Artem Babaian is a PhD candidate in the laboratory of Dr. Dixie Mager at the BC Cancer Agency. When he’s not exploring mountains, Artem studies endogenous retroviruses as a contributor to Hodgkin’s Lymphoma. We sat down with Artem to discuss his research and where he plans to take it in the future.
What have you been studying throughout your time as a PhD student?
About eight percent of our genome is made up of endogenous retroviruses (ERVs), which are viruses that infected us long ago and then amplified throughout our genome. While these ERVs are no longer active (meaning that they’ve lost their ability to mobilize), they can retain their regulatory function, especially in the promoters. We have somewhere in the ballpark of 600,000 of these promoters dispersed across our genome, and fortunately they’re normally epigenetically silenced.
The paper that got me really interested in the idea behind my project was one published by Lamprecht, et al. in 2010. The authors showed that one of these ERV promoters was reactivated in Hodgkin’s lymphoma, driving the overexpression of a nearby oncogene, CSF1R. Everyone has this particular promoter, even chimps, but in Hodgkin’s Lymphoma it’s exploited to allow for CSF1R, which is normally only expressed in the myeloid lineages, to be expressed in B cells. In other words, the gene finds a way to be transcribed by using this alternative promoter from junk DNA. It’s really the birth of a new gene regulatory unit.
As soon as I heard the idea that these ERV promoters can be exploited in this way, I realized that this likely happens all the time. And that’s what I’ve been studying ever since. I’m trying to figure out just how widespread of a phenomenon this is, and how it affects the whole transcriptome.
How did you go about answering this question?
The invention of RNA-seq really potentiated this project. Because that first oncogene was discovered in Hodgkin’s Lymphoma, we decided to focus on the same cancer. Dr. Christian Steidl at the BC Cancer Agency is Canada’s expert on Hodgkin’s Lymphoma, and he had RNA-seq data from a dozen Hodgkin’s Lymphoma cell lines that he was willing to share with us. This was incredibly helpful, because whenever we found an ERV promoter activating an oncogene in the RNA-seq data, we could go right back to the cell line and confirm it.
How many of these oncogenes have you identified?
Molecularly we’ve probably identified on the order of 20‒30 of these genes, but for a lot of them the oncogenic potential is still a bit up in the air. There have been other groups that have either knowingly or unknowingly shown the same thing. For example, several groups showed that SLCO1B3 has an alternative promoter that is important in colorectal cancer. But in a recent review in which we explore these oncogenes, we were then able to point out that the cancerous SLCO1B3 promoter is actually an ERV.
Could identification of these reactivated ERVs have any therapeutic benefit for Hodgkin’s Lymphoma?
Yes. The cancer cells in Hodgkin’s Lymphoma are super rare – they usually make up only 1‒2% of cells in a biopsy. Furthermore, antibodies against CSF1R, which is a prognostically important oncogene in Hodgkin’s Lymphoma, are notoriously unreliable. Plus there’s an isoform of CSF1R that doesn’t express its extracellular domain, making that antibody useless. On top of that, the protein is also often glycosylated, masking the epitope. For all these reasons Hodgkin’s Lymphoma is difficult to diagnose by immunohistochemistry.
Fortunately, it’s much easier to spot CSF1R at the transcriptional level, and one of my projects has been to use specific transcription from ERV promoters, like CSF1R, as biomarkers for Hodgkin’s Lymphoma. We’re using a new technology called NanoString, which uses probes to hybridize to mRNA directly to give you ultra-sensitive (single molecule) resolution. This means the ERV-oncogene panel I designed can quantify oncogenes in the Hodgkin’s cells, while the mRNA in 99% of the bulk cells is ignored.
This allows you to take a bulk biopsy sample, perform an RNA extraction, and quantify a specific isoform from the rare cells expressing it. It could be very important prognostically, and allow physicians to identify which patients would benefit from drugs specifically targeting the oncogene.
Now that you’re approaching the end of your graduate studies, you must be thinking about the research you’d like to explore during your postdoc. Any thoughts on what’s next?
Yes. I’m really interested in the idea of epigenetic evolution in cancer. If you have epigenetic variation in a population of cells, then if there’s any benefit to turning on an ERV promoter epigenetically, those epigenetic marks should be selected for. So in cancer biology, evolution can act at the epigenetic level. This hasn’t been proven rigorously, but if you accept it, then an ERV promoter that is specifically activated at a very high frequency in certain cancers can act as a marker for the oncogenes it regulates. The recurrence occurs because of selection.
I’d really like to pursue this epigenetic evolution idea. There are many labs I could postdoc in where I could set up the project, but epigenetic evolution isn’t actually a field yet. That’s one of the things I love about it though. If you’re reading papers that describe why something is exciting, and it’s a rigorous paper, then the ship has sailed. Like CRISPR-Cas9. Everyone has jumped on board that ship, but a lot of the really interesting biology is now already done. I want to work on things that are the future. The project might fail miserably, but it has a lot of really interesting basic biological potential.
What advice would you give to new graduate students beginning their research journey?
My supervisor gave me a piece of advice when I started that she’d received from her own PhD supervisor. The advice was that you need to have three things in your life as a scientist – your science, your family, and a hobby. That way, so long as one of those three things is going okay, then you will be okay. Personally, my hobby is mountaineering and rock climbing. When the research gets hard, I can always go climbing and forget about work. So my advice is to find something that really makes you happy, and try to excel at it as well.
Thank you for taking the time to discuss your research, Artem. We wish you the best of luck as you move forward in your scientific career!