Old specimens yield new clues to disease

Four years ago, when Maya Lodish, M.D. ’03, and her young daughter visited the Cushing Center for a scavenger hunt at Lodish’s class reunion, both were struck by the unfamiliar, even eerie setting—and its contents. Soft warm lighting illuminated hundreds of jars containing brains and tumors excised in the last century by Harvey Cushing, M.D.

Known as America’s father of successful neurosurgery, Cushing introduced practices a century ago that reduced an 80 percent mortality rate to 8 percent, according to Dennis D. Spencer, M.D., the Harvey and Kate Cushing Professor of Neurosurgery and former chair of the Department of Neurosurgery. Cushing also procured many, many brains for future research.

Today, those brains, which once gathered dust in a basement storeroom at the medical school, have received fresh formalin—and offer a renewed avenue for research. On seeing the specimens, Lodish wondered whether any DNA survived in the preserved tissues—and whether it might reveal genetic links connecting Cushing’s patients with contemporary pituitary diseases.

“I can’t express enough how important genetics is,” Lodish said. “It goes hand in hand with the care of the patient.” Investigating the genes of long-deceased patients is “contributing to understanding the genetics of disease,” Spencer said. He and Lodish sought out a medical student to take up the investigation as a thesis topic. The undertaking was a natural fit for Cynthia Tsay, who studied the history of medicine during her undergraduate years at Yale.

“It was her dream-come-true project,” Lodish said. In the early stages of the project, Tsay and Lodish were flipping through Cushing’s clinical notes when they came across an intriguing patient. Today known simply as G.B.S., his photograph from Cushing’s autopsy report looked familiar to Lodish, one of the few people who regularly sees patients with the smattering of freckle-like pigmentation that could indicate a rare disorder called Carney complex. Symptoms vary, but G.B.S. was a patient with a pituitary tumor secreting excess growth hormone, resulting in a condition called acromegaly.

“It was a fortuitous discovery,” Tsay said, “because all the pieces lined up.” The patient’s photograph and records from a century ago could be matched to his brain specimen preserved in the Cushing Center. It fell to Tsay to line up the most challenging piece—the genetic code.

“Cynthia worked tirelessly in the lab,” Lodish said, “trying to isolate DNA from these samples.” The effort paid off in a posthumous diagnosis for G.B.S.: Carney complex was indeed written in his genetic code. Could she go back in time, Tsay would have a great deal to tell Cushing about his former patient. But Cushing would also have a great deal to tell current doctors about the link between environmental factors and disease.

“Cushing would find out where you came from, what your work was, what your background was,” said Terry Dagradi, the Cushing Center coordinator who orchestrated the cataloging of Cushing’s images and records for the project. “You had to just get to the details of people’s lives and see if there was a hint of something that you could put together.”

An inherent fascination with brains in jars enthralled Cushing in the 1900s, Lodish and her daughter in 2013, and continues to fascinate today’s visitors to the Cushing Center. “It does really spark the interest of younger people,” Lodish said.

Dagradi recalls an architect’s young daughter visiting the center, peering up at the specimens, and wondering out loud whether they were still thinking. “It was this very sweet little moment,” she said. “And you think, ‘Oh—they’re not thinking, but they’re still telling us stuff.’ ”