Download A Case for Evolutionary Thinking

Dear Sister,
I have received your letter of February 29 in which you
express concern and question the teaching of evolution
at BYU-Idaho. I thank you for expressing your feelings,
and I will try to relate to you why I feel that the teaching
of evolution is important here.
Evolution is a fact of nature and is the backbone of
modern biology. It unites all the fields of biology and
other sciences under one theoretical umbrella. In fact, it
is safe to say, if one does not understand evolution one
does not understand biology. The principle is that
important. Most modern day research including
genetics, cell biology, and the development of new drugs
used to fight diseases are based on this principle. This
being the case, the topic of course is always addressed,
if not central to any biology class.
Death Toll of Major Epidemics.
Disease
Deaths
Spanish influenza
75 million
Smallpox
60 million
Bubonic plague
28 million
AIDS
30 million
50 million by 2020
AIDS is now responsible for about 5% of all deaths worldwide
Sub-Saharan Africa
•
•
•
•
Sub–Saharan
Botswana
Zimbabwe
Swaziland
•
AIDS epidemic has cut the average life expectancy from 62 years to 47 in
Sub-Saharan Africa.
9%
37%
34%
39% (Highest in the world)
A Case for Evolutionary
Thinking
Understanding HIV
An Evolutionary Perspective can Inform
Researchers about the following
questions:
• Why have promising Aids treatments, like the drug
azidothymidine (AZT) proven ineffective in the long run?
• Why does HIV kill people?
• Why are some people resistant to becoming infected or
to progressing to disease once they are infected?
• Where did HIV come from?
Background of the HIV/AIDS
Epidemic
What is HIV?
Life Cycle of HIV
How Does HIV Cause AIDS
• HIV infects macrophages and helper T cells (CD4+ cells).
• Once these cells are depleted, the immune system
collapses.
• Patients are diagnosed with AIDS when their helper T
cell count falls below 200 cells per cubic millimeter.
An Evolutionary Perspective Informs
Researchers about the following
questions:
• Why have promising Aids treatments, like the drug
azidothymidine (AZT) proven ineffective in the long run?
• Why does HIV kill people?
• Why are some people resistant to becoming infected or
to progressing to disease once they are infected?
• Where did HIV come from?
Why Does AZT Work in the Short
Run but Fail in the Long Run?
AZT works by stoping reverse
transcriptase
• AZT uses an anolog of
Thymidine.
• The Thymidine in AZT
has an azide group (-N3)
in place of the normal
hydroxyl group (-OH) on
the 3’ carbon.
• Reverse transcriptase
can not add more
nucleotides to the 3’ end
of the growing strand.
The effectiveness of AZT
• In early test, AZT worked, though it caused side
effects
• After a few years of use, patients stopped
responding to treatment and their CD4 cell
counts again began to decline.
• Why?
– Patient’s own cellular physiology could change.
– The population of virions living inside the patient
changes so that their reverse transcriptase no longer
is effected by AZT.
HIV Populations Evolve
Brendan Larder
Hypothetical difference between AZT
sensitive and resistant reverse transcrtiptase
Create an experiment to test the
hypothesis
• Use a mutagenic chemical or ionizing radiation
to generate strains of HIV with altered nucleotide
sequences.
• Grow strains of HIV in the presence of AZT.
• Strains that have the ability to differentiate
between AZT thymidine and normal thymidine
will produce more often
• Strains unable to replicate in the presence of
AZT would decline in numbers
Analytical Results From Resistant
Patients
• Researchers sequenced the reverse
transcriptase gene.
• Strains of HIV that were resistant
produced changes in the gene that were
not their previously.
• The mutations changed amino acids in the
active site of the reverse transcriptase.
• In most cases it was the same amino acid
substitutions from patient to patient.
How do mutations occur in HIV’s
reverse transcriptase
• Reverse transcriptase is
error prone when it
copies the RNA into DNA.
• HIV has the highest
mutation rate of any
organism.
• Changes in the genetic
makeup of HIV over time
have led to drug
resistance.
How Populations of HIV Evolve
1. Transcription errors
produce mutations in the
reverse transcriptase
gene. Some mutations
bestow resistance to
AZT.
2. The mutant virions pass
their AZT resistant
reverse transcriptase
genes to their progeny.
How Populations of HIV Evolve
Cont.
• In an AZT rich
environment the
resistant mutant
strains survive and
reproduce better than
others.
• The population
evolves and becomes
resistant.
Understanding how resistance evolves,
helps in the design of better treatments
• With any single drug just one or a few mutations
can render the virus resistant.
• What is needed is a way to increase the number
of mutations that must occur before the virion
can become resistant.
• The simplest way to increase the number of
mutations that must occur at once is to use two
or more drugs.
• These Multidrug treatments are known as High
Active Anti-Retroviral Therapy (HAART)
Drugs in use or under development
• Reverse transcriptase inhibitors
– AZT
– 3TC
• Protease inhibitors
– Indinavir
• Fusion inhibitors
• Integrase inhibitors
Resistant Strains
• In the presence of AZT, mutated new strains of
HIV or most efficient at reproduction.
• Are these new resistant strains also more
efficient at reproduction when host cells do not
contain AZT?
• NO. If AZT therapy is stopped, the proportion of
AZT-resistant virions in the virus population falls
until it reaches the level before therapy.
Mutations and the Environment
• Mutations occur randomly - but
• it is the environment that selects the type of
genetic variation that will survive and reproduce.
• Or, traits conducive to surviving and reproducing
spread throughout the population while traits
that are conducive to dying - - - disappear.
Why is HIV Fatal?
• The rapid Evoluton of the HIV population
inside a host hastens the collapse of
host’s immune system.
• This is short-sighted, because it also
hasten the extinction of the HIV population
The immune System’s Reaction.
• The body produces an immune response with
antibodies and killer T-cells.
• These bind to epitopes on the surface of the
virus or infected cells.
• It takes antibodies and T- cells about a week to
become active against a particular epitope.
• An HIV population can produce up to 100 million
new virions each day.
HIV’s Ability to Mutate
• Researchers periodically
harvested and checked
the genetic make-up of
gp 120 of virons in a
patient.
• First seven years: went
from nearly identical to
the original, to differing by
8%.
• By year eight the strain
differentiation slowed.
Why?
Viral Load.
• The patient’s viral
load increased over
time.
• Error prone Reverse
Transcriptase still
churning out
genetically variable
types.
T-cell count
• Immune system crashes
at the same time the HIV
strains stops diverging.
• HIV population free from
the selective agent that
was forcing it to evolve.
• The strains most capable
of rapid replication
simply spread, and those
less capable became
rare.
• Evolution by natural selection does not
look to the future. It is just a natural
process that happens automatically.
• As a result, the HIV population in any
particular host ultimately evolves itself
right out of existence.
CCR5 and CXCR4
• Virons that attach to the co-receptor CCR5
are predominant early and then again late
in the infection
• CXCR4 become predominant between 5
and 8 years and then rare again by year
11.
• Why?
CCR5 and CXCR4
• At the beginning of an infection CXCR4 T-cells
divide less often than T-cells displaying CCR5
• As the infection progresses CXCR4 T-cells
begin to divide more rapidly.
• Short sighted evolution?
– Virions that use the CXCR4 T-cells do not get
transmitted to a new host
– Also, virions that kill CXCR4 T-cells cause the
immune system to collapse and the host to die.
A Correlation between Lethality
and Transmission
• There are rare strains of HIV that may not
kill their host.
– Sydney Bloodbank Cohort
• Fail to synthesis Nef protein.
• Important in helping HIV virions gain entry into the
host.
– HIV-2
• Viral loads are lower
• Why are these less harmful strains rare?
Correlation between Lethality and
Transmission cont• Evolutionary point of view.
– All host die at some point.
– To persist beyond the life span of the host the
successful strain must colonize new host.
– Thus there are two levels that virions are
selected at.
• The ability to survive inside a particular host.
• The ability to transfer to a new host.
– The second level is more important than the
first.
Why are some people resistant to
infection by HIV?
• Some people who are
repeatedly exposed to
HIV do not become
infected?
• Studies show that
some of these
individuals the CCR5
has been mutated
that inhibits HIV
– CCR5-D32
Where did HIV Come From?
• Nucleotide sequences can be used to
determine phylogeny and to construct
cladograms.
• The closer two nucleic acid sequences are
the closer the two organism are related to
each other.
The Origin of HIV
• Two main types of HIV,
HIV-2 and HIV-1, were
transmitted from different
sources.
• HIV-2 originated in sooty
mangabeys.
• HIV-1 was originally
transmitted to humans
from chimpanzees