When Xiao Wang applied to faculty jobs, many of the institutions where she interviewed thought her research proposal - to study the life cycle of RNA in cells and how it influences normal development and disease - was too broad.
However, that was not the case when she interviewed at MIT, where her future colleagues embraced her ideas and encouraged her to be even more bold.
"What I'm doing now is even broader, even bolder than what I initially proposed," says Wang, who holds joint appointments in the Department of Chemistry and the Broad Institute of MIT and Harvard. "I got great support from all my colleagues in my department and at Broad so that I could get the resources to conduct what I wanted to do. It's also a demonstration of how brave the students are. There is a really innovative culture and environment here, so the students are not scared by taking on something that might sound weird or unrealistic."
Wang's work on RNA brings together students from chemistry, biology, computer science, neuroscience, and other fields. In her lab, research is focused on developing tools that pinpoint where in a given cell different types of messenger RNA are translated into proteins - information that can offer insight into how cells control their fate and what goes wrong in disease, especially in the brain.
"The joint position between MIT Chemistry and the Broad Institute was very attractive to me because I was trained as a chemist, and I would like to teach and recruit students from chemistry. But meanwhile, I also wanted to get exposure to biomedical topics and have collaborators outside chemistry. I can collaborate with biologists, doctors, as well as computational scientists who analyze all these daunting data," she says.
Imaging RNA
Wang began her career at MIT in 2019, just before the Covid-19 pandemic began. Until that point, she hardly knew anyone in the Boston area, but she found a warm welcome.
"I wasn't trained at MIT, and I had never lived in Boston before. At first, I had very small social circles, just with my colleagues and my students, but amazingly, even during the pandemic, I never felt socially isolated. I just felt so plugged in already even though it's very a close, small circle," she says.
Growing up in China, Wang became interested in science in middle school, when she was chosen to participate in China's National Olympiad in math and chemistry. That gave her the chance to learn college-level course material, and she ended up winning a gold medal in the nationwide chemistry competition.
"That exposure was enough to draw me into initially mathematics, but later on more into chemistry. That's how I got interested in a more science-oriented major and then career path," Wang says.
At Peking University, she majored in chemistry and molecular engineering. There, she worked with Professor Jian Pei, who gave her the opportunity to work independently on her own research project.
"I really like to do research because every day you have a hypothesis, you have a design, and you make it happen. It's like playing a video game: You have this roughly daily feedback loop. Sometimes it's a reward, sometimes it's not. I feel it's more interesting than taking a class, so I think that made me decide I should apply for graduate school," she says.
As a graduate student at the University of Chicago, she became interested in RNA while doing a rotation in the lab of Chuan He, a professor of chemistry. He was studying chemical modifications that affect the function of messenger RNA - the molecules that carry protein-building instructions from DNA to ribosomes, where proteins are assembled.
Wang ended up joining He's lab, where she studied a common mRNA modification known as m6A, which influences how efficiently mRNA is translated into protein and how fast it gets degraded in the cell. She also began to explore how mRNA modifications affect embryonic development. As a model for these studies, she was using zebrafish, which have transparent embryos that develop from fertilized eggs into free-swimming larvae within two days. That got her interested in developing methods that could reveal where different types of RNA were being expressed, by imaging the entire organism.
Such an approach, she soon realized, could also be useful for studying the brain. As a postdoc at Stanford University, she started to develop RNA imaging methods, working with Professor Karl Deisseroth. There are existing techniques for identifying mRNA molecules that are expressed in individual cells, but those don't offer information about exactly where in the cells different types of mRNA are located. She began developing a technique called STARmap that could accomplish this type of "spatial transcriptomics."
Using this technique, researchers first use formaldehyde to crosslink all of the mRNA molecules in place. Then, the tissue is washed with fluorescent DNA probes that are complementary to the target mRNA sequences. These probes can then be imaged and sequenced, revealing the locations of each mRNA sequence within a cell. This allows for the visualization of mRNA molecules that encode thousands of different genes within single cells.
"I was leveraging my background in the chemistry of RNA to develop this RNA-centered brain mapping technology, which allows you to use RNA expression profiles to define brain cell types and also visualize their spatial architecture," Wang says.
Tracking the RNA life cycle
Members of Wang's lab are now working on expanding the capability of the STARmap technique so that it can be used to analyze brain function and brain wiring. They are also developing tools that will allow them to map the entire life cycle of mRNA molecules, from synthesis to translation to degradation, and track how these molecules are transported within a cell during their lifetime.
One of these tools, known as RIBOmap , pinpoints the locations of mRNA molecules as they are being translated at ribosomes. Another tool allows the researchers to measure how quickly mRNA is degraded after being transcribed.
"We are trying to develop a toolkit that will let us visualize every step of the RNA life cycle inside cells and tissues," Wang says. "These are newer generations of tool development centered around these RNA biological questions."
One of these central questions is how different cell types control their RNA life cycles differently, and how that affects their differentiation. Differences in RNA control may also be a factor in diseases such as Alzheimer's. In a 2023 study , Wang and MIT Professor Morgan Sheng used a version of STARmap to discover how cells called microglia become more inflammatory as amyloid-beta plaques form in the brain. Wang's lab is also pursuing studies of how differences in mRNA translation might affect schizophrenia and other neurological disorders.
"The reason we think there will be a lot of interesting biology to discover is because the formation of neural circuits is through synapses, and synapse formation and learning and memory are strongly associated with localized RNA translation, which involves multiple steps including RNA transport and recycling," she says.
In addition to investigating those biological questions, Wang is also working on ways to boost the efficiency of mRNA therapeutics and vaccines by changing their chemical modifications or their topological structure.
"Our goal is to create a toolbox and RNA synthesis strategy where we can precisely tune the chemical modification on every particle of RNA," Wang says. "We want to establish how those modifications will influence how fast mRNA can produce protein, and in which cell types they could be used to more efficiently produce protein."
