David Wright was tired of repeating the script "I'm sorry, but there's nothing we can do" to parents whose children had just suffered a brain injury. More than 2 million Americans suffer head trauma each year, yet no drug exists to stop the brain from wreaking havoc on itself in the ensuing chaos. In March 2010, Wright will launch a 5-year national trial to test whether progesterone, a hormone produced naturally by men and women and packaged in birth-control pills, can protect the brain after it's bonked too hard.
Wright expected to launch his own lab on skin research when he joined the faculty at the Emory University School of Medicine. However, he got sidetracked by professor Donald Stein, who had found a way to reduce brain trauma in rats. Female rats recovered better from head blows than male rats, and progesterone seemed to be the link, but Stein couldn't find a clinician to listen to him. Intrigued, Wright took a six-month sabbatical with Stein and replicated his experiments. He wrote the first National Institutes of Health grant in 1998 to use progesterone in a clinical trial, which he conducted between 2001 and 2005 with 100 traumatic brain injury (TBI) patients in an Atlanta hospital. Wright found that patients were more likely to live if they were given the progesterone, and the patients with mild brain injuries had better outcomes.
Now, the clinical trial will expand to 1,400 patients, who are enrolled (side-stepping normal consent requirements) if they are wheeled into trauma centers across the nation with brain injuries. The baby-faced neuroscientist—who, in his southern drawl, admits he was hit a bit too hard playing football in junior high—is antsy to know the results already. SciCom's Marissa Cevallos sat down with Wright in February at the 2010 meeting of the American Association for the Advancement of Science in San Diego, where he gave a talk about the trial.
The Iraq War has elevated traumatic brain injury to the public awareness and is steering more dollars toward research. Why was it underappreciated before?
To be honest with you, it's still underappreciated. It's still underfunded compared to cancer research. In medical school, you get a 30-minute lecture on TBI, maybe an hour, and you'll get 6 weeks on HIV.
It's almost taboo to have a brain injury. It means you're mentally impaired. No one wants to come out and be a spokesman. You ever see some star come out and talk about TBI?
What did Don Stein, the fellow who turned you on to treating brain injuries, tell you about it when you met a dozen years ago?
He knew progesterone helped the swelling. He had a few studies that validated it. He basically said, "I've done what I can do in animals. This looks like a treatment. Can somebody try it?"
How does progesterone stop swelling in the brain?
The skull is actually a fixed box. If you add any volume to a fixed space, what happens? There's pressure, and that pressure causes damage to the neurons and the blood vessels. Progesterone rebuilds the blood-brain barrier so when ions and water particles want to go across, they can't.
There's another way it works. If you bump your elbow and get a big bruise, your body makes more skin and muscle tissue. That's caused by cytokines that signal to the body, there's an injury here, send in the cleaners. Macrophages come in and clean up—they take a bottle of chemical, pour it all on the floor, and start sweeping it up. That's OK if it's your elbow, or even your heart. But tiny damage to certain areas of the brain is devastating. So when a macrophage [called a microglia in the brain] starts spilling its chemical to clean up, the problem is it's spilling it indiscriminately and it's killing neurons and pathways all around it that were working. The progesterone stops cytokine production.
How does the progesterone keep cytokine levels down?
It's a hormone. It turns on and off certain genes. Some of the genes it inactivates are cytokines. It probably has the same purpose in pregnancy. In third trimester pregnancy, you have a foreign body. You don't want mom to attack the baby. Progesterone probably protects the fetus from its mother rejecting it. We know this, because if your progesterone levels are low, you'll have a spontaneous abortion. All those little hints in nature are there.
Do you have friends or family with TBI?
I've had a mild concussion. The first time was falling off monkey bars in fourth grade. The second time, I was playing football. Anybody who's played football knows someone who's had a concussion. I've had chronic headaches since.
How'd it happen?
The monkey bars? I was swinging..
[Laughs] No, the football.
Oh yeah, yeah, football. Just got nailed, wasn't looking. I was confused, I didn't know which end we were supposed to be going to. I remember the coach yelling at me because I wasn't in the right position. But back in those days, it was a badge of honor. You just kept going. ‘Course now, they would have pulled you out of the game.
How did you know you had a concussion?
I knew I was dazed. I don't remember anything about the game after that, or that night.
Did you tell your family? Were you still wearing your badge of honor?
That's part of the problem with concussions. The person doesn't have any obvious evidence of injury. Your mind is going "What did I just say? What am I supposed to be doing?" That's one of the reasons it's been such a problem in sports and in people returning from the military. Unless a piece of shrapnel goes into you, or you tear your skin, you can't see what's happening in the brain. So it's a hidden injury.
Can people get counseling for TBI? Or is that a silent problem too?
"Families think, you're doing fine, let's get you back to your routine. In reality, you can't. Even if the patient survives, they come back and they're different."
Families think, you're doing fine, let's get you back to your routine. In reality, you can't. It causes struggles at work, at school, and with your friends. If everyone knew that up front, managing it would go a long way in the healing process. That's one of the things that's so devastating to families. Even if the patient survives, they come back and they're different. They could have emotional outbursts, drink more, or have problems with drugs.
Did you have any success stories from your first trial?
We had a patient, Marc, with severe TBI. He was close to being in a coma. But he was in our study, and we didn't know until the study was over whether he'd gotten the drug or not. [About three-quarters of the trial participants received progesterone; the others were given a placebo, standard practice in medical research.] But it turns out he was in the progesterone group, and he's totally normal now. He's an athletic trainer. His family says he's himself again.
Was it the progesterone? Or was he one of those rare people who had a bad injury, but did OK? We won't know until this new clinical trial is over.
The injuries people get are profound. There's no drug that's going to stop the bruising that occurs from the shearing and tearing. That's part of the primary injury. It's all that secondary stuff that happens, turning on the switch, where most of the devastation occurs. If we can stop that, maybe we can leave them with an improved outcome.
When will you know the outcome of the trial?
Not soon enough, that's all I can say. It will probably take 5 years.
If we're still in Iraq or Afghanistan. . . .
We're already developing an injectable form. If this turns out to work, there will be a progesterone auto-injector in the soldiers' medical kits.
Will the U.S. Food and Drug Administration adopt this quickly, if the study shows progesterone works?
They would probably approve this on an orphan status [an accelerated process for diseases with a small market] because of the safety profile of progesterone. It's so well known and it's been out there for other diseases. I would imagine they'd put this on the fast burner.
If the side effects are so benign, shouldn't you prescribe it all the time?
If it's cheap, and it's safe, why would you withhold it from a motor vehicle collision if someone appeared to be impaired? So what, they got a little dose of progesterone. Big deal.
You mentioned in your lecture that you work on injury prevention in Mozambique. When you first visited, what surprised you the most?
The poverty. Around the city are miles and miles of mud huts. They're all attached to each other. There's no electricity, there's no running water. It's just tremendous.
What do you do on your visits?
Injury is the second highest cause of death there after HIV. We train people to understand injury control who can advise the ministry of health, traffic, and police to create campaigns for people to wear seat belts. Within the main city in Mozambique, they do have paved roads and traffic signals, but no one obeys them.
The biggest problem with injury in a third world country is that once an injury has occurred, the hospital doesn't have the supplies to deal with it. You go to the ER and they have a couple of IVs, maybe some fluid, but they don't have a lot of supplies to take care of you. If you survive the injury, you might die in the hospital. There's seven surgeons in Maputo, the capital, where there's four or five million people. It's triaging to the ultimate.
How do they handle all those patients?
The disease burden is incredible. You go there and you know what's wrong with the patient, but you don't have the resources to take care of them. I wouldn't know what to do.
As a child, did you think you'd be a doctor?
My birth announcement—around the time of the space program—was "New Astronaut Comes Into the World." Really, that's what I wanted to do. I was in junior high when my mother developed breast cancer, and that got me thinking about medicine. Here was someone very dear to me who I could lose, and there weren't many treatments for breast cancer.
What happened with your mom?
She had a radical discectomy, where you take the whole breast off. They took the whole breast plus the muscle tissue, all the way down to the rib cage. She ended up having to have it done on the other side too.
Was she really proud of you going into medicine?
Yeah, she's proud. She's doing well, she's a survivor. She's 83 now.
What a woman!
What a woman.
With your new progesterone study almost underway, do you think you'll finally see an end to telling parents "I'm sorry, there's nothing I can do"?
Heck yeah, that's the reason I do it.
Marissa Cevallos, a graduate student in the Science Communication Program at UC Santa Cruz, earned her bachelor's degree in astrophysics from the California Institute of Technology. She has completed newspaper internships at the Santa Cruz Sentinel and the San Jose Mercury News, and will work this spring at the news office of the SLAC National Accelerator Laboratory. This summer, she will work as a Kaiser Family Foundation health reporting intern at the Orlando Sentinel.
© 2010 Marissa Cevallos
