In our latest episode of Lexicon, we sat down with Dr. Liam Holt, associate professor at NYU Langone Health, to discuss one of the most enigmatic parts of the human genome, LINE-1.

When scientists first cracked the human genome, they expected to find treasure such as genes that would explain life, health, and disease. Instead, they discovered that only about 1% of our DNA codes for proteins. The rest? Largely dismissed as “junk.”

But, it turns out, so-called junk holds secrets that could change how we understand cancer, aging, and even human evolution. Let’s find out how.

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What is LINE-1?

“There are half a million LINE-1 elements in your genome—compared to just 20,000 human genes,” Holt told us. “For every one gene, there are 20 LINE-1s. We are more LINE-1 than gene,” he added.

LINE-1, or Long Interspersed Nuclear Element-1, is a retrotransposon, or a segment of DNA that copies and pastes itself throughout the genome. Unlike viruses that infect us from the outside, LINE-1 has co-evolved within us for millions of years, passing from parent to child, generation to generation.

“They’ve been called selfish DNA,” Holt explains. “They replicate themselves and expand their number over evolutionary time. For a long time, people thought they were just like viruses—parasitic passengers with no real function,” he added.

But that view has changed. Researchers now believe LINE-1 may be both a genomic threat and a crucial evolutionary force.

From genetic junk to evolutionary driver

Despite their chaotic tendencies, LINE-1 elements have made significant contributions to reshaping the human genome.

“They’ve done really interesting things to create evolutionary change,” says Holt. One example: the loss of tails in apes.

“One of these elements (or something like it) jumped into a gene and disrupted it. That disruption appears to have helped early apes lose their tails. That’s evolutionary impact in real time,” he added.

This capacity to cause significant changes rapidly may help explain sudden evolutionary leaps, a concept popularized by thinkers such as Richard Dawkins. “LINE-1 is one mechanism by which you can get big changes,” Holt explained.

But the same mechanisms that can transform species can also destabilize individuals, sometimes with devastating consequences.

When LINE-1 turns against you

LINE-1’s ability to jump around the genome poses a constant threat to genetic stability. Fortunately, our cells have developed a suite of defenses to keep it in check.

“There’s a huge amount of cellular machinery dedicated to silencing these elements,” Holt explains. “Only about 100 LINE-1s in your genome are even capable of being active. And most of those are being repressed by default,” he added.

But when that repression system breaks down (as it does in cancer), the consequences can be dire.

“In cancer, that machinery tends to fail,” Holt says. “You get a big increase in the expression of these elements. That might cause the cancer cells to mutate more rapidly and progress more quickly,” he added.

In fact, some researchers are investigating whether LINE-1 can serve as a biomarker for cancer, i.e., a genomic marker for early detection.

The role of LINE-1 in aging and inflammation

LINE-1 also appears to play a crucial role in aging, especially by triggering the body’s inflammatory responses.

“A huge thing that is strongly associated with aging is inflammation,” Holt explains. “And LINE-1 is being considered as a driver of that inflammation,” he added.

As we age, our ability to repress LINE-1 activity diminishes. When LINE-1 elements activate, they mimic viral infections, producing RNA-DNA hybrids that our immune system mistakenly identifies as invaders.

“The immune system sees that as a threat and turns on an inflammatory response,” Holt says. “That inflammation can damage tissues over time—and that’s what we see in aging and in diseases like arthritis and neurodegeneration,” he explained.

This process may also be linked to motor neuron disease, including ALS. Holt references the work of his colleague, Molly Gale Hammell, who found elevated LINE-1 activity in certain subtypes of the disease.

Can we silence the rogue element?

Given its connection to cancer, inflammation, and aging, scientists are investigating methods to silence LINE-1, or at least reduce its activity.

“Most efforts are along the lines of silencing its activity,” Holt says. One promising approach involves repurposing reverse transcriptase inhibitors, a class of drugs originally developed to treat HIV.

“LINE-1 relies on the same RNA-to-DNA copying mechanism that retroviruses do,” Holt explains. “And drugs that block that process in HIV may also block LINE-1 replication,” he added.

However, there’s a catch: telomerase, the enzyme that maintains the ends of our chromosomes (telomeres), also uses reverse transcriptase. Targeting LINE-1 without harming telomerase is a tricky balancing act.

“If you turn off LINE-1 to prevent aging, you might accelerate aging by degrading your telomeres,” Holt cautions.

Genetic glue and cancer progression

In Holt’s most recent research, his team uncovered a new mechanism by which LINE-1 may cause cellular chaos. The key player? A protein called ORF1, produced by the LINE-1 element itself.

“ORF1 forms a sort of sticky protein cluster that wraps around LINE-1’s RNA. It looks like glue—and it can literally stick two chromosomes together,” says Holt.

“When a cell tries to divide, it pulls those chromosomes apart. But if they’re stuck together, you get missegregation, chromosomal errors—and that could drive cancer progression,” he added.

This idea that LINE-1’s own machinery may physically disrupt chromosome separation offers a new way to understand genome instability in cancer cells.

The evolutionary trade-off

So why does LINE-1 persist? Why didn’t evolution eliminate it?

“It’s an occupational hazard of being a species that evolves,” Holt says. “Evolution needs LINE-1 for long-term change—but when it hits you in the short term, it’s usually not great,” he added.

In other words, LINE-1 is a genetic gamble. It fuels innovation but sometimes breaks the system.

“It’s like throwing spanners at your car hoping to improve it,” Holt jokes. “Most of the time, it’s not going to work. But once in a while, something sticks,” he added.