Resource allocation governs economies and biology alike. Each biological function has an associated resource cost while also conferring a fitness benefit by contributing to a cellular objective, such as growth (Appendix A). Cells optimize for these objectives under the constraints of their resource budget. The accumulation of resource allocation decisions to fulfill cell objectives results in observed cell phenotypes. As such, resource constraints limit cells' activity and, consequently, their range of possible phenotypes(Shoval et al., 2012). In this sense, resource allocation can be viewed as a cost-benefit(Dekel and Alon, 2005) or supply-demand(Hofmeyr and Cornish-Bowden, 2000) analysis (Fig. 1). Despite the complexity of mammalian cells, resource allocation is a fundamental principle underlying decision-making. From an evolutionary perspective, organisms that best apply resource allocation strategies will have higher fitness. As such, the consideration of resource allocation illuminates how and why cells respond to their environment. Specifically, resource costs limit how a cell can achieve its objective by constraining the possible mechanisms the cell can use. Fitness illuminates why the cell chooses one specific mechanism over other possibilities.

Decision-making depends strongly on cellular context(Shakiba et al., 2021). To make decisions, a cell perceives extracellular cues(Jerby-Arnon and Regev, 2022) such as nutrient availability and communication signals(Armingol et al., 2022a), and processes this information based on its intracellular state (e.g., cell type, genomic variants, epigenetic state). Consequently, the extracellular cues act as signals that a cell can use to assess its resource budget and shape its objectives. Intracellularly, the relayed information of resource availability and objectives in a given context determine pathway activity(Hofmeyr and Cornish-Bowden, 2000). Finally, context can change with time(Gerashchenko et al., 2021; Ghosh et al., 2022; Rooyackers et al., 1996), space(Ben-Moshe and Itzkovitz, 2019; Kleinridders et al., 2018), and disease(Gazestani et al., 2019; Smillie et al., 2019), dynamically shaping cellular objectives that cause trade-offs and transitional costs that further constrain the cell.

Mammalian cells do not act in isolation, but rather in multicellular systems to achieve higher-order functions(Almet et al., 2021; Armingol et al., 2021; Toda et al., 2019). Constraints, contexts, and phenotypes are ubiquitous across biological scales. Thus, the insights into resource allocation may be generalized to tissues and even the whole-organism (Appendix C). With multicellularity, cells become specialized to limit the burden of trade-offs. Additionally, decision-making accounts for coordination and competition from other cells, leading to synergistic effects(Rueffler et al., 2012).

In this Review, we discuss how resource allocation impacts mammalian cell decisions and multicellularity. We begin with two questions at the cellular scale (Fig. 2a):

(1) How do metabolic resources (nutrients, machinery, and bioenergetics) constrain the cell?

(2) How do cells allocate resources to coordinate activity across molecular processes?

Building on these concepts to understand multicellularity (Fig. 2b), we ask:

(3) How do trade-offs imposed by resource constraints affect cellular decision-making, leading to cell specialization?

(4) How do specialized cells with distinct tasks coordinate within multicellular systems to achieve higher-order functions?

Here we highlight the role of resource allocation, which is one valuable concept among many to understand biological mechanisms. Our aim is to demonstrate the broad utility and unique insights provided by resource allocation across various areas of biology. Resource allocation provides a unique perspective to uncover fundamental principles that can be applicable across diverse systems. We structure our discussion by first introducing an overarching principle and subsequently illustrating them with wide-ranging examples from various systems in both health and disease. While optimality is not always the driving force, or not yet fleshed out in mammalian systems, such a perspective has been invaluable to the study of prokaryotes and lower eukaryotes in support of mammalian systems, which we also highlight here.

Throughout these discussions, we explore the plasticity of resource allocation as it changes across contexts. We also briefly highlight powerful systems biology methods that now help address such questions (Appendix B, Table 1). Quantifying and modeling resource allocation provides insights into how cells regulate gene expression, intracellular pathway activity, cell-cell interactions, and ultimately phenotypes. Associated technological and computational innovations are providing high-throughput measurements and analysis tools to decipher how resource allocation, as a governing design principle, shapes the complex processes underlying mammalian phenotypes.