Meet another talented CIRM Scholar, Helen Fong. She is a Research Scientist at the Gladstone Institutes and completed her graduate work at UC Irvine. She loves stem cells, disease modeling, and testing differentiation protocols—the methods that guide stem cells to become specific tissues. As part of CIRM’s educational training program, Helen published four first‑author papers. Her most recent, in Stem Cell Reports, used induced pluripotent stem cells (iPSCs) to model front temporal dementia, a brain disease that destroys nerve cells.
We interviewed Helen to learn more about her stem cell research.
Q: What was your graduate school research on?
HF: I did my graduate work in Dr. Peter Donovan’s lab. He is a leading germ cell and stem cell scientist and had just joined UCI when I started. I was his first graduate student at UCI. Dr. Donovan focused on understanding early human development using embryonic stem cells (ESCs) and improving human pluripotent stem cell culture. He also studied the mechanisms that keep stem cells pluripotent and the genetic factors needed to maintain that state.
My graduate research examined the basic biology of human ESCs. I specifically studied how the gene Sox2 helps maintain pluripotency and self‑renewal in these cells.man ESCs.
Q: What about your postdoctoral research?
HF: After my PhD, I chose to keep working with stem cells because I knew the field would grow and still had many unanswered questions. I also loved working with these cells and couldn’t imagine not seeing them every day. I realized I understood the basic biology of ESCs, but I wanted to use stem cells to study human disease. Human induced pluripotent stem cells (iPSCs), which reprogram adult cells back to a pluripotent state, make that possible.
The Gladstone Institutes offered the ideal place to continue my training and start using iPSCs to study neurological disorders. I joined Dr. Yadong Huang’s lab in 2011 and now use human iPSCs to study brain‑degenerative diseases such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer’s disease (AD).
My recent Stem Cell Reports publication used patient‑derived iPSCs to investigate FTD. The patient carried a rare MAPT gene mutation, TAU‑A152T, which several studies suggest may increase the risk of FTD, PSP, and AD. But no one knew how the mutation caused disease.
To study this, we used iPSCs made from the patient’s skin cells. I then used zinc finger nuclease (ZFN) genome editing to correct the mutation and restore the normal sequence. This let me test whether fixing the mutation would produce healthier neurons without FTD symptoms. By comparing neurons made from the corrected iPSC line with neurons from the mutant line, I could identify how the TAU mutation drives disease.
The neurons that I differentiated from the iPSCs carrying the TAU mutation showed an increase in TAU protein fragmentation [meaning the protein gets degraded and isn’t present in its normal form], an abnormal characteristic that can be associated with FTD and AD. We didn’t see this phenomenon in the neurons from the corrected (normal) human iPSCs, indicating that removal of this TAU mutation could improve the symptoms of these diseases. These results were exciting because we now had a culprit for what could be causing disease in these patients with this mutation. There is still much to be learned about the mechanisms of this mutation and the iPSCs have been an invaluable resource.
Q: What was your experience like as a CIRM scholar?
HF: CIRM has funded me for almost all of my stem cell training and research. I got my first CIRM training grant as a graduate student at UCI in 2006 and was funded for three years as a postdoc at the Gladstone. So I have CIRM to thank for all of my training.
When I first started out as a CIRM scholar, I believe I was part of one of their earlier pre-doctoral training grant programs. As the program expanded, I got to meet many of the other trainees at CIRM research conferences and interact with prominent stem cell scientists in the area. This was an incredible experience because I was exposed to stem cell research outside of my own institute, and I was able to meet all the big players in the field!
CIRM has also been very generous and provided me a travel allowance to attend any scientific conference of my choice. Over the years, I’ve gone to a lot of conferences nationally and internationally including ISSCR (International Society for Stem Cell Research), Keystone symposia, and the Society for Neuroscience (SfN). I have given scientific talks both at Keystone and SfN, and they proved to be excellent exposure for my work as well as a good place to get feedback. Another one of my favorite perks was the ability to purchase reagents for my own work at my own discretion, which gave me some freedom in dictating which direction I wanted my project to go. If I wanted to study a particular protein and needed a specific antibody to do that, I was able to get it with my CIRM funding.
Q: What’s next for your career?
HF: Currently, I am hoping to wrap up the project I am working on in the lab right now and generate a publication. I plan to continue to work on stem cells in the next step of my career and to work on challenging and cutting-edge projects. I feel fortunate for all the training and resources that I’ve received that got me to where I am today, and I hope to pass on many of my skills and knowledge to budding, young scientists.
Q: What is your favorite thing about being a scientist?
HF: I really enjoy the fact that I have so much control over the fate of my stem cells. They have the ability to turn into almost any cell type, and we’ve developed so many protocols to guide them into the exact cell type we want. They don’t always behave, but I think figuring out the personality of each and every cell line is part of the fun.
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