HARVARD GAZETTE ARCHIVES

Junying Yuan (left), Alexei Degterev, and their colleagues have discovered a new pathway to cell death. Knowing details about this lethal route could provide new targets for drugs that can prevent unwanted cell deaths. Yuan's group has already found a way to use this knowledge to reduce stroke damage in mice. (Staff photo Jon Chase/Harvard News Office)

Damaged or unusable cells in our bodies will commit suicide to protect us from harm. That's a well-known process with the awkward name of "apoptosis." There's also necrosis, meaning "to make dead," when brain, heart, and other cells die from disease and trauma. These suicides and uncontrolled deaths have always been thought of as separate processes, comparable to killing one's self as opposed to dying by accident or malignancy.

Now a connection has been found between them. Researchers at Harvard Medical School have uncovered a common pathway by which necrosis can take over when apoptosis runs out of energy. The same scientists have also discovered how to brake the necrosis part, a finding that might lead to new treatments for everything from Alzheimer's disease to heart attacks and strokes.

Taking their experiments one step further, the researchers have looked for and found a molecule that can block necrosis-like cell death in mice undergoing strokes. If it works as well in humans, it could provide physicians with extra time to limit the deadly and disabling effects of strokes.

"We have found a new pathway to cell death," says Junying Yuan, a professor of cell biology in whose lab the research was done. "We used to think that, in necrosis, cells get so sick they break apart and die in a completely unregulated fashion. That would make it impossible to develop specific drugs to block such deaths. Now we know there's more to it than that. We have started to understand that a general process exists to allow cells to die by necrosis when apoptosis fails. That process provides a target for drug therapy. This is very important for medicine because necrosis is so common in human diseases. Furthermore, we have already found a compound that blocks a critical step on the road to necrosis."

Yuan and her colleagues describe this research and its human potential in the cover story in the July issue of Nature Chemical Biology. The colleagues include Alexei Degterev of Harvard Medical School and others from Massachusetts General and Brigham and Women's hospitals in Boston and The Tokyo Metropolitan Institute of Medical Science in Japan.

Interfering with stroke

The team calls the new death pathway "necroptosis," a word that connects programmed cell death, or suicide, and unavoidable lethal breakdown. "We wanted to understand what happens to cells when they become activated to commit suicide but can't go through with it," Yuan explains. "Apoptosis needs energy and there might not be enough available. That's the case in strokes, which are caused by a lack of blood and oxygen in the brain. Such a lack is also common in many other human diseases." In such cases, necrotic machinery might take over and do what cell suicide cannot.

Yuan's team began looking for compounds that can block necrosis without interfering with apoptosis. They screened some 15,000 compounds in cells undergoing necrosis before they scored a hit. In keeping with a necrotic theme, they named the compound necrostatin-1, or nec-1. Further tests led to the exciting realization that nec-1 operates in many cell types involved with different diseases. The number "1" indicates they expect to find more such compounds.

The researchers then went on to show that nec-1 limits brain damage in mice that receive it to counteract strokes. "Nec-1 clearly shows a unique ability in inhibiting necroptotic death as compared with other known biologically active molecules," they note in their report in Nature Chemical Biology.

At first, no one understood exactly how nec-1 works. They did know that necrosis is activated by a group of aptly named "death-domain receptors," proteins on the surfaces of the cells, but it was not clear what triggers the activation. Yuan and her group have continued to work on this mystery, and in a telephone interview she said that they are very close to solving it.

Human possibilities

When might they test a nec-1-type drug on humans? "We are applying to the National Institutes of Health for funds to do such tests," Yuan says. If such support is forthcoming, they could begin in a short time.

If nec-1 works on humans, it could provide an extra degree of protection against cell death not now available. Currently, the only drug approved for stroke by the U. S. Food and Drug Administration is known as tPA, which must be given within two to three hours after the stroke begins in order to decrease permanent damage such as paralysis. Also, tPA works only with strokes caused by blockage of brain arteries, not by bursting of blood vessels in the brain. In mice, nec-1 provides such protection six hours after the stroke starts, and it should work in all types of strokes.

Yuan is not sure, but she thinks the extra protection involves the death-domain receptors. "They must be activated by compounds released outside the cell in response to injury," she notes. "This activation does not occur immediately, giving nec-1 more time to act."

Experiments continue at Yuan's lab on additional ways to take advantage of what has been learned about the necrotic path to cell death. Tests are being done to determine how necrosis-blocking might inhibit conditions such as brain injuries caused by trauma and the nerve cell degeneration typical of Alzheimer's and Parkinson's diseases.