Insights

Cancer is difficult to treat for two main reasons: therapies must kill cancer cells while sparing healthy tissue, and tumors can evolve resistance over time. Even with progress in treatments, many tumors still do not respond or eventually return

LINE-1 offers a new class of targeted therapy that is complementary to existing treatments. LINE-1 is a virus-like genetic element that is usually silenced in healthy adult tissues but can become active in stressed or diseased cells, including about 40% of cancers

LINE-1 is most active in:

• Gastrointestinal cancers
  • Esophageal
  • Colorectal
  • Stomach
• Lung cancer
• Head and neck cancer
• Uterine cancer
• Ovarian cancer

In cancer cells, LINE-1 can promote survival, resistance to treatment, disease progression and spread. Unlike cancer genes, which typically have two copies in the genome, LINE-1 has about 100 copies that can be reactivated. Until recently, however, it was difficult to identify patients with LINE-1-active tumors or to inhibit LINE-1 effectively and safely

Long ago, before retroviruses such as HIV existed, there were simpler genetic elements called retrotransposons. These are virus-like genetic elements inside DNA of cells. They selfishly spread copies of themselves across the genome. If this happens in eggs or sperm, they can also be passed from parent to child. Today, retrotransposons make up a large part of human DNA

Retroviruses and retrotransposons are linked because both use an enzyme called reverse transcriptase. This enzyme copies RNA into DNA. Over time, retroviruses evolved from ancient retrotransposon-like elements, gaining the ability to move between individuals rather than only within a genome. Even though these enzymes have changed over millions of years, key parts stayed similar because they still do the same job

Some HIV medicines take advantage of this similarity. These medicines are called nucleoside or nucleotide reverse transcriptase inhibitors, or NRTIs. They look similar to normal DNA building blocks. When the enzyme uses one of these molecules by mistake, DNA copying stops too early. In HIV treatment, this helps block the virus from making DNA and inserting it into the cell’s genome. NRTIs are very effective in HIV and can be used by patients for many years

Some NRTIs also inhibit LINE-1, a human retrotransposon that can reactivate in aging and cancer. However, they do not significantly inhibit other enzymes that use DNA building blocks. This makes LINE-1 a possible target for new therapies. But LINE-1 is only one factor in these diseases. L1 Therapeutics was founded to figure out when LINE-1 reactivation matters most, which patients might benefit, and how much blocking LINE-1 can help treat diseases of aging. Scientific advances, better diagnostics and new technology (including AI) are now making this possible

The Galapagos giant tortoise lives on isolated islands near the equator, where the environment has been stable for a long time. With few predators and less pressure to adapt to major environmental change, evolution has favored long life over flexibility. Humans followed a different path. Over millions of years, our ancestors moved into new environments, changed how they lived, changed their diets, developed larger brains, language, and tools. This meant humans faced stronger evolutionary pressure to adapt

One possible contributor to this adaptability are retrotransposons. These ancient virus-like sequences found in our DNA copy themselves to new places in the genome, which can change how genes are controlled. This has helped drive evolution and adaptation. But it also comes at a cost. When retrotransposons become active at the wrong time, they may contribute to disease, including neurodegeneration, rare developmental disorders, and cancer

Retrotransposons and other transposable elements make up about 45% of the human genome. LINE-1 is the only type of retrotransposon that can still copy itself, and sometimes other DNA sequences, to new places in the genome. Humans have about 500,000 LINE-1 copies, although only about 80 to 100 are functional as the other copies have been inactivated by mutations. Giant tortoises also once had active retrotransposons, but all of their copies have been inactive for tens of millions of years. This may be one reason for their unusually long lifespan, and they're not the only long-lived species that shows this pattern...