For a problem that has no doubt been around as long as humans have been falling on hard objects and bashing one another's skulls with clubs, brain injuries are still surprisingly mysterious.
Scientists, including a cadre at the University of Pennsylvania, are lifting the veil, though, and what they're seeing is already "dramatically" changing American sports, said Douglas Smith, who heads Penn's Center for Brain Injury and Repair.
Everyone from parents to pro athletes to military leaders is suddenly paying more attention to "mild" brain injuries, or concussions, and their long-term consequences.
Brain injury, Smith said, is the "signature wound" of the wars in Iraq and Afghanistan. That, coupled with a Philadelphia-based lawsuit by professional football players, who say the explosive hits they took on the job put them at risk for brain damage and dementia, has heightened interest in the damaged brain.
For a guy whose life's work had "no resonance" for decades, Smith says, this new popular fascination with brain injuries is "almost like winning the lottery."
There are still so many questions to answer. Scientists are only beginning to unravel why most who suffer mild traumatic brain injuries seem to recover just fine while some have lasting problems; why misshapen proteins associated with dementia develop in some brains after injury but not in others; or how those proteins affect thinking. They don't know how to fix the damage.
Smith said the study of chronic traumatic encephalopathy (CTE), the name for what happens to the brains of athletes whose heads take a lot of battering, is "not even to the starting line."
All of this is giving Smith and the 25 senior investigators who work with him at Penn plenty to do. Penn uses a multidisciplinary approach that brings together Smith, a doctor who calls himself a neurotraumatologist, with a loose coalition of neurologists, neurosurgeons, bioengineers, neuroscientists, neuropathologists, physiatrists, psychiatrists, and emergency medicine doctors. Several have their own labs. Smith says he has tried, unsuccessfully, to figure out how much grant money they all have, but says they attract "multiple millions" from the National Institutes of Health, the Department of Defense, the Veterans Administration, and foundations.
Smith likes to say their fields of study range from "molecules to man." For decades, the center has been known for its focus on "diffuse axonal injury," the stretching of fibers that connect nerve cells. Penn researchers are also working with Baylor University colleagues to develop biomarkers, the equivalent of a pregnancy test for the long-term brain damage in concussion. If doctors could predict which 15 percent of the 1.5 million concussions would cause long-lasting symptoms, they'd know which patients would make the best clinical trial participants. One researcher will soon test a drug in pigs as a precursor to treating children.
The center partners with a Scottish neuropathologist to study cellular changes in injured brains. And, Smith said, it's working on "living extension cords" to reconnect damaged nerves.
Ramona Hicks, a program director at the National Institute of Neurological Disorders and Stroke who oversees research traumatic brain injury research, was reluctant to compare Penn's center with others. She did say that grants are based on rankings by other researchers and that the Penn center has been "very successful" at securing funding. "They're strong in lots of areas," she said.
She added that Penn's work represents a "shining example of interdisciplinary approaches." It was in the forefront of studying neurodegeneration from brain injury, she said, and axonal injury is still under-studied elsewhere.
Smith, who at 53 still has thick brown hair and a retro mustache, was doing postdoctoral work in biochemistry when a friend suffered a brain injury while skiing. A CT scan revealed no problems, and the friend was expected to recover, but he was never the same. Smith switched careers and finished medical school in 1986, but didn't do the clinical training.
His colorful way with language is a plus for one who often must explain complex neuroscience to the public. It's not surprising that he plays a significant role in Head Games, a documentary about brain injuries in sports that was released last year.
In one of his favorite metaphors, Smith likens the brain to molded gelatin. Brain cells are injured as the gelatin sloshes against the hard skull and then rebounds. The axons, some of which are long enough to traverse the brain, are stretched or injured, disrupting the chemical and electrical signals they transmit. Injured axons can swell so much that they disconnect. If the connection breaks, they cannot be repaired - yet.
Unlike, say, your dog, who has a smaller brain and a stronger neck, humans are at a disadvantage because of our "weak little necks and the way our heads can roll around like a lollipop," Smith said.
He liked football, but his high school was too small to field a team. He still managed to get at least one concussion in a pick-up game.
Asked how long players with concussions should wait before playing again, he takes an extreme view: "I say 50 years."
It is well-known, he said, that even a single concussion increases the odds of developing dementia later. Doctors have known since the 1920s that boxers were at risk for a condition then called "dementia pugilistica." It's no surprise, Smith said, "that other contact sports with other repeated head injuries would have the same problem."
Smith's group is studying genes that may make some people more susceptible than others to pathological brain changes. About one-third of people with moderate to severe brain injuries develop deposits of amyloid - a protein that clumps in the brains of people with Alzheimer's disease - almost immediately. The Penn team identified a gene that almost all of them have. Another gene that puts people at higher risk for Alzheimer's also increases the risk of these brain changes after injury.
Someday soon, genetic tests may raise a new question: Should some people avoid contact sports or the military?
The center is on the verge of getting a Department of Defense grant to study what happens to tau, the other hallmark Alzheimer's protein, after axonal injury. It has been found in an abnormal form in the brains of athletes who suffered multiple concussions.
It's a lot to think about, and Smith is glad the country is finally paying attention to injuries that can be devastating.
"It was like coming to work one day," he said, "and all of a sudden, the sky is blue and we have some sense . . . that we can begin to solve some of these problems."