Exploring New Territory In Structural Biology

I was immersed into modern biological sciences at Tsinghua. Fascinated by how proteins’ structures determine biological functions, I joined structural biologist Dr. Christopher Akey’s lab at Boston University to pursue my PhD. I still remember the day I built a pseudo atomic model for the first helical resolution map of the human apoptosome, a protein complex central to the intrinsic apoptosis pathway, after countless days and nights collecting images in a dark EM room. For the first time, we could “see” how the Apaf-1 protein changes its conformation, from a compact, inhibitory monomer, to an extended structure that can oligomerize, bind and activate downstream initiator caspase-9. The structure explained naturally occurred mutations in cancer and biochemical mutagenesis studies – it was like putting the puzzle pieces together – and that was the underlying mechanism I had looked for since childhood. But how can I translate such knowledge to development of new medicines?

Membrane proteins constitute more than 60% of current drug targets; I decided to join Dr. Bob Stroud’s lab at UCSF to work on these difficult targets. A main challenge for membrane protein is the difficulty to express and purify them in good quantity, homogeneity and stability. At Stroud lab, we optimized expression and purification, and produced well-behaved integral membrane proteins including transporters, receptors, and channels, some of which are drug targets from our industrial collaborators. I was on a Bayer collaboration project, and started to learn how drug discovery works, which eventually led to my joining the Biologics Research division at Bayer.

At Bayer, I utilized a wealth of structural information to design and engineer proteins to facilitate therapeutics discovery and optimization, including traditional antibodies, bi-specifics, Ab-fusions, and cytokine-fusions. As a project leader, I got firsthand experience in drug discovery, from target validation, to lead discovery and optimization. It was a fun and rewarding journey at Bayer. Some of the novel biologics molecules I worked on had moved from Research to Development, getting closer to patients.

It became clear to me that combining rational design and high-through put (HTP) approaches can be powerful in drug discovery for target discovery and new therapeutics lead generation, and I joined Five Prime Therapeutics in 2017. As the Associate Director of Molecular and Protein Sciences, I oversee production of thousands of extracellular human proteins to support proprietary screens. By integrating automation platforms and big data analysis, we can complete the entire process from protein production to screening in weeks and quickly identify new targets and pathways. My team further leveraged in-house automation capability, brought in new technologies, and increased throughput of protein engineering, cloning, expression and purification to provide optimized protein reagents and biologics leads in a faster and more consistent way. We are deep into the process of developing novel cancer therapies, which I hope, one day will cure the incurable.

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