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    Douglas R. Green, PhD

    Cell Suicide: A "Howdunit" Mystery

    If Doug Green, PhD, were to give you the shirt off his back, chances are it would sport big, bright tropical flowers. It is hard to imagine that this joyful, Hawaiian-shirt-wearing scientist who describes certain proteins as “outrageously cool” is the same man who penned scientific reviews titled “Ten Minutes to Dead,” “A Matter of Life and Death” and “At the Gates of Death.”

    This Don Ho-meets-Stephen King dichotomy mirrors the good-versus-evil, protagonist-versus-antagonist dynamic that Green studies—apoptosis, or cell death.

    In a multi-cellular organism like the human body, the death of a cell is just as important as the proliferation of tissue in sustaining life. Just as in a good thriller, it’s when those factors become out of balance that trouble begins. By studying apoptosis, researchers hope to understand the delicate equilibrium between cellular life-and-death forces. With that knowledge, scientists may one day have the ability to make life-saving plot changes when the story line takes a turn for the worst.

    Stranger than fiction

    Clearly, the main character of the cell death saga is the cell itself. But unlike most murder mysteries, this is no “whodunit.” There is no smoking gun in the library—rather, the cell kills itself. Thus, researchers at St. Jude Children’s Research Hospital are intrigued with the “howdunit” of the process.

    “The remarkable thing we have learned is that cells in our body, which are dying all the time, don’t always die the way we usually think of death, as being worn out, torn up or broken apart. A cell receives a signal from the body when it’s infected or if it’s a cancer, and then it commits suicide. That remarkable process of a cell killing itself is the study of apoptosis,” says Green, who holds the Peter Doherty Chair in Immunology at St. Jude. “We can also refer to the process as active cell death. Because the cell wasn’t killed by something—it actively killed itself.”

    Green, one of the top 20 most-cited scientists in the country, explains that a cell can die from many causes, but the two most common ways are through apoptosis and necrosis. A cell has a choice of whether or not to undergo apoptosis, but it has no choice in necrosis. In the latter process, the cell may burst, become torn or be destroyed by external forces. This distinction is important because when cells die by necrosis, a powerful signal activates an immune response. This response typically results in inflammation and can pose serious health issues. Apoptotic cell death, however, proceeds silently.

    “It’s like the cell was never there,” Green says. “It’s more than silent, it’s aggressively silent, and there is no inflammatory response.”

    Why is the focus on apoptosis important in the treatment of diseases such as cancer?

    “Everything we do in the attempt to kill a cancer is involved in inducing apoptosis in the cancerous cells,” Green explains. “And every problem we have in performing that induction is related either to the cancer not undergoing apoptosis or to healthy cells dying.”

    Investigating the mystery

    The human body is composed of millions of cells. Every day tremendous numbers of cells in our body die and are replaced by other cells. If just one of them becomes cancerous, it can kill us.

    Safeguards built into our biology prevent that. Most of those protective mechanisms rely on the cell realizing something is wrong. When this altered cell gets the message to start reproducing with no constraints, it responds to the signal by committing suicide—apoptosis.

    “Otherwise, every one of us would have cancer by the time we were 7 months old,” Green says. “As a good friend of mine once said, the question isn’t why there is so much cancer; the question is why there is so little.”

    Apoptosis is one answer. It’s a central component in halting the reproduction of cancerous cells, according to Green, who is a pioneer in the field.

    The plot thickens

    If apoptosis is the good guy in this story, what is stopping its heroic measures? That is where the plot thickens.

    “We have a paradox,” Green says. “Cells are poised to die, but in cells that have a mutation or some other defect, the same signal that tells the cell to die will activate oncogenes [cancer genes] and cause the cell to start reproducing. If we can get a grasp on that signaling process, we can get cancer.”
    Unfortunately that isn’t as simple as sending in apoptosis on a white horse.

    “Killing the cancer isn’t the problem; it’s keeping the patient alive,” Green explains. “You can kill Godzilla, but if you take out Tokyo in the process, it didn’t do any good.”

    The key in treatment is to find that delicate balance between a cell’s life-and-death mechanisms—to induce apoptosis in cancerous cells while minimizing cell death in normal cells.

    “I think that’s achievable,” Green says. “Our real success in cancer treatment comes from combined treatments and therapies that work together to prevent collateral damage to the patient, while being effective against the cancer.”

    Green says when he began studying apoptosis it wasn’t a household word in the scientific community. Today the subject is studied by scientists in disciplines such as genetics, molecular pharmacology and infectious diseases, to name a few.

    A crucial discovery occurred when researchers identified a family of proteins called Bcl-2, which play a key role in apoptosis.

    “We are learning that there are some members of this protein family that block cell death, but there are other members of the family called Bax and Bak that are absolutely required for apoptosis to occur,” Green explains. “So now the question is, ‘How are Bax and Bak activated?’ It’s a very controversial, active area of investigation.”

    A tantalizing cliffhanger

    What sounds like a bad family reunion may lead to the next chapter in this page-turning cell death thriller.

    “A lot of attention and excitement is being paid to a new class of drugs that inhibit Bcl-2,” Green says. “In the simplest form, diseases are caused by too much or too little cell death. So the hope is that the more we can understand about that balance at the fundamental level, the better our chances are to manipulate it.”

    It was that kind of hope that inspired Green to come to St. Jude last year.

     “I came here because of the incredible promise of St. Jude—of what we are able to do here, of the fantastic advances we are already making. At St. Jude, an overlying mission surrounds us, which is driven by kids with catastrophic diseases. No one can say that is not a worthwhile and personally important mission,” he says.

    Green admits that finding cures for catastrophic diseases is not an open-and-shut case.

    “Every day for the last 15 years the newspapers have announced possible cures for cancer. So where is this victory cure we were promised years ago?” Green asks. “These things take time. There’s nothing that we’re doing in the lab today that I can make any prediction about except to say, ‘I hope we’re going to learn something from it.’”

    Inspired by that hope, Green vigilantly studies the fragile balance of life and death at the cellular level. When he seeks balance in his own life, he finds it by spending time with his family, playing the guitar and inventorying his collection of 150 Hawaiian shirts.

    But when it comes to his research, it’s much like a good book—he can’t put it down until he figures out “howdunit.”

    Reprinted from Promise magazine, autumn 2006

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