Dr. Andrew Hsieh didn’t realize that a childhood glance through a microscope would be just the first step on a path of lifelong exploration. The glimpse gave Hsieh an entirely different perspective: “What I thought was just a speck of tissue was actually a whole new world,” he recalls.
Seeing the world within became Hsieh’s lifelong passion. His mother, who examined cells’ characteristics to diagnose early stage cancers, was the strongest supporter of his desire to explore the complex yet hidden cellular domain. During Hsieh’s childhood, she gifted him his first cell biology books and gave him free rein in her laboratory, where he saw firsthand how scientific inquiry can advance human health.
Several decades later, Hsieh has made a career of exploring uncharted scientific territory. In Fred Hutch’s Human Biology Division, he focuses on deciphering how cancer cells tick and finding therapies for under-studied cancers or those impervious to current treatments, such as bladder cancer and hormone deprivation therapy-resistant prostate cancer. But unlike the many cancer biologists who look to our DNA to understand how healthy cells become cancerous, Hsieh studies how our cells make proteins and how cancer can usurp this process for its own ends.
Proteins are integral to every cellular process, from replication to movement to death. The DNA in our genomes essentially exists as a protein recipe book, each gene a recipe for one or more proteins. But cells need hundreds to thousands of copies of each protein. Even though each cell has many protein-building factories, trying to make thousands of proteins from a single genetic sequence would be like thousands of chefs trying to cook from a single recipe at once. Each “chef” needs its own copy of the gene recipe, which cells provide in the form of RNA molecules: compact transcripts of genes that get translated by the factories into proteins.
But the multistep process isn’t foolproof. The most obvious mistakes happen when mutations garble the original DNA message. Hsieh, however, examines mistakes that occur as RNA is translated to synthesize protein. Errors at this stage can result in too many or too few copies of particular proteins, which can dramatically affect normal cellular functions — like growth and death — and may ultimately lead to cancer.
Hsieh estimates that changes in the DNA recipe and its RNA transcripts only account for a portion of the alterations that ultimately drive cancers. Changes in how cells make proteins, which proteins they make, or how much of any given protein they whip up influence many of the processes that lead to cancer development and progression, Hsieh says — but how this occurs remains murky.
It’s not just the details of protein synthesis that attract Hsieh, who also treats patients with genitourinary cancers. “I want what I do to have a human impact,” he explains. Prior to entering medical school, Hsieh volunteered with cancer patients at an infusion clinic in Oakland, near his alma mater, the University of California, Berkeley. The experience taught him that “the relationship between patient and provider is sacred” and prompted him to consider oncology as a specialty. A few forays into molecular and cell biology research guided by enthusiastic, visionary mentors solidified Hsieh’s desire to improve patients’ lives through basic research.
Now, Hsieh is working at the forefront of his field, studying cancers with few effective therapies, where he envisions that his lab will make the biggest impact on human suffering. He’s already shown that prostate cancer cells alter the production of specific proteins to help the cells invade their surroundings, a key step in the spread of cancer through the body. Hsieh suspects that such changes could give researchers critical new information about tumor behavior, define new therapeutic targets, and enhance the ability to predict disease progression in patients.
Hsieh’s exploration will continue unabated. “I think about biology and I think about patients, it’s just a part of me now,” he explains. It’s a thirst for knowledge Hsieh hopes to pay forward, inspiring younger scientists just as he was inspired from childhood. “My goal is to be at the cutting edge of basic science research and innovative patient care while training the next generation of cancer biologists. Being an investigator at Fred Hutch is an amazing jumpstart to achieving this lifelong dream.”
— By Dr. Sabrina Richards, Dec. 9, 2014