Rx: Germs are Us

In a peculiar sense, it is okay to refer to our individual selves as “we” without belonging to royalty, yet be scientifically precise since our bodies which have a thousand billion cells harbor ten thousand billion bacteria. Germs are Us. The male of our species may find it particularly hard to accept the idea that it is cooperation and not competition that drives evolution. The story of how we got here is replete with extraordinary examples of networking and compromises over the last four billion years. The question “What is Life?” asked by Erwin Schrodinger half a century ago has been answered in the most concise manner by Lynn Margulis. Life is bacteria. “Any organism, if not itself a live bacterium, is then a descendant, one way or another, of a bacterium or, more likely, mergers of several kinds of bacteria. Bacteria initially populated the planet, and have never relinquished their hold.”

Life on our planet began with bacteria. They precede what you may know as the smallest unit of life or a “cell”. Human and most animal and plant cells have a nucleus which serves as a repository of their DNA, but bacteria (or prokaryotes) are simpler living organisms which do not even have a nucleus. They existed alone on earth for almost two billion years. The greatest revolution in biology was set off when two of these bacteria began a symbiotic relationship, forming the eukaryotic cell; one which has a distinct nucleus as well as pieces of circular extra-nuclear DNA bound in little dark bodies called mitochondria. Mitochondria, it turns out, were once independently living bacteria which apparently fused with another bacterial cell that they invaded. Through a process of cooperative living, different varieties of bacteria came together to give birth to “cells”. These eukaryotes which emerged as a confederacy of bacteria, existed as unicellular organisms for another billion years until they learnt to live in groups or colonies, eventually joining together to form the multi-cellular organism. The proliferation of all the splendid life forms and species we see today has occurred in only the last 600 hundred million years, humans arriving on the scene very recently.

To place the existence of humans into perspective, there is an interesting way to look at the history of our earth in 24 hours as described below:

 

Or as Lynn Margulis says, “The entire human history from cave to condo represents less than 1% of the history of life.” The great biologist Lewis Thomas had the best description when he wrote, “Perhaps we have had a shared hunch about our real origin longer than we think. It is there like a linguistic fossil, buried in the ancient root from which we take our species’ name. The word for earth at the beginning of the Indo-European language thousand of years ago (no one knows for sure how long ago) was dhghem. From this word meaning simply earth came our word humus, the handiwork of soil bacteria. Also to teach us the lesson, humble, human and humane.”

Here are a few more humbling facts. Microbial life is 25 times the mass of animal life and equals the total mass of plant life on earth. There are 500 pounds of microbes per acre of agricultural soil. There are more bacteria in one human’s mouth than all humans that have ever lived on earth. In fact, bacteria make up 10% of our dry body weight. Some live and replicate in the various organs of our body, and others have become a permanent part of our DNA. The mouth, gut and vagina harbor their own garden of living flora. There is increasing evidence that a balanced existence of these pathogens is critical for the health of the host, and that significant metabolic functions are performed by these microorganisms.

Disease states may occur when the normal symbiotic relationship between pathogens living in one of our organs is disturbed. For example, we often develop diarrhea while taking antibiotics. This happens because antibiotics kill some of the microbes, causing a redistribution of the growth advantage among the many species of pathogens that reside normally in our gut and result in diarrhea. Another example is Crohn’s disease. This is a chronic inflammatory reaction that may affect any part of the gastrointestinal tract. Analysis of the mucosa associated bacteria of patients with active disease suggests that patients have a reduction in the diversity of intestinal bacteria. Interestingly, this disease is common in parts of the world where infestation of the gut by the helminthic worms is rare such as in the developed countries, and uncommon in the third world where people frequently carry worms. Exposure to helminths may help prevent or even ameliorate Crohn’s disease. Researchers from the University of Iowa put this hypothesis to test using the eggs of Trichuris suis, the porcine whipworm, to treat patients with Crohn’s disease. All patients ingested 2500 live T suis ova every three weeks for 24 weeks. The eggs hatch in the duodenum, releasing larvae that ultimately grow in 6–8 weeks into adult worms, but cannot replicate in the human host, dying after completing their short life-cycle. By repeatedly giving the eggs by mouth, a constant source of adult worms can be maintained in the gut without causing disease. While in the gut of Crohn’s disease patients, these worms reset the balance of pathogens back to normal and the inflammation disappears. In fact, the trial yielded a response rate of nearly 80% with no side effects. While a disturbed normal gut flora can produce a chronic inflammatory disease, introducing a live worm may reset the balance.

Microbes not only make up 10% of our body weight, a single organism is capable of a myriad of pathogenic manifestations. An example of this involves the virus called Varicella Zoster. Most of us get infected with this virus in childhood where it causes chicken pox. Once the clinical infection subsides however, not all viral particles disappear. Some of them find refuge in the nerves, where they remain in a latent form. As adults, we can experience a reactivation of these viruses, and depending on the competence of the host’s immune system, Varicella Zoster is capable of causing a variety of diseases as shown in the diagram, including the painful disease called Shingles.

Acute diseases are commonly ascribed to pathogens today. It is likely that many of the chronic diseases such as cancer, diabetes, heart disease, inflammatory bowel diseases, even mental disorders like schizophrenia have some association with pathogens. Cancers are chronic diseases that reach clinical manifestation after passing through a number of stages including initiation in a single cell, expansion, invasion, evasion of the immune responses and finally metastasis. Already, some 15% of cancers globally have been etiologically linked to pathogens. To name just a few, associations between cervical cancer and the human papilloma virus (HPV), liver cancers and hepatitis viruses, certain types of lymphomas and herpes viruses, adult T-cell leukemia and HTLV virus, and gastric cancer and helicobacter pylori are now proved and accepted. The encouraging news is that if pathogens are identified as the etiologic agents, then preventive measures such as vaccines can be designed. This has already been accomplished for cervical cancer where the vaccine against HPV is quite effective. Below are a few recent examples to illustrate how more and more malignant diseases are being linked to an infectious etiology:

• There is an inordinately high incidence of lung cancer among women in Taiwan who do not smoke. Recently, HPV has been found in their tumors. This is the same family of viruses known to be the causative agent for cervical dysplasia and cancer in women. The same is not true for non-smoking women who develop cancer elsewhere implying that there may be other etiological agents (pathogens) involved. This makes sense if you think of lung cancer like pneumonia. Pneumonia could be caused by viral, bacterial, or fungal agents, but the organ response is quite similar and by looking at an X-ray of the lungs, we cannot say whether the pneumonic patch is viral or bacterial. In the same manner, lung cancer could be caused by a variety of pathogens.
• Aplastic anemia, a potentially lethal bone marrow failure syndrome, is more common in the rural areas of Thailand and has been linked to drinking un-bottled water. Having eliminated the chemical and physical causes, an as yet unidentified pathogen is strongly suspected as the probable cause.
• The human genome sequencing has yielded over 1000 retroviruses that have apparently been subdued over millennia of evolution, and made a permanent part of our genome. Yet only two retroviruses have so far been found to be associated with human diseases (HIV and HTLV). This is not because there are no other retrovirally induced cancers, but rather because of the enormous technical difficulties related to accurately identifying these elusive agents. Using an exquisitely sensitive “Viral Chip” which can screen for the presence of hundreds of viruses, researchers have been able to show just last week that a potential causal link exists between a retrovirus called XMRV and a rare familial type of prostate cancer. “In order to understand cancer, we must understand the microorganisms that reside in and control our body functions just as aggressively as the DNA sequences that make up our genes”. (L. Margulis).

It is high time that we start paying due respect to our formidable microbial fellow passengers on the planet. In the words of Niles Eldredge, “For microbes will not only inherit the earth (should, for example, we complex multicellular creatures fall prey to the next spasm of mass extinction); microbes got here long before we did, and in a very real sense, they already “own,” and most certainly run, the global system.”