For decades, scientists at St. Jude Children’s Research Hospital have made steady progress in finding cures for children with life-threatening diseases. In spite of numerous discoveries and advancements, we still have gaps in our knowledge. These diseases are incredibly complex and understanding them requires expertise from many scientific fields.
That’s the reason St. Jude launched Research Collaboratives as part of the strategic plan. What if we brought together the world’s experts, regardless of where they work, to tackle some of the toughest questions related to pediatric catastrophic diseases? Via funding provided by St. Jude, these Collaboratives unite the focus of star scientists from many different institutions to focus attention on pediatric disease and to collaborate with our own St. Jude scientific stars. These projects are chosen based upon the potential to transform science and medicine. The Research Collaboratives go to the heart of the St. Jude mission.
Below, you’ll find a snapshot of the first four initiatives St. Jude has funded to foster these extraordinary collaborations.
Gene editing for sickle cell disease
Sickle cell disease is the most common inherited blood disorder in the U.S. About 900 patients turn to St. Jude for treatment for this disease, which causes chronic pain, organ damage and early mortality. Since sickle cell disease is caused by a single mutation, could gene-editing techniques cure it?
“We’re exploring different approaches for genetic correction,” he explains.
Within the next couple of years, Weiss anticipates that the Hematology department and the Bone Marrow Transplantation and Cellular Therapy department will open a St. Jude-based clinical trial that uses the gene editing protein CRISPR-Cas9 to induce gamma globin. This protein’s expression can inhibit the harmful effects of sickle cell disease. That clinical trial represents the first generation of gene editing therapies and will create a clinical research infrastructure for testing new gene editing technologies in the future.
To develop these new technologies, Weiss has joined forces with Shengdar Tsai, PhD, of St. Jude Hematology; and Shondra Pruett-Miller, PhD, who directs the St. Jude Center for Advanced Genome Engineering (CAGE), in a project supported by the St. Jude Research Collaboratives.
Other renowned innovators in the field of gene editing have also joined the collaborative. They are Daniel Bauer, MD, PhD, of Boston Children’s Hospital; Gerd Blobel, MD, PhD, of Children’s Hospital of Philadelphia; Keith Joung, MD, PhD, of Massachusetts General Hospital; David Liu, PhD, of the Broad Institute of Harvard and MIT; and John Tisdale, MD, of the National Heart, Lung, and Blood Institute.
“A few months is a long time in the fast-moving field of genome editing,” Weiss says. “We’re working with our collaborators to develop the next generation of genome editing techniques that will fuel future clinical trials for treating blood diseases and other genetic disorders.” Gene editing tools developed through the collaborative are being made available to all St. Jude researchers through the CAGE.
Chromatin regulation in pediatric cancers
In 2010, St. Jude teamed with Washington University in the Pediatric Cancer Genome Project—the world’s most ambitious effort to discover the origins of childhood cancer and seek new cures. As part of that project, scientists compared the complete genomes from cancerous and healthy cells of more than 800 childhood cancer patients.
As a result, researchers have made groundbreaking discoveries on the genetic factors driving some of the most challenging childhood cancers. A particularly surprising finding is that one of the most common pediatric cancer mutations takes place in a class of genes called chromatin regulators.
“Chromatin regulators function to tell other genes when to turn on and off, similar to foremen at a construction site,” says Charles Roberts, MD, PhD, executive vice president and director of the St. Jude Comprehensive Cancer Center. “We’re beginning to learn that mutations in chromatin regulators contribute to cancer by causing mistakes in the control of genes that determine whether a cell continues to divide or matures to perform a specific job. While it is clear that disruption of chromatin control is at the heart of many cancers, our understanding of this process is still rudimentary.”
Roberts has assembled a team of scientists, including St. Jude pathologist Charles Mullighan, MBBS, MD, and developmental neurobiologist Paul Northcott, PhD. Joining them are Scott Armstrong, MD, PhD, of Dana-Farber Cancer Institute, and Rockefeller University cell biologist David Allis, PhD. Together, they are pooling their expertise in biochemistry, gene regulation, and chromatin structure and function.
“Together we hope to understand the mechanisms of chromatin regulation and how they drive cancer with the long-term goal of developing better therapies,” Roberts says. “Chromatin regulators also play a role in adult cancers, so discoveries by our team could transform the entire field.”
Biology of liquid organelles
Did you label and color the parts of the cell in science class? Then you understand there are distinct structures inside cells, such as the nucleus and mitochondria.
But cells also contain liquid droplets. For many years, scientists could not explain them. Then, a decade ago, researchers discovered that these “liquid organelles” form by condensation, similar to how droplets of oil and vinegar form in salad dressing.
“Today, we know that liquid organelles directly or indirectly control most cellular functions,” says J. Paul Taylor, MD, PhD, St. Jude Cell and Molecular Biology chair and Howard Hughes Medical Institute investigator. “We suspect that a large number of diseases, including cancer and neurodegenerative disorders, are caused by disturbances in how liquid organelles assemble.”
In 2013 and 2017, Taylor and his St. Jude colleagues discovered gene mutations in a specific liquid organelle that cause amyotrophic lateral sclerosis and frontotemporal dementia. They also found that some of these same mutations drive certain cancers such as leukemia and Ewing sarcoma.
“We’ve begun to tease apart the underlying biology of liquid organelles, but there’s much still to learn,” Taylor says. “If a gene mutation changes the viscosity of a liquid organelle, does that cause disease? If so, we need to understand that process.”
To find answers, Taylor invited Tanja Mittag, PhD, and Richard Kriwacki, PhD, both of St. Jude Structural Biology, who collaborated with Taylor on previous discoveries of gene mutations in liquid organelles, to join the team. Biomedical engineers Rohit Pappu, PhD, at Washington University and Clifford Brangwynne, PhD, at Princeton University are contributing their expertise in biophysics to explore how liquid organelles assemble.
“No single lab has all the skills necessary for this work,” Taylor says. “Our group has been highly productive and published many papers since we started two years ago. We’re finding answers that no one lab could have answered on its own.”
3D genomics of pediatric cancer
Can new insights on how DNA is packaged shed light on the biology of pediatric cancers?
Every human cell has about two meters of DNA wound up in a tight package inside the nucleus. For genes to be activated or suppressed, they must come into physical contact with other genes.
Scientists have discovered that a ring-like structure made of proteins, called the cohesin complex, holds bits of DNA together and controls how the genes are expressed. Mutations in the cohesin complex are present in pediatric acute myeloid leukemia, T-lineage acute lymphoblastic leukemia and neuroblastoma.
St. Jude scientists have been collaborating with world-renowned colleagues at other institutions for many years to understand these processes. Now, they are pooling their expertise and tapping into the latest next-generation sequencing technologies to discover how mutations in structural regulators like CTCF and cohesin drive cancer development.
Jinghui Zhang, PhD, St. Jude Computational Biology chair, heads the team, which includes St. Jude colleagues Suzanne Baker, PhD, of Developmental Neurobiology; and John Easton, PhD, and Brian Abraham, PhD, of Computational Biology.
Collaborating experts from other institutions are Richard Young, PhD, of the Whitehead Institute and Massachusetts Institute of Technology; Kimberly Stegmaier, MD, of the Dana-Farber Cancer Institute; and Thomas Look, MD, of Dana-Farber/Harvard Cancer Center. In total, the group combines expertise in gene regulation in pediatric cancers, next-generation sequencing techniques and advanced genomic analysis.
“These mutations have not been well studied yet because the recently developed sequencing and analysis techniques are complex,” Abraham says. “By applying these methods to many models, we hope to better understand the mechanisms causing cancer.”
Zhang notes: “By identifying a new vulnerability in gene expression, we may be able to identify novel targets for the development of future therapies.
“In the meantime, our datasets will be a valuable resource for the pediatric cancer research community.”
From Promise, Winter 2020