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Disease Forecasting

Cell Suicide by Melissa Hendricks, Page 1

Apoptosis—the intricately orchestrated self-annihilation of cells—is vital to human life, but can prove deadly when it goes awry. Marie Hardwick contends that a better understanding of this process could mean new treatments for everything from AIDS to Alzheimer's.

Soon after sperm meets egg, when cells are dividing and dividing again to form the tiny sphere that will grow into an embryo, another—quite opposite—activity begins. Cells die. Specifically, some of the cells inside this little ball commit suicide. Many questions remain about how and why these cells annihilate themselves; however, scientists know that their suicide, termed apoptosis, is essential. If it is prevented, the tiny sphere does not develop.

For life, there must be death.

This yin and yang of cell birth and self-inflicted death repeats itself throughout the human lifespan. Cell suicide helps rid the body of cells that are infected, damaged or simply old and in the way. In fact, every cell in the human body contains the genetic instructions for carrying out its own demise. And under the right circumstances, any cell will.

But scientists took many years to accept the theory of cell suicide and to appreciate that cells conduct their own deliberate and intricately orchestrated murder—a programmed cell death. "It's counterintuitive," admits Marie Hardwick, the David Bodian Professor of Molecular Microbiology and Immunology. Why would a cell kill itself? What good does it do the cell?

Yet Hardwick, PhD, has spent the past 20 years conducting experiments to demonstrate that programmed cell death is as vital to an organism as cell division, and championing theories (hers and others) about when and how cell suicide occurs. Those ideas have not infrequently clashed with scientific dogma, but Hardwick says that challenging convention is essential to good science. "If you don't predict things that are a little out of the box, you don't get anywhere."

Hardwick's office is on the fifth floor of the Bloomberg School. Her window offers a glimpse of the School of Medicine, where she has collaborated with many researchers. Hardwick has also worked closely with scientists at the Bloomberg School, Hopkins' School of Arts and Sciences, and institutions outside Hopkins. She is a basic scientist, who studies the cellular and molecular biology of programmed cell death. Investigators in many different specialties seek her advice and the tools of her lab.

"I think it would be hard to find a disease that does not entail programmed cell death," says Marie Hardwick

This research cuts across so many scientific disciplines because programmed cell death is a fundamental cell activity, says Hardwick. It is required for proper development; programmed cell death melts away the webbing between a fetus's fingers and between its toes. It destroys cells the body no longer needs; millions, perhaps billions of old cells—skin, liver, lung, intestine and other types—succumb to suicide each day.

Programmed cell death also guards against the slings and arrows of everyday existence. It helps fight off viral infections. It helps prevent cancer—the sloughing of skin following a sunburn being one visible sign of the body ridding itself of potentially pre-cancerous cells. And when apoptosis does not work properly, it can cause disease. Over-zealous cell death contributes to a variety of diseases, such as Alzheimer's disease and AIDS, while cancer involves too little cell death. "In my serious professional opinion, every human disease has the regulation of cell survival at its core," says Hardwick. "I think it would be hard to find a disease that does not entail programmed cell death."

Down the hall from Hardwick's office is her lab where a dozen graduate students and postdocs conduct experiments on cells from mammals, insects and yeast. In one small windowless room, graduate student John Clayton removes a Petri dish of mosquito cells from an incubator and places it on a microscope viewing platform. "Oh, my God. This is so dramatic," he exclaims, peering into the microscope. "Just an hour ago, I was looking at these cells and they looked okay. Now they're floating all over the place."

Healthy cells normally appear flat and asymmetrical, something like a bug gone splat on a windshield. But 20 hours ago, Clayton infected these cells with an engineered virus that carries a cell death gene. Now the cells are balled up, and small pieces have broken off, a process biologists call "blebbing." As Clayton moves the plate, these balls and blebs jiggle and roll. A more powerful microscope would reveal the tightly choreographed series of steps that take place during apoptosis, which comes from the Greek word for "falling off."

It was the sight of this death choreography that first sparked Hardwick's interest in cell death, when she was a graduate student in the late 1970s and early '80s studying the measles virus. Peering into the microscope every day, she found herself wondering exactly how the measles virus killed cells. Her advisor explained that a virus assaults a cell, like a hammer smashing holes. Hardwick was not satisfied. "It didn't intuitively seem logical to me. I remember coming away thinking, something else is going on."

A small number of researchers had been studying apoptosis, but few scientists knew about or were paying attention to this research. Interest grew in the mid-'80s when scientists working in cancer cells discovered a gene that appeared to prevent cell death. They named this first anti-apoptotic gene Bcl-2. At the same time, Robert Horvitz, an MIT biologist, was elucidating the genes that controlled cell death in the nematode worm, research for which he would eventually share the Nobel Prize.

Hardwick was enthralled by such findings, and after joining the Hopkins faculty in 1986, she became one of a small band of researchers who began to explore the molecular underpinnings of apoptosis. She also began talking about cell suicide to any colleague who would listen. Programmed cell death, says Hardwick, "has been the most fascinating thing that I've worked on. It's been this mysterious [idea,] a whole new way of thinking—that cells have a purposeful destruction mechanism. And that mechanism is key to health and key to disease."

Healthy cells normally appear flat and asymmetrical, something like a bug gone splat on a windshield. A cell in the throes of apoptosis loses the protuberances of its surface.

Uncovering those mysteries has been an all-consuming passion, although she devotes some of her free time to playing violin duets with her younger son and cooking with her older son, Matt Boersma, a Hopkins neuroscience graduate student. "I'm lucky my hobby is my profession," she says. "The thrill of finding something new is so driving. It's like putting together a jigsaw puzzle." The anticipation of finding where the next piece belongs sometimes keeps her awake at night.

At first, not everyone shared Hardwick's enthusiasm for this new field. She remembers speaking to members of the National Academy of Sciences who told her, "Oh, programmed cell death, that's preposterous!"

The skeptics had good reason to question the theory, acknowledges Hardwick. "We lacked hard evidence," she says.

So, piece by piece, Hardwick and other cell death researchers went about collecting evidence, which has turned out to be an elaborate assortment of genes and proteins—the components of the cell's death machinery.

Hardwick picks up a pen and some sheets of blank paper. She starts writing, and soon she has covered the front and back side of several pages with acronyms, arrows, symbols and terms, each illustrating a piece of the complex molecular process contributed by many different researchers.

A virologist by training, Hardwick began to study cell death by investigating whether the cell death gene, Bcl-2, would alter the course of a viral infection. Working with a mosquito-borne virus called Sindbis, she demonstrated that infection triggered cell suicide in various cell types. However, Hardwick took the experiment one step further. She and her colleagues genetically engineered some cells so that they contained extra copies of the Bcl-2 gene. They then infected those cells with the Sindbis virus. This time the cells did not undergo suicide. It appeared that Bcl-2 could help cells outwit an inducement to self-annihilation.

Hardwick reported her findings in the journal Nature. Since then, she and other investigators have shown that the anti-death apparatus (a broad family of genes that includes Bcl-2) can be more active in some types of cells than in others. This might be nature's way of protecting cells that come in limited quantities. If a virus infects the epithelia of the lungs for instance, those epithelial cells can kill themselves and easily be replaced by new cells. But if a virus infects a precious neuron, that cell might activate its mechanism for repressing cell suicide.

These findings help explain why some viruses can linger in the body for months or even years. The varicella zoster virus, for example, can cause chicken pox in a child, then lie dormant for decades until it flares up again to cause the painful red rash known as shingles. Where does the virus hide all those years? In neurons, but other viruses select different parts of the body where the cell death apparatus is idling. To make matters more complicated, some viruses (such as the herpes simplex virus, which causes cold sores) are endowed with their own version of anti-death genes, which enable the virus to prevent its host from committing suicide. It's like a thief disarming a house's burglar alarm, says Hardwick.

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