When much of our DNA isn’t our own, how are scientists reclaiming hidden elements of the genome?
As a new group leader in the year 2005, George Kassiotis was studying immune responses to viruses in the lab.
Examining immune cell activity in mice, he observed that some mice were building an immune response to more than just the live virus. Now head of the Crick’s Retroviral Immunology Lab, his scientific career to date has been focused on finding and harnessing the forgotten triggers of immunity – viral DNA left behind by the infections of our ancestors.
The relationship between virus and host is ancient. The retroviruses that infected our ancestors inserted copies of viral DNA into the genome and these sequences were copied to allow for the viruses to replicate. This viral DNA has been passed down through generations and now the human genome is littered with hundreds of thousands of integrations of endogenous retroviruses (ERVs), amassed over millions of years. They are part of the so-called ‘dark genome’, sections of DNA that also includes other diverse and often larger families of transposable elements. Collectively they make up around half of the human genome but are not well annotated or understood.
"Recombinases derived from these retroviral elements are naturally evolved gene editing tools," says George. "They give our immune system the ability to adapt to novel challenges, producing many billions of different T-cell and B-cell receptors. And our ability to give birth to live young is thanks to the role of ERV-derived genes in the evolution of the placenta. Even the fact that we don’t have a tail any more is because of viral interruption in the responsible gene."
It’s hard to build a complete picture of the scale and impact of ERVs and other transposable elements because they have co-evolved with humans over so many years. Initially, viruses would have been kept in check by epigenetic repression, stopping the viral RNA being expressed. And over time, the viral DNA sequences would be subject to the usual mutations and deletions, rendering them harmless and unrecognisable from ‘self’ by the body, at least most of the time.
In some cells, including cancer cells, researchers have observed immune responses to these endogenous retroviruses. This is because, in cancer, the body effectively loses control of much of the genome, including these repetitive viral elements. This means that formerly repressed DNA sequences are transcribed, sparking excitement about the potential of the newly expressed proteins as targets for cancer immunotherapies.
"The advantage of targeting endogenous retroviruses is the antigens they express are only awakened in diseased cells, so there’s less risk of autoimmune side effects. And these viral elements are shared across humans, meaning the treatments don’t need to be tailored to an individual patient."
Since moving his lab to the Crick, George and his team have been focussed on identifying retroviral antigens uniquely associated with cancer, using predictive models to find the novel RNA and protein sequences that are produced when transposable elements are reactivated in cancer. It’s a task that requires a huge amount of bioinformatic expertise and computing power to tackle the data – George has estimated that the first iteration of their search for cancer-specific endogenous retroviral sequences would take 24 years on an average desktop. But thankfully, George and team have been able to exploit the Crick’s advanced computational capacity and they quickly developed a screening pipeline.
Their early work in this field attracted the interest of investors and in 2019, George co-founded Enara with the support of the Crick’s Translation team. The company name is appropriately derived from an Arabic word that means ‘illumination’, bringing light to what was once the ‘dark genome’. Enara continues to grow with $32.5 million in Series B financing to advance its pipeline of TCR-based immunotherapies against novel Dark Antigen targets for solid tumours. And George’s lab continues to collaborate with the company.
“Enara are leading the way on identifying antigen targets across multiple types of cancer, providing the most promising targets for treatment,” says George. "My lab is now working on identifying and cloning the T cell receptors that recognise these antigens, so that we can create possible T-cell therapies, in addition to cancer vaccines.”
The lab team are also interested in whether ERVs can help overcome a major problem associated with most cancer treatments, which is that in some people over time, they simply stop working. “Cancer is a constantly evolving disease,” adds George. "Tumours adapt to their environment and can become resistant to treatment by evolving new ways to evade the immune system. In order to overcome this hurdle, we need to get ahead of it.”
Researchers in the US have shown that transposable elements overexpressed in cancers are detectable in the blood, suggesting they could be used to develop early tests for many types of cancer. And George’s team are interested in looking for the predictable epigenetic changes in cancer, which parts of the genome have been newly derepressed. They hope that spotting the earliest signs of cancer development could open the doors to preventative therapies.
“Preventing cancer by targeting a virus is not a new idea, says George. “The HPV vaccine has massively reduced instances of cervical cancer. The idea would be to see if targeting an ERV that is associated with cancer, even if it doesn’t cause it, can be safe and effective in preventing cancer development. But there’s a long way to go to understand how this would work.”
The lab team is now looking at antibody responses in people with and without cancer through a series of observational studies. They want to better understand where, when and why a response is triggered – is there a signature associated with the body’s natural response to ERVs and can it be exploited?
If there’s a lot of work to do, there are now more researchers than ever interested in illuminating the dark genome. But George describes his early research endeavours in this field as quite isolated. “Historically there’s been a fair amount of scepticism about the potential of exploiting the link between cancer and viral infection. Recent technological advances have completely transformed our understanding of these parasitic elements hiding in the genome, and have enabled us to grow a larger global network of researchers and tackle this challenge together, bringing the dark genome closer to the limelight.”
