The Wisnovsky Lab uses cutting-edge CRISPR genomic screening technologies to study the genetic factors underpinning changes to cell-surface glycosylation. We spoke with Dr. Simon Wisnovsky to learn more about this important work and potential implications for cancer and autoimmune disease treatment.
What are glycans and the glycome?
Simon Wisnovsky: Simply put, the surface of every one of our cells is coded with something that looks like a “forest” of molecules. These can be all different kinds of molecules, like fat molecules or proteins. However, a big part of what makes up cell surface coding is sugar and sugar molecules. Glycans are chains of sugar molecules linked together. Chemically they are distinct from the kind of sugar that we eat, but our body metabolizes the sugar we eat and uses it to make different structures that attach to our cell surface. There’s a huge number of different types of sugar molecules that can be attached to the surface of our cells. What’s interesting about this, is that obviously there are many different types of cells in the body and every cell has a slightly different pattern of different types of sugars that are expressed on the surface.
What role does the glycome play in the immune system and cancer?
The patterning of sugar molecules determines a lot about how cells interact with the immune system. Immune cells are constantly patrolling our bodies for viruses, bacteria, or cancer cells. One way they achieve this is by using little receptors—called lectins—that “taste” the sugar molecules and detect what specific sugar structure is expressed on the surface of the cell. That tells the immune cell: does the sugar structure “taste” like something associated with normal body functioning or not?
Over the past ten years researchers have discovered that one of the hallmarks of cancer is the ability to evade detection by the immune system and prevent the immune system from activating against cancer cells. One way cancer cells achieve this is by systematically changing the patterns of sugar molecules that they express on their surface to “taste” good to the immune system.
There’s a balance between activation and inhibition of the immune system. When glycosylation changes it can tilt that seesaw either way: either towards inappropriately attacking healthy tissue—as in the case of autoimmune disease development—or ignoring tissue that is pathological, as in the case of cancer.
Like a kind of cellular subterfuge?
Exactly. It’s almost like a cloaking device where they express exactly the right trigger molecules to falsely signal to the immune system that there is nothing to be concerned about. That allows cancer cells to evade detection, grow and proliferate.
The challenge with cancer is that these diseases are so heterogeneous. There are so many different types of cancers, each genetically unique, and this makes it difficult to formulate strategies with broader applicability across different types of tumors. It’s early days but there’s some suggestion that these glycosylation changes could potentially be thought of as markers for future broad spectrum cancer drug targets.
How is your lab using CRISPR technology to examine cell surface glycosylation?
Cancer is a genetic disease that emerges because of many accumulated genetic mutations that happen in a normal cell, driving the cell towards the hallmarks of cancer: uncontrolled proliferation, resistance to cell death, and ability to metastasize. There have been decades of exceptional work by different labs around the world showing that cancer cells systematically change expression of their cell surface carbohydrates. What is not known is exactly how this process happens. It’s not clear exactly what genes and mutations are driving that process in cancer cells.
My lab is using CRISPR genetic screening to systematically delete the function of thousands of different genes in parallel in the cells we grow. We can then evaluate what genes—when deleted—trigger a shift in cell surface glycosylation. Eventually what this will give us is a genome-wide map of the different factors within the cancer cell including the genes, the proteins, and different functional molecules that are producing these glycosylation changes.
What are your hopes for the long-term translational potential for this research?
Our niche is very much in the basic science space, but long-term what we hope to contribute from a translational perspective are targets for drug discovery. Once we have a target molecule or gene we can reach out to collaborators to help us develop that story in mouse models, by developing the types of blocking antibodies that may inhibit these cellular interactions. But for us, we’re very much focused on the first step of identifying a good genetic target that may pay off down the road.
What do you find rewarding about your work on a day-to-day basis?
Oh my goodness, there are so many things I find rewarding. Working in cancer biology and having a sense that we can impact patient health in the long term feels valuable and rewarding. On a day-to-day basis, I find the creative work of helping students design an experiment and overcome problems in the lab rewarding. I’ve always been attracted to the intellectual creativity of scientific research.
One of the other cool things about research is that you can form collaborations and learn from people around the world who you may not have had the opportunity to talk to otherwise. When we get a data set with a gene we’re interested in examining further I’ll Google that gene and find out who has been focusing on that particular gene in their lab and I will often reach out to them.
Your lab is currently recruiting new graduate students. What advice would you share with new grad students or those seeking to pursue a research career?
I think one of the most important things to keep in mind is that there is no standardized graduate school experience. If you go to medical school, for example, no matter where you are in the country the curriculum is going to be similar. You're going to take the same classes. You're going to learn the same techniques. There's an accreditation at the end of it. Whereas in grad school, your experience is so dependent on whether you’re passionate about your specific research topic and whether you “click” with your supervisor.
Your relationship with your supervisor is incredibly important. They will be the ones who mentor you and help you drive your research project forward. It’s critical that you find a supervisor who you have a rapport with, whose personality and mentorship style aligns with yours, and who you are excited to talk about science with. Similarly, the peers in your lab are very important. I would encourage future graduate students to think carefully about this when you’re preparing your applications and selecting your lab. You really need to consider and seek out the experience you want to get in grad school. It will pay off in the long term.
Learn more about the Wisnovsky Lab here.