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SQI: Simpson Querry Institute

Meet the Researchers: Randy Atwal

Randy S. Atwal is a Research Assistant Professor in the laboratory of SQI member Shana Kelley and the featured speaker for the upcoming Rising Stars of SQI Lecture on Feb. 3. In this interview, Atwal previews his lecture titled “LEAPFROG: Large-Scale Cell Profiling Based Discovery Engine” and discusses his role in the translationally focused Kelley group.

Can you give an overview of your Rising Stars Lecture topic? 

Current cell-sorting technologies allow you to profile about 50 to 100 million cells per hour. But the technologies that we are developing, which are based on magnetic ranking cytometry, allow you to profile cells on the order of billions per hour. This lecture is essentially going to walk through two projects that leverage this capability to demonstrate what kind of research is possible.

The first story covers how we found genetic regulators of CD47, which is a target that is critical for oncology research. CD47 is often referred to as the “don’t eat me” signal, as it allows your immune system to differentiate between the body’s normal cells and harmful invaders. Cancer cells exploit this signal by overexpressing CD47 on the cell surface so they can evade the immune system. It’s a very sought-after target because if you can modulate the expression of CD47 on cancer cells, then you can make them amenable to targeted therapeutics.Randy Atwal working in the lab

The second story is about trying to understand genetic regulators of traditionally undruggable proteins. In the oncology space, for example, KRAS is a very well-studied oncogene that is involved in many different types of human tumors given the nature of what the protein does. It’s essentially a molecular switch that controls the growth and signaling cues of all your cell types. Normally, the switch is tightly controlled to ensure optimal growth conditions. Many of the human cancer cells harbor KRAS mutations that cause this switch to be stuck in the “on” state, leading to downstream signaling cascades that result in uncontrolled proliferation that is typical for a cancer.

Traditionally, you try to use something like a small molecule or an antibody that could block the function of a signaling protein. But KRAS has an overall shape that is not amenable to that kind of small molecule binding. It also has a very high affinity for its natural ligand GTP, which makes it extremely challenging to design a competitive inhibitor. Those are some of the main reasons why KRAS has traditionally been considered undruggable.

Our approach aims to leverage the power of genetics and whole-genome CRISPR screening to work around the KRAS limitations. Using a strategic panel of cell lines that express the normal (known as the “wild-type”) or the mutant KRAS variants, we can deploy whole-genome CRISPR screening to identify druggable regulators. If you can design a screen for expression changes in the wild-type versus the mutant protein, then you can find allele-specific genetic regulators of KRAS, and that’s the work that is ongoing in the lab.

You were also part of the Kelley Lab at the University of Toronto before recently setting up shop at Northwestern. How has the transition gone for you?

From a scientific point of view, it’s taken us about a year to get set up. As you can imagine, there is quite a bit of infrastructure involved with the kind of technology that we use. I think we’re finally up and running and have the necessary resources.

What has been fantastic, at least from my experience, is all of the core facilities at Northwestern. For example, ANTEC has a lot of the equipment that we need so you don’t necessarily need to have that in your own lab, and we also use core facilities for some of the cell sequencing that we do.

Having access to these cores is wonderful, as well as the expertise with different types of research that is going on within the institute and broader university. There are a lot of opportunities for setting up new collaborations.

What has been your impression of Chicago after moving, and what are your hobbies outside of research?

Weather-wise, it’s not that much different from Toronto. It’s a big city, which has its pros in terms of the diversity of options that are available. Having a family with two young kids (ages 6 and 4), it’s been fun getting them to explore the city and neighborhoods. I would say my hobby is being a full-time dad because I really enjoy spending time with them.

Can you tell me a bit about your role as a Research Assistant Professor in the Kelley Lab?

I’m helping to lead one of the three spokes of the lab, which is rare and single-cell analysis (the others being biomolecular sensors and intracellular molecular delivery). Phenotypic screening is the main focus of our downtown Chicago lab. 

There are specific projects that I’m leading but I like to think of myself as more of a stagehand. We have many graduate students that are pursuing interesting projects, and given the interdisciplinary nature of the lab, a lot of the students work on projects together.

Given my background in molecular and cellular profiling, computational studies and large-scale disease modeling, I lend those kinds of expertise to many different projects. I also help from an experimental design perspective. Asking the right questions can make the difference with how much progress is made, and appropriate experimental design also helps us deploy our existing funds with the maximum return on investment.

How would you describe Professor Kelley’s personality and leadership style in running a lab? 

I think it’s the can-do attitude. She’s extremely positive, very supportive of the people and the projects, and is also extremely knowledgeable. Even though her background is in chemistry, she’s really plugged into many different areas. And because she has this keen eye toward translation, she knows what it takes to take a discovery in a lab and translate it to the bedside.

That’s what motivates me working with her and learning from her. To me, the whole reason people get into science is because they want to make changes or differences in people’s lives, and I’m now part of that process.