RNase L

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Dr. Robert Suhadolnik Talks to Congress about RNase L

Suhadolnik's Remarks to Congress, 5/16/97

My name is Robert J. Suhadolnik. [Ed. note: pronounced Sa-dol-nik.] I am Professor of Biochemistry at Temple University School of Medicine in Philadelphia. Thank you for the opportunity to speak with you today and to share with you the results of our studies on CFIDS. I participated in the 1995 Congressional briefings. It is a pleasure to be here again and to tell you that we have made progress. The results I will describe to you today have been made possible by research support from The CFIDS Association of America and the hard work of graduate students and staff in my laboratory.

Today, I will describe CFIDS to you as we see it in the laboratory. As you know, CFIDS is a complex illness. I will talk about biochemical changes we have observed in white blood cells of people with CFIDS compared to healthy people. The defects we have observed in CFIDS are in the immune system. These defects could also have application to other human diseases.

In the laboratory, we have a saying, "Research is like a baby - you don't know what it is going to be until it grows up." This certainly applies to our research efforts in CFIDS.

My laboratory has been involved in studies of virus-associated diseases and cancers for the past 15 years. In addition to the CFIDS research grant awarded to me by the National Institutes of Health, I currently hold an NIH research grant directed to the study of AIDS.

Our research in CFIDS began in 1988 when a package of frozen white blood cell (lymphocyte) pellets arrived in Philadelphia from Dr. Dan Peterson in Incline Village, Nevada. These pellets were from Dr. Peterson's CFIDS patients. I would like to describe what we learned in studying these lymphocyte pellets and in two subsequent studies -- a pilot study and a placebo-controlled, multi-center double-blind trial in CFIDS. I will also describe our most recent results.

The research in my biochemistry laboratory is directed to the understanding of the actual antiviral defense pathways in humans. This pathway is called the 2-5A synthetase/RNase L pathway. When all components of this antiviral pathway are functioning correctly, the human body can effectively control virus infections. Our research has demonstrated that several components of the antiviral pathway are not functioning properly in people with CFIDS. Specifically, the antiviral pathway is upregulated (or overactive) in people with CFIDS.

The name of the molecule that drives this pathway is 2',5'-oligoadenylate trimer 5'-triphosphate. With a name like that, you can understand why the molecule has been nicknamed 2-5A. What does 2-5A do in the human body? 2-5A is the molecule that activates RNase L, the enzyme that degrades viral RNA. With RNase L that works properly, we can overcome virus infections. However, if RNase L is defective, we have a problem.

We can specifically measure RNase L activity in biochemical assays of lymphocytes that we isolate from whole blood. From one tube of blood, we isolate a lymphocyte pellet. When we measure the RNase L in people with CFIDS, we observed something we had never seen before. RNase L in people with CFIDS is overactive. In the first study we did with Dr. Peterson, 13 of 15 people with CFIDS had this overactive RNase L.

Let me share with you the information we obtained about RNase L in expanded studies in CFIDS. We have tested samples from more than a hundred people with CFIDS from across the country. What have we learned about CFIDS from all this testing? We've learned that there is an enzyme defect in people with CFIDS -- a defect in RNase L. SOMETHING NEW IS GOING ON IN CFIDS. RNase L WAS OVERACTIVE, UNLIKE ANYTHING WE HAD EVER SEEN BEFORE, and we have studied RNase L activity in people with AIDS, multiple sclerosis, lupus, human T-cell leukemia, and kidney cancer.

When we observed this, we were intrigued and wanted to know more. We needed to find a biochemical explanation for why this RNase L in CFIDS patients was so overactive. Where do we go from here? I tell my students that it takes more time to discuss and design an experiment than to do it. This planning is the MENTAL GYMNASTICS involved in research. In a lymphocyte extract, there are thousands of proteins. We wanted to look at just one -- RNase L. How can we do that? In order to determine why the RNase L in people in CFIDS is overactive, it was necessary to develop a new two-part technology in the laboratory to advance our studies. We were able to develop this technology using ultraviolet light and an antibody to human RNase L.

So, with these new technologies, what have we learned about CFIDS?

From the blood samples we obtain, we can detect the presence and measure the activity of RNase L. We have had another surprise in CFIDS - we have seen A NEW FORM OF RNase L, a smaller form of RNase L, in all people with CFIDS. These studies have been accepted for publication and will appear in the Journal of Interferon and Cytokine Research in a few months. On the basis of what we know now, it is tempting to speculate that the presence and activity of the new form of RNase L correlates with the severity of clinical symptoms in people with CFIDS.

I am pleased to be able to report to you today that our results have been confirmed. Using CFIDS patients selected by an independent physician and biochemical techniques similar to ours, the presence of the small form of RNase L in CFIDS has been reported from an independent research group.

As with our original observation on the overactive RNase L in CFIDS, we must ask where to go from here? Time is money. We are continuing to analyze lymphocyte samples from more individuals with CFIDS. We have just received a bridge grant from the NIH to continue and expand our studies on the fundamental biology of CFIDS. We are very excited about the POTENTIAL OF THESE RESULTS as a marker for CFIDS.

CFIDS, as currently defined, may well represent a heterogeneous group of disorders. No unifying pathophysiology for CFS has been established. Expanded studies are underway to determine if our results are representative of all patients with CFIDS and if these findings can distinguish individuals with CFIDS from those with clinically similar illnesses. Longitudinal studies are also underway to establish if the RNase L enzyme dysfunction observed in CFIDS is characteristic of a particular stage in the course of the illness or if the dysfunction fluctuates over time.

A remarkable group of people have contributed to this research effort I have described today. First, I would like to acknowledge The CFIDS Association of America for the financial support we have received from this research. Second, the efforts of Drs. Peterson and Cheney were essential to this research project. They are truly pioneering physicians in the diagnosis of CFIDS. Third, the graduate students and staff in my laboratory are remarkably dedicated people. What a wonderful opportunity this CFIDS research has been to train promising young scientists.

I would also like to thank the members of Congress for the funds that have been appropriated to NIH extramural programs for CFIDS research. I am confident that these funds will be put to good use.

In closing, let me say that I have been fortunate to hold uninterrupted research support from the National Institutes of Health and the National Science Foundation since 1965. Without a doubt, this CFIDS research is the most challenging research effort of my scientific career. Why? Because it crosses a wide range of disciplines -- biochemistry, immunology, virology, and molecular biology. CFIDS is a complex illness that demands a multi-disciplinary research effort.

What else is necessary? At the research level, continued and expanded research support of course. There is now a critical mass of scientists that is aware of CFIDS and interested in addressing its pathogenesis and treatment. At this point in the understanding of CFIDS, we don't know what we don't know. I would strongly encourage international collaborations in the investigation of CFIDS. This disease doesn't recognize borders. There are fundamental questions that remain to be answered -- as with any emerging disease. The call from AIDS researchers a few years ago was to go back to basic science. The same applies to CFIDS.

Thank you for your attention.

(Dr. Suhadolnik's article can be found online: RNase L: Biochemical Evidence for a Novel Low Molecular Weight 2-5A-Dependent RNase L in Chronic Fatigue Syndrome)

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