PERSPECTIVE Evolutionary cell biology: Two origins, one objective Michael Lyncha,1, Mark C. Fieldb,2, Holly V. Goodsonc,2, Harmit S. Malikd,e,2, José B. Pereira-Lealf,2, David S. Roosg,2, Aaron P. Turkewitzh,2, and Shelley Sazeri,1 aDepartment of Biology, Indiana University, Bloomington, IN 47405; bDivision of Biological Chemistry and Drug Discovery, University of Dundee, Dundee DD1 5EH, United Kingdom; cDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556; dDivision of Basic Sciences and eHoward Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Seattle, WA 98195; fInstituto Gulbenkian de Ciência, P-2781-901 Oeiras, Portugal; gDepartment of Biology, University of Pennsylvania, Philadelphia, PA 19143; hDepartment of Molecular Genetics and Cell Biology, University of Chicago, Chicago, IL 60637; and iVerna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030 Edited by W. Ford Doolittle, Dalhousie University, Halifax, NS, Canada, and approved October 20, 2014 (received for review September 3, 2014) All aspects of biological diversification ultimately trace to evolutionary modifications at the cellular level. This central role of cells frames the basic questions as to how cells work and how cells come to be the way they are. Although these two lines of inquiry lie respectively within the traditional provenance of cell biology and evolutionary biology, a comprehensive synthesis of evolutionary and cell-biological thinking is lacking. We define evolutionary cell biology as the fusion of these two eponymous fields with the theoretical and quantitative branches of biochemistry, biophysics, and population genetics. The key goals are to develop a mechanistic understanding of general evolutionary processes, while specifically infusing cell biology with an evolutionary perspective. The full development of this interdisciplinary field has the potential to solve numerous problems in diverse areas of biology, including the degree to which selection, effectively neutral processes, historical contingencies, and/or constraints at the chemical and biophysical levels dictate patterns of variation for intracellular features. These problems can now be examined at both the within- and among-species levels, with single-cell methodologies even allowing quantification of variation within genotypes. Some results from this emerging field have already had a substantial impact on cell biology, and future findings will significantly influence applications in agriculture, medicine, environmental science, and synthetic biology. evolutionary cell biology | cell biology | adaptive evolution | random genetic drift | cellular evolution The origin of cells constituted one of life’s levels, much of today’s study of evolution is motivate and illustrate the potential for this most important early evolutionary transi- only moderately concerned with cellular fea- new field. tions, simultaneously enabling replicating en- tures, perhaps due to lack of appreciation for Why Are Cells the Way They Are, and tities to corral the fruits of their catalytic their wide variation among taxa. However, Why Aren’t They Perfect? labor and providing a unit of inheritance nec- a full mechanistic understanding of evolu- essary for further evolutionary refinement tionary processes will never be achieved with- Although it is easy to marvel about the re- and diversification. The centrality of cellular out an elucidation of how cellular features fined features of cells and their robustness to features to all aspects of biology motivates the become established and modified. perturbations (1), the field of bioengineering focus of cell biology on the biophysical/bio- The time is ripe for bridging the gap imagines and even implements more efficient chemical aspects of a broad swath of traits between the historically disconnected fields cellular mechanisms in extant organisms. that include gene expression, metabolism, in- of cell biology and evolutionary biology and What, then, limits the levels of molecular/ – tracellular transport and communication, cell integrating them with the principles of cellular refinements that have been ach- cell interactions, locomotion, and growth. No biophysics and biochemistry into a formal ieved by natural selection? one questions the rich contributions that have field of evolutionary cell biology. Recent resulted from this focus on how cells work. To What Extent Is Cell Biology Beholden advances in cell-biological analysis and the However, with an emphasis on maximizing to Historical Contingency? We have learned acquisition of ’omic-scale datasets have experimental consistency in a few well-char- an enormous amount about the genetic broadened the opportunities for research acterized model systems, cell biologists have mechanisms of evolution since Darwin, and on nonstandard model organisms, thereby generally eschewed the variation that moti- it remains true that evolution is an opportu- facilitating the incorporation of phyloge- vates most questions in evolutionary biology. nistic process of “descent with modification,” Because all evolutionary change ultimately netic diversity into cell-level studies. Our requires modifications at the cellular level, vision for this synthesis is motivated by the growing realization in both communi- Author contributions: M.L., M.C.F., H.V.G., H.S.M., J.B.P.-L., D.S.R., questioning and understanding how cellular A.P.T., and S.S. wrote the paper. ties that an intellectual merger will yield features arise and diversify should be a central The authors declare no conflict of interest. dramatic increases in our understanding research venue in evolutionary biology. How- This article is a PNAS Direct Submission. of cell-biological structures, functions, and ever, if there is one glaring gap in this field, it 1To whom correspondence may be addressed. Email: milynch@ is the absence of widespread cell-biological processes, as well as insights into the cellu- indiana.edu or [email protected]. thinking. Despite the surge of interest at lar basis for evolutionary change. Although 2M.C.F., H.V.G., H.S.M., J.B.P.-L., D.S.R., and A.P.T. contributed the molecular, genomic, and developmental not an exhaustive list, the following questions equally to this work. 16990–16994 | PNAS | December 2, 2014 | vol. 111 | no. 48 www.pnas.org/cgi/doi/10.1073/pnas.1415861111 Downloaded by guest on September 29, 2021 working with the resources made available order structures such as dimers, tetramers, etc. pathways (19–23), protein transport (24), PERSPECTIVE in previous generations. Once established, Remarkably, however, unlike the strong, gen- nuclear organization (25), and ribosome useful features cannot be easily dismantled eral trend toward dramatic increases in gene production (26, 27). These kinds of obser- and reassembled de novo unless there is an structural complexity from prokaryotes to vations imply that there are often numerous intermediate period of redundancy. unicellular eukaryotes to multicellular species degrees of freedom for reorganizing the un- Oneremarkableexampleofhowhistory (7), higher-order structural complexity of derlying determinants of otherwise constant continues to influence today’s cell biology is proteins does not noticeably scale with cellular processes. thenearuniversaluseofATPsynthaseas organismal complexity across the Tree of a mechanism for energy generation (2). Em- Life (8). Comparative biochemical and How Much of Cellular Complexity Is the bedded in the surface membranes of bacteria protein-structural analysis within a phylo- Result of Adaptation? Acommonlyheld and organellar membranes of eukaryotes, this genetic framework has great potential to but incorrect stance is that essentially all of complex molecular machine uses the potential address many outstanding questions in this evolution is a simple consequence of natural energy of a proton gradient to generate a ro- area, including whether variation in the selection. Leaving no room for doubt on the tational force that converts ADP to ATP, multimeric states of proteins is a simple process, this narrow view leaves the impres- much like a turbine converts the potential consequence of stochastic mutations of ad- sion that the only unknowns in evolutionary energy of a water gradient into electricity. hesive interface residues, with minimal biology are the identities of the selective However, the proton gradient does not come effects on catalytic efficiency. agents operating on specific traits. However, for free: cells first use energy derived from Similar questions arise about the biophysical population-genetic models make clear that metabolism to pump protons out of mem- properties of supermolecular structures, such the power of natural selection to promote brane-bound compartments, creating the as microtubules, actin filaments, and the beneficial mutations and to remove deleteri- gradient necessary for reentry through ATP endomembrane systems of eukaryotic cells ous mutations is strongly influenced by other synthase. Even assuming that ATP pro- (9). The self-assembly of lipid bilayers factors. Most notable among these factors is duction is an essential requirement for emerges spontaneously from the biophysical random genetic drift, which imposes noise in the origin of life, it is by no means clear properties of amphiphilic molecules, and re- the evolutionary process owing to the finite that the path chosen for ADP-to-ATP cent origin-of-life research suggests