Back From the Dead

Dr. Lance Becker, director of Penn's year-old Center for Resuscitation Science, frequently dreams about mitochondria: tubular structures within cells, encasing convoluted membranes where oxygen and glucose combine to produce the energy the body uses in moving everything from molecules across cell membranes to barbells. Recently mitochondria have been in the news because they have their own DNA, which is inherited exclusively down the female line of descent, making them a useful tool for geneticists and anthropologists.

But Becker is interested in mitochondria for another reason: he believes they are the key to his audacious goal of tripling the time during which a human being can go without a heartbeat and still be revived. That the five-minute rule is not absolute has been known for a long time, and the exceptions seem to involve low temperatures. Children who fall through ice may survive unexpectedly long immersions in cold water. On Napoleon's Russian campaign, his surgeon general noticed that wounded infantrymen, left on the snowy ground to recover, had better survival rates than officers who stayed warm near the campfire. Becker is hoping to harness this effect to save lives today.

Becker is 53, slender and boyish in a way that belies his thinning hair; his typical greeting to colleagues is a jaunty "What's up, guys?" For his lab he has assembled a high-powered team from a wide range of specialties, including a brilliant young neuroscientist, Dr. Robert Neumar; an emergency-medicine specialist, Dr. Ben Abella; plus cardiologists, biochemists, bioengineers and a mouse-heart surgeon. His associate director, Dr. Vinay Nadkarni, comes from pediatrics. Becker has in effect re-created at Penn, on a more ambitious scale, the laboratory he founded in 1995 at the University of Chicago, with a grant of $50,000 from the philanthropist Jay Pritzker. Ten years earlier Pritzker had walked into the emergency room at Chicago's Michael Reese Hospital complaining of chest pains, and crumpled to the floor. Becker resuscitated him, the beginning of both a rewarding friendship (Pritzker lived for 14 more years) and a new direction for Becker's career. "Every day since then," he says, "I would go home and wonder why Jay Pritzker got a second chance and so many other people didn't."

Becker's interest in mitochondria reflects a new understanding about how cells die from loss of circulation, or ischemia. Five minutes without oxygen is indeed fatal to brain cells, but the actual dying may take hours, or even days. Doctors have known for a long time that the consequences of ischemia play out over time. "Half the time in cardiac arrest, we get the heart going again, blood pressure is good, everything is going along," says Dr. Terry Vanden Hoek, director of the Emergency Resuscitation Center at the University of Chicago, "and within a few hours everything crashes and the patient is dead." It took some time, though, for basic research to supply an explanation. Neumar, working with rats, simulates cardiac arrest and resuscitation, and then examines the neurons at intervals afterward. Up to 24 hours later they appear normal, but then in the next 24 hours, something kicks in and they begin to deteriorate. And Dr. James R. Brorson of the University of Chicago has seen something similar in neural cells grown in culture; deprive them of oxygen and watch for five minutes, or even much longer, and not much happens. "If your car runs out of gas, your engine isn't destroyed, it just needs fuel," he says.

Cell death isn't an event; it's a process. And in principle, a process can be interrupted. The process appears to begin in the mitochondria, which control the cell's self-destruct mechanism, known as apoptosis, and a related process, necrosis. Apoptosis is a natural function, destroying cells that are no longer needed or have been damaged in some way. Cancer cells, which might otherwise be killed by apoptosis, survive by shutting down their mitochondria; cancer researchers are looking for ways to turn them back on. Becker is trying to do the opposite, preventing cells that have been injured by lack of oxygen from, in effect, committing suicide.

It's a daunting problem. "We're asking the questions," says one leading researcher, Dr. Norm Abramson of the University of Pittsburgh. "We just haven't found the answers." Until recently, the conventional wisdom was that apoptosis couldn't be stopped once it was underway. It proceeds by a complex sequence of reactions—including inflammation, oxidation and cell-membrane breakdown—none of which seems to respond to traditional therapies. Becker views cell death in cardiac arrest as a two-step process, beginning with oxygen deprivation, which sets up the cell for apoptosis; then the heart starts up again and the patient gets a lungful of oxygen, triggering what is called reperfusion injury. The very substance required to save the patient's life ends up injuring or killing him.