Cells replicate, grow and communicate by transporting specific molecules to specific targets. But how exactly do cells carry out these vital and intricate movements among themselves?
The 2013 Nobel Prize winners in Physiology or Medicine, announced last week by committees in Stockholm and Oslo, produced an insightful answer when they discovered the machinery that allows for molecule-containing vesicles to arrive at their destination and fuse with their target.
Laureates Randy W. Schekman from Yale University, James E. Rothman from UC Berkeley and Thomas C. Südhof from Stanford University uncovered the mechanism responsible for the precision of the delivery system in the cell. The prize acknowledges their breadth of research conducted from 1979 to 1993.
Analogous to human organs, organelles are specialized subunits within a cell that exchange molecules via bubble-like vesicles. They function much like shipment containers. The transport of molecules within, between and out of cells is necessary for hormone molecules, proteins and neurotransmitters to illicit a response from cells. For example, neurons package and deliver the neurotransmitter dopamine to the neurons of the brain’s reward system after consuming a meal. Understanding the principles governing this transport system came from the combined research of Schekman, Rothman and Südhof.
While researching cells’ transport system, Randy Schekman noticed that certain yeast cells he was working with had a defect that caused an accumulation of vesicles. It was as if mail was being sent out but no one was home to pick it up. Schekman isolated and effectively cloned the yeast cells with expressed transport defects. Reasoning that the issue was genetic, Schekman identified the faulty genes and realized the genetic basis of vesicle transport regulation.
Rothman further explored the genetic influence on transport regulation in mammalian cells by proving that specific proteins need to be present on a vesicle to allow it to fuse to its target and release its cargo. He removed select proteins found on the vesicles — the same ones produced by Schekman’s yeast genes — and observed how it affected the vesicle’s success in accurately delivering molecules. The vesicle fused and released its contents only to a target with a specific and compatible protein-binding site.
Rothman explained that a spike in enzyme concentration inside the cell allowed him to recognize and isolate mutant genes and later generate the entire genome of the yeast cell.
“The genes in the yeast were screened for enzyme secretion. The concentrations of the enzymes were compared inside and outside of the cell. The mutants had a higher amount of enzymes inside the cell. The mutant yeast cells were cut open and the vesicles containing the enzymes were observed via electron microscope,” Rothman said. “The genetic library of the wild type yeast was sequenced and inserted into the yeast cell via recombinant DNA.”
Südhof was interested in how neurons released neurotransmitters to neighboring neuron cells at a precise time. He found that calcium-sensitive proteins were located on the cell membrane of neurons. In the presence of calcium, the proteins on the neuron cell membrane bind and fuse with a vesicle filled with neurotransmitters. The fusion of the vesicle with the cell membrane releases neurotransmitters out of the excited neuron and toward a neighboring neuron, thus relaying a signal. This is substantiated by Rothman’s findings that explain a scenario when vesicles are released on demand.
The synergy of Schekman, Rothman and Südhof’s research unraveled the essential cell function of vesicle transport. Vesicle transport guarantees that molecules that are not limited to hormones, neurotransmitters and proteins arrive at their desired target. Without this precise transport, inefficient transport of molecules can lead to cell death and ultimately human death. The genetic principles discovered by the Nobel laureates may aid in identifying genetic disorders, including neurological and immunological diseases and diabetes.
As for winning the prize, Rothman said the experience was difficult to describe.
“There was a phone call and my wife said it is finally happening. I have been nominated for the award several times before. It was surreal.”
A version of this article appeared on page 5 of Tuesday October 15th’s print edition of the Daily Nexus.