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Keeping the Promise: Prockop and Krogstad

April 5, 2005

Tulanian Staff
Michael DeMocker

Darwin Prockop, Director of the Tulane Gene Therapy Center: As a medical student, you quickly learn that people develop many devastating diseases. For most of them, you as a doctor can do little. So, I decided early on that I wanted to work on the causes and treatments of diseases. The earliest research that I carried out was on collagen, the tough fibrous protein that holds us together.

tulspr_05_prockop_1Thinking that collagen might have a role in diseases, my colleagues and I worked for years on the molecular steps by which cells make collagen. We isolated and cloned the first human genes for collagen and used those genes to produce pure human collagen. Then it occurred to us that mutations in collagen genes might be the cause of severe diseases of bone, a tissue whose strength depends in part on the presence of a large amount of collagen.

We began to study the genes for collagen in children with osteogenesis imperfecta, a condition causing severely brittle bones in children. The idea that mutations in the genes for collagen caused bones to be brittle was a long shot. A grant review committee of the National Institutes of Health called us naive. However, the long shot was more successful that we had ever dreamed. We and others quickly found that more than 90 percent of children with severely brittle bones did in fact have mutations in the genes for collagen. After we had been detecting mutations causing diseases of bone and other tissues for several years, we wondered what we could do to help the patients.

We tested the idea that we could develop a strategy using stem cells, because there were indications that stem cells could replace hundreds of kinds of cells. We decided not to use stem cells from human embryos but, rather, to use stem cells obtained from the patient who was to be treated -- the class of cells now referred to as adult stem cells.

Again the grant review committees of the National Institutes of Health thought we were naive, and we had to scramble for other sources of funding. Again, we were lucky. Stem cells infused into mice or rats have the remarkable ability to seek out and repair damaged tissues. Based on our work, our colleagues at the St. Jude Childrens Hospital in Memphis used adult stem cells to treat children with severe osteogenesis imperfecta.

The encouraging results opened the floodgates for clinical trials to test adult stem cells as treatments for many diseases. We at Tulane are planning to use adult stem cells to treat people who become permanently paralyzed because of injuries to the spinal cord. Also, we are making plans for a clinical trial in which the cells are used to treat patients with cystic fibrosis and, sometime later, to treat people with chronic heart failure.

Throughout all of this, we remain fascinated by the basic biological questions that this work has raised. In spite of all the research carried out on stem cells, they remain mysterious. I think stem cells may well be among the last unsolved mysteries of biology. Understanding them fully, however, holds the promise of developing safe and effective treatments for many of the devastating diseases that now affect millions of people and for which there are no therapies. 

Donald Krogstad, Professor and Chair of the Department of Tropical Medicine: The request for this piece reached me while I was in in West Africa for three weeks working on a malaria, public health and training project we share with the University of Bamako. That project, with its mix of science and public health, exemplifies both the opportunities and challenges in global health at Tulane. It illustrates the challenge because the need is enormous.

tulspr_05_krogstad_1There are from 300 to 500 million cases and two million deaths from malaria each year. At a time when the power of molecular biology and modern chemistry has never been greater, the morbidity and mortality of malaria are rising because of increasing drug resistance. This challenge is being addressed primarily through academia at institutions such as Tulane because the profit motive simply does not work if the persons for whom those drugs are intended cannot afford to pay $3-5 per pill (adults in malaria-endemic countries typically earn $1-3 per day).

With the only Department of Tropical Medicine in the continental United States and a School of Public Health and Tropical Medicine that is focused on global health, Tulane is well positioned to address this global challenge. Consider our work developing antimalarial agents. Here we see how basic research at a university can contribute to global health. We know that modest structural changes in drugs that had lost their effectiveness because of resistance can produce new compounds that are active against all known drug-resistant malaria parasites.

The chemical syntheses and structural characterizations of these compounds have been performed in collaboration with the Department of Chemistry. Testing for biologic (antiparasite) activity in vitro has been performed at the Center for Infectious Diseases. Testing for activity in vivo in monkey models of human malaria has been performed at the Tulane National Primate Research Center.

In addition, the Phase 1 Human Studies for safety have been performed at the Tulane-Louisiana State University -- Charity Hospital General Clinical Research Center. The upcoming Phase 2 Human Studies of efficacy in Mali will take place in newly renovated clinical research space. Now consider how the Human Genome Project is likely to change our understanding and control of tropical diseases such as malaria. Based on a collaboration with the Center for Gene Therapy, these studies have shown that the host response to malaria is fundamentally similar in non-human primates and human subjects.

The goal of Tulane researchers is to understand the basis of protection against severe malarial disease in humans and a woman's vulnerability to malaria during pregnancy. These and the other research projects in tropical medicine and global health illustrate opportunity because they are inextricably linked to training. In fact, this linkage defines the "Tulane niche" in global health-quality research linked to graduate training.

This combination of basic and applied research, with the clear potential to improve global health, is the reason students are attracted to Tulane for training, and that quality faculty are so engaged in leading this process.

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