Inside the Lab with Crystal Zhao
The HeART grant award that Crystal Zhao, PhD, Associate Professor at the Sanford Burnham Prebys Medical Discovery Institute, received just last month from Rettsyndrome.org gives her needed resources to begin the first Rett syndrome research project of her career.
“[This] opens a door for me,” Zhao says, “I can see the medical need of this type of research…If I think about it, more and more I feel it could be truly satisfying if we could translate what we learn…to help solve this medical problem.”
Zhao is an established scientist who didn’t necessarily expect the exciting opportunity to help create a world without Rett syndrome because she works on a type of research called basic science.
All research begins as basic science. The goal of basic science research is to find out how nature works. These findings enable translational research (converting basic science discoveries into therapeutics) and clinical research (testing new disease-fighting therapeutics in humans). However, basic research itself rarely applies directly to a treatment, and basic scientists don’t always get to link their work to the patients themselves.
“You may not see as direct an effect from it as translational research,” Zhao explains, “However, if some breakthrough comes from basic science, it can totally change the way you view science and the way you view a disease.”
Hope and Curiosity in Basic Science
The recent history of Rett syndrome science shows us how this can happen.
Take Dr. Huda Zoghbi’s decade-long study on the genetic origins of Rett syndrome as a starting point. This basic research effort discovered that mutations in the MECP2 gene cause Rett syndrome. This finding suggested that the symptoms of Rett syndrome were caused by a defect in the function of MECP2: controlling the activity of other genes. Importantly, it also provides the target for current Rett syndrome gene modifying therapy research.
There would be no thought of such therapies without Zoghbi’s work. Nor would gene modifying therapies be possible without the basic research that discovered how the genes inside cells can be altered. And while Zhogbi expected her efforts to impact Rett syndrome, the scientists that enabled the creation of gene modifying therapies were not studying this disorder specifically and thus could not have made a similar guarantee. Instead, they produced the necessary breakthroughs through simple curiosity and the hope that what they did would make a difference over the long-term.
Zhao has this same curiousity and hope in the basic research to which she has dedicated her entire career.
“I think this is mostly because of the influence of my father who is also a professor doing research,” Zhao says, “Growing up, my curiosity about nature [was] always encouraged by my parents.”
Through years of research, Zhao has made a basic biology discovery that may provide a new option for Rett syndrome treatment development. Zhao now has an opportunity rarely available to basic scientists like her-the opportunity to help meet a critical need for patients and their families.
RNA Biology and Rett Syndrome
Zhao’s lab studies RNA biology. The goal of this field of research is to learn about RNAs, a class of molecules that play key roles in determining what happens inside and among cells.
“Their function is very diverse,” Zhao says as she articulates her interest in the tens of millions of RNAs inside cells that contribute to life processes, “Lots of effort [has been made] to understand what they do, but our knowledge is still quite limited.”
Zhao’s Rettsyndrome.org-funded research focuses on a specific RNA called Xist, which may hold the key to unlocking the healthy (but inactive) copy of MECP2 already present in the cells of females with Rett syndrome.
Xist is the primary regulator of a process known as X-chromosome inactivation. X-inactivation turns “off” one of the two copies of the X-chromosome present inside female cells during development. As a result, none of the genes on the silenced X-chromosome- including MECP2- are available to affect cell activity.
Zhao has discovered a new genetic element that regulates Xist activity. Her new research project will determine how this regulation is achieved and if it can be leveraged to reactivate the silenced X-chromsome and MECP2 in cells in culture. If it works, it will open the door for Zhao to continue working on Rett syndrome. Her lab will be able to proceed to the next steps of treatment development: testing in animal models and finding a method suitable for modulating the Xist regulatory element in patients.
This would create a new method of gene modifying therapy for Rett syndrome that could prove advantageous because X chromosome reactivation approaches rely on a copy of a gene that cells already have rather than one that has been synthetically added to them. However, only future work will tell us if it safely and reliably provides the cells of diverse patients with a working MECP2 gene. This is the same challenge faced by every Rett syndrome gene modifying therapy approach, including the other different MECP2 reactivation methods Rettsyndrome.org-funded scientsits Dr. Jeannie Lee and Dr. Kyle Fink are investigating.
“Rett syndrome is a complex disorder that is caused by so many different MECP2 mutations. As such, we can’t assume that one method or type of approach will help everyone,” Rettsyndrome.org’s CSO Dominque Pichard, MD, says “At Rettsyndrome.org, we invest in multiple approaches because we want to create treatments and ultimately a cure for all.”