About
Paula V. Welander is a microbiologist and Associate Dean for Research at Stanford University, where she is also a Professor of Earth System Science. She received her undergraduate degree in Kinesiology from Occidental College in Los Angeles and completed her PhD in microbiology at the University of Illinois at Urbana-Champaign in 2007. Her postdoctoral studies were conducted at MIT in the Departments of Biology and of Earth, Atmospheric, and Planetary Sciences. Since joining the Stanford faculty in 2013, her research program has focused on understanding the biosynthesis and physiological function of 'molecular fossils' or biomarkers in extant bacteria.
Research topics
- Biology
- Computational biology
- Chemistry
- Ecology
- Genetics
- Astrobiology
- Microbiology
- Evolutionary biology
- Paleontology
- Biochemistry
Selected publications
bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-23
articleOpen accessThe Lyme disease agent Borrelia burgdorferi belongs to a class of metabolically compromised bacteria that cannot survive without host-derived lipids. Survival of the agent in tick and vertebrate hosts requires substantial nutrient acquisition and potential cell envelope remodeling. While prior studies identified cholesterol, cholesterol glycolipids, and phosphatidylcholines as membrane lipids in B. burgdorferi, the identity of many other membrane lipids, their origin, and their physiological relevance remain unknown. Here, we used a suite of untargeted and targeted high-resolution mass spectrometry methods to reveal a complex lipid profile of the pathogen and to identify the origin of its lipids. The analysis detected more than 500 lipids in B. burgdorferi, the majority of which are sourced from the environment. However, the bacterium selectively accumulates certain lipids while excluding others, suggesting discriminatory uptake. These include cholesteryl esters and triglycerides that are organized in foci within the pathogen. Intriguingly, the pathogen also synthesizes predominantly eukaryotic lipids such as the lysosomal bis(monoacylglycerol)phosphate and the plant glycolipid sulfoquinovosyl diacylglycerol (SQDG). The biosynthesis of the latter is carried out by enzymes that exhibit structural homology to plant oxidoreductases and galactosyltransferases, yet their closest orthologs are found in bacteria. This hints that the capability of SQDG synthesis is more widespread in spirochaetes and other bacteria. Together, the comprehensive lipid profiling we report here uncovers novel aspects of the physiology of the metabolically challenged B. burgdorferi and highlights lipid acquisition and synthesis pathways as potentially critical for pathogen survival.
Open MIND · 2026-01-01
datasetThis dataset includes the custom Python pipelines used for proteomics data filtering and figure generation, as well as raw and processed qPCR data, accompanying the manuscript submission "Characterization of aliA and aliB deletion mutants reveals a dominant role of AliA in Haloferax volcanii lipoprotein lipidation". This dataset can be used to reproduce the results described in the manuscript.
The Origin of Life in the Light of Evolution
ArXiv.org · 2026-05-06
articleOpen accessThe origin of life is often framed primarily as a chemical problem, yet life's defining feature is evolution. Advances in geochemistry, prebiotic chemistry, and molecular biology have produced diverse scenarios for the emergence of genomes, metabolism, and cellular compartments on the early Earth, but most of these models lack a population-genetics framework. Here, we argue that origin-of-life research must expand from asking simply how life began to exploring how it evolved from pre-biological systems. Synthesizing evidence from comparative genomics, phylogenetics, biochemistry, and geoscience, we emphasize that the last universal common ancestor (LUCA) was already a complex, ecologically adapted population far removed from the starting point of life, implying a deep pre-LUCA evolutionary history. We highlight how population genetics, ecology, and synthetic biology can constrain origin-of-life scenarios by making explicit the roles of selection, drift, mutation, horizontal gene transfer, parasites, and compartmentalization in shaping early communities. Finally, we outline an evolutionary research agenda spanning protometabolic and autocatalytic networks, protocells, the emergence of translation, and the transition to DNA genomes, in which qualitative models can now be buttressed and formalized by evolution-driven hypotheses subject to testing using theory and laboratory experiments, including those with synthetic cells.
bioRxiv (Cold Spring Harbor Laboratory) · 2026-02-27
articleOpen accessSenior authorCorrespondingAbstract Sterols are a class of lipids that play a crucial role in human health through their essential physiological roles and as a point of interaction between commensal and pathogenic bacteria. The biosynthesis and modification of these lipids is a well-characterized process in many eukaryotes and increasingly in bacteria. However, the proteins responsible for formation of the unusual 8(14)-unsaturation found in the sterols produced by aerobic methanotrophs, dinoflagellates, nematodes, and marine sponges, remains unknown. Here, we utilize a heterologous expression system to identify a bacterial 8,14-sterol reductase (8,14-Bsr) responsible for generating the 8(14)-unsaturation in the aerobic methanotroph Methylococcus capsulatus . This enzyme modifies the direct product of C-14 demethylation, reducing one double bond in the nuclear core structure and isomerizing the other to produce an 8(14)-sterol. We subsequently tested the requirement of putative active site residues for catalysis through site directed mutagenesis, identifying residues likely involved in interacting with the sterol substrate and directly catalyzing this reaction. Bioinformatic analysis of the distribution of 8,14-Bsr reveals it is unique to the bacterial domain, found primarily in the Methylococcaceae family, the Mycobacteriales order, and yet uncultured members of the Myxococcota phylum. Further phylogenetic analysis of 8,14-Bsr suggests it shares an evolutionary history with the C-14 demethylase in these organisms and that these two enzymes were likely inherited together. These results provide insight into novel sterol biochemistry, further delimiting sterol biosynthesis in the bacterial domain from eukaryotes and illustrating the importance of molecular characterization to identify bacterial proteins that interact with sterols. Importance Many of the eukaryotic proteins required for the biosynthesis of sterols, such as cholesterol, have been characterized. However, the pathways governing analogous processes in the bacterial domain are less characterized. Here, we identify an 8,14-sterol reductase in aerobic methanotrophs. This enzyme carries out a unique biochemical reaction, saturating and isomerizing double bonds in the nuclear core structure to produce an 8(14)-sterol. This reductase is restricted to the bacterial domain, further separating the evolution of bacterial sterol production from eukaryotes. Additionally, we find this reductase is prevalent in members of the sterol degrading order Mycobacteriales, highlighting a potential role for this protein in the remodeling of host sterol production by these pathogens.
Open MIND · 2026-02-16
datasetRaw LC-MS data for the paper "AliA and AliB exhibit distinct enzymatic activities in lipoprotein lipidation in the model archaeon Haloferax volcanii". Includes both core lipid data and methyl-iodide treated lipoprotein extract data for the YH_57 (∆aliB) and YH_113 (∆aliA) strains. Data for the parental strain (H53) and double deletion strain (∆aliA∆aliB) are provided in a separate deposit: https://doi.org/10.25740/vq241jx8767.
The Origin of Life in the Light of Evolution
arXiv (Cornell University) · 2026-05-06
preprintOpen accessThe origin of life is often framed primarily as a chemical problem, yet life's defining feature is evolution. Advances in geochemistry, prebiotic chemistry, and molecular biology have produced diverse scenarios for the emergence of genomes, metabolism, and cellular compartments on the early Earth, but most of these models lack a population-genetics framework. Here, we argue that origin-of-life research must expand from asking simply how life began to exploring how it evolved from pre-biological systems. Synthesizing evidence from comparative genomics, phylogenetics, biochemistry, and geoscience, we emphasize that the last universal common ancestor (LUCA) was already a complex, ecologically adapted population far removed from the starting point of life, implying a deep pre-LUCA evolutionary history. We highlight how population genetics, ecology, and synthetic biology can constrain origin-of-life scenarios by making explicit the roles of selection, drift, mutation, horizontal gene transfer, parasites, and compartmentalization in shaping early communities. Finally, we outline an evolutionary research agenda spanning protometabolic and autocatalytic networks, protocells, the emergence of translation, and the transition to DNA genomes, in which qualitative models can now be buttressed and formalized by evolution-driven hypotheses subject to testing using theory and laboratory experiments, including those with synthetic cells.
Zenodo (CERN European Organization for Nuclear Research) · 2026-01-01
datasetOpen accessThis dataset includes the custom Python pipelines used for proteomics data filtering and figure generation, as well as raw and processed qPCR data, accompanying the manuscript submission "Characterization of aliA and aliB deletion mutants reveals a dominant role of AliA in Haloferax volcanii lipoprotein lipidation". This dataset can be used to reproduce the results described in the manuscript.
bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-11
articleOpen accessABSTRACT Protein lipidation is a widespread strategy for anchoring proteins to cellular membranes across all domains of life, yet the mechanisms underlying this process in archaea remain poorly understood. Recently, the first archaeal enzymes involved in lipobox-containing protein (lipoprotein) biogenesis, AliA and AliB, were identified and characterized in the model archaeon Haloferax volcanii . Although these paralogs share significant sequence similarity, distinct deletion phenotypes suggest differences in their substrate specificity and function. Here, we employed large-scale Triton X-114 fractionation followed by quantitative proteomics and lipid-specific mass spectrometry to systematically analyze AliA- and AliB-dependent lipoprotein lipidation. Deletion of aliA affected substantially more lipoproteins in Hfx. volcanii than deletion of aliB , markedly diminishing their TX-114 enrichment—indicating reduced hydrophobicity—and abolishing thioether-linked archaeol modification. This establishes AliA as the primary enzyme responsible for archaeal lipoprotein lipidation. In contrast, deletion of aliB affected only a small subset of lipoproteins and did not significantly reduce thioether-linked archaeol levels. In addition to defining distinct and non-redundant roles for AliA and AliB, this study provides the first large-scale experimental validation of predicted archaeal lipoproteins and identifies candidate components of the archaeal lipoprotein biogenesis pathway, substantially advancing mechanistic understanding and enabling improved lipoprotein prediction in this previously underexplored field.
The Evolutionary History and Modern Diversity of Triterpenoid Cyclases
Molecular Biology and Evolution · 2025-08-15 · 2 citations
articleOpen accessSenior authorCyclic terpenoids are a class of lipid compounds containing immense structural and functional diversity, with many cyclic triterpenoids acting as regulators of the physical properties and spatial organization of lipid membranes. Cyclic terpenoids are also readily preserved as terpane fossils, such as steranes and hopanes, forming a rich record of the evolution of life on Earth. Formation of the multiple ring structure of all cyclic terpenoids is catalyzed by terpenoid cyclase enzymes, among which are whole clades of proteins-many from environmental metagenomes and uncultured organisms-whose substrates and products are completely unknown. We investigate the function of these divergent cyclases through biochemical assays, and the evolutionary processes that produced them by testing and applying a variety of evolutionary models. We find deep divergence between the diterpenoid cyclases and triterpenoid cyclases, with other clades branching between the two, rooting the triterpenoid cyclase subtree between squalene-hopene cyclases and sterol cyclases. Through a simple test of evolutionary rate shifts, we find an elevated evolutionary rate in the enzyme active site on the squalene-hopene cyclase stem, potentially indicative of positive selection. Finally, by testing the activity of divergent cyclases for a variety of substrates, we find a group of early branching sterol cyclases from bacteria that synthesize arborinols, two of which produce the molecular precursor to a Permian "orphan biomarker." Together, our data present an evolutionary framework for triterpenoid cyclases that can inform both the biochemical potential of these proteins and their products' occurrence in the geological record.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-12-22
articleOpen accessSenior authorCorrespondingAbstract The capacity to methylate sterol side-chains via sterol methyltransferases (SMTs) was thought to be widespread in fungi, algae, and plants but limited in animals and nonexistent in bacteria. We have previously demonstrated that yet-uncultured bacteria have the genomic capacity to produce side-chain methylated sterols de novo. Further, we identified three bacterial SMTs capable of producing 24-isopropyl sterols and showed that each of these SMTs was biochemically sufficient for all three of the side-chain methylation steps necessary for 24-isopropyl sterol synthesis. To date, no eukaryotic SMT has been identified that is capable of sequentially adding three methyl groups to generate this propyl structure. To better understand this unique biochemical feature of bacterial SMTs and to potentially identify key amino acid residues involved in sequential methylations on the sterol side-chain, we performed site-directed mutagenesis of propylating bacterial SMTs. Through these analyses, we identified a glycine residue that is necessary but not sufficient for side-chain propylation. This residue is located outside known SMT substrate-binding domains, but inside the active site of an SMT protein model docked with 24-methylenecholesterol. We also show that phenylalanine residues in sterol-binding Region I increase the production of 24-isopropyl sterols, and that 25 residues are conserved among methylating, ethylating, and propylating SMTs. Together, the presence of these residues may allow us to predict if an organism has the genomic capacity to produce C-24 propylated sterols directly from sequencing data, and to generate hypotheses about the environments in which bacterial sterol side-chain propylation may be occurring through analysis of metagenomes. Given the high preservation potential of side-chain alkylated sterols and their use as molecular fossils indicative of ancient life deep in time, a better understanding of the distribution of these unique lipids in modern life and present-day ecosystems will allow for more robust interpretations of side-chain alkylated steranes in the rock record.
Recent grants
NSF Minority Postdoctoral Research Fellowship for FY2008
NSF · $189k · 2008–2011
Investigating the Biological Function of Sterols and Hopanoids in Methylococcus capsulatus
NSF · $198k · 2012–2014
Investigating the Biological Function of Sterols and Hopanoids in Methylococcus capsulatus
NSF · $121k · 2014–2015
3-Methylhopanoids in modern bacteria: molecular fossils of stress survival?
NSF · $393k · 2015–2018
Determining the function of sterol lipids in the bacterial domain
NSF · $822k · 2019–2024
Frequent coauthors
- 78 shared
Clyde A. Smith
Stanford University
- 77 shared
Liting Zhai
Hunan University of Science and Engineering
- 77 shared
Hannah Oo
Stanford Synchrotron Radiation Lightsource
- 77 shared
Jonathan Chiu‐Chun Chou
Stanford University
- 77 shared
Laura M. K. Dassama
Stanford Medicine
- 77 shared
Amber C. Bonds
National Institute of Neurological Disorders and Stroke
- 39 shared
Roger E. Summons
Massachusetts Institute of Technology
- 23 shared
Jeremy H. Wei
Stanford University
Labs
Microbial Lipid Biomarkers Lab
Education
B.A., Microbiology
Occidental College
Ph.D., Microbiology
University of Illinois at Urbana-Champaign
Other, Biology and Earth, Atmospheric, and Planetary Sciences
MIT
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