MD-PhD Program Student Has Paper and Interview Published

Joseph A. Brazzo III has completed the first two years of medical school and is currently in his fourth year in the doctoral program in computational cell biology, anatomy and pathology in the Department of Pathology and Anatomical Sciences.

The study, titled “Mechanosensitive Expression of Lamellipodin Promotes Intracellular Stiffness, Cyclin Expression and Cell Proliferation,” was published June 21 in the Journal of Cell Science.

Brazzo’s mentor, Yongho Bae, PhD, assistant professor of pathology and anatomical sciences, is the paper’s senior author.

“The central tenet of our lab’s research is to gain better insight into how the hardening or stiffening of a cell’s microenvironment regulates its internal biology and, ultimately, how that cell behaves,” Brazzo says.

Both scientists and medical doctors alike have known for quite some time that when healthy tissues — made up of billions of cells — become diseased, they also become stiffer or harder.

Examples include diseased blood vessels of the cardiovascular system, tissue stiffening with liver and pulmonary fibrosis and in many types of cancers.

“This is a direct result of the aging process, which explains why these diseases occur more frequently as we get older,” Brazzo notes.

“We found that the expression of a cell protein called lamellipodin is particularly sensitive to the hardening of the cell’s environment,” he adds. “When lamellipodin was first discovered, it was shown to be very important to a cell’s ability to migrate, and thus a great deal of research since has largely focused on its role in cell migration.”

Researchers in Bae’s lab found that in response to a stiff environment, lamellipodin also tightly controls the cell’s ability to grow and divide, and the cell’s own internal stiffness or hardness.

“We also have described a pathway inside the cell that allows lamellipodin to directly sense the cell’s stiff environment,” Brazzo says. “These are novel findings in the rapidly growing field of mechanobiology, in that we show that in response to a cell’s stiff environment, lamellipodin, an essential protein in cell migration, controls cell growth, division and internal stiffness of the cell.”

“Dr. Bae and I are attempting to unravel how mechanical forces inside the cell drive cell behavior and thus tissue function,” he adds. “This is really the theme in the new and burgeoning field of mechanobiology, which is a merging of the fields of biology, physics and bioengineering.”

Brazzo says one thing he has been postulating is the existence of a “mechanical aether” inside the cell.

“I believe that it influences spatial arrangement/confirmation of all proteins and their localization within the cell (which is not random). What is most riveting is that we unraveled a cell pathway that I believe controls this aether in lamellipodin,” he says.

Brazzo says his research group has enlisted help from the lab of Ram Samudrala, PhD, professor of biomedical informatics and chief of the Division of Bioinformatics, and says the potential public health benefits of the research are significant.

“In our recent publication we provided evidence of how cells translate stiffness from the extracellular compartment to cell behaviors. But there is so much more work to be done,” he says.

“We are embarking on a new field of research. Dr. Bae and I seek to design a drug-like compound — with the help of Dr. Samudrala’s team — that would target lamellipodin and the lamellipodin pathway that we described in our publication.”

“By doing so, we hope to directly reduce and potentially prevent the stiffening process that we see with aging as well as in many different types of diseases including lung and liver fibrosis and many types of cancer,” Brazzo adds.

“This would really be the first of its kind of therapy to directly target the cellular and molecular pathways responsible for tissue stiffening, which we call ‘mechanomedicine.’ We are really excited.”

Brazzo notes that as well as being first author on the Journal of Cell Science paper, he is also the corresponding author.

“This is a highly respected position as it indicates that I was lead correspondent in seeing that the paper went from submission to publication,” he says.

The First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. 

Brazzo says the opportunity was unexpected and a bit daunting, but he is grateful for it.

“I thought I was going to just submit the paper and nothing more,” he says. “The First Person interview really gave me the opportunity to showcase myself as an aspiring scientist in my field while also providing a raw insight into my research to complement the well-tailored story that is the publication. I believe this gives more meaning to my findings.”

Brazzo credits Bae with helping him immensely in becoming a better physician-scientist.

“Beyond the hard science that is the PhD, my time earning my doctoral degree has given me incredible insight about myself, my abilities and limitations,” he says.

“In science, there is a lot of heartache and feelings of doubt; a psychology that one is indoctrinated to and part of the discovery process. In this field you are pushing and breaking the limits of human knowledge. Inherent to this process is failure and intellectual isolation.”

“Dr. Bae has allowed me to face this reality in the most meaningful way by dancing with me: guiding me with a loose grip, allowing me to fall, but always in reach,” Brazzo says.

Brazzo says he is looking forward to defending his dissertation research and completing the clinical years of medical school.

“Clinically, I look forward to finding novel ways to treat disease using ‘mechanomedicine,’ regenerating tissues and organs, and reducing and possibly reversing the aging process and associated diseases as a result of tissue stiffening, he says.

Before coming to the Jacobs School of Medicine and Biomedical Sciences in 2016, Brazzo received an undergraduate degree in behavioral neuroscience from Northeastern University, a master’s of science degree in medical sciences from Boston University School of Medicine and a master’s of public health degree in epidemiology from the University of Massachusetts-Amherst.

Brazzo was born and raised in Boston and later lived in Charlestown, Massachusetts.

“I moved a lot when I was a young boy as a result of my family’s lack of financial stability,” he says. “My mom was a single parent who raised my brother and me to the best of her abilities. She really valued education and is a big reason I am in my position today.”