Physicist Amok

(This is a continuations of Koch’s Postulates I)

Three serious issues remain with the Koch program for establishing that a given organism is the etiological agent of a disease: the accuracy of animal models, how to proceed in the absence of animal models, and how to define “etiologic agent” in more complex cases.

HIV has two animal models: mice, in which the virus does not cause AIDS, and chimpanzees, which can only be infected by the less virulent of the two major strains, and which are simply impractical for large studies. It can infect cells in tissue culture, but many times these cells are disrupted by the culturing process, and even if they are not, the larger physiology is lost.

Actually, HIV has fulfilled Koch’s postulates: laboratory workers who have accidentally been infected with various virus cultures develop precisely the same disease as normal transmission (see here). But this is not data you can intentionally collect. That was firmly established by the Nuremberg Code and the aftermath of the Tuskagee experiment.

Animal models go further afield. Some groups are studying broad spectrum pathogens in C. elegans, a tiny worm. Others are studying the same pathogens is systems closer to humans. What if the mouse model disagrees with the C. elegans model? There is no
general solution to how to select what is relevant from a given animal model. For instance, tuberculosis in mice causes macrophages to release strong bursts of nitric oxide. Some investigators find that human macrophages infected in a culture dish don’t release these same bursts. Is this an important difference or an artifact of culturing?

But what if there is truly no animal model available? Generally we fall back on a phantom “fifth postulate”: treat the disease in patients as if it were caused by the proposed organism. If the treatment works, then perhaps you have found the right organism.

This is medically sound, but scientifically inconclusive. Consider a bacterium which has become symbiotic with a virus. It carries the virus’s genome in its own, and when it infects a host, expresses that genome to create virus particles which it secretes into the host. These virus particles infect and destroy cells of the immune system which would control the bacterium.

When you study the disease, you see the immune system being destroyed, and search for what is doing it. You find the virus, and devise retrovirals against it. When you treat the patient, it controls the disease. The fifth postulate would say that the virus was the etiological agent of the disease.

The fifth postulate can be used to disprove connections, however. The bacteria and virus symbiosis I describe above bears a vague resemblance to one disproved idea about HIV, but we can show that HIV is not like this: an AIDS patient will recieve large quantities of antibiotics to fight off other diseases. Tuberculosis alone, one of
the major killers, requires administration of four powerful antibiotics at once. In short, HIV and any possible symbiont are exposed to every class of antibiotics known. Any bacterial symbiont should have been handily slaughtered by at least a subset of these.

But why can’t this show that HIV is the cause? What if there were another virus affected by the same retrovirals that we for some reason just weren’t noticing? There is no way to control for this short of isolating the HIV virus and showing that it, and it alone, is sufficient to cause disease — in short Koch’s program.

These same difficulties show up more strongly in what are termed microbiota shift diseases, diseases resulting from a change in the composition of the body’s native microbes. The standard example is bacterial vaginosis. There is an incredibly strong correlation between a certain shift in the bacterial population of the human vagina (from mostly Gram positive species to mostly Gram negative species) and possible minor symptoms like vaginal discharge and a bad odor, and premature births. If you treat with antibiotics that target Gram negative bacteria, you can restore the original balance, and remove the symptoms. But how do you even go about defining “etiological agent” in a complex of many species?