Pipettes and Politics

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.