Northwestern Medicine scientists have discovered new details about how the human genome produces instructions for creating proteins and cells, the building blocks of life, according to a pioneering new study published in Science Advances.
While it’s understood that genes function as a set of instructions for creating RNA, and thus proteins and cells, the fundamental process by which this occurs has not been well-studied due to technological limitations, said Vadim Backman, PhD, the Sachs Family Professor of Biomedical Engineering and Medicine, who was senior author of the study.
“It is still not fully understood how, despite having the same set of genes, cells turn into neurons, bones, skin, heart, or roughly 200 other kinds of cells, and then exhibit stable cellular behavior over a human lifespan which can last for more than a century – or why aging degrades this process,” said Backman, who directs the Center for Physical Genomics and Engineering at Northwestern. “This has been a long-standing open question in biology.”
Igal Szleifer, PhD, professor of Medicine in the Division of Pulmonary and Critical Care, and Luay Almassalha, MD, PhD, a fellow in gastroenterology and hepatology, were co-authors of the study.
In the study, investigators utilized nanoscale imaging and sensing technologies along with modeling techniques developed at Northwestern to individually label and observe chromatin fibers: the bundle of DNA and proteins that form chromosomes within the nucleus of cells.
The scientists observed that chromatin self-organizes into “packing domains” – distinct, compact regions of molecular structures that play a crucial role in regulating gene expression.
“In the nucleus of each cell, the genome is folded in such a way as to form thousands of tiny nanoscale ‘packing domains,’ the three-dimensional structure of which creates ‘memories’ of transcription and which, amazingly, operates as a powerful geometric computational device – just like the reinforcement learning that powers neural networks in AI tools like ChatGPT and the behavior of cells in our brains,” said Backman, who is also Associate Director for Engineering and Technology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
The findings show that cells use transcriptional memories to establish predictable, stable behaviors within tissues, Backman said. These genetic memories can degrade over time, resulting in a wide array of diseases associated with aging, including autoimmune disorders, cancer, Alzheimer’s and atherosclerosis.
“The discovery of how transcriptional memories are encoded potentially explains how and where to reverse these processes and could lead to entirely new kinds of therapies targeting cancer, enhancing tissue regeneration, and promoting longevity by developing strategies to preserve or even reprogram these transcriptional memories,” Backman said.
“Even just focusing on cancers alone, this has significant implications,” Almassalha said.
Previously, Backman had found that in every type of cancer, chromatin packing domains are disrupted. Understanding the rules of this geometric system gives investigators insight into why cancers form and how they can rapidly evade treatments.
“Unlike mutations, domains can both be used to store information for decades and be transformed in minutes, so cancer cells have an ‘extra gear’ that our other cells just can’t match,” Almassalha said. “We can now design therapies to slow down the calculations in cancer cells while speeding up the calculations immune cells can do – potentially leveling the playing field.”
On the heels of this discovery, Backman and his collaborators will begin work to translate the findings into practical applications for health and disease and explore the development of powerful new computational techniques designed on the principles of geometric genomic calculation.
“The findings could also inspire efforts in synthetic biology, potentially enabling the design of artificial organisms with custom-built transcriptional memories,” Backman said.
The Center for Physical Genomics and Engineering will also explore whether similar structures and processes exist in other complex organisms such as plants or fungi and study the evolutionary implications.
“This may provide insights into the evolution of species over millions of years as genome geometries became more complex and computationally powerful,” Vadim said.
The study was supported by National Science Foundation grants EFMA-1830961, EFMA-1830969, ECCS-2025633 and DMR-2308691 and by National Institutes of Health grants R01CA228272, U54 CA268084 and U54 CA261694.
About the Center for Physical Genomics and Engineering
Launched in 2019, the Center for Physical Genomics and Engineering at Northwestern aims to develop new super-resolution microscopy, modeling and genome mapping technologies with the goal of understanding the fundamental relationship between genome structure, gene expression, and organismal phenotype and behavior. By bringing together multidisciplinary experts and developing new technologies, the center studies physical genomics and its impact in human health, disease and longevity.
