Today's date:
  Summer 2003


Of Men and Microbes

Joshua Lederberg won the Nobel prize in 1958 at age 33 for his pioneering work on genetic mutation of bacteria. He is formerly president of the Rockefeller University in New York.

New York—The great scientific news that greeted this century was the campaign to decode the human genome. We must now remind ourselves that much of the biological composition of our bodies consists of genomes other than the human. Multitudes of bacteria and viruses occupy our skin, our mucous membranes and our intestinal tract. They are likely to play a much larger role in developing—and resisting—disease than we realize. Understanding this cohabitation of genomes within the human body—what I call the microbiome —is central to understanding the dynamics of health and disease.

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

Throughout history, infectious disease has regulated our 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, for better or worse, in trying to control how microbes affect human life.

The child born in the United States in 1900 had an average life expectancy of 47 years. By the end of that century, due mainly to our conquest of infectious disease, it was 80 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 mid-century, many were claiming that "plagues will be forever banished from the Earth"—only to be humbled after the tragic advent of the AIDS epidemic, which showed us how far we really were from that goal. Clearly, complacency about infection was a byproduct of our campaign against the germs. Now SARS is today’s new challenge.

Rather than complacency, the metaphor of conquest and the notion of eradication of infectious disease, we should learn a more nuanced lesson: that we best aspire to a relationship of symbiotic coexistence with germs, living with them in a "truce" rather than victory. That coexistence can track the spectrum from vicious lethal pandemics to mutual tolerance.

CHARACTERISTICS OF MICROBES VS. HUMANS | Microbes abound in populations with exponents of 15 and 20. Let’s just say they are in the zillions. These are tiny organisms that can grow and evolve in cycles of 20 minutes or less. Individuals are entirely dispensable, when 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 population size of less than 10 billion, quite modest on the microbial scale. Each organism is multi-cellular and large with a costly, long developmental cycle. Each of us as individuals would be the first to resist violent fluctuations in population size. Nor could human society flourish without the nurture and protection of most individuals.

In further contrast of the germs’ biological capacities, they 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 new-found immunity to the genes of other microbes, including pathogenic species that foment human disease.

Humans get no biological benefit from innovations that have evolved in birds or mice or monkeys—except that now we have an evolved intelligence that can generate an informational web for acquisition and sharing of information, of ideas.

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 that appears to be a variation of the common cold virus.

Not only are we genetically isolated from other species, 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 a fresh cycle.

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 domestication and survival of the host—humans and other multicellular creatures. The bug that kills its host is at a dead end. If it is a victorious conqueror, it extinguishes its life as well as our own. Biologically speaking, the reason we are still here is because microbes need live hosts for their own survival.

THE GROUND RULES | This reality allows us to establish some of the ground rules of evolutionary success in the microbial world—the cardinal rules of parasite behavior.

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 and secure 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.

The symptoms of disease that we see are very often secondary to our defense mechanism, but are exploited on behalf of the bug’s capacity to disseminate.

For example, once an organism like cholera gets into your gut, it provokes the most intense diarrhea imaginable. To effect 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. Indeed, with appropriate hydration, cholera does not have a very high mortality. That insight escaped us for 75 years, for lack of understanding that a "water secretion hormone" was all we need look for to understand how cholera works. So it is fair to say that millions of lives were hostage to wrong-minded philosophy of disease.

Sometimes, a germ will even protect the host against other competing pathogens. A promising example of this in AIDS research is the discovery that infection with a variant hepatitis C virus seems to be correlated with considerable resistance against the progress of HIV. It is not surprising that one virus would try to crowd out another one. That is part of its strategy to maintain its competitive advantage.

The best strategy of all is to fuse with the host by becoming part of the host’s genome.

After such a long evolution, we are, in fact, carrying around 500 different integrated retro-viruses in our own genomes that are a testimony to a history of experience with the relatives of the HIV virus. After millions of years, the ancient viruses we encountered now perform indispensable defense functions for the host.

SELF-RESTRAINT | In short, 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 staphylococcus or streptococcus—that long ago invaded and live within our bodies—rarely secrete extreme toxins. In consequence, probably a third of us are walking around as healthy carriers of these bugs.

MICROBIOME | It would thus broaden our philosophical horizons if we think of a human—a body space in any human—as more than an organism. It is a superorganism with an extended genome that includes not only its own cells but also the fluctuating microbial genome set of bacteria and viruses that share that body space. 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 pray for more research on how they impact our lives, besides the flare-ups, the blunders, we call disease.

Understanding this means that we live in a cooperative arrangement—a truce—with those microbes that don’t kill us.

IMPLICATIONS | The implications of our new understanding are that 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 that we live with all the time—don’t cause disease and instead protect us against their competitors.

Another implication is that, philosophically, we have to be very suspicious about the concept of eradication, of nailing a stake through the heart of a bacterial infection once and for all. In such a world, we would not have the stark experience of accommodating infectious stimuli and become more vulnerable.

We see an example of this today with our dilemmas about smallpox. We once thought we had eradicated it and, indeed, we had a world policy premised on its total eradication. As a result we totally dropped our guard, became immunologically naive and suspended all of our research on improvements of vaccines and antiviral medications that might have blunted an accidental or malicious recurrence. Now we hasten to repair the gap.

Finally, we must realize that hygiene can sometimes be too much of a good thing. In the effort to have infinitely clean environments, we may sometimes deprive ourselves of the stimuli our bodies need to become "street smart" and develop defenses against infection.