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Great Transformations

March 17, 2004

Heather Heilman
hheilman@tulane.edu
Michael DeMocker

The line between nature and magic is very thin indeed. Stem cells are a case in point. These simple cells, as they replicate and divide, have the ability to transform themselves into whatever kind of cells surround them. And they seem to know just where they're needed. If they're in the heart they'll replace damaged heart cells; if they're in the brain they will turn into brain cells.

We all have these cells throughout our bodies -- they probably play a role in our physical development as we grow from infants to adults. In human adults, their potential is somewhat suppressed. We're not like starfish, which naturally grow a new limb when one is lost. But if we could help them out -- if we could get enough of these cells into the right place -- damaged tissue could be healed and diseases cured.

Stem cells represent a potential revolution in medicine. And Tulane is at its forefront. It started with a gamble. Several years ago, when the Tulane University Health Sciences Center was being reorganized, administrators committed to a strategic plan that called for the development of five broad areas. Four of those were areas of historical strength for Tulane -- infectious diseases, cancer, cardiovascular health and neuroscience. The fifth was something entirely new, a field of great promise and great uncertainty -- gene therapy.

"We knew we had to focus on getting it right," said Paul Whelton, senior vice president for health sciences. "It's like roulette. If it wins you could do very, very well and establish prominence for your institution. But you could also lose a lot of money."

The university and HCA Inc., which owns a majority stake in Tulane Hospital and Clinic, each committed to investing in this young field of research. At the same time, Louisiana State University also was interested in building a presence in gene therapy. It was clear that the institutions had a lot to gain by cooperating. And it was clear to the state legislature that Louisiana had a lot to gain by attracting such research to the state.

So the schools successfully lobbied for the creation of the state-funded Louisiana Gene Therapy Research Consortium, which supports research at the Tulane and LSU health sciences campuses in New Orleans and Shreveport. Much of that money went to building and equipping state-of-the-art labs. The consortium has been so successful, it has served as a model for the new Louisiana Cancer Consortium, also a collaboration between Tulane, LSU and the state.

Gene therapy researchers at Tulane and LSU meet weekly, share equipment and collaborate on projects. But each university has a distinct approach to gene therapy. Most of LSU's research involves the use of viral vectors -- sort of the traditional approach, if such a young field can be said to have traditions. In this approach, viruses are used to deliver genetically modified cells into the body in order to correct abnormal genes. Tulane's Center for Gene Therapy initially focused on using adult stem cells to deliver gene therapy, and has since expanded into using stem cells directly to heal and regrow tissues. The stem cells Tulane uses are taken from the bone marrow of adults.

"There are places for both the viral-vector approach and the stem-cell approach," said Brian Butcher, research professor at the center. There are some researchers at Tulane, like Bruce Bunnell at the primate center, who are working with viral vectors. And some work at the center focuses on simply identifying the genes associated with different diseases. Lena Ala Kokko, for example, worked with the gene associated with Marfan syndrome -- a condition seen in very tall people like basketball players that can cause early death -- to develop a diagnostic test. Tulane now offers that test for the Marfan gene.

Tulane's focus on adult stem cells is a result of recruiting Darwin Prockop, the foremost authority in the field, to be the center's director. "He's an outstanding figure, really the father of this whole area," said Whelton. "It turned out to be a very good match."

Prockop, a member of the Institute of Medicine and the National Academy of Sciences, came to Tulane in 2000 after serving as the director of the Center for Gene Therapy at MCP Hahnemann Medical School. Early in his career as a research fellow at the National Institutes of Health, he began studying the structure and biosynthesis of collagen, a protein that forms connective tissue and provides structure in the body. It's found in skin, cartilage and bone, which is made up of collagen and mineral crystal.

One of Prockop's accomplishments was to develop a way to grow human collagen in the lab. He also identified the genetic defect that causes osteogenesis imperfecta, or brittle bone disease. Children with this rare, debilitating disease consistently had mutations in the same genes, though they might be mutated in different ways. Because of these mutations, their bodies make either too little collagen or collagen of a poor quality. The result is bones that break easily. The disease varies in severity. Some people are vulnerable to fractures but attain a normal height with little or no bone deformity. Others fracture bones regularly, are very short in stature and have a number of other health problems, including hearing loss, brittle teeth and respiratory problems.

"We had to face the question of what we could do to help these children, because you had to fix every bone in the body," said Prockop. Scientists had known for 30 years that bone marrow contained stem cells. Those cells had even been shown to make bone cells in culture. Prockop thought these cells might be able to help children with brittle bone disease. He was able to show that stem cells could find and heal broken bones in mice. His lab was the first to show that marrow stromal stem cells, from bone marrow, will travel to many different organs when introduced into the bloodstream. They also developed a way to rapidly multiply these cells in the laboratory.

Then Edwin Horwitz at St. Jude Children's Research Hospital in Memphis conducted a clinical trial in which five children with brittle bone disease were given mesenchymal stem cells from a healthy brother or sister using the method developed by Prockop. All five children showed bone density growth. They can now sit up on their own, and some can even walk. "We saw a slide of one of the little girls walk down a hallway, climb up three steps onto a slide, and slide down with a huge grin on her face," said Butcher. "There wasn't a dry eye in the house."

And there has been no sign of any adverse side effects. Of course, the treatment doesn't represent a cure. That might be done by using stem cells to fix the mutant gene. Researchers are working on it, though there are many difficulties involved. But such an approach, if successful, could be useful for several diseases that are caused by a single mutant disease -- cystic fibrosis being one fairly common example. "One would take stem cells from an individual, alter the gene and give them back," said Butcher.

But other diseases call for something simpler -- something that could be called cellular therapy or regenerative medicine. "We've switched to the idea that for many diseases, all we need to do is make more of the patient's own stem cells to speed up the process of repair," Prockop said. A clinical trial taking that approach to treat spinal-cord injuries is being planned. Every year several thousand people suffer spinal-cord damage in car or motorcycle accidents, or because of gunshot wounds. They end up wheelchair-bound and paralyzed, at staggering financial, emotional and social costs.

But if clinical trials are successful, it may become standard to take a bone marrow sample from such patients when they first arrive at a trauma unit. While the patient is recovering from the shock of the accident, their stem cells will be growing in a lab. After several weeks their spines will be treated with the stem cells.

"We're not trying to change the cells in any way before we put them in the body. These are very early precursor cells. They have the potential to become almost anything, and they adapt quickly once they're inside," said Butcher. Tests on rats with damaged spines have shown that cell growth occurs in the spine and allows the animals to walk again. The clinical trials will be conducted at Tulane and elsewhere, and Tulane will grow the cells that will be used. They can begin as soon as the Food and Drug Administration validates the new "good manufacturing process" facility where they will be grown.

"In order to do these kinds of clinical trials, you have to have an FDA-regulated and approved lab like this. It's very time-consuming because you have to document everything, every step of the way, and have detailed standard operating procedures for everything that you do," said Butcher. Once the lab is validated and in use, the door would be open for other clinical trials to take place. There's a great deal of interest, for example, in using stem cells to treat various types of heart disease. They might also prove useful in treating Parkinson's disease and Alzheimer's.

Donald Phinney, associate professor of gene therapy, has gotten stem cells from mice to develop into brain cells and has studied ways to use stem cells to reverse or prevent the deterioration of brain tissue caused by genetic diseases. When Prockop first began working with adult stem cells, the field was so obscure it was sometimes hard to find funding to study them. There was and still is a debate about the merits of using adult stem cells as opposed to embryonic stem cells.

Using adult stem cells sidesteps some of the legal and ethical issues involved in using fetal cells -- the Bush administration has curtailed federal funding for research using fetal or embryonic stem cells. And there may be other benefits as well. "We're not against stem-cell research of any kind," said Butcher. "But we think there are advantages to using adult stem cells. For example, with embryonic stem cells, a significant number become cancer cells, so the cure could be worse than the disease. And they can be very difficult to grow, while adult stem cells are very easy to grow."

But perhaps the biggest advantage to adult stem cells is that they sidestep immunological concerns because the cells used to treat a patient come from his or her own body. They also avoid worries associated with the viral-vector approach to gene therapy, where there's the challenge of rendering the virus itself safe and not introducing a new disease along with the altered gene.

"It seems intuitively very safe," said Whelton. In the last few years adult stem cells have become a hot area of research. But as more studies are done, scientists are finding they have a hard time replicating each other's results. "The problem is they're difficult to prepare reproducibly in a standardized way. Different laboratories prepare them in slightly different ways and get different results, and nobody can sort out the truth," Prockop said. But if everyone started with the same raw material, the results of one lab could be duplicated in another and meaningful comparisons could be made between experiments.

It's a sign of Tulane's prominence in the field that the center recently received a five- year, $4.3 million grant from the National Center for Research Resources -- the first and only of its kind -- to prepare, test and distribute stem cells for use in non-clinical research. The National Institutes of Health received letters from 164 scientists in 12 countries who supported Tulane's application for the grant, even though many of them were competing for money from the same pool. The cells will come from the bone marrow of adult humans and of rats. They can replicate themselves so rapidly that a teaspoon of bone marrow can, in two weeks, yield a billion cells.

It would be hard to overstate the impact that Darwin Prockop and the Center for Gene Therapy have had on Tulane and on Louisiana. Newly recruited faculty at the Health Sciences Center cite the chance to work with Prockop as one of the determining factors in their decision to come here. Prockop arrived at Tulane with a team of 15 researchers, but that number has more than quadrupled in three years. The center has already had an economic impact on the city and state, with the potential for much more. And across the world, researchers working with adult stem cells know that Tulane is the leader in the field. "It's serving the purpose of being broadly stimulating," said Whelton. The center's faculty members have their academic appointments in different departments throughout the health sciences center.

With success comes growth, and growing pains -- the new, state-of-the-art offices and labs built for the center a few years ago are now bursting at the seams as the center has grown. But the university is in the process of acquiring space that will allow the center and other labs to keep growing.

"In a way, I'm surprised that we have done so well so fast," said Whelton. "It turns out that we got it right. We picked the right area, the right person and the right team, created the right kind of partnership with the state and had the right strategy."

Heather Heilman is an editor in the Office of University Publications and a regular contributor to Tulanian.

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