he long and winding road to a cure for paralysis runs straight through the University of Miami School of Medicine. Here, unrivaled new facilities house the most active and productive neuroscience center in the world focusing on paralysis and spinal cord injury. Because of the dedication and brainpower of top clinicians and scientists, and the means to make things happen, The Miami Project to Cure Paralysis is making progress toward solving one of medicine’s most ambitious objectives. “History tells us that by communing a massive amount of human, technical, and financial resources, you can do what is thought to be impossible,” says Miami Project cofounder and neurosurgeon Barth Green. “There is a lot of excitement here now, a tremendous amount of momentum. I’m convinced there is a solution.” The beginnings of The Miami Project are intertwined with Barth Green’s emergence as a renowned neurosurgeon. After completing his residency in neurosurgery at Northwestern University, he was hired by the University of Miami and Miami Veterans Affairs Medical Center to build a spinal cord injury program. He built a laboratory, hired technicians, and began a number of research projects with funds from the National Institutes of Health (NIH) and the VA. By 1985 the NIH was faced with having more good research applications than dollars of support.

Frustrated and discouraged, Green was about to abandon his research when several children from some of Miami’s most influential families coincidentally became paralyzed in a string of tragic accidents. Within a few months, a core group headed by Don Misner, Beth Roscoe, Nick Buoniconti, Tom Bomar, and Bill Ryan had collected $1 million to support Green’s research. He immediately began to lure some of the best scientists in the world, and The Miami Project to Cure Paralysis was born.

Today, still relying heavily on private donations, The Miami Project has received more than $85 million in philanthropy to further its research. This strong support has enabled the project to achieve a series of impressive clinical, patient care, and scientific breakthroughs that have earned it a reputation as the leading spinal cord injury research center in the world.

nlike programs focusing entirely on laboratory research, Miami Project clinicians and scientists take a holistic approach to spinal cord injury. They tackle practical problems, such as bladder control and intractable pain, in order to change the quality of life for people confined to wheelchairs. They rehabilitate the injured body to improve strength and circulation and activate deep-seated, involuntary motor control circuits.

In state-of-the-art laboratories, Miami Project neuroscientists, cell biologists, geneticists, electrophysiologists, and biochemists employ the latest scientific methods to find procedures and treatments for reversing paralysis. Some are focused on developing new drugs and protocols to help the spinal cord survive its injury. Others are directed toward the regeneration of damaged nerve fibers across the area of injury—a process that will allow messages from the brain to reach the area below the injury.

While a solution that enables paraplegics and quadriplegics to toss aside their wheelchairs and resume a normal life remains elusive, progress comes as scientific obstacles are surmounted one by one. Although less dramatic than a total cure, these findings are playing important roles in limiting the damage from spinal cord injury and improving quality of life.

“Advances have been made in the development of better and safer technology for spinal cord monitoring in the operating room, as well as in new agents given to patients immediately after injury to protect the spinal cord, and emergency protocols that prevent patients from suffering potentially fatal reactions, such as a drop in blood pressure, body temperature, or hypoxia (lack of oxygen),” Green says. “Much of this work has come from The Miami Project.” The pro-ject also was the first to offer scientific proof that functional electrical stimulation makes muscles contract more effectively than conventional exercise and is important in the rehabilitation process, and to prove conclusively that most people who are paralyzed can have their own children.

Recently, a Miami Project researcher discovered the importance of gender in the response of the nervous system to injury. A neurohormone missing in men and postmenopausal women may be protective in spinal cord and brain injury. Another researcher has detailed the delicate natural balance between proteins that kill other cells and ones that save injured cells. Collaboration with pharmaceutical companies is essential to produce drugs that help both processes work.

Advances such as these could do much to improve quality of life for people with spinal cord injuries. “When you talk to a spinal cord-injured person, getting up and walking is not the first thing they mention,” Green says. “It’s bladder control, bowel control, return of sexual function. For quadriplegics, it’s getting off the breathing machine or enabling their fingers to work so they can drive a car or use a computer. I think that restoring function in an arm or hand or getting people walking again is a pretty realistic expectation in the next five to ten years.”

As scientific director of The Miami Project, neuroscientist Dalton Dietrich continuously evaluates where the research is headed and what is needed to make progress. With an abundance of enthusiasm to match his knowledge, he is a strong advocate of the environment that moves The Miami Project in the right direction.

“This is not an ivory tower,” Dietrich points out. “We put basic scientists beside clinicians who work with patients every day so we can exchange ideas. We also have M.D.-Ph.D.s on staff who conduct research three days a week and perform surgery on the other days. These folks have an excellent perspective.

“I think this is the most exciting area of medicine,” he continues. “Every day you learn something. You figure out a little part of the puzzle, and you make progress to open the door.”

Miami Project clinicians and scientists agree that functional recovery will probably result from a combination of strategies that include neuroprotection, regeneration, and rehabilitation.

The first goal is to enable the spinal cord to survive after being severed or crushed. The sudden decrease in blood flow causes tissue to die. Scientists discovered that giving patients a steroid called methylprednisolone (Solu-Medrol) within eight hours can prevent a number of secondary injuries. “A big push is to develop new drugs to treat the patient in the early injury setting to make the contusion smaller,” he explains. “If it’s smaller, you’re going to have an easier time promoting recovery.” Dietrich and his team also recently reported that mild hypothermia is protective after spinal cord injury.

But the most exciting thrust can be found in the area of nerve regeneration, or regrowth—an extremely complex process. “It’s a five-step process. We have to get the nerve cell to survive, regrow its process (tail), grow across the injury, grow into the right area of the spinal cord, then make a connection,” explains Mary Bunge, lead researcher at The Miami Project.

About ten years ago, researchers discovered a way to regrow neurons. Now, efforts are focused on forming cellular bridges across the area of injury. The research involves Schwann cells, which apparently release a type of growth hormone that fertilizes nerves, encouraging their growth. However, Schwann cells are found only in peripheral nerves.

Bunge and her husband, the late Richard Bunge, longtime scientific director of The Miami Project, were pioneers in Schwann cell research. These cells, which wrap around, or ensheathe, the long tail of the nerve cell, help speed messages between the nerve ending and the brain. When a peripheral nerve is damaged, it grows back through the existing tunnel of Schwann cells. Mary Bunge and her colleagues at The Miami Project have transplanted cables of Schwann cells in spinal cord-damaged rats and found that the nerve fibers will grow across the Schwann cell bridge.

The use of olfactory ensheathing glial cells is another approach to bridge-making. These unique cells are found only in the nose, one of the few areas where new nerve cells are continuously replaced throughout life. When a new nerve cell is born, olfactory ensheathing glial cells escort the nerve fibers that grow from the new nerve cells in the nose to the brain. When placed in a severed spinal cord next to the Schwann cell bridge, these cells help escort nerve fibers from the bridge into the spinal cord.

The number of olfactory ensheathing glial cells needed for human research, however, is difficult to obtain, and exactly how these cells work is still unknown. For this reason, The Miami Project continues to focus on research with Schwann cells, millions of which can be quickly grown in the laboratory from one inch of ankle nerve.

rowing nerves across a bridge is only one step toward a solution. The next challenge is getting the nerves to leave the bridge and grow into the cord, hopefully completing the connection. Inhibitory molecules at the junction appear to prevent this from happening. For five years, The Miami Project has used sophisticated gene chips that reveal which genes are being expressed by a tissue sample. Scientists hope to identify several possible proteins that may play a role in the inhibitory process.

Another approach is to introduce growth factors called neurotrophins that will lure these fibers from the bridge into the cord. “We already know this can make a difference,” says Bunge.

Miami Project scientists are trying to figure out which receptors on cells and processes interact best with specific neurotrophins. “You have to be very precise about what neurotrophin you use and in what concentration,” says Dietrich. “You just can’t throw ‘chicken soup’ in there and expect everything to work.”

Which approach ultimately produces the number of nerve cells needed to regain control over muscles and body functions has yet to be seen. The research is a painfully slow process. “It takes a few weeks to get the cells ready,” Bunge says. “Then you do surgery on the rats and observe them for one to four months. Then it takes months to work up the tissue to see how good the growth has been and whether or not the fibers are growing into the distal cord (the spinal cord on the opposite side of the lesion from the brain). So all in all, it takes a year to know the results from one experiment.”

Even when the outcome is favorable, it cannot always be explained. “Rats do not get up and walk normally, so they are not cured,” Bunge continues. “However, when we put them on a treadmill, they will show some alternating stepping in their hind limbs. We are working toward understanding these movements.”

The response likely stems from nerve cells in the spinal cord that are part of a pattern generator. Although contact with the brain has been cut off, the rats’ legs may be receiving signals from these remaining circuits. The same process may cause 20 to 30 percent of people with spinal cord injuries to experience pain and spasticity in their legs—sure signs that nerve conduction is still occurring. “How to utilize these nerve cells to improve locomotion as well as bladder, bowel, and sexual control is our challenge,” says Bunge.

“Patients know how much progress we have made with research and would like to take advantage of our findings, but we are not ready,” Dietrich says. “They don’t understand that what works in a rat may not work in a human. The worst-case scenario is that something very positive in an animal study causes abnormal sensations and an increased amount of nontreatable pain in a human. That’s the type of thing that can happen when new nerve fibers start growing. They may start transmitting pain messages, not normal sensory or motor function messages. So I ask individuals who beg to be research subjects why they would want to put themselves through something that could actually negatively impact their life. Our goal is to conduct a clinical trial in the near future to treat paralysis based on compelling evidence to suggest the procedure would be effective in humans.

“In the meantime, we advocate pretraining,” he continues. “We think that once we get new fibers growing, rehabilitation strategies will help the body develop functional circuits, just like a baby learning to crawl, then walk, then run.”

he Miami Project is, in fact, conducting a human clinical trial in preparation for surgical treatment. In this study, quadriplegics are placed in a sling so that less than 10 percent of their body weight rests on a treadmill. An assistant picks up their feet to re-create walking. “If you do that every day, you activate spinal cord circuits involved with involuntary stepping,” says Dietrich.

So while The Miami Project may be making headway, being first with a cure is not its goal. Finding a scientifically sound cure is, and Miami Project researchers believe that sharing information helps speed the process. “We are very free with our data,” Dietrich says. “We tell other scientists what we are working on and what kind of problems we are having. They tell us where their problems are, and together we usually work our problems out.”

And, with every scientific advance, the goal of reversing paralysis becomes more attainable.

“I have no idea how long it will take,” Bunge says. “We could have a breakthrough tomorrow or much later. I’m optimistic it will come in our lifetime.”

Five Critical Steps to Recovery

n this age of quick fixes, it is hard to understand why a severed or bruised spinal cord cannot be patched to heal like a broken bone. But researchers at The Miami Project to Cure Paralysis believe that a combination of the following strategies likely will be needed to help people recover from spinal cord injuries:
Pretraining In the physical version of “chance favors the prepared mind,” The Miami Project believes in preparing bodies to accept treatment options when they are ready for human trials. “You have to get the patient in the best physical and psychological state before they enter a trial,” says Dalton Dietrich, scientific director of The Miami Project. “If you do not, experience has shown that the therapy will work in the patient who was prepared and will not in the one who was not. Even if we could offer a therapy that would enable spinal cord-injured people to walk again, their bones and muscles would not support their weight. They also need exercise to keep their heart and circulatory system in shape.”
Surgical Intervention For reasons unknown, the body responds to spinal cord injury by flooding the area with chemicals that prevent healing. Chemicals called neuro-trophins appear to create a more permissive environment for repair. Following a spinal cord injury, a neurosurgeon opens the spinal cord, removes scar tissue, cleans the area, and infuses the neurotrophins. Surgeon and Miami Project cofounder Barth Green and his team are conduc-ting clinical studies to evaluate the effect of these neurotrophins and find optimal ways of infusing them.
Growth Factors Whether Schwann cells or olfactory sheathing glial cells will be the best promoter of nerve regeneration remains to be seen. Miami Project researchers have achieved a significant level of motor axon regeneration with both, but are convinced they need to encourage a larger number of nerve fibers to grow across the injury and into the cord.
Inhibitory Molecules Once they can identify what inhibits newly regenerated nerves from reentering the spinal cord, Miami Project neuroscientists will be able to overcome inhibitory barriers.
Rehabilitation After nerve transplantation, rehabilitation will be necessary to help the nerves reestablish normal, functional circuits.