A vast uncharted territory
For decades, drug discovery has focused on modulating proteins or the genetic instructions that encode those proteins — targets that collectively account for just 2% of the human genome.
It’s past time to explore the rest. At ROME, we are illuminating the “repeatome,” the 60% of our genome that consists of repetitive sequences of nucleic acids, known as repeats.
These repeats have long been dismissed as “junk DNA.” We disagree.
We believe that medicines targeting the repeatome will revolutionize the way we treat cancer and debilitating autoimmune diseases, enabling patients to live long and productive lives.
A peek inside the repeatome
The repeatome is a vast uncharted landscape of DNA that connects the entire genome. The repeats themselves consist of many different families, including small simple sequence repeats, large arrays of tandem repeats in the center and ends of chromosomes (satellite and telomere DNA) and complex mobile repeats that can transpose to different locations in the genome (SINEs, LINEs and HERVs).
On the surface, this landscape appears unimportant, but it contains a complex ecosystem of repeat families that can alter the very structure of our chromosomes. They can expand, contract and rearrange our genes to change the behavior of individual cells.
The origins of this rich ecosystem, activated in times of stress and in specific diseases such as cancer, can be traced back to particular moments in our evolutionary and developmental history.
Infographic adapted from the-scientist.com
From ancient hitchhikers to modern guardians
Many repeat sequences are derived from ancient retroviruses that integrated into the human genome throughout evolution. Over hundreds of millions of years, these sequences have become an integral part of what makes us human.
Just as dark matter in the universe is essential for galaxy formation, the “dark genome” — the repeatome — plays an important role in early embryonic development. The system then deactivates. In healthy people, the repeats remain dormant. However, under the stress of disease onset, the DNA repeats “switch on” and are transcribed into RNA.
This activation sets off alarm bells in the body. The repeats are perceived as foreign invaders and can switch on the innate immune system, signaling the body to remove damaged cells and thereby quiet the repeats. In this way, repeats serve as guardians; they sound an alarm at the emergence of disease and draw the body’s natural immune defense mechanisms into the fray.
Repeats: A powerful force
Long-dormant repeats can activate when the cell is under stress, such as during cancer. At first, that can be helpful.
As a cell transforms from healthy to malignant, the DNA repeats within the genome switch on and are transcribed into RNA.
As they do, they generate strands of RNA that look very much like virus RNA.
This surge in viral-like RNA can act like an alarm bell, switching on the innate immune system…
… and leading to an immune response that can cause the cancer cell’s death either directly or indirectly by signaling immune cells to attack.
But too often, cancer cells find a way to survive. They manage to neutralize the powerful force of the repeats in their own defense.
To stop the repeats from harming it, a cancer cell can adapt by turning on pathways that shield themselves from repeats to mute the alarm bell.
Switching off the alarm helps cancer cells evade the immune system. The tumor infiltrating lymphocytes cease their attack. The cancer grows and spreads.
Integrating the repeat DNA back into the genome leads to mutations and structural changes in chromosomes that can give growth advantages to the cancer cell. These changes lead to more aggressive cancers than can spread to distant sites.
At ROME, we are developing medicines that intervene in this process. We will strip cancer cells of their powerful survival mechanisms.
We will bring new hope to patients with intractable disease.
Long-dormant repeats can activate when the cell is under stress, such as during cancer. At first, that can be helpful.
Advancing a new frontier
This is a new frontier of biology and there is still much to learn, but already we have made tremendous strides. We know how to switch off the viral-like mechanism that gives cancer cells an unfair survival advantage. We have identified promising targets for intervention.
We have the team and the tools we need. And we have the motivation.
We will bring powerful new treatments for cancer and autoimmune diseases to the patients who need them most.
Explore the scientific literature
It’s only in the last decade or so that scientists have had the tools to shine light upon the “dark genome.” This research has uncovered the role repeats play in human disease and suggested a path forward for drug discovery that leverages the repeatome.
Here are some of the scientific papers that informed and inspired us when we first began to explore this field. We have since added our own insights and expertise, which you can view in the Publications & Presentations section of our News page.