Hidden in plain sight

by Sylvia Wrobel | Photography by Jack Kearse

Progesterone offers the hope of being the first new treatment for traumatic brain injury in 30 years and the first-ever safe and effective treatment. It was there, under our noses, the whole time.

The progesterone story began as a scientific puzzle, obstinately pursued by a stubborn Emory neuroscientist.What caused some female rats to survive brain injuries virtually unscathed while males with similar injuries died or had severe problems finding their way around once familiar mazes?

Many colleagues thought Don Stein was too obsessed with a potentially career-killing research dead-end. Two Emory doctors—Art Kellermann, then head of emergency medicine, and David Wright, an ER clinician and researcher—looked at Stein’s findings in rats and thought that maybe, just maybe, the scientist was on to something that could change the too often dismal outcomes of the traumatic brain injury(TBI) patients they saw in the emergency department. Other Emory doctors and researchers stepped up to help them find out, in a clinical trial funded by the NIH, conducted from 2001 to 2005 at Grady Memorial Hospital, where TBI patients arrive with heartbreaking regularity.

This winter, based on the promising results of that study, a second NIH clinical trial of the progesterone treatment developed at Emory will begin at 17 trauma centers across the United States, including at Grady. Headed by Wright, the study will enroll 1,140 TBI patients. If progesterone works as well as it did in the smaller trial, clinicians will have the first new treatment in 30 years, and the first-ever safe and effective treatment, for TBI. Progesterone could transform the way doctors treat head injury, not only in emergency rooms but also at the site of car wrecks or bombings and explosions in Iraq and Afghanistan, where TBI has become the signature wound.

The final answer could take five years, but hope of an effective treatment for TBI no longer sounds so crazy. Ask the NIH. Or, just ask Marc Baskett and his parents.

  don stein  

The journey of progesterone as a treatment for traumatic brain injury began in Don Stein’s lab decades ago. Working withrats, Stein wanted to know why female rats typically did better than male rats after brain injury. His search led him to progesterone, a naturally occuring hormone produced in the brains of both sexes. Turns out, he was onto something.


Coming to say goodbye

Three weeks before high school graduation, everything went dark for Baskett. He was riding in the car with his girlfriend near his hometown of Commerce, Ga. She had taken her eye off the road for an instant, then looked up to see a truck filling the windshield, crushing the passenger side of the car so completely that emergency rescuers at first thought Baskett had been thrown from the vehicle. Unconscious, unresponsive, he was airlifted to Grady, the region’s only level-1 trauma center, some 70 miles away.

There, a shifting phalanx of doctors began to treat the 19-year-old’s multiple injuries: damaged organs, cuts (650 stitches in his right arm alone), a metal rod through his knee into his shattered right femur, another rod to hold together his crushed ankle. But no effective treatment existed for his most devastating injury, that to his brain. Unable to open his eyes or respond to painful stimuli, Baskett scored 4 on the 15-point Glasgow Modified Coma Scale. He had almost no brain activity.

“Jeff and I believed we had come to Grady to say goodbye to our boy,” says his mother, Johanna Baskett. “And not just us.” It seemed as if half of the small town of Commerce had closed up shop and followed the popular young athlete to Grady. When a young woman asked to talk to the family about a study Emory was conducting, a dozen of Baskett’s coaches and teachers joined them.

The study coordinator explained that the researchers did not know if progesterone could do for humans what it had done in lab rats. In fact, ProTECT (progesterone for traumatic brain injury–experimental clinical treatment) was a pilot study designed primarily to evaluate whether progesterone could be safely and reliably administered intravenously. The 100 participating patients all would receive state-of-the-art care; 80 would be randomly chosen to also receive progesterone. The cluster of family and friends agreed that the Basketts should sign. They had nothing to lose.

Within minutes, a vial was added to the drip of medicines already flowing through Baskett’s veins. Because the study was double-blinded, neither his family nor the researchers knew whether the numbered vial contained progesterone or saline, a standard research method to make sure researchers do not unconsciously score patients in the experimental group as doing better. As the researchers would find out when the data were analyzed, Baskett was one of the lucky ones.

For three days, a steady infusion of natural, sterilized, human-grade progesterone bathed Baskett’s brain cells. Some cells had been killed outright by the impact and by the swelling that began even while paramedics rushed him to Grady. These cells would not revive (but other cells would take over some of their tasks). The progesterone treatment was intended to intervene in the post-injury destruction of injured cells or in further damaging healthy cells.

On impact, Baskett’s brain had slammed back and forth inside the inflexible skull. Injured nerve cells began releasing free radicals, toxic by-products that punched holes in the walls of nearby still-functioning cells. Other brain cells called glia worked to mop up dead or dying cells, only to collapse and die themselves, releasing yet more toxins. Hemorrhages of tiny vessels freed blood cells into the brain, and immune cells struggled to repel these unfamiliar invaders, causing inflammation and then more swelling.

According to Stein’s animal studies, progesterone should slow these processes down. And something appeared to be working for Baskett. After 2-1/2 weeks, he emerged from his coma, confused by the tubes, the blur of unfamiliar and familiar faces, but speaking, trying to smile. He had missed his high school graduation; his teachers brought his diploma to him. After three weeks, he was transferred to Children’s Healthcare of Atlanta for rehabilitation.

Given the usual outcomes, he could expect to be in the hospital for at least a year. But Baskett’s case was proving to be anything but usual. He left the hospital four weeks later, returning only to participate in a rehab program with a dozen others who had suffered car crashes, falls, a horseback riding accident.

“I didn’t feel like I was going through what they were,” says Baskett, “and I promised myself then I would do whatever I could to make sure other head injury patients had access to the drug that I knew I must have been given.”

A persistent pursuit

Don Stein sometimes jokes that his becoming a scientist seemed unlikely. “If you grow up in an apartment complex in the Bronx,” he once told a reporter, “the last thing your parents want you to do is to work with rats.”

As a graduate student in the 1960s, Stein learned just how much those rats can contribute to science. His job was to surgically injure the brains of anesthetized rats to see how the brain damage would affect their behavior. At the time, this approach was the basic tool critical to understanding the functioning of the nervous system in health and disease. What fascinated him, however, was why about a third of the female rats recovered, while others with the same injury remained seriously impaired.

His professors, like all neuroscience leaders at the time, thought the findings were merely natural variation in brain injury outcome because it was then taught that in the damaged brain, there was no possibility of repair or functional recovery. Stay focused, they urged. You have a PhD to complete, a career to build.

Thus began a kind of double life for Stein that would continue for more than two decades. He spent his days doing the more traditional “real work”—at the University of Oregon and MIT, where he completed doctoral and postdoctoral studies, at Clark University in Massachusetts, where he ran the brain research lab, and at Rutgers, where he was dean of the graduate school and associate provost for research. He spent his free time trying to solve the mystery of those injured but still normally functioning female rats.

When Emory brought him on board in 1995, it was not so much for his progesterone research but rather his administrative talents. Here too, for five years, he spent his days as dean of the graduate school and vice provost and his evenings in a research lab in a double-wide trailer previously discarded by the Veteran’s Administration, not uncommon during Emory’s then-building boom. With typical Stein humor, he purchased a stash of plastic flamingos from a nearby hardware store. The grounds crew would yank them up whenever they could, only to find a new pair gleaming in the morning sun. Stein finally decided he had been outsmarted when the crew replaced the lawn with a rock garden of artfully placed boulders.

When it came to his work with rats, however, he did not quit.

Since the females typically did better, Stein thought that the difference had to be hormonal. That helped explain anecdotal or single-case clinical reports that women were more likely than men to recover from similar brain injuries. Estrogen was the obvious candidate, but he observed no correlation between estrogen levels and recovery. He turned to progesterone.

;“Progesterone was hidden in plain sight as a neuroprotective agent,” says Stein. A naturally occurring hormone produced in the brains of both sexes, progesterone’s protective properties become most obvious during pregnancy when levels shoot up dramatically and stay elevated until the baby is born. Stein and others began to recognize that many processes involved in fetal development are similar to those that take place during tissue repair after injury. Perhaps, Stein theorized, the higher levels of progesterone in females at the time of their injury accounted for their better outcomes. And since progesterone levels fluctuate sharply during rats’ estrus and women’s menstrual cycles, perhaps the outcome depended on where females were in their cycle when injured.

By tricking the female rats’ bodies into thinking they were pregnant (a little like birth control pills do), Stein was able to produce high levels of progesterone in the animals. It soon became evident that female rats injured when their progesterone levels were high did much better after injury than either males or females with lower progesterone levels. The first thing he and his students noticed was that the high-progesterone females had virtually no brain swelling compared with those in other phases of their estrus cycles. He was on the right track. But would it work for males? And if so, why?

In the years since Stein’s graduate school days, science had advanced considerably. Brain swelling was recognized as a major cause of cell death after TBI. Many treatments, then and now, focused on preventing swelling to preserve still healthy brain tissue. In 1991, Stein and his laboratory put progesterone to the test. In earlier work, he had manipulated naturally occurring progesterone. Now he gave progesterone by injection to both male and female rats within
24 hours after identical brain injuries. The progesterone-treated male and female animals showed no signs of brain swelling.

Research elsewhere also had found that injured brain cells release free radicals and neurotoxins and that the immune response to injury causes inflammation. Stein showed that, in rats, progesterone also intervenes at these points.

  david wright  

Emergency medicine physician David Wright is leading the national research trial for progesterone, which patients will receive within four hours of traumatic brain injury. During the next four years, 1,140 brain injury patients will be enrolled across 17 different institutions, each at a level 1 trauma center.


Heroic attempt or pig-headed waste?

Although the scientific and medical world did not exactly beat a path to Stein’s trailer door, first the CDC and then the NIH began to support his work. A few researchers in other labs repeated his findings, validating his results. But what really turned the corner, says Stein, was when he met Art Kellermann, a passionate advocate for public health who introduced him to David Wright. For Stein, the maverick scientist, and Wright, the former flight physician and rock band drummer, it was the beginning of “a beautiful friendship.”

Wright wanted to believe that Stein had found something that would help brain-injured patients, but he also was a scientist. He had been part of the team that discovered the protein involved in Marfan’s syndrome (a disorder many believe afflicted Lincoln). With appointments in emergency medicine, injury control, biological and biomedical sciences, and biomedical engineering at Emory, he had strong and cautious research instincts. He carefully repeated some of Stein’s rat studies and got the same promising results.

After that, Wright too became convinced that progesterone held serious promise as a potential treatment for TBI. He and Stein worked with a statistician at Emory’s Rollins School of Public Health and with clinicians from neurosurgery, trauma surgery, and other Emory departments to design a clinical study to see if progesterone would work on injured humans without causing serious side effects. Progesterone had a long track record of safety for treatment of other diseases, but not at levels the researchers believed would be most effective for treatment of TBI in humans. In 2001, the first of 100 patients enrolled in a three-year pilot study funded by NIH and headed by Kellermann and Wright. All had suffered TBI within 11 hours before arriving at Grady, and all had an initial Glasgow Coma Scale score ranging between 4 (severe TBI like that of Baskett) and 12 (moderate TBI).

At the end of the study, Wright and others on the team went to Washington, D.C., to find out the results from NIH analysts, the only people aside from the team statistician who knew which patients had received progesterone, which placebo. The researchers’ nervousness was palpable. Were they closer to treatment?

Back in Atlanta, Stein was driving when his cell phone rang. When Kellermann told him to pull over before he heard the results, Stein’s blood ran cold. What worked in rats did not always work in humans. Would progesterone end up in the graveyard of failed neuroprotective drugs? Had his research career been a heroic attempt or a pig-headed waste of time?

Not only had progesterone caused no side effects, but fewer than half the patients receiving progesterone (13%) had died compared with those on placebo (30%). Furthermore, functional outcomes and the level of disability were significantly improved among progesterone patients with moderate brain injury.

Soon after, a similar study in China also found progesterone to be completely safe and patients receiving it to have superior outcomes at three and six months after the injury.

And in September 2007, a front-page article in the Wall Street Journal reported on Stein’s quest to heal brain injury.

Although not every progesterone patient in the Emory/Grady trial did as well as Baskett, there were a number of other marked successes, including a prominent businessperson who prefers that people don’t know about the injury and a young man who continues to pursue a successful, prominent athletic career.

Saving time and brain cells

Results in hand, Wright, Stein, and the team began planning a larger clinical trial to more completely test progesterone’s clinical effectiveness. The process involved six Emory departments and three schools (Emory’s schools of medicine and public health and Morehouse School of Medicine). Wright then reached out to potential partner institutions in a plan the size and scope of a small military campaign. Last fall, the NIH awarded the proposal more than $27 million in funding—news that again made the pages of the Wall Street Journal.

During the next four years, 1,140 TBI patients will be enrolled across 17 different institutions, each at a level 1 trauma center. Participating institutions will work under shared protocols and operating and quality control standards developed at Emory. The progesterone, a natural substance, will be purchased from a pharmaceutical company and prepared, tested for quality control, and packaged in Emory laboratories, then distributed to all participating centers.

As in the earlier study, patients must be 18 or older, with blunt head trauma (no penetrating injuries). In the new study, however, patients will begin treatment within four hours of injury. Given the safety results of the first study, the FDA will allow the use of exception from informed consent—a special research allowance for cases where time to treatment is critical to the conduct of the research. Patients will be monitored daily for safety and clinical management. At six months, memory, cognition, and behavior will be measured, with outcomes stratified by severity of injury.

The safety of progesterone makes for numerous possibilities, say the researchers. Stroke, for example. Stein’s recent animal studies suggest that progesterone is highly effective in reducing the size of blood clots and, unlike tPA, has no risk of causing bleeding in the brain. Wright and Michael Frankel, director of Emory’s Stroke Center, are readying for a stroke trial.

Children with TBI were excluded from the first progesterone studies because researchers were uncertain how the hormone would affect development. Clinicians in the Emory-Children’s Center, Emory Center for Injury Control, and Children’s Healthcare of Atlanta have brought their expertise to studies now being designed.

Stein, Wright, and the other researchers also would like to explore getting progesterone to patients faster to save more brain cells. They are working with Emory chemists to create a stable, heat-resistant progesterone product. If an injection device loaded with progesterone became part of emergency response med-pacs at home and in the military, a person with a possible head injury could receive an injection of progesterone at the scene of the injury.

The progesterone story—the science, teamwork, perseverance, and ability to think outside the box—shows what can happen when science is at its best.

The Basketts take a more direct view. “This drug and all the people who believed in it gave us back our son, with his mind, personality, and sense of humor intact.” EH

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