In a lab in California, Jacqueline Estevez studies long-term outcomes for hepatitis patients who’ve developed liver cancer, trying to identify how the progress of their disease correlates to particular markers in the blood.
At Brigham and Women’s Hospital, Joseph Park uses a sophisticated new genome-editing method to investigate a nasty shellfish bacteria that’s usually contracted by eating the wrong oyster.
And while neither is a doctor—yet—both hope to incorporate their research into their future careers.
Estevez and Park, graduate students at Boston University’s School of Medicine (MED), were recently awarded Howard Hughes Medical Institute (HHMI) fellowships, which fund a year of biomedical research, offering a challenging but rewarding time-out from their medical school studies. The HHMI Medical Research Fellows Program, open to medical, dental, and veterinary students who want to pursue a research project full-time, allows fellows to select their own mentor, develop a research project, and conduct research at an academic or nonprofit institution.
Estevez (MED’17) and Park (MED’18) were among 68 students from 37 schools chosen for this year’s program. Each fellow receives a $30,000 stipend and up to $11,000 for expenses, such as health insurance and travel to research conferences. More than 1,600 students have participated since the program began in 1989.
“Physician-scientists play a vital role in translating scientific discoveries from the laboratory to treatments that can significantly improve human health,” says Melanie Daub, fellowship program officer. “At a time when the pipeline of physician-scientists is declining, it is critical to support the development of the next generation. For medical students with an interest in, and commitment to, scientific discovery, a year of full-time biomedical research can be an influential and inspirational experience at a pivotal point in their education.”
“We are extremely pleased that two of our medical students have been chosen for this opportunity,” says Karen Antman, MED dean and Medical Campus provost.
“I wanted to take a research year just to learn a lot more about clinical research, because I had already had a few years’ experience with basic science and I wanted to try out something different,” says Estevez, who has long been interested in focusing on gastroenterology and hepatology, looking at the digestive tract and the liver. She is particularly interested in patients with hepatitis who then develop liver cancer.
“That area of research is still a little mystery box,” she says. “We don’t know the exact progression, and it’s very hard to predict which patient is going to get cancer and how well they are going to do with treatment.”
Looking online for labs working in the field of gastroenterology/hepatology, she found Mindie Nguyen, a hepatologist at the Stanford University School of Medicine. “Her vision and her projects were really where I wanted to go and what I wanted to experience,” Estevez says. After an initial conversation via Skype, Nguyen invited her to join her lab for the year. At that point Estevez applied for the HHMI research fellowship.
“Now I’m here in California,” she says. “I was very lucky.”
In Nguyen’s Stanford lab, Estevez is studying cytokines, a type of protein used in cell-to-cell communication. By combining laboratory research with a study of patient histories, she says, “we’re hoping to see if these biomarkers can help us predict if a patient is going to develop cancer or not, and how well they’re going to do on certain treatments.” The treatments include liver transplant, surgery, radiation, and chemotherapy. “The system for deciding which treatment to use is not 100 percent effective,” she says, “and part of our project is to improve the current system using biomarkers in the patient’s blood.”
Estevez says that she and Nguyen will soon pick a specific piece of what is a huge and ambitious task for her main study during the yearlong fellowship.
“I have no doubt she will have a very productive year,” says Nguyen, adding that while Estevez is her first HHMI research fellow, she has previously mentored several medical students who took a year off to conduct research. “Jackie will be trained in study design and statistical analysis, as we have done with many other past and current students not enrolled in formal courses. I know the year is very important for these students, and I am committed to helping Jackie achieve her goal.”
Park’s project may be even more daunting in its complexity. He is using a cutting-edge genetic technique to take on Vibrio parahaemolyticus (V. para), a marine bacterium found in brackish salt water. It is a leading cause of gastroenteritis from eating shellfish, most often raw oysters.
Armed with what is essentially a molecular syringe that injects human cells with toxic proteins, V. para is nasty even on the microscopic level. It causes diarrhea, often accompanied by cramps, nausea, vomiting, fever, and chills, and it can be severe in people with compromised immune systems, according to the Centers for Disease Control and Prevention.
“It certainly makes for a very miserable experience after going to your favorite seafood restaurant,” says Park. “It is quite a virulent bacterium.”
He is going after V. para by working with mentor Matthew Waldor in his Brigham and Women’s Hospital lab, which studies the evolution, cell biology, and pathogenicity of enteric bacteria that cause human disease. Park is using CRISPR, a new method of editing specific genes with an enzyme called Cas9, which functions like a molecular scissors. Park has been “disrupting” nearly 20,000 individual genes to see whether each change confers resistance to V. para infection, screening the results by computer.
He likens the painstaking process to a control panel with a lot of switches: “V. para wants to manipulate an unknown subset of switches in order to achieve its purpose: to infect and ultimately kill our cells. Suppose I go about breaking one switch at a time. If I happen to break a switch that V. para uses to infect and kill, then the result will be remarkable: survival against V. para infection. The control panel is our entire genome and the switches are our genes.”
“Joseph is rapidly assimilating new ideas and learning cutting-edge technologies, and I look forward to working with him for the remainder of the year,” says Waldor, the Edward Kass Professor of Medicine at Harvard Medical School and an HHMI investigator.
The effort has already turned up several compelling leads that Park says he will now follow up on, in hopes of validating the connection.
“My hope is that eventually, much down the road, we can find pharmacologic ways to circumvent the mechanism that ultimately kills these human cells,” he says.