SCI Research from Scientist at the University of California San Diego
Paul Lu, a scientist at the Center for Neural Repair at the University of California, San Diego, focuses his work on repair of the injured spinal cord. His motivation is in many ways personal: Lu’s own spinal cord injury (SCI) drives him toward finding cures.
“My goal is to solve the mysteries of spinal cord repair, for all of medicine, and also for myself,” says Lu. “It’s an exciting time in my field of work, and I have always believed that science will restore a meaningful degree of my lost function.”
Lu’s recent work has demonstrated unprecedented growth of spinal cord nerves (axons) up and down the cords of injured animal models treated with fetal-derived stem cells. There is evidence of connectivity, though functional recovery has not been as robust as it might be. As Lu and his lab mates refine their techniques to assure both efficacy and safety of the stem cell treatments, they are quite bullish on their chances for success. “It’s a time of great hope,” Lu says. “We have new tools and new approaches. There’s a lot of work still to do, but the door is open to new developments.”
Neuroscience, by Accident
Lu didn’t pick neuroscience; it picked him. He is an expert in SCI regeneration but he started out studying plants, not animals. He came to the U.S. in 1990 to study biology at UC Davis. “I had been a teacher in my native China but things were opening up for young people back then—closed doors were suddenly opened, and my country sent me to the U.S.”
After getting his Ph.D. in molecular plant biology at Davis, Lu stayed on for a post-doctoral fellowship. His career was going according to plan, until he was in a car accident on a Christmas trip to Las Vegas in 1996. Lu was spinal cord injured; married with a son, he had no health benefits.
Lu says he wanted to stay in academia but was discouraged that UC Davis didn’t offer him a full-time program. “I was about ready to give up. I had my ticket and was all set to go back to China [where] my brothers would have taken care of me.” Days before his flight back to China, he visited the Resource for Independent Living Center in Sacramento, 20 minutes up the road. “I told them, ‘I need a job, any job.’ The director asked me if I could type. ‘Of course, I told her, I’m a Ph.D.’ She hired me for a social work job, which I learned quickly, and for a few months I helped other people with disabilities find work and housing. Being able to work and knowing I could work was really important in regaining my confidence.”
Social work as a career wasn’t quite right, however. Lu was a trained scientist and wanted to re-enter the field. Naturally, he began to explore the science of the spinal cord. He looked at the scientific literature to see who was doing SCI research. He recalls seeing the Miami Project, the Fred Gage Lab at the Salk Institute in San Diego, and the Mark Tuszynski Lab, also in San Diego. He wrote to each of the labs, told them he had a Ph.D. in biology and that he wanted to be involved somehow in SCI research. “I didn’t hear from them, but one day Mark Tuszynski was in Davis to perform some animal surgeries. He called me and asked if I had time to meet. I told him my story and he said, ‘You deserve a chance to work,’ and offered me a post-doc position at UCSD.”
Tuszynski recalls this first contact. “I remember an email from a man at UC Davis who had his Ph.D. in plant molecular biology. He said he had recently sustained a spinal cord injury and wanted to volunteer to be a research subject or to do research. Since I visited Davis frequently, and this was a fellow scientist who was in need, I owed him the respect and decency to at least meet with him. The man I met, Paul Lu, was startlingly intelligent, dignified and accomplished. I didn’t really have sufficient funding at that time to hire him, but I did anyway, taking a chance that both he and the funding would work out. It was one of the best decisions I’ve made. Paul is an exceptional individual and human being, before one takes his injury into account. After taking his injury into account, he is even more impressive.”
Lu already had expertise in molecular biology and histology. He quickly got up to speed on the basic biology of spinal cord trauma; his first publication showed how to clone the important axon growth factor BDNF, leading to an experimental gene therapy to promote motor axonal regeneration after spinal cord injury.
Lu hadn’t been in San Diego long before Tuszynski published a paper that generated high publicity, and high hopes. Tuszynski’s initial strategies for enhancing regeneration after SCI focused on delivery of growth-promoting factors to lesion sites. Says Lu, “In 1997 Tuszynski had a paper in the Journal of Neuroscience that got a lot of attention, even in Chinese newspapers. Mark had used gene therapy to promote axon growth—he used a genetically modified fibroblast, a skin cell, to express a growth factor called NT-3. When grafted into the spinal cord, there was significant functional recovery. This was exciting for the field. At the time, I thought we were really close to the solution. However, delivery of NT-3 promotes corticospinal tract axonal growth around the lesion site and not through or into the lesion site; also, this experiment used an incomplete dorsal hemisection model that does not occur in human spinal cord injury.”
Axon Bridges, But No
In 2003, Lu was co-author of a study that grafted NT-3 in a chronic SCI model. Grafted animals showed significant growth of corticospinal axons up to 15 mm beyond the lesion site and showed a modest but significant improvement in locomotor scores, compared to control-grafted animals. The next year, the lab combined NT-3 with a molecule called cAMP, which activates nerve cell signaling. This time, axons regenerated not only into the cell graft that was expressing NT-3, but also beyond the injury site. Lu and his colleagues believed this to be a major advance toward spinal cord repair. “We observed, in our own hands for the first time, convincing evidence of axonal bridging in mid-cervical spinal cord lesion sites.” Nice result, but still not ready to be a treatment.
In 2007, Lu and Tuszynski tried to coax their growing axons to cross the tough scar tissue that surrounds the lesion site of chronically injured animals. They grafted bone marrow stromal cells (MSCs) into mid-cervical SCI sites of adult rats, six weeks post-injury; this provided a hospitable environment for axons across the scar. Other animals received MSCs genetically modified to express NT-3, which further stimulated axon growth.
Getting on the Stem Cell Track
Meanwhile, Lu had become interested in the potential of stem cells. “Cell lines were becoming available to study. I asked Mark if we could pursue this area. He wasn’t convinced and advised against it but told me, ‘You can try.’” So starting in 2002 or so Lu began to graft embryonic stem cells in the spinal cord. Once transplanted, however, the cells did not stay in the lesion area. They died. “My challenge was how do I get the stem cells to survive in the spinal cord injury site?”
Lu came up with a cocktail approach, using a combination of stem cell transplantation and a unique blend of 10 growth factors imbedded in a sticky fibrin paste. The work was detailed in a widely cited 2012 paper in the journal Cell.
Lu noted that this regeneration could even occur in a chronic injury, “even after substantial delays from the original injury, even after three months in rodent models.”
The study was widely reported in the news media. Tuszynski described the results as “astonishing.”
“Using this method, after six weeks, the number of axons emerging from the injury site exceeded by 200-fold what had ever been seen before. The axons also grew 10 times the length of axons in any previous study and, importantly, the regeneration of these axons resulted in significant functional improvement.” The procedure created new nerve circuitry that could be detected electronically. And when Lu and his team recut the spinal cord above the implant, the animals lost function, confirming that recovery was due to the growth of axons. Results were replicated using two human stem cell lines, one already in human trials for ALS and approved for spinal cord injury, from the company Neuralstem.
Ready for the clinic? Not quite. Recovered function in the animals was indeed meaningful but didn’t restore walking ability, or even the ability to bear weight. The stem cell approach is not ready for clinical therapies, but according to Tuszynski “it would not be crazy to think they will be useful for humans.”
Chronic Injury, Why Not?
What’s next? Lu of course has his eye on chronic spinal cord injury repair. Using genetic techniques to stimulate the intrinsic growth of a nerve cell, plus the addition of molecules to condition the environment to encourage growth, and perhaps the addition of other molecules to direct nerves toward the proper targets, Lu is confident he can bridge the area of damage, including the scar tissue, and make new, functional connections.
Lu is also very encouraged about new types of engineered cells, induced pluripotent stem cells (iPSC), which behave very much like embryonic stem cells but because they are derived from adult cells, there is no ethical controversy. One drawback to iPSC cells is that after transplantation there’s some risk of tumor formation, so Lu is experimenting with a drug used in cancer research to stop unwanted cell division.
“Our hopes are high,” says Lu. “We will continue to fit the pieces together, with the goal of moving a therapy to humans.”
Article previously appeared in Progress in Research, a Reeve Foundation publication.