Welcome to the Sáenz lab!Evolution and Engineering of Living Membranes
Our laboratory studies the design principles of living membranes. We combine lipid biochemistry, membrane biophysics, and synthetic genomics to unravel and harness the role of lipids in organizing bioactivity, from synthetic protocells to minimal organisms. A central aim is to identify the minimal set of components required to build a robust and responsive synthetic cell membrane. Every cell is encapsulated by a lipid membrane. The cell membrane is a responsive organizational interface that protects the cell while facilitating its interactions with the environment, including signaling, transport, growth and division, and energy metabolism. We focus on lipids because they are the chemical backbone of the membrane: lipids form the bilayer, determine its physical and chemical properties, and influence the function of membrane proteins. The lab is currently focused on two complementary directions. We use genomically minimal cells, such as JCVI-Syn3B, to elucidate the simplest lipidomes that can support life and to probe why life has evolved such complex lipidomes. In parallel, we are exploring the molecular dialogue between membranes and RNA, in which lipid composition and membrane properties modulate RNA activity, structure, and localization through sequence-dependent interactions. An evolutionary perspective frames our approach: ancestral membranes and genomically minimal organisms together provide a window onto the constraints and evolutionary pressures under which membranes first emerged as a heritable element of early life, and subsequently evolved into their modern form and function. We are now beginning to ask how membrane phenotypes are genomically encoded, and whether the design principles we uncover can be used to engineer them through synthetic genomics. Research themesMinimal lipidomes and the design principles of living membranesWhat is the minimal chemical complexity required to build a living membrane? Using the bacterium Mycoplasma mycoides and its derived minimal cell JCVI-Syn3A, we have developed approaches to tune and minimize membrane lipid composition, demonstrating that two lipids are sufficient (though far from optimal) for life (Justice et al., Nature Communications 2024). Systematic reintroduction of lipid diversity into this minimal background lets us ask which features of the lipidome, including acyl chain variety, headgroup variety, and chirality, are important for growth, robustness, and adaptation. These observations establish the lipidome as a determinant of cellular fitness, and extend the concept of minimal life from the genome to the lipidome. RNA-lipid interactions and membrane regulationHow do lipid membranes organize and regulate RNA? We discovered that lipid membranes can act as RNA organization platforms, modulating RNA activity through direct, sequence-dependent interactions (Czerniak and Sáenz, PNAS 2022). Short RNAs bind lipid membranes in a manner that depends on nucleotide content and secondary structure, with G-rich sequences and G-quadruplex motifs binding most effectively, and changes in lipid phase state modulating ribozyme activity. We are now using these interactions to develop RNA-based sensors of membrane physical state, to engineer lipid-sensitive riboswitches, and to investigate the role that RNA-lipid interactions could have played in the origin and early evolution of cellular life. Encoding membrane phenotypes in synthetic genomesHow are membrane physical properties encoded in the genome, and how can we program them? The physical properties of a membrane (its fluidity, thickness, and permeability) are determined by its lipid composition, which in turn is determined by metabolic networks encoded by the genome. The map between genotype and membrane phenotype, however, remains largely uncharted. We use genomically minimal bacteria such as JCVI-Syn3B as experimental systems to dissect the genotype-to-membrane-phenotype relationship, and we apply synthetic genomics to explore how genomic information encodes membrane phenotype. This work, supported by our affiliation with the Carl Zeiss Stiftung Center for Synthetic Genomics at Heidelberg, lays the foundation for engineering and extending the function of living membranes. For ongoing research notes and an annotated bibliography of our work, see our lab website and our research wiki. Selected publicationsOriginal PapersJustice IG, Kiesel P, Safronova N, von Appen A, Sáenz JP# (2024) A tuneable minimal cell membrane reveals that two lipid species suffice for life. Nat Commun. 15:9679. Safronova N, Junghans L, Sáenz JP# (2024) Temperature change elicits lipidome adaptation in the simple organisms Mycoplasma mycoides and JCVI-Syn3B. Cell Rep. 43(7):114435. Nguyen HNA, Sharp L, Lyman E, Sáenz JP# (2024) Varying the position of phospholipid acyl chain unsaturation modulates hopanoid and sterol ordering. Biophys J. 123(13):1896-1902. Czerniak T, Sáenz JP# (2022) Lipid membranes modulate the activity of RNA through sequence-dependent interactions. PNAS. 119(4):e2119235119. Thornburg ZR, Bianchi DM, Brier TA, Gilbert BR, Earnest TM, Melo MCR, Safronova N, Sáenz JP, Cook AT, Wise KS, Hutchison CA, Smith HO, Glass JI, Luthey-Schulten Z (2022) Fundamental behaviors emerge from simulations of a living minimal cell. Cell. 185(2):345-360.e28. Chwastek G, Surma MA, Rizk S, Grosser D, Lavrynenko O, Ruci?ska M, Jambor H, Sáenz JP# (2020) Principles of membrane adaptation revealed through environmentally induced bacterial lipidome remodeling. Cell Rep. 32(12):108165. Sáenz JP, Grosser D, Bradley AS, Lagny TJ, Lavrynenko O, Broda M, Simons K (2015) Hopanoids as functional analogues of cholesterol in bacterial membranes. PNAS. 112(38):11971–11976. Sáenz JP, Sezgin E, Schwille P, Simons K (2012) Functional convergence of hopanoids and sterols in membrane ordering. PNAS. 109(35):14236–14240.
§ equally contributed |
