San Francisco Chronicle - The Voice of the West, 901 Mission Street, San Francisco, CA 94119 - Sunday, January 12, 1997 - Page 1/Z1
Sabin Russell, Chronicle staff writer

At the stately Sagamore Hotel overlooking the lake, 400 scientists from around the globe were gathered to discuss an oddly appropriate subject for such a setting: programmed cell death, or cellular suicide.

This burgeoning new field of microbiology is grounded in the discovery that virtually every living cell carries within it the seeds of its own destruction. We are equipped with an array of death genes, and scientists are finding them.

"The blueprints of death are there, in every one of us," said Stanford cancer researcher Amato Giaccia.

The process of cellular suicide -- called apoptosis (ap-po-TOE-sis), a word that refers to falling leaves -- was described by biologists nearly 25 years ago. But only recently has it dawned on scientists just how broad a role it plays both in normal life processes and in disease.

The Lake George conference in October focused on cancer, but medical researchers studying a wide spectrum of illnesses -- Alzheimer's disease, stroke, arthritis and AIDS, to name a just a few -- are learning that the phenomenon may be crucial to their work.

"From the fertilized egg, until you die, apoptosis is a fundamental property of animal cells," said Dr. Martin Raff, a neurologist at London's University College.

A lanky, engaging man who bears an eerie resemblance to the actor Alan Alda, Canadian-born Raff is widely regarded as a leading light in the arcane field of apopotosis research. Yet he describes his subject in refreshingly simple terms.

"If a cell is injured or infected, it will activate this suicide program. If a cell becomes isolated from other cells, it kills itself. In every person, billions of cells die of this every hour. This is the way cells behave as good citizens," said Raff.

But when apoptosis fails, and the natural balance of cellular death and renewal is disrupted, "good citizen" cells may turn into psychopaths. The result can be the onset of disease that threatens not just individual cells, but the survival of the entire creature.

Cancer is the most obvious example. Apoptosis is one of nature's brakes on uncontrolled cell growth. If a cell senses that that its genetic machinery has been damaged -- a common condition that can lead to cancer -- it will kill itself for the common good. But if the death program is disabled as well, the cell is prone to multiply, unchecked, into an aggressive and potentially lethal tumor.

"There is a lot of reason to suspect that if we can understand apoptosis better, we can design drugs to tell cancer cells to do what they are supposed to do -- to die as aberrant members of society," said Douglas Hanahan, a cancer scientist at the University of California at San Francisco.

Scientists also believe that many autoimmune diseases, such as lupus and rheumatoid arthritis, may be caused by infection-fighting cells that hang around in the bloodstream longer than they should. Instead of dying, they begin to attack the body's own tissues. Committing suicide is a surprisingly neat and efficient way for a cell to die. It happens so quickly, so cleanly, that biologists basically missed it for decades. Stanford's Giaccia describes apoptosis as a two act-play. In the first part, a set of chemical signals -- originating either inside or outside the cell -- give the order to start the death program. The second part is the activation of what he calls "the death engine."

Locked inside chains of protein in every animal cell are sets of death enzymes called ICE proteases, which carry out the task of cellular suicide. So far, scientists have identified 11 such enzymes, which act like knives to cut up the vital internal works of a cell. When the death engine revs up, the ICE proteases are pried loose from their chemical chains -- and they in turn release more of their brethren, creating a cascade of molecular mayhem.

The tiny knives chew up the cell's DNA, the chemical blueprints of life. They butcher molecules that connect the cell to its neighbors. They clip the structural proteins that, like flexible tent poles, give a cell its shape.

Seen from the outside, the cell first detaches itself from its surroundings. Its contents "bleb," or slowly boil into bubble-shaped islets. Then the pieces -- each still intact -- are quietly cannibalized by neighboring cells. It can all be over in 20 minutes.

Scientists throughout the world are now feverishly dissecting the death engine and its signal system. By identifying both the components and sequence of programmed cell death, researchers think they can find ways to restart it when it stalls, or halt it when it slips into overdrive.

Too much apoptosis has its own set of devastating consequences:

-- Researchers at the National Institutes of Health reported last month that a mutant gene, carried by people with an inherited form of Alzheimer's disease, appears to speed up programmed cell death in brain cells.

-- Patients who suffer heart attacks or stroke and survive the initial event often die afterward, when apoptosis destroys heart or brain tissue in the hours after blood flow has been restored.

-- Overly active apoptosis may be the culprit behind progressive nervous diseases such as Huntington's chorea, amyotrophic lateral sclerosis (Lou Gerhrig's disease) and Parkinson's disease.

-- Programmed cell death may explain why HIV, the virus that causes AIDS, undermines the body's own complex system of self-defense. A core of AIDS researchers -- including Luc Montagnier, the French scientist who discovered the AIDS virus -- believe the microbe somehow tricks human immune cells into committing suicide without even infecting them.

The discovery that programmed cell death is a fundamental part of every animal cell has led some researchers to speculate that even the human lifespan itself is beholden to a predetermined death program.

William Clark, a retired UCLA immunologist and author of the book "Sex & the Origins of Death," notes that apoptosis will begin in human tissue cells, called fibroblasts, after about 50 rounds of cell division. "Death is too important to be left to chance," he said. "Programmed cell death is nature's backup mechanism, in case all else fails."

Most biologists take a more cautious view of the link between apoptosis and life span. "It is different from senescence. You don't get old and die because of programmed cell death," said University College's Raff.

Yet there is a widespread recognition among apoptosis researchers that they are studying a process with profound implications. "Death is just as organized as life," said Dr. David Wallach, a researcher at Israel's Weizmann Institute of Science. "We are looking for drugs controlling death."

A dignified, rangy man with a brow chiseled from granite, Wallach was an imposing figure at the Lake George cancer meeting. He said no one studying programmed cell death can escape the observation that death is a normal and necessary process.

"It is natural for death to occur, and can be very dangerous if it does not occur," he said. "This is a revolutionary attitude towards death -- that it is something to be accepted, that it is something that should occur at the right time."

A gallows humor permeates scientific research on the subject. The work is laced with death puns -- proteins involved in programmed cell death are named ICE, RIP, Reaper, GRIM. One team at University of Texas Southwestern Medical Center calls itself "The Death Squad."

Programmed cell death opens the imagination to a different way of looking at diseases. Instead of metaphors of war, where battling organisms attack, defend and destroy, apoptosis suggests a cloak-and-dagger netherworld, where cells are constantly passing coded chemical messages, spelling out orders to replicate, to change form or to die.

Indeed, many apoptosis researchers have come to the conclusion that death is a standing order for all animal cells, and that only by bathing cells with constant messages of reassurance -- Raff calls them "survival signals" -- do they keep their own suicide programs in check.

Gerard Evan, an ebullient young researcher at the Imperial Cancer Research Fund in London, draws a computer analogy. He said cells maintain their existence with a steady diet of data. Tiny proteins called growth factors instruct cells not to execute their death programs. "It's stay-alive software," he said. "Cells are kept alive not only by nutrients, but by software."

The spectacular growth in apoptosis research has been gratifying for biologist Andrew Wyllie of the University of Edinburgh in Scotland. A delicate man with a wisp of white hair and a keen intellect, Wyllie postulated the existence of apoptosis in a pathbreaking article published in the British Journal of Cancer in 1972.

The paper proposed that the same process that causes a tadpole's tail to disappear, or the webbing between the fingers of a human fetus to fall away, happens throughout life. Wyllie and co-authors Alastair Currie and John Kerr also predicted that failure of this unique death process would be found to play a role in cancer and other diseases.

After consulting with a resident classics scholar at Aberdeen University, the trio coined the apt but ungainly term "apoptosis" to describe this cellular suicide. "It means, `leaves falling away from trees,' " Wyllie said. For two decades, the work was largely ignored.

Then the painstaking work of a Massachusetts Institute of Technology biologist began to yield attention-grabbing results.

Robert Horwitz had made it his life's work to map the development, from egg to adult, of every cell of a microscopic roundworm, C. elegans. He and his colleagues discovered that precisely 131 of the nematode's 1,090 cells disappeared by the time it matured into an adult, and that those cells disappeared through a suicide program controlled by specific genes -- confirming Wyllie, Kerr and Currie's predictions.

"I thought that by studying cell death in a worm, we'd learn something," said Horvitz.

The big breakthrough occurred five years ago, when Horvitz's lab discovered that one of the genes involved in the worm cell's programmed death, dubbed CED-9, was nearly identical to a human gene, Bcl-2, implicated in a lymphatic cancer.

"That's what caused the community to sit up," said Horvitz. Biologists immediately grasped the implication: If the genes that control apoptosis in worms survived eons of evolution and still play a role in human health, then programmed cell death must be a universally important biological function. What's more, it tied a gene that slows down apoptosis to a human protein that was known to cause cancer.

"The stuff Horvitz did was fascinating," said UCSF's Hanahan. "It shows how disparate areas of research converge to discover something very important."

Since then, there has been an explosion of apoptosis research. Bcl-2, which was known as a cancer- causing protein, is now understood to be a potent inhibitor of programmed cell death, and scientists are attempting to figure out how it works, and how it could be turned on, or off, as needed.

Researchers are also focusing on the role of a protein called p53 that can order programmed cell death when genes in a cell's nucleus are damaged. When the p53 protein itself is hobbled, however, a cell cannot kill itself so easily, and cancer may develop. "Forty to 50 percent of all solid tumors involve mutations of p53," said Giaccia.

It will be years, if not decades, before practical therapies to treat cancer by tinkering with apoptosis reach the bedside. The biggest barrier is finding a way to use programmed cell death to kill only cancer cells, while leaving healthy cells alone. Scientists also know that apoptosis is dauntingly complex, and that there are many different ways cells commit suicide. "Apoptosis is so fundamental in cells that, if you knock out one pathway, there are still others. No one gene will protect you against apoptosis," Hanahan said.

But the hunt for death genes and the understanding of apoptosis is now widely regarded as an important step toward the hoped-for conquest of cancer.

For Andrew Wyllie, the intense interest in apoptosis is the capstone to a long career. "It is a very exciting experience," he said, "to see a whole field of biology developing under your feet."

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CAN CELLS BE TOLD TO SELF-DESTRUCT?

If apoptosis researchers have a Holy Grail in their quest for an anti-cancer drug, it would be a substance that killed cancerous cells while leaving normal cells alone.

At the American Association for Cancer Research's conference on programmed cell death in Lake George, N.Y., last fall, a quiet young Dutch scientist described a protein snipped from a chicken virus that appears to do just that.

Leiden University biochemist Astrid Danen van Oorschot told the gathering that a protein she called "apoptin" stimulated programmed cell death in a variety of malignant human cells grown in a petri dish, yet did not harm normal cells culled from human skin, muscle and immune system tissues.

Like most test-tube discoveries that seem promising at first, the chances are overwhelming that apoptin will turn out to have limited effectiveness -- or dangerous toxicity -- in human beings. But the humble strand of chicken virus is certain to draw more attention from drug researchers around the globe, and hints at the broader commercial possibilities that may spring from basic research on apoptosis.

"I think it's going to be a bonanza," said Gerard Evan, a cancer scientist at London's Imperial Cancer Research Fund.

In the Bay Area, a world center of biotechnology research, teams of scientists are weaving programmed cell death into their drug discovery efforts.

At Emeryville-based Chiron Corp., a small team of apoptosis researchers is studying ways to either block or promote programmed cell death with molecules so small they can be absorbed by individual cells. Animal studies are already under way on an experimental drug that promotes apoptosis in prostate cancer cells.

"When people first heard about apoptosis, they were skeptical," said Dr. Rusty Williams, president of Chiron Technologies, the research arm of the biotechnology company. "Now, it is quite clear that it is a specific process. The more you look, the more you see it in the body. The field is a wide opportunity, and a lot of companies will take advantage of it."

Venture capitalists have begun placing bets with a handful of new drug companies focused almost entirely on apoptosis research.

La Jolla-based Idun Pharmaceuticals in 1994 raised $7 million in venture capital backing, and since then has received an undisclosed sum from the giant Swiss drugmaker Ciba-Geigy. "We're focused on several aspects of death control," said Lawrence Fritz, Idun's vice president of research and development.

One of Idun's immediate targets is stroke, in which a blood clot blocks the flow of oxygen to parts of the brain. If a drug can be found to stop apoptosis in brain cells in the hours after blood flow is restored, brain damage could be substantially reduced.

Idun counts among its founding scientific advisers Dr. Stanley Korsmeyer, a researcher at the Washington University School of Medicine in St. Louis and a leading expert on Bcl-2, a protein inside cells that blocks apoptosis.

Company researchers have found that mice bred to produce excess amounts of Bcl-2 are better able to survive a stroke. On the opposite front, Idun scientists are looking for drugs that reduce Bcl-2 levels, in hopes of restoring programmed cell death in cancer cells.

Tom Chittenden, director of research at Apoptosis Technology Inc., a Cambridge, Mass., subsidiary of the biotechnology company Immunogen Inc., said the first large-scale human trials of cancer drugs stemming from apoptosis research are about five years away.

One approach being explored at Apoptosis Technology is to find a way to block the effects of Insulin Growth Factor-1, a molecular "survival signal" that under normal circumstances tells a cell not to activate its death program. Cancer cells may exploit this molecule by sprouting on their surface extra proteins to detect it -- in effect, turning up the volume of the "don't kill yourself" message. Chittenden's group is developing a drug that tones down that signal, making it more likely that a cancer cell will respond to internal messages ordering it to self-destruct.

"What is exciting people about apoptosis is that this is a different line of attack," said Chittenden. "Most chemotherapy drugs target the proliferation of cells. We want to regulate this intrinsic suicide mechanism."

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BAMBOOZLING THE T-CELLS

One of the great mysteries of the AIDS virus is why it kills so many T-cells, the white blood cells that are the foot soldiers of the immune system.

The answer, according to some AIDS researchers, may be that the virus can not only kill T-cells directly through infection, but can also trick them into killing themselves.

T-cells carry out their defensive role with an elegant mechanism for culling the body's own cells that have been infected by viruses. Instead of assaulting its target, a T-cell displays proteins on its surface that, like keys, neatly fit into suicide switches on the surface of the infected cell. A mere brush of this key, called Fas-ligand, against the suicide switch, called Fas, and the target cell's death program kicks in. Scientists call it the T-cell's "kiss of death."

The same process is used by T-cells to control their own numbers. Billions of them are created every day. If they are not quickly recruited by the immune system to battle a particular enemy, they dispose of themselves by displaying both Fas and Fas-ligand, triggering their own death sequence.

It is thought by some researchers that the AIDS virus has the ability to confuse T-cells into activating their self-disposal program without actually infecting them. Dr. Terri Finkel, a researcher at National Jewish Medical and Research Center in Denver, describes it as a "bystander effect."

She envisions a sequence like this: A fragment of HIV, the virus that causes AIDS, hooks onto the T-cell's outer surface. The T-cell misreads the viral fragment as a signal to prime its own death program. It prematurely sprouts Fas, the suicide switch, on its surface.

If that T-cell subsequently picks up the scent of an infected cell, it dutifully begins producing Fas-ligand, the key that will turn on its own suicide switch. As a result, the cell's death program goes off like a booby-trap.

"Instead of launching an offensive, it kills itself," said Finkel.

The theory is controversial. Many virologists, Finkel acknowledged, think this bystander effect is not unique to HIV, the virus that causes AIDS. But because studies show that more T-cells are killed by apoptosis than by direct HIV infection, Finkel believes that research may yet yield a new strategy to save T-cells in AIDS patients.
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