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Scientist Wins Wachtel Award for Mapping Complex Cancer Gene Networks

genetic mapping of cancer genes
Gilbert used systematic maps to measure hundreds of thousands of genetic interactions and classify the function of individual genes. | L. Gilbert et al., Science Translational Medicine (2020)]

The 2020 AAAS Martin and Rose Wachtel Cancer Research Award has been awarded to Luke Gilbert for his pioneering cancer research, which has intricately mapped out the networks of gene interactions that support the progression and characteristics of tumors.

Since his time as a postdoctoral fellow, Gilbert has refined genetic engineering techniques to systematically explore a crucial question in cancer research: how human genes contribute to processes such as the formation of secondary tumors and the evolution of drug resistance. His research has shed light on the highly convoluted field of cancer genetics and has revealed several potential treatment strategies for lung cancer and other dangerous malignancies.

Gilbert, an assistant professor at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, wrote an essay about his work that was published in the August 26 issue of Science Translational Medicine. He also presented on his prize-winning research on August 28 during a virtual ceremony hosted by the U.S. National Institutes of Health.

The AAAS Martin and Rose Wachtel Cancer Research Award is an annual prize that highlights early-career scientists who have made outstanding contributions to the field of cancer research, according to Sudip Parikh, chief executive officer of AAAS. As part of an endowment bequeathed by Martin L. Wachtel, Gilbert will receive a cash award of $25,000.

"These are challenging times for many early-career investigators," said Tom Misteli, director of the Center for Cancer Research at the National Institutes of Health. "It's very important for institutions to step up and support them at this time, because they really are the future."

"There were many highly qualified applicants for this award, making it a challenge to identify only a single winner," said Yevgeniya Nusinovich, a senior editor at Science Translational Medicine. "Ultimately, the judging committee decided to recognize Dr. Luke Gilbert for his research combining cutting-edge approaches in the fields of gene editing and machine learning to identify previously unknown aspects of tumor biology at the single-cell level."

Researchers have spent years attempting to understand the exact roles of cancer-linked genes, but this endeavor has proven a challenge due to the sheer complexity of cancer genetics. There are thousands of genes that are linked to dozens of cancers, and these genes can interact with each other in myriad ways, according to Gilbert.

He likened cancer research to the old analogy of many people with blindfolds touching different parts of an elephant, all trying to describe the whole animal from one, limited perspective.

"I studied anti-cancer drug responses as a graduate student and from this work it was clear to me that single genes are important in cancer but usually not the full story," said Gilbert. "From there it was clear to me that we need to understand how genes function within the context of a gene network."

Luke Gilbert

To get a sense of the bigger picture, Gilbert developed an unbiased approach based on CRISPR, a form of gene engineering that has revolutionized medical and biological research. Instead of making assumptions about a gene's function, he uses CRISPR tools to turn many genes on and off within a population of cancer cells, measuring how changes in either individual genes or pairs of genes affect the cells' behavior.

His team performs the experiments in a "pooled" manner, such that each cell in the population has its genes perturbed by CRISPR in a different way. The end result is that an entire network of genes can be changed in aggregate across the population of cancer cells, allowing the scientists to use other techniques such as next-generation sequencing to gauge the cellular effects of these genetic changes.

One of the key advantages of the CRISPR approach is that it allows researchers to precisely perturb genes in an easily scalable manner, Gilbert said.

"A single person can perform these genetic interaction mapping experiments using only a small amount of specialized equipment," said Gilbert. "CRISPR has really democratized the robust genetic manipulation of human cells."

In recent years, Gilbert and his colleagues have refined their CRISPR gene network approaches to study up to hundreds of thousands of gene interactions in a single experiment, allowing them to identify rare pairs of synthetic lethal genes and to construct highly detailed maps of gene network interactions.

Their studies have also identified new treatment targets in prostate cancer, acute myeloid leukemia, and a form of non-small cell lung cancer. Gilbert said his team is already pursuing research in early animal models to test the efficacy of focusing on these targets, and is excited to further advance their ideas into the clinic.

When asked about his future plans, Gilbert said he is eager to apply his genetic interaction mapping approach to other high-risk cancers and to noncancerous cells that still influence the characteristics of tumors, with the goal of revealing new cancer treatments.

"I would love to apply these approaches in non-cancer cell types that compose the tumor microenvironment such as immune cells, endothelial cells or fibroblasts," he said. "This would enable us to map gene networks that are re-wired within the tumor microenvironment and potentially point to new therapies."