Understanding Carcinogens and Causation in Cancer Research

 
How can we identify a novel carcinogen?
Do Now
 
 
What did Bruce Ames say about how useful the
Ames test is at identifying carcinogens?
 
How would you prove HPV causes cervical
cancer?
 
Who was Robert Koch?
 
Robert Koch
 
Connecting the dots to disease
 
Identify that there
is a disease.
 
Isolate the
agent
suspected
of causing
the
disease
 
Re-introduce the agent into
a healthy animal
 
The animal should
get the same disease
as the original animal
 
Robert Koch’s postulates –
An infectious microbe must:
 
 
 
1.
Associate
 with every case of the disease
2.
B
e isolated from the sick animal
3.
Cause
 the disease when introduced into a second
healthy animal
4.
Be
 the same microbe when re-isolated from the second
sick animal.
Which of these could we do to show that
HPV causes cervical cancer?
 
Can you give an example of a carcinogen
known to cause cancer?
 
 
Could you use Koch’s postulates to prove it?
 
No, because we couldn’t isolate the carcinogen
from the person, unlike an infectious agent and it
would be unethical to use cigarettes to try to
produce cancer in a healthy person
What is the major problem if you can’t
use Koch’s postulates to prove causation
for a particular carcinogen?
 
If we cannot definitively establish that an
agent causes cancer, it is difficult to make the
argument that people need to change their
behavior to prevent cancer
The problem of causation vs. correlation
 
What is the difference between them?
Correlation = relationship between 2 variables
Causation = one variable causes a change in
the other variable
Why is it important?
Determining causation vs. correlation
Different types of study:
Observational (epidemiological)
Ex.  How many people in this lung cancer population,
smoke?
Interventional
Ex.  How many people in this population who smoke,
develop cancer?
Randomized control studies
Ex. If we randomly give half the people cigarettes to
smoke, how many will develop lung cancer compared to
the non-smokers
 
Can’t do randomized control studies with
cancer in humans!
 
Bradford Hill - wrestling with correlation
 
Bradford Hill (1897 – 1991)
 
Hill ran a 
controlled study
 showing
that cigarette smoking correlated
with lung cancer.
 
He could not prove ‘causation’ by
Koch’s standards.  Observational
and Interventional studies cannot
prove causation.
 
But by eliminating alternate
explanations, he could 
statistically
show causality
 in complex diseases
like cancer.
 
How Hill’s postulates work
 
Each postulate 
eliminates
 alternate
explanations.
 
The more postulates fulfilled, the less likely it
is to be a correlation, the more likely it is to be
causation.
 
Postulates must fulfill scientific rigor.
 
Hill’s postulates
The relationship between a proposed carcinogen and
a cancer must be:
 
Plausible
Strong
Consistent
Specific
Coherent
Time - Cause has to precede effect
Dose - Bigger doses must produce larger effects
Different forms of the carcinogen must behave similarly
Different circumstances of exposure must give similar results
Hills’ postulates for cigarette smoking and
cancer
 
Two independent studies came up with the same result
 
Smoke enters mouth & lung. Cancer is in mouth & lung
 
All studies on tobacco tar give similar results
 
Likelihood of cancer related to time person smokes
 
Likelihood of cancer related to amount a person  smokes
 
Painting tobacco tar on the skin also causes cancer
 
Smoking also correlated with lung, lip, throat and
esophageal, also exposed to tobacco tar.
 
Smoke is inhaled: cancer is in the lung
 
Smokers have a 5-10 fold higher risk of lung cancer
 
Activity:
 
 
Use Hill’s postulates to identify whether the following
agents act as carcinogens:
 
HPV and Cervical Cancer
Sunbathing and Skin Cancer
Cell Phones and Brain Cancer
Obesity and Breast Cancer
Wrap up
Do Hill’s postulates prove causation? 
 
From the evidence which relationships do you think
are causal?
Strong Relationships – HPV/Cervical Cancer & Tanning/Skin
Cancer
Weaker Relationships – Obesity/Breast Cancer & Cell
Phone/Brain Cancer
How many postulates are required to prove causality ?
Can’t ever prove causality, but the more postulates supported
the higher the likelihood
Are some postulates more important than others?
NO
If there is evidence supporting each postulate does
that mean the relationship is likely to be causal?
No, quality of evidence is important/confounding variables
may play a role at any time
 
 
The Challenge of Causality
 
 
If a behavior can be associated with cancer and
stopping that behavior can be shown to decrease
cancer, then this correlation is effectively equivalent
to causation.
 
But if a strong argument can’t be made upfront, then
it is difficult to get people to change behavior.
 
See reading on tobacco and lung cancer.
 
Homework
 
Lesson 1.4 Homework  
- The Case Against Smoking
Read the chapter from 
The Emperor of All Maladies
 that
describes how tobacco companies exploited the
challenges of proving causality to avoid regulation.
Answer the questions that follow.
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Exploring the identification of novel carcinogens and proving causation in cancer research through examples like the Ames test, Koch's postulates, and distinguishing between causation and correlation. The challenges in attributing cancer causation and the importance of conclusive evidence for behavior changes to prevent cancer are highlighted.


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  1. Cancer Lesson 1.4 How can we identify a novel carcinogen?

  2. Do Now What did Bruce Ames say about how useful the Ames test is at identifying carcinogens? How would you prove HPV causes cervical cancer?

  3. Who was Robert Koch? Robert Koch Identify that there is a disease. Connecting the dots to disease The animal should get the same disease as the original animal Isolate the agent suspected of causing the disease Re-introduce the agent into a healthy animal

  4. Robert Kochs postulates An infectious microbe must: 1. Associate with every case of the disease 2. Be isolated from the sick animal 3. Cause the disease when introduced into a second healthy animal 4. Be the same microbe when re-isolated from the second sick animal. Which of these could we do to show that HPV causes cervical cancer?

  5. Can you give an example of a carcinogen known to cause cancer? Could you use Koch s postulates to prove it? No, because we couldn t isolate the carcinogen from the person, unlike an infectious agent and it would be unethical to use cigarettes to try to produce cancer in a healthy person

  6. What is the major problem if you cant use Koch s postulates to prove causation for a particular carcinogen? If we cannot definitively establish that an agent causes cancer, it is difficult to make the argument that people need to change their behavior to prevent cancer

  7. The problem of causation vs. correlation What is the difference between them? Correlation = relationship between 2 variables Causation = one variable causes a change in the other variable Why is it important?

  8. Determining causation vs. correlation Different types of study: Observational (epidemiological) Ex. How many people in this lung cancer population, smoke? Interventional Ex. How many people in this population who smoke, develop cancer? Randomized control studies Ex. If we randomly give half the people cigarettes to smoke, how many will develop lung cancer compared to the non-smokers Can t do randomized control studies with cancer in humans!

  9. Bradford Hill - wrestling with correlation Hill ran a controlled study showing that cigarette smoking correlated with lung cancer. He could not prove causation by Koch s standards. Observational and Interventional studies cannot prove causation. But by eliminating alternate explanations, he could statistically show causality in complex diseases like cancer. Bradford Hill (1897 1991)

  10. How Hills postulates work Each postulate eliminates alternate explanations. The more postulates fulfilled, the less likely it is to be a correlation, the more likely it is to be causation. Postulates must fulfill scientific rigor.

  11. Hills postulates The relationship between a proposed carcinogen and a cancer must be: Plausible Strong Consistent Specific Coherent Time - Cause has to precede effect Dose - Bigger doses must produce larger effects Different forms of the carcinogen must behave similarly Different circumstances of exposure must give similar results

  12. Hills postulates for cigarette smoking and cancer Smoke is inhaled: cancer is in the lung Plausible Smokers have a 5-10 fold higher risk of lung cancer Strong Two independent studies came up with the same result Consistent Smoke enters mouth & lung. Cancer is in mouth & lung Specific Coherent All studies on tobacco tar give similar results Likelihood of cancer related to time person smokes Time Likelihood of cancer related to amount a person smokes Dose Different forms give same results Painting tobacco tar on the skin also causes cancer Smoking also correlated with lung, lip, throat and esophageal, also exposed to tobacco tar. Different exposure gives same result

  13. Activity: Use Hill s postulates to identify whether the following agents act as carcinogens: HPV and Cervical Cancer Sunbathing and Skin Cancer Cell Phones and Brain Cancer Obesity and Breast Cancer

  14. Wrap up Do Hill s postulates prove causation? From the evidence which relationships do you think are causal? Strong Relationships HPV/Cervical Cancer & Tanning/Skin Cancer Weaker Relationships Obesity/Breast Cancer & Cell Phone/Brain Cancer How many postulates are required to prove causality ? Can t ever prove causality, but the more postulates supported the higher the likelihood Are some postulates more important than others? NO If there is evidence supporting each postulate does that mean the relationship is likely to be causal? No, quality of evidence is important/confounding variables may play a role at any time

  15. The Challenge of Causality If a behavior can be associated with cancer and stopping that behavior can be shown to decrease cancer, then this correlation is effectively equivalent to causation. But if a strong argument can t be made upfront, then it is difficult to get people to change behavior. See reading on tobacco and lung cancer.

  16. Homework Lesson 1.4 Homework - The Case Against Smoking Read the chapter from The Emperor of All Maladies that describes how tobacco companies exploited the challenges of proving causality to avoid regulation. Answer the questions that follow.

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