At the beginning of the 20th century, infections were the leading cause of death in the United States. Today, only pneumonia and influenza combined rank among the top 10 leading killers, largely because of widespread use of drugs and vaccines.

Even AIDS, once eighth on the top 10 list, has slipped to No. 14, thanks to powerful combination drug therapies.

But our dominance over germs is threatened. Our lineup of drugs is losing its effectiveness as microbes use biochemical tricks to neutralize even our most powerful antiviral agents and antibiotics -- the class of compounds that work against bacteria.

Already, there are strains of HIV, the virus that causes AIDS, that can evade the first generation of drugs. And while pharmaceutical companies have responded quickly with a second generation, there is little doubt that HIV will evolve to counter this new assault.

Research also has revealed that bacteria are continually creating new biochemical weapons with which to attack the human body. More importantly, we now know that bacteria can actually trade such weapons among themselves, making even familiar bacteria, such as the Escherichia coli that inhabit the intestines of mammals like us, more dangerous.

Finally, human activity is creating new threats. Intercontinental travel and global trade create opportunities for migration of pathogens (things that cause disease, from the Greek words for "suffering maker") to new environments, bringing them in contact with new populations of people with no built-up resistance.

But science is fighting back. Thanks to the tools of modern molecular biology, our understanding of the tiny life-forms called microbes -- their complete genetic sequences, how they attack the human body, how they reproduce and spread, how they develop resistance to drugs -- has provided marvelous new leads for researchers seeking to develop new antimicrobial agents and vaccines.

With luck, and with continued application of all that we are learning, we may someday look back at this and say it was one of the research community's finest hours.

AN UNEASY PEACE

Every second of every day, countless numbers of potentially harmful bacteria confront us. There are 10 times more bacteria living in our intestines than there are human cells in our bodies. In fact, there are more microbes in one gram of human feces than there are people on Earth.

The fact that we can peacefully coexist with these potentially hostile neighbors is a testament to the deterrent power of our immune systems, which evolution has fine-tuned to respond quickly to microbial assault yet tolerate the normal mix of bacteria that lives in our intestines and elsewhere.

In general, the immune system consists of two sets of weapons. One includes a special kind of cell that directly attacks and kills invading germs. The other is an amazingly versatile method in which other kinds of cells identify foreign microbes and generate substances called antibodies in response.

Those antibodies then bind to the surface of the invaders, either killing them directly or marking them for death by yet other cells.

Our bodies also have received a powerful assist from drugs that can slow the growth of microbes or kill them outright. But microbes evolve rapidly, developing numerous biochemical tricks to circumvent the immune system and infect the human body.

In some cases, such as with the many viruses that cause the common cold, the immune system eventually responds, and we recover. In other instances -- such as infection by HIV and hepatitis C virus, which causes liver damage -- the immune system often does not regain the upper hand, leading to persistent infection and sometimes death.

As recently as the great influenza pandemic of 1918, quarantine was our only effective weapon against the spread of infection. Ten years later, Scottish physician Alexander Fleming discovered that a fungus produced a bacteria-killing substance called penicillin, and he used a crude preparation to cure one of his assistants of a sinus infection.

It took another 12 years for biochemist Ernest Chain and pathologist Howard Florey to isolate pure penicillin and determine methods for mass-producing it, but their work forever changed the practice of medicine.

Ironically, at the same time Chain was working with Florey to perfect those production techniques, he was also discovering the Achilles' heel of penicillin and other antibiotics: Certain strains of the common bacterium E. coli could produce some factor that neutralized penicillin.

Today, we know that many such "resistance factors" exist, and more importantly, that bacteria can pass these among themselves and even across species. As a result, antibiotic resistance has become a major problem, with infectious diseases such as tuberculosis again threatening human health on a large scale.

Research has shown that the key to antibiotic resistance in bacteria lies in their genes, often on small, circular strands of DNA called plasmids. These exist in the cell, separately from the bacterium's own DNA in its nucleus.

Plasmids contain genes that allow a bacterium to produce proteins beyond its normal repertoire. These extra proteins can help the bacterium to fight off drugs.

In some instances, the proteins prevent an antibiotic from entering the bacterium. In others, they pump the antibiotic back out of the cell as fast as it enters. Resistance proteins also can degrade antibiotics or strengthen the bacterium's own defenses against antibiotic attack.

PASSING DNA

The development of antibiotic resistance is actually a modern-day proof that evolution is indeed fact, not theory. Antibiotics constitute a form of natural-selection pressure on a population of bacteria, a force that allows some rare trait to become more prevalent and give rise to what is, in a sense, a new organism.

If, for example, one individual Staphylococcus bacterium out of 1 trillion has a random genetic mutation that allows it to defeat the powerful antibiotic vancomycin, then that individual will grow and reproduce in a patient taking vancomycin. All other bacteria will die. The result is that the random mutation becomes the gene of choice in the new population of bacteria.

In addition to the many mechanisms for resistance that research has identified, the most troubling discovery has been that bacteria can pass DNA among each other, even to members of different species. Indeed, we now think of bacteria as having their own "genetic Internet" that allows them to download whatever genes they need to survive in myriad environments, including those bathed in toxic antibiotics.

This genetic downloading can occur by direct exchange between two individual bacteria, through an intermediary such as a bacteria-infecting virus or when one bacterium picks up DNA released by a bacterium that died and fell apart. Viruses can develop resistance and exchange genes, too, albeit by somewhat different mechanisms.

Bacteria also can exchange so-called pathogenicity factors -- genes that help an organism to infect and cause harm. Recent research has shown, for example, that pathogenic E. coli, which can trigger severe food poisoning, possesses a molecular harpoon that it shoots into a cell's outer membrane in order to bind there.

We now know the gene that gives rise to this harpoon, and it is clear from its makeup that it must have come from some other species since it is so unlike the rest of the genes of E. coli. We still don't know where or how E. coli acquired this gene, which turned the bacterium from a relatively harmless species into a potential killer [see illustrations].

We've also discovered recently that many unrelated bacterial species use a kind of molecular syringe to inject proteins into a cell. Numerous studies have shown that the makeup of this syringe is constant among species, although each uses it to inject different toxic proteins. We presume that these bacteria obtained their common syringes via the genetic Internet.

Although interspecies sharing obviously does give bacteria an advantage in the war against humans, it offers us an opportunity to strike back in a big way at many species simultaneously.

The common molecular syringe, for example, is an ideal target for drug developers since a single drug might be able to cover the end of the syringe and block a wide range of organisms. Better yet, a vaccine might trigger an immune response to the syringe and provide immunity against all of the many organisms.

Whether or not that strategy works, science will continue to compete with microbes in the ongoing molecular arms race.

Don Ganem is a Howard Hughes Medical Institute (HHMI) investigator at the University of California, San Francisco. B. Brett Finlay is an HHMI international research scholar and professor at the University of British Columbia in Vancouver. They are this year's speakers at HHMI's Holiday Lectures on Science, an annual series in Chevy Chase, from which this material was adapted. Their complete lectures may be viewed at http://www.holiday lectures.org, which also includes scientific animations, "virtual laboratories," teaching materials and other free resources.

THE FIRST STEP in any bacterial infection occurs when a bacterium binds to its target cell so it can begin growing and reproducing. If we can understand how binding occurs, we hope to develop drugs or vaccines to block it.

Over the last few years, my colleagues and I have determined how one pathogenic strain of E. coli -- EPEC, or enteropathogenic E. coli, a type that causes severe diarrhea and is a leading cause of infant mortality in developing nations -- carries out its assault. In doing so, we solved a biological puzzle.

We began our investigations with Tir, a mysterious protein that is found on the surface of infected human cells and that serves as the receptor for EPEC when it binds to mammalian cells. We knew that Tir exists only in the membranes of cells infected previously by other bacteria. But we had no idea why or how this "priming" occurred.

It turns out that Tir is not a human protein at all. Rather, it is a bacterial protein that EPEC can inject into the human cell membrane. This occurs via a complex interaction that resembles a syringe injecting its contents into the human cell, shown in the six illustrations here.

In essence, EPEC installs its own harpoon in the human cell. It then grabs this harpoon and anchors itself tightly on the cell surface. We have since determined that Tir also is employed in a similar manner by another type of E. coli (0157) that contaminates apple juice and hamburger.

1. EPEC uses hair-like strands called pili to anchor itself above a human cell.

2. A protein called EspA forms a tubular appendage that penetrates the cell membrane, much like the needle of a syringe, creating a pore (green) through which Tir (red) can pass.

3. Inside the cell, part of the Tir protein protrudes into the interior and binds tightly to another bacterial protein called intimin (blue) on the bacterial surface.

4. Tir gains a phosphate (orange) and begins to accrete a human protein filament called actin (yellow) that is used in cell and muscle structure.

5. The actin strands grow, projecting into the cell like streamers from a ballroom ceiling.

6. The actin activity pushes upward on the cell membrane to bundle into a pedestal under the E. coli bacterium, binding it to the cell and raising the bacterium above the cell. This process leads to severe diarrhea and is critical to disease.

-- B. Brett Finlay