Bacillus anthracis LESSON 2.3 WORKBOOK Lesson 2.3 Identifying infectious bacteria: Correlation and causation In the last lesson we learned how the invention of microscopes allowed bacteria to be observed for the first time, allowing researchers to discover that disease can be transmitted by creatures too small to see. We also learned how bacteria can be cultured and how the invention of superfine filters allowed viruses to be identified. But how do we actually prove that a particular microbe is the cause of a specific disease? Here we will draw on what we have learned in previous lessons to establish a set of principles to test whether a microbe causes a particular disease. If a disease is infectious what will you see? As we have discussed before, people have known for a long time that some diseases can be transmitted from one person to another, they just didn t know how. Here is the ancient Greek historian Thucydides, describing the infectiousness of the plague of Athens in the 5th Century BC: People in good health were all of a sudden attacked by violent heats in the head, and redness and inflammation in the eyes, the inward parts, such as the throat or tongue, becoming bloody and emitting an unnatural and fetid breath. These symptoms were followed by sneezing and hoarseness, after which the pain soon reached the chest, and produced a hard cough. When it fixed in the stomach, it upset it; and discharges of bile of every kind named by physicians ensued, accompanied by very great distress. In most cases also an ineffectual retching followed, producing violent spasms, which in some cases ceased soon after, in Figure 2.3.1: A mass grave from the plague of Athens. others much later. (over...) Lesson 2.3 1
DEFINITIONS OF TERMS Correlation: a connection between two things. Causation: When a change in one thing results in a change in another. For a complete list of defined terms, see the Glossary. LESSON MATERIALS Externally the body was not very hot to the touch, nor pale in its appearance, but reddish, livid, and breaking out into small pustules and ulcers. But internally it burned so that the patient could not bear to have on him clothing or linen even of the very lightest description; or indeed to be otherwise than stark naked. What they would have liked best would have been to throw themselves into cold water; as indeed was done by some of the neglected sick, who plunged into the rain-tanks in their agonies of unquenchable thirst; though it made no difference whether they drank little or much. Besides this, the miserable feeling of not being able to rest or sleep never ceased to torment them. The body meanwhile did not waste away so long as the distemper was at its height, but held out to a marvel against its ravages; so that when they succumbed, as in most cases, on the seventh or eighth day to the internal inflammation, they had still some strength in them. But if they passed this stage, and the disease descended further into the bowels, inducing a violent ulceration there accompanied by severe diarrhea, this brought on a weakness which was generally fatal. For the disorder first settled in the head, ran its course from thence through the whole of the body, and, even where it did not prove mortal, it still left its mark on the extremities; for it settled in the privy parts, the fingers and the toes, and many escaped with the loss of these, some too with that of their eyes. Others again were seized with an entire loss of memory on their first recovery, and did not know either themselves or their friends......by far the most terrible feature in the malady was the dejection which ensued when any one felt himself sickening, for the despair into which they instantly fell took away their power of resistance, and left them a much easier prey to the disorder; besides which, there was the awful spectacle of men dying like sheep, through having caught the infection in nursing each other. This caused the greatest mortality. On the one hand, if they were afraid to visit each other, they perished from neglect; indeed many houses were emptied of their inmates for want of a nurse: on the other, if they ventured to do so, death was the consequence. (http://classics.mit.edu/thucydides/pelopwar.html) In this case, Thucydides described the disease as being infectious because those who visited and cared for the sick fell ill themselves. As we saw in the Ghost Map reading, the link between exposure and sickness is not always so clear. Not all communicable diseases have such a distinct mode of transmission. If someone coughs on you and you get sick, it is intuitively easy to say this is what made me sick. But can you be sure? Figure 2.3.2: Thucydides If an infectious disease is transmitted from human to human, what would you expect to observe over time and why? What clues does Thucydides account give you about possible routes of transmission? Lesson 2.3 2
LESSON MATERIALS Think about what we have seen so far in the course. What do infectious diseases have in common? How would you know that a given disease is infectious? Consider athlete s foot. Athlete s foot is a transmissible infection caused by a parasitic fungus that lives in the skin. It is transmitted when an infected person contaminates surfaces that others touch with their bare skin, like the floor in a public shower. Would you say that it is an infectious disease because it can spread? How does this differ from poison ivy? The poison ivy rash is caused by exposure to a toxin produced by the plant Toxicodendron radicans. Both are caused by skin coming into contact with something. So what makes one an infectious disease but not the other, and how can you tell the difference? We need to prove that the disease can spread. The reason that athlete s foot is an infectious disease whereas poison ivy is not is that poison ivy is caused by a toxin from a plant, rather than a replicating microbe. More importantly, poison ivy is not contagious; you cannot give poison ivy to another animal, you must directly contact the oil from the plant. Conversely, athlete s foot can spread from person to person quite easily. Just think, if one person on a basketball team gets athlete s foot, the others will soon follow! We need to be able to associate the disease with a source of infection. This requirement is relatively straightforward; all people with the disease need to be exposed to the same source of infection. If you theorize that contaminated water causes an illness, then sick people must be exposed to the same contaminated water. Inversely, if a group of people becomes ill and they all use the same water, then it is a possible source of contamination (remember the Ghost Map). However, just correlating the symptoms with the exposure does not prove that the disease is caused by the exposure. For example, people who use common water may have other things in common such as listening to the same music. Just because the shared water is more plausible as a cause of disease than music doesn t make it true. We need to isolate an infectious agent from all infected individuals. If some people with a disease are not infected with the expected microbe, can the disease be caused by that microbe? Say you are trying to prove that Lyme disease is caused by a bacterium passed to humans through ticks. You must be able to find that bacterium both in the tick and Figure 2.3.3: Top: Athletes foot. Bottom: Lesson 2.3 in the infected human. But some bacteria are hard to grow Poison ivy 3 - they might be present but you just can t see them. Can you think of any eamples where an infectious disease is not transmitted from human to human? If we find that people with a disease are infected with a certain microbe would we be justified in saying that the microbe caused the disease? Why or why not?
LESSON MATERIALS We need to show that the infectious agent that we isolated can cause the disease. You will need to isolate the microbe and then use it to infect the person, animal or other host you are proposing will get the disease, and then show that the infection produces the symptoms of the disease in the new host. This requirement is often the most difficult to fulfil - its obviously unethical to deliberately infect someone. To get around this scientists often use animals as models of disease. But sometimes an animal model is hard to find - armadillos are the only model of leprosy for example. Correlation versus Causation Perhaps the most common mistake when interpreting data is to assume that correlation means causation. Although there will always be a correlation between a causative agent and its outcome, most correlations are not causative. For example say there is an epidemic in a neighborhood that shares a common water supply, but the neighbors also all drink milk supplied by the same company. Both the water supply and the milk supply are correlated with the disease, so how do we decide which one is causing the illness? Isolating a mcirobe from sick people that is also found in the milk or the water is a start, but still not proof - people, milk and water probalby share millions of microbes - we can only prove causation by using a single microbe to cause disease in healthy hosts. The tragedy of mistaking correlation for causation: You can see how tough it is to prove that a particular exposure causes disease! This has resulted in grave errors in both directions. For example: It is now widely accepted that tobacco can cause lung cancer, but for a long time the tobacco industry used scientific studies as proof that it didn t. They are able to do this legitimately because we can only make definite statements about how much tobacco alters the probability of getting cancer. For the latter half of the twentieth century, tobacco companies capitalized on this technicality and claimed that the inability to absolutely prove a causal link means that tobacco is harmless. As evidence they would say that non-smokers get lung cancer and many smokers never get lung cancer, therefore. Figure 2.3.4: The bad science that linked vaccines with autism has caused a public health nightmare. More recently another mistake of correlation for causation has had horrible consequences. Both the use of vaccines and the diagnosis of autism have increased dramatically since the 1930s, and many concerned parents have mistaken this correlation for causation based on poor evidence that was highly publicized. The resulting mania has led to parents refusing to provide their children with the MMR vaccine (Measles, Mumps and Rubella), which prevents serious and highly infectious diseases that often result in death or permanent injury. The dangerous consequences of the misinterpretation do not only affect the people who actually made the mistake. Lesson 2.3 The thousands of unvaccinated children put those they are in contact with at risk as well as themselves. In 4 addition, this controversy has diverted valuable resources away from other promising areas in autism research. How would you show that a microbe actually caused a disease (causation?) If vaccines did cause autism what kind of predictions could you make about vaccination?
DEFINITIONS OF TERMS For a complete list of defined terms, see the Glossary.. LESSON MATERIALS The first person to formalize a process to demonstrate that a disease is caused by an infectious agent was Robert Koch. Robert Koch was a German physician at the turn of the 20th century whose research won him the Nobel Prize in 1905. He successfully isolated the anthrax, tuberculosis, and cholera bacteria and proved that anthrax spores in the soil are the source of a severe wasting disease in cows. He is known as one of the fathers of microbiology. His other major contribution was to develop a set of four criteria he called postulates that have to be satisfied in order to definitively prove a causative relationship between a microbe and a disease. Koch s postulates are summarized below: Figure 2.3.5: Robert Koch was the first to describe the principles behind infectious disease. Robert Koch s postulates does the microbe cause disease? 1. Associa>on It must always be present in every case but not in healthy animals. 2. Isola>on It must be isolated from the sick animal into into pure broth (culture). 3. Causa>on The pure microbe must cause the disease in a healthy animal. 4. Re- isola>on - When the microbe is re- isolated from the sick animal it must be the same as the original. What is an example of a disease we have seen earlier that does not exactly fit Koch s postulates? Lesson 2.3 5
STUDENT RESPONSES Remember to identify your sources. In you own words describe each of Koch s postulates: Lesson 2.3 6