Disease and Fever

The real story is not quite that simple. The good guys, your body and it's defense systems, aren't always perfect. The first hints that there was more to disease than a good guy / bad guy scenario came when scientists were developing the first vaccines for typhoid fever.

Vaccines are based on a simple concept. A small number of a particular bacteria are introduced to a persons body. The bacteria are crippled in some way or even dead so they can't start any trouble. The immune system will then have a very easy-to-win fight on it's hands and in the meantime will develop the necessary antibodies to be able to combat further infections in the future.

Scientists developing these first vaccines found that the vaccines of heat-killed bacteria were causing fevers in patients who received vaccine. How could this be? The bacteria were dead and dead bacteria can't make a person sick. But they did! They discovered that it was the cell membranes of these gram negative bacteria that were somehow responsible for causing fever. They called these unknown compounds "pyrogens," which means "burning bodies". These pyrogens are also known by another name; endotoxins.

The important thing is that it was discovered that these pyrogens (ie., endotoxins) were composed of the lipopolysaccharide molecules that make up the cell wall of the Gram negative bacteria. This material, used as a structural component of the bacterial membrane was somehow able to elicit a dramatic and sometimes fatal reaction in people even when it wasn't associated with living bacteria. This introduced the once-heretical notion that the body's immune system itself may actually "cause" some aspects of disease and this notion has been borne out through continued research.

Gram negative bacteria are a "thin-skinned" aquatic organism. Little bits of LPS break off as they move in their environment. Killed or crushed, they release larger amounts. This material isn't toxic in and of itself but it does serve as a very convenient signal to any immune cell who's job it is to prevent a bacterial invasion. Like the old saying "where there is smoke, there is fire" so it might be said "where there is endotoxin there is bacteria." As a result, the immune systems of many organisms (meaning their blood cells) have developed very sensitive chemical means to detect LPS. When the endotoxin is detected, the cells release their own signals which the body can then use to combat infection. In mammals (like us) one way to combat infection is to turn up the body temperature. Many species of bacteria don't do well at high temperatures and fever is your own bodys attempt to rid itself of infection. Raise the temperature, you kill the infection. Raise it too high though, and you can kill the body too. Endotoxin has a variety of effects on the bodies of organisms but most of them are created by the body's own normally functioning immune system. In human beings, endotoxemia is a serious and often deadly condition. which can be induced by trauma and shock. The protective membrane that separates the intestinal lining from the bloodstream breaks down and endotoxins flood the circulatory system.

The prevention of endotoxin contamination is not only a healthy endeavor it is also big business. Injectable medicines, surgical instruments and fluids, dialysis tubing and other internal devices must not only be sterile but endotoxin-free else they could cause endotoxemia in people receiving them. Companies providing such materials spend large amounts of money to ensure these products are endotoxin-free. The standard way to do this in the past is the "rabbit test."

Rabbits are susceptible to endotoxin just as humans are. A tiny amount of a suspect solution can be injected into a rabbit. Should the rabbit develop a fever, the presence of endotoxin is indicated. Aside from the costs and ethical concerns raised in the use of large rabbit facilities, there are other problems with this method. One is that the rabbit assay can take up to 48 hours to return a definitive result.

A more effective method would be to develop some other method to detect endotoxin. If the release of little bits of the endotoxin molecules serves as a reliable indicator of the presence of Gram-negative bacteria then perhaps there is some molecular analog of a "smoke detector" out there in the natural world waiting to sound the alarm when these organisms are present. In retrospect, it seems logical that the place we might look for such a detector would be in the organisms that live in the shallow waters of our oceans where Gram-negative bacteria inhabitat literally every drop of seawater. And such systems do exist. They are just waiting for the right person to ask the right question.

[NEXT: Fred Bang and Limulus Lysate]