Charles M. Perou, PhD: From studying one gene, to studying thousands in breast cancer

Before he set out to understand how tens of thousands of genes are behaving in breast cancer, Charles M. Perou, PhD, was hunting just one gene.

Charles M. Perou, PhD: From studying one gene, to studying thousands in breast cancer click to enlarge Charles M. Perou, PhD

August 7, 2019

Before he set out to understand how tens of thousands of genes are behaving in breast cancer, Charles M. Perou, PhD, was hunting just one gene.

As a graduate student at the University of Utah in the 1990s, Perou was focused on finding the genetic cause of a rare and fatal inherited genetic disorder that leads to albinism, infections and other symptoms.

It took time, but the researchers discovered the gene in mice first, and then confirmed that patients who had Chediak-Higashi syndrome had mutations in that gene also.

“I spent five years as a graduate student hunting down one gene,” Perou said. “Fortunately, we got it, but it also made me realize – I don’t want to study just one gene. I want to study all genes.”

That insight proved to be the first step in Perou’s journey to becoming a world-renowned expert in genomics, which is the study of all of the genetic material in a cell or organism.

‘Many discoveries to be made’

Perou, the May Goldman Shaw Distinguished Professor of Molecular Oncology in the UNC School of Medicine Department of Genetics, co-director of the Computational Medicine Program, and a member of UNC Lineberger Comprehensive Cancer Center, always had a love of nature, an interest in science and a drive to understand how things work.

He grew up in a small town in northwestern Illinois. As the son of a doctor, he visited the pathology lab where his father worked. Perou said seeing his father use a microscope to identify diseases, including cancer, sparked his interest in medicine and human disease.

He studied biology in college in Maine, and discovered he had a love of hands-on scientific research while studying primitive plants for his senior thesis.

“I was maybe not such a good book learner, but when I could sit down and do it myself, I just loved it,” he said.

Perou was introduced to genetics in his first job as a research technician at the University of Chicago, where he studied yeast. This single-celled fungus is a model for genetics research, he said, because it allowed for sophisticated genetic manipulations in the lab.

“In that time, this was the beginning of true molecular biology and genetics era,” he said. “It was really impressive exposure for me, particularly in ’87, to see what we could do from a genetic perspective, and since then I’ve just been hooked.”

After earning his doctorate at the University of Utah, Perou continued his training at Stanford University. Perou said it was a case of being the “right guy at the right time” when David Botstein asked if he wanted to join his lab, which was starting a new project to study how all of the genes in a cell are expressed, or not expressed, in breast cancers.

“I went, ‘where do I sign?’” Perou recalled. “Cancer had usually been tackled one, two or 10 genes at a time. And suddenly, we had this tool that allowed us to look at thousands of genes at once. I knew there would be many discoveries to be made.”

It was in Botstein’s lab where Perou and his colleagues determined that breast cancer was not just one disease, but multiple distinct subtypes based on their gene expression patterns. This seminal finding, published in Nature in 2000, would prove itself to be valuable both in the lab and in the clinic.

Among their findings was that a subtype known as basal-like breast cancer was a distinct disease type. Known commonly as triple negative breast cancer, this is a subtype of breast cancer that doesn’t have any of the three receptors that guide most therapeutic decision-making in breast cancer.

“In retrospect, it’s hard to believe we didn’t see it before,” Perou said. “It’s so different than the other breast cancers. If you look at it in the microscope and compare it to the other breast cancers, it doesn’t look that much different…however, when you’re using thousands of genes as the lens, it clearly looks different than all of the others.”

Perou’s work has resulted in many accolades, including the Susan G. Komen’s highest scientific honor, the Brinker Award for Scientific Distinction, and last October, the Association of American Cancer Institute’s Distinguished Scientist Award.

At UNC Lineberger for the past 19 years, Perou has continued his research in cancer genomics to help to redefine multiple cancer classification methods. Since he was awarded the May Goldman Shaw professorship, funded by Wally and Lil Loewenbaum of Austin, Texas, he has gained additional flexibility and stability to pursue bold ideas in the lab. “The May Goldman Shaw professorship gives me some stability in a grant-driven world, which has a lot of ups and downs,” he said.

‘Pleasure and a privilege’

Perou is continuing to study the complex genomic interactions driving cancer, but with an expanded view. He’s now working to incorporate other molecular characteristics of cells and their surrounding environment to understand how tumors work and respond to drugs.

“We need to think on the next level now,” Perou said. “The future is to look at tumors and their microenvironment from a systems perspective. When you hit the cell with the drug, the cell adapts by changing its signaling, and the microenvironment also changes. We need a network-type understanding of how these signaling pathways work, and how different cell types talk to each other, in order to come up with effective drug combinations as an improved means of targeting cancers.”

Together with UNC Lineberger’s Timothy C. Elston, PhD, the Jeffrey Houpt Distinguished Investigator and professor in the Department of Pharmacology, Perou is co-director of the new Computational Medicine Program, which the UNC School of Medicine established to bring together advanced computing, data analysis expertise, and biologists to make discoveries to improve care for cancer and other human diseases.

Perou and Elston are establishing the program on the 11th floor of the newly renovated Mary Ellen Jones Building on the UNC-Chapel Hill campus, betting that the computational technology that has made self-driving cars and facial recognition possible could play a role in the next big cancer research discovery.

They’ve already begun research in this area themselves. With a five-year grant, Perou and Elston are investigating whether they can predict drug resistance in breast cancers. Specifically, they are studying a particular pathway of cellular signals, the RAS-MAP kinase pathway, which can be dysregulated in breast cancer. The plan is to develop mathematical models of how, exactly, signals are sent and how cells also develop resistance to inhibitors of this pathway by using data from breast cancer samples, while at the same time using these data to develop predictive models in the computer.

“We’re in a revolution now where we have the ability to collect huge amounts of data, but we have to take advantage of it,” Perou said. “The insights just don’t come out of it, you’ve got to develop new mathematical methods to extract the insights, and then have the biological expertise to understand what was just found.”

Perou said they hope to produce the next level of breakthroughs. The ultimate goal is to improve upon patient care.

“We have many of the scientific tools and drugs that we need, but we just don’t know how to use them in the right combinations and when and where to apply these tools, in part because of our incomplete knowledge of these networks,” he said.

Outside the lab, Perou is typically spending time with his family, or running and mountain biking on trails in nearby forests, particularly the Carolina North Forest. He has two children, Erik, 24, and Emily, 20, and his wife, Amy, is a manager at the UNC High Throughput Sequencing Facility, thus making genomics a family affair. He is a big Carolina basketball fan, and of his daughter’s field hockey team at George Washington University in Washington D.C.

It’s a pleasure and a privilege to do science at UNC-Chapel Hill, he said.

“No job is all fun, and no scientist should have the expectation that most aspects of science are brilliant discoveries,” he said. “But I will honestly say, to this day, I can’t believe I get paid to do this.”

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