipid metabolite levels are seen in AML patient samples with either high levels or low levels of ROS [16], whilst suppression of NOX2 has also been shown to increase FAO [121]. Furthermore, inhibition of the FAO using Avocatin B results in decreased NADPH levels and ROS dependent cell death in primary human AML samples but not normal mononuclear cells [122]. In ALL, use of L-asparaginase has been shown to increase FAO activity as a metabolic escape mechanism, however use of the FAO inhibitor etomoxir in combination with L-asparaginase has been shown to increase sensitivity of both leukemic cell lines and patient samples [123].
In the last twenty years, it has become increasingly clear that ROS play a significant role in cellular signalling, particularly pathways associated with growth, differentiation and survival, whilst its roles in HSC quiescence and normal hematopoiesis have started to be delineated. In many cancers including hematological malignancies, ROS levels have been shown to be elevated, leading to aberrant signalling in these pathways. Previously, arguments for both the use of anti-oxidant and pro-oxidant treatments in leukemia have been made (reviewed in [124]). Despite the transformation of survival rates in patients with acute promyelocytic leukemia using arsenic trioxide [125] cancer cells often upregulate the production of antioxidants, and downregulate pro-apoptotic pathways such as TP53, as a response to high ROS, allowing them to escape apoptosis. In addition, it has been shown that both cancer stem cells [126, 127] and leukemic stem cells [128] exhibit low ROS levels, suggesting that even if treatment with pro-oxidants eliminates the bulk of cancer cells, cancer/leukemic stem cells may survive and relapse occur. Conversely, studies involving the use of antioxidants in treatment and epidemiological studies of antioxidant use, have shown mixed results (reviewed in [129, 130]). Increasingly it is becoming apparent that increased levels of ROS are leading to changes in signalling pathways directly or indirectly controlling metabolism, as a mechanism for managing oxidative stress. Whilst, it has long been known that cancer cells exhibit greatly altered metabolism, only recently have the purposes behind this altered metabolism, started to be elucidated. Consequently, synergistic treatments involving the use of metabolic inhibitors, alongside classical treatments for leukemias are being explored. Future work, elucidating the intricate mechanisms governing the interplay between ROS and metabolism, alongside new and more specific metabolic inhibitors provide much promise for the future treatment of leukemia.
We are grateful to Blood Cancer UK for programmatic funding and to Tenovus Cancer Care for funding Andrew Robinson. We are grateful to Wellcome ISSF for funding aspects of ROS research. We are grateful for support from the NCRI AML trials cell bank and the AML patients for providing primary samples used in several of our studies.
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\\n\\nThe University of Massachusetts, Amherst is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
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\\n\\nThe University of Surrey is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\\n\\nCorresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
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\n\nCSIC affiliated authors can also take advantage of a central Open Access fund (amounting to 10,000 EUR) to cover up to 50% of the rest of the OAPF until it expires. Effective for chapters accepted from January 1, 2020.
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\n\nCorresponding authors will receive a 25% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters. A 20% discount for publishing a long-form monographs, 25% for compacts and 23% for short-form monographs.
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\n\nThe Claremont Colleges are pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\nCorresponding authors will receive a 15% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
\n\nThe University of Massachusetts, Amherst is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\nCorresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
\n\nThe University of Surrey is pledging funds via the Knowledge Unlatched program to ensure academics can publish Open Access content more easily.
\n\nCorresponding authors will receive a 10% discount on their Open Access Publication Fees (OAPF) for Open Access book chapters or monograph publications. To use the discount you will need to verify your institutional email address. These discounts are valid from 2020 to 2022.
\n\nMonographs Only
\n\n\n\nImportant: You must be a member or grantee of the above listed institutions in order to apply for their Open Access publication funds.
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