|
Go HERE to view an illustrated version of the article, and also be able to hear (or download) a RealAudio© version of each broadcast part. |
As a result, being able to grow a microbe in culture forms part of a series of rules, or steps, originally developed by Koch to determine whether a given organism causes a given disease, called Koch's postulates. In essence, not only do you have to find the microbe in all cases of the disease, but you also have to be able to grow the organism in the lab, and then re-introduce it into a healthy animal or person and produce the disease again. Then - and only then - can you declare the germ to be the cause of the disease.
But Koch's postulates were based on bacteria, which are only one type of micro-organism that can cause disease. Relman notes that subsequent decades have since brought the recognition of an increasingly broad diversity of microbes, including viruses, which require another living cell in order to replicate. He says this complicates the picture, in some cases making it difficult, if not impossible, to fulfill Koch's original three postulates for proving causation.
Some researchers have suggested Koch's postulates are outdated, and ought to be abandoned. Others, like Richard Tilton, editor-in-chief of the Journal of Clinical Microbiology, take a more moderate stance. "Rather than abandon them, we should modify them," he says, "because it is now possible to detect the causative agent of a disease without isolating the organism."
One way of doing this is using a technique for homing in on the genetic material that makes up a disease organism and duplicating that genetic material millions of times - PCR, which stands for polymerase chain reaction. Tilton likens the technique to finding a needle in a haystack: "If there's one needle in the haystack, it's very difficult to find. However, if you can play tricks on that neddle, and make a million needles, then it's very easy to detect."
Using PCR, medical detectives have been able to find previously undetectable microbes in all sorts of illnesses. One of these medical detectives is Garth Nicolson, scientific director at the Institute for Molecular Medicine in Huntington Beach, California, who studies chronic illnesses, which strike up to 6% of the population of North America. Nicolson has found that much if this chronic illness is due to stealth bacteria that have gone undetectable.
He says "These new technologies have just come to the forefront in the last decade, and before then there was really no evidence that these types of infections were even present.
Now that we can find them, we can study their role in the disease process much more thoroughly." Nicolson feels the over-reliance on Koch's postulates has slowed the process down in finding out the role of these infections. "These organisms are extremely hard to culture, but we can fulfill many of Koch's criteria by monitoring the presence of these organisms and looking at animal models."
Because identifying the precise cause of a disease has significant ramifications for treatment, it's important to be sure you have the right bug. And with the advent of these new molecular DNA techniques comes a danger: the risk of blaming diseases on newly discovered microbes without stopping to think whether something else is involved. David Relman notes, "It is much easier to detect or amplify a DNA or RNA sequence in a clinical sample than it is to attribute some important role to this putative organism with respect to disease. As we start to apply these incredibly sensitive methods, we are starting to find that the diversity and number of organisms that occupy the human body is far greater than we thought, and it really prompts us to ask: what are these things doing there?"
Garth Nicolson insists there are a number of criteria that need to be fulfilled in order to pronounce a micro-organism the cause of a disease, including finding it in sick - but not healthy - people, detecting it in the part of body where there is illness, measuring an immune response to the infection (not always present), seeing if the patient responds to therapy, at which point the agent should be eliminated. Other pieces of evidence include developing an animal model in order to reproduce similar types of illness. Injecting organisms into humans is not considered ethical anymore, he notes, but one researcher - Barry Marshal - used it to prove Helicobacter pylori as cause of ulcers. "With some of the stealth infections we deal with, one would not want to try this, because they're potentially lethal and some people have actually died of these infections and that's in the medical literature."
Relman argues that number of independent approaches are going to be required in order to prove causality, and adds that one of the most interesting things about these molecular approaches is the new concepts of disease causation that will emerge as a result. He cites the example of molecular mimicry, in which certain bacteria can fool our immune systems into attacking not just the invading organism, but our own bodies as well. This may be the case, for example, with the bacteria Chlamydia pneumoniae, which researchers recently found shares genetic sequences with our heart muscle.
On the 10th floor of the new Princess Margaret Hospital on University Avenue in Toronto, Dr. Tak Mak, of the Ontario Cancer Institute, notes, "Our immune system is set up to make very subtle differentiations between infectious agents and yourself, because for infectious agents you would like to turn your immune system all the way up to kill every one of the infectious agents, but we talking about millions of proteins that our immune system is processing, and there will be overlaps. "
"After all, don't forget we evolved from bacteria. Bacteria make proteins often to do the same work as our own proteins, and we've only been separated for several hundred million years in evolution. A lot of the proteins are still identical from a bacterium to a man, so there will still be remnants of amino acid sequences that are shared. And when you mount an immune response against a bacterial or viral protein, and they have shared codes, our immune system can go overboard and start attacking our own tissues."
Dr. Josef Penninger works in the University Avenue lab, which is funded by Amgen Canada, a division of the giant U.S. bio-pharmaceutical company. He studies how the genetic structure of microbes can mimic parts of our own body, working on mouse models of auto-immune inflammatory heart disease.
Penninger, along with his colleague Kurt Bachmaier, was able to show that a piece of the Chlamydia pneumoniae germ, bore a striking resemblance to a protein in heart muscle. He did this by lining up the genetic sequences of chlamydia and the heart muscle protein, using DNA databases he found on the Internet. He points out "we would never have found this using Koch's postulates."
For years, there's been the suspicion that bacteria were involved in heart disease, especially since some people treated with antibiotics for other reasons seemed to have fewer heart attacks. But no one had been able to definitively prove a connection between Chlamydia pneumoniae and heart disease - that is, until February 1999, when Penninger and his colleagues published their findings in Science magazine. As Penninger notes, "Our paper made the first causal link to say that bacteria are not just these little innocent bugs sitting around - they can actually trigger heart disease. Our model explains lots of anecdotal data - why people with no risk factors are getting sick, why some people who are smoking, drinking, and obese never get heart disease - our model can completely explain this, and why in some circumstances antibiotic treatment helps against heart disease. As long as no one comes up with a better model, it's a fairly reasonable assumption this contributes to heart disease."
But why do so many people infected with Chlamydia pneumoniae - 1 in 2, according to most statistics - escape its effects? Penninger says it has to do with how white blood cells detect the presence of foreign organisms, which they do in association with a molecule called MHC (Major Histocompatibility Complex), a part of the immune system's built-in control mechanism. It's the MHC molecule that picks up little parts of chlamydia to show to red blood cells, but these MHC molecules differ from person to person. "If I'm unlucky, and my MHC molecules shows this part which looks like my heart to the immune system, then they are tricked. But the next person might pick up another part of chlamydia, so their immune system kills chlamydia but never attacks the heart. But you still have to explain why does the treatment work for some and not others."
The answer may have to with *when* someone takes antibiotics. If the auto-immune reaction produced by chlamydia has already started, it may keep on going even after the bugs are killed off. "We think the bug is probably the trigger, but once auto-immunity is established it is self-maintaining." He says this explains why some people report antibiotics are working - "you probably hit Chlamydia infection very early."
But this business of molecular mimicry is only one mechanism bacteria use to make us sick. Relman notes there are also examples of disease where an organism may die and yet still persist in the form of pieces which may be sufficient to induce disease. Others may release a toxin capable of causing disease, or may be lurking in an anatomic site one would never think to go looking at. He favours the idea of embarking on a search using broad methods, which are not necessarily specific to any one bacterium. "There is going to be no one study which is going to give everyone the answer - it's really going to be an incremental process."
The idea that we have been using dangerously outdated methods to find infections is one shared by evolutionary biologist Paul Ewald, who has been thinking a lot about various infections and the diseases they might cause.
Ewald says "People have worked on the misunderstanding that any fewer diseases are caused by infection than really are caused by infection. The way to evaluate whether this has in fact been the case is to look at the track record, which is that, over the last hundred years, really, we have a steadily increasing number of diseases that we accept as being caused by infection."
Ewald has put forward the radical idea, dubbed "The New Germ Theory of Disease", that says that most of our chronic killers - from heart disease to Alzheimer's to cancer - must be due to infection. "If diseases have strong negative effect on the survival and reproduction of humans, and if they're pretty common, it's very unlikely that these diseases will be caused strictly by bad genes, because those bad genes would be lost through time, because of the negative effects that the disease has on the people who would harbour those genes for the disease."
A good example is the epidemic of infertility among women in the 1970s, which mystified researchers at the time. "Let's say they had some sort of bad gene", Ewald hypothesizes. "Think what would happen over next few generations: those genes would be lost in quite short order. The fertility problem decreases fitness so much it would disappear" (as it turns out, the epidemic of infertility was caused by an epidemic of Chlamydia trachomatis).
The notion that infections are at the root of most chronic diseases is surprising for some people, Ewald admits, because we supposedly "know" about the genetic basis for diseases like Alzheimer's or atherosclerosis. "But one has to be careful", he warns, "because often that genetic basis that you identify may be a genetic vulnerability to some other cause." Pointing to recent studies, such as Penninger's, he notes "the genetic basis for those diseases is really a genetic basis for vulnerability to an infectious agent, that then starts the whole disease process rolling, and then all the other risk factors excacerbate the progresssion of the infection and the disease that results from that."
Professor Ewald's ideas have their critics. Dr. Tak Mak in Toronto isn't sure that genetic mutations might still not be responsible for certain diseases, especially those like cancer, which strike most people well past their reproductive age. He says, "The major problem is that we, as a race, reproduce earlier than the incidence of most cancer. Most of us develop cancer starting from our 40s and 50s - by that time most of us have already reproduced, so the natural selection in a Darwinian way is not there. Therefore we are going to develop cancer for many billions of years."Ewald responds that because chronic conditions like cancer and Alzheimer's are so common, they actually have more of a fitness cost than one might think. "The real problem in calculating how much of a negative effect they have on our survival and reproduction is that it's very difficult to know how important the effects of people - who are no longer reproducing themselves - can be on grandchildren. Older people may have a strong positive effect on their fitness if they're healthy by influencing the survival of grandchildren even if they're not actually reproducing themselves."
He adds, "The fact that where so many other chronic diseases that are having negative effects on fitness are turning out be infectious certainly should encourage us to look and see whether or not some of these other diseases, that aren't having such strong negative effects on fitness, might be caused by infection."
Microbiology has evolved into a very sophisticated science since the days of Robert Koch. When you compare Koch's simple methods for culturing bacteria to the incredible range of detection techniques available today, it's no wonder we're in the midst of a bacteria revolution - the technology we use governs the way we look at the world. Before the invention of the telescope, we had no way of seeing deep into the cosmos. Likewise, in the microbial universe: these new diagnostic tools are bringing a whole range of previously unknown disease-causing entities into sharp focus. Correctly interpreting the world of information these tools provide will be a challenge for medicine in the new millenium.
