Mike Piazza remembers the first time he died.

He was pumping his failing brakes as he neared an intersection in Berkeley, but his tow truck would not stop and Piazza plowed into a parked semi.

Piazza's story begins like those of so many other victims of trauma. Some people recover. Some don't. Now some DNA researchers are set to find out why. They want to know how one trauma victim pulls through against all odds, while another dies.

Paramedics revived Piazza, 25, of Maplewood, after his crash.

That was Sept. 10, 2002.

He woke up in Barnes-Jewish Hospital 13 days later. His back was broken. His internal organs were in disarray. Burning metal had seared through his foot and knee and left scars all over his body. Surgeons removed almost 4 feet of his intestine. Piazza's husky body - he is 5 feet 8 inches tall and weighed about 215 pounds at the time - ballooned to more than 300 pounds as his immune system triggered massive inflammation.

A few weeks later, Piazza died again during a blood transfusion. Again doctors brought him back but didn't give his family much hope of recovery.

"They pretty much labeled me done, cooked," Piazza said.

But on Halloween, Piazza returned home after 52 days in the hospital. He was weak, exhausted and weighed 150 pounds.

Now, most people who meet Piazza can't tell he was ever in an accident, he says. He works at an auto supply store and has an auto repair business in his garage. He plans to wed his fiancee, Gina Imo, 26, in November.

For every Mike Piazza who pulls through, there is another person who should have gotten better and didn't.

Dr. J. Perren Cobb has seen it happen too many times.

"I'm completely frustrated and tired of standing at the foot of the bed with a loved one watching a young person die," said Cobb, a trauma surgeon and director of the Cellular Injury and Adaptation Laboratory at Washington University.

Cobb and his colleagues are about to start wielding one of the most powerful surveillance tools of molecular genetics in their fight to save lives. The tools are known as microarrays - DNA grids on glass slides or silicon chips no bigger than postage stamps.

Microarrays allow researchers to see the activity of every gene in the human genome at once - the molecular genetic equivalent of monitoring every citizen in a small city for signs of suspicious behavior.

The human genome project, completed this year, cataloged the entire set of genes that make up a human. (Scientists are still working to determine how many genes are contained in the chemical code of the human genome. Current estimates range from about 30,000 to 70,000 genes.)

Genes and disease

Geneticists traditionally have tracked down single genes that cause disease when they go wrong. Examples abound: cystic fibrosis, Huntington's disease, numerous metabolic disorders. All are caused by mutations in a single gene.

Most of the killers stalking people now - cancer, diabetes, heart disease, high blood pressure, obesity - are far more complex, says Dr. Paul A. Welling, director of the Functional Genomics and Molecular Medicine Training Program at the University of Maryland School of Medicine in Baltimore.

"In these diseases, it's not just one gene that's gone wrong," Welling said. "It's whole constellations of genes going awry."

In the past, scientists tracking syndicates of killer genes could do little more than round up a handful of usual suspects. Sometimes they uncovered some of the culprit genes. But scientists know that many more genes may be involved in the disease-causing syndicates.

"The challenge with complex diseases isn't that people aren't smart enough and aren't working hard enough, it's that the technology hasn't been there before," said Janet Warrington, senior director of Clinical Applications, Research and Development for Affymetrix, a microarray manufacturer based in Santa Clara, Calif.

Microarray technology was in its infancy in the mid-1990s as large-scale sequencing projects began to yield data about the genetic composition of worms, yeast, fruit flies, humans and other life forms. Researchers promised a whole new way of looking at genetic diseases. They said designer drugs and therapies created with the help of microarrays were just around the corner. And when the rough draft of the human genome was announced in 2000, microarray proponents said their techniques could help sift through the mountain of DNA data and uncover the true causes of disease.

"Three years ago, a lot of what you heard was hype," Cobb said.

But now microarrays are beginning to fulfill some of the promises.

"We're still learning"

Many researchers believe that microarrays are the best hope for uncovering the roots of illness. But in their zeal to understand diseases and relieve suffering, scientists sometimes can overlook the limitations of a promising new technology.

"My colleagues always ask me when we're going to see the payoff" from microarrays, Welling said. "It is expensive and it takes a lot of time. This field has been around for less than a decade and we're still learning how to do it right."

Over the course of the last decade, researchers published about 1,200 reports of experiments using microarrays manufactured by Affymetrix, Warrington said. About 600 of those reports hit scientific journals only in the last year, indicating an explosion in knowledge thanks to data from the Human Genome Project and the expanded use of microarrays.

At more than $1,000 a pop, commercially produced microarrays are too expensive for many academic researchers, Welling said. Many academic centers have established their own facilities to make the arrays, bringing down costs to hundreds instead of thousands of dollars per slide, he said.

"Cost is everything to all of us, but there is a trade-off between cost and quality," Welling said.

The process of making a microarray is technologically challenging. Each stamp-size glass slide carries a grid of 15,000 to 30,000 spots, each containing DNA from a single gene. Each dot is only 10 microns to 25 microns across - averaging about half the diameter of the finest human hair.

Studying trauma

Trauma researchers realized the limitations of the technology, but turned to microarrays, in part, because nothing else they have tried has worked, Cobb said.

For decades doctors have been looking for clues that would allow predictions about a patient's fate, said Dr. Bradley Freeman, a trauma surgeon at Barnes-Jewish Hospital and Washington University. But nothing - not age or degree of injury or health status or hemoglobin levels - has helped doctors understand why some trauma patients get sick and die and others don't.

Countless clinical trials that aimed at improving care for trauma patients failed, too. Some of the most promising therapies actually caused patients more harm than good.

So the standard treatment hasn't changed much, Cobb said.

"We stand at the foot of the bed and hold their loved one's hand and wait."

Researchers like Cobb grew increasingly frustrated with their inability to make a difference in the outcome for many victims of trauma. So when microarrays appeared, the scientists realized that they could use the devices to study trauma - one of the most complex assaults the body could ever face.

Cobb and Freeman banded with researchers from around the country for a massive study of trauma. The study is funded by the federal government under a so-called glue grant, which brings together scientists from several disciplines to work on one subject.

The researchers suspect that some secret ingredient in the genetic makeup of people like Mike Piazza could help them withstand trauma. Or maybe it's not so much that Piazza has better genes, but that his body knows what to do with them. Piazza's body may be able to turn on and off his genes in a way that promotes healing. People who aren't so fortunate may flip the wrong genetic switch at a crucial time and end up dead.

Cobb and his colleagues are proposing to collect blood samples from trauma patients at various stages of their stays in the hospital. Genetic material harvested from the blood samples would be placed on microarray slides or chips and read by a computer. Researchers then could compare results from trauma patients who recover with patients who die to detect patterns of gene activity that might indicate when a patient is in trouble.

Clinical payoffs

That kind of system could work for other diseases, too. By comparing the pattern of gene activity between, say, an aggressive tumor cell and a more benign cancer cell, researchers hope they will be able to tell what turns a tumor into a killer. Then, they may be able to interrupt the process that leads to death and cure the patient.

The new technology may find its way more quickly to the clinic for use against diseases that have well-defined treatment options, but Cobb and other trauma physicians and researchers have set much more modest goals. The trauma glue grant is not going to yield a magic bullet in a few years, Cobb said.

"We're so ignorant of the right thing to do that this $25 million grant will do nothing more than describe the degree of injury," Cobb said.

But Cobb remains hopeful that microarrays will lead to clinical payoffs. Laboratory studies of yeast, mice and worms suggest that the technology can help researchers understand disease and do something about it, he said.

But the multibillion-dollar question remains.

"Will we be able to do this in people?" Cobb said. "If you ask this very biased investigator, I'd say 'absolutely.'"

Reporter: Tina Hesman
E-mail: thesman@post-dispatch.com
Phone: 314-340-8325