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The Stem Cell Divide

AMACOM BOOKS

Chapter One

It is strange to think that a tiny piece of matter, so small that it cannot be seen by the naked eye, could change the entire world. And yet, the promise of the human stem cell is as vast as anything the scientific community has yet seen.

Stem cells have two unique properties. First, they can give rise to other more specialized cells of the body, particularly in the case of embryonic cells. Second, they are self-renewing, with the ability to grow in laboratory culture for long periods without losing their ability to give rise to other cell types.

But stem cell biology is also replete with unanswered questions. Only a few can be definitively answered today, but there are signs and portents in abundance that offer us clues as to where the research might yet lead.

Human stem cell research is a young field-arguably dating back to as recently as 1998. But it is a pivotal one. Perhaps no other area of research today offers as great a potential for alleviating great amounts of human suffering. Consider one possible scenario that could easily take place in the next decade or two.

Shortly after dawn on a humid July weekend, the worst storm seen in a decade engulfed southwest Colorado in black, roiling thunderclouds. Leaden sheets of rainpounded the landscape, opening up sluices where earthen cracks or old ditches lay open to the sky. The stretches of prairie to the east absorbed most of the water like a grass-covered sponge. But near the towns of Cortez and Yellow Jacket, only a few plants broke the expanse of gray silt and pink gravel: handfuls of mesquite trees, patches of blue stem, and a few scraggly tumbleweeds that looked like refugees from a B-grade western.

Flash flood warnings crackled over the radio and the CB frequencies used by truckers and highway patrolmen. Most of the drivers on the main highway, Route 666, coped with the blinding rain by pulling to the side of the road or sheltering under a convenient overpass.

Route 666 is often referred to by locals in three states as "Satan's Highway" or the "Highway to Hell." The road owes its colorful nickname to the unfortunate coincidence of the "number of the beast" cited in the New Testament. However, the name is fairly well given. Route 666 is a tortuous stretch of asphalt running through high desert and golden layer-cake mountain canyons stretching hundreds of miles from Arizona to Utah.

The road holds two claims to fame, or at least infamy. First, there is an ongoing problem with signage theft. The local police blame thieves looking for souvenirs and not the Devil, who is presumably occupied with more important things than stealing highway signs. Second, Route 666 has some of the highest fatalities per mile of any highway in the southwest. This is in part due to the questionable condition of the road, which suffers from frequent rock falls, gaping potholes, and washouts.

Kelley Michaelson, a twenty-year-old junior at the University of North Carolina, uttered a small curse as the rain spattered across her windshield. She shifted her Hyundai SUV into a lower gear and switched her lights on. The northbound lane she was in began to slow, but the traffic kept moving. Since she was getting off in the next couple of exits, she thought she could make it through okay despite the torrential downpour.

Kelley was a compactly built young woman with shoulder-length brown hair, a dark tan that masked a crop of childhood freckles, and a no-nonsense attitude. She was a standout at UNC in both her anthropology classes and women's track events.

Her friends had encouraged her to leave behind anything relating to her major over the summer. But with graduation a disturbingly close apparition on the horizon-and the prospect of graduate school only a little further out-she needed more field experience, and some cash. With more than a few persuasive phone calls, she'd finally snagged a paid internship doing fieldwork at one of the Native American ruins out west.

The job met her expectations. It gave her some pocket money as well as some badly needed references. She had picked up the deft sureness of the senior hands at piecing together shattered pottery. She'd also learned the useful "annoyed scowl" that kept the tourists from constantly going "Whattaya doing?" while she was trying to work.

Back East, Kelly had never seen anything like that storm she was now facing. She couldn't see more than a couple yards through all the rain and wind. Suddenly, some kind of sound began cutting through the din of the beating raindrops and the howling wind. One part monster-like rumble, two parts banshee shriek. The sound of metal scraping on asphalt. Goosebumps rippled up her arms as the sound ratcheted up the Doppler scale. It was heading her way.

Ahead of Kelley's car, Route 666 made a wide turn, slashing through the side of an inconvenient hill as it angled towards the left. The hill was not solid. It was made up of tumbled, rough-edged stone ranging from suitcase to boxcar size.

The bare, water-saturated soil gave way and tore loose from the slope, taking a sizeable chunk of the hillside with it. The mass of dirt and rock punched through the cement barrier at the end of the road. It spilled across the southbound lanes, coating the asphalt with a deep layer of slick mud and a jumble of loose stones.

As the southbound lanes disappeared under the wave of mud, a heavily loaded big rig truck slid out of control. The rig jackknifed, skidding into the highway's open center divide. The rig's tires blew out on the sharp gravel like gunshots. The trailer swung around the cab and into Route 666's northbound lanes like a steel wall.

Blinded by the rain, the only hint that the northbound traffic had as to what was coming was the high-pitched squeal of the trailer scraping across the asphalt. In a ghastly domino effect, twenty cars piled into one another and the rig's trailer. One of the cars burst into flame. The fireball rose into the gunmetal gray sky, adding a hellish orange flicker to the morning light.

Kelley saw the chaos ahead only for a split second. The red brake lights of the cars ahead glowed bright red, then pinwheeled in all directions. She swerved desperately to avoid broadsiding a blue pickup that veered into her path. The SUV skidded completely around before it crunched into the mass of cars. Her windshield shattered and she closed her eyes as a bright glare poured through the open space. She felt another car slam into her. The white brilliance of xenon headlights plunged into black, and she immediately lost consciousness.

After the Crash

The first responders decided right away to call in helicopters to airlift the worst cases to the nearest ER. After a quick consultation with authorities in the neighboring states, the helicopters were sent to a hospital in Gallup, New Mexico.

Kelley arrived in dire straits. The staff treated her for assorted bruises and lacerations, but by far her worst injury was a spiral fracture of her left femur. The femur is the thickest, strongest bone in the human body. Kelley's had snapped like a wet matchstick in the mass collision.

Initially, she appeared to make good progress towards recovery. In the first forty-eight hours after the accident, she was awake and lucid, even under heavy pain medication. Her parents flew to Gallup and found her in good spirits. In a separate operation, her femur had been set with rods and plates without incident and the initial healing had begun.

On the third day, Kelley began to complain of a pain in her gut. It was a shooting, twisting pain, and she cried out if anyone touched her abdomen. She was checked for appendicitis, and an ultrasound examination of her organs did not detect anything unusual. She became unable to keep food down.

Kelley began to regurgitate in increasing waves of severity, continuing long after her stomach was empty. The thin gruel of fluid in her vomit had the bitter smell of bile. Her eyes became watery and bloodshot, she became less responsive to stimuli, and her face turned a soupy whitish color.

Kelley's physician, Dr. William Glazier, was one of the lead surgeons at the hospital. He had had his hands full as the accident victims had arrived en masse by air rescue. Glazier was a Minnesota native who had moved to Gallup ten years earlier when his wife demanded that they live closer to her family. He was known for being somewhat short-tempered. This was in part because he was constantly pushing for the hospital to keep up with the latest surgical techniques. Mostly it was because, although his first name was William, people kept calling him "Gil", as he bore a striking resemblance to Gil Grissom, the main character on the television show CSI.

Kelley's condition was a mystery, but Glazier had one clue to go on: The young woman's tests showed that she had elevated levels of amylase and lipase in her bloodstream. Amylase and lipase are digestive enzymes formed in the pancreas. The abnormal spike in these substance's levels was a clear indicator that pancreatitis-inflammation of the pancreas-was evident, even if the cause was not.

Pancreatitis was very bad news. In severe cases, there may be bleeding into the pancreas, serious tissue damage, infection, and cysts. Enzymes and toxins leaking from the damaged organ may enter the bloodstream and severely injure the heart, lungs, and kidneys.

Marrow of the Matter

Further examination showed that Kelley's pancreatitis had been caused by a rare but not unknown event known as a "fat embolism." The primary location of human bone marrow, the material which produces the oxygen-carrying red blood cells, is inside the body's long, thin bones. When one of these bones-such as Kelley's femur-is shattered, marrow fat is commonly released into the bloodstream. These droplets of fat scatter freely through the body, similar to the way a gobbet of hot fat will jump out of the frying pan when the burner is turned to "high."

Most commonly, the body will reabsorb this fat. Some may be deposited in the lungs. Other fat droplets can lodge like leaves in a storm drain in organs like the brain, kidney, and skin. In Kelley's case, they had lodged in the vessels that supplied blood to her pancreas. The organ, deprived of its cellular needs of oxygen and waste transport, had died. The resulting rot was slowly spreading and the process was irreversible.

The pancreas is one of those amazingly complex, subtle organs. We don't even know everything it does-only that you can't function without it. That's why pancreatic cancer is a death sentence. But Glazier wasn't about to go out to her parents and tell them that it was time to say good-bye to their daughter.

Glazier conferred with the hospital's director and convinced him that this was a textbook case where the use of stem cells could be the difference between saving or losing the patient. Simply put, Kelley Michaelson needed a new pancreas if she was going to live. By using a nucleus from one of her cells, it would be possible to create a new, genetically identical organ for her. This form of therapeutic cloning wouldn't run the risk of transplant rejection. Her own white blood cells wouldn't even notice the new pancreas as anything but the body's own.

The question now became which stem cell facility could create a new pancreas for Kelley in time. The Supreme Court had steadfastly refused to make a concrete decision, concerned about further politicizing the issue in the manner of abortion. So the matter had been kicked back to the state level, with mixed results.

The medical facilities that could handle and direct high-speed stem cell growth had been growing, but were still small in number and always in high demand. One facility in Arizona was not yet up and running. The stem cell center in Denver was in the middle of a batch of critical experiments and could not be interrupted.

The search continued further afield. The issues involving stem cells were still being debated in California, the labs in Michigan were booked solid until the next decade. There was one facility sitting idle in Amarillo, Texas. The area is home to over 300 Evangelical churches, and they didn't approve of the use of embryonic stem cells.

Ironically, the right timing and the right facility was available-at the medical school of Kelley's college, the University of North Carolina. Dr. Susan Nguyen, the director of Therapeutic Genetic Research at UNC, called Glazier immediately upon hearing of his need. She confirmed that they had the equipment that could quickly recreate the damaged organ.

Staff at the hospital in Gallup took a sample of healthy cells from Kelley and prepared the sample for immediate shipment. Not one to take chances, Glazier hired a professional courier service, one that was experienced in transporting items as varied as exotic deepwater fish or a shipment of live brain tissue. Within seven hours, the sample had been handed off to the doctors at UNC.

Road to Regeneration

Dr. Susan Nguyen is the daughter of two Vietnamese doctors who had fled Vietnam during the fall of Saigon back in 1975. She is coolly contemplative and direct to the point of being blunt. Despite the availability of inexpensive vision correction surgery, she continues to wear glasses that hold thick lenses in a sturdy tortoiseshell frame. Her explanation for this anachronism is that while she understands genes and cell cultures, she is terrified of scalpels, lasers, and needles.

Dr. Nguyen took one of Kelley's cells and teased the nucleus from the cell's cytoplasm with a tiny glass pipette. She then painstakingly transferred the nucleus-the microscopic dot containing all the genetic information that made up the young woman who lay dying in a hospital in New Mexico-to the inner mass of a fertilized egg whose nucleus had already been removed.

The images Dr. Nguyen used to complete the transfer were projected in a nearly three-dimensional view screen. Her instruments precisely scaled her movements down so that she could manipulate all the pieces of the cellular jigsaw puzzle with relative ease. Even so, it wasn't until some time later that Nguyen called her task complete.

The newly created hybrid cell rested securely in its accelerator growth medium. As she watched, the cell's installed genetic "machinery" took over and began to divide at an astonishing rate. As the cells continued to split and multiply, the researchers at UNC were alert to the cell's needs and re-plated the colony on fresh culture dishes.

The rate of division and the level of cell differentiation were watched as closely as the volatile pile of rods in the core of a nuclear reactor. Too little in the way of nutrients was like placing too much graphite between the rods of uranium in the reactor: By starving the reaction of fuel, the fire would go out. On the other hand, overabundance of resources risked a cellular meltdown: Cells would begin to grow uncontrollably and mature to the point where they lost the ability to morph into the kinds of cells that were needed.

Dr. Nguyen points out that a lot of people think that it's a challenge to get stem cells to grow on culture medium. "That's not just wrong," she says, "it's exactly wrong. These cells just love to grow-it's what they're designed to do! Our problem is convincing them to grow just in the way we want them to."

The dimpled, yellow clump of undifferentiated stem cells, each bearing Kelley's unique genetic blueprint was the size of a pinhead when it was next placed in a bioreactor chamber. The shiny plastic vessel looked like an ice-cream maker as re-imagined by modernist architect Frank Lloyd Wright. Tubes connected to the unit at impossible angles served to manipulate the growth medium with complex combinations of human growth factors and organic compounds.

These mixtures, incomprehensible in composition to anyone without a Ph.D. and carefully guarded by individual researchers, acted like flagmen directing fighter jets to land on a crowded aircraft carrier. Amount X of Factor Y told the cells to grow in one direction. A different amount or combination nudged the development in another way. The mixture injected into the bioreactor by Dr. Nguyen and her staff gave a direct order to the clump of cells: to quit remaining in a sort of biological "ready state" and differentiate.

(Continues...)

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Excerpted from The Stem Cell Divide by Michael Bellomo Copyright © 2006 by Michael Bellomo. Excerpted by permission.
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