Biology 466    Unsolved Problems Fall 2010

Why no cure has been discovered or invented for autoimmune diseases

The Three Main Reasons why no cure has been discovered or invented for autoimmune diseases: 1) Cortico-steroids 2) the word "recognize" 3) the word "self"

1) Cortico-steroids (Because they give physicians a reliable way for temporarily relieving the symptoms, although unfortunately with zero chance of any permanent cure.) The eventual side effects are bad enough that steroids canŐt be continued, and there aren't even enough variations in response to reveal useful information about the causes of disease, or guide anyone toward real cures. But they do distract people from looking for actual cures, and create an illusion of progress.

If we imagine that medical science is now 80% or more of the way toward inventing real cures for autoimmune diseases (which I hope is true!), then without past treatment with cortico-steroids we would already have reached 100%. Please discuss.

2) Use of the word "recognize" in discussing any molecular event in either normal immunity or in the pathological events of autoimmune diseases. For example, when a T-lymphocyte damages a virus-infected cell, people explain that the lymphocyte has recognized the foreignness of virus proteins. In contrast, when a lymphocyte damages one of your own myelin sheaths, then those people say this is because the lymphocyte has failed to recognize that the myelin is not foreign.

What effect does it have on your effective intelligence to think about a phenomenon using words and phrases that sound like they mean something causal, but don't carry any meaning at all? (Not even a false meaning that could at least be disproved!) When something happens that you wish hadn't happened, either a germ not being attacked or a myelin sheath being destroyed, that's due to failure of recognition. Conversely, when lymphocytes do something normal, that you like, whether it's to attack a germ or not attack myelin, the explanation is the lymphocytes have succeeded in recognizing them.

When the shapes of molecules specifically fit together, then that's recognition when the effect is good, but it's a failure of recognition when the effect is bad. The point is that precise fitting-together of molecular shapes is sometimes caused "recognition" and other times called "non-recognition"! The difference whether you call it recognition or non-recognition doesn't depend on any difference in the molecular fitting-together. It depends on whether you are glad or sorry that it happened. This is worse than the old joke about the "dormative property" of opium. And 2 points for whoever can tell me where that come from.

3) Use of the word "self" as if it could explain why antibodies and T-cell receptors fit and bind to some molecules, but don't bind to others, is almost as harmful. This is left over from some very old and long-disproved theories about how the immune system might work. The idea was that all your own cells and molecules should share something equivalent to a badge or a passport. The immune system would somehow notice when cells or molecules didn't have the same badges as your leucocytes, or something like that, and attack anything that had the wrong badges, or had no badges.

Unfortunately, there are some true facts that can seem to be confirmations of this very mistaken way of thinking about the immune system. In particular, all our cells except red blood cells have cell surface proteins of a special kind called "histocompatibility antigens". Tissue grafts get fiercely attacked if these particular proteins are even slightly different on the grafted cells as compared with those on the surfaces of the ("host") animal into which the graft is made. It was a paradox why the immune system should be so paranoid and ferocious about these particular proteins. A related paradox was why there are so many common genetic variants of the genes for these proteins. The explanation is that the function of these proteins is to hold peptides, and to be bound to by T-cell receptors and antibodies. The net result is that it's very difficult to find an exact match for tissue grafts, as compared with blood transfusions. But there is no advantage to rejecting grafts. The system mistakenly treats them as virus-infected "self" cells.

In addition, so called "natural killer" cells (a sub-category of T-lymphocytes) selectively attack cells that for any reason happen to have abnormally few histocompatibity antigens. Without "NK" cells, viruses be able to escape the usual cell killing method, simply by inhibiting the synthesis of histocompatibity antigens. There would be nothing to hold up peptides to check for binding to antigens, etc.

Much excitement has focused evidence that some cancer cells get killed by NK cells. Of course, this is only going to help cure cancers that for some reason happen not to make as many histocompatibility proteins as normal cells (which there is no particular reasons why they should or shouldn't, unfortunately). Please notice that cancer cells could equally well be selectively killed if they could be induced to synthesize peptides with an amino acid sequence similar enough to any of the viruses against to which you have been immunized. Meanwhile cancer researchers continue stumbling around in the dark, endlessly.

Antibodies "attack" any molecule whose shape fits their binding site. So do T-lymphocytes. During embryonic development of the immune system, an unknown mechanism weeds out all those lymphocytes whose binding sites happen to fit any molecule that is present in high enough quantities to activate this mechanism. If any of you know Greek, it could be a genuine contribution to medical progress for you to invent a new scientific name for this unknown weeding-out mechanism. "Aweedosis". People had been studying "Programmed Cell Death" for 100 years before the name apoptosis was coined by an Australian in 1982. Previously he had been calling it "shrinkage necrosis", which was just as incorrect as apoptosis. The proper term was "programmed cell death". But that took too long to say, or didn't sound scientific enough, or something. A lot had already been learned, but with this new name the field took off. Then there was much dispute as to whether the second p in apoptosis should be silent, or not. So it might help promote acceptance of our newly invented word "aweedosis" if disputes were to develop about whether the first e is silent, or the second e!

All kidding aside, people's reasoning power can be helped by having a short, catchy name for a complicated process. Consider: "Partial failure of aweedosis is the cause of autoimmune diseases."
"Controlled reactivation of aweedosis would cure M.S." etc.

Talking about "recognizing self " is like trying to run with your foot stuck in a waste basket.


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