A renowned genome scientist has joined Johns Hopkins University to advance our understanding of how DNA's three-dimensional structure controls which genes turn on or off, potentially unlocking new approaches to treating cancer, developmental disorders, and neurological diseases. Ana Pombo, now the Bloomberg Distinguished Professor of Genome Biology, brings with her a groundbreaking technique called Genome Architecture Mapping, or GAM, that has transformed how researchers visualize and study the intricate folding patterns of chromosomes inside cells.

Why Does the Way DNA Folds Matter So Much?

Human DNA is approximately 6.5 feet long, yet it must fit inside a cell nucleus that is only 10 micrometers in diameter, roughly one-tenth the width of a sheet of paper. This extreme compaction creates a three-dimensional configuration that brings distant regions of the genome into close physical contact. The way DNA folds is not random; it is precisely organized and directly determines how cells function.

Consider two cells in your body: a liver cell and a skin cell contain identical DNA sequences, yet they behave completely differently. The difference lies in how their DNA is folded. Genes require regulatory enhancers, which are control switches located elsewhere along the DNA strand, to turn genes on or off. When the genome folds correctly, these distant switches move closer to their target genes, enabling the interactions that control cellular activity. Incorrect folding can contribute to disease, including cancer and developmental disorders.

"Within the genome, we have not only sequences that encode the building blocks of cells, but we also have many sequences that are instructions for reading the genome itself. Learning how this regulation occurs is important across many fields of the life sciences," explained Ana Pombo.

Ana Pombo, Bloomberg Distinguished Professor of Genome Biology at Johns Hopkins University

What Makes Genome Architecture Mapping Different From Previous Methods?

Pombo developed GAM while at the Max Delbrück Center and Humboldt University of Berlin. The technique works by freezing cell nuclei and cutting them into extremely thin slices. DNA is then extracted from individual nuclear slices and sequenced to identify which genomic regions are present. When this process is repeated many times, patterns emerge showing which parts of the genome sit close to each other in three-dimensional space.

The innovation lies in what GAM can detect. Previous techniques primarily identified two-way interactions between genetic elements. GAM captures far more complex, multi-way interactions between active genes, regulatory regions, and super-enhancers across large genomic distances. This approach has revealed organizational principles and novel genomic interactions that were previously invisible to researchers. Because GAM is rooted in electron microscopy, it preserves the structure of genome organization, allowing for a more holistic understanding of how chromosomes actually fold.

Another advantage is practical: GAM makes it possible to access specific cell types within complex tissues, such as the brain, which contains dozens of different cell types. Researchers can select a particular cell type to study in detail, even with a small sample size, such as a clinical biopsy. This capability opens doors to personalized diagnostics and targeted research.

How Is This Research Being Applied to Human Health?

A significant portion of Pombo's work focuses on how genome organization relates to human health and disease. Disruptions in the three-dimensional configuration of the genome can lead to serious conditions. Many neurodevelopmental disorders are caused by mutations in chromatin enzymes, which result in neurological symptoms such as memory impairment or intellectual disability. Pombo is also investigating how genome structure may hold epigenetic memory of external insults, such as exposure to addictive drugs, with the hope that her research can contribute to novel diagnostics, prognostics, and therapeutics.

Beyond studying the genome itself, Pombo's methods can be applied in other contexts. She currently develops strategies to map the preferred positions of different bacteria species relative to each other in microbiota environments, such as the intestine. This broader applicability suggests that understanding three-dimensional organization principles may unlock insights across multiple biological systems.

Steps to Understanding Pombo's Research Impact

• Genome Structure Analysis: Pombo employs a combination of advanced genomics and imaging techniques, computational biology, and statistical analysis to understand how the physical positioning of genes and their regulatory sequences affects their activity.
• Multi-Way Interaction Detection: Unlike previous methods that detected only two-way interactions, GAM captures complex, multi-way interactions between active genes, regulatory regions, and super-enhancers across large genomic distances.
• Cell-Type Specificity: The technique allows researchers to access and study specific cell types within complex tissues, even from small clinical samples, enabling personalized research approaches.
• Disease Mechanism Understanding: By revealing how genome folding relates to disease, Pombo's work aims to uncover novel diagnostic and therapeutic targets for conditions ranging from cancer to neurodevelopmental disorders.

What Does Pombo's Move to Johns Hopkins Mean for the Field?

At Johns Hopkins, Pombo will be part of the Epigenome Sciences Bloomberg Distinguished Professor cluster, an interdisciplinary group that unites researchers from across the university who share a commitment to understanding the fundamental principles of genome organization and function in eukaryotic organisms. This collaborative environment provides an ideal setting for Pombo to extend her research while working alongside experts in complementary areas.

Pombo holds a BS in Biochemistry from the University of Lisbon and a DPhil in Physiological Sciences from the University of Oxford. Her appointments span the Department of Biology in the Krieger School of Arts and Sciences and the Department of Molecular Biology and Genetics in the School of Medicine, positioning her to influence research and training across multiple disciplines.

"My research interests are rooted in central and basic questions that are important across species, from bacteria to plants to humans. Through my appointment in the Department of Biology, and through the Epigenome Sciences cluster, I will be able to have a much broader scope of where my research can contribute," noted Pombo.

Ana Pombo, Bloomberg Distinguished Professor of Genome Biology at Johns Hopkins University

The arrival of Pombo and her GAM technique at Johns Hopkins signals a shift in how the institution approaches fundamental questions about genome organization. Her work bridges basic science and clinical application, offering researchers new tools to understand disease mechanisms and develop targeted interventions. As genome folding emerges as a critical factor in human health, Pombo's methods and insights are likely to influence how researchers across multiple fields approach questions about cellular function and disease prevention.