Extracellular vesicles (EVs) have long been hailed as molecular messengers that shuttle proteins and RNA between cells. But Nobel laureate Randy Schekman, Ph.D., is not convinced. In his June 10 Rodbell Lecture, Schekman argued that these tiny sacs of material are more likely byproducts of routine cellular activity than purposeful agents of intercellular communication.

Still, he thinks EVs hold valuable information that can advance environmental health research, particularly in understanding how the body responds to the environment.

“Since these vesicles are produced by all the tissues in the body, they may be viewed as reporters or sentinels of what’s going on in the body,” said Schekman, a cell biologist at the University of California, Berkeley (UC Berkeley). “And since they are easily accessed in all the bodily fluids, I think they will become important biomarkers for detecting the initiation and progression of disease.”

Secreted signals

Although researchers have known about EVs since the mid-20th century, they continue to debate the purpose of these particles. At first, scientists thought EVs did little more than serve as cellular trash bags to help dispose of waste. But then studies showed that EVs carried functional molecules — such as proteins and RNA — that could influence other cells. That led to the idea that EVs might instead represent a sophisticated mechanism for cell-to-cell communication.

“EV biology is a topic of strong interest for many at NIEHS, as environmental factors can modulate vesicle-mediated signaling in ways that influence disease susceptibility, immune response, neurodegeneration, and cancer progression,” said Carlos Guardia, Ph.D., head of the NIEHS Placental Cell Biology Group and host of the Rodbell Lecture.

Response to stress

In recent years, Schekman’s laboratory has focused on uncovering the forces that drive the formation of EVs. One question they have explored is whether EVs are produced as part of the cell’s response to membrane damage. To test this, the team passed cells through a narrow-gauge needle and exposed them to chemicals like bacterial toxins. When the membrane was stressed physically or chemically, the production of a type of EV known as an exosome increased dramatically, by as much as 30 times.

“We argue that many, perhaps most, of the extracellular vesicles that are floating around in our body are not produced to inform some process involving the transfer of molecules between cells, but rather as a byproduct of a normal plasma membrane repair pathway.”

Tubes, not bubbles

Recent experiments from Schekman’s lab have suggested that direct cell-to-cell contact, rather than exosomes, may be responsible for transferring information from one cell to another. They showed that this transfer occurs through thin, bridge-like connections between cells known as membrane tubules. The team found that such exchange is mediated by syncytins, proteins that are involved in cell fusion. Schekman said these findings suggest that tumor cells may be able to hijack material from nearby healthy cells using these tubules.

“The syncytins become an attractive target, possibly for chemotherapy, because they may be involved in the growth or metastasis of tumors,” he said.

Give it away

“His groundbreaking science has inspired generations of cell biologists, including myself,” said Guardia. “Schekman is a passionate advocate of open access, scientific transparency, and public education.”

Schekman was awarded the 2013 Nobel Prize in Physiology or Medicine for his discovery of the genetic machinery essential for vesicle transport within cells. He donated his entire Nobel Prize honorarium to UC Berkeley to create an endowment for the Esther and Wendy Schekman Chair in Basic Cancer Biology, in honor of his mother and sister. More recently, he created a similar award at the University of California, Los Angeles, his alma mater, to support early-career investigators.