Although it’s not the type of challenge that involves an ice bucket, this year’s Doerr Stem Cell Challenge Grant has brought together two young scientists from different USC labs to tackle ALS.
“These $10,000 grants make it possible for our students and postdocs to connect and collaborate on one-year interdisciplinary projects spanning different labs,” said Andy McMahon, PhD, chair of the executive committee of USC Stem Cell; W.M. Keck Provost Professor of Stem Cell Biology and Regenerative Medicine and Biological Sciences; Chair of Stem Cell Biology and Regenerative Medicine; director, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC. “The students and postdocs initiate and propose the projects themselves — thus developing their creativity and independence.”
The winning project was conceived on a typical Friday in the seminar room of the Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC. Haoze (Vincent) Yu, a graduate student studying hearing loss in the laboratory of Neil Segil, PhD, was delivering a talk about his latest discovery: a new technique for identifying gene regulatory regions. A lightbulb went off for Kate Galloway, PhD, a postdoctoral fellow in the laboratory of Justin Ichida, PhD, who studies motor neurons derived from ALS patients.
Even though Galloway and Yu study two different organ systems in two different labs, they now are working together. Their collaborative project will tackle a fundamental mystery surrounding ALS: although scientists have identified gene mutations that can cause ALS, more than 80 percent of patients with the disease do not actually have these known mutations. This suggests that something else underlies the disease — such as a problem not with the genes themselves, but with the section of the genome that regulates the genes.
Previously, studying gene regulatory regions required large numbers of cells. However, motor neurons, the cells that degenerate in ALS, are not easy to obtain. Harvesting motor neurons, which communicate critical signals from the brain to the muscles, would inflict serious damage on patients. Alternatively, while Galloway and her colleagues in the Ichida lab can reprogram easier-to-obtain skin cells from patients into motor neurons, they can only make small numbers of cells.
However, these small numbers of motor neurons are now sufficient for identifying and analyzing their gene regulatory regions, thanks to Yu’s game-changing new technique, which is called “Assay for Transposase-mediated Chromatin Immunoprecipitation followed by sequencing (ATM-ChIPseq).”
“The technique that Vincent has developed for the analysis of small numbers of cells, when fully developed, will be a powerful tool for many fields that face similar problems,” said Segil, professor of research stem cell and regenerative medicine at the Keck School of Medicine of USC. “The idea to investigate the gene regulatory networks in developing motor neurons addresses a fundamental hole in the field, and seems a great place for them to join forces.”
Through their experiments, Galloway and Yu will confirm that the gene regulatory networks of the motor neurons created in the lab resemble naturally occurring motor neurons at specific stages of embryonic development. A positive finding would further validate lab-created motor neurons in neural disease modeling in the lab.
The team also will be able to search for genetic regulators that might make specific types of motor neurons more vulnerable to ALS. For example, larger cells called alpha motor neurons have proven more sensitive to the disease than their smaller counterparts.
“Katie and Vincent will build a vital tool for characterizing the regulatory profiles of motor neurons, allowing us to address fundamental questions about motor neuron development, subtype specification, and the regulatory fidelity of motor neurons derived in the lab,” said Ichida, assistant professor of stem cell biology and regenerative medicine.
In the future, Galloway and Yu would like to compare the gene regulatory networks of two types of lab-created motor neurons: those derived from ALS patients and those derived from healthy individuals. By identifying differences in the way that ALS patients regulate their genes, they may discover new targets for therapeutic drugs to treat the fatal neurodegenerative disease.
“I’d like to thank the Doerrs for supporting this exciting collaborative research,” Yu said.
Galloway added, “Vincent’s innovative ATM-ChIPseq method will be transformative for understanding motor neuron biology. Finally, we will illuminate the fundamental regulatory programs unique to motor neurons and extend our search for the molecular dysfunctions that cause ALS.”
— Cristy Lytal