2024 Discovery at UTSW Scientific Report

DISCOVERY @ UTSouthwestern

2024 2

CancerAnswers@Simmons F A L L 2 0 2 0

UTSWMED.ORG/CANCER

Welcome

Contents

By the Numbers

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Howard Hughes Medical Institute Investigators

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members National Academy of Sciences

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members National Academy of Medicine

5,400+ 6,000+ clinical trials annually

research projects annually

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$715m

$285m

500

in research expenditures in FY23

in National Institutes of Health funding in FY23

Nobel Prize recipients since 1985

basic science and translational research labs on campus

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Artificial Intelligence

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Regenerative Medicine Comes of Age

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The Foundations of Precision Medicine

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Translating Biochemical Discoveries to Transform Health

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Personalizing Neuromodulation

Red blood cells’ intricate journey through the vasculature of a mouse as revealed by high-resolution volumetric imaging. on the front/back cover

Photo Credit: Kevin Dean, Ph.D., Assistant Professor, Lyda Hill Department of Bioinformatics

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Updates and Accolades

Letter From Leadership

Drs. Lee, Conaway, and Peterson.

Photo Credit: Mei-Chun Jau/UT Southwestern Medical Center

W

elcome to the first edition of Discovery at

shared by two UT Southwestern experts who are

UT Southwestern, a publication featuring

using an array of strategies, including harnessing

our institution’s latest developments in

stem cells for bone and muscle growth, to develop

basic science and clinical research.

new therapies.

UT Southwestern is renowned for its investigators,

An article on the Dallas Heart Study illustrates

who work across the spectrum of biomedical

how two decades of longitudinal data gathering

research and clinical care to unravel the complexities

helped lay the groundwork for precision medicine.

of human biology. Their research is central to our

Our Biochemistry leadership explains how

mission to promote health and a healthy society that

transformative drug discovery is enabled through

enables individuals to achieve their full potential.

These pages showcase the impactful work emerging from our laboratories and clinical practice.

a collaborative environment in which chemists and biochemists work closely together.

We are inspired by the ingenuity of our faculty,

You will find a report on applications of artificial

postdoctoral fellows, students, and staff who work

intelligence in biomedicine from the perspectives

tirelessly to push the boundaries of what’s known in

of basic researchers and clinical faculty alike. The

their fields. Their collaborative scientific approach is

latest advancements in regenerative medicine are

furthering discovery at UT Southwestern.

Sincerely, W. P. ANDREW LEE, M.D.

JOAN W. CONAWAY, PH.D.

ERIC PETERSON, M.D., M.P.H.

Academic Affairs and Provost,

Dean for Basic Research

Senior Associate Dean

Executive Vice President for

Dean, UT Southwestern Medical School

Vice Provost and

Vice Provost and

for Clinical Research

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Artificial Intelligence

Building a Hub for Clinical Informatics

UT Southwestern’s Clinical Informatics Center is leveraging AI and big data to advance research, patient care, and training.

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“The ultimate decision-maker for AI tools applied in the clinical setting must be a human.”

he widespread adoption of artificial intelligence (AI) and large language model technologies such as ChatGPT and Bard reveal the importance of thoughtful and ethical leadership, research, and education as the technology evolves. Machine learning (ML) and natural language processing continue to drive discovery, care, and health care decision-making in a rapidly evolving, global context.

UT Southwestern established the Clinical Informatics Center in 2019 to develop and implement clinical informatics solutions for health care providers, including AI models, and to train practitioners in the field.

Led by Christoph Lehmann, M.D., Professor of Pediatrics, Bioinformatics, and Public Health, and Associate Dean of Clinical Informatics, the Center has grown to include more than 31 faculty members, who are united by the goal of harnessing the power of informatics, AI, and big data to improve quality, safety, and cost in health care.

Applying Machine Learning Models

Christoph Lehmann, M.D., is Professor of Pediatrics, Bioinformatics, and Public Health, Director of the Clinical Informatics Center, and Associate Dean of Clinical Informatics.

His research focuses on improving clinical information technology and clinical decision support.

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The Center is actively working to integrate ML models into clinical workflows using the appropriate care, ethical considerations, and human oversight. ML models can be applied to a variety of health care datasets, including electronic health records, text databases, pathology slides, imaging and diagnostic tests, genetic information, and many others.

A prime example is the development of a plainlanguage health information text generator that uses a large language model similar to ChatGPT. The project was pioneered by John Hanna, M.D., a Clinical Informatics fellow working in collaboration with Nelly Estefanie Garduno-Rapp, M.D., a graduate student in the Master of Science in Health Informatics program, and Jonathan Reeder, M.D., Assistant Professor of Emergency Medicine and one of the course directors.

With one click, the model takes complex medical writing like a progress note copied into a text field and generates a plain-language summary that can be understood by patients.

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Other examples of models in development at UT Southwestern include a clinical decision support tool designed to predict iron-deficiency anemia as early as three months in advance, a model predicting patients who will benefit from surgery for hyperparathyroidism to reduce the risk of bone fracture, and a model that uses electroencephalogram data to predict early hypoxic ischemic encephalopathy, or oxygen deprivation during birth.

Shaping Priorities for AI Research

While Dr. Lehmann is excited about AI’s increasing role in supporting staff making clinical decisions, he cautions that using such technologies requires a great deal of responsibility and oversight to ensure that they are used ethically.

“Performance of AI models tends to degrade over time. Thus, the ultimate decision-maker for AI tools applied in the clinical setting must be a human,” Dr. Lehmann says.

He notes that many of the ML tools under development are intended to be algorithms that support clinicians in their decision-making, rather than independent actors. One of his ambitions for the Center is to become a national advocate for patients and physicians to help ensure that AI systems entering the market are up to the highest quality and ethical standards.

“We hope to develop measures so that the professionals managing these new tools integrated into daily clinical care know the performance benchmarks they need to reach,” he adds. “This goal includes educating the next generation of engineers and clinicians who will be working with these tools.”

New Frontiers in Education

Ultimately, educating future physicians and trainees is key to expanding access to the best and most innovative AI and big-data tools. As public awareness grows and more programs prioritize education around these technologies, Dr. Lehmann expects that more clinicians and researchers will attempt to incorporate them into their workflows.

UT Southwestern researchers use an AI system to track how cancer cells change from a state of high metastatic potential to low metastatic potential. Photo Credit: Andrew Jamieson, Ph.D., Assistant Professor, Lyda Hill Department of Bioinformatics.

Beyond Human: How AI Is Transforming Basic Science and Clinical Medicine

processes that confer survival and proliferation of malignant cells in the body.

“The notion that morphology by itself controls cellular signaling is new in the context of cancer,” Dr. Danuser says.

His laboratory uses deep learning-based methods to identify the properties of cell shapes that are predictive of complex phenotypes but are too subtle to be identified by the human eye.

In a July 2021 study published in the journal Cell Systems, he and his team put one such method to the test. By employing a generative neural network in combination with supervised machine learning, the researchers classified patient-derived melanoma xenografts with high and low metastatic potential.

The AI system was able to accurately predict which melanoma cell lines were most likely to metastasize.

“We validated a generalizable framework that allows us to take tissue samples and predict mechanisms inside cells that drive disease,” Dr. Danuser says. He anticipates that similar AI-based tools will augment pathology workflows for cancer and a host of other diseases.

AI-Driven Real-Time Localization From uncovering secrets of cellular function to redefining cancer diagnosis and treatment, AI research has widespread applications at UT Southwestern.

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eep learning has been the driving force behind recent advances in artificial intelligence (AI). These algorithms employ multiple layers of interconnected nodes to refine their decision-making capabilities through pattern recognition and modeling complex relationships between inputs and outputs.

Across UT Southwestern, researchers are utilizing deep-learning technology to untangle complex biological processes and improve patient care. Here, Gaudenz Danuser, Ph.D., Professor and Chair of the Lyda Hill Department of Bioinformatics, and Steve Jiang, Ph.D., Professor and Vice Chair for Digital Health and AI in the Department of Radiation Oncology and Director of UT Southwestern’s Medical Artificial Intelligence and Automation Laboratory (MAIA), discuss how AI is advancing their research.

Predicting Metastatic Potential

The Danuser Lab studies the mechanisms by which cell architecture controls cell function, investigating how cell shape and cytoskeletal architecture directly influence the molecular

Gaudenz Danuser, Ph.D., is Professor of Cell Biology, Chair of the Lyda Hill Department of Bioinformatics, and Director of the Cecil H. and Ida Green Center for Systems Biology. He is a member of the Cellular Networks in Cancer Research Program at the Harold C. Simmons Comprehensive Cancer Center.

The MAIA Laboratory is a thriving ecosystem facilitating AI research, clinical translation, education, and commercialization. Dr. Jiang and his colleagues are applying AI technologies to assist clinical decision-making, enable clinical procedure automation, enhance imaging and therapy technologies, and improve patient safety and clinical workflow.

“Among our key initiatives is an AI-powered real-time location system developed by the MAIA Lab,” Dr. Jiang explains. “Clinically implemented since January 2019, this advanced system monitors nearly 1,000 tags daily, which are attached to patients and medical equipment, across two radiation oncology buildings at UT Southwestern through a network of 379 detectors called Raspberry Pis. AI-enabled features like a touchpad checklist and exam-room workflow management not only bolster patient safety and improve patient experience, but also streamline clinical operations.

By identifying bottlenecks and enabling adaptive scheduling, the initiative represents a quantum leap in mitigating clinical inefficiencies through AI.” While AI is transforming basic science and clinical medicine, it doesn’t undermine the importance of the human researchers and clinicians, Drs. Danuser and Jiang explain. “Researchers must remain engaged and use their knowledge and training to apply the art of science. AI is augmenting and improving the efficiency of what we’re already doing today,” they conclude.

Steve Jiang, Ph.D., is Professor of Radiation Oncology, Director of UT Southwestern’s Medical Artificial Intelligence and Automation Laboratory, Vice Chair for Digital Health and AI, and Division Chief of Medical Physics and Engineering. His interests include AI technologies to improve patient care.

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Regenerative Medicine

Regenerative Medicine Comes of Age

Two distinguished UT Southwestern scientists discuss new developments in regenerative medicine.

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egenerative medicine offers the potential to heal or replace tissues damaged by age, disease, or trauma, as well as to cure congenital diseases.

It encompasses numerous strategies – many of which are being employed by UT Southwestern Medical Center scientists, among whom are some of the top researchers in the field.

A prime example is Sean Morrison, Ph.D., founding Director of the Children’s Medical Center Research Institute (CRI) at UT Southwestern, who is leading a team performing innovative research aimed at understanding mechanisms that maintain stem cell function in adult tissues and the ways in which cancer cells hijack these mechanisms to enable tumor formation.

“We study the regulation of stem cell function – and the role that stem cells play in regenerating adult tissues,” Dr. Morrison says. “Our focus is on the bone marrow, where two important types of stem cells are found: hematopoietic and mesenchymal stem cells.”

Focusing In on Stem Cells

Recent research by Dr. Morrison and his colleagues provided new insights into the ability of specialized cells in the bone marrow to regulate hematopoiesis and osteogenesis, including the roles of endothelial cells and leptin receptor-expressing mesenchymal stromal cells.

Dr. Morrison further explains that his laboratory found that leptin receptor-expressing stromal cells serve three crucial functions in stem cell biology.

These cells are the main source of growth factors required for the maintenance of hematopoietic stem cells, serve as precursors to osteoblast cells needed for bone growth, and produce bone-forming growth factors required to maintain skeletal bone mass.

“We recently discovered a new bone-forming growth factor that has the potential to reverse bone loss associated with osteoporosis,” Dr. Morrison says.

The researchers named the new bone-forming growth factor Osteolectin, which is produced by the leptin receptor-expressing cells in the bone marrow. Dr. Morrison and his team at CRI were the first to demonstrate that Osteolectin promotes new bone formation by stimulating the formation of osteoblasts from the leptin receptor expressing skeletal stem cells.

“The identification of Osteolectin is just one example of the highly innovative work at UT Southwestern that is creating new opportunities for tissue regeneration therapies,” he adds.

Heralding Advances in Cardiac Medicine

Akansha Shah, Ph.D., studies the development of the childhood muscle tumor rhabdomyosarcoma and the basis of heart regeneration in newborn mice at the Olson Lab.

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Another prominent UT Southwestern scientist working in regenerative medicine is Eric Olson, Ph.D., Professor and founding Chair of the Department of Molecular Biology and Director of the Hamon Center for Regenerative Science and Medicine. His research seeks to understand how stem cells adopt specific fates and how programs of cell differentiation and morphogenesis are controlled during muscle development.

“We’re working to decipher the genetic networks that direct the formation of muscle tissues during development,” Dr. Olson says.

“We recently discovered a new bone-forming growth factor that has the potential to reverse bone loss associated with osteoporosis.”

“Our current focus is on the development of gene therapies that could provide solutions for treating heart disease where traditional therapies have failed,” Dr. Olson says.

In collaboration with the Christine Seidman, M.D., Lab at Harvard Medical School, Dr. Olson and his team recently showed that CRISPR–Cas9 base editing and prime editing can be harnessed to correct genetic and acquired models of cardiac disease in mice and human cells. Dr. Olson notes that this is an important milestone for the application of gene therapy to treating heart failure.

“Technical proof of concept has now been established for how to treat cardiomyopathies caused by mutations in the MYH7 and the RBM20 genes,” Dr. Olson says. “The first gene therapies for tackling heart failure are making progress toward the clinic.”

Future Directions The Olson Lab is studying how stem cells adopt specific fates and how programs of cell differentiation and morphogenesis are controlled during muscle development. The current focus is the development of gene therapies that could provide solutions for treating heart disease when traditional therapies have failed.

Sean Morrison, Ph.D., is Professor and founding Director of the Children’s Medical Center Research Institute at UT Southwestern and a Howard Hughes Medical Institute Investigator.

His laboratory studies the mechanisms that maintain adult tissues and how cancer cells hijack these mechanisms.

Drs. Morrison and Olson anticipate that many gene correction treatment approaches will eventually be implemented into clinical practice.

However, they note that these approaches are still in the preclinical stage and that much effort is ongoing at UT Southwestern and elsewhere to realize their lifesaving potential.

Eric Olson, Ph.D., is Professor and founding Chair of the Department of Molecular Biology. He directs the Hamon Center for Regenerative Science and Medicine and co-directs the Wellstone Muscular Dystrophy Cooperative Research Center. He studies muscle regeneration.

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The Dallas Heart Study: Laying the Groundwork for Precision Medicine The landmark investigation, now known as the Dallas Hearts and Minds Study, has resulted in 20 years of data and 230 papers in leading journals – but, more importantly, its detailed participant data documented the feasibility of precision medicine worldwide.

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Helen H. Hobbs, M.D., (left) was one of the designers of the Dallas Heart Study, which grew to include Jonathan Cohen, Ph.D., (right) and others as part of the core team.

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While precision medicine is discussed in medical circles across the globe today, the Dallas Heart Study exemplifies UT Southwestern’s early start in the field and ability to anticipate the medical needs of tomorrow.

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f there is a key to biomedical discovery at UT Southwestern it lies in the ability to integrate pioneering basic research with exceptional clinical care. This mindset has made the Medical Center fertile ground for research that recognizes the important ties between genetics, environment, and health. While precision medicine is discussed in medical circles across the globe today, the Dallas Heart Study exemplifies UT Southwestern’s early start in the field and ability to anticipate the medical needs of tomorrow.

At its inception in 2000, the Dallas Heart Study aimed to gather data on the cardiovascular and metabolic risks of the people of Dallas County. Assembling more than 6,000 residents to participate in the Study, the research team collected

THE ROAD TO DISCOVERY

1999

2000

2002 2005

2006

Drs. Victor, Hobbs, and Williams design the Dallas Heart Study as part of a grant application to the Donald W. Reynolds Foundation to gather a cross section of the heart and metabolic health of residents of Dallas County. The team was awarded a $24 million grant in 2000.

The Dallas Heart Study is announced to the citizens of Dallas County by then-mayor Ron Kirk and other city leaders.

Enrollment closes with 6,101 Dallas County residents from ethnically diverse backgrounds registered to participate.

Using data available from the Dallas Heart Study, Drs. Hobbs and Cohen identify mutations in the PCSK9 gene as a genetic driver of low cholesterol, leading to the development of new cholesterollowering drugs that target the protein product of this gene. These therapies are now routinely used in clinics across the world and have been shown to reduce rates of heart attacks and strokes.

Jonathan Cohen, Ph.D., is Professor in the Center for Human Nutrition and in the Eugene McDermott Center for Human Growth and Development.

He studies the genetic basis of metabolic disorders.

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The Dallas Heart Study is expanded to a longitudinal cohort study with additional support from the Donald W. Reynolds Foundation and other donors.

James de Lemos, M.D., is Professor in the Department of Internal Medicine, and Chief of the Division of Cardiology.

He studies cardiovascular biomarkers.

Helen H. Hobbs, M.D., is Professor of Internal Medicine and Molecular Genetics, Director of the Eugene McDermott Center for Human Growth and Development, and a Howard Hughes Medical Institute Investigator.

Dallas Heart Study unprecedented amounts of health information including general health surveys, state-of-the-art imaging data, blood assays, and genetic information with the goal of correlating a person’s genes with yet-unknown markers for disease.

The late hypertension expert Ronald Victor, M.D., Professor of Internal Medicine, R. Sanders Williams, M.D., President Emeritus of Gladstone Institutes, and Helen H. Hobbs, M.D., Professor of Internal Medicine and Molecular Genetics, and Director of the McDermott Center for Human Growth and Development, designed the Dallas Heart Study as part of a grant application to the Donald W. Reynolds Foundation. The core team eventually grew to include cardiologists James de Lemos, M.D.,

Darren McGuire, M.D., and Amit Khera, M.D., geneticist Jonathan Cohen, Ph.D., and molecular biologist Eric Olson, Ph.D. Even though this founding group was an early adopter of the theory that a person’s genetic information could provide clues to their risk of disease and response to therapies, the researchers could not have anticipated the global impact of their endeavor. Information collected through the study has been used worldwide to identify causative genes for heart attacks, liver disease, and mental health disorders.

Now known as the Dallas Hearts and Minds Study, it expanded its focus to include brain health, cognitive function, and memory loss to further our understanding of diseases and potential therapies for people worldwide.

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2018

2020

2022

Dr. de Lemos uses data from the Dallas Heart Study to identify troponin T level as a general indicator for structural heart disease and risk factor for death from any cause. A simple blood test for troponin T is now available for early detection of heart disease, allowing intervention before the disease becomes clinically evident.

PNPLA3 gene variants are identified by Drs. Hobbs and Cohen to be a genetic cause of nonalcoholic fatty liver disease, the most common cause of liver disease in the U.S. The researchers find that obesity can significantly amplify this genetic risk.

The Dallas Heart Study expands its focus to the study of factors associated with heart and brain health with aging, and is renamed the Dallas Hearts and Minds Study.

Researchers plan to measure how risk factors impact healthy aging, or the ability to avoid disease, and maintain good physical and mental function across the life span.

Amil Shah, M.D., an international expert in heart disease research, is recruited from Harvard University to be the new director of the Dallas Hearts and Minds Study.

Amit Khera, M.D., is Professor of Internal Medicine and Director of the Preventive Cardiology Program.

He specializes in cardiac risk assessment and risk factor modifications.

Darren McGuire, M.D., is Professor of Internal Medicine and Director of the Parkland Hospital and Health System Outpatient Cardiology clinics. He studies cardiovascular disease prevention.

Present UT Southwestern researchers continue to gather health information from study participants, making the Dallas Hearts and Minds Study one of the largest and most in-depth longitudinal studies of its kind.

Eric Olson, Ph.D., is Professor and Chair of Molecular Biology and Director of the Hamon Center for Regenerative Science and Medicine. He studies muscle regeneration, muscle development, and disease.

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Collaboration Is Key to Biochemistry Department’s Drug Development Success Thirty years ago, leadership in the Department of Biochemistry set out to build bridges of collaboration and communication between faculty members and to establish and grow five core facilities. Today, discoveries abound.

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Biochemistry post-baccalaureate researcher Alyza Roman works in a campus lab. The synergistic environment that has accelerated drug discovery from the UT Southwestern Department of Biochemistry has also made for rich training grounds.

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Biochemistry

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tartups acquired by major pharmaceutical companies; multiple drug discoveries, including a kidney cancer drug poised for major impact: The results are pouring from the Department of Biochemistry at UT Southwestern Medical Center, where vibrant interdisciplinary research at the crossroads of chemistry and biology is accelerating innovations into the real world.

The synergistic environment supporting these discoveries didn’t happen overnight. It is the culmination of decades of thoughtful planning and guidance by UT Southwestern leaders.

Nearly 30 years ago, Steven McKnight, Ph.D., Professor and then-Chair of the Department of Biochemistry at UT Southwestern, embarked on a mission to build a department that works collaboratively across disciplines to tackle complex scientific problems.

Margaret Phillips, Ph.D., Professor and Chair of the Department of Biochemistry at UT Southwestern, has continued this mission to promote research at the interface of chemistry and

Margaret Phillips, Ph.D., is Chair of the Department of Biochemistry.

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biology, including supporting the Department’s five core facilities, which foster state-of-the-art drug discovery and biology.

Their approaches have been implemented across many basic science departments and graduate programs on campus, which complement efforts in Biochemistry and expand faculty research into other areas, encompassing structural, molecular, and cellular biology.

With the infrastructure for collaboration in place, UT Southwestern chemists and biochemists study human diseases that span cancer, immune diseases, metabolic disorders, and infectious diseases.

Existence and Integration of Five Core Facilities

Dr. McKnight recognized early on that the most successful research groups flourish through collaboration. To achieve maximal benefit, the activities of collaborating groups must be integrated.

With these thoughts in mind, the Biochemistry Department has grown deliberately and strategically, recruiting faculty with complementary research interests and ensuring their access to state-of-the-art core facilities that provide shared services in an integrated fashion.

Appreciating that the personnel, equipment, and workflows are different across the cores, Dr. McKnight knew that trying to impart one way of doing things was not going to work. Instead, he mandated that faculty who direct each core facility talk openly with each other to maximize efficiency and coordination.

Dr. Phillips, who became chair of the department in 2016, emphasizes that this business plan, along with housing the five cores under one roof, have been the driving force behind the translation of multiple discoveries into the clinic.

The high-throughput screening methods used in the early phases of drug discovery are a prime example of this synergy, she explains.

These methods are designed to link biological discoveries with the tools of chemistry to rapidly identify chemical leads – the starting point for drug discovery.

“Our Department’s unique structure enables the translation of scientific discovery from bench to bedside,” Dr. Phillips says. “Our foundation empowers research teams to tackle ever more complex disease-focused questions – ultimately driving innovation.”

“Our Department’s unique structure enables the translation of scientific discovery from bench to bedside.

Our foundation empowers research teams to tackle ever more complex disease-focused questions – ultimately driving innovation.”

A Shared Vision of Translation

In recent years, several discoveries made within the Department have resulted in the clinical investigation and approval of new drugs, most notably belzutifan, which was approved by the U.S. Food and Drug Administration in 2021 for treating von Hippel-Lindau diseaseassociated renal cell carcinoma, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors.

The success of belzutifan grew out of the discovery of a protein, hypoxia-inducible factor 2-alpha (HIF-2α), which is key to the growth of kidney cancer and other types of cancer. HIF-2α was first identified by Dr. McKnight and David Russell, Ph.D., former Vice Provost and Dean of Research, and Professor of Molecular Genetics, who collaborated with Dr. McKnight in the early stages of the research in the 1990s.

HIF-2α was considered undruggable for many years until two scientists then at UT Southwestern – Richard Bruick, Ph.D., Professor of Biochemistry, and Kevin Gardner, Ph.D., Professor of Biophysics, who now directs a structural biology center at the City University of New York – carried out structural and biochemical studies showing that the HIF-2α molecule contains a pocket that makes it druggable.

Subsequently, and making full use of core facilities in the Biochemistry Department, the two scientists identified multiple compounds that fit into this pocket and inhibited the activity of HIF-2α.

Further development efforts were conducted by a spinoff company named Peloton Therapeutics, which was launched on the UT Southwestern campus in 2011 and acquired

by Merck in 2019.

“The history of belzutifan’s development demonstrates the value of cross-disciplinary collaborations at academic medical centers and

how these can translate to new treatments for diseases,” says Joan W. Conaway, Ph.D., Vice Provost and Dean for Basic Research. “It also underscores the value of investing in basic science discoveries to drive advancements in medicine.”

The development and recent acquisition of Rodeo Therapeutics is another example of successful clinical translation. The biotech startup was co-founded in 2017 by Joseph Ready, Ph.D., Professor and Vice Chair of the Department of Biochemistry at UT Southwestern, and was bought

by Amgen in 2021. The company developed small-molecule therapies designed to promote regeneration and repair of multiple tissues.

Dr. Ready explains that Rodeo was focused on identifying first-in-class, orally available modulators of prostaglandin biology. Their lead 15-prostaglandin dehydrogenase (15-PGDH) modulators, again developed through unfettered access to the Department’s core facilities, generated compelling data in extensive preclinical studies that showed clinical potential across multiple indications. As a result, Amgen acquired the company and plans to further evaluate the drugs in clinical trials.

“The scientific groundwork for building Rodeo was laid right here in the Department,” Dr. Ready says. “At the heart of translating novel therapeutics is strong interdisciplinary collaboration between research teams.”

Steven McKnight, Ph.D., is Professor and former Chair of the Department of Biochemistry. His research focuses on transcriptional regulation.

Margaret Phillips, Ph.D., is Professor and Chair of the Department of Biochemistry. Her research focuses on biochemistry and drug discovery in parasitic protozoa.

Joseph Ready, Ph.D., is Professor and Vice Chair of the Department of Biochemistry. His research focuses on natural products synthesis, medicinal chemistry, and synthetic methodology.

Future Directions

The field of biochemistry has made rapid advances in recent decades, fueled by innovations in areas such as structural biology, genomics, and mass spectrometry, which allow for global analyses of cellular proteins and metabolites, and the impact of disease or drugs on the cellular makeup of these key molecules.

Joan W. Conaway, Ph.D., is Vice Provost and Dean for Basic Research.

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Innovation

Personalizing Neuromodulation for Neuropsychiatric Disorders

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euromodulation, or brain stimulation, has emerged as a viable treatment option for neuropsychiatric disease, augmenting existing treatments such as drug-based and psychological therapies. At the Peter O’Donnell Jr. Brain Institute, UT Southwestern researchers are utilizing their knowledge to build infrastructure for personalized neuromodulatory therapies to treat patients with depression, obsessive compulsive disorder, psychosis, and anxiety.

According to William T. Dauer, M.D., the inaugural Director of the Peter O’Donnell Jr. Brain Institute and a Professor of Neurology and Neuroscience at UT Southwestern, the evolution of electrical and magnetic brain stimulation technologies has led to the creation of high-tech stimulation devices and more

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UT Southwestern researchers study the life-changing potential of neuromodulation to personalize neuropsychiatric care.

precise imaging. These advances have opened the door to understanding the complex neural pathways that contribute to neuropsychiatric disease and are helping clinicians target these diseased brain circuits.

A UT Southwestern team of surgeons and researchers is now on the cusp of delivering personalized stimulation treatment, which tailors therapy to an individual’s unique characteristics, including their clinical history, symptoms, brain anatomy, and biology, and living environment.

The O’Donnell Brain Institute has over 7,000 square feet of “dry lab” space dedicated to brain circuitry-related research where physician-scientists, neurosurgeons, bioinformaticians, electrical and biomedical engineers, psychiatrists, and theoretical neuroscientists are working together to advance these interventions.

“We believe that personalizing strategies tailored to the specific brain anatomy of each patient will significantly enhance the success of deep brain stimulation for treatment-resistant depression.”

Evolving Applications

Modern neuromodulatory interventions include both invasive and noninvasive approaches such as deep brain stimulation (DBS) and responsive neurostimulation (RNS), which enable targeting of specific brain structures.

Building on pioneering depth electrode research, DBS was first applied to movement disorders in the late 1990s. Recent work is exploring its utility in conditions such as treatment-resistant depression, obsessive compulsive disorder, schizophrenia, eating disorders, and chronic pain.

Due to recent technological progress, implantable neuromodulation devices are now more precise, reliable, durable, and biocompatible.

Furthermore, substantial leaps in MRI technology, such as diffusion tensor tractography, and optimization of electroencephalogram (EEG) data have yielded a wealth of knowledge about how neuronal circuits operate and interact in these disorders.

By utilizing these technologies, UT Southwestern researchers are examining electrode recordings from patients who have undergone DBS surgery. Moreover, they are noninvasively measuring brain electrical activity through EEG, working to decipher how different amplitudes, frequencies, bandwidths, and polarities of brain waves affect the excitation of nerves.

Pilot Studies Test Efficacy in Treatment-Resistant Depression

Under the direction of Nader Pouratian, M.D., Ph.D., Professor and Chair of the Department of Neurological Surgery, UT Southwestern researchers are leading two clinical trials exploring the utility of DBS in treatment-resistant depression.

The first (NCT03952962) is utilizing MRI tractography to determine the most effective treatment site within an area of the brain termed the subcallosal cingulate (SCC) for stimulation.

The trial is enrolling 12 patients and is designed

to identify personalized targets to guide neuromodulation programming and therapy. “We believe that personalizing strategies tailored to the specific brain anatomy of each patient will significantly enhance the success of DBS for treatment-resistant depression,” Dr. Pouratian says.

The second study (NCT03437928) is examining the simultaneous stimulation of two regions of the brain: the ventral capsule/ ventral striatum and the SCC. Since each target area connects to different parts of the depression network, the trial will examine the effects of separate or combined stimulation in a cohort of six patients.

“This trial is unique because the team will implant temporary recording electrodes to map the biosignatures of depression to both improve treatment and learn more about how depression affects brain circuits,” Dr. Pouratian explains.

Pathway to Clinical Care

At present, an array of neuromodulatory treatments – both invasive and noninvasive alike – are under investigation for use in neuropsychiatric conditions. “The enduring interest in techniques such as DBS speaks to their potential as a treatment with longer-term impact,” Dr. Pouratian says. “DBS also has the ability to target deeper brain areas that are largely inaccessible to noninvasive methods.”

Though the O’Donnell Brain Institute’s umbrella of research spans from basic to translational science, neuromodulation is particularly beneficial in that it caters to the patient’s urgent clinical needs.

“My basic science colleagues are doing important work to understand the pathophysiology of depression, while my clinically based colleagues are eager to explore the neuromodulatory options newly becoming available to help patients forge healthy paths forward,” Dr. Dauer says. “It’s an exciting time to be working in this field.”

William T. Dauer, M.D., is Professor of Neurology and Neuroscience and the inaugural Director of the Peter O’Donnell Jr. Brain Institute.

His research focuses on the molecular basis of dystonia and mechanisms of neurodegeneration in Parkinson’s disease.

Nader Pouratian, M.D., Ph.D., is Professor and Chair of the Department of Neurological Surgery.

His research focuses on developing brainmapping techniques to improve the precision and targeting of neurosurgical procedures.

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Updates + Accolades

A New Era of Collaboration in Biomedical Engineering

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he recently opened Texas Instruments Biomedical Engineering and Sciences Building catalyzes a unique partnership between UT Southwestern Medical Center and UT Dallas, bringing their biomedical engineering programs together to foster innovative solutions for unmet medical needs.

The 150,000-square-foot building, located on the East Campus of UT Southwestern, also houses the Biodesign Center, which includes a large assembly/design studio, a metal fabrication shop, and rooms for 3D printing.

“Faculty members from the two institutions will create a collaborative research model that unites investigators with the complementary expertise and skill sets needed to improve human health and unravel the underpinnings of biological processes through technological innovations,” says Samuel Achilefu, Ph.D., Professor and inaugural Chair of the Department of Biomedical Engineering.

Nationally recognized for his expertise in molecular imaging, Dr. Achilefu is forging ambitious multidisciplinary partnerships, positioning the Department – established in 2021 – as a hub for innovation globally.

“Our goal is to create an exciting and collaborative environment for researchers, teachers, and trainees – and we have gotten off to a great start,” Dr. Achilefu says.

Catherine Spong, M.D., elected to National Academy of Medicine

Samuel Achilefu, Ph.D., is Professor and inaugural Chair of the Department of Biomedical Engineering. He is also Professor in the Harold C. Simmons Comprehensive Cancer Center and the Department of Radiology. His research interests include imageguided cancer surgery, portable imaging devices, and nanotechnology.

Pew Charitable Trust Recognizes Promising Faculty

Two UT Southwestern early-career investigators, Gerta Hoxhaj, Ph.D. (left), and Yuuki Obata, Ph.D. (right), were selected for Pew Charitable Trusts biomedical research fellowship programs in recognition of their work and service to the scientific community. Both will receive $300,000 in funding over four years.

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Dr. Hoxhaj, Assistant Professor at the Children’s Medical Center Research Institute at UT Southwestern and of Pediatrics and Biochemistry, studies how cellular metabolism is reprogrammed in cancer. She was selected as a Pew-Stewart Scholar for Cancer Research because of the potential impact of her work.

Dr. Obata, Assistant Professor of Immunology and Neuroscience, studies how the circadian clock in gut nerves regulates immunity and behavior. He was selected as a 2023 Pew Scholar in the Biomedical Sciences and is one of five new Pew Scholars who will make up the eighth class of the Kathryn W. Davis Aging Brain Scholars.

Catherine Spong, M.D., Chair and Professor of Obstetrics and Gynecology, has been elected to the National Academy of Medicine in recognition of her contributions to the field of maternal-fetal medicine, her leadership in women’s health research, and her dedication to advancing health care for mothers and babies.

Dr. Spong has contributed to multiple landmark clinical trials in obstetrics, gynecology, and fetal surgery that have defined the standard of care in the fields of maternal and fetal medicine and best practices in obstetrics and gynecology. She also has served as a staunch advocate for improving inclusion of pregnant and lactating women in vital clinical research.

Her major research interests include the developing fetus, improving the understanding of stillbirth, fetal surgery for myelomeningocele, Zika in pregnancy, and the human placenta.

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Updates + Accolades

School of Public Health Addresses Pressing Health Needs

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he O’Donnell School of Public Health (OSPH) strives to address the nation’s and the world’s most pressing public health problems through creative cross-disciplinary research and a focus on effecting change.

Approved by the UT System Board of Regents, endorsed by the Texas Legislature, and supported by a

transformative $100 million gift from the O’Donnell Foundation, the OSPH is the fourth school to be created in the UT Southwestern Medical Center, and the first in the past half-century. It ties together the foundational research expertise and experience of UT Southwestern’s Medical School, School of Health Professions, and Graduate School of Biomedical Sciences.

OSPH welcomed its inaugural class of M.D./M.P.H. and Master of Public Health students in 2023 and will launch doctoral degree programs in 2024.

“Our programs address some of society’s most challenging problems, which affect communities in North Texas and beyond,” says internationally recognized epidemiologist Saad B. Omer, M.B.B.S., M.P.H., Ph.D., Professor and founding Dean of the O’Donnell School of Public Health. “Our ultimate goal is to influence public health policy and clinical practice.”

Saad B. Omer, M.B.B.S., M.P.H., Ph.D., is the founding Dean of the O’Donnell School of Public Health. He is an internationally recognized epidemiologist and policy adviser whose work has positively impacted communities around the world. His research has been cited in global and country-specific public health policy, practices, and legislation.

Molecular Geneticist, Physiologist Elected to National Academy of Sciences Two UT Southwestern researchers – Russell DeBose-Boyd, Ph.D. (left), and Duojia Pan, Ph.D. (right), were elected to the National Academy of Sciences (NAS) in recognition of their scientific discoveries.

Election to the NAS is one of the greatest honors a scientist can receive.

Dr. DeBose-Boyd, Professor of Molecular Genetics, discovered the biochemical pathway by which sterol and nonsterol isoprenoids combine to regulate the degradation of HMG-CoA reductase, a basic cellular mechanism that informs the prevention and treatment of heart disease.

Dr. Pan, Professor and Chair of Physiology, and a Howard Hughes Medical Institute Investigator, identified the “Hippo” signaling pathway, which plays important roles in the determination of organ size, tissue regeneration, and tumorigenesis.

With their elections, UT Southwestern now has 26 faculty who are members of the NAS, surpassing all other institutions in Texas.

Physician-scientist Receives White House Moonshot Cancer Scholar Award Todd Aguilera, M.D., Ph.D., Assistant Professor of Radiation Oncology and a member of UT Southwestern’s Experimental Therapeutics Program in the Harold C. Simmons Comprehensive Cancer Center, has been named one of 11 inaugural Cancer Moonshot Scholars

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as part of the Unity Agenda sponsored by President Biden and the National Institutes of Health.

Dr. Aguilera, a radiation oncologist with expertise in molecular engineering, molecular imaging, and tumor immunology, will receive nearly $3.3 million from the National

Cancer Institute over five years to fund research seeking new treatments for rectal cancer.

The Cancer Moonshot program recognizes emerging leaders in cancer research and innovation. Launched in 2016, the national program aims to cut the cancer mortality rate in half in 25 years.

Todd Aguilera, M.D., Ph.D.

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