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Early-career faculty experiences in mentorship and lab leadership by ASBMB

In conversation with Tara Davis, a structural biologist, protein biochemist and scientific consultant, discusses her path from academia in structural biology to a career in scientific consulting supporting biotech and pharmaceutical companies. She reflects on how following her interest in protein structure influenced her career trajectory and shares advice for navigating non-linear paths in science and trusting individual career decisions.

Shagha Ostadjoo discusses her transition from fungal enzyme research in academia to leading an assay development team at New England Biolabs. She shares insights on moving into management, navigating career transitions, and advice for international scientists seeking industry opportunities. ASBMB's interview series features engaging discussions with biological and life sciences professionals about their career journeys and the various opportunities available to graduate students and postdocs.

In conversation with... Carter Palmer by ASBMB

Malaria exerts a devastating impact on communities in the Global South, with upwards of 600,000 deaths yearly, primarily young African children. Using genetic approaches, we have explored the molecular basis of Plasmodium falciparum antimalarial drug resistance, which poses a constant threat to malaria treatment and control efforts. Using a genetic cross, we earlier identified that mutations in PfCRT conferred parasite resistance to chloroquine, the former first-line antimalarial drug. Structural and functional studies reveal that these mutations enable this transporter of globin-derived peptides to efflux chloroquine away from its heme target in parasitized erythrocytes. We also identified novel PfCRT variants that mediate resistance to piperaquine, a first-line combination partner drug that recently failed across Southeast Asia. We and others have also shown that mutations in Kelch13 are causal for parasite resistance to artemisinin, the core component of all current combination therapies, and have identified their emergence in east Africa. Kelch13 mutations affect multiple intracellular processes including hemoglobin endocytosis and degradation, mitochondrial physiology, and artemisinin-induced cellular quiescence. In anticipation that artemisinin partial resistance will lead to this drug becoming ineffective at treating severe malaria, we also have also leveraged a genetic cross to explore parasite susceptibility to quinine, an alternative treatment for severe disease. This work has identified a novel drug-metabolite transporter, DMT1, as a novel determinant of quinine resistance. Our ongoing efforts to identify new therapeutic approaches to treating artemisinin-resistant malaria include developing parasite-specific proteasome inhibitors, which synergize with artemisinin and restore its activity including against resistant parasites. Insights gained into molecular resistance mechanisms and genetic markers are being incorporated into global efforts to mitigate the emergence and spread of multidrug-resistant malaria.

In conversation with... Betsy Martinez–Vaz by ASBMB

This episode features Dr. Sarah Smaga and covers what science policy roles look like in practice, as well as opportunities for scientists interested in advocacy and government engagement.

In conversation with... Sannie Culbertson by ASBMB

In conversation with... Chris Heinen by ASBMB

The first growth factors identified and studied during the early 1970s were Epidermal Growth Factor (EGF) and Nerve Growth Factor (NGF). It was soon demonstrated that EGF and NGF mediate their cellular and physiological effects by binding to specific cell membrane receptors: the EGF receptor (EGFR) and the NGF receptor (NGFR), respectively. The mechanisms of activation and signaling of these receptors were compared to those of insulin and IGF1, which bind and activate the Insulin Receptor (IR) and IGF1 Receptor (IGF1R). These comparisons gained further significance with the discovery that EGFR, NGFR, IR, IGF1R, and many other membrane receptors belong to the receptor tyrosine kinase (RTK) family of cell signaling molecules. Early insights into the activation and signaling mechanisms of EGFR revealed that ligand binding to its extracellular domain induces and stabilizes the formation of EGFR dimers. This dimerization plays a critical role in activating the receptor's intrinsic tyrosine kinase activity. Through an intermolecular process, this activation leads to the autophosphorylation of multiple tyrosine residues in the C-terminal tail of EGFR. The cytoplasmic domain of EGFR serves not only as an enzyme that phosphorylates various substrates but also as a scaffold that recruits and regulates multiple signaling proteins through complex formation. While different ligands induce RTK dimerization and activation through variations on a shared theme, this paradigm is universal among all RTKs and is similarly observed in the activation of other surface receptors. Further important discoveries regarding the mode of action of EGFR and other RTKs made during the 1970s and 1980s include the following: Signaling Modules: Molecules containing SH2, SH3, and other small protein modules were found to play key roles in mediating cellular activities downstream of RTKs and many other signaling molecules. Ligand-Dependent Endocytosis: Ligand binding to the extracellular domain of RTKs stimulates receptor-mediated endocytosis and intracellular trafficking ,which are essential for proper signal transduction. Oncogenic Mutations: A variety of gain-of-function oncogenic mutations were identified in EGFR and other RTKs. These mutations were shown to be critical drivers of many human cancers. These early discoveries, along with others made during the 1980s, laid the conceptual groundwork for the development of targeted therapies. They paved the way for the discovery and clinical application of more than 50 targeted small-molecule cancer drugs and therapeutic antibodies, which have significantly improved patient outcomes in oncology.

The joy of teaching lies not only in helping students surpass their own expectations but in the collaborative process that makes learning a shared journey. In my approach, fostering a love for science and learning happens through meaningful collaboration—with students, colleagues, and the broader academic community. I believe that when we embrace collaboration, we empower students to actively engage with material, rediscover their scientific curiosity, and take ownership of their learning. By creating discussion-based classrooms and utilizing evidence-based pedagogies, I work alongside students to foster inquiry and critical thinking, helping them develop the skills to ask insightful questions and seek meaningful answers. Incorporating my own research into the classroom enriches this process, bringing real-world insights and cutting-edge developments into our discussions. This not only keeps students connected to the latest in the field but also demonstrates the dynamic relationship between teaching and research. Collaboration with peers further enhances my teaching by enabling me to share ideas, refine methods, and experiment with new approaches. While challenges such as administrative pressures and discipline-specific cultures can pose obstacles, our commitment to supporting one another’s growth—through both successes and setbacks—strengthens the teaching community as a whole. This collaborative mindset not only enhances student engagement and critical thinking but also fosters a deeper love for the work we do and a shared passion for teaching and learning that transforms the classroom experience. A good teacher, by necessity, is also a good researcher—constantly questioning, experimenting, and refining their approach to foster an environment of collaborative inquiry and growth.

The study of DNA damage has broad relevance to human pathophysiology with its involvement in birth defects, cancer, premature aging syndromes, and certain neurologic disorders. Single strand breaks (SSBs) are among the most common form of endogenous DNA damage. Here we will describe mechanisms by which SSBs threaten genome integrity in mitotic and post-mitotic cells. If they are not resolved in a timely manner, SSBs can derail passing replication forks converting them to toxic double strand breaks (DSBs). These so called “collapsed forks” arise spontaneously in every S phase and are believed to be the primary physiological trigger of homologous recombination. We will describe a recent study using the CRISPR/Cas9 nicking enzymes to examine the interaction of the human replication machinery with SSBs. We combine direct analyses of DNA end structures at sites of DNA nick-induced fork collapse with detailed mapping of repair factor binding to establish a comprehensive high-resolution view of how replication-coupled DSBs are generated, processed, and repaired. Our recent studies have also identified unexpected high levels of single strand breakage in neurons, which arise during metabolic processes intrinsic to neuronal development, differentiation, and maintenance. The source of this “programmed” DNA breakage in neurons will be described, and how this physiological process can be corrupted to drive neurodegenerative diseases and neurotoxicity after chemotherapy. Through these basic research efforts, we hope to identify vulnerabilities specific to cancer cells and to discover mechanisms underpinning chemotherapy-induced neurotoxities, which may contribute to new preventive and treatment strategies.

Science is not performed in a vacuum, and scientists do not make strides without other who have helped them along the way. Throughout my career, I have been fortunate to have had many mentors who have been instrumental in my scientific journey. Now with a career in academia, I have worked hard to improve academia for scientists at all levels, especially those that have been historically marginalized. I will discuss my scientific career path through the lens of all the people that have supported, encouraged and inspired me throughout the years.

A multitude of hydrophobic lipids are present within the cell. Their distribution between the aqueous milieu of the cytosol and amphipathic membranes, and between different organellar membranes, is remarkably variant. In addition to their direct involvement as substrates and intermediates for energy storage and utilization, lipids play key roles in determining membrane physical-chemical properties as well as in regulating gene expression and intracellular signal transduction pathways. Intracellular lipid-binding proteins (LBPs) are thought to participate in establishing and maintaining the spatial and compositional variabilities in membrane structure and in regulating the activities of lipid involvement in metabolism, cell signaling, and gene regulation. Discerning their precise functions at the molecular level, however, has posed challenges. While in vitro studies establish binding affinities and specificities, and structural determinants of lipid binding and LBP-membrane interactions, intracellular activities and physiological functions are less amenable to reductionist methodologies. The LBP field has therefore used a combination of biochemical, biophysical, molecular genetic, and physiological approaches to undertake analysis of the specific functions of these proteins. This talk will focus on studies of two types of LBPs, the large multigene family of Fatty Acid Binding Proteins (FABPs) which present with distinct and overlapping tissue distributions, and the cholesterol-binding protein Niemann Pick C2 (NPC2), expressed in the endolysosomal compartment in all tissues. Initially named according to the first tissue in which they were identified, it is now known that the mammalian FABP family is comprised of a dozen separate gene products with unique and intersecting tissue expression patterns. All bind long chain fatty acids, thus we asked why so many different proteins had evolved, and why multiple FABPs may be expressed in a single cell type. We demonstrated that, despite similar tertiary structures and equilibrium binding properties, different members of the FABP family have dramatically different mechanisms of ligand transport to membranes and have identified the protein structural domains responsible for these differences, and the membrane properties that promote FABP-membrane interactions. Studies of mice null for different FABPs, particularly those that are co-expressed in the small intestine, have further revealed the unique functions of these proteins in fatty acid and endocannabinoid uptake and transport. Indeed, the effects of FABPs are evident not only in their tissues of origin, but also in their regulation of peripheral tissues and systemic metabolism. The cholesterol-binding NPC2 protein, unlike the FABPs, is expressed in all tissues. We demonstrated its role in intracellular cholesterol transport, and its functional and specific interaction with the unique lysosomal phospholipid lysobisphosphatidic acid (LBPA; also known as bismonoacylglycerol phosphate or BMP). We have further shown that enrichment of NPC1-deficient cells with LBPA via its metabolic precursor phosphatidylglycerol, leads to sterol redistribution and clearance via exosome biogenesis and the stimulation of autophagy. Thus, cellular cholesterol reduction using LBPA enrichment is being explored as a new therapeutic approach to the neurodegenerative storage disorder, Niemann Pick C.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the fastest-growing etiology of hepatocellular carcinoma (HCC). This work identifies novel gene and lipid associations in human MASLD-driven HCC that may be exploited for therapeutic benefit. Methods: Human HCC tumor (n=8) and adjacent non-tumor samples (n=8) were obtained from the Biospecimen Procurement and Translational Pathology Shared Resource Facility at the University of Kentucky Markey Cancer Center. All patients met cardiometabolic MASLD criteria and were negative for viral hepatitis. Hematoxylin and eosin (H&E) staining was used for pathological determination of tumor and adjacent nontumor tissue. Lipids were extracted using a methyl-tert-butyl ether extraction method and subjected to lipidomics by the West Coast Metabolomics Center. RNA was isolated and used for bulk sequencing. Data were analyzed using paired nonparametric analyses via a Wilcoxon or Mann-Whitney test, as appropriate. Results: Histological analysis by H&E showed significant lipid vacuole accumulation in HCC tumors relative to nontumor tissue. Lipidomic analysis revealed significant increases in long-chain nonesterified monounsaturated fatty acids (MUFAs; C16:1, C18:1, C20:1) and MUFA-enriched phospholipids (PC30:1, PC32:1, PE32:1, and PC36:1) in tumors relative to nontumor tissue. No significant differences were observed in nonesterified polyunsaturated fatty acids (PUFAs; C18:2, C20:4, and C22:6), PUFA-enriched phospholipids (C36:4, C38:4, C38:6, C40:6), or in fatty acid esters of hydroxy fatty acids (FAHFAs; C38:2, C38:4, C38:6). However, both MUFA- (C14:1, C18:1) and PUFA-enriched acylcarnitines (C18:2, C18:3) were collectively reduced in human tumors. Differential analysis of RNA sequencing revealed fatty acid oxidation genes (CPT1A, CPT2, ACADL, ACADM, ACADS, HADHA) were significantly reduced in tumor versus nontumor tissue. Further, genes involved in de novo lipogenesis were largely dysregulated (e.g. no differences in SREBF1 or FASN; increases in ACLY, ACACA, and SCD1; decreases in ACSL1) in tumor versus nontumor tissue. Conclusions: These results suggest human HCC tumors exhibit a reduced capacity to undergo mitochondrial β-oxidation resulting in accumulation of free and esterified MUFAs with concomitant reductions in MUFA-carnitines. Current studies are underway to determine the mechanisms by which impairment of hepatic MUFA catabolism via FAO promotes the development of HCC in mice.