#WhyIScience Q&A: A molecular biologist boosts experimental science with innovative new methods

Aziz Al’Khafaji shares his approach to science and his thoughts on the value of team-based research.


Aziz Al'Khafaji
Credit: Allison Dougherty, Broad Communications
Aziz Al'Khafaji

When he began his undergraduate studies at the University of Central Florida, Aziz Al’Khafaji was initially interested in a career as a physician, so the idea of being a research scientist was not on his radar. Through a fortunate enrollment in an undergraduate research program, Al’Khafaji quickly found his passion in the lab.

Motivated to get a more holistic understanding of what he was researching in the lab, Al’Khafaji expanded his tracks of studies to include molecular biology, biotechnology, and chemistry. Unless he could examine a problem at all levels, he said, he’d worry about what he might be missing.

During his graduate work in cell and molecular biology at the University of Texas at Austin, Al’Khafaji explored his interest in methods development. He created an experimental tool known as ClonMapper, which enables scientists to identify and characterize cellular clones and isolate them so they can be studied further. While pursuing his PhD, Al’Khafaji split his time between Austin and Boston, where he collaborated with Cathy Wu and Catherine Gutierrez at the Broad Institute of MIT and Harvard and Dana-Farber Cancer Institute. They worked together to use ClonMapper to study clonal dynamics and tumor evolution in chronic lymphocytic leukemia.

He enjoyed the collaboration — and seeing the application of his method to a real biomedical problem — so much that he decided to focus his postdoctoral work on developing and optimizing new experimental methods. Working in the labs of Broad core member Paul Blainey and institute member Nir Hacohen, he developed a sequencing approach that can resolve RNA isoforms resulting from genes that are alternatively spliced. Known as Multiplexed ArrayS sequencing, or MAS-seq, the method gives researchers a much finer resolution tool for studying the transcriptome than previous methods, and it will soon be published in Nature Biotechnology (online now as a pre-print publication).

Al’Khafaji is now the associate director of technology development at the Genomics Platform and leads Broad’s new Methods Development Lab, which he launched in 2022. The lab builds, optimizes, and shares innovative tools like MAS-seq and other -omics-based technologies and engages closely with researchers applying the methods. We spoke with him about how his interest in philosophy has influenced his research and about the impact of new methods on biomedical science in this #WhyIScience Q&A.

Q: How has your interest in philosophy informed your academic and scientific careers?

As early as I could remember, I was always thinking about topics like morals, ethics, purpose, happiness, and epistemology. The rigor and process of philosophical thinking really helped out when it came time for me to apply the scientific process and think through things.

With these approaches, I try to take a holistic view and go back to first principles and ask: With the tools we have now, how can we completely reimagine this process and how are we stuck in existing ways of thought? The momentum in a given field can often be so great that it becomes limiting and hard to escape. If we’ve been using a certain technology for decades, that’s a red flag to me that there could be a better way to do it now.

Q: Why is it so important to keep developing and refining our experimental methods?

As scientists, we run experiments, collect and analyze data, and evaluate it along with previous work in the field. From this, we synthesize a model in an attempt to describe the complex phenomena that we're studying. I like to think of this as “data-driven storytelling.” And so as scientists, the stories we tell are necessarily constrained by the data and evidence we collect. From this, it reveals the influence that methods development has on our scientific understanding and ultimately paradigms that are formed.

In the Methods Development Lab, we try to pay special attention to this dynamic and we specifically aim to develop methods that enable an expanded perspective. It’s amazing when we have very powerful technologies to do precise things, but we need to ask if there are ways we can complement those and be more expansionary in that space.

Q: How do you ensure that the methods you develop reach the scientists who need them?

In the Methods Development Lab, we’re excited to get on the front lines with people using our tools and make sure their experiences are enabling and inspiring further refinement. We also aim to make methods that are accessible and that can be applied at scale. The lab is a part of the Broad’s Genomics Platform, where we have incredible expertise in productionizing and automating workflows, bringing necessary scale to these efforts.

Q: What’s been most rewarding about your work?

Early in my scientific career, I learned that uncovering the beauty and complexity of biological systems is fascinating. But I learned that it’s also a social science. The breadth and depth of things you’re trying to tackle is immense: no one human has expertise to answer these questions alone. I came in excited about the science, but what I also ended up really loving about this career path is the human aspect of this work — brainstorming with people who have different experiences, expertise, and perspectives, with each person seeing something different. When I’m going to those meetings, I can’t wait to share ideas with friends and colleagues and understand how they see this problem and how they’re going to tackle it.

The Broad Institute is a marketplace of ideas and there’s so many inspiring things going on. We’re excited to keep pushing the boundaries of experimental capabilities to support research at the institute and beyond.