To find new treatments and a cure for ALS, it’s vital to have a dedicated network of scientists working to advance our understanding of the disease and thinking creatively about solutions.

We are proud to support the development of bright, young researchers – and their innovative ideas – through our Milton Safenowitz Postdoctoral Fellowship Program. Established in memory of Milton Safenowitz by the Safenowitz family, this unique program encourages young scientists to enter and, importantly, remain in the ALS field. After completing this fellowship, more than 75% of awardees stay in ALS research. Many go on to establish their own laboratories and mentor more ALS researchers along the way.

During the 2022 funding cycle, five new Safenowitz fellows were selected from a highly competitive applicant pool, including Dr. Caiwei Guo, a postdoctoral fellow at the Stanford University School of Medicine. We talked with her to learn more about her research, as well as her interests outside the lab.

What made you want to focus on ALS research?

When I was a graduate student in Dr. Joshua Shulman’s lab at Baylor College of Medicine, I was very intrigued by how mistakes in RNA splicing contribute to the degeneration of neuronal cells in another neurodegenerative disease – Alzheimer’s disease. For context, the DNA that makes up our genes contains the instructions for cells to produce proteins that carry out all of the different cellular functions. Before genes can be turned into proteins, the DNA is first transcribed into RNA and then processed in various ways, including having some parts spliced in or out, which is called the RNA splicing process.

As I was finishing up my Ph.D. studies, I read about emerging ALS research that implicated defects in RNA splicing as a key feature of the disease. I thought that I could use the techniques and insights I gained during my Ph.D. training to help figure out how RNA splicing defects were contributing to ALS and what we might be able to do to correct it.

I joined Dr. Aaron Gitler’s lab at Stanford University for my postdoctoral training. The lab had just identified abnormal RNA splicing of a major ALS risk gene, UNC13A, and dozens of other novel targets. I was able to jump right into this exciting project and start exploring the role of RNA splicing defects in ALS.

What are the goals of your funded research project?

An exciting new area of ALS research involves the key ALS protein, TDP-43, which seems to repress so-called cryptic exon inclusion during RNA splicing. When TDP-43 becomes dysfunctional in ALS (either clumping up in the cytoplasm of nerves or becoming depleted from the nucleus), RNA molecules are produced that contain extra snippets of inappropriate sequences. These inappropriate sequences are referred to as cryptic exons, which could result in loss of function or gain of toxicity of certain genes. The challenge is to figure out which ones are the key drivers of disease and then to devise therapeutic strategies to either prevent the cryptic exons from getting incorporated into the RNA or helping the nerves deal with them better.

Our lab and others recently discovered dozens of cryptic splicing events that happen when TDP-43 function is impaired. Strikingly, many of these events happen in genes that encode proteins that function at neuronal synapses – the communication portal between two nerves or between a nerve and muscle. My goal is to test the hypothesis that cryptic splicing in synaptic genes leads to neuronal dysfunction and eventually neuronal death in ALS with TDP-43 pathology. Moreover, I want to identify additional proteins that can regulate the cryptic splicing process together with TDP-43, such that manipulating these proteins may suppress the toxic splicing events even when TDP-43 is lost. My overall goal of this research project is to define how cryptic RNA splicing contributes to ALS development and how we can utilize this knowledge to generate novel therapeutic strategies.

How might your work impact the ALS community?

Since defects in TDP-43 are seen in almost 97% of all ALS cases no matter the genetic cause, the findings from this research could provide new insights into potential therapeutic targets that are broadly applicable to most people living with ALS. Firstly, we will learn more about the cryptic splicing targets of TDP-43 and how they cause neurodegeneration. With this knowledge, we will be able to design gene-targeted therapies to inhibit each toxic cryptic splicing event, which could prevent or stop neurodegeneration and disease progression. We also will have a better idea about other factors that regulate the cryptic splicing process. Instead of correcting cryptic splicing events one by one, these regulators may be better therapeutic targets as they could potentially suppress the cryptic splicing process all at once.

What role will this fellowship play in your research efforts?

I am very grateful to receive this fellowship at the early stage of my postdoctoral training. This support will give me the time and freedom to explore risky research ideas. In addition, I not only will be able to learn more experimental techniques but also develop career-advancing skills that will help me become a more successful neuroscientist in the near future.

What do you like most about working in the ALS research field?

The scientists in the field. The ALS research community has been tremendously welcoming and supportive. I am continually inspired by the dedication, hard work and generosity of other ALS researchers. The level of open collaboration in the ALS field is truly remarkable, especially the willingness to bring in diverse expertise and points of views.

What gives you hope that there will one day be a world without ALS?

There has been an explosion of new insights into the causes of ALS. We now have new targets and understanding that are already leading to novel therapeutic strategies. Gene-targeted therapies against FUS and SOD1 are just now showing efficacy in the clinic. At the same time, there are more and more people who are making their best efforts to fight against this devasting disease all around the world, including people living with ALS and their families who generously share their experiences, the caregivers and the donors who support the ALS community in every way they can, and the scientists and the clinicians who work intensely to understand disease mechanisms and develop novel therapies.

What do you like to do outside of the lab?

I like to play with my cat, chat with my family and friends, do yoga and go jogging in my free time.

Is there anything else you’d like to add?

There are a lot of people I’d like to thank without whom it would have been impossible for me to reach this point. I’m extremely grateful for having a terrific mentor, Aaron, who gives me all the support and resources I need to do science. I’d also like to thank my family, friends and colleagues who keep encouraging me along the way. Most importantly, I’d like to express my deepest appreciation to The ALS Association and the Safenowitz family for this amazing opportunity to help turn my scientific ideas into a reality.

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