Download Week 9 Pre-Lecture Slides

Monday February 27th,
2017
Class 31 Learning Goals
Why We Get Sick: Immune Interactions
• After this class, you should be able to:
– Describe multiple pathways for human disease that involve the
immune system
– Predict the general health outcome for a patient depending on
the binding targets of antibody-derived receptors
– Predict the development of allergies and be able to describe a
model for allergic development in young humans
– Choose and defend the better of two possible vaccination
schemes
How are memory B- and T-cells formed?
Why are these memory cells useful?
Initial exposure to antigen
Peer Instruction
Second exposure to antigen
Secondary
immune
response
Response
is larger
Primary immune
response
A few cells
survive longer…
Response
is faster
Peer Instruction
But what if the 1st exposure to a virus is fatal?
Smallpox, caused by the variola virus, is an
example of a rapidly lethal disease.
10th century Chinese doctors took cotton plugs from the noses of
patients with mild smallpox infections. These were briefly inserted
into the noses of healthy people. Why?
In 1798, an English doctor observed that milkmaids rarely contracted
smallpox. They contracted the less dangerous but related cowpox.
How was this observation used to develop vaccination?
Peer Instruction
Usually, antibodies and immune cell
receptors bind only to non-self epitopes.
What would happen if a B-cell and T-cell
were created that bound to a common
epitope on the surface of a cell type in
arm and leg joints?
Would you expect to see this condition develop in old or
young patients more often?
(hint: How often are B- and T-cells made?
Overall, would you expect to see evidence that the immune
system is overworking or underworking?
Colostrum:
• First produced
• Heavy in antibodies
• Absorbed through the
porous infant stomach
Peer Instruction
75-80% of all
antibodies in body
Most common and
consistently abundant.
Not well understood.
Why is the
IgM:IgG ratio
useful?
Creates hypersensitivity
and allergies.
Most common in
breastmilk and for creating
immunity in babies.
Made first to battle new
infections.
B-cell
Peer Instruction
1) Explain how IgEs combine the innate
and adaptive immune responses.
This response is extremely
sensitive, and is needed to
defend against parasitic worms
which can otherwise hide from
the immune system.
2) How do IgEs cause allergies?
Peer Instruction
Prevalence of human-parasitic
worms in a country
1) What do these data say?
Prevalence of
allergies
2) Hypothesize an explanation for this correlation.
Peer Instruction
So what?
A new strategy for finding antibiotics?
Common strategy:
Try many, many molecules
See if they poison bacteria
Antibiotic
A new hope?
“Isolation Chip”
House many,
many microorganisms
Isolate
molecules
See if they prevent bacterial growth
Teixobactin (2015)
Concept Questions
•
•
•
•
•
Virus survivors were often employed in earlier history to act as caregivers for the
sick. How were the bodies and cells of survivors different from their patients?
Byzantine doctors placed small pieces of scabs from small pox survivors under
the skin of young children. Why? What were the risks and benefits of this
procedure?
What IgM:IgG ratio would you expect from:
• A human with many commensal bacteria?
• A human under attack by a new Martian virus?
• A human under attack by common E. coli?
Which autoimmune disorder would be more likely to directly destroy the human
body:
• An autoimmune disorder where B cells were targeted at muscle cells
• An autoimmune disorder where killer T cells bound to surface receptors on
dendritic cells
Would a molecule that implanted more ATP into T-cells be a good antibiotic?
What about a molecule that produced random epitopes that bound on the
outside of bacterial cells?
Tuesday February 28th, 2017
Class 32 Learning Goals
Why We Get Sick: Human Diversity and Aging
• After this class, you should be able to:
– Describe human genetic diversity in terms of likely mutation
differences between individuals, localized groups, and races
– Use a polymorphic locus or a mtDNA tree to correctly judge the
identity of a human or pathway of a human movement
– Explain multiple models for parts of the overall progress of
aging, including:
• Buildup of DNA
• Telomere degradation
• Radical oxidation
– Assess the potential success of a proposal for prevention of
aging-related symptoms or for extending the human life span
Got a calculator?
Get it out and handy for our first few questions.
Peer Instruction
The interleukin-2 protein-coding gene is 824 basepairs long,
and is relatively conserved between humans and mice
(even though they diverged ~80-100millions years ago).
Draw a tree to describe DNA homology between a fly, a
mouse, a chimpanzee, you, your future child, and a
random other person.
Human coding DNA is ~85% alignable with mouse DNA
and 96% alignable with the DNA of chimpanzees.
How many interleukin DNA differences would you expect:
Between humans and mice?
Between humans and chimps?
Peer Instruction
If two humans are 99.999% similar by DNA, do you expect to
see any differences in the DNA of the interleukin-2 gene
between you and the person sitting next to you?
The human genome contains 3.1 billion base pairs.
How many total SNPs are likely between any two people?
SNP: Single Nucleotide Polymorphism (a different of one base pair)
Peer Instruction
Explain this data.
Are humans genetically identical?
A small chunk of a single human chromosome.
• Same as reference DNA
• Common difference
• Rare difference
Two genes
A single “race”
A name of a locus
Sequences from 1,092 individuals
The 1000 Genomes Project Consortium Nature 491, 56-65 (2012) doi:10.1038/nature11632
Is race biologically relevant?
Peer Instruction
If you wanted to be sure, what would you need to test this?
a N_ _ _ H _ _ _ _ _ _ _ _ _ , and a P _ _ _ _ _ _ _ _ _
This has been done (way back in 1967).
Using a large number of gene sequences from the hypothesized
races of humans, Lewontin et al compared amount of variation in
sequences and compared variation within to between races.
What would you expect if race is biologically relevant?
What would you expect if race is not biologically relevant?
“Race is Relevant”
Variation
Within:
Variation
Between:
“Race is Bogus”
Actual data:
Fastest rates of DNA change in humans
Peer Instruction
Polymorphic loci
(unstable regions of repeated
non-necessary sequences)
Genes in conflict
(like sperm vs egg)
DNA of transposons
New genes after duplication
Structural DNA
(centromeres, telomeres)
Mitochondrial DNA
Less-crucial
protein coding genes
What kind of gene would you
sequence and analyze if you
wanted to examine:
• How human biology works?
• Where humans were
moving just a few thousand
years ago?
• Who committed a murder
last year?
Crucial protein coding genes
Slowest rates of DNA change in humans
Peer Instruction
Map of human migration based on mtDNA
1) What can mitochondrial DNA tell us about human history?
2) Use these #s of polymorphic repeats to determine the guilty
suspect.
DNA Region
Crime Scene DNA
Suspect 1 Suspect 2
Suspect 3 Suspect 4
Polymorphic locus 1
16 repeats
10
17
21
15
Polymorphic locus 2
33
8
33
19
91
Polymorphic locus 3
4
4
3
8
4
Peer Instruction
What is senescence?
Why do we age?
Thinking cynically: For people that can understand and assist
with aging, is the market increasing or decreasing?
Peer Instruction
Some cells absolutely need to keep
all of the DNA intact.
Missing DNA on
lagging strand
Which cells?
How does telomerase help?
Telomerase with its
own RNA template
DNA polymerase
RNA primer
If you are interested:
Stress! Phospholipids!
Concept Questions
– Draw a phylogenetic tree of the following alleles:
• The ATP synthase gene in you, your parent, and an unrelated friend, and
a person from the other side of the planet to where you were raised
• The homologous gene in a gorilla, a cat and a fish
• The homologous gene in yeast and archaea
• Estimate the % difference between each node
• What is the likelihood (in your opinion) that each version of this gene
would work in each other species?
– Write a 4-sentence explanation to a jury detailing:
• How microbiome evidence is gathered and used to identify a person
• How polymorphic loci evidence is gathered and used to identify a person
– Explain why each of these drugs would not prevent aging:
•
•
•
•
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A pill of telomerase
An injection of telomerase into the bloodstream
A protein that makes DNA un-bindable by any protein to protect it
A molecule that absorbs all free radical energy
A virus that inserts new, fresh mitochondria into every cell in your body
Wednesday March
1st, 2017
Class 33 Learning Goals
Why We Get Sick: Evolution
• After this class, you should be able to:
– Interpret disease-causing mutations in terms of selective
advantage and evolution
– Discuss the time scale and likelihood for eradication of
evolved diseases
– Categorize biologically relevant substances as ‘poisons’ or
‘safe’ at historical and present concentration
Polling Question #1
Why do your toes get wrinkled
after being in water?
1.
2.
3.
4.
5.
The water damages the toe cells
Signaling molecules in the water
Apoptosis of toe cells
Toes evolved to act like this
It is a bi-product of genes that make
your skin smooth
Case Study
Babies in the US are screened for a deficiency
in glucose-6-phosphate dehydrogenase (G6PD). G6PD catalyzes
an important side reaction of early glycolysis in all cells.
G6PD
Other
metabolic
precursors
If a G6PD-deficient patient eats the wrong
foods (like fava beans) then red blood cells
build up too much Glucose-6-phosphate.
Normal RBC
G6PD-
Bursting
Loss of red blood cells leads to weakness, anemia, heart
problems, and is 8% fatal in affected children without treatment.
Case Study
RBC
This is a plasmodium. This
parasite causes malaria, which
killed >600,000 people in 2015.
(Nearly half of all people on earth are at risk of contracting malaria.)
G6PD is encoded on the X.
Male G6PD patients, with only
one copy of the gene, are
protected from severe, lifethreatening cases of malaria
(although they can still get it).
Peer Instruction
Cases of malaria
Cases of G6PD deficiency
What narrative might explain this data?
The world is getting warmer:
What effect might this have on G6PD deficiency and malaria?
Concept Questions
•
For each of the four diseases listed, explain:
• Why a genetic engineer might want to change a baby’s DNA to avoid the lessrepresented allele
• Why an early culture of homonids might gain a fitness advantage from this allele
• How understanding an evolutionary phenotype might change the mode of treatment for
this disease
•
For all four disease phenotypes:
• What aspects do all have in common?
• What major aspects is specific to each?
•
Describe new disease-causing alleles for each of the following:
• A disease with an advantage at one part of life but a disadvantage at another part
• A disease that is only advantageous when in a heterozygote
• A disease that has a tradeoff that might be advantageous overall
• A disease that could block a pathogen or parasite
Thursday March 2nd,
2017
Class 34 Learning Goals
Why We Get Sick: Cancer
• After this class, you should be able to:
– Assess a set of related mutations within a single cell lineage and
predict whether or not the organism is at risk for cancer
– Predict the likely effects on cancerous phenotypes based on changes
in human populations
– Explain the recent rise in cancer in human populations
Frequency
1) Frequency of violent deaths
2) Death by bacterial infection
3) Death by infectious disease
4) Amount of mutation-causing pollution
5) Average lifespan of humans
1650
1700
1750
1800 1850
Year
1900
1950
2000
A gene that pushes the cell cycle forward: Proto-oncogene
A mutation that pushes the cell cycle forward TOO MUCH: Oncogene
A gene that stops or slows the cell cycle: Tumor suppressor
A mutation that FAILS to stop or slow the cell cycle: Oncogene
A very common
cancer mutation: p53
A problem of multi-cellularity: Cancer
• Cancer-causing Cells Acquire:
– Tissue-level characteristics:
• Rapid mitosis and growth
• Recruitment of blood vessels
• Movement to other tissues (metastasis)
– Cellular characteristics:
# of Mutations
•
•
•
•
Lack of cell cycle controllers (tumor suppressor)
Telomerase activity
Increased cell cycle progression (oncogene)
Lack of a protective ‘off switch’ (apoptosis)
Cancerous level of mutations
Normal progression
Age 10
20
30
40
50
60
70
80
A problem of multi-cellularity: Cancer
# of Mutations
Cancerous level of mutations
Normal progression
Age 10
20
30
40
50
60
70
80
Concept Questions
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Would you expect to see more cancer in a population at war or at peace?
Would you expect to see more cancer in a population with better or worse
medicinal science? (This answer might be complicated…)
•
A cell can crawl, skip the G1 checkpoint, and recruit blood vessels. It is likely
to cause a cancer?
A cell cannot crawl but can completely pass through the cell cycle each hour.
Would this cell eventually cause damage to a multicellular organism?
•
•
What would happen to the rate of cancer if:
• All p53 proteins were removed from an entire species?
• All cells in an organism were able to turn on the promoter of the
telomerase gene?
• A virus was bioengineered that could infect every cell and:
• Insert randomly into the genome?
• Insert copious nutrients into the cell?
• Disable checkpoint-passing proteins?
• The earth moved slightly closer to the sun?