Note: This is the first in a series of profiles of promising young scientists at BBI’s institutions – UW Medicine, Seattle Children’s Hospital, and the Fred Hutchinson Cancer Research Center.
The year was 1994 and the median price for a home in King County, Washington was about $225,000; Tom Hanks, playing Forrest Gump, won his second consecutive Oscar for Best Actor; and the word “spam” became part of our online lexicon.
And a promising young scientist, Moez Dawood, was born in a suburb of Chicago. A self-described “work hermit,” Dawood’s professional journey started in 2010 with an internship at the National Cancer Institute of the National Institutes of Health (NIH) during the summer after 10th grade. Today, at age 27, he is an MD/PhD student at the Baylor College of Medicine and is interning at the Brotman Baty Institute (BBI), focusing on saturation genome editing, a CRISPR/Cas9-based method for the high-throughput assessment of the effects of genetic variants.
He has numerous opportunities to explore saturation genome editing working alongside BBI’s Dr. Lea Starita, the co-director of the BBI Advanced Technology lab, as part of the Center for Multiplexed Assessment of Phenotypes (CMAP), one of 10 Centers of Excellence in Genome Science in the United States. The centers, funded by the NIH’s National Human Genome Research Institute, have several goals, including:
- Developing technologies to reliably assess the functional impact of variants in human genes and to improve throughput, scale, and quality of these methods;
- Training early career experimentalists, clinical geneticists, and data scientists to obtain and use large-scale functional data; and
- Sharing technologies, methods, and resources with others.
That last goal especially resonates with Dawood.
“We’re hoping to foster a long-term collaboration among the BBI, CMAP, Dr. Starita’s lab, and the Human Genome Sequencing Center back at Baylor,” Dawood said. “We’re already sharing information, resources, and variant effect data to determine clinically meaningful variant effects in genes involved in cancer and rare disease. And determining new mechanistic applications for saturation genome editing. It definitely reminds me of the phrase, ‘iron sharpens iron.’’’
Dawood’s affiliation with Baylor, as well as his self-driven determination, were key factors in his selection for the CMAP internship, according to Starita.
“Moez is a PhD student in one of the top human genetics labs in the country and distinguished himself by pushing himself out of his comfort zone and applying for the position,” said Starita. “He also had a great project proposal that would make excellent use of our technology to address unanswered questions in human genetics.”
Breaking out of his comfort zone seems to be a hallmark of Dawood’s character.
At age 15, he emailed more than 100 investigators throughout the country asking for an opportunity to work in a lab conducting HIV research. One of those investigators said “yes,” Dr. Sriram Subramaniam, a Senior Investigator at the National Cancer Institute in Bethesda, Maryland. This launched an engaging mentorship that continues today. Dawood went on to complete six consecutive NIH summer internships, three with Subramaniam and three with Dr. Louis Staudt, Chief of the NIH Lymphoid Malignancies Branch.
“The NIH Summer Internship Program and belief of NIH intramural investigators gave me my first opportunity to pursue research,” Dawood said. “It also laid the foundation for me to arrive where I am today.”
Dawood’s internship at BBI is supported by his two mentors at Baylor, Drs. Richard A. Gibbs and Dr. James R. Lupski, whom he calls “two pioneers of next-generation sequencing and Mendelian genomics.” Gibbs is the founder and director of the Human Genome Sequencing Center (HGSC) at the Baylor College of Medicine. HGSC was one of the five sites worldwide to sequence the first draft of a human genome. Lupski, a decades long collaborator with Gibbs, has elucidated the molecular diagnosis and genomic mechanisms of thousands of rare diseases and genomic disorders.
They urged Dawood to read the landmark paper “Accurate classification of BRCA1 variants with saturation genome editing,” published in September of 2018 in the journal Nature. Starita and BBI Scientific Director Dr. Jay Shendure are the senior and corresponding authors, respectively. The study engineered and analyzed the effects of nearly 4,000 genetic mutations in the BRCA1 gene using saturation genome editing.
“Dr. Starita has spent much of her career studying variant effects in BRCA1,” Dawood said. “She has leveled up the technology to be more high-throughput and more accurate in determining BRCA1 variant effects.”
Skimming Dawood’s 12-page curriculum vitae, it is evident that his wide range of experience – research projects, teaching, community engagement, independent studies, and panel discussions from high school to the present – has given this young scientist an in-depth perspective on an array of applications for human genetics research. One such revolutionary application is for Xia-Gibbs Syndrome (XGS), a neurodevelopmental disorder that affects the way the brain and nervous system function and the way an individual develops.
Gibbs’ grandniece was the first individual ever diagnosed with XGS at just 18 months old. Using next generation sequencing and their newly developed exome capture methods, Gibbs, together with Fan Xia, a fellow in the Department of Molecular and Human Genetics, and the HGSC team, provided a molecular diagnosis to end the diagnostic odyssey endured by the girl and her parents. The key gene in XGS was AHDC1, about which little was known.
“To better understand XGS is one of the driving forces of why I’m here in Seattle to learn saturation genome editing,” said Moez. “When I head back to Baylor I want to have a better understanding of the structure of AHDC1 changes and the interplay with surveillance mechanisms in the cell using saturation genome editing.”
The goal, he said, is to elucidate the effect of every possible single base change in AHDC1 to create a map of variant effects of every possible single nucleotide variant. XGS is considered a rare disease, but in just the last seven years after the child’s diagnosis nearly 300 individuals have been molecularly diagnosed with it. That map could have helped diagnose many of those individuals.
Starita believes Dawood has made important contributions to her lab, using skills that will also serve him in the future.
“Moez really thinks about all his experiments from first principles,” Starita said. “He has come here to learn from us, but he has stripped down all of our protocols and improved all aspects of our pipeline. He also is an excellent collaborator. He has gotten me and my lab excited about many new directions.”