Small steps lead to enormous success in Hippo pathway discovery
Identifying the Hippo signaling pathway that regulates tissue growth across the animal kingdom began with small steps in a research journey spanning the evolution of science across two continents.
Duojia “DJ” Pan, Ph.D., Chair of Physiology and one of UT Southwestern’s newest National Academy of Sciences members, is also a recent Passano Award Laureate. He won the 2022 Passano Award, an annual prize given to an established U.S. researcher for work expected to lead to clinical applications. Those prestigious scientific distinctions mark more than two decades of work by Dr. Pan to identify and characterize an intracellular pathway now known to govern organ-size control and regeneration. The pathway also plays a role in immunity and the initiation of cancer.
“The development of animal organs is controlled by just a handful of signaling pathways, which are often dysregulated in human anomalies such as birth defects and cancer,” said Eric Olson, Ph.D., Chair of Molecular Biology and a 2012 Passano Laureate. “The Hippo pathway – which controls growth tied to the number of cells generated (hyperplasia) rather than the size of individual cells (hypertrophy) – is now considered one of those canonical mechanisms and included in textbooks,” Dr. Olson said.
“It was a deep honor and very humbling to receive these recognitions. My lab did our foundational work on the Hippo pathway when I was an Assistant Professor at UT Southwestern from 1998 to 2004,” said Dr. Pan, also a Howard Hughes Medical Institute Investigator.
Deep dives into a pathway
How creatures grow their organs to just the right size during development – then keep them in proportion throughout a lifetime – remains a great mystery, one Dr. Pan has spent his career trying to solve.
Many animals like sharks and salamanders can regenerate teeth and tails, respectively. In fact, starfish can regrow a limb and even precisely recreate an entire creature from the severed piece. With the exception of the liver, human organs do not regenerate much.
The Hippo signaling pathway controls tissue growth and organ size. After identifying the pathway, Dr. Pan launched a journey to characterize and understand the various steps in the signaling cascade, publishing three major papers in Cell in 2003, 2005, and 2007 that laid the foundation for the field.
He took the project with him when he moved to Johns Hopkins University School of Medicine in 2004 and back again when he returned to UTSW as Chair and Professor of Physiology in 2016.
Based on investigations initiated at UTSW and published in Cell in 2007, Dr. Pan found that mutations in the Hippo signaling pathway can cause mouse organs to overgrow to five times their normal size and become cancerous. His work showed that the pathway was conserved from insects to mammals.
Driven from an early age
Dr. Pan grew up in China in the 1970s, following the Cultural Revolution. As the country opened to the wider world, scientists were revered, and many parents wanted their children to choose such careers.
“Here in the U.S., you focus on the individual from a very young age,” he said, adding that in China, the desires of the group took precedence.
Those social influences matched young Duojia’s temperament, and he pursued education relentlessly, skipping two grades in elementary school and slowly developing an interest in science.
He studied biochemistry at Peking University in the city now known as Beijing. Despite being at the nation’s top university, undergrads lacked access to laboratory experiences at that time. Luckily, the China-United States Biochemistry Examination and Application (CUSBEA) program selected him for its final cohort, and he arrived for graduate school at the University of California, Los Angeles (UCLA) in August 1989.
Dr. Pan spent that summer adjusting to life in California and deepening his understanding of science.
“In high school and even early college, I had only a very vague idea that being a scientist is cool,” he said.
That aha moment
In graduate school he learned the thrill of discovery.
“It’s when you first put your hands on doing real experiments and learning that you can uncover something that nobody else has seen in all of human history,” he said, still awestruck at the memory.
He became interested in developmental biology, using fruit fly embryos to study gene transcription – the process of copying DNA into RNA in order to instruct the making of proteins that carry out the work of the cell.
In addition to the excitement of experimentation, he was dazzled by scientists he met across a range of disciplines. As a graduate student, Dr. Pan would start his day at the lab and then spend several hours wandering around UCLA’s campus talking to trainees and investigators to learn about their work. He’d return to his home lab in the afternoon and run experiments until midnight.
“I feel that was very unusual behavior for a graduate student. In retrospect, I think that was very important for me to develop,” he said.
Mirroring his conversations, his research was becoming more interdisciplinary. Dr. Pan studied biochemistry as an undergraduate, developmental biology and transcription in grad school, and genetics as a postdoctoral fellow.
Solving new puzzles
Although he was recruited to UTSW on the basis of his postdoctoral work on how cells acquire different identities, Dr. Pan said he decided to go in a different direction upon arrival – switching to study how tissues acquire specific sizes, an area where fewer questions had been answered.
“Science is like solving a puzzle. If I continued my old project, it would be the safest path. I could probably find some missing pieces, but I was not going to have a brand-new puzzle to solve. I decided to work on a new question that I had never touched on as a postdoc: tissue growth control,” he said.
Still using the fruit fly as a model organism, Dr. Pan began to look for mutations related to tissue growth, specifically searching for any genetic variance that made eyes, wings, or other organs larger. This effort led him to isolate mutations with increased cell size (hypertrophy) or increased cell number (hyperplasia). Dr. Pan initially characterized the hypertrophy mutations, which culminated in the discovery of several missing components in the mTOR pathway.
He then took a second risk, switching from studying hypertrophy, which scientists were beginning to associate with the mTOR pathway, in favor of the less studied hyperplasia mutations. “Could such mutations indicate an entirely new signaling pathway? It was a black box and wide open back then,” he said, smiling at the memory of how choosing the less traveled route proved rewarding.
An evolutionary path forward
Since publication of the three landmark studies, the Pan Laboratory has determined that the Hippo pathway also plays important roles in tissue regeneration, polycystic kidney disease, and the body’s immune response to tumors and to infectious diseases.
Dr. Pan’s risk-taking paid off. His close-knit lab continues to open new doors to understanding growth regulation while his wide-ranging outlook makes him a natural leader of Physiology, a department with diverse research interests across the scales of molecules, cells, organs, and systems.
“Physiology draws upon nearly every aspect of modern biology and provides a fertile ground for cross-pollination and for training the next generation of scientists,” he said.