Distinguished Investigator

A conversation with Mayo Clinic's Moses Rodriguez, M.D.

Designing New Treatments for Multiple Sclerosis

ROCHESTER, Minn. — When Moses Rodriguez, M.D., established a small research lab to study multiple sclerosis at Mayo Clinic in 1983, he was told that he was wasting his time.

Dr. Rodriguez is a physician trained in neurology. Adding basic science research to his portfolio would be impossible, he was told.

But Dr. Rodriguez is very much both a physician and researcher. As a physician he specializes in identifying and treating neurologic problems, but then as a researcher, he takes those problems back to the lab where he begins looking for solutions and over the course of a 28–year career at Mayo Clinic, he's found some. He has been instrumental in helping to put six FDA treatments for multiple sclerosis (MS) on the map, including one that has actually reversed the effects of multiple sclerosis in some patients.

Dr. Rodriguez received Mayo Clinic's top honor last year when he was named a Distinguished Investigator.

To understand Dr. Rodriguez is to understand his story, which begins in Havana and Santiago de Cuba, Cuba.

Q. Why did you begin your acceptance speech for Distinguished Investigator by thanking Fidel Castro?

A. I was born in Cuba, but my family fled to Jamaica in 1961. We left as if we were going on vacation, but we were actually leaving the country. We only took things we would take on vacation like swimming suits and goggles. I was only nine years old, but I remember my father telling my sister and I and my mother, that if we got separated to just keep going. We were just petrified. We lived in Jamaica for a couple of weeks, but then flew to Miami and eventually Pittsburgh.

We didn't know anything about the United States and we didn't speak any English. It was a complete culture shock. We arrived in Pittsburgh in October where a family helped us find an apartment to live in and gave us coats (we weren't used to the cold). It was around Halloween and I remember that people were all dressed up in costumes knocking on our door. I was petrified! ¿Qué está pasando? We were like, 'What do we do?!"

My dad, who was a chemist for Texaco before we came to this country, got a job for Texaco in Port Arthur, Texas where I grew up until going to university.

Q. Port Arthur is also the hometown of singer Janis Joplin, correct?

A. Yes. Janis' father was my Scout master. I used to go to Janis' home for Scout meetings, but we weren't really friends (she was in high school). She wasn't very well liked, but she was very creative. I still enjoy her music and think she is the greatest blues singer that ever lived.

Q. Port Arthur is a blue collar town and has spurred some great football players, but few scientists as best I know.

A. I always felt like an outsider there because most of the kids wanted to work in a refinery, but I was always interested in medicine and science. When I was a junior in high school, I went to Michigan State University as part of a National Science Foundation summer student program. It was exciting! I was taking college science classes and for the first time I was exposed to laboratory research. I thought, 'This is exactly what I am gonna do.' I was in heaven, but then going back to high school was a big drag.

Q. You ended up working your way through college and medical school and you were accepted into a prestigious six–year honors program at Northwestern University. How did you end up at Mayo Clinic?

A. I applied for residencies in neurology and was accepted everywhere — Harvard, Washington University in St Louis and Johns Hopkins — but I chose Mayo. It was so different from the other universities. It was the perfect educational and clinical environment and just where I wanted to be. From Mayo I went on to the University of California at San Diego and Scripps Clinic where I devoted time exclusively to research, including work on viruses in how they affect the nervous system, multiple sclerosis and the immune system.

I wanted to come back to Mayo to continue my research. San Diego couldn't understand why I wanted to return to Mayo because there was no one at Mayo doing MS research at the time. I said, 'That's exactly why I want to go back. I wanted to establish something totally new.

Q. Like many young investigators, you met some resistance from the Mayo establishment — in particular over the fact that you were a physician pursuing research.

A. Yes, but I was determined to succeed. That is when I met Chella David and Larry Pease — investigators in immunology. They set me up in a larger lab in Guggenheim where I began working on immunology, MS and viruses.

I brought with me from San Diego a virus called Theiler's virus, which was a virus discovered by Nobel Laureate Max Theiler in the 1930s. He discovered that this virus, which when put into animals, the animals would develop an MS–like disease. I found that no one was doing virus–specific MS research at Mayo, so I started an animal colony and started collaborating with Chella David, Ph.D. We mapped the mouse genes to see what aspects of their genes are important in the development of MS.

We identified a gene in the mice called MHC (major histocompatibility complex) which is the same gene found in MS, but we also found that MHC controlled the virus in mice, which was an exciting discovery. It was published in the Journal of Experimental Medicine

We started using the model to test different drugs. We addressed it with interferons — drugs that interfere with virus replication, which is why they are called interferons. As it turns out, today that is the primary way we treat MS and we were one of the first laboratories to work on interferons in the animal models before it was even considered for MS. There are now three different interferon preparations that are marketed for MS patients.

Q. Your next discovery was so important and so significant that it's coverage in the national media drove hundreds of patients to Mayo Clinic jamming the phone lines.

A. Yes. During that time I was working with patients who were quadriplegic or parapalegic. Some were on respirators who had massive attacks of MS. We tried everything, but nothing would work. I had this crazy idea that antibodies could be playing a role and that we should try plasma exchange. We tested plasma exchange in five patients who were quadriplegic and on respirators and remarkably, they walked out of Mayo Clinic Hosptial, Saint Marys Campus.

We reported this in a journal in 1993, but the rest of the scientific world thought it was bogus. They just couldn't believe that you could take patients who were quadriplegic and have them walk again.

My neurology colleagues at Mayo also thought it was also bogus. It's something that was so controversial, they just couldn't believe it.

Q. How did you convince the non–believers?

A. We followed up with a placebo–controlled trial funded by the NIH. In collaboration with my colleagues at Mayo (including Brian Weinshenker, M.D.), we repeated the experiment by giving half of the patients in the trial plasma exchange. In the second group, we removed blood from patients, but gave it right back to them unchanged. So one group had the true removal of the blood through plasma exchange and the other group did not.

The results were remarkable — 40 percent of the patients who had the real treatment, had dramatic improvements over days to a few weeks as compared to 5 percent of patients who got the placebo.

Today, plasma exchange is a common way for treating MS patients with acute devastating attacks who meet the criteria for treatment. The results are still the same: about 40 to 50 percent of the patients will have a remarkable recovery.

Q. How does plasma exchange work?

A. Plasma exchange is the process of removing plasma, the liquid portion of blood, and replacing it with new plasma fluid. We think that the antibodies in the plasma of MS patients are attacking the myelin material that acts as a protective covering over nerve cells in the brain and spinal cord.

While it works in some MS patients, the effects typically don't work in patients who have had the devastating symptoms for more than three months. We recommend this treatment for people with sudden, severe attacks of MS who have not responded to the standard course of treatment (high doses of steroid treatment).

Q. That discovery was soon followed by a series of studies on T Cells, specifically Cytotoxic T Cells (CD8). What role does CD8 play in MS?

A. In MS, myelin (the protective coating around the nerve) is damaged by genetic or environmental factors. As the myelin becomes injured this triggers an immune reaction from T cells. We found that CD8 was really critical in injuring axons, which are responsible for carrying electrical impulses from the nerve. That was a really novel finding to the point where we received a patent for that observation and now Mayo owns the patent for the rights of any treatment that involves the use of deleting CD8 as an approach to MS or any other viral or autoimmune disease. When we discovered this no one was talking about CD8 in MS.

However, now CD8 has since become the buzz word in MS. There are no drugs that specifically target CD8, but I am convinced that this is the cell that finally induces the long term injury in MS.

Q. What are you working on right now?

A. Reparative antibodies. I had this idea that antibodies could be both damaging and reparative. The idea was that if antibodies were effective in treating infections, why couldn't they be important in preventing diseases like MS, Parkinson's or Alzheimer's disease. Why can't they be the first line of defense against injury to the nervous system?

We found that when natural auto antibodies are injected into animals with MS, they basically repair the animal of MS. We've made a natural auto antibody that binds to the oligodendrocyte that makes myelin. We've showed that these antibodies stimulate the oligodendrocyte to create new myelin in animals.

We've since cloned the sequence of these antibodies and are actively producing the antibodies for the purpose of using them in clinical trials at some point in the future. The idea would be that we may be able to repair MS with these antibodies. This has always been my long term dream — to make a scientific observation that can make a real difference for patients.

The results in animals has been very striking and rapid. Within five weeks we've seen 50 to 60 percent repair of the nervous system. We're very excited about trying these antibodies in humans.

We've already started a phase I clinical trial in patients with metastatic melanoma using a similar class of antibody that stimulates cells of the immune to clear tumors. In animals this antibody clears the tumors and promotes long–term survival. This work has been done in collaboration with Dr. Larry Pease.

Q. What does receiving the Distinguished Investigator honor mean to you?

A. Obviously this award is a great honor for me but it represents the work of a large number of people: from research colleagues to technicians, fellows and students — six of whom are now established investigators at Mayo Clinic (Chuck Howe, Ph.D., Allan Bieber, Ph.D., Isobel Scarisbrick Ph.D., Dean M. Wingerchuk, M.D., Sean Pittock, M.D. and Claudia Lucchinetti, M.D.). Finally, though, the ones I really need to thank are the patients because they really provide all of the ideas and relevance for these experiments. We're hoping to put a few more treatments on the map and hopefully, one of these will be a cure.

— Reprinted with permission from Inside Mayo Clinic Research