Copyright, Daniel Fylstra
Dr. Martin's Stealth Virus Research: A Closer Look
Daniel H. Fylstra
Recently, rumors have been flying in the CFIDS community about the "Stealth virus" research being done by Dr. W. John Martin at the University of Southern California School of Medicine. Starting from informal reports of a fund-raising meeting for Dr. Martin's research held on the USC campus, there has been an explosion of hearsay and speculation, based on little hard information and understanding of the basic science involved. The result is that some CFIDS patients, relatives and friends have received a very distorted picture of Dr. Martin and the significance of his work -- ranging from expectations for a quick cure to doubt and suspicion of Dr. Martin's methods and even his motives.
As a prospective donor, hoping to help friends with CFIDS but wanting to make my charitable contributions wisely, I set out to learn about Dr. Martin's work firsthand. I contacted Dr. Martin's lab and wound up spending many hours on the phone with Dr. Martin and his colleague Khalid Ahmed, finally visiting the lab and seeing the Stealth virus cultures for myself. I also talked with the Dean's office at the USC School of Medicine; corresponded by phone and fax with a number of other scientists and physicians working on CFIDS; studied with care Dr. Martin's recently published paper on the Stealth virus research; reviewed past articles on Dr. Martin's work in The CFIDS Chronicle and the popular press, going back to 1991; and scanned the recent Internet traffic discussing the Stealth virus research.
This article is intended to pass on to others -- patients, friends, and prospective donors -- what I've learned. The judgments and opinions expressed in this article are mine and should not be taken as representing either Dr. Martin or other researchers in the field.
Here's my quick summary: Dr. Martin's research is sound and is promising for CFIDS patients and for persons suffering from other neurological illnesses which may have a viral origin. Though some exciting developments may indeed be forthcoming, the idea that there will be near-term "FDA clinical trials" and/or availability of a new drug called "Epione" is a misunderstanding of what Dr. Martin has said. Setting aside the rumors, the claims Dr. Martin has actually made himself have a reasonable scientific basis. At the same time, some of his claims will not be accepted as "proven" by other scientists until more of his recent work has been published in peer-reviewed scientific journals, and perhaps replicated by others. Finally, every shred of evidence I have seen suggests that Dr. Martin is eminently qualified, completely ethical, and above all dedicated to alleviating the suffering of patients. Research carries no guarantees, and Dr. Martin's work might not yield all of the hoped-for results; but it is the most advanced work of its kind, and I feel it deserves support. I back this up, I have made my own contributions to the Stealth Virus Fund at USC.
The rest of this article will try to answer some of the common questions, and correct some of the misconceptions about Dr. Martin's research, providing a little background information about viruses and how they cause disease. Portions of this article will be somewhat technical, but they can be understood by non-scientists who are willing to read and think carefully. I believe that CFIDS patients and their relatives and friends should seek to understand the research as best they can so they can make their own informed decisions.
What is the "Stealth Virus"?
A virus is a microbe that consists of a strand of DNA or RNA, usually encased in a sheath or capsid made of proteins. Stealth viruses are a novel group of related viruses which were originally found by Dr. Martin in the blood of a patient diagnosed as having CFIDS, as reported in Dr. Martin's paper in the American Journal of Pathology. This paper described the characteristic tissue culture features of these viruses and reported partial DNA sequence information on a prototypical Stealth virus. Stealth viruses have since been found in the blood and cerebrospinal fluid of many other patients diagnosed with CFIDS and with other neurological diseases.
What are Viruses and How Do They Affect Us?
To grow and propagate itself, a virus enters a living cell, usually migrating to the cell nucleus, and uses the cell's machinery to replicate its DNA or RNA and the proteins making up its capsid. One virus entering a cell may succeed in making many copies of itself. These new viruses then escape from the cell, either by overwhelming and lysing (bursting) the cell or by "budding" through the cell membrane, and proceed to find other target cells which they can infect, starting the process anew.
In carrying out their own survival and growth, viruses may cause various harmful effects on their host cells. The worst is cell destruction, which occurs when viruses escape by cell lysis. Viruses may also trigger the cell's own destructive mechanism through a process called apoptosis. Finally, the cells infected by viruses may be destroyed by the body's immune response to some of the viral components (called antigens) present on the cell membrane.
Not all viruses kill the cells they infect; in fact, some viruses cause cells to grow and/or inhibit their normal apoptotic process, leading to cancer. Other viruses can compete with normal cellular metabolism, leading to a functional impairment of the host cell. Sometimes (but not always) the functionally impaired cells will show an altered appearance when viewed under a microscope. Observable changes such as cell death and altered appearance are called cytopathic effects.
Viral infections can also lead to secondary effects. For example, by destroying the immune system's CD4 lymphocyte cells, the HIV virus leaves patients susceptible to many infections normally controlled by the immune system. Other viruses which stimulate the immune response lead to overproduction of transmitter chemicals called cytokines which can affect the body's normal functions. A serious condition occurs when viral infections evoke an immune response against normal cells, which is called auto-immunity. Some researchers believe that the symptoms of CFIDS are due to an overproduction of cytokines, reflecting a dysfunctional immune system. This is why "Chronic Fatigue Syndrome" is now more often referred to as "Chronic Fatigue Immune Dysfunction Syndrome."
A great many plant and animal viruses have been discovered, and they are classified into various families such as the enterovirus, herpesvirus, adenovirus and retrovirus families, based on their size and shape, genetic sequence, and other properties. The broadest classification distinguishes between those with DNA and those with RNA in their core. Novel viruses do not arise "spontaneously" but evolve and adapt through mutation from other (hopefully known) viruses, so the hunt for new viruses usually begins by looking for variants of those that are known.
A very important characteristic of viruses is that most are able to infect only certain types of cells. For example, the HIV virus can infect CD4 lymphoctypes but does not infect CD8 lymphocytes. This selectivity is referred to as the virus's tropism. Relatively few viruses can grow in cells in the brain; those that can are called neurotropic.
Why is This One Called the Stealth Virus?
Most microbes, including viruses, provoke a response from the immune system when they enter the human body. The immune response is very elaborate and involves coordinated interactions between several types of lymphocytes, including the CD4 and CD8 T cells, B cells and natural killer (NK) cells. These lymphocytes communicate (via cytokines) with each other and with other cells (macrophages and neutrophils). The macrophages (literally, "big eaters") have the ability to engulf dead cells, bacteria and other large parasites. The clustering of lymphocytes and macrophages at the site of an infection is called chronic inflammation and is one of the more readily observable aspects of the immune response to viral infections.
Physicians are so accustomed to finding signs of inflammation when an infection is present that, when inflammation is not seen, they may be skeptical that any infection exists. But as shown in the American Journal of Pathology article, the viruses Dr. Martin is studying can be cultured from cerebrospinal fluid in which there is no accompanying inflammatory reaction. Further, as described by Dr. Martin in Dr. Byron Hyde's book The Clinical and Scientific Basis of the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, viral particles have been observed in an electron micrograph of a brain biopsy which showed no inflammation. Because of these and related findings, Dr. Martin has tentatively named this group of viruses the "Stealth viruses."
In routine tissue cultures, the Stealth viruses cause relatively little cytopathic effect. (This may explain why they have not been noticed previously.) Under the right conditions, however, these viruses can be grown in many different cell types (both human and animal cell types), including neural cells. Their growth leads to a characteristic cytopathic effect, best described as large "foamy" cells with vacuoles in the cell's cytoplasm. The appropriate culture conditions and other growth characteristics of these viruses were well described in Dr. Martin's American Journal of Pathology article.
The demonstrated existence of a cytopathic, neurotropic, but non-inflammatory virus is one of the important results of Dr. Martin's research, since it suggests a different view of the probable causes of several poorly-understood diseases (more on that below).
Is the Stealth Virus a Retrovirus?
The Stealth virus is not a retrovirus; it is a virus with DNA in its core. Retroviruses have RNA cores, but their genes convert to DNA within infected cells. This switch from RNA to DNA is achieved by a special enzyme called reverse transcriptase. Two well known types of retroviruses are HIV which (as far we know) causes AIDS, and HTLV which causes some types of T cell lymphomas (cancers) as well as a rare form of neurological illness called spastic paraparesis. Many CFIDS patients are aware of the research done by Dr. Elaine DeFreitas, in which she found evidence of HTLV-related DNA sequences in patients with CFIDS. This work was based on positive findings using the polymerase chain reaction (PCR) which is a very sensitive but not entirely specific method of detecting viruses. However, these results were not replicated by others, and due to a series of unfortunate accidents and illness, as well as a lack of funding, this work is not being actively pursued today.
Dr. Martin's early work also relied on use of the PCR assay. He reported at several conferences that he had detected herpesvirus-related sequences in several CFIDS patients. When he eventually obtained a definite cytopathic effect in blood cultures from CFIDS patients, the "foamy cell" appearance of the infected cells led him to consider a type of retrovirus called a spumavirus (the term "spuma" is Latin for foam). Unlike other retroviruses, spumaviruses induce a foamy cell cytopathic effect in fibroblast cells of many species. The foamy cell inducing property of these viruses is not due to typical retrovirus genes but rather to additional genes (called bel genes) which have become incorporated into an otherwise non-cytopathic retrovirus.
However, molecular studies on several of the Stealth viruses isolated by Dr. Martin clearly demonstrated that they have DNA in the core and are therefore not retroviruses. Electron micrographs of these viruses suggested a type of herpesvirus; but their growth characteristics and reactivity patterns in both PCR and immunological assays were not those of the known herpesviruses.
The herpesvirus family includes the HHV-6 (human herpesvirus-6), EBV (Epstein-Barr virus), CMV (cytomegalovirus) and VZV (varicella zoster virus). Many CFIDS patients are aware that CFIDS was originally thought to be caused by a strain of the Epstein-Barr virus (which causes infectious mononucleosis) and for a time was called the "Chronic Epstein-Barr Syndrome." Dr. Martin's DNA sequence studies of the prototype Stealth virus suggest that it was derived from CMV. It is quite possible that Stealth viruses can also be derived from other members of the herpesvirus family. But since they are novel viruses, their classification at present is uncertain.
Retroviruses have not been ruled out in CFIDS, and it is entirely possible that more than one virus is involved, and that they may reinforce each other. Other researchers are continuing to hunt for a novel retrovirus which may be implicated in CFIDS. So far, however, no retrovirus has been conclusively identified or clearly associated with CFIDS in the research literature.
What is a "Cytomegalovirus-Related Sequence..."?
As reported in his American Journal of Pathology paper ("Cytomegalovirus-Related Sequence in an Atypical Cytopathic Virus Repeatedly Isolated from a Patient with Chronic Fatigue Syndrome"), Dr. Martin employed gene sequencing to identify portions of the DNA of the prototype Stealth virus which were obtained using PCR. These DNA sequences were matched against the GenBank, a database of known DNA sequences including those of CMV, EBV, VZV and portions of HHV-6. One of the PCR products showed no significant sequence homology (i.e. match) to any of the GenBank sequences; this established the virus as novel and not previously described. The other PCR product contained a sequence which could be matched to a portion of the genome of the CMV. This matching was confirmed by sequencing a portion of the viral DNA directly cloned from purified viruses. The partial homology with CMV suggested that while the virus may have been derived from CMV, it has undergone extensive mutations and deletions.
The prototype Stealth virus is a "small to medium-size" virus, possibly in multiple segments, with about 80,000 elements (nucleotide base pairs) in its DNA sequence. In contrast, the CMV virus consists of about 240,000 base pairs. One interesting point is that some of the sequences of the CMV's DNA which have been deleted and/or mutated from the Stealth virus's DNA are genes coding for the major proteins that are recognized and attacked by the cellular immune system. The absence of these sequences may explain the lack of an inflammatory response to the Stealth virus, which gives the virus a survival advantage as well as its name. A "price" of some of these mutations may be a lessened ability to replicate efficiently in host cells and in routine tissue cultures. The latter property has no doubt made them difficult for other researchers to detect without careful attention to Dr. Martin's tissue culture methods. Much more insight could be gained from studying the virus's DNA sequence; unfortunately Dr. Martin has not had the funds to complete the task of gene sequencing the entire Stealth virus (more on that below).
How Do Other Scientists View Dr. Martin's Work?
Most scientists are basically conservative and skeptical of new claims in general, which is appropriate for people working in research. They will tentatively accept results which have been published in peer-reviewed scientific journals (though even this is subject to verification by others) and not much else. The medical research community tends to frown on the practice of publicizing results before they have appeared in peer-reviewed journals, and some journals are reluctant to accept papers reporting work which has received prior publicity. This attitude may be a little outdated in an age of patient awareness and widespread use of resources like the Internet, but it is common nonetheless.
Dr. Martin's research did receive publicity as early as 1991 in Newsweek and The Wall Street Journal, largely as the result of the CFIDS Association of America's efforts to draw attention to the reality of CFIDS and the plight of patients. Reaction to this early publicity by other researchers was generally negative, and they did not take this work seriously until the publication of Dr. Martin's paper in the prestigious American Journal of Pathology. At this point, researchers active in this field whom I contacted generally do accept the results documented in that paper, but will not accept as "proven" any further results from Dr. Martin's more recent research, until this work also appears in a respected, peer-reviewed scientific journal. This involves a cycle in which reviewers submit their comments and the author responds by revising and resubmitting the paper, sometimes several times; it can easily take a year or more. In the meantime, Dr. Martin's work continues to receive publicity which the medical research community may view as "premature," but he has little choice about this if he is to raise the funds needed to continue the Stealth virus research.
What About the 1992 "Case-Control" Study?
In 1992, the CFIDS Association of America funded a study supervised by Dr. Walter Gunn, who had recently retired from the Centers for Disease Control, to determine whether CFIDS patients (cases) could be distinguished from non-patients (controls) by testing their blood for the presence of a virus, such as the HTLV-like virus reported by Dr. DeFreitas or the novel virus reported by Dr. Martin. A third investigator, Dr. C.V. Herst of Oncore Analytics, also participated in this study. It was hoped that a clear ability to distinguish cases from controls would help confirm the reality of CFIDS, which has only a "working case" definition from the CDC. Without belaboring all the details, it was found that none of the three researchers, including Dr. Martin, had a test which could reliably distinguish cases from controls. In all three labs there were both "false positives" -- in Dr. Martin's case, non-patients from whose blood the virus was successfully cultured, and "false negatives" -- CFIDS patients from whose blood the virus could not be cultured. Naturally, everyone involved was disappointed with these results.
Some people have thought that this study effectively disproved a relationship between the Stealth viruses (or other viruses) and CFIDS. This is incorrect; the study simply failed to find a consistent correlation between the tests for viruses performed at that time and certain diagnosed cases of the disease. In presenting the study, Dr. Walter Gunn said that "Although the results do not support the involvement of a [retro]virus in CFS, they do not prove that no [retro]virus is involved with the illness" (CFIDS Chronicle, Summer 1993).
Although the case-control study received a good deal of publicity, it was not the only instance where researchers have been frustrated in attempts to link a causal agent with the diagnosis of CFIDS. In fact, a variety of efforts to associate other viruses, elevated levels of cytokines, and other factors with CFIDS have yielded ambiguous results, often with false positives and/or false negatives. For example, the recent tests for a "marker" for CFIDS in urine reported in 1994 by researchers at the University of Newcastle found "positives" in 85% of CFIDS patients and in 48% of controls.
What is the source of this ambiguity? One must consider the complex working case definition of CFIDS (which was finally revised in December 1994) and its interpretation by different clinicians who have supplied blood samples for these studies. The working case definition had no less than 15 symptoms which could be satisfied in various combinations to constitute a case; it would be easy, for example, for a patient to satisfy the case definition even if he/she had no cognitive symptoms. In a very early paper ("Viral Infection in CFS Patients" in the book The Clinical and Scientific Basis of M.E./CFS) Dr. Martin had noted that "The rate of viral positivity has varied somewhat depending on the referring clinician. It has ranged from 40% to over 70%." But the source of ambiguity may be even more subtle. In the case of CFIDS, clinicians are obliged to diagnose cases based on patients' reports of symptoms experienced, plus the few physical factors that they can measure. If, as is widely suspected, the disease involves the brain, a highly complex system, the potential for variation in the symptoms experienced and how they are reported, as well as for overlap with other conditions which might yield similarly reported symptoms, is very great.
More than two years after the case-control study, there is still no test which can distinguish CFIDS cases from controls. Several researchers are continuing to devote effort to identifying a "marker" for CFIDS which would make this distinction, and the CFIDS Association of America continues to fund research of this type. Considering all the attempts that have already been made, however, there is certainly no assurance that these efforts will succeed, or that they will be useful for finding a treatment for all (or any) of the symptoms of CFIDS.
How Does the Stealth Virus Relate to CFIDS?
CFIDS patients have struggled for a long time for recognition of the illness from the medical community. Hence it is easy to understand the strong desire for a definitive test for CFIDS, and for research results that dovetail perfectly with the current clinical description of the disease. But Dr. Martin (and other researchers) have to follow the clues they uncover wherever they lead, even if they don't fit preconceived notions of CFIDS and CFIDS alone. These clues have led to Dr. Martin's recent hypothesis of a "Stealth virus encephalopathy" (disease of the brain) which may be a common feature of CFIDS and certain other neurological illnesses (more on this below). What is more exciting is that if this hypothesis (of Stealth viruses as a cause of neurological illness) proves correct, it may also be possible to treat such illnesses by inhibiting replication of the Stealth viruses.
The battle for recognition and acceptance of CFIDS by the medical community is in some sense "fighting the last war." Great progress has been made towards recognition of the disease, but still there is no treatment for CFIDS. Moreover, there are many other diseases with neurological symptoms, some of which have been recognized for decades, which still have unknown causes and no effective treatments. If, on the other hand, there is even a realistic possibility of explaining and potentially treating certain neurological symptoms which may be common to CFIDS and other important illnesses, it would seem very prudent to explore this possibility.
A Marker -- Or a Treatment?
The ultimate goal of CFIDS research is, of course, to understand, treat, and conquer the disease. One approach is to study a large number of patients diagnosed with CFIDS; try to find a biological "marker" or suspected causal agent that is common to all (or nearly all) of them; and then (and only then) try to establish how, on the molecular or cellular level, the agent acts to cause the disease. CFIDS research has generally been frustrated at the first step, because it has been so difficult to find a "marker" common to nearly all patients. Dr. Martin's work on the Stealth viruses falls into this category because the viruses have been found in many, but by no means all patients.
But there is another avenue of attack. Dr. Martin has a suspected causal agent -- the Stealth viruses -- and evidence to suggest how, on a molecular and cellular level, the agent could act to cause disease. Since the Stealth viruses also infect animal cells, it is possible to perform experiments to see if the agent does in fact cause disease, at least in animals. If it does, one cannot generalize immediately to humans, and of course one cannot perform similar experiments on humans (as some pioneering researchers did a hundred years ago!) But Dr. Martin also has evidence of a substance which inhibits the causal agent -- and if that substance can be shown to be safe, it can be tried on a few seriously ill human subjects under special "compassionate care" conditions. While this is in some sense a "long shot," if such a test were to succeed, it would accomplish many things at once: It would lead to a better understanding of the illness itself, the causal agent, its mechanism of action, and possible avenues for treatment.
Dr. Martin is pursuing this approach, while other researchers pursue theirs. Because he is trained in pathology as well as in medical microbiology and virology, he is uniquely qualified to do this. And, as I have seen close up, he is a very compassionate person who is motivated by the patients he has seen to do whatever he can to alleviate their suffering. Moreover, he has made progress beyond that which has been reported in the peer-reviewed journals, as described below, and he is excited about the possibility of further progress. Were it not for this, he would have given up this line of research long ago in favor of a more "popular" and better-funded research area.
It should be understood that there is no guarantee that Dr. Martin's research will succeed. And even if it succeeds, it may have as much bearing on other important neurological illnesses as it does on CFIDS. It could account for all, some, or none of the symptoms of CFIDS, although the last alternative seems remote given the likely involvement of the brain in CFIDS and the large number of CFIDS patients who have tested positive for the Stealth viruses. I view my own contributions of funds for this work as something of an intelligent bet on a "dark horse." But it is a bet which I've carefully weighed and feel is worthwhile. And there's no other research of which I'm aware which offers any near-term possibility of a treatment for even some of the symptoms of CFIDS.
What About Dr. Martin's Latest Results?
Up to this point, this article has dealt either with historical events, generally accepted principles of science, or with research that has appeared in peer-reviewed scientific journals. But much of the commentary and speculation which prompted this article has to do with Dr. Martin's more recent research, which has gained publicity because of his efforts to raise funds. To answer questions about these developments, we will need to discuss this more recent research, which has not yet been through the peer review publication cycle. Most researchers wouldn't consider the results discussed below as yet "proven," and CFIDS patients, relatives and friends would be well advised to consider them in the same light. But since they have already received some publicity which has been widely misunderstood, this article will seek to clear up some of the confusion and misunderstanding.
What is a "Stealth Virus Encephalopathy"?
In an invited article published in the October 1994 issue of CAP Today (a publication of the College of American Pathologists, which is not peer-reviewed), Dr. Martin advanced the idea of a spectrum of neurological illnesses potentially attributable to a Stealth virus infection of the brain. Rather than attempt to define CFIDS as an etiologically distinct illness (having a unique cause), he suggested that Stealth virus infections of the brain may have varying manifestations depending on the actual location and severity of the infection. To bolster this concept, he described the isolation of Stealth viruses from patients diagnosed with a wide range of neurological and neuropsychiatric diseases, including depression, dementia, fibromyalgia and other pain syndromes, multiple sclerosis, schizophrenia and even autism. (The finding of a Stealth virus in an autistic child has been accepted as a Letter to appear in a peer-reviewed journal.) Dr. Martin mentioned that he has seen families in which several members are Stealth virus culture positive and have been diagnosed as having one or more of these diseases. He also noted that some asymptomatic family members, and well as other symptom-free individuals, have tested positive for Stealth viruses. Whether DNA sequencing or other approaches will reveal the biological basis for differing disease manifestations, and for the lack of apparent disease in some individuals, has yet to be investigated.
How Does the Stealth Virus Affect Animals?
Dr. Martin has shown that the Stealth virus is able to survive in both human cells and animal cells in culture, as reported in his American Journal of Pathology paper. He has also done experiments (not yet published in a peer-reviewed journal) in which laboratory animals injected with isolates of the Stealth virus have exhibited neurological and behavioral symptoms indicative of an encephalopathy. Virus infection of the brain in these animals has been confirmed histologically and by electron microscopy. The fact that the Stealth viruses can infect animals helps distinguish these viruses from CMV, and more important, it provides a model system to better understand the encephalopathy and develop therapies.
Is the Stealth Virus Contagious?
Dr. Martin has not yet published any direct evidence to indicate that the Stealth viruses are contagious. Generally speaking, viruses in the herpesvirus family, like HHV-6 and EBV, can be communicated in a variety of ways; indeed, it is believed that the majority of the population has been exposed to certain of these viruses. But this does not lead to serious disease in most cases, because our immune system readily develops T cell immunity. Disease occurs when the immune system is depressed or impaired and is unable to "fend off" these viruses. Dr. Martin believes, however, that the Stealth viruses may be able to establish a persistent ongoing infection even in individuals with an intact immune system.
Can the Stealth Virus be Destroyed?
There is evidence from cell line experiments that replication of the Stealth virus can be inhibited. Some background may be helpful: A cell line is a collection of living human or animal cells which will survive and grow in a test tube or Petri dish, as long as they are "fed" or supplied with certain nutrients. One way to study a virus is to introduce it into a cell line and observe its effect on the cells. In Dr. Martin's early research, he found that when the Stealth virus was introduced into certain standard cell cultures, it would often disappear within a few days. Much effort went into finding a cell culture method that would allow the viruses to induce a cytopathic effect so that they could be studied.
More recently, the fact that the virus would not grow readily in standard cell cultures has provided a starting point for isolating a substance that might inhibit the growth of the virus in actual tissues. Such a substance, if shown to have a therapeutically beneficial effect in a few severely ill virally infected patients, would provide the most direct way of validating Dr. Martin's hypothesis of a Stealth virus encephalopathy -- i.e. that the virus is the cause of the disease symptoms.
What is "Epione" and What Will It Do?
Epione is not the name of an existing drug, and it cannot be found in a pharmaceutical directory, where at least some people have looked! Epione is simply a term coined by Dr. Martin to describe the Stealth virus inhibitor he is trying to develop in his lab, starting from the cell culture experiments described previously. The name comes from Greek mythology and is highly appropriate: Epione was the wife of the god Asclepios, the father of medicine. The names of two of their daughters, Hygeia and Panacea, are easy to recognize. Still, patients should not expect that Epione will be a panacea!
Ideally, Epione would be reduced to a single protein which would interact chemically with a critical Stealth virus gene to inhibit synthesis of viral proteins. Isolation of such a protein would be much easier to accomplish if the complete DNA sequence of the Stealth viruses were known. However, Dr. Martin feels he is far enough along with this work to plan for the next step: Testing of the viral inhibitor on animals, and then on humans.
Will There Soon Be "FDA-Approved" Trials?
Any experimental test of a drug or other substance on a human patient requires both "informed consent" and approval from the FDA. This rule applies even to the earliest research steps, far in advance of large scale FDA approved clinical trials which are one of the last steps in the process of gaining approval for public release of a new drug. Such clinical trials are extremely expensive and time-consuming, costing millions of dollars and requiring many months or even years to complete. Results from preliminary tests on humans, plus support from a well-financed drug company are practical prerequisites for a major clinical trial. Epione is clearly nowhere near this stage.
Dr. Martin does, however, hope to apply to the FDA soon for an IND (Investigational New Drug) permit to conduct very limited tests on one or two human subjects who are "compassionate care" cases and who have given informed consent. These subjects are much more severely afflicted with neurological illness than the typical CFIDS patient: One candidate has been in a near-vegitative state for some time. Some people in the CFIDS community have misinterpreted this to mean that clinical trials would start soon, causing both undue excitement and consternation.
Dr. Martin has additional work to do before he can apply for an IND even for these limited tests. This involves further reducing and characterizing the substance to be administered, and conducting safety tests on several species of animals. Until very recently, however, Dr. Martin did not have the funding to complete an IND application.
Have Any Funds Been Raised?
Fortunately, a group of CFIDS patients and non-patients (including the author) have responded to Dr. Martin's appeal and contributed a total of over $135,000 to fund the Stealth virus research program. This means that Dr. Martin's work will go forward, at least in the near-term. Given the expense of basic research it should come as no surprise, however, that more funds are needed. In particular, with the funds available Dr. Martin can either pursue his IND application and compassionate case trials, or complete the DNA sequencing of the Stealth virus, but not both. Dr. Martin plans to pursue the IND application based on the knowledge he has from partial sequencing of the virus, but the information gleaned from further DNA sequencing would improve the chances for success by allowing him to further refine the viral inhibitor Epione.
What is the "Adopt-A-Clone" Program?
Since the main feature of a virus is the strand of DNA (or RNA) in its core, a great deal can be learned about the virus by determining the exact composition of its DNA. Every DNA molecule consists of two polynucleotide chains wound together in a double helix. Each "link" between the two chains consists of a base pair of nucleotides, either adenosine and thymidine, or cytosine and guonosine. The unique sequence of base pairs determines the virus's genetic structure. This sequence can be determined, one base pair at a time, through a series of chemical experiments plus some computer processing.
Thanks to the remarkable progress of biotechnology, determining the complete nucleotide sequence of a DNA molecule, such as the core of a virus, is a fairly straightforward process. With the availability of automated gene sequencing equipment, the process need not be very time-consuming, but it is expensive. A rough estimate is $1 per base pair, or a total of about $80,000 for the complete Stealth virus (this is in addition to the ongoing cost of running the laboratory, paying salaries, etc.) Dr. Martin hasn't had this amount of money available, but he has been able to begin the process of sequencing the virus, including a first step which involves breaking up the DNA strand into shorter segments "cloned" from the original.
Recently Dr. Martin appealed to CFIDS patients, relatives and friends in a couple of fund-raising meetings with the idea of the "Adopt-A-Clone" program. The message is that contributions, no matter how small or large, will translate directly into increased knowledge of the Stealth virus through DNA sequencing, which can be done "a piece at a time." These contributions are tax-deductible and may be made to the USC School of Medicine, earmarked for the "Stealth Virus Fund." They may be sent either directly to Dr. W. John Martin, USC School of Medicine, Edmondson Building, 1840 N. Soto Street Room 156, Los Angeles, CA 90033, or to William K. Stone, Executive Director of the USC School of Medicine Office of Development (Admin-516), 1975 Zonal Avenue, Los Angeles, CA 90033.
PostScript: It's Up to Us
I hope that this article has answered many questions about Dr. Martin's Stealth virus research effort. As mentioned earlier, research carries with it no guarantees of success. For reasons outlined in this article, however, Dr. Martin's research seems to be a reasonably good bet -- the best we have at present. Moreover, if he is really successful, the implications could go far beyond CFIDS to encompass a number of diseases which involve unexplained neurological and cognitive impairment. For me, the chance to participate in an effort that could break new ground in science and medicine is a chance worth taking. For CFIDS patients and their loved ones, the "upside" if Dr. Martin succeeds is immeasurably greater. This is certainly not a time to be discouraged. What do you think -- and what will you do?