Download 4. - Tufts

Outline
OVERVIEW
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Le s s o n L e s s o n
Unit1.2 Unit2.4
Rationale: This lesson grapples with the problem of arriving at causation from correlation. You will re-visit Koch’s postulates emphasizing these
complex concepts, and have students apply the principles to other diseases,
investigating whether Koch’s postulates have truly been fulfilled. There is an
opportunity to make this into an advanced exercise by asking the students
how Koch’s principles could be applied to what is currently considered a noninfectious cancer.
Do Now: It is important to emphasize the difference between correlation and
causation because they are often used inappropriately and interchangeably.
Begin by having students define the difference.
Lecture and Socratic Discussion: This lesson formally introduces Koch’s
postulates and the students will have the opportunity to model how Koch
postulates were applied to cholera.
Homework: Case study of Helicobacter: The case study offers students a
chance to apply Koch’s postulates to a disease in which infectivity is less
clear cut. The case study emphasizes that diseases may be associated with
infectious agents that have yet to be identified because isolation of many
microbes is still limited by technology. It also emphasizes that if the microbe
will not grow and/or cause similar diseases in animal models it will be difficult
or impossible to definitively prove causation.
The
Lesson
Plan
What is an infectious agent?
II. What viruses do to make us
sick.
1. Do Now (5 min):
Brainstorm the difference between correlation and causation.
2. Lecture/Discussion (20 min):
Formally introduce Koch’s postulates and lead the students through a
discussion of how they can be applied to cholera. Emphasize that only
if Koch’s postulates are fully met can a disease unequivocally qualify as
infectious. Discuss the difficulties of fulfilling Koch’s postulates.
3. Wrap Up (10 min):
Emphasize that not all diseases can be unequivocally proven with his
postulates, and discuss some examples of why not. Question the implications of calling a diseases infectious if it has not been fully proven
with Koch’s postulates, and vice versa – does it mean that a disease is
not infectious if Koch’s postulates have not been met?
4. Homework:
Introduce background knowledge for the homework. Case study of helicobacter: This case study is an opportunity to apply Koch’s postulates
to a more ambiguous disease.
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1.
NOW
DO
Do Now
•  What is the difference between correla2on and causa2on? •  How could you prove causa2on? The students may start to talk about Koch’s
postulates. If so, ask them to elaborate on
what they know.
Koch’s postulates:
1.
2.
3.
Ask the students:
4.
Association – The infectious agent must always be present in every case – but not in healthy animals.
Isolation – It must be isolated from the sick animal into pure culture.
Causation – The pure microbe must cause the disease in a healthy animal.
Re-isolation - When the microbe is re-isolated from the sick animal it must be the same as the original.
What is the difference between correlation and causation? In
other words, how can we determine whether a microbe causes a
disease or whether it is simply associated with a disease?
■■ For example, obesity is associated with heart disease, but it is not the
cause because there are obese people that do not have heart disease.
■■ Perhaps a microbe colonizes people that have a genetic disorder, yet
the microbe is a bystander that causes no disease.
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Le s s o n
Unit2.4
Guide the students to return to the principles
they developed in the last lesson for their answers.
How can you prove causation?
■■ We need to isolate an infectious agent that is found at both the source
of the infection and in the infected person.
■■ We need to show that the infectious agent we have isolated can cause
disease.
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2.
Lecture and Socratic Discussion
Robert Koch
Robert Koch
– connec2ng the dots to disease
Bacillus anthracis Robert Koch generated his principles to prove that an infectious
agent causes a specific disease.
■■ Robert Koch was a Prussian physician who graduated from medical
school in 1866.
Prompt the students to recall what they
learned about anthrax in the first part of
Unit 1.
■■ Anthrax can survive in a hostile environment by making spores.
The spores are on the grass the cows eat. Once the cows eat the
spores they recover from dormancy and begin to replicate quickly,
making the cattle sick
Koch realized that he could use the same principles to
isolate other infectious microbes.
■■ To prove this point, he isolated the bacterium that causes tuberculosis Mycobacterium tuberculosis in 1877 and the bacterium
that causes cholera, Vibrio cholera in 1883. He was awarded the
Nobel Prize in 1905.
■■ He worked on cattle that had symptoms of anthrax - staggering, trembling, convulsions, bleeding from body openings and quick death.
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Unit2.4
■■ When Koch took a blood sample from the cattle infected with anthrax
they always had large numbers of Bacillus anthracis. But the cattle
didn’t infect each other, so how was the Bacillus anthracis involved?
Was it an important causative agent, or was it just there by coincidence?
■■ He took a small sample of blood from an infected cow and injected it
into a healthy one – the healthy animal became sick.
■■ He then filtered the bacteria out of the blood and grew it in a broth
containing nutrients. Then he injected the infected broth into a healthy
animal. This cow too got sick.
■■ The second set of sick cows were also infected with Bacillus anthracis.
Identifying the infectious agent –
Koch’s postulates
1.  Associa2on – It must always be present in every case – but not in healthy animals. 2.  Isola2on – It must be isolated from the sick animal into pure culture. 3.  Causa2on – The pure microbe must cause the disease in a healthy animal. 4.  Re-­‐isola2on -­‐ When the microbe is re-­‐isolated from the sick animal it must be the same as the original. Emphasize to the students that Koch went
through the same stages of argument as they
did to come up with his principles. He just
went a step further to devise a test for them.
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2.
Lecture and Socratic Discussion
The next few slides use Cholera to exemplify how Koch’s postulates can be applied.
The teacher should walk the students through
the postulates.
Postulate 2: Isolation
Applying Koch’s postulates to
cholera!
Postulate 1: Association
1. 
Applying Koch’s postulates to
cholera!
Associa2on – It must always be present in every case – but not in healthy animals. 2.  Isola2on – It must be isolated from the sick animal into into pure culture. 3. 
Causa2on – The pure microbe must cause the disease in a healthy animal. 4. 
Re-­‐isola2on -­‐ When the microbe is re-­‐isolated from the sick animal it must be the same as the original. Sack et al., 2004 1.  Associa2on – It must always be present in every case – but not in healthy animals. 2. 
Isola2on – It must be isolated from the sick animal into into pure culture. 3. 
Causa2on – The pure microbe must cause the disease in a healthy animal. 4. 
Re-­‐isola2on -­‐ When the microbe is re-­‐isolated from the sick animal it must be the same as the original. Vibrio cholera Sack et al., 2004 All people with the disease have diarrhea (rice water
diarrhea) that is turbid with the bacteria.
Background on Cholera:
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Unit2.4
■■ Vibrio cholera normally inhabits coastal estuaries where it lives in close
association with phytoplankton.
■■ Humans can be infected when they enter this ecosystem or when the
bacteria contaminate drinking water or food.
■■ High temperatures can lead to Vibrio ‘blooms’, increasing the likelihood of transmission and epidemic spread. In fact we can think of the
diarrhea that V. cholera causes as an evolutionary mechanism that
encourages dispersal of the bacteria and transfer to new hosts.
■■ Diagnosing cholera is relatively easy since the bacteria can be
isolated directly from the massive amounts of ‘rice water’ stool
produced following infection. A drop of infected stool contains
massive amounts of the bacterium Vibrio cholera, which is
never found in the stool of healthy individuals. There are about
100,000,000 bacteria/ml - easily detectable under the microscope.
■■ These bacteria can be positively identified as cholera by treating
them with specific antibodies against the cholera flagella, causing
them to stop swimming - a diagnostic step not often carried out in
developing countries.
Ask the students:
What are some potential problems that might arise in isolating bacteria from an infected individual?
■■ The disease may require so few microbes that it is exceptionally
difficult to isolate them. This is true of neisseria meningitides. Only
a few thousand bacteria are necessary to produce enough toxin
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2.
Lecture and Socratic Discussion
How could you maximize your chances of finding the infectious
agent?
Postulate 4: Re-Isolation
■■ Take the clinical sample from the area that is affected. Like the stool in
cholera or the spinal fluid in meningitis.
Applying Koch’s postulates to
cholera!
Postulate 3: Causation
1. 
Associa2on – It must always be present in every case – but not in healthy animals. 2. 
Isola2on – It must be isolated from the sick animal into into pure culture. 3. 
Causa2on – The pure microbe must cause the disease in a healthy animal. 4.  Re-­‐isola2on -­‐ When the microbe is re-­‐isolated from the sick animal it must be the same as the original. Applying Koch’s postulates to
cholera!
1. 
Associa2on – It must always be present in every case – but not in healthy animals. 2. 
Isola2on – It must be isolated from the sick animal into into pure culture. 3.  Causa2on – The pure microbe must cause the disease in a healthy animal. 4. 
Re-­‐isola2on -­‐ When the microbe is re-­‐isolated from the sick animal it must be the same as the original. Sack et al., 2004
Vibrio cholera Vibrio cholera The bacteria can be used to infect mice and they will exhibit
the diseases.
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■■ Giving a potentially infectious microbe to humans is not usually possible, because of ethics! So animal models are usually used as the next
best thing.
Can you think of any potential problems that might arise?
■■ The microbe may not cause the disease in the animal model. An example of this is the common cold. There are still no good animal models
for the cold caused by the rhinovirus that infects humans.
The bacteria can then be re-isolated from the mice
in the same way they were from the human, to cause
subsequent infections.
Can you think of any potential problems that might arise?
■■ The microbe may have changed to adapt to the mouse. It may
become less infectious. The idea that a microbe that causes
disease in humans is less infectious in animals underlies the idea
of vectors and reservoirs of infection that we will deal with in the
next unit. For example the deer tick that causes Lyme disease in
humans has no effects on the deer or the ticks.
■■ The major treatment for cholera is oral rehydration with a solution
of salt, sugar and water to replace the electrolytes lost. This
relatively simple treatment could potentially save millions of lives
a year, and with access to it no - one should succumb to cholera.
However it has been difficult to instruct people how to make up
the electrolyte solution accurately as well as how to give the right
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3.
Wrap Up
Wrap up:
Sometimes Koch’s postulates
can’t be fulfilled!
1.  Associa2on – It must always be present in every case – but not in healthy animals*. 2.  Isola2on – It must be isolated from the sick animal into pure culture**. 3.  Causa2on – The pure microbe must cause the disease in a healthy animal. 4.  Re-­‐isola2on -­‐ When the microbe is re-­‐isolated from the sick animal it must be the same as the original. Below is a summary of exceptions that make fulfilling all
Koch’s postulates difficult or impossible:
■■ Postulate 1: The microbe may be there but be
hard to find if only low levels are enough to cause
disease (typhoid, tuberculosis hepatitis C, HIV) - we
are therefore unable to isolate the microbe.
*Typhoid Mary. **Leprosy or the plague. Important points:
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■■ Postulate 2: We aren’t able to grow all microbes yet
– for example we can’t grow the bacteria that cause
leprosy and syphillis – we are therefore unable to
isolate the microbe.
Ask the students to reflect on the postulates in the light of what
they’ve learned to think of cases when they don’t seem to apply.
■■ Postulate 3: Not everyone will get sick from every
■■ For example, the first postulate says the microbe must always be
present in every case – but not in healthy animals. Does this mean that
typhoid is not an infectious disease because Marry was infected with
the microbe without being sick?
■■ Postulate 3: The microbe may only infect or cause
■■ Again from the Typhoid Mary case, some microbes only cause disease
in only a subset of the people infected, how does this fit into Koch’s
postulates?
■■ Postulate 4: the microbe may change during the
infection (Typhoid Mary) – imperfect association.
disease in humans – inability to prove causation.
infection, making it less or more infectious –
inability to re-isolate the same microbe.
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4.
Homework
Homework
■■ In both cases symptoms also include vomiting and in some
cases peritonitis (an infection of the abdomen).
■■ Ulcers were thought to be caused by stress and/or diet.
•  Complete the case study For homework the students will complete a case study about stomach ulcers.
This disease was chosen because stomach ulcers were only recently associated with an infectious agent, helicobacter pylori.
This case illustrates two main points:
1.
2.
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Diseases may be associated with infectious agents that have yet to be determined because technologies limit the isolation of many microbes.
If the microbe will not grow and/or cause diseases in animal models it is difficult or impossible to prove causation.
In preparation for the homework describe the basic pathophysiology of a stomach ulcer.
■■ An ulcer is a persistent wound in the epithelium of the stomach that does
not heal.
■■ Stomach (peptic) ulcers are incredibly painful because of the strong acid
found in the stomach. The pain usually arises during a meal, when acid is
being secreted.
■■ Duodenal ulcers are found in the small intestine close to the stomach. In
this case eating food soothes the pain.
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