A developing cell in the human body sits on the edge of death. Proteins called Grim, Reaper and Hid stand poised, ready to unleash other toxic proteins. Only if a protein messenger from another cell arrives in time to call off the killing, will the cell then mature into any one of the various types of body cells, such as skin, liver and brain.
But how these protein messengers command cells to survive has remained a mystery until now. For the first time, the entire team of molecular messengers responsible for issuing certain brain cells with orders to survive has been identified by a Rockefeller University scientist and his colleagues.
They report their results in the Feb 1 issue of Developmental Cell.
"Cell death is important during development and in adulthood because it is a very stringent quality-control mechanism that makes sure there are no unwanted, potentially dangerous cells in the body," says principal investigator Hermann Steller, Ph.D., Strang Professor at Rockefeller and a Howard Hughes Medical Institute investigator.
"In fact, right now cells in our body are dying at a rate of 100,000 cells per second, while at the same time 100,000 new cells are being born."
The new research may one day lead to novel treatments for diseases in which too much or too little cell death occurs: too much cell death is associated with neurodegenerative and muscular diseases such as Alzheimer's, Parkinson's, Huntington's and stroke, while too little leads to the survival of cells with mutations, the hallmark of cancer. For example, the 55 percent of human cancers containing a mutated copy of the p53 gene no longer possess the protective ability to kill off harmful cells.
"We might be able to reinstate the mechanism of cell death in cancer cells so that they kill themselves," says Steller, who heads the Strang Laboratory of Apoptosis and Cancer Biology at Rockefeller University.
Conversely, by activating this newly discovered molecular pathway, researchers may be able to rescue dying cells in the treatment of neurodegenerative and muscular diseases.
In the article, Steller and colleagues outline the entire molecular pathway by which a population of neuron cells in the brains of developing fruit flies communicate a message of survival to a different class of neighboring cells in the brain, called glial cells.
The research was conducted at the Massachusetts Institute of Technology in Cambridge, Mass., and the Weizmann Institute of Science in Israel.
Steller says that these findings may serve as a model for what takes place in human brains, and possibly in other parts of the body, such as our immune system, skin, liver and colon, where this type of programmed cell death naturally occurs throughout life.
The human brain, as well as the fly brain, consists of two main types of cells: neurons and glial cells. Neurons are the primary cells of the brain and are responsible for a host of essential body functions, including learning, memory, behavior and sensory perception. Glial cells, on the other hand, play a more backseat role to neurons, acting mainly to support their activities.
During development, billions of both cell types arise, but only a small percentage actually survive to form the adult brain. The rest undergo a type of cell suicide known as "apoptosis" (pronounced a-pop-TOE-sis), from the Greek word for "falling away." This natural cell death occurs throughout the body, both during development as a means to sculpt critical organs and tissues, and in adults as a housekeeping function that eliminates potentially harmful cells.
Just how cells "know" whether to survive or perish has been the subject of intense study for nearly 50 years. In the last decade, researchers have learned that during development, virtually all cells require specific external signals called "survival" factors or "trophic" factors - which are secreted from neighboring cells - to survive. Those that do not receive the trophic signals commit suicide by default. That is, cells have to compete for trophic signals in order to survive.
"This 'social control' theory of cell survival explains why no one cell type outnumbers another," says Steller. "The body has essentially figured out a way to keep its cell numbers in check."
The brain's trophic survival signals work by suppressing a cell's "cell death machinery" - which includes Grim, Reaper and Hid and a family of enzymes called caspases.
"Normally, caspases, which are the key executioners, are locked up by other proteins, which I refer to as the 'brakes on death,'" says Steller, who discovered the Reaper family in 1994.
"But in order to get cells to self-destruct, these brakes have to be released, and that's the job of Reaper, Hid and Grim. Like keys unlocking the door to a dangerous beast restrained behind it, they activate other proteins called caspases to chop up all sorts of proteins, and death ensues."
Although scientists understood the mechanics of this cell suicide process, they did not know how it was suppressed by survival signals; the molecular link between these two crucial life processes remained a black box.
Now, Steller and his colleagues have identified the entire series of proteins that relay a message of survival from a neuron to a glial cell in the fruit fly Drosophila melanogaster. The surviving glial cells are required for proper formation of axons - the long extensions that allow neurons to communicate with other distant cells. According to Steller, there may be other cell death pathways with similar outcomes, but this one is the first to be elucidated in full.
"Although the regulation of cell survival and cell death has been studied intensely, in not one case has the precise, step-by-step mechanism by which survival factors suppress the apoptotic cell death program been identified," says Steller.
The scientists report that a growth factor called SPITZ binds to its receptor and triggers the activation of what is known as the RAS/MAPK pathway. This pathway, in turn, puts the brakes on Hid, which then prevents the chains on the beastly caspases from falling open, thus averting death.
The RAS/MAPK pathway plays a well-known role in cancer: it both promotes cell growth and blocks apoptosis, thereby preventing the body from eliminating, via cell death, harmful cells. Consequently, the new research has implications for the treatment of cancers in which this pathway has gone awry - in addition to a host of other cancers that have lost the protective cell death mechanism.
Other authors of this study include Andreas Bergmann at MIT and Michael Tugentman and Ben-Zion Shilo at Weizmann Institute of Science. Part of this work was supported by a National Institutes of Health grant and a Meyerhof Visiting Professorship awarded to Steller from the Weizman Institute of Science in Israel. Howard Hughes Medical Institute also supported the research.
John D. Rockefeller founded Rockefeller University in 1901 as The Rockefeller Institute for Medical Research. Rockefeller scientists have made significant achievements, including the discovery that DNA is the carrier of genetic information. The University has ties to 21 Nobel laureates, six of which are on campus. Rockefeller University scientists have received this award for two consecutive years: neurobiologist Paul Greengard, Ph.D., in 2000 and cell biologist Günter Blobel, M.D., Ph.D., in 1999, both in Physiology or Medicine. At present, 33 faculty are elected members of the U.S. National Academy of Sciences. Celebrating its Centennial anniversary in 2001, Rockefeller - the nation's first biomedical research center - continues to lead the field in both scientific inquiry and the development of tomorrow's scientists.
Journal
Developmental Cell