Principal / Sr. Principal Scientist - Molecular Biology & Protein Expression

Position Summary

The Principal Scientist / Senior Principal Scientist in Molecular Biology & Protein Expression will join a centralized molecular biology and protein expression platform team within Lilly Small Molecule Discovery (LSMD). This role focuses on molecular biology and recombinant expression of diverse protein targets, including challenging targets such as membrane proteins, across multiple host systems. The scientist will serve as a key member of the technical team, owning complex expression challenges, mentoring less experienced colleagues, and driving platform development, including automation and higher-throughput workflows.

Key Responsibilities

• Independently design and execute molecular cloning strategies, including Gibson assembly, Golden Gate, In-Fusion, restriction/ligation cloning, SLIC, and site-directed mutagenesis, and design constructs (tags, truncations, fusion partners, codon optimization) tailored to each target.
• Perform small-scale expression of recombinant proteins across multiple host systems, including E. coli, baculovirus/insect cells, and mammalian cells, using transient transfection, baculovirus infection, and adherent/suspension cell culture workflows to screen constructs, hosts, and expression conditions.
• Execute large-scale expression of recombinant proteins in E. coli and insect cells, using shake flasks, Wave/rocker bag systems, and stirred-tank bioreactors to deliver material for purification and project needs.
• Assess expression and small-scale material using SDS-PAGE, Western blot, capillary electrophoresis, analytical SEC, and UV spectroscopy in support of construct triage and expression optimization.
• Develop and improve platform workflows, including parallelization, standardization, and automation of cloning and expression screening, to increase throughput and reproducibility.
• Collaborate with purification, structural biology, and project teams to align construct design and expression strategies with downstream needs.
• Maintain accurate and timely records of all experimental data in a Laboratory Information Management System (LIMS) and electronic laboratory notebooks, upholding high standards of scientific rigor and data integrity.
• Communicate experimental progress, key results, and risks clearly, verbally and in writing, to project stakeholders and team leadership, ensuring consistent visibility into program status and proposed next steps.

Basic Qualifications

B.S. or M.S. in Biological Sciences, Biochemistry, Molecular Biology, Chemistry, Biophysics, or a related discipline, with typically 5 or more years of relevant hands-on molecular cloning and recombinant protein expression experience, or equivalent demonstrated impact.

Preferred Qualifications

• Proficiency with molecular cloning techniques (Gibson, Golden Gate, In-Fusion, site-directed mutagenesis) and proven ability to design constructs for structurally and biochemically diverse targets.
• Hands-on proficiency across all three host systems (E. coli and baculovirus/insect), with experience selecting the appropriate host for a given target.
• Strong organizational skills and attention to detail.
• Effective written and verbal communication skills.
• Proficient with standard laboratory and office software.
• Experience with yeast expression and large-scale mammalian expression (e.g., CHO, HEK293).
• Experience with membrane protein expression (e.g., GPCRs, transporters, ion channels); this is required at the Senior Principal Scientist level.
• Experience with bioreactor process development (DO, pH, feeding strategy) and Wave/rocker bag scale-up workflows.
• Experience with large-scale (≥10 L) purification workflows, including AKTA FPLC.
• Experience with laboratory automation and high-throughput cloning/expression workflows (e.g., liquid handling, colony picking).
• Familiarity with cell-free protein synthesis systems and/or other specialized expression strategies.
• Demonstrated experience mentoring and providing technical guidance to junior scientists is highly valued and may indicate suitability for the more senior level.
• Experience with electronic laboratory notebooks (e.g., Benchling), LIMS, or protein sample tracking databases.

Work Environment & Physical Demands

This role is based on-site in laboratory/bench setting. Must be able to meet the physical requirements of the position, including lifting up to 25 lbs., with or without reasonable accommodation. The appointed candidate will work on site, full-time, in San Diego, California.