Hail to the fiber king

Filed Under: MolE PhDNews

Hao Shen is the first student to graduate from UW with a PhD in molecular engineering

Student jumping in graduation regalia

In the fall of 2012, while studying abroad at the University of Washington, Hao Shen met two people who would become major parts of his life his fiancée, Simin Wang, currently a student at UW Law, and UW professor of biochemistry, David Baker.

Hao came to UW as an exchange student from Tsinghua University in Beijing, China where he was studying biological science. Originally interested in studying physics, Hao was trying to find his niche in biology.

He remembers his biochemistry professor at Tsinghua saying that to really understand the function of a protein it isn't enough to know its amino acid sequence, you really need to know its structure. Recalls Hao, "This professor also said that he had worked on protein structure prediction, and that it is really, really hard, basically impossible. So, when I came to UW and learned that there is actually a program called Rosetta that is quite good at protein structure prediction and that the scientist behind its development was here on campus, I was very intrigued."

Determination is key

At the time, the Baker lab was already crowded with little space to take on any undergrads let alone an exchange student who was only around for two months. Hao emailed Professor Baker expressing interest in conducting research in the lab, to which Baker replied saying that unfortunately, there was simply no space to take on more students. But Hao was determined.

Hao working in the lab.

"I looked for opportunities to talk to David and met directly with grad students and postdocs in the lab to learn about their research," he recalls.

Baker quickly recognized that Hao's persistence reflected his passion, interest and work ethic and invited him to join the lab for the fall.

A perfect mix

When it came time to apply for graduate school, Hao knew he wanted to return to UW to continue studying protein design. Having come from an interdisciplinary undergraduate program at Tsinghua University, Hao valued and looked for graduate programs where this was a key feature. The UW Molecular Engineering & Sciences Institute had just started to recruit students to a new molecular engineering (MolE) PhD program designed to foster the translation and communication of ideas across multiple academic disciplines. Hao joined the first cohort in 2014 as the only international student.

Says Hao, "The MolE program, through unique coursework and seminars, gave me the opportunity to learn and integrate information from multiple disciplines, including biochemistry, physics and computer science. The flexibility of the program allowed me to structure my degree in a way that matched my interests. I also think my research ultimately benefited from the training I received in that it gave me both a deep and holistic understanding of molecular science as well as the ability to approach my research with an engineering mindset."

In protein design, Hao found the perfect mix of computational and wet lab research. He uses computational modeling to design novel proteins, then employs cellular machinery to synthesize them, and ultimately characterizes them to see whether they have the intended structure and function.

"Proteins are amazing they carry out so many different, complex functions and yet they follow a relatively simple set of rules," says Hao. "The fact that we can create, from scratch, proteins with the structure and function we designed and that can work in biological contexts is astounding. The ability to design proteins that don't exist in nature but have new and useful functions is so cool."

A whole new [protein] world

After successfully defending his dissertation, Hao celebrated with a cake featuring the first page of his Science article.

In 2012, when Hao was at UW as an undergrad, the Baker lab was just starting to explore the materials side of protein design. Neil King, a postdoc in the lab at the time, was developing methods to design self-assembling proteins and by 2014, King had successfully built self-assembling protein cages. Hao saw great potential in this nascent area of protein design even if its applications were somewhat unclear. When the opportunity arose to develop self-assembling filaments, something that had never been done before, Hao was up for the challenge.

Though it took several years of hard work, and help from countless collaborators, Hao showed for the first time that protein filaments could in fact be built from scratch.

Recalls Hao, "The first time I looked under the microscope and actually saw fibers I was so excited. An idea that had been completely theoretical was now real." His work was published in Science last year.

Currently, Hao is trying to figure out how to better control fiber assembly for material applications. Says Hao, "We do have some control over the assembly and disassembly of the current fibers, but to make it more efficient and elegant, we are building multi-component and pH sensitive fibers, so that whether the fiber is undergoing assembly or disassembly depends on mixing components or the pH of the surrounding solution."

A diverse and collaborative learning environment

Looking back on his graduate school experience, Hao reflected on how hard it can be at first to figure out how to approach a new problem and tackle it. Over time, though, it got much easier.

Says Hao, "It took me awhile before I learned that I don't need to figure everything out myself. It's okay to not know everything or to need help. Asking for help when you need it saves so much time and effort and it prevents you from getting stuck on small things, leaving more time to focus on the big, important things."

Hao is grateful for the many colleagues he's worked closely with in the Baker lab. Particularly Jorge Dallas, a senior fellow in the lab, who served as his primary mentor, teaching him just about everything he needed to know, giving him ideas and support. Will Sheffler, a research scientist in the lab, pioneered much of the foundational computational work in the lab and also helped with many of the computational aspects of Hao's project. Eric Lynch, a postdoc in Justin Kollman's lab, taught Hao about cryo-electron microscopy and helped solve the structures of numerous protein fibers.

Members of the Baker lab enjoying the outdoors in the Pacific Northwest.

"I feel fortunate to have learned from so many talented people with such diverse backgrounds," says Hao. "One of the things that I have enjoyed most about conducting research within the molecular engineering community here has been people's willingness to collaborate. Sometimes I found myself working with so many other labs simultaneously that I struggled to keep track of whose lab I was working in that day!"

When it comes to what's next for Hao, he will be staying in the Baker lab as a postdoc for the time being. He's interested in tackling the emerging field of designed, self-assembling materials. Says Hao, "Our initial work sparked lots of exciting new research directions and potential applications that I'm either in the process of following up on or would like to explore further."