Undergraduate researcher uncovers molecular secrets of HPV cancer-causing mechanisms

When Sean Fletcher joined Sam Biswas’s Medical and Molecular Sciences (MMSC) lab at the University of Delaware College of Health Sciences the summer of his freshman year, he had no research or lab experience.

Two years later, the senior medical diagnostician published a paper as first author after revealing new insights into how human papillomavirus (HPV) works at the molecular level.

In a study recently published in Journal of Virology, Fletcher and co-authors Biswas, MMSC professor, and Esther Biswas-Fiss, MMSC professor and president, used bioinformatics to identify conserved regions of the HPV E2 protein, which plays a critical role in the virus’s ability to replicate and cause cancer. The team found that specific mutations can change the function of proteins, significantly increasing the risk of cancer.

It is rare for an undergraduate to be the first author in a peer-reviewed journal. This really sets Sean apart. It’s a very medically focused document with implications for HPV – a global health problem – and possible treatments.”

Esther Biswas-Fiss, professor and president of MMSC

Sean Fletcher (right), an aspiring physician, talks about the role of bioinformatics in his research with mentors Esther Biswas-Fiss (left), professor and chair of the Department of Medical and Molecular Sciences, and Sam Biswas (center), professor of medical and molecular sciences.

It’s a feat that Fletcher, a first-generation college student and Delaware native who will go to medical school, never dreamed of when he first came to UD.

“I knew UD had a strong research portfolio, and I am grateful to have taken advantage of the early opportunities to get involved and explore the vast world of HPV research,” said Fletcher.

The day after Fletcher’s paper was published, Fletcher received a call from Thomas Jefferson’s Sidney Kimmel Medical College to schedule an interview—a timely development that underscored the value of his publication.

“That’s the power of a first-author paper,” Biswas said proudly. “It’s given him a huge advantage.”

Decoding the HPV cancer-causing proteins

HPV is the most common sexually transmitted infection (STD) in the world, affecting up to 80% of sexually active adults. The complex virus has more than 200 strains and is the leading cause of head and neck cancer.

“A person can be infected with a dozen or more types of HPV at the same time,” Biswas said. “We still don’t know how they interact with each other; there’s a lot that remains unknown.”

While younger adults with stronger immune systems clear HPV within two years, the 400-million-year-old virus can lie dormant in the body for years, making it harder to eradicate in people over 40.

“Doctors may say that a person is cured, but that may not always be true,” Biswas said. “The virus may no longer be detectable through Pap smears in women, but the virus could have left a copy in a cell that could lead to cancer a decade later.”

From left to right, Esther Biswas-Fiss, professor and chair of medical and molecular sciences, Senior Distinguished Medical Diagnostic Professor Sean Fletcher, and Sam Biswas, professor of medical and molecular sciences, collaborated to discover specific mutations that can alter protein function and significantly increase cancer risk, paving the way for improved approaches to HPV cancer diagnosis and treatment.

For men, there is no test for HPV, and many only find out they have the virus after a cancer diagnosis. Biswas-Fiss emphasized that understanding the virus at the molecular level is key to preventing and treating HPV.

“Many studies have focused on clinical and epidemiological approaches, including our work to determine which genotypes are more prevalent in different parts of the world,” he said. “But to prevent and treat HPV, we need to better understand how it causes cancer at the molecular level.”

Fletcher’s publication furthers this goal.

“We need to study the virus both computationally and in the lab, and with this paper, we’ve made significant progress,” said Biswas-Fiss. “It opens up a new avenue for researchers to explore.”

Over the next year, Fletcher plans to continue using computational biology as a microscope to examine each person for HPV proteins. His ongoing research is supported through the Delaware INBRE Academic Year Undergraduate Fellows Award, following his participation in the Delaware INBRE Summer Student Research Program.

“What I’m doing now couldn’t have been done five years ago. Using machine learning, we can identify hidden patterns in proteins and test ways to block protein interactions to prevent them from causing cancer,” Fletcher said. “I’m really excited to see these data-driven ideas applied to medicine and clinical data in the future.”