Good and evil: endogenous retroviruses and cancer treatment

14 May 2017

We all know that our DNA serves as the cookbook of sorts for every part of our body. All the instructions on how to build our hair, kidneys, and toenails are lined up in neat little strings of A, T, G, and C- the genetic alphabet that makes us who we are. But what turns these genetic “recipes” into life? How are the decisions to be read, translate, and build regulated? Dr Danny Chi Yeu Leung (Innovation Award 2017) is studying the regulatory properties of noncoding DNA.

Of the 3 billion base pairs in the human genome, only two percent of our genome is coding. This means that only two percent of our DNA is directly responsible for the assembling and building of proteins.

The other 98% of our DNA is known as “noncoding DNA”, and this DNA acts as a regulator, telling the body when to read, transcribe into RNA, and translate into proteins. Think of the coding DNA as the recipes in a cookbook, and the noncoding DNA as instructions on when and how to serve the food. There’s no use in knowing how to build proteins if they aren’t synthesised and utilised at the appropriate time and in the appropriate place.

Endogenous Retroviruses

Leung and his lab are investigating the activity of cis-regulatory elements and a less well-understood element of non-coding DNA: endogenous retroviruses (ERV).

ERVs are fragments of viral DNA that have been integrated into our genome. Retroviruses are viruses that attack cells by incorporating their own genetic information into the host’s DNA. Way back in our evolutionary history, rogue retroviruses were able to incorporate themselves into our genome, and today we still carry their genetic information in us.

Little is known about these ancient genetic parasites, which Leung refers to as “the dark matter of the genome”, but it is known that ERVs can play a role in regulating different parts of our genome, and that errors in regulation can often lead to diseases like Cancer.

However, the effects of ERV on our genome are not all negative. Some ERVs are necessary for important cell functions.

In his lab, Leung uses embryonic stem cells as a model. In these cells, the presence of ERVs is necessary for the stem cells to maintain their pluripotency, or ability to differentiate into any of the myriad cells types in the human body.

As genetic invaders, the ERVs are constantly trying to “escape” silencing. That is, get around the block our cells place on the reading and translating of their genetic code.

“It’s an arms race,” says Leung, “they want to multiply and we don’t. Through evolution, some of them have been co-opted to perform normal functions as a way to escape silencing.”

By acting in a way that benefits their hosts (i.e. our cells), ERVs have evolved a trick by which to escape the translational embargo our cells have enforced.

It’s simple evolution in action going on in our cells. Since the ERVs want to escape silencing, they perform a function that our cells want from them. For example, some ERVs give our embryonic cells their most important feature: pluripotency.

The effects the epigenetic changes on cancers like melanoma have been known for decades, but sequencing technologies in the late 20th century were not able to process the huge amounts of data needed for any worthwhile investigation.

Now, using the high-throughput capabilities of Next Generation Sequencing (NGS), Leung is able to look closer at the effects that ERVs can have on regulation.

ERVs are repeated all throughout the genetic code, with the same sequence found copy-pasted into many different loci. This makes them difficult to track and find within the genome. Fortunately, the incredible speed of current sequencing technology has enabled the kind of high-throughput sequencing needed to study these elusive bits of genetic code in a quick, precise and cost effective manner.

ERVs and Cancer

In some instances, the regulatory activity of ERVs can be cancer specific, which opens up possible avenues for treatment.

The regulatory activity of the ERVs acts like a volume knob, with variable effects on cells and their gene expression. Normally, there is no effect, but in cancer cells with damaged epigenetic regulatory mechanisms, the ERVs could be turned on.

With the volume knob cranked all the way up, transcription and translation get out of control, leading to genomic instability that can result in cell death. Leung hopes that with a greater understanding of the regulatory activity of ERVs, cancer treatments could be explored, targeting the regulatory ERVs and causing them to induce the kind of genomic instability that leads to cell death.

The missing piece is an understanding of the mechanisms by which cancer cells keep the ERVs at a “low volume”. If we are able to target that, then the whole process that malignant cells use to keep the ERVs from sending signals that would result in genomic instability and cell death, cancer-specific treatment would be possible.

Some epigenomic treatments for cancer have already been approved by the FDA, which opens up the possibility of getting it more readily available to the public.

Current treatments, however, don’t have the type of specificity that would really set this kind of treatment apart. Chemotherapy works, for example, by just killing everything. It’s a broad stroke attack that leaves patients crippled. What makes potential treatments that target ERVs desirable, is that they could be specifically engineered to target only cancer cells.

Leung stresses that what’s needed now is a better understanding of the basic science.

“We’re understanding more and more about how the epigenome works. As that progresses, the translation into therapy will become even better,” says Leung, “Right now epigenetic therapy is more at the broad strokes level.”

Fortunately, sequencing technology has been advancing at a breakneck pace in recent years, enabling more complex analysis and, in turn, more monumental breakthroughs.

As our understanding of the molecular mechanisms that keep our cells running (both good and bad) sharpen, we are better able to hone our precision attacks on cancer, avoiding the kind of collateral damage caused by current treatments.

Dr Danny Chi Yeu Leung received his BSc. in Genetics from University College London and his MSc. in Molecular Genetics from Imperial College London. He completed his PhD research in the Department of Medical Genetics at the University of British Columbia. Leung carried out his postdoctoral fellowship under Prof Bing Ren at the Ludwig Institute for Cancer Research. Leung is currently an assistant professor in the Division of Life Science at the Hong Kong University of Science and Technology. Leung received a Croucher Innovation Award in 2017.

To view Dr Leung's Croucher profile, please click here.