A plea for broad leukemia virus research

Robert A. Heinlein said:
A human being should be able to change a diaper, plan an invasion, butcher a hog, conn a ship, design a building, write a sonnet, balance accounts, build a wall, set a bone, comfort the dying, take orders, give orders, cooperate, act alone, solve equations, analyze a new problem, pitch manure, program a computer, cook a tasty meal, fight efficiently, die gallantly. Specialization is for insects.

While I fall far short of the above ideal, I keep trying to look beyond the incredibly narrow perspectives of most researchers in biomedical fields, and the ephemeral subjects of disputes which dominate their working lives. Admittedly, this is moving upstream against a powerful current which drives cautious researchers to end up knowing everything about a subject of no particular interest to anyone else.

Just in case anyone out there buys the argument that research into possible human leukemia viruses is nothing more than wasted effort, and a sop for crazy patients who don't have any real disease, I thought I'd build a case for research on diseases which are both acknowledged and fatal. The reason certain viruses are called leukemia viruses is simple, they have been shown to cause leukemia in a number of species. The causes of most human leukemias remain unknown.

The primary examples are murine leukemia viruses, but this is not a single virus with a straightforward sequence. You need to distinguish between Abelson, Friend, Moloney and Rauscher murine leukemia viruses, for starters. (Did I mention that what we commonly call mice are actually many different species?) Another kind of classification splits this group into ecotropic, polytropic, amphotropic and xenotropic. You also need to worry about the role of helper viruses, which make it possible for another virus to replicate, even though defective, e.g. myeloproliferative leukemogenic virus (MPLV). If similar complexity exists in human pathogens a lack of repeatable initial findings should be expected. It is far easier to experiment on mice than humans, and it took quite an effort to reach our present understanding of mouse viruses.

Mice are not the only species affected by these. Perhaps it is to be expected that there should be a feline leukemia virus (FLV) corresponding to MLVs. The are several similar endogenous retroviruses in cats, with at least one still exogenous. Gibbon Ape leukemia virus (GALV) jumped to that species recently enough so that it is still exogenous. (BTW: a receptor used by this virus is also present in humans.) Another similar exogenous virus shows up in domestic fowl, reticuloendotheliosis virus (REV). This is a rare example of a virus jumping from one class of animal host to a completely different class. (This is beyond species, genus, family and order, but less extreme than jumping to a different phylum or kingdom. Sorry kids, you are probably safe from diseases affecting broccoli, and Mom can be expected to know this.)

Homologous sequences to GALV also show up in a new koala retrovirus (KoRV), a jump to marsupials. This is not ancient history, even on human time scales. Epidemiology shows this infection has invaded new territory after 1900. It is not clear that it even existed in its present form at earlier dates.

These are all gamma retroviruses, and we still have not exhausted their range. What we can show is that recent speciation events reach into historical times, and this group exhibits remarkable versatility in terms of hosts.

Not all leukemia viruses are gamma retroviruses. One of the most widespread in a human environment is bovine leukemia virus, a delta (and complex) retrovirus. Many animals shedding virus are asymptomatic. Tests for antibodies to this virus have now found them in humans. Even if the structural differences are substantial, there is a human leukemia virus in this group, HTLV-1. It is known to cause adult T-cell leukemia/lymphoma (ATL), a fatal disease. I will only mention that HTLV-2 through HTLV-4 exist.

This virus and disease are notable in two respects: this is a human leukemia with a clear viral etiology; the latency between infection and appearance of the progressive and fatal disease is over 20 years, and may be closer to 40 years. What about etiology of other human leukemias? If you read current literature you will find that researchers have damn near emptied the bit bucket in the search for possible explanations. If you compare this with earlier literature on say, cervical cancer, you will see corresponding confusion over etiology prior to proof that a strain of human papilloma virus (HPV) caused most such.

HTLV-1 also causes another fatal disease, HAM/TSP, originally called tropical spastic paraparesis. This is a neurodegenerative disease which typically manifests clear symptoms 20 to 30 years after infection, which often takes place around birth and before weaning. The virus was isolated from cases of ATL and HAM/TSP which showed geographic localization in very different places: the Caribbean and islands near Japan. There was clear epidemiological evidence of transmission from mother to child, and of sexual transmission from male to female. If it had not been localized to island populations, or had not had a distinctive and fatal pathology, it is doubtful it would have been isolated and identified on the basis of symptoms, (at least not until technology has advanced beyond its present state.) We now know about 97% of those infected are asymptomatic carriers. (Has any infected individual ever been cured?)

My point here is that it is not special pleading to insist that a human version of a leukemia virus should be expected to have a very long latency and relatively low short-term lethality. We have clear evidence that the characteristics of well-adapted viruses match host life cycles, and human life cycles from weaning to reproduction are longer than almost any mammal except elephants. A leukemia virus in humans should not be expected to behave exactly like a mouse virus. If it did it would kill human hosts before it could be passed on to the next generation. HIV-1 is an anomaly among human retroviruses with about 99% lethality and only 5 year latency.

This brings me to an important point: a virion is not living, it is not even a complete organism; it has no metabolism. (Virions can even be crystallized and stored like salt or sugar. X-ray crystallography was used to deduce some properties that were not visible.) Essentially all the activities caused by a virus are carried out by the host cell. Expecting a virus to behave exactly the same way in different hosts is foolish. Assuming behavior will be completely unrelated is foolish in a different way, it denies the common ancestry of host animals.

There is another lesson in the story of HTLV-1, it causes two very different diseases: a neurodegenerative disease and a hematological disease. These are ordinarily treated by different medical specializations. But this is not the end of the problem. Below is a quote from the Wikipedia entry:

Patients with HAM/TSP may also exhibit uveitis (inflammation of the uveal tract of the eye), arthritis (inflammation of one or more joints), pulmonary lymphocytic alveolitis (inflammation of the lung tissues), polymyositis (an inflammatory muscle disease), keratoconjunctivitis sicca (persistent dryness of the cornea and conjunctiva), and infectious dermatitis (inflammation of the skin).
We have now brought in ophthalmologists, rheumatologists, immunologists, pulmonologists and dermatologists. Since urinary incontinence is common we might throw in a urologist. (Would other malfunctioning sphincters bring in a gastroenterologist? I'm not sure how patient organ systems are currently gerrymandered.) But this is not the end, sensory disturbances are very common. Could a TSP patient end up in the hands of a psychiatrist? And, could this fine fellow, reaching back two decades to recover memories from medical school obscured by a fog of student fatigue, classify this as a somatization disorder? Surely, all these disparate symptoms could not possibly be caused by a single thing, let alone something that happened 30 years ago.

Not to worry, this disease is almost invariably fatal, so any momentary confusion caused by misdiagnosis will be cleared up eventually -- at autopsy.

A better adapted pathogen would not kill the host. What would modern medicine do with the patient in that case?


Terrific science writing, anciedaze. Thank you.

I'm particularly interested in this topic because my mother (who for decades had ME/CFS symptoms but was never diagnosed) late in life developed myelodysplasia syndrome, a pre-leukemia. She was told that the condition is rare. But a couple of years after her death in 1997, the father of one her daughters-in-law was also diagnosed with myelodyspasia syndrome. One of this man's other daughters had been diagnosed with CFS (as I had been some years before after years of symptoms). So here are two families socially connected, rather than genetically connected, with members coming down with the same illnesses.
Merry, your report is not the first I have heard. Even before I considered the possibility of a virus causing my troubles, I was aware of a cluster of leukemias/lymphomas in a friend's family. My friend was told such clusters do not exist. When I raised the question with another doctor, I was told these were diseases with unrelated causes. After a little library research (remember when we had to go to libraries?) I found there was no clear etiology for any of these. How do you know diseases have different causes if you haven't pinned down causes for any?

On the subject of HTLV-1, I've had other interactions with doctors. A response from two was that this was extremely rare, because they just don't see a lot of cases. When I asked "How often do you test for HTLV?" I got responses indicating that generally they don't, because the disease is always fatal. Which takes me back to questions about incidence. If you never test for it how do you know? How many cases are never correctly diagnosed? An analysis of many reported causes of death indicates that doctors were aware the patient's heart stopped, or he/she stopped breathing. This is not the basis for any kind of epidemiology.
A public response to some private messages: I am not saying I know that viruses A, B, C must cause diseases P, Q, R - quite the contrary. What I am saying is that the potential for totally unexpected discoveries concerning disease etiology is high with this group of viruses. This is precisely the opposite of what funding agencies want to hear. The predictable advances which look good on proposals and progress reports are the least valuable discoveries I can imagine. If we have to explore the entire immune system to solve the mystery of this illness I would describe that as the scientific equivalent of trench warfare in a swamp. To have some chance of benefiting those of us who may not live to see the next transit of Venus we need to think outside the box of the last quarter century. Even if this does not benefit me, it has a real chance to benefit other patients with diseases of unknown etiology.
There is an infinite amount of possible research that can be done to understand human disease (and hopefully find effective treatment).
Knowing the etiology may or may not lead to better treatment and cure. HTLV-1 is an excellent example. As opposed to other leukemias we clearly know the etiology, yet this is currently the most incurable leukemia.
Understanding the pathogenesis, is many times more important (for developing effective treatments) than knowing the exact etiology.
The pathogenesis of Chronic Myeloid Leukemia is the best understood (even if we do not know what causes it), and there is excellent (potentially curative) treatment for this leukemia.
The same is true for childhood acute lymphoblastic leukemia.
We (human kind) are really not smart enough to know where to target our research efforts. That is probably why many important developments were the result of serendipity or research with no obvious target ( or even the result of errors).
Quite often it is not the "leading experts" but the little child who says that the emperor is naked, that eventually lead to significant paradigm changes.
Sometimes it is not the high budget/well conducted fully funded research that leads to novel findings, but that which is done in a small lab (or maybe even in someone's basement). See for instance the discovery of H.pylori.
various micro-organisms are normal constituents of our body, and many are even incorporated into our genome. Many of them are dormant and only become virulent under certain conditions.
It is not unusual for family members of patients with HTLV-1 leukemia to carry the virus. Why does one develop leukemia and one doesn't? This is the major question. Just like we do not know why some people who have had chicken pox will develop Herpes Zoster and others will not. Or why some people have streptococcus in their throat, but are completely asymptomatic whereas others will become very ill.
Knowing the etiology can give a big boost to understanding pathogenesis. Without this you have to work backward from the train wreck of a late disease state, exploring every possible option. There is also a big win from having extensive laboratory work on similar pathogens suddenly connected to a particular pathology.

An argument based on the difficulty of curing a late-stage progressive disease is actually a strong argument for prevention. This is where current work on HTLV-1 is deficient. Whatever moral failings those infected with HTLV may have their children do not deserve to start life with a countdown timer running.

We now know that people who have had the infection for over 40 years die at a rate of about 2% per year. If you keep running simulations of this disease behavior forward in time you find that few will reach the age of 80. The primary way of avoiding the progressive disease seems to be dying before it sets in.

Childhood leukemias may or may not have the same cause. In animal models the presence of a leukemia virus does often manifest itself early in some individuals and late in others. The problem is that we have trouble separating inherited immune defects from acquired ones. Advances in treatment are certainly laudable, but the ideal solution would be to prevent the pathology from ever starting in children, if that is possible. At present we don't know, and we won't know until we rule out pathogens known to cause parallel diseases in other species. The possibility of such a major win should not be precluded by narrow focus.
I am not against any type of research. Like I have said, it is hard to know where the answers are going to come from. I was just addressing the problems arising from limited resources. If you over-emphasize the importance of one type of research, you will inevitably decrease the amount of research in other directions. I fully agree with you that research should be done with the widest and most broad minded focus as possible.
The problem of limited resources is always present. From this standpoint I would like to weigh the cost of intervention at different stages in the pathology. Prevention may cost far less than any late-stage intervention. The wasted opportunity in infectious diseases with long latency is that we can't very well intervene if we don't know a person is infected. From a medical standpoint they are not patients. This is also the period when it is possible to study the change which turns chronic low-level disease into progressive life-threatening disease. The possibility of intervention prior to the nightmare of a progressive decline ending in death should not be lost simply because the disease is not considered lethal in the short term. In the case of HIV-1 this has led to a holding action which gives patients years of relatively normal life, and buys time for directed research on cures.
The best prevention is living a healthy life style. But, most people in the modern world abuse their body by exposing themselves to numerous substances and unbalanced nutrition and exercise from a very early age. Prevention of diseases by medications that address risk factors is not as beneficial as we would like to think. In some diseases (including various types of cancer) early intervention (with the currently available treatments) causes much more harm than benefit. One of the flaws of modern medicine is its tendency to treat lab tests and not patients. No medical intervention is harmless, mostly if it involves many years of treatment. Significant morbidity and mortality (at times exceeding that of the disease itself) can be caused by such interventions.
I'm curious about how you expect a healthy lifestyle to prevent a retroviral infection like HTLV described above. The virus is transmitted sexually, primarily from men to women. It is also transmitted from mothers to children via breastfeeding. From that point on it is like a timer is running. After 20 years a fraction of a percent die each year from the progressive disease, after 40 years about 2% per year. This population where the studies were conducted lives by fishing, gets plenty of exercise, and eats a diet low in saturated fats, etc. Their worst habit is probably smoking cigarettes, like many Japanese. Other than that I can't think of anything which you might blame for the diseases caused by the retrovirus.
Using universal precautions (such as condoms), screening breastfeeding women for potential viral diseases (such as HIV or HTLV1) are in the realm of life style management. I was not referring to prevention of transmission of infectious diseases (which is very effective but many times practically limited) but to medical interventions (such as pharmacological treatment and vaccines), The exact percent of patients which will become symptomatic is not clearly known in HTLV1 (as opposed to HIV). There is also a difference among areas which are endemic for this infection and areas in which it is a rare occurrence.
Those Japanese results used people in the same area as controls to compare with incidence in people who tested positive. The numbers I quoted were for the infected population, and the cumulative effect is dramatic. Condoms have multiple consequences. Are you telling people with this infection they can have no children? On top of the expectation of early death that is a crushing burden.

The exact percentage in HIV is not precisely known, but the implications are known, and the disease is recognized. I've run into recent graduates from medical school who knew nothing about HTLV. Under those conditions it is hard even to judge incidence. As for tracing consequences of such long-term infection, in the environment of a modern city it is simply impossible. People move constantly. Many medical practices destroy records when legal requirements for keeping them end. If you wait for definitive results, large numbers of people will die.
I would be interested to know broadly what drives the current research priorities (I do not work in this field so could only speculate). I appreciate your point Don Quichotte about limited resources, but *if* the current research balance falls into "easy" patterns that can not be expected to meet "societal ideals" (whatever they may be) then a call for a change of focus would be supported. If there is reason to believe the current mechanisms and natural pressures are actually close to optimised already then less so?

In as similar way that market forces in economics can (afaics anyway) only be expected to be reactive and therefore never deal with certain proactive requirements , is it possible that current research funding will focus on fire-fighting in a way that misses a trick that would be open to a more planned focus (untrendy though the economic equivalent may be)?

P.S. Same argument may apply to long term vs short term optimisation if that was not clear. More theoretical research is likely to have a long lead time to payback (if any) but is still necessary IMHO. Engineers would be a long way back if theoretical physicists did not exist and both further back without esoteric mathematicians . I have a limited knowledge of this area but from that viewpoint it does seem the medical field is (has been?) dominated by engineers with large areas of the body (the gut springs to mind) not really understood or even particularly investigated. Maybe this is changing with modern tech breakthroughs, again I ask the question genuinely from a position of relative ignorance.
Detailed understanding of the forces behind current research priorities would require knowing many individuals involved, which I do not. This is a kind of internal politics which plagues every organization I know. However any system for allocating resources starts out it ends up discouraging any innovation which would alter social structure of that organization. Anything which would alter that structure meets vociferous opposition, which is mysteriously lacking in other cases. The end result is that the best predictor of future funding is success in grabbing past funding, not success in producing significant change. This is not always bad, but in cases where there has been virtual stasis for decades I believe it is time to shake things up.

We have not cured AIDS; we scarcely know how HTLV-1 is spreading; most forms of leukemia are of unknown etiology. Many other cancers and neuro-degenerative diseases are neither preventable nor curable, and remain of unknown origin. I don't know which diseases will turn out to be caused by which pathogens, I simply observe that diseases caused by HTLV-1 would be considered quite separate without the link provided by the virus. Other diseases may have similar unsuspected relationships. There are already strong clues.

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