Finding the Magic in Cell Death

Cell death: a Goldilocks dilemma

With his ready laugh, the guitar-playing, theater-hopping immunologist is neither a one-note nor a one-hit wonder. Donning Hawaiian and tie-dyed shirts at scientific conferences to stand out to peers—on the advice of a long-ago mentor—Green could never merely blend in. Three decades ago, during his earliest probes into the mechanisms of cell death, many scientists agreed with him that this phenomenon might carry wide-ranging health implications. But Green was one of only a handful at the time who decided to actually figure out how.

At its core, cell death, which occurs through processes known as apoptosis or necroptosis, is basic to human life. Millions of cells in our bodies die each day. Most die because they’re worn out, damaged, infected or otherwise unneeded. These cells are quickly replaced by new ones. But sometimes it’s not desirable for them to die, such as when the cells of a transplanted kidney are stressed due to lack of oxygen, triggering inflammation after re-oxygenation that can threaten the new organ’s success. Other times, killing cells rapidly is the goal, such as in cancer treatment.

“Cell death is a Goldilocks situation: Too much is a bad thing, and not having enough is a bad thing. You want it to be just right,” Green explains. “I’d say that’s the case for every tissue in the body.”

Proteins grant cells stay of execution

But life and death, even in cellular terms, isn’t a fairy tale to the prolific writer. Green has authored more than 500 research papers, along with numerous books and scientific reviews, including one with the sinister title “Ten Minutes to Dead.” His latest article, published in the journal Cell, revealed a set of proteins that can rescue a damaged cell from its death sentence.

Green led a team of St. Jude immunologists to discover how these proteins, called ESCRT-III, can delay or prevent the “executioner” machinery that kills damaged or infected cells in necroptosis. The list of far-reaching health advantages of controlling cell death by activating these proteins is spellbinding. They range from stopping cancer’s spread through blood vessels eroded by necroptosis; to protecting otherwise doomed brain cells from dying in neurodegenerative disorders such as Lou Gehrig’s disease; to extending the lives of cells infected by viruses such as influenza, granting them more time to mount an immune response.

But as charmed as the findings may seem, Green’s research didn’t involve wizardry. Instead, he and his team methodically manipulated isolated cells in the lab to trigger the last phase of necroptosis, performing a plodding, time-course analysis to examine what happened at each step.

 “It had generally been accepted that once you activate the final step in necroptosis, the cells die. That’s what everybody noticed,” he says. “But our data now says that you can actually activate this ESCRT pathway to make the cell survive.”

No hocus-pocus in drug discovery

Green hopes one day to develop a mind-reading trick known as mentalism that would make audiences believe he’d plucked a thought straight from their brains. “It’s impossible,” he acknowledges. “But we can create an illusion of that.”

More than hocus-pocus will be needed, however, to develop drugs to control the cellular rescue mechanism at will, dictating a cell’s life or death according to medical needs. And Green holds no fantasies about how long this process may stretch. It’s a process that will potentially incorporate St. Jude chemical biologists, as well as pharmaceutical companies and even existing drugs repurposed for this new use.

“There’s a slow pace to science. It basically takes a generation to go from a fundamental discovery to an actual treatment,” he says. “The treatments developed at St. Jude that actually cure patients were completely unfeasible 50 years ago. They were crazy. Now they’re routine.”

With findings of this magnitude, Green is well aware his efforts could help patients of all ages, not just children. He tips his hat to the leadership at St. Jude, which emboldens faculty members to pursue research revelations without a crystal ball to predict exactly who will benefit in the end.

“In discovery research, we don’t know where the next breakthrough is going to come from. We’re encouraged here to explore things that may, on the surface, appear to have no important implications for treating catastrophic diseases in children,” he says. “But you never know … and breakthroughs are breakthroughs. Of course, the clinical translation of research we do here is always going to be in children.” 

From Promise, Summer 2017