nagalase

It seems those of us who are so perverse we refuse to fit in convenient medical diagnostic categories with neat billing codes can't help but stumble around in minefields of medical controversy. This is one of them.

The name in this title is a sort of nickname for a molecule with full name α-N-acetylgalactosaminidase. (Such shorthand is as essential to avoid nominal overload as identifying the notably eccentric William John Cavendish-Scott-Bentinck as the 5th Duke of Portland.) This is an enzyme with highly specific action against Gc-protein, a.k.a. vitamin D3 binding protein (DBP), a precursor of Macrophage Activating Factor (MAF). This results in immunosuppression and interferes with the antigen presentation on somatic cells which makes them targets for immune cells. In terms of guilt by association nagalase is in bad company: cancer, HIV infection, and many other viral diseases.

All this supplies reasons to demonize this molecule. Finding out it is included as an adjuvant in some vaccines appears to expose a vast conspiracy by big pharma to lock in profits from expensive cancer drugs. You can find reports out there on the Internet that link this to 8 murders of doctors advocating alternative medicine. (I'm not sure all the people accessible on the Internet are part of our physical Universe, a possible research topic for those more adventurous than myself.)

Unfortunately, for any simple story, a complete absence of this molecule caused by inheriting two recessive genes causes Schindler disease. That's right, most humans are born with genes coding for this dastardly molecule! The gene is designated NAGA, which helps explain why the enzyme produced is called nagalase.

The molecule in question is scarcely large enough to hold onto its full name, let alone all the moral qualities associated with it. It has a number of roles, not all of them easy to classify. (In this it resembles that duke mentioned above.) I've said before, but will reiterate here, scarcely anything in biology serves a single function. Evolution is supremely opportunistic, and presses the most unlikely things into service when they are available.

The problem we get into here is that immune systems seem to recognize nagalase as a signal indicating the special circumstances created by cancer or viral infection. These molecules included in vaccines are not alive, and cannot replicate, which limits their effect. Immune systems which recognize them are alive and able to replicate, which means a small amount of this potentially nasty stuff can trigger a substantial host immune response against a range of pathogens, even if the immediate local effect is immunosuppression. It is important to realize that living things are systems with feedback where cyclic causation is the rule, not the exception. Attempts to reduce this to linear chains of causation are always misleading. This has been a problem in arguments over vaccination since the 18th century.

(Does nagalase appear in paraneoplastic diseases without explicit cancer? At this point I don't know, but it seems a good question to ask.)

A different kind of linear thinking takes place in the form of "if a little is good, a lot is better" and GcMAF used to reduce levels of nagalase. You will find that several papers by N. Yamamoto, which are regularly cited in literature of enthusiasts along with claims of eradicating various cancers, have been retracted. GcMAF may be helpful in a number of situations, but it is not a panacea, and there are limits to improvement based on simply reducing nagalase levels. Part of the problem here may be a bias caused by potential profits from a patent. Yamamoto is a real cancer researcher, and sincere in beliefs, but also has a financial interest which may distort judgment.

High levels of nagalase, comparable to those in cancer, are found in many ME/CFS patients. Cutting these to a moderate level generally benefits patients. Reducing them to zero is typically harmful. The problem is that you don't want to completely remove a signal indicating to the immune system that something like cancer or viral infection is wrong unless the problem is fully corrected. We need to find out what is going on, and guide immune systems to specifically target the cause, not disable the fire alarm while the fire is still burning.

This parallels some earlier controversies.

During the controversy over XMRV I repeatedly asked experts where the envelope proteins in the virus carrying an immunosuppressive domain originated. This was simply assumed to come from ancient mouse ERVs. One problem with this interpretation was that those ERVs were highly defective, but the immunosuppressive domain was still functional. Such domains have complicated 3D shapes which are easily disrupted by mutations. Furthermore, mouse genetics and immune systems have changed since the parent exogenous retrovirus inserted its provirus. Experiments had shown that the immunosuppressive domain was functional in chimeric mice with approximately human immune systems. This was frankly weird, as was the ability of seriously defective fragments to stitch themselves together like a Frankenstein monster without help from either Dr. Frankenstein or Igor. It would be easier to explain recombination ending with the sequences in XMRV if you started with a similar active slow retrovirus in human cancer tissue xenografted into mice. I was asking about possible HERVs or human viruses containing a sequence which would produce the immunosuppressive domain in question. Prostate cancer would be an excellent candidate as a source of extremely slow human retroviruses. It usually develops over a period of a decade or more. This is slower even than HIV, which is called a lentivirus (Latin for slowly is lente).

From an evolutionary standpoint, an infection which causes local immune suppression in reproductive organs, thus boosting fertility by reducing immune destruction of gametes or zygotes, would make sense. If this also caused cancer in people past reproductive age, that would have no effect on differential reproductive success, the primary measure in evolution.

We have since seen that slow infection by bovine leukemia virus (BLV) does take place in humans, and does affect breast tissue. This is another way in which local immunosuppression can increase differential reproductive success, either by increasing capacity to nurse infants, or indirectly via sexual selection (as seen widely on the Internet, even in feminist contexts, cf. FreeTheNipple), even if it causes lethal cancer after reproductive age, which was typically below 35 years for all human prehistory and most history. The 40-year-old celebrity mother remains an exception even today.

The two ERV fragments called pre-XMRV1 and pre-XMRV2 were discovered in a database search of mouse sequences. If anyone tried to match the envelope domain in which I was interested in a database of human sequences I never heard about it. The problem is that there are simply too many candidates among HERVs and common human herpes viruses, or even influenza RNA viruses, for a source of envelope proteins with roughly similar immunosuppressive domains. You could even find parallels with HIV, and that would never do if you wanted to avoid public panic.

A great deal of argument in the XMRV controversy amounted to showing that ME/CFS patients, as defined during the investigation, did not have a progressive disease likely to end in death. I'm not especially aware of any specialist doctor claiming that, but I might well have missed some.

Questions about chronic disease resulting from well-known immunosuppressive domains producing enzymes like nagalase were lost in the noise. If we can avoid conspiracy theories, and frank paranoia, it might be time to revisit this question.

What does this digression have to do with the original topic? Let's review the known causes of high levels of nagalase: late-stage cancer, HIV infection, common viral infections. There is also the problem of elevated nagalase in conditions which could be autoimmune. Could these be the result of transcription of HERVs, which also takes place in cancers? That seems quite plausible, though data are lacking. Without better diagnostic criteria we are not likely to get big data soon.

Even if this molecule indicated nothing more than cancer, viral or autoimmune activity, as opposed to bacterial infections, it should be valuable. There are a lot of potential viral infections or autoantibodies one might have to test for to conclusively diagnose such diseases, having a general marker indicating a need to direct testing toward cancer, viral infection or autoimmunity should reduce wasted effort. Combining results from several other markers in a single panel of results should be even more useful when convenient clinical signs are lacking. This is particularly relevant to diagnosis of paraneoplastic diseases where we have not identified all possible antibodies, and undiagnosed cancer is a real possibility.

One thing not known to raise levels of nagalase is thinking the wrong kind of thoughts. It is a sign of physiological disease. Ruling out physiological disease is difficult and expensive, but testing for this marker is much easier, assuming doctors are willing to find a physiological disease in this context.

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