Emory research offers new hope to those with brain injuries


The Atlanta Journal-Constitution
– January 1, 2011

Emory University professor Donald Stein became captivated years with ago with a question: Why would women recover better from brain injuries than men?

After years of research in the lab, he found a simple answer in progesterone. The developmental hormone turned out to have a remarkable ability to help lab rats recover from brain injuries. And Stein suspected that it could also help people recover from the devastating effects of car crashes, falls and assaults.

Stein's theory immediately encountered resistance in the scientific and medical community. "Everybody said this is ridiculous, it's just a female hormone, it's not going to work. You're a dreamer," Stein said.

But Stein didn't drop the work. He couldn't, after what he had observed in his lab. "The results were so clear," he said. "I was aggravated enough that I said I'm going to pursue this because it just seems so reasonable."

Stein is no longer the only believer. Emory University is now leading a major evaluation of Stein's theory, with a study sponsored by the National Institutes of Health that is testing the healing possibilities of progesterone on brain injury patients at 17 medical centers in 15 states.

The stakes are high because there is very little doctors can do to heal an injured brain, with study after study failing to find an effective treatment. And it's a serious public health problem: between 1.5 and 2 million people suffer traumatic brain injuries every year. About 50,000 of them die and another 80,000 are disabled for life.

"If this pans out and in fact does make a difference and helps people survive and recover, I think it will be considered one of the greatest medical discoveries of the century," said Dr. Arthur Kellermann, the former chairman of Emory's Department of Emergency Medicine who pushed Stein's research from the lab into the clinic.

‘Hiding in plain sight'

Dr. David Wright, an associate professor of emergency medicine at the Emory School of Medicine, is leading the national study and Atlanta's Grady Memorial Hospital is its lead hospital.

Wright has spent a career in emergency medicine. He has had too many heartbreaking waiting-room conversations with parents whose kids have been rushed to the hospital after a car accident.

"There are huge numbers of head injury patients coming into Grady and frankly there is nothing to offer them," Wright said.

It's not that scientists haven't tried. But time after time, the theories about what might help have failed.

That may be one of the reasons that Stein's theory was brushed off by so many people. It seemed too simple a solution for a problem that had proved so elusive. Progesterone is best known as a hormone that helps support pregnancy. But progesterone is also present in the brains of both men and women, and studies suggest is it a critical component of normal brain development. A brain injury begins with an event but continues as a process, with damage continuing after the trauma occurs. Stein discovered that progesterone administered within hours of the trauma can protect cells and tissues that might otherwise be damaged.

"In some respects, Don's discovery was hiding in plain sight for decades," Kellermann said.

Kellermann, one of the nation's leading emergency medicine and public health researchers, now heads the health research division of the RAND Corp. in Washington.

Stein, a neuroscientist who is the director of Emory's emergency medicine brain research lab, first identified progesterone's potential 25 years ago. The breakthrough that began to silence many doubters came when Kellermann and Wright persuaded the National Institutes of Health to authorize a small three-year study of 100 patients to determine whether the hormone was safe to use in brain injury patients. The results of the experiment conducted between 2001 and 2005 were electrifying: Not only did the study show progesterone to be safe, it strongly suggested that the hormone helped patients survive and recover.

Stein clearly remembers the moment when Kellermann called him from Washington, where the results were revealed. Neither Wright, Stein nor Kellermann knew, until the unveiling of the data in a hotel conference room, whether the experiment had supported Stein's theory or invalidated his life's work.

Stein was in his car driving on Ga. 400 near Sidney Marcus Boulevard when his phone rang. It was Kellermann.

"My first words, when I learned Don was driving, were, ‘Pull off the road,' " Kellermann said.

And then he told Stein the results. The news strongly supported his decision to ignore all the naysayers.

"When you have spent all of your life working on something and suddenly something like this happens," Stein said, "it's awe-inspiring."

Experiment continues

While the first study was promising, it focused on safety and did not definitely establish progesterone's effectiveness. That's what the current study seeks to do.

The study, which began last year, has already enrolled 130 patients. It will take about four years to complete the experiment, with a total of 1,140 patients. Half get progesterone. Half get a placebo. None of the doctors will know until the study concludes which patients got the drug.

Patients with severe and moderate brain injuries are eligible. To participate, a patient must be given the drug within four hours of the accident.

That need for quick treatment was one factor that led the study to seek — and gain — approval for placing people in the trial without their consent, a standard requirement in most medical experiments. Such trials are rare, Wright said, but this one was authorized because it met a set of criteria: no alternative therapy, no way for patients to consent to enrollment themselves and a critical time window for treatment. The study does, however, include a consent process if a patient's family arrives at the hospital in the first hour after the accident.

Hopes for a positive outcome have only increased since a small study in China in 2008 also found that progesterone helped with survival and recovery.

"The burden of this disease far outweighs many of the much more well-known and funded diseases," Wright said. "Nothing against breast cancer, nothing against HIV, nothing against any of those, but the numbers [for brain injury] trump any of those."

Marc Baskett has been convinced for years that progesterone is a powerful healer of the brain.

Baskett was only a few weeks away from his high school graduation in 2004 when the car in which he was riding veered into oncoming traffic and crashed. Baskett's side of the car was crushed. Unconscious and not responding, he was airlifted to Grady.

Doctors determined that Baskett had a severe brain injury. He was in a coma. And it was so bad that his parents began to prepare themselves for the possibility that their son, a popular athlete at the beginning of his adult life, might soon be dead. Baskett's doctors asked whether they could enroll their son in the first clinical trial of progesterone and they quickly agreed.

"My parents didn't hesitate," Baskett said, "because they knew I was one foot in the grave and one foot on the banana peel, as my mom said."

If Baskett survived, his parents were told he could expect to be in the hospital for a year. While they couldn't know at first whether he got the drug or the placebo, Baskett's parents soon began to believe that he did get the progesterone. He came out of the coma after 2 1/2 weeks. Four weeks later he was out of the hospital — his broken bones needed time to heal, but his brain seemed to be working.

"I was in the hospital for a total of seven weeks, when I should have been in there at least a year," Baskett said.

After the clinical trial was over, Baskett was told that he did indeed receive progesterone, not the placebo.

Today, Baskett is 26. Amazingly, he is fine. He won't be the professional athlete he once aspired to be, because of a shattered ankle sustained in the crash. But the part of his body his parents worried most about — his brain — completely recovered. He works in his parents' cleaning business as well as a side job. He's invested in some low-priced real estate that he hopes will someday give him financial security. But he knows he is lucky. Doctors say he had an 80 percent chance of a permanent disability. And he knows another young man from his hometown who had a very similar injury who will never be able to take care of himself.

Baskett said he was "very, very grateful" to have ended up in the study: "I think it's an amazing drug."

Whether it truly is the cure that scientists have been searching for won't be known until the trial is over.

"Are we really going to be the first success?" Kellermann said. "Many other promising drugs have failed at a certain point."

The results already mean that the scientific community can't brush off Stein's theory.

"Thanks to the NIH, they're in a position to get the definite answer," Kellermann said. "If the answer is positive, this is Georgia science done in Georgia's top trauma center in a leading medical school based in Atlanta. And that's really cool."