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Scientific Report 2019
Scientific Report 2019
stjude.org/scientificreport
262 Danny Thomas Place
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General Information
Translating Science
901.595.3300
into Survival
Behind the Cover
The cover depicts the 3-dimensional structures of proteins and drug
molecules inside a cell. During a catastrophic disease, the functions
of proteins and other biomolecules change. Structural biologists use
various sophisticated techniques to study the structural basis of those
deleterious changes and determine the best therapeutic strategy. The
Faculty Editorial Board
Department of Structural Biology is expanding to become the world’s Terrence L. Geiger, MD, PhD
premier center for structural analyses and imaging of biomolecules in Michael A. Dyer, PhD
health and disease. Department Chair Charalampos Babis Kalodimos, Charalampos Babis Kalodimos, PhD
PhD, is recruiting leaders in the field to join our faculty and bringing Charles W. M. Roberts, MD, PhD
innovative technologies to the St. Jude campus. Carlos Rodriguez-Galindo, MD
David J. Solecki, PhD
Editoral Direction
Angela J. McArthur, PhD, ELS
Creative Direction
Jerry L. Harris
Photography
Peter Barta
Seth Dixon
Ann-Margaret Hedges
Jere Parobek
Prepared by
Departments of Scientific Editing
and Biomedical Communications
St. Jude Children’s Research Hospital and
ALSAC are registered trademarks.
ST. JUDE FREELY SHARES
THE DISCOVERIES WE MAKE.
EVERY CHILD SAVED AT ST. JUDE
PROVIDES DOCTORS AND SCIENTISTS
WORLDWIDE WITH THE KNOWLEDGE
TO HELP SAVE THOUSANDS
MORE CHILDREN.
Privileged communication. Copyright © 2019 St. Jude Children’s Research Hospital. No part of this communication may be cited, reproduced, stored in a
retrieval system, or transmitted by electronic or other means without prior written permission of the President and CEO and the appropriate investigator.
This report reflects the activities of St. Jude Children’s Research Hospital during 2018.
4
CEO STATEMENT
6
IN MEMORIAM
8
CANCER CENTER
34
STRUCTURAL BIOLOGY
54
ADVANCED MICROSCOPY
64
ST. JUDE GLOBAL
88
AFFILIATE PROGRAM
90
SHARED RESOURCES
94
SCIENTIFIC HIGHLIGHTS
114
ACADEMIC DEPARTMENTS
124
BOARDS & EXECUTIVE STAFF
127
OPERATIONS & STATISTICS
Mario Halic, PhD
2019 Scientific Report | 2 3 | 2019 Scientific Report
In science and medicine, collaboration is the spark of knowledge, technology, and organizational
that ignites progress. At St. Jude Children’s Research skills. Also, the World Health Organization (WHO)
Hospital, talented faculty and staff work together— designated St. Jude as the first WHO Collaborating
and with colleagues worldwide—to advance the Center for Childhood Cancer. Representatives from
research and treatment of pediatric cancer and WHO and St. Jude announced this new effort—the
other catastrophic diseases. In this Scientific Report, WHO Global Initiative for Childhood Cancer—at
we showcase how the power of team science the United Nations General Assembly in New York
enhances the discovery process. Collaborative City in September 2018. The goal of this initiative
efforts in the laboratory, the clinic, and with partners is to increase the survival of children with the most
around the globe are fueling discoveries and giving common pediatric cancers to 60% by 2030.
new hope to families everywhere. Beyond the stories in this Report, St. Jude
In the first feature, we highlight how the saw continued growth and progress last year. We
St. Jude Comprehensive Cancer Center brings broke ground on a $412 million advanced research
together scientists from various fields to focus on a center that will open in 2021 and launched 2 new
shared problem and accelerate progress. In 2018, the online data-sharing portals for the global research
Center received its second consecutive “Exceptional” community: St. Jude Cloud, which offers next-
rating after its 5-year review by the National Cancer generation sequencing data and analysis tools for
Institute. This is the highest-possible ranking, placing pediatric cancer and other life-threatening diseases,
St. Jude among the nation’s elite Cancer Centers. and PROPEL, which freely shares patient-derived
The second story outlines how the Structural xenograft samples of leukemias with researchers
Biology department is recruiting and expanding around the world to accelerate leukemia biology
to transform into one of the world’s most research.
comprehensive structural biology research centers In 2018, St. Jude committed resources to tackling
that houses imaging and analytical modalities that several faculty-proposed blue sky initiatives—ideas
examine dynamic cellular processes at the atomic with the potential to have a game-changing impact
level. Under the leadership of Charalampos Babis on health. Several projects are underway, including
Kalodimos, PhD, the department has established 6 expanding our cloud-based genomic data–sharing
centers to facilitate cutting-edge structural biology resources, initiating a gene therapy trial for
research and transdisciplinary collaborations with hemophilia B in LMICs, and establishing a program
St. Jude investigators in other departments. to explore the molecular pathology of pediatric
In the third feature, we describe how neurological diseases.
developmental neurobiologists at St. Jude are using St. Jude also gained recognition from several top
James R. Downing, MD technologic innovations to propel neuroscience workplace resources, including Fortune’s “100 Best
President and Chief Executive Officer
and gain new insights into the nervous system Companies to Work For” list, Glassdoor’s “Best Places
during health and disease. Michael A. Dyer, PhD, to Work” ranking, and “No. 1” on the National Society
David Solecki, PhD, and Daniel Stabley, PhD, are of High School Scholars’ Annual Career Survey of
part of an elite group of 4 laboratories working with places where high school and college students wish
Nobel Laureate Eric Betzig (University of California, to work.
Berkeley) to co-build the next-generation lattice The past year has been a time of great
“IMAGINE WHAT GREAT FEATS WE CAN light-sheet microscope. This new instrument will
enable scientists to visualize changes as they occur
productivity for our clinical, scientific, and
administrative operations. By building on this
ACHIEVE TOGETHER, WORKING ACROSS
in living cells deep within the brain or other nervous foundation, working in transdisciplinary teams, and
system tissues. collaborating with colleagues around the world,
The fourth story details a new St. Jude effort to St. Jude will advance cures for pediatric cancer and
DISCIPLINES, ACROSS BORDERS, AND close the global gap in childhood cancer survival. other catastrophic childhood diseases worldwide.
Today, one of the strongest predictors of whether
AROUND THE WORLD.” a child is cured of cancer is where that child lives.
More than 80% of all children live in low- or middle-
income countries (LMICs) that often struggle to
meet the healthcare needs of local populations. In
2018, St. Jude Global was launched, with the mission
to improve the survival of children with cancer or
blood disorders worldwide, through the sharing
2019 Scientific Report | 4 5 | 2019 Scientific Report
In Memoriam
The St. Jude family mourns the passing of Brian P. Sorrentino, MD, Wall Street Committee
Endowed Chair in Bone Marrow Transplant Research, Director of the Division of Experimental
Hematology, Member of the Department of Hematology, and a tremendous scientist who was
also a fierce Corvette-racing, target-shooting, blues guitar–playing lover of life.
Dr. Sorrentino was born and raised in Schenectady, NY. As a teenager, he battled Hodgkin
lymphoma. Late effects of the high doses of radiation therapy and chemotherapy that cured
him of that childhood disease caused health complications throughout his adult life and,
ultimately, the lung cancer that took him from us too soon.
Dedicating himself to becoming a physician–scientist, Dr. Sorrentino attended medical
school at The State University of New York Upstate Medical Center (Syracuse, NY) and
completed an internship in internal medicine at the University of North Carolina (Chapel Hill,
NC). In 1988, he accepted a position as a hematology-oncology fellow at the National Heart,
Lung, and Blood Institute and National Cancer Institute and joined the laboratory of Dr. Arthur
Nienhuis to conduct gene therapy and hematology research, a decision that would set the
course for the rest of his career.
In 1993, Dr. Sorrentino followed Dr. Nienhuis to St. Jude and spent the next 25 years
leading his own research laboratory, which pioneered new approaches to hematopoietic
stem cell (HSC) gene therapy for various diseases. He became renowned in his field and
served on the Advisory Council of the American Society of Cell and Gene Therapy and various
committees for the American Society of Hematology. He also chaired numerous National
Institutes of Health study sections to award grant funding. Dr. Sorrentino was elected to the
American Society of Clinical Investigation, and in 2005, he received the McCulloch and Till
Lectureship Award from the International Society of Experimental Hematology. He served on
the editorial boards of major scientific journals and held several patents on his work.
During his career at St. Jude, Dr. Sorrentino developed an interest in congenital immune
disorders. In a 1998 article in Nature Medicine, his group was the first to report curing an
animal model of human immunodeficiency by using HSC gene therapy. When early clinical
trials of gene therapy were halted because the treatment vectors caused leukemia,
Dr. Sorrentino refocused his laboratory to work on ensuring the safety of gene therapeutic
approaches for monogenic disorders, while also increasing their efficacy and potency.
His most recent project was gene therapy for X chromosome–linked severe combined
immunodeficiency (X-SCID). He and his colleagues engineered a lentiviral vector that inserts
a healthy copy of the IL2RG gene into the defective HSCs obtained from patients with X-SCID.
The modified cells were produced in the Children’s GMP, LLC, on the St. Jude campus and
then transplanted back into the patients. Nine infants born with X-SCID received this therapy
and are now producing fully functional immune cells for the first time. It is uncertain whether
this reconstitution of their immune systems will endure for their lifetime; however, as of now,
all the patients appear to have been cured without any immediate adverse side effects. In
addition, this therapy has the potential to help children with other disorders, such as Wiskott-
Aldrich syndrome and sickle cell disease.
This groundbreaking work was reported in the April 18, 2019, issue of The New England
Journal of Medicine. Although the reward of Dr. Sorrentino’s labor is a posthumous one, it is a
remarkable stamp on the life of the man who was a colleague, mentor, and friend to so many
at St. Jude and around the world.
Brian P. Sorrentino, MD
1958–2018
2019 Scientific Report | 6 7 | 2019 Scientific Report
UNITING RESEARCHERS TO IMPROVE
CURES AND SURVIVAL FOR CHILDREN
WITH CANCER: THE ST. JUDE
COMPREHENSIVE CANCER CENTER
RECEIVES AN “EXCEPTIONAL” RATING
FROM THE NATIONAL CANCER INSTITUTE
As the only National Cancer Institute children with the most common cancer geneticists, surgeons,
(NCI)–designated Comprehensive childhood cancer, acute lymphoblastic population scientists, and many
Cancer Center focused exclusively on leukemia (ALL), to more than 90%. others—to identify the most promising
children, St. Jude plays a crucial role Despite these achievements, much ways to pursue new treatments and
in the nation’s portfolio of Cancer work remains to be done in all areas of cures for solid tumors, hematological
Centers. During the 2 most recent pediatric oncology. malignancies, and brain tumors and
NCI 5-year reviews, St. Jude received Cancer is still the leading cause to minimize the long-term effects of
a score of “Exceptional,” the highest- of disease-related death in children cancer and its treatments.
possible ranking, placing our Center aged 1 to 14 years in the U.S., and the The Center also leads the pursuit
among the nation’s elite Cancer probability of cure for many pediatric of institutional strategic plan goals
Centers. cancers continues to be dismal. that guide work in precision medicine;
Children with cancer are a distinct Moreover, the growing population immunotherapy; proton therapy;
population. The biological anomalies of adult survivors of childhood preclinical and clinical research
that cause oncogenesis in children are cancer is at risk of severe long-term infrastructure; and basic, translational,
often different than those in adults, sequelae associated with their disease, and clinical research collaborations.
and the resulting diseases are distinct its treatment, or both. Therefore, Finally, Center leaders and members
from their adult counterparts. Thus, childhood cancer survivors need collaborate with St. Jude Global
most pediatric cancers cannot be lifelong medical surveillance and new investigators and international
treated in the same manner as adult interventions to improve their quality partners to expand the reach of
cancers and warrant independent of life. the Center and ensure that our
research that specifically addresses To advance research, treatment, discoveries benefit countless patients
the features of those diseases. Under and cures of childhood cancer, the and survivors of childhood cancer
the direction of Charles W. M. Roberts, Center provides an overarching worldwide.
MD, PhD, the St. Jude Comprehensive strategic vision and scientific direction,
Cancer Center is leading the nation in a robust collaborative framework,
these efforts. state-of-the-art shared resources, and
Throughout its history, St. Jude an administrative hub that supports
has directly contributed to seminal its members in making scientific
advances in pediatric oncology. Work breakthroughs. The Center is designed
from the Center has helped increase to bring together investigators
the overall survival of children with with diverse expertise—oncologists,
cancer to more than 80% and for pathologists, molecular biologists,
2019 Scientific Report | 8 9 | 2019 Scientific Report
What is a Cancer Center?
The NCI is the primary federal funding agency for cancer
research in the U.S. Its Cancer Center Support Grant is awarded to
institutions to recognize and support their scientific leadership,
resources, and cancer-focused research in basic, clinical, and/or
population science. Comprehensive Cancer Centers demonstrate
an added depth and breadth of research, as well as substantial
transdisciplinary research that bridges these scientific areas.
Cancer Centers must also provide cancer-related professional
training and community outreach activities.
St. Jude plays a crucial role in the nation’s portfolio of 70 Cancer
Centers, which includes 49 Comprehensive Cancer Centers, by
advancing research and cures designed specifically for pediatric
patients. St. Jude was designated an NCI Cancer Center in 1977
and was named a Comprehensive Cancer Center in 2008. Today,
the Center includes laboratory-based and clinical faculty members
working in 5 interactive research programs headed by program
co-leaders; a dedicated administrative team; and directors, staff
scientists, and technologists working in 9 NCI-funded shared
resources that support research activities. (See p. 90 for details.)
The Center also oversees strategic initiatives and the clinical trials
enterprise for St. Jude.
Dr. Roberts is assisted in leading the overarching direction of
the Cancer Center by Deputy Director Charles G. Mullighan, MBBS,
MD, and a senior leadership team of 8 Associate Directors who
oversee Administration (Dana Wallace), Shared Resources (James
I. Morgan, PhD), Basic Science (Suzanne J. Baker, PhD), Clinical
Research (Victor M. Santana, MD), Population Sciences (Leslie Charles G. Mullighan, MBBS, MD; Charles W. M. Roberts, MD, PhD
L. Robison, PhD), Outreach (Carlos Rodriguez-Galindo, MD), and
Education & Training (Gerard P. Zambetti, PhD).
2019 Scientific Report | 10 11 | 2019 Scientific Report
INCREASED PUBLICATIONS
IN JOURNALS WITH THE
HIGHEST IMPACT FACTORS
In the recent vs. previous 5-Year Review Period
CELL
+360%
NATURE SCIENCE
+23% +40%
Dana Wallace, Charles W. M. Roberts, MD, PhD
THE NEW ENGLAND NATURE
JOURNAL OF GENETICS
Driving Scientific leadership, extensive
resources, and accomplished research
The Center supports 5 multi-
disciplinary research programs. The MEDICINE
Transdisciplinary
+700% +163%
in basic, clinical, and/or population Cancer Biology Program is engaged
science distinguish the 70 NCI- primarily in laboratory-based research.
Collaborations designated Cancer Centers from other
research institutions in the U.S. The
Three disease-focused programs,
Developmental Biology & Solid
primary function of the Center is to Tumor, Hematological Malignancies,
drive transdisciplinary collaboration and Neurobiology & Brain Tumor,
by bringing together diverse clinicians
and scientists from across the
translate fundamental discoveries
into curative therapies. The Cancer NATURE
institution, the country, and the globe.
The Center also oversees the St. Jude
Control & Survivorship Program
assesses adverse effects of childhood
MEDICINE
+200%
clinical research enterprise, which cancer and treatment to improve the
treats patients in clinical trials both at quality of life of long-term survivors of
St. Jude and through the St. Jude childhood cancer. Brief descriptions of
Affiliate Program comprising 8 clinics. the 5 Center programs and examples
(See p. 88 for details.) The Center of their recent achievements are
additionally provides educational described in the following pages.
opportunities about cancer and
healthy living to the community CANCER CELL TOTAL
PUBLICATIONS
and educates and trains the next
generation of pediatric cancer
+55%
researchers.
Reprinted by permission from SNCSC GmbH:, Nature Immunology, 16, 2. © 2015 Nature Springer. Reprinted from Cell Stem Cell, vol 17/1. © 2015; Molecular Cell, vol. 62/4.
2290
2019 Scientific Report | 12 © 2016; and Stem Cell Reports, vol. 10/8. © 2018, all with permission from Elsevier.
13 | 2019 Scientific Report
Establishing the Genomic and cancer study of pediatric cancers. The term
Epigenomic Landscape of Pediatric “pan-cancer” indicates that multiple types of
Cancer cancer, regardless of the cell of origin or tissue
Cancer arises from DNA mutations, epigenetic in which they initiated, were included in the
alterations, or a combination thereof. analysis. The team integrated whole-genome,
To understand the fundamental driving -exome, and -transcriptome sequencing to
mechanisms of pediatric cancers, Jinghui identify somatic alterations in 1699 pediatric
Zhang, PhD (Computational Biology), led a leukemias and solid tumors. The findings,
team of cancer biologists and computational published in Nature, demonstrated that most
biologists in pioneering next-generation alterations were unique to pediatric cancer
approaches to detailed analyses of pediatric and underscore the need to develop precision
cancer genomes and epigenomes. This work therapies designed specifically for pediatric
was initiated in 2010 through the St. Jude cancers. (See p. 97 for details.)
Children’s Research Hospital—Washington Genomic discoveries and their integration
University Pediatric Cancer Genome Project. into clinical care continue at a rapid pace;
More recently, members of 3 programs every eligible St. Jude patient with cancer
(Cancer Biology, Hematological Malignancies, is now offered clinical whole-genome
and Neurobiology & Brain Tumor) identified sequencing. An innovative data-sharing
germline mutations in cancer-predisposition platform, St. Jude Cloud (www.stjude.cloud),
genes in 8.5% of children and adolescents was launched in April 2018 to provide genomic
with pediatric cancers. Published in The datasets, analysis tools, and visualizations to
New England Journal of Medicine, this work the global research community. The platform,
demonstrates the importance of genetic a collaboration with Microsoft and DNAnexus,
counseling in this population and has shaped currently offers more than 10,000 whole-
the development of the St. Jude Cancer genome sequences from pediatric patients
Douglas R. Green, PhD; Martine F. Roussel, PhD
Predisposition Program, which is led by Kim with cancer and childhood cancer survivors.
E. Nichols, MD (Oncology). To date, it has 800 registered users from 400
Cancer The primary goal of the Cancer Biology
Program is to explore and understand
control, identify genetic mutations
and anomalies as new therapeutic
In 2018, Dr. Zhang’s team led a pan- institutions around the world.
Biology the biology of cancer cells. The diverse
nature of pediatric cancers and the
targets for translation into clinical
trials, and advance our understanding
Program complex molecular, genetic, and
developmental contexts in which they
of the cancer microenvironment. To
address unmet needs and maximize
form necessitate a broad spectrum opportunities for translation, research
of basic research to build a strong in this Program spans 4 areas: signaling
foundation. Basic science discoveries networks and therapeutics; cell stress,
have driven numerous key advances in repair, metabolism, and death; tumor
our understanding and treatment of microenvironment and immunology;
pediatric cancers. and genome structure and function.
The Program leads integrated, Here, we describe advances made in
multidisciplinary efforts to define 2 of these key areas.
pathways related to cancer and its
Kim E. Nichols, MD; James R. Downing, MD; Jinghui Zhang, PhD
2019 Scientific Report | 14 15 | 2019 Scientific ReportTumor Immunology and autophagy pathway, LC3-associated
Immunotherapy phagocytosis (LAP), in the myeloid response to
Although cancer cells evolve mechanisms to dying cells. A recent collaborative study led by
escape immune surveillance, experimental Drs. Green and Opferman and Charles Gawad,
manipulation of the immune system has MD, PhD (Oncology, Computational Biology),
the potential to deliver substantial tumor- in Cell, showed that LAP influences anticancer
killing benefits. Efforts in the Program have T-cell responses and inhibits anticancer
provided fundamental insights into the immunity. Targeting LAP-specific proteins may,
immune system’s ability to regulate cancer therefore, be a promising therapeutic strategy
and effective approaches to exploit metabolic that will not interfere with the canonical
events to generate an antitumor response. autophagy processes that are important for
These studies represent ongoing collaborative tumor suppression.
efforts among the laboratories of Hongbo The Program has also made strides
Chi, PhD (Immunology), Thirumala-Devi toward understanding the molecular basis of
Kanneganti, PhD (Immunology), Joseph T. inflammation, a key process in tumorigenesis.
Opferman, PhD (Cell & Molecular Biology), and Dr. Kanneganti has led multiple studies
Program Co-Leaders Douglas R. Green, PhD on the inflammasome, a protein complex
(Immunology), and Martine F. Roussel, PhD involved in restricting the immune response
(Tumor Cell Biology). to microbial challenges and tumorigenesis.
In Science Immunology, Dr. Chi and In Gastroenterology, her team reported that
colleagues recently reported that the the sensor protein pyrin, which initiates the
integration of metabolic and signaling assembly of the inflammasome complex,
pathways dictates lineage choices for T cells. protects against colon inflammation
They found that metabolic processes guide and tumorigenesis in mice. Furthermore,
the fate of immune cells. Signaling pathways work published in The Journal of Clinical
affecting metabolism are essential to the Investigation identified tumor necrosis factor
developmental fate of not only T lymphocytes as a critical modulator of pyrin expression and
but also dendritic cells, which are crucial inflammasome activation. These studies point
for stimulating T cells and guiding their to pyrin and its regulators as potential targets
differentiation, as Dr. Chi’s team reported in for therapeutic intervention. Collectively,
Nature. (See p. 103 for details.) these and other key mechanistic insights
Collaborative studies on macrophage have contributed to the foundation for our
activity in the tumor microenvironment have rapidly expanding translational efforts in
revealed an important role for a noncanonical immunotherapy.
R. K. Subbarao Malireddi, PhD; Thirumala-Devi Kanneganti, PhD
Joseph T. Opferman, PhD; Douglas R. Green, PhD; Charles Gawad, MD, PhD
2019 Scientific Report | 16 17 | 2019 Scientific ReportDevelopmental Origins and To hasten progress in pediatric solid tumor
Therapeutic Approaches to research, all O-PDXs and their associated data
Rhabdomyosarcoma are freely shared with researchers around the
Rhabdomyosarcoma (RMS) is the most world through the CSTN, with no obligation to
common soft-tissue cancer in children. collaborate. To date, 507 requests for O-PDXs
Histologically, these tumors resemble have been received from 200 investigators
embryonic skeletal muscle and have been working at 99 institutions in 16 countries.
thought to arise from that tissue, but they The O-PDXs have enabled crucial insights
can also arise in sites devoid of skeletal that are driving innovative clinical studies
muscle. Mark E. Hatley, MD, PhD (Oncology), in RMS and other solid tumors. For example,
recently found that cellular reprogramming work in these models identified an inhibitor
of nonmyogenic cells can also lead to RMS, of the signaling kinase WEE1 as a promising
demonstrating the disease’s diverse origins. therapeutic agent. In Cancer Cell, Elizabeth
(See p. 105 for details.) A. Stewart, MD, Sara M. Federico, MD (both of
A major barrier to developing new Oncology), and their colleagues reported the
therapies for solid tumors has been the lack of most comprehensive analysis to date of RMS
preclinical models that accurately recapitulate that integrated transcriptomic, epigenomic,
human disease and predict clinical responses and proteomic/phosphoproteomic data to
to novel therapeutics. The Program launched a elucidate the cellular origins and therapeutic
large-scale effort to develop better preclinical vulnerabilities of the disease. RMS has 2
models, with a focus on orthotopic patient- major histologic subtypes: alveolar RMS and
derived xenografts (O-PDXs). This led to the embryonic RMS. Dr. Stewart’s team found that
development of the Childhood Solid Tumor alveolar RMS, which is the more aggressive
Network (CSTN; www.stjude.org/CSTN). Since subtype, arises at a later stage in the
the CSTN was established, 498 patients have developmental program than does embryonal
donated surplus tumor tissue, resulting in the RMS. Their comprehensive preclinical testing
successful generation of 201 independent also revealed that targeting WEE1 is the most
Alberto S. Pappo, MD; Michael A. Dyer, PhD xenografts that represent 27 tumor types. effective approach to treating high-risk RMS
All models have undergone comprehensive in vivo. These results prompted the Children’s
Oncology Group to expand their multicenter
Developmental Some of the most devastating, poorly The Developmental Biology & Solid genomic and epigenomic analyses, including
understood cancers that affect Tumor Program aims to improve the whole-genome and whole-exome sequencing, Phase I/II clinical trial of the WEE1 inhibitor
Biology & Solid children arise in the peripheral nervous
system, muscles, or bones. Despite
survival and quality of life of children
with solid tumors by integrating basic,
RNA-sequencing, and whole-genome
bisulfite sequencing; approximately half
AZD1775 and the chemotherapy agent
irinotecan to include pediatric patients with
Tumor Program recent advances in genomics that
have enabled us to better understand
translational, and clinical research. The
Program has 4 working groups focused
of the models have undergone chromatin
immunoprecipitation sequencing analysis.
high-risk RMS.
the etiology of pediatric solid tumors, on recurrent disease, immunotherapy,
the overall survival of children and rare tumors, and precision medicine.
adolescents with high-risk or recurrent Here, we present recent advances in
disease has not improved in more than elucidating the developmental origins
20 years. This lag in improved cure of pediatric solid tumors, developing
rates reflects the heterogeneity and unique preclinical resources and
relative rarity of pediatric solid tumors. research pipelines, and identifying
promising new therapeutic approaches.
Sara M. Federico, MD; Elizabeth A. Stewart, MD
2019 Scientific Report | 18 19 | 2019 Scientific ReportPrecision Therapy for Tumors this study were combined with those from a
Bearing a TRK Fusion Oncogene Phase I study on adults and a Phase II study on
Gene fusions involving NTRK1, NTRK2, or NTRK3 adolescents and adults and published in The
(TRK fusions) are found in several childhood New England Journal of Medicine. The cohort
and adult tumors. In 2018, a large multicenter included 55 patients (aged 4 months–76
trial testing the TRK inhibitor larotrectinib as a years) with 17 unique TRK fusion–positive
new precision therapy for TRK-bearing tumors tumors, and 75% of the tumors responded to
was completed. Collaborating with Theodore the drug. Larotrectinib was well tolerated, and
Laestch (University of Texas Southwestern 30 (55%) patients remained progression-free
Medical Center) and David Hyman (Memorial after 1 year. As a result of these studies, the
Sloan Kettering), Program Co-Leader Alberto U.S. Food and Drug Administration approved
S. Pappo, MD (Oncology), served as the larotrectinib as the first targeted, oral, tumor-
St. Jude investigator on the landmark Phase agnostic therapy. Tumor-agnostic therapy
I/II trial of larotrectinib. is defined as immunotherapy that attacks
In The Lancet Oncology, the investigators any type of cancer that arises in any location,
demonstrated that larotrectinib was well as long as the tumor cells have a specific
tolerated by pediatric patients and showed molecular anomaly (e.g., TRK fusion) that is
impressive antitumor activity in all patients targeted by the drug.
with TRK fusion–positive tumors. Results from
Alberto S. Pappo, MD; Armita Bahrami, MD
2019 Scientific Report | 20 21 | 2019 Scientific ReportA Genomic Portrait of Acute Mixed-phenotype acute leukemia (MPAL)
Lymphoblastic Leukemia is a rare, difficult-to-treat subtype that
ALL includes a spectrum of disease subtypes includes features of both ALL and acute
with distinct mutations. Program Co-Leader myeloid leukemia. By integrating genome
Charles G. Mullighan, MBBS, MD (Pathology), sequencing, experimental modeling, and
and colleagues have conducted multiple tumor xenografting, Dr. Mullighan and
in-depth genomic investigations of ALL and colleagues identified the genetic alterations
defined numerous novel disease subtypes that define the most prevalent subtypes of
and mechanisms of pathogenesis. Recently, MPAL. (See p. 101 for details.) Their findings,
this work has contributed to the molecular published in Nature, are now being tested in
reclassification of ALL in the revised World clinical trials of MPAL that are determining
Health Organization guidelines. It has also whether disease subtype and treatment
provided the basis for using targeted agents response can be correlated with the genetic
in precision medicine trials, including the features of leukemic cells.
ongoing St. Jude Total Therapy 17 clinical To promote research on leukemia biology
trial for newly diagnosed ALL, which is led and help develop more effective cures, the
by Hiroto Inaba, MD, PhD (Oncology). Program launched the Public Resource of
Genomic discovery studies continue to Patient-derived and Expanded Leukemias
accelerate. Earlier this year in Nature Genetics, (PROPEL; www.stjude.org/PROPEL) in 2018.
Dr. Mullighan’s team reported their integrated PROPEL is a St. Jude–hosted resource for
genomic analysis of 1988 pediatric and adult sharing unique patient-derived xenografts
cases of B-progenitor ALL, thereby revising (PDXs) from patients with B- or T-lineage
the classification of ALL to comprise at ALL, acute myeloid leukemia, or relapsed
least 23 genetically distinct subtypes. This leukemia. In addition, PROPEL provides a tool
comprehensive sequencing approach enabled with which to explore genomic data from
the researchers to not only identify new both the PDXs and matched primary patient
subtypes but also demonstrate the samples. This information is freely shared
Ching-Hon Pui, MD: Charles G. Mullighan, MBBS, MD power of transcriptome sequencing for with researchers around the world, with no
guiding classification, risk stratification, and obligation to collaborate. Currently, PROPEL
contains approximately 250 samples of adult
Hematological Hematological malignancies remain sparked innovative precision medicine tailored therapy.
a leading cause of cancer-related studies and therapeutic strategies. and pediatric leukemias and continues to grow
Malignancies death in children, despite therapeutic
advances that have improved
Program accomplishments have had
a global impact on the diagnosis,
with the addition of other subtypes of leukemia.
Program outcomes. The Hematological
Malignancies Program aims to improve
classification, and treatment of various
hematological malignancies.
the cure of childhood leukemias Research in the Program
and lymphomas, while minimizing encompasses common and rare
treatment-related adverse effects. childhood leukemias and lymphomas
This highly interactive, and ranges from defining molecular
transdisciplinary Program has a long taxonomy to experimental
record of major discoveries in cancer modeling, preclinical studies,
biology and treatment. The translation pharmacogenomics, and clinical trial
of fundamental discoveries on the development. Here, we focus on recent
genetic basis of leukemogenesis advances in our understanding of
and treatment-related toxicities the molecular basis of ALL, the most
into new diagnostic and treatment common childhood malignancy.
approaches has changed the
standard of care for children with
hematological malignancies and
Hiroto Inaba, MD, PhD
2019 Scientific Report | 22 23 | 2019 Scientific ReportPredisposition to Acute nonsilent TP53-coding variants, 22 of which
Lymphoblastic Leukemia were predicted to be pathogenic. Children
Growing evidence indicates that germline carrying TP53 pathogenic variants had poorer
genetics influence the development of ALL, survival and a substantially higher risk of
which was once regarded as a nonhereditary subsequent cancers. This study confirms the
disease. For example, the IKZF1 gene, a known importance of TP53 in ALL development and
somatic driver of high-risk ALL, is mutated in treatment response. Germline mutations
families in which multiple members have ALL in TP53 also have implications for family
and in patients with ALL with no known family members, who are now being screened for
history. This work was published in Cancer this cancer-susceptibility gene through the
Cell. After identifying 2 members of the same St. Jude Cancer Predisposition Program
family with B-progenitor ALL and an IKZF1- to enable early diagnosis of cancer among
truncating mutation, the team conducted siblings and parents. This work was published
targeted sequencing of 4963 childhood ALL in the Journal of Clinical Oncology.
samples. They found 28 unique predisposing Taking a more agnostic approach, Dr. Yang
germline variants in 45 children, thereby and colleagues conducted genome-wide
establishing IKZF1 as an ALL-predisposition association studies to seek novel ALL-
gene and further emphasizing the importance susceptibility loci in Hispanic individuals who
of heredity in ALL development. have a high proportion of Native American
In another targeted sequencing study, Jun ancestry and an elevated risk of ALL and
J. Yang, PhD (Pharmaceutical Sciences), and his poorer outcome. In the journal Blood, the team
team followed up prior work from St. Jude that reported that the ERG gene is a novel ALL risk
showed TP53 germline variants are common locus that correlates with Native American
in childhood hypodiploid ALL. By conducting ancestry and is enriched in certain ALL
targeted germline sequencing of TP53-coding subtypes. Thus, ERG has been added to the
regions in DNA samples from 3801 children growing list of genetic factors that contribute
with ALL, the researchers identified 49 unique, to racial/ethnic disparities in ALL.
WITHIN 30 DAYS OF A CANCER DIAGNOSIS,
90% OF PATIENTS ENROLL IN A CLINICAL TRIAL;
60% ENROLL IN A THERAPEUTIC TRIAL.
In the recent vs. previous 5-Year Review Period
NEW PATIENTS INTERNATIONAL PATIENTS ENROLLED
WITH CANCER PATIENTS WITH ON THERAPEUTIC
CANCER TRIALS
+9% +30% +40%
Jun J. Yang, PhD
2019 Scientific Report | 24 25 | 2019 Scientific ReportModeling an Incurable Tumor: inducible H3 K27M mutation. In Cancer Cell,
Diffuse Intrinsic Pontine Glioma they reported that the K27M-dependent,
In 2012, Program Co-Leader Suzanne J. Baker, genome-wide decrease in H3K27me3 causes
PhD (Developmental Neurobiology), and a selective increase in neurodevelopmental
Cancer Biology Program member Dr. Zhang gene expression by releasing the epigenetic
discovered recurrent histone H3 mutations regulation of poised promoters. The K27M
in diffuse intrinsic pontine glioma (DIPG), mutation enhances the self-renewal of neural
an incurable tumor of the brainstem, and in stem cells, which could expand the pool of
pediatric high-grade gliomas. As a result, the cells susceptible to malignant transformation.
histone H3 K27M mutation was defined as a Expression of the K27M mutation throughout
molecular hallmark of DIPG, and an essential the central nervous system (CNS), combined
connection between histone regulation and with DIPG-associated mutations in the Trp53
DIPG was revealed. and PDGFRaα genes, selectively accelerated
To determine how the H3 K27M mutation tumorigenesis in the brainstem. Thus, these
drives oncogenesis and why mutations in murine models revealed novel epigenetic
this histone selectively drive gliomas in the contributions to DIPG pathogenesis
developing brainstem, Dr. Baker and colleagues and will enable detailed studies of
genetically engineered mice carrying an therapeutic response.
Suzanne J. Baker, PhD; Amar J. Gajjar, MD
Neurobiology Despite rapid advances in our
understanding of the biology of
Pediatric brain tumors arise during
development; thus, the Program
& Brain Tumor brain tumors, these diseases remain
the leading cause of cancer-related
addresses regulatory mechanisms
that affect normal growth and
Program death in children. Current treatment
approaches are lacking for some
tumorigenic growth in the developing
brain. Program members continue to
patients and lead to long-term investigate neural development, tumor
debilitating side effects for others. cells of origin, key pathways that drive
The Neurobiology & Brain Tumor tumorigenesis, and the epigenetic
Program aims to improve survival landscape of brain tumors. Genome-
and morbidity of children with brain wide studies of the major pediatric
tumors by developing effective, brain tumor types have identified
relatively nontoxic therapies through novel mutations, defined molecular
a better understanding of disease subgroups, and opened new avenues
pathogenesis. By integrating the latest of basic, translational, and clinical
genomic and genetic technologies investigation. Furthermore, advances
with studies of the developing nervous in the fields of molecular pathology,
system, members of this Program are imaging, and radiation oncology hold
translating laboratory findings into promise for advancing the treatment
opportunities for new treatments. of these formidable diseases. Here we
present recent advances made in 3
types of pediatric brain tumors.
Jon Larson, PhD; Lawryn Kasper, PhD; Suzanne J. Baker, PhD
2019 Scientific Report | 26 27 | 2019 Scientific ReportMolecular Characterization of Brain Hopp Children’s Cancer Center (Heidelberg,
Tumors Guides Treatment Germany) and The Hospital for Sick Children
Medulloblastoma is the most common CNS (Toronto, Canada). Using whole-genome
tumor of childhood. It includes 4 molecular and whole-exome sequencing, the teams
subtypes (SHH, WNT, Group 3, and Group 4), assessed the prevalence of rare variants in 110
and each subtype has a distinct biology and cancer-predisposition genes in 1022 patients
treatment outcome. Work by the Program has with medulloblastoma. This study, which
been instrumental in further characterizing also appeared in The Lancet Oncology, is the
medulloblastoma subtypes and identifying the largest to date on genetic predisposition to a
contribution of germline predisposition to single pediatric brain tumor entity. The team
the disease. discovered that genetic predisposition plays
Children younger than 3 years at the a major role in causing medulloblastoma,
time of diagnosis of medulloblastoma particularly in patients with the WNT or
often have poorer overall survival, because SHH subtype. They also identified APC,
radiation therapy must be delayed or the dose BRCA2, TP53, PALB2, PTCH1, and SUFU as key
reduced to avoid debilitating side effects on medulloblastoma-predisposition genes. These
the developing brain. A multicenter Phase II results indicate an urgent need to provide
clinical trial (SJYC07) led by Giles W. Robinson, genetic counseling and testing for patients
MD (Oncology), Program Co-Leader Amar with WNT or SHH medulloblastoma.
J. Gajjar, MD (Pediatric Medicine, Oncology), Ependymomas are neuroepithelial tumors
and Paul A. Northcott, PhD (Developmental of the CNS. They represent nearly 10% of all
Neurobiology), used a risk-stratified treatment pediatric CNS tumors and about 30% of CNS
strategy that omitted or minimized radiation tumors in children younger than 3 years.
exposure in 81 patients younger than 3 years Comprehensive DNA-methylation profiling
with medulloblastoma. The findings, published led by the Program has demonstrated distinct
in The Lancet Oncology, support the pursuit of molecular groups of ependymoma and refined
a molecularly driven, risk-adapted approach for approaches to disease classification, but these
treating young children with medulloblastoma. developments have yet to be incorporated
(See p. 96 for details.) into standard clinical practice. In Acta
Historically, most medulloblastomas Neuropathologica, David W. Ellison, MD, PhD
were thought to arise sporadically. A (Pathology), and colleagues characterized the
team led by Drs. Gajjar, Northcott, and molecular heterogeneity in posterior fossa
Robinson challenged this long-held belief type A ependymomas, revealing a role for a
in collaboration with investigators at the previously uncharacterized gene, CXorf67. (See
p. 112 for details.)
INCREASED FUNDING OF
CANCER CENTER RESEARCH
In the recent vs. previous 5-Year Review Period
PEER-REVIEWED NCI FUNDING
FUNDING
+13% +9% Giles W. Robinson, MD
2019 Scientific Report | 28 29 | 2019 Scientific ReportIdentifying Genetic Risk Factors for toxicity to cells and tissues. However, St. Jude
Late Effects of Treatment is helping to pioneer a relatively nascent
Some childhood cancer survivors fare better area of investigation—financial toxicity faced
than others, even among those who had by childhood cancer survivors. The term
similar diagnoses and completed comparable “financial toxicity” is used to describe problems
therapeutic regimens. However, the way in experienced by cancer survivors resulting
which survivors’ genetic makeup influences from the financial implications of receiving
their long-term health outcomes has been a diagnosis and subsequent medical care
poorly understood. In 2018, Dr. Zhang and for cancer. A team led by I-Chan Huang, PhD
Program Co-Leader Leslie L. Robison, PhD (Epidemiology & Cancer Control), assessed 3
(Epidemiology & Cancer Control), led a study domains of financial hardship (i.e., material,
of whole-genome sequencing of germline psychological, and coping/behavioral) in 2811
DNA from more than 3000 pediatric cancer long-term survivors in the SJLIFE cohort.
survivors participating in the SJLIFE study. The majority (65%) of survivors reported
This first-in-kind initiative was designed to hardship in at least 1 domain, with higher risks
enable integrated analyses of genomic data found in middle-aged survivors (40 years or
and comprehensive clinical data to identify older) versus younger survivors (18–39 years).
new genetic risk factors for late effects of Depressive symptoms and suicidal ideation
treatment, such as second neoplasms. This were associated with all 3 hardship domains.
work was published in the Journal of Clinical This work was published in the Journal of
Oncology. (See p. 110 for details.) the National Cancer Institute. The discovery
that financial hardship is widespread among
Understanding Financial Toxicity in childhood cancer survivors emphasizes the
Childhood Cancer Survivors importance of systematically addressing the
Minimizing the toxicity of anticancer therapy impact of health policies on survivors and
is generally considered only in terms of developing strategies for early detection
and intervention.
Melissa M. Hudson, MD; Leslie L. Robison, PhD
Cancer Control As treatments for childhood cancers
improve, the number of long-term
This Program, which spans the
breadth of epidemiological, clinical,
& Survivorship survivors in the U.S. is expected to
surpass 500,000 by the end of 2019.
and interventional research, has
defined the landscape of childhood
Program The Cancer Control & Survivorship
Program conducts research to reduce
cancer survivorship, influenced the
design of contemporary pediatric
treatment-related complications and cancer treatment strategies, and
improve the long-term outcomes and provided crucial data to guide
quality of life of individuals surviving surveillance and health-preserving
childhood cancer. Two unique survivor interventions for survivors. Efforts to
cohorts, the Childhood Cancer Survivor characterize the challenges faced by
Study (CCSS) and the St. Jude Lifetime childhood cancer survivors and design
Cohort Study (SJLIFE), include more effective interventions are a major
than 40,000 participants who have ongoing focus.
survived childhood cancer for at least
5 years after completion of therapy.
I-Chan Huang, PhD
2019 Scientific Report | 30 31 | 2019 Scientific ReportAS THE ONLY NCI-DESIGNATED CANCER
CENTER DEVOTED TO PEDIATRICS, WE HAVE
AN OBLIGATION TO USE OUR TALENT AND
RESOURCES TO ADVANCE CURES FOR
PEDIATRIC CANCER WORLDWIDE.
Charles W. M. Roberts, MD, PhD
Measures of Every 5 years, the Center must reapply
for funding and formal designation
NCI review, the Center’s total peer-
reviewed funding (i.e., federal and Looking With the arrival of Dr. Roberts in
2015, the Center developed a new
Looking ahead, the Center will
advance this vision through large-
Success of an as a Comprehensive Cancer Center.
For the recent renewal, Center
private foundation awards) to support
cancer research increased by 13%.
Ahead vision to bring about a new era of
precision therapies and cures for
scale strategic initiatives, build on its
strong foundation of transdisciplinary
Exceptional administrative staff, shared resources The NCI awarded the Center its children with pediatric cancer via collaboration, and serve as a model
Center
directors, and leadership spent more second consecutive highest-possible pursuit of discoveries in epigenetics, for pediatric cancer research and
than 18 months writing the 2300-page “Exceptional” ranking and the best genomics, and immunotherapy. To treatment across the globe.
application. In May 2018, a panel of numerical score in the Center’s realize this vision, the Center is tapping
20 reviewers representing the NCI history. NCI reviewers referred to into the remarkable intellectual and
conducted a site visit of the Center. St. Jude as a “national treasure,” philanthropic resources of St. Jude
Dozens of examples of scientific invoking our remarkable success in to engage leading experts within the
achievements across the Center translating science into advances Center and beyond in the fight against
were presented. These included for the benefit of pediatric patients childhood cancer.
an increase in the number of peer- with cancer everywhere. Exceptional
reviewed publications, including a marks were also awarded to all 6 of the
27% increase in the number of articles essential characteristics of a Cancer
published in scientific journals with Center: physical space, organizational
an impact factor greater than 10 capabilities, transdisciplinary
since the last NCI review. The Center collaboration and coordination, cancer
also saw substantially more patients focus, institutional commitment, and
with new diagnoses; accruals to the Center Director. The outcome of
therapeutic clinical trials increased by the 2018 NCI review further reinforces
9%. Within 30 days of diagnosis, 90% the position of St. Jude, the only NCI-
of new patients with cancer enrolled designated Cancer Center dedicated
in a clinical trial; 60% enrolled in a solely to children, as one of the nation’s
therapeutic trial. Finally, since the last elite Cancer Centers.
2019 Scientific Report | 32 33 | 2019 Scientific ReportTHE STRUCTURAL BIOLOGY
DEPARTMENT EXPANDS TO BECOME
THE WORLD’S PREMIER CENTER FOR
STRUCTURAL ANALYSES AND IMAGING
OF BIOMOLECULES
Biomolecules are dynamic; changes addition, complementary techniques discovery campaigns. Crystallographic
in their 3-dimensional (3D) shape are used to probe specific details structure determination of targets
endow them with an array of of biomolecular mechanisms. in complex with ligands is the gold
activities. Proteins are the main class These include mass spectrometry, standard in drug discovery, facilitating
of biomolecules in our bodies; they which reveals changes in the rational design and iterative chemical
perform functions that make life composition and stoichiometry of synthesis and testing. Cryo-EM/TM
possible. Proteins come in a range of protein complexes; single-molecule has great potential for enabling drug
shapes and sizes and possess distinct imaging techniques, which monitor discovery for difficult targets, such as
capabilities. Understanding how the structure and movement of membrane proteins that are difficult
structural changes in proteins impart specific parts of biomolecules; and to visualize with other techniques.
function is, therefore, fundamental computational simulations, which Some drug targets of interest to St. Jude
to all biology, whether in health or use powerful computers to study investigators in structural biology
disease. Providing this understanding the motions that occur when include kinases, E3 ligases, protein–
is the task of structural biologists. biomolecules function. protein interactions, proteins involved
Structural biologists use In catastrophic diseases, the in programmed cell death, essential
sophisticated instruments to functions of biomolecules are altered. bacterial enzymes, ribosomes, and
elucidate protein structures at the Structural biologists examine the various membrane proteins.
highest (atomic) resolution to study structural basis for such functional
their functions and understand alterations to gain insights into
how abnormal proteins give rise to new therapeutic strategies. This
diseases. Three frontline techniques can occur, for instance, through the
are used to examine biomolecular generation of new drugs that are able
structures: cryogenic electron to counteract disease by targeting
microscopy and tomography deleterious alterations in the activities
(cryo-EM/TM), nuclear magnetic of proteins and other biomolecules.
resonance (NMR) spectroscopy, and The Department of Structural Biology
X-ray crystallography. Each of these has built an infrastructure to not only
techniques has unique strengths and elucidate biomolecular structures
limitations, and structural biologists fundamental to health and disease
often must integrate the results from but also enable the drug-discovery
different techniques to fully visualize process at every step. For instance,
and understand the structures of NMR-based binding screens can be
complex biomolecular systems used to identify the ligands of any
(e.g., multicomponent assemblies macromolecule assembly, irrespective
and macromolecular machines). In of shape and size, to spearhead drug-
2019 Scientific Report | 34 35 | 2019 Scientific ReportStructures are blueprints for developing nanometers; and large-scale domain motions
hypotheses about biomolecular functions can take milliseconds to seconds and are
that can be tested using genetic, biochemical, measured in tens of nanometers. The
and cell biological approaches. However, techniques used to study these processes
to fully understand function in detail, depend on the time scale and extent of the
structural biologists need to examine the structural change. Cryo-EM/TM and X-ray
movement of biomolecules, which is termed crystallography can distinguish biomolecular
protein dynamics. Proteins are not static conformations but typically not the movement
objects; they are rapidly changing molecules that gives rise to them. NMR spectroscopy is
that move, bend, expand, and contract. particularly adept at determining the time
Without such motions, many proteins and scale and amplitude of molecular movements.
nucleic acids cannot function properly. The Single-molecule fluorescence imaging
overarching goal of structural biology is captures individual molecules in different
to elucidate all conformations needed for states, thereby enabling us to understand how
a biomolecule to function and determine an interconversion occurs.
how those conformations interconvert and No individual technique provides all the
how this interconversion between structural information needed to understand structure
conformations leads to biological functions. and activity, which is why structural biologists
Structural changes in proteins and other must integrate results from comprehensive
biomolecules span orders of magnitude analyses of protein structure and dynamics
in time and space. For example, methyl acquired using multiple methods. By deploying
sidechain rotations take picoseconds and and actively developing the wide range of
lead to changes measured in angstroms; sophisticated techniques available, St. Jude
different conformations of intrinsically has positioned itself at the forefront of
disordered proteins occur in nanoseconds the emergent field of integrative
to microseconds and are measured in structural biology.
Building The Department of Structural Biology has expanded to join premier
research centers and aspires to become the top center for imaging
Cutting-Edge and biophysical modalities, enabling St. Jude researchers to
examine intricate cellular processes at the atomic level. Department
Structural Chair Charalampos Babis Kalodimos, PhD, a world-renowned
Biology
structural biologist, is directing this effort by recruiting world
leaders in structural biology to join the St. Jude faculty and bringing
Technologies innovative technologies to the St. Jude campus. The department
has created 6 centers: Cryo–EM/TM, NMR Spectroscopy, X-ray
at St. Jude Crystallography, Single-Molecule Imaging, Mass Spectroscopy,
and Protein Technologies. Researchers working in these centers
will engage in cutting-edge structural biology research, and the
Protein Technologies Center will facilitate collaborations between
the department and St. Jude investigators working in other fields.
Here we describe the technologic capabilities of those centers and
introduce the scientists working in them.
STRUCTURES ARE BLUEPRINTS FOR
DEVELOPING HYPOTHESES ABOUT
BIOMOLECULAR FUNCTIONS IN HEALTH
AND DISEASE.
2019 Scientific Report | 36 37 | 2019 Scientific Reporttomography (cryo-TM), also uses cryogenic houses all essential auxiliary equipment for
methods for sample preparation and electron sample preparation, including a Vitrobot Mark
microscopy methods for image acquisition, IV, a Solarus II plasma cleaner, and a carbon
but cryo-TM includes added tomographic- coater. The Center plans to expand into cryo–
reconstruction methods to reveal 3D correlative light and electron microscopy for
structures of cells and tissues. This makes it high-resolution imaging of cells and tissues.
possible to visualize structures of biological Cryo-EM experiments generate
molecules in their native cellular environment. several terabytes of imaging data per day
Thus, recent advances in cryo-EM/TM are per instrument. The images need to be
transforming many life science and processed to generate a 3D map of the
biomedical disciplines. biomolecule being studied, which requires
Last year, St. Jude recruited Mario Halic, high-performance computing. The Center is
PhD, a prominent leader in the field, to supported by state-of-the-art computational
establish a preeminent research program in resources, including a dedicated cluster with
cryo-EM. Dr. Halic’s research combines cryo- hundreds of computing central-processing
EM, biochemistry, and genetics to determine units and a range of high-performance
how enzymes and structural proteins modify computing facilities available at the St. Jude
nucleosome and chromatin structure. Data Center.
In so doing, he is defining the molecular The Center is committed to delivering
mechanisms that recognize specific genetic the latest technology to the broader research
elements and target them for epigenetic community at St. Jude. Its goal is to enable
silencing by heterochromatin, a specialized researchers to visualize intricate biological
silent chromatin structure. Furthermore, structures at atomic or near-atomic resolution
Dr. Halic’s laboratory uses structural methods and cellular structures in their native context
to understand how heterochromatic proteins with unprecedented detail and clarity.
recognize and modify chromatin to establish The Center is opening avenues to various
this silent state. His long-term goals are applications in basic and translational research
Mario Halic, PhD
to understand the regulation of genome and is expected to have an immediate,
expression by chromatin and discover why substantial impact on drug-discovery and
mutations in chromatin proteins lead to the biomedical research at St. Jude.
Cryo–Electron In cryo-EM, biological samples are
rapidly frozen to the solid state in a
cameras. These detectors have
superior signal-to-noise performance, formation of cancer cells.
Microscopy and manner that prevents dehydration
and ice crystallization. Biomolecules in
making it possible to generate
images with unprecedented clarity
The Cryo-EM/TM Center at St. Jude has
capabilities to perform single-particle cryo-EM
Tomography aqueous solutions are blotted to a thin and extract structural information and cryo-TM. Under the direction of Liang
Tang, PhD, the Center houses a 300-keV
Center
layer and plunged into liquid ethane of the finest detail. These advances
(−182 °C) cooled by liquid nitrogen. have led to a “resolution revolution” Titan Krios transmission electron microscope
Rapid cooling traps the biomolecules in cryo-EM, which is now routinely that features a brilliant, highly coherent
in their native hydrated state, used to generate 3D structures of X-FEG electron source, a cryo-autoloader for
embedded in glass-like vitreous (or biomolecules. This development was automated and contamination-free sample
amorphous) ice. The samples are then recognized with the Nobel Prize in loading, the latest K3 direct electron detector,
transferred to an electron microscope Chemistry in 2017. and a BioQuantum energy filter, all of which
and imaged by electrons near the Cryo-EM is particularly powerful are built onto an ultra-stable platform,
temperature of liquid nitrogen (−196 °C). for studying large macromolecular ensuring maximal performance, throughput,
The recorded images represent 2D complexes. Recently, it was used and resolution. The Krios is equipped with a
projections of the sample and are used to solve the structures of several Volta phase plate, which extends its ability
to reconstruct the 3D architecture of fundamental biomolecules, including to image smaller proteins and perform
the biomolecule through intensive ribosomes and ion channels, and high-resolution cryo-TM. The Center also
computational analyses. Single- human pathogens, such as Zika virus, has a 200-keV Talos Arctica transmission
particle cryo-EM technology has influenza virus, and Ebola virus. These electron microscope equipped with a K3
made remarkable progress in recent discoveries have greatly influenced direct electron detector and a BioQuantum
years due to the development of medicine and public health. A related energy filter and a 120-keV Talos transmission
direct electron detector device technique, electron cryogenic electron microscope for sample screening Liang Tang, PhD
and optimization. In addition, the Center
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