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Seeking to Understand Chemotherapy Resistance

A visit with Stephen and Hannah Alexander, of the Alexander Lab

By Spencer Melgren
Published: - Topics: cancer biology The Alexander Lab chemotherapy

Doctors Steve and Hannah Alexander, the duo behind the Alexander Lab, have spent the past 26 years at the University of Missouri. The Alexander Lab, founded in 1987, focused on developmental biology until the late nineties. Since then, the lab has studied DNA repair and drug resistance in cancer cells. With their current work, they hope to contribute to our ability to successfully treat cancers of all types, by providing insights into the biological process by which tumors develop resistance to anticancer drugs.

The Alexander Lab’s early years were spent researching developmental biology with the goal of better understanding how the human body forms from a single fertilized egg. In pursuit of this objective, the Alexanders examined development in a simpler “model organism” – a soil amoeba named Dictyostelium discoideum. In the lab, they were able to “use this very simple organism to understand the molecular basis for how embryos develop,” Steve tells us. The Alexanders’ work with this organism eventually lead them into new territory. “We were asking very fundamental questions about development, and we got interested in some genes that are involved in DNA repair.”

The Alexander’s examination of DNA repair took a new direction fifteen years ago, after a life-changing conversation with Dr. Phil Hanawalt of Stanford University. During a discussion on proteins with DNA repair functions, Dr. Hanawalt pointed the Alexanders towards a chemical called cisplatin that he believed would be useful in their research. This chemical, they discovered, was the most widely used chemotherapeutic agent in the world. Unfortunately, many cancers can develop resistance to cisplatin’s effects, rendering treatment ineffective. “We said, I wonder if we can use this really simple model we’re working on to understand this mechanism better,” Steve recalls. “The approach was to see if we could get cells that would live in in the presence of cisplatin, and could we identify what genes were involved.”

The model that the Alexander Lab utilized in studying developmental biology also provided benefits in the study of anti-cancer drug resistance. With the model, Hannah says, researchers had the advantage of working with an organism that can be grown in a Petri dish and more easily analyzed. “All of its genetic material has been decoded, so we know if we mutate a gene we can identify what the gene is and what it does.” With the help of graduate students in their lab, the Alexanders unexpectedly identified a cisplatin-resistance causing mutation involving a lipid metabolizing enzyme. Not having the specific enzyme, it seemed, led to cisplatin resistance. Further, “it turned out that humans have exactly the same enzyme, and there was something known about it,” Steve tells us. With this breakthrough, they proceeded to develop testable theories as to why lacking this specific enzyme led to resistance. The Alexander Lab spent the next several years testing this idea in their model, and then proving that their theories also applied to human cancer cells.

These days, the Alexander Lab studies the basis of cancer and further examines the specific ways that cancer cells develop resistance to anticancer drugs. “Cancer biology today is focused on the idea of finding specific molecular targets in cancer cells that you can zoom in on with specific drugs to kill the tumor,” Steve tells us. “I think there is a real need for identifying more unique targets, and trying to make this process work better in humans. Some of the things we discovered, I think, are useful in this regard.”

Working together in the lab has been advantageous for the Alexanders, but not without difficulties. “After working together for 20 years, we had to learn to write in a single voice,” Hannah says. They agree that this process, while difficult at times, helped to produce the excellent writing that has been crucial in both publishing their work and petitioning for research funding grants. Steve also reflects that “the intellectual continuity, [and] the intellectual commitment” from working together has been a huge factor in their success, by enabling the Alexander Lab to operate without the difficulties that come from frequent personnel turnover. A downside, they say, is that the work often bleeds over into the rest of their lives for both good and ill. “The failures are together, and the successes are the same,” Hannah says.

Outside of their lab, Drs. Steve and Hannah Alexander are interested in improving the public’s understanding of science research. They believe that people often misunderstand how science progresses and have unrealistic expectations for research. They are proponents of discovery-based science, and explain that scientific breakthroughs generally arise through a process of general exploration rather than from specific, answer-focused inquiries. Steve points out that cisplatin—like penicillin and many other impactful advancements—was an unintended byproduct of discovery-based research. They believe that modern scientists should work to make the daily-life consequences of their research more clear to the general public, and thereby increase popular support for research in important areas that may not have immediate or obvious ramifications.

To help promote science and educate the next generation of researchers, the Alexanders are both active in teaching and outreach. Steve teaches cancer biology to MU undergraduates and advanced cancer biology to graduate students, works with students in the lab, and also delivers talks to community groups. Hannah officially retired from the lab in 2008, and she has spent the past few years developing and promoting outreach programs at MU. These include the graduate courses “Public Understanding of Science” and “Integrating Science with Outreach,” along with a for-credit Science Outreach Certificate that trains students to explain science to the general public. Hannah has recently organized a large regional meeting devoted to science communication and public outreach, which was sponsored by the American Society for Biochemistry and Molecular Biology in collaboration with many of the science departments at MU.

For the Alexanders, teaching and research are deeply connected. “Research allows you to teach your courses with a clarity and enthusiasm I don’t think you can match if you don’t have a major [research] program,” Steve tells us. He also believes that their work in the lab improved as a result of teaching. “Having to teach makes you a better writer, and a better explainer, and a better grant writer because you have to learn how to articulate concisely, simply, clearly,” Hannah adds.