Harald zur Hausen's discovery of the link between infection and cancer provides a window into what may turn out to be one of the most fascinating lines of inquiry in twenty-first century medical research: the link between microorganisms and what have been traditionally considered chronic diseases.

This line of inquiry is founded on an evolutionary truth. Bacteria and viruses have been human beings' most constant companions, existing on this planet billions of years before we did and greeting us as we climbed out of the trees and walked out of Africa. Since the very beginning we have been engaged in an arms race with microbes. The conventional wisdom is that these arms races have led to an essentially benign co-existence between us and "them". But recent thinking has challenged this widespread belief and the truth appears to be more complicated.

Whether microbes will evolve to be benign or malign depends on one thing- whether they can transmit their genetic material more efficiently by the former or latter kind of existence. The purpose of evolution is the transmission of genetic material, and bacteria will exploit any route possible for achieving this. Consider malaria. When malaria afflicts an individual, the malarial protozoan can transmit itself through a mosquito vector. It therefore does not need its human victim to be healthy in order to spread its genes. Consequently, victims of malaria do not need to be healthy enough to be mobile and are thus confined to bed with acute chills and fevers. Without treatment they can die a quick death. This confinement serves another obvious diabolical purpose for the malarial parasite; it renders the victims immobile enough for mosquitoes to be able to feed on their blood and thus propagate malarial genes. This explanatory hypotheses would seem to suggest that the severity of malaria would correlate with the ease with which mosquitoes can transmit the disease. Indeed, countries with better methods for mosquito control seem to have less severe cases of malaria; in these cases, because mosquitoes are not readily available to spread the malarial genes, it is in the interests of the malarial parasite to not kill its victims too soon. Cholera which spreads through contaminated drinking water is another disease where this logic seems to be substantiated. In countries where efforts have been made to supply clean drinking water, cholera is not as pernicious as in countries where water is easily contaminated. In the latter cases, the cholera bacterium does not care about quickly killing its victims since it can easily spread into other human bodies through water. In striking contrast to these deadly diseases, the common cold has essentially evolved to a wholly benign co-existence with human beings since the cold virus critically depends on a well-timed sneeze from a completely mobile human being.

Extending these ideas, an even more controversial role for microbes that has been suggested is in molding our very personalities in a way that encourages their propagation. Recent research for instance found that the exact composition of microbes in the guts of normal and obese rats differs. Fascinatingly, transporting some of the dominant microbes from obese to normal rats actually induced food cravings in them, which was decidedly an effect on behavior. The implications of such possible effects for humans is extremely provocative and controversial. The parasite Toxoplasma gondii for instance affects cats and transmits itself to mice. Since it now needs to get back into a cat for its continued perpetuation, this parasite apparently makes mice lose their fear of cats so that cats can easily catch them. Microbes inducing suicide in their hosts seems to be the ultimate manifestation of their selfish genes. Perhaps most controversially, some researchers think that the same parasite which can be sexually transmitted makes human beings more neurotic, promiscuous and adventure-seeking when it infects them, thus ensuring its propagation. In fact, promiscuity as a means for efficient microbial transmission has been suggested for many sexually transmitted diseases including zur Hausen's cervical cancer. This would literally mean that the bacteria in question have seized control of their victims' minds and radically changed their personalities and behavior. A closer analogy to mind-control experiments devised by malevolent dictators in movies would be hard to find. As with all such hypotheses, these extrapolations should be constructed very carefully and the available evidence should be judiciously sifted and interpreted. But the implications of tiny bugs controlling our brains and behavior for their self-interests certainly boggles the mind.



"Here, kitty kitty...eat me please"

All this seems to suggest some kind of intelligence and purpose on the microorganisms' part, and one must quickly dismiss any such thinking. The logic is simpler than that. In the arms race between humans and bacteria, bacteria have to essentially deal with a tradeoff. They have to reproduce quickly enough to make sure they produce lots of progeny, but at the same time they have to make sure their rapid reproduction does not kill their victim so quickly that it dooms their chances to get into another human body and spread their genes. The best or "fittest" bacteria over the millennia are those which have finely honed this tradeoff. Those are the ones which produce enough progeny to weaken their victim, but leave him healthy enough for vectors such as mosquitoes or drinking water to do the job of transmitting them to other fertile bodies. That's why a virus like the Ebola virus has (fortunately) been so (far) unsuccessful from an evolutionary perspective. Ebola spreads so fast and kills its victims so quickly that it also kills its own chances of propagating over wide areas.

But if microorganisms have been in an arms race with human beings for millennia, couldn't they have also influenced the manifestation of not-so-obvious disease symptoms in our bodies? That's where the fascinating idea of disease as an evolutionary adaptation comes in. Cancer for a long-time was thought to be a non-infectious disease, but it was pioneering work by zur Hausen and others that established the infectious cause of some cancers. Ulcers were thought to be bona fide chronic conditions, until Barry Marshall drank a concoction of H. pylori and gave himself excruciatingly painful ulcers, which were then cured by antibiotics. What other diseases could be discovered to be of infectious origins? The possibilities are tantalizing. The biggest chronic diseases that we face today are cancer, heart disease, diabetes and artherosclerosis. Could any of these diseases be directly caused by microorganisms?

They may very well be, but a much more interesting idea is that one or more of these diseases developed as evolutionary adaptations in the arms race between germs and humans. Like bacteria, human beings can and do evolve defenses. Some of the defenses such as those employed by the immune system are obvious, but there could be more subtle clues about fighting infections hidden in chronic diseases. This line of thinking leads us to a profound and fundamental question about chronic disease: if these diseases are so bad for us, why have they persisted in the first place? If the principles of evolution apply to them, then the genes for these diseases should have been weeded out of the gene pool many years ago. Yet if we think about it, the existence of these diseases may in fact resoundingly confirm the principles of evolution, those based on the millennia-long struggle between bacteria and humans.

If these diseases have persisted, could it be because, as bad as they seem to us today, they may have served a beneficial purpose in fighting bacteria in the past? Perhaps we think that they are bad in the present because, with improved sanitation and medical advances, their infection-fighting function is no longer relevant and we only see their side-effects which admittedly are nasty. This idea is profound and sounds exotic, but we don't have to look far to find an example. The best example of disease as protection against infection is sickle-cell anemia. Those victims in Africa who are homozygous carriers of the gene for this disease have significant immunity against malaria. Indeed, in the US where malaria is under control, sickle-cell anemia seems to be much less prevalent among black Americans. But this is a current scenario. Could there be other diseases which imparted such immunity in the past?

One of the most interesting examples is hemochromatosis, where sufferers lock up iron stores in their bodies which spikes up blood iron concentrations to dangerous levels. There is a fascinating piece of history that may support the evolutionary role of such a condition, but be warned that the theory is quite controversial. In the Middle Ages, when the Black Death struck Europe on a terrible scale, Jews were often accused of bringing this malady into people's homes through some kind of mystic powers. Thousands of Jews were killed for the sake of this superstitious belief. And the fact that Jews as a population seemed to be less affected by the plague only encouraged the paranoia and madness. One of the reasons that's traditionally offered for this relative immunity is the hygenic kosher conditions which Jews practised which made their homes less attractive to rats. But another hypothesized factor is the higher prevelance of the hemochromatosis gene among Jews, especially Ashkenazi Jews who are widespread among Jewish communities. It seems that Yersinia pestis, the plague bacterium, needs iron to survive, as do many other bacteria. By locking up iron stores, the bodies of Jewish individuals denied this valuable nutrient to Yersinia, which made the germ less successful in colonizing its victims. Thus hemochromatosis, while causing harm by storing excessive iron, might have compensated for that harm by serving as a defense against the deadly plague. This theory is quite controversial and may indeed be wrong, but it underscores the basic point that diseases which may seem to be presently harmful could have served a useful purpose in the past by defending against infections. Since Yersinia is largely no longer a concern in the modern world because of medical advances, we see only its bad side.

Tantalizing as these historical clues are, one has to be very careful in ascribing an infectious cause to disease. Several of the stories which suggest such links are convenient evolutionary stories that lack hard evidence to support them. But at the very least they provide provocative ideas that can be further explored and tested.

We will end by looking at possible infectious causes for a disease under whose burden the world is increasingly bending- Alzheimer's disease (AD), that terrible malady which snatches the very personality and humanness of its victims. There are millions affected with Alzheimer's and this proportion is supposed to exponentially increase as the world's population grows older. Nobody knows the cause or cure for this disease, but its most high-profile feature is a mass of entangled protein called amyloid that aggregates in the brains of its victims. There is a lot of controversy about whether amyloid is the cause or consequence of the disease, but few will disagree that it seems to be associated in some important way with AD. Amyloid is also very interesting because it seems to be produced from the misfolding of a protein that's a normal and probably essential component of our body. Much of the current research in AD is trageted towards understanding its role in the disease, although therapies designed to stop the accumulation of amyloid seem to be failing.

One very interesting hypothesis is that amyloid is a defense against infection. I find this idea to be very provocative, and I have penned a post a while back on how amyloid might aid the body in the fight against bacterial infection. I wouldn't want to plug in my own ideas here, but to summarize, I think that amyloid may have fought against bacteria by binding to metal ions like copper and iron and generating free radicals. The interaction of amyloid with metals is known to generate free radicals and these are very bad for us, but they may be even worse for bacteria. Amyloid might have served as a reservoir of free radicals in the brain which might have been very effective especially against bacteria which invade the brain, such as those causing meningitis. My hypothesis remains to be verified or falsified, but a recent article from Harvard Medical School corroborates at least the general idea. A team of researchers demonstrated that amyloid can kill microbes by interacting with receptor proteins that are involved in the body's inflammatory response. Inflammation is well known to be a protective response against infection, and that's surely another way in which amyloid can act as an antibiotic. It is likely that it did act as one in multiple possible ways in the past. More research would be necessary to decipher the exact factors, but the visibility of such research demonstrates the fact that people are taking such links between infection and chronic disease seriously.

If we one day discover that most chronic diseases are indeed responses against infection, either directly caused by microbes or caused as evolutionary adaptations by microbes in the past, we shouldn't be surprised. Microbes permeate our bodies and have lived with us and inside us since the beginning of time. Most of them have been good tenants and have indeed been benign. But evolution's march continues unabted, and it would continue to fashion us and our resident companions in its own image. During this process it will leave thousands of clues behind, in microbial behavior, in human behavior, in the very architecture and soul of our bodies. Investigating these facets of the interaction of the most "intelligent" denizen of this planet with its smallest ones can only be rewarding and humbling. Such research will uncover riches that will challenge our pre-conceived notions about our place on this planet. And it may even tell us if we are indeed as intelligent as we think.