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Getting in Tune With the Enemy--Microbes

Ned Shaw After a lapse of some decades, germs and disease have again been very much on our minds, largely because of the dreadful effect of AIDS throughout the world. We also have had a reawakened consciousness that globally prevalent diseases like tuberculosis and malaria remain historical scourges. Now the daily news tells us of new outbreaks such as severe acute pulmonary syndrome, or SARS, spreading from China, with an outcome that cannot be confidently predicted at this time. Throughout

By | June 2, 2003

Ned Shaw

After a lapse of some decades, germs and disease have again been very much on our minds, largely because of the dreadful effect of AIDS throughout the world. We also have had a reawakened consciousness that globally prevalent diseases like tuberculosis and malaria remain historical scourges. Now the daily news tells us of new outbreaks such as severe acute pulmonary syndrome, or SARS, spreading from China, with an outcome that cannot be confidently predicted at this time.

Throughout history, infectious disease has regulated lives. Only in the 20th century, thanks to simple hygienic measures like washing our hands regularly and separating drinking water from sewage runoff, have we taken a larger role in trying to control how microbes affect human life.

A child born in the United States in 1900 had an average life expectancy of 47 years. By the end of that century, mainly because of our conquest of infectious disease, it was 80 years for women and 75 or so for men. Since the late 1920s, the metaphor we optimistically adopted concerning our relationship to germs has been that of the "microbe hunters'" conquest over specific diseases. By the 1960s, reinforced by the wonder drugs and vaccines of midcentury, many were claiming that "plagues will be forever banished from Earth" only to be humbled after the tragic advent of the AIDS epidemic. SARS is today's new challenge.

Rather than being satisfied with the metaphor of conquest and the notion of eradication of infectious disease, we should learn a more nuanced lesson: that we had best aspire to a relationship of symbiotic coexistence with germs. Multitudes of bacteria and viruses occupy our skin, our mucous membranes and our intestinal tracts, and we must learn to live with them in a "truce" rather than victory. Understanding this cohabitation of genomes within the human body--what I call the microbiome--is central to understanding the dynamics of health and disease.

THE ENEMY SHOULD HAVE WON ... From an evolutionary point of view, microbes are extremely successful. They can grow and evolve in cycles of 20 minutes or less. A community of a billion cells can be replaced overnight from a single seed. Tens of billions of cells can be cultured in a single small test tube.

By contrast, the human species has a total population of less than 10 billion, quite modest on the microbial scale. Each human is multicellular and large, with a costly, long developmental cycle. Unlike people, germs readily exchange genes within and between various species. They don't speciate or differentiate into genetically isolated organisms as we do. In fact, these bugs engage in promiscuous lateral gene transfer, making the microbial world a kind of DNA-based worldwide Web that shares genetic information that can move from one bug to another.

When, for example, antibiotics get into our sewage system and kill some bugs, it is the occasional resistant mutant that survives. These survivors can then transfer their newfound immunity to the genes of other microbes, including pathogenic species that foment human disease.

These rapidly evolving bugs can gang up on humans through synergies of organisms that provoke mild disease, which, when joined with others, become virulent. This may prove to be the case with SARS, which appears to be a variation of the common cold virus. Humans, by contrast, are not only genetically isolated from other species (we get no biological benefit from evolutionary innovations in mice or monkeys), but the cells of the human germ line are sealed off in our gonads, insulated from most of the vicissitudes of the body. Whatever that body might learn by way of generating immunity, let's say against a new virus, cannot be passed on to one sperm or egg to the next generation. New generations have to learn it all over again.

In short, the competitive evolutionary odds seem cast very much in favor of the bugs. We see this mismatch when great plagues and epidemics sweep the world. By the raw evidence, the capability of evolving bugs should have trounced us eons ago.

So why haven't they? Why are we still here, sharing the planet with the bugs? They haven't extinguished us simply because microbes have a shared interest in the survival of the host, humans and other multicellular creatures. The bug that kills its host is at a dead end.

BUT THEY NEED US Biologically speaking, the reason we are still here is because microbes need live hosts for their own survival. This reality allows us to establish some of the ground rules of evolutionary success in the microbial world. It is as if they have read the Bible and know Genesis: They go forth and disseminate as their first rule. They multiply. Next, according to Malthusian and Darwinian doctrine, they have to be the fittest in order to survive so that they can produce the largest number of offspring they can.

Then they face a dilemma: If they extinguish their host too quickly, they will not be able to propagate. But, of course, they also have an imperative of securing a lodging post in the host, a bridgehead, fighting off local defenses and establishing a reservoir for dissemination. This is what disease as experienced by humans is all about: the establishment of a foothold so the obliging host will provide warm food and shelter and be domesticated to the service of that parasite. In fact, the symptoms of disease that we see are very often exploited on behalf of the bug's capacity to disseminate.

For example, once an organism like cholera gets into your gut, it provokes intense diarrhea. To create diarrhea, cholera secretes a hormone that results in the release of water in the gut. As long as the patient plays the game of massive rehydration, he is likely to balance the loss of fluid, survive and also have disseminated the bugs by the billions.

Cholera doesn't "want" to hurt us, but its survival as a species depends on polluting water supplies. The disease is then transmitted to other hosts. If it could get away with never killing its host, it would be even better off.

Sometimes a germ will even protect the host against other competing pathogens. And the best strategy of all is to fuse with the host by becoming part of the host's genome.

Today, we are carrying around 500 different integrated retroviruses in our own genome. After millions of years of evolution, the ancient viruses now perform indispensable defense functions for the host. The microbes that co-inhabit our bodies show considerable self-restraint by moderating the virulence of disease, especially in well-established relationships with animal hosts. Systemic pathogens such as staphylococci and streptococci, that long ago invaded us and now live within our bodies, rarely secrete extreme toxins. In consequence, probably a third of us are walking around as healthy carriers of these bugs.

It would thus broaden our philosophical horizons if we thought of a human as more than an organism. We are superorganisms with an extended genome that includes not only our own cells but also the fluctuating microbial genome set of bacteria and viruses that share our bodies. Some of these onetime invaders have become permanently established in our cells, even crossed the boundary line and entered our own genome. I call that extended set of companions the microbiome, and I pray for more research on how they affect our lives, besides the flare-ups, the blunders we call disease.

We need more research, not only on how bacteria are virulent but how they withhold their virulence and moderate their attacks. We need to investigate how our microbiome flora, the ones we live with all the time, don't cause disease and instead protect us against their competitors. We need to find a cooperative arrangement, a truce with those microbes that don't kill us.

Joshua Lederberg, former president of the Rockefeller University in New York, won the Nobel Prize in 1958 for his work on the genetic mutation of bacteria.


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