May 2008

Staving Off Cell Death

Researcher finds a pathway to deter cell destruction in traumas such as heart attacks, which could lead to improved therapies

By Jacqueline Mitchell

Researchers from Tufts and Harvard have identified a means of preventing one kind of tissue damage that can occur during heart attack, stroke or other traumas, findings that may open up new avenues for drug development. Alexei Degterev, an assistant professor of biochemistry at the School of Medicine, and his colleagues developed three molecules that inhibit a cellular protein that plays a key role in this type of cell death, called necroptosis.

In multi-cellular organisms, cells are dying all the time. Programmed cell death-when cells reach an end to their useful life-is called apoptosis. It's a well-understood biochemical pathway that happens in normal organisms under normal conditions, as with skin cells that slough off to reveal fresh new ones.

In contrast, cell death by necrosis happens as the result of acute tissue injury, such as a stroke or heart attack. Necrosis was long thought to be a random, unregulated response to such a trauma. But in 2005, Junying Yuan's lab at Harvard Medical School, where Degterev worked at the time, discovered one regulated necrosis pathway, which they dubbed necroptosis. Recognizing this pathway-a series of biochemical steps the cell undergoes before dying-meant researchers could find a way to interfere with and possibly arrest the process altogether.

"The underlying cause of a significant portion of deaths, disabilities and long-term functional impairment is massive tissue injury," says Degterev, who is also a member of the biochemistry program at the Sackler School of Graduate Biomedical Sciences. "If we can prevent cell death and keep cells alive until the trauma has passed, we may be able to significantly reduce some of these injuries."

To that end, Degterev, in collaboration with the Yuan lab at Harvard, developed three small molecules that obstruct the necroptosis process. All three molecules, called necrostatins, work by inhibiting the cellular protein RIP1 kinase, which plays a crucial role in the necroptosis pathway. "It's a very interesting drug target," says Degterev. "We'd like to pinpoint the role of this protein in human diseases."

But blocking this pathway won't mean the end of cell death as we know it. "The tools are in people's hands," says Degterev. "But there are still a lot of unresolved questions."

For one, researchers need a deeper understanding of the necroptosis pathway, which is not nearly as well understood as apoptosis. Scientists have been working to develop apoptosis inhibitors for the last decade and have yet to find a really good one, says Degterev.

Moreover, necroptosis is just one kind of necrotic cell death. How many types are there? "It's impossible to say," he says. "Down the road, we'll have a better understanding about other types of cell death. It's very clear that no single drug will cure all. Most likely, we'll have multiple agents targeting different forms of cell death."

Researchers have their work cut out for them. Degterev and his colleagues will continue to study necroptosis to optimize the timing and dosage of their potentially therapeutic necrostatins. These analyses are relatively straightforward in vitro, where the cells are kept under strict, measurable conditions. Things get less predictable, however, in vivo-in living organisms. Nonetheless, Degterev looks forward to the pre-clinical work. "We have to get the building blocks somehow," he says, "if we are to develop new therapies that are not currently available."

Jacqueline Mitchell can be reached at

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