Gene editing using a technique called CRISPR to edit and replace defective genes is increasingly important in cancer research, but there are many barriers to using it for directly treating patients. A new researcher at The University of Texas MD Anderson Cancer Research Center hopes to understand more about how CRISPR works, with the goal of enabling the development of precision personalized medicine for cancer therapy.
Structural biologist Fuguo Jiang was recruited in 2018 from the University of California, Berkeley, where he was a postdoctoral fellow, with the help of a First-Time Tenure-Track Award from CPRIT.
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Gene editing using a technique called CRISPR to edit and replace defective genes is increasingly important in cancer research, but there are many barriers to using it for directly treating patients. A new researcher at The University of Texas MD Anderson Cancer Research Center hopes to understand more about how CRISPR works, with the goal of enabling the development of precision personalized medicine for cancer therapy.
Structural biologist Fuguo Jiang was recruited in 2018 from the University of California, Berkeley, where he was a postdoctoral fellow, with the help of a First-Time Tenure-Track Award from CPRIT.
CRISPR relies on a deactivated virus to transport short strands of DNA directly into the nucleus of a cell. An effector protein, called Cas9, snips a defective gene out of the host DNA, and replaces it with a strand of DNA containing a normal gene. For all of that to work, the Cas9 protein has to be able to access the DNA it needs to cut.
One of the barriers is the way DNA is packaged inside a cell — proteins help package the DNA compactly so that it doesn’t get tangled, in a DNA-protein complex called chromatin. The cell efficiently unwinds the DNA when it needs to reproduce.
A “chromatin remodeling complex” inside cells makes particular loops or portions of DNA more accessible as needed to express certain genes. Jiang wants to understand how this complex remodels chromatin structure in order to develop a CRISPR system that can more effectively interact with DNA even if the target is hidden deep inside wound up DNA.
About 20% of cancer patients have mutations in the remodeling complex itself, which lead to genes being improperly singled out for expression, triggering runaway growth. Jiang hopes to find out more about how the complex works in order to understand how cancer arises when it’s defective.
The complex itself is very large and dynamic, posing challenges for determining its structure. Jiang is using single-particle Cryo-Electron Microscopy to essentially get snapshots of parts of the complex in action. He’s also using CRISPR to knock out certain portions of the remodeling complex to see which are the most crucial for its proper function.
“Many drug companies are looking for inhibitors, or drugs, that can target this complex, either to block or increase its activity,” Jiang says. “This drug-discovery process is really hindered by the lack of structural information. Once we know the structure, this will really aid the process of drug design for targeted cancer therapies.”
Jiang eventually hopes to use CRISPR itself to treat cancer directly. “I’ve done a lot of work in understanding how CRISPR works, and now it’s time to move forward and learn how we can use CRISPR for cancer therapy,” he says. “It’s a high-risk, but high-reward project, and I really appreciate the support of CPRIT, which allows me to do really challenging research.”
He also appreciates MD Anderson’s reputation as one of the best places in the world to do cancer-related research, both basic science and translational research.
Jiang received his bachelor’s of medicine degree from Shandong University, and began graduate studies in biophysics at Tsinghua University, both in China. He received a Ph.D. in biochemistry from Rutgers University and began as a postdoctoral fellow at UC Berkeley in 2013.
Dr. Jiang unexpectedly passed away in November 2019.
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