Dr. Alan R. Davis and Dr. Elizabeth Video (Text Version)
Alan: My research is on heterotopic bone formation and the mechanism, the way it forms. And it's a major clinical problem in the war in Afghanistan and Iraq. The reason is the nature of the weaponry used in these theaters of operation; the fact that car bombs are used and you get traumatic brain injury, which seems to paradoxically cause bone formation at places where bone is neither wanted nor needed.
Previously it was thought that bone formation is driven by cells in the bone marrow, but we find that the nerve is intimately involved-not for just regulation but also providing the stem cells for bone formation. It's a very striking departure from what is thought.
Heterotopic bone formation is caused by problems in a very important protein called bone morphogenetic protein-type two signaling. This protein is involved embryonically in formation of the nervous system, the skeletal system, and other systems. We have established an animal model enabling us to study this process by injecting cells into the mouse muscle that produces high-levels of this protein. And we're able to form bone very rapidly but it also enables us to study the process of how this molecule works because we are sure that this is the way also that the problems of traumatic brain injury and spinal cord injury work in forming this unwanted bone.
We've determined that the process of bone formation involves the nervous system; that's a major point and that it is cells coming from the peripheral nerves themselves that are involved in the process. We've discovered that neurological inflammation is critical for this process. So other cells are involved, cells you typically think of as immune cells-mass cells, neutrophils, platelets.
Another area that is important is fat. The first step in this process involves the generation of brown fat. There's been quite a debate over what brown fat does or whether it's even present in the adult human. But we see very clearly that it is present during this process, and it provides energy for the process and it also provides a low-oxygen micro-environment so that cells can differentiate into cartilage and bone. The other side of the coin is just to use this process for rapid bone repair in orthopedic trauma really and it's worked really well.
Elizabeth: I've been collaborating with my husband Alan Davis for the past 10-12 years since we arrived at Baylor. We're trying to work on a nonsurgical approach to healing back pain. As you know, many of the people in the military due to the weight that they carry and the body armor and all of the different things that they're doing often end up with a lot of back pain. And the idea would be to rigidly fix two to three or however many vertebrate clinically are required so that they don't compress on a disc or any other additional areas where movement would cause or create pain. And so basically what we are attempting to do is fuse the vertebrae so this is traditionally done now through a very massive type of surgical procedure. And what we'd like to do is actually bring that to nonclinical and just an injectable type of approach or therapy. I had a lot of knowledge about bone biology and Alan is actually a vector person. I mean he's developed a lot of the adenovirus vector systems that are used traditionally in gene therapy so it really allowed us to take the information that then Alan was pursuing in heterotopic ossification and implement it with our system to understand how you would implement it.
So what we've managed to do is show that in animal models we can deliver a factor that's known as an osteoinductive factor. There are proteins that will cause bone to form from nothing; we call it de novo bone formation. They can recruit all of the materials in the body to produce a piece of bone at a targeted location, and the proteins themselves are used clinically but they're somewhat controversial because when you deliver the protein itself, it has a very short half-life. It doesn't stick around very much. And so the efficacy of it and the way that you can actually even deliver it still requires kind of a massive surgical approach.
And so we took the approach being gene therapists that we would deliver cells that carried the gene to produce this protein. We can then place the cells at a very targeted spot that we want the bone to actually form-where it can then fuse the two vertebral bones. We do this actually in collaboration with the laboratory at Rice University. It's a bioengineering lab and run by Dr. Jennifer West, and she and I had developed a system where we use an adenovirus or a virus that genes have been removed so it no longer has its viral properties but it can carry the gene for the protein that we want to deliver into the cells very effectively and make a lot of it. The protein is secreted then to the area where you want to have the bone, and the secretion of that protein long-term causes the new bone to form very rapidly within 7 days. This is much quicker than any of the studies where people have just used the protein itself, and we think it's because you can get a pretty good expression of it.
Dr. West's contribution to the project is that she's developed a material that encapsulates these cells. It masks the cells so the body doesn't actually see them as foreign. And so we can actually safely put them exactly where we want to place them. They stay put and they produce the protein and then we can have bone forming around it. So these are tiny little what we call microspheres that can lead to then the fusion and bone formation.
And so we've managed to now move in this award-into rats and complete a lot of the studies required for showing what our final product would be and how we want to proceed if we were to move it into the clinic.
It's kind of interesting to think that you could go into your orthopedics office and have an instrument-guided injection and in 2 to 4 weeks you'll have fusion of your spine without any down time, so that to us is huge. In both my mind and Dr. West's minds we're really at a point where we think we have a product that could really revolutionize orthopedics. I think it not only will help the military population greatly with back pain, but I think there's other applications for it as well that are critically needed.
Alan: What we'd like to do now is move closer into the clinic with both of these projects actually. This one we have some drug targets we'd like to develop; the other one we have some actual biological materials we'd like to use for bone repair. Orthopedic trauma is a serious, serious problem and even though there are marvelous facilities for rehabilitating these soldiers, sometimes it just isn't enough and it's-it needs to be addressed.