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Immunity through Sickle Cell: Treating


Malaria through a Sickle Cell stimulate.
Emmanuel Mekasha
Independent Research GT
May 6, 2019

Abstract

Malaria is a plasmodium transferable by mosquito. It is a massive problem in the world

today. Sickle Disease is a recessive genetic disorder that worsens its host. Sickle Cell Disease,

however, provides immunity to Malaria. Carriers, individuals heterozygous for the Sickle Cell
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trait, demonstrate an immunity to Malaria without any of the other negative symptoms. This

provided immunity is the most effective solution, as proven by the selective advantage, to

Malaria and can be implemented through CRISPR.

Introduction

Sickle Cell disease is a genetic disorder that causes sickling of the cell. Patients with

Sickle Cell disease are inherently immune to Malaria. Malaria is a Plasmodium that acts similar

to a Parasite. It flourishes in tropical regions resulting in it becoming a major problem in

environments such as Africa. Several solutions have been proposed but none of the solutions that

have been implemented have been effective. Although certain experts have suggested solutions

such as the use of vaccines derived from dead P. Falciparum and the use of T cells to combat

Malaria, simulating phenotypic expression similar to one implemented by a heterozygous sickle

cell genotype through the use of CRISPR and plasmids is the superior method for dealing with

Malaria.

Literature Review

Malaria is a Plasmodium that uses vectors, female mosquito contact with infected blood,

for transportation. As such, Malaria is not openly communicable from person to person and is

only transferable from mosquito to human (Gong, Parikh, & Rosenthal, 2013). Upon interaction

of a human with a female mosquito that possesses the Malaria Plasmodium, Malaria infiltrates

the red blood cells through diffusion in the cellular membrane. Malaria then interacts with the

genetic coding of the cell. Here, the Plasmodium acts as a parasite through inserting its own

DNA into the target host’s genome in order to transcribe and translate that section of DNA. This

will encode for proteins that allow for further reproducing of the Malaria protist (Gong, Parikh,
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& Rosenthal, 2013). In order to more effectively reproduce, the Malaria alters the cell’s cellular

peripheral clocks and SCH in order to alter its rhythm. This allows for the cell to work around

the clock and reproduce more of the Malaria protist (Animal activity around the clock with no

overt circadian rhythms).

During reproduction and mitosis, the Malaria infected cell uses one’s bodily resources

through taking advantage of the cell cycle. The plasmodium uses Interphase to grow inside a

newly created cell. This new cell eventually matures, reproduces, and repeats the cycle again.

After the Malaria has reproduced enough, it ruptures the cell membrane. As the cell membrane is

vital in osmosis, diffusion, and maintaining the shape and organelles of the cell, the previous host

cell of the Malaria is killed after departure. The created Plasmodium then infects more red blood

cells to do the same thing.

After the stage of infestation of the red blood cells has been completed, the Malaria then

transports to the liver cells of the patients. Here, it undergoes the same process as with the red

blood cells. The killing of both red blood cells and liver cells accounts for all the symptoms of

Malaria including fever, halted glucose intake, headaches, and vomiting (Choby, Buechi,

Farrand, Skaar, & Barber, 2018). After these two phases are done, a vector interacts with the

blood of an infected patient. Doing so will cause the vector to transport the plasmodium. Here,

the process repeats itself.

Sickle Cell Disease is an inheritable genetic disorder caused by mutations in genes

present in the short arm of the 11th chromosome. These mutations cause changes that result in

the improper construction of Heme iron and unoxygenated hemoglobin present. (Pishchany &

Skaar, 2012). Usually, in normal individuals, when under anaerobic conditions, hemoglobin

stacks up on top of each other in a cell. However, in sickle celled individuals, when under
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anaerobic conditions, hemoglobin is produced with binding and receptor parts. The receptor and

binding parts of the hemoglobin bind to each other causing the hemoglobin to line up. This

causes the cell to form a sickle shape and causes sickling in oxygen deprived environments

(Choby, 2019). This sickle shape of a cell results in decreased oxygen intake to the cell.

Symptoms of the disease on the organismal level derive from the sickle shape. They range from

clogging of blood vessels due to the immobility of shape to decreased energy due to less aerobic

respiration. However, on the cellular level, other than decreased oxygen intake, nothing else is

changed. Sickled Cells maintain the same constant circadian clock, peripheral clock, and SCH as

the cell operates (Johnston & Scheer, 2016).

The decreased oxygen intake in Sickled cells due to the sickle shape results in choking of

the Plasmodium within Sickled cells. This is due to cellular respiration. All cells, including

Malaria infected cells, go through respiration. Cellular respiration is divided into four portions.

These portions consist of glycolysis, the Link Reaction, the Krebs Cycle, and oxidative

phosphorylation. First, when glucose is consumed or produced, through photosynthetic

processes, and ready to be used, glycolysis begins. In glycolysis, a process that occurs in the

cytoplasm of the cell, a six-carbon glucose molecule is used to construct 2 PGAL molecules,

each consisting of 3 carbon. From here, these 2 PGAL molecules demonstrate reduction as an

electron is used to bind the positively charged NAD+ and positively charged H+, originally from

the 2 ATP molecules, to form NADH and two 1, 3 BPG molecules. From these 1,3 BPG

molecules, the 2 pyruvates needed for the link reaction is constructed. Continuing on to link

reaction, a process that occurs in the inner matrix of the mitochondria, the products of glycolysis

become the reactants of the Link Reaction with 2 pyruvates, a 3-carbon acid each, forming 2

Acetyl CoA, a 2-carbon molecule each. This is done when the Coenzyme A binds with the
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pyruvate, forming a molecule with differences in the amount of carbon. While this process is

occurring, 2 CO2 is released into the external environment, explaining the carbon difference

between the pyruvate and Acetyl CoA. The 2 acetyl CoA is then used for the next process, the

Krebs Cycle. The Krebs Cycle converts oxaloacetate produced in the cycle, 4 carbons each, into

alpha ketoglutarate. Then, as oxidative phosphorylation occurs, reduction and phosphorylation

transpire including the conversion of NAD to NADH and ADP and a phosphate group into ATP.

CO2 molecules are also released into the external environment. In oxidative phosphorylation, a

process that occurs in the inner membrane of the mitochondria, high potential electrons are

extracted from NADH and FADH2 to form NAD+ and FAD+. These high potential electrons,

the H+ and 2H+ from the NADH and FADH2 respectively, go through the electron transport

chain and allow for active transport, a process that requires energy to commence the movement

of molecules against the concentration gradient, to occur. During this process of active transport,

channel proteins transfer positively charged hydrogen inside of the intermembrane space. After

this, oxygen acts as an electron receiver (The contributions of respiration and glycolysis to

extracellular acid production, 2014). Oxygen receives the electrons from this transport chain, and

hydrogen and oxygen bond in order to produce water. The ATP synthase is another channel

protein that removes hydrogen ions from the intermembrane space to the mitochondrial matrix

and phosphorylates ADP to form ATP. During this process, 34 ATP and 6H2O is produced

(Gnaiger, Steinlechner-Maran, Méndez, Eberl, & Margreiter). If there is decreased oxygen intake

from sickling, there will not be enough reactants for glycolysis to occur. This leads to a chain

reaction in which future steps of cellular respiration do not occur either. Instead, however,

fermentation occurs producing drastically lowered ATP amounts (Variation in the link between

oxygen consumption and ATP production, and its relevance for animal performance). The
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amounts produced are so low cell reactions cannot be maintained. This kills the cell and anything

in it, including Malaria. This causes immunity from Malaria (INCREASED SICKLING OF

PARASITISED ERYTHROCYTES AS MECHANISM OF RESISTANCE AGAINST

MALARIA IN THE SICKLE-CELL TRAIT, 2003).

Now, there can be carriers of Sickle Cell as Sickle Cell is a recessive genotype. Carriers

can express no Sickle Cell Disease symptoms but possess the allele for Sickle Cell by being

heterozygous for Sickle Cell. Carriers or heterozygous patients do not experience regular

sickling in deoxygenated environment. Only partial sickling on cells with detected plasmodium.

This process occurs through hormone secretion and cell signaling (Liemburg-Apers, Willems,

Koopman, & Grefte, 2013). This is a great positive due to none of the negative symptoms of

Sickle Cell occurring in heterozygous individuals while they do experience the sickling

advantage of Malaria immunity. The viability of being heterozygous for Sickle Cell is

demonstrated through the natural selective advantage. Those with heterozygous Sickle Cell have

been rising in Malaria infested regions. This means they have been surviving and reproducing

more than those who are recessive or dominant for Sickle Cell (Ackerman, 2005). If this is

simulated in patients with Malaria, this would be the most effective solution as patients

demonstrate immunity to Malaria without having any negative symptoms of Sickle cell.

There have been other suggested solutions to the Malaria pandemic that have been

demonstrated as not effective. Beginning with the first one, one suggested solution is Vector

control through elimination of vector populations or destruction of breeding nests. Though this

would control the transportation of Malaria, there would be negative effects that would follow

including trophic cascade in both the predator and prey levels (Long & Hoffman, 2002). This is

therefore not an effective solution. For the second one, another suggested solution is pesticide
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use in recreational and residential areas to prevent exposure to vector and therefore Malaria.

Though this would again control the transportation of Malaria, there would be negative effects

on the human population as there is a demonstrated connection between these pesticides and

cancer. This is therefore not an effective solution. For the third solution, a suggested solution is

vaccination through use of dead p. Falciparum. This has been recorded to have provided

immunity for 10 months (Long & Hoffman, 2002). Though this solution has provided immunity

for these 10 months, this solution would not ultimately be effective long term as Malaria would

naturally select allowing plasmodium strains to become immune to the vaccination. This would

therefore not be an effective solution. Simulating a heterozygous Sickle cell environment does

not cause trophic cascade, does not harm the human population, and cannot be adapted to due to

Malaria needing oxygen to go through cellular respiration. As a result of this, simulating a

heterozygous Sickle cell environment is the most effective solution to Malaria.

As previously establishing, constructing a simulate to the environment created by patients

that are heterozygous for Sickle Cell is the most effective solution. This simulate can be

administered through the use of plasmids and CRISPR. Plasmids are untangled, circular portions

of DNA within bacteria. They provide a sufficient “canvas” through removal, genome

manipulation, and reinsertion. Through placement of portions of wanted DNA inside of a

plasmid, genomes can be edited with that particular DNA. Implementation of new DNA through

plasmids results in transcription of DNA to mRNA, transporting of mRNA to cytosol creating

complementary tRNA anticodons, and translation of mRNA into polypeptides and proteins to

influence phenotype. Implementation of these plasmids can be done through the use of CRISPR.

CRISPR can be used by specifying a targeting sequence within the RNA in order to efficiently

edit a genome (Ran, 2013). CRISPR is an effective editing tool for several reasonings. Firstly,
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CRISPR is easily customizable due to change in oligos. Secondly, CRISPR possesses Cleavage

Pattern, mutations in the nuclease allowing for nicking and verification. Thirdly, CRISPR has the

ability to target multiple sections at one. Fourthly, CRISPR contains HDR, a structure possessing

the power of mammalian repair assists, which is made more reliable through Double nicking in

Cas 9 which prevents error (Doudna & Charpentier, 2014). Fifthly, the Programmable sequence

specific endonuclease within CRISPR are really helpful for particular binds to membrane

proteins allowing different simulation of DNA or direct editing allowing for amazing efficiency

(Development and Applications of CRISPR-Cas9 for Genome Engineering, 2014). Sixthly, the

DNA oligonucleotides present allow for preciseness with use of CRISPR (Development and

Applications of CRISPR-Cas9 for Genome Engineering, 2014). These benefits make plasmids

through the use of CRISPR the most effective way to implement the most effective solution of a

simulate of a heterozygous Sickle cell environment in malaria induced cells

Data Collection

Meta-analysis is the data collection strategy that was picked for this paper. Originally,

experimental data collection was going to be used to compile data that would be able to prove

the thesis. Practically, carrying out experiments or studies of populations to get the data that is

required would be impossible to do with the resources present. So instead of carrying out

experiments or studies, Data was compiled from a multitude of studies and experiments in order

to accomplish the same goal of supporting the thesis and proving the side of the argument argued

by the paper. There were other particular reasons why Meta-analysis was picked over the other

data collection strategies. Firstly, experimental data collection would not work for the reason

given above. Observational data collection was not picked as once again resources are not

sufficient enough for one to observe Sickle Cell and Malaria and collect data based on those
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observations. Data collection based on questionnaires, surveys, and interviews was not picked

because the collection of opinions of a population will not prove the thesis nor argument.

Sources D. J. Weatherall. A. C. Allison Eric Elguero and H. Ackerman S.

Genetic variation Protection Lucrèce M. Usen M. Jallow

and Afforded by Délicat- F. Sisay‐Joof M.

susceptibility to Sickle-cell Trait Loembet. Pinder D. P.

infection: the red Against Malaria Kwiatkowski. A

cell and malaria. Subtertian continues to Comparison of

09 April 2008 Malarial select for sickle Case‐Control

Lucio Luzzatto, Infection. 1954 cell trait in and Family‐

E.S.Nwachuku- Feb 6 Central Africa. Based

Jarrett, and June 2, 2015 Association

S.Reddy. Methods: The

INCREASED Example of

SICKLING OF Sickle‐Cell and

PARASITISED Malaria.

ERYTHROCYT 05 April 2005

ES AS

MECHANISM

OF

RESISTANCE

AGAINST
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MALARIA IN

THE SICKLE-

CELL TRAIT.

14 February

1970

Criteria Study examining Study examining Study examining Study examining

a lengthy(above a lengthy(above a lengthy(above a lengthy(above

100) group. 100) group. 100) group. 100) group.

Compared Compared Compared Compared

variables within variables within variables within variables within

each study each study each study each study

consist of an consist of an consist of an consist of an

equal equal equal equal

examination examination examination examination

group: Check. group: Check group: As there group: As there

Total 200 Total 290 were not equal were not equal

variables within variables within

the groups being the groups being

compared, I used compared, I used

the proportions the proportions

determined from determined from


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the data and the data and

applied them to a applied them to a

group with the group with the

same number of same number of

participants. participants.

Adjusted Adjusted

Total(1000) Total(583)

Data Malaria induced Patients without Diagnosis of Those with

cells experienced Sickle Cell heterozygous Sickle Cell have

2 to 8 times experienced Sickle Cell has demonstrated

more sickling in diagnosis of been increasing decreased

Sickle Cell different in younger susceptibility to

induced patients. versions of the generations Malaria. Several

Sickling Malaria compared to examples of this

demonstrated Plasmodium in older exist. The first

linear growth great amounts. generations. This example that

when induced to One example can be shown as demonstrates

an anaerobic includes patients in individuals this would exist

environment. diagnosed with 65+, 23.1% of with Severe

Conditions M2B1(strain of them were Malaria

allowed for data Malaria). 8 days diagnosed with infections among

to be collected. after the study heterozygous those without


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Possible began, 3 sickle cell. In Sickle Cell and

conclusions to individuals were individuals 55- those with

this increased diagnosed with 64, 23.3% were heterozygous

sickling and M2B1. 12 days diagnosed with Sickle Cell. 5%

what it result in after the study heterozygous of those with

made in began, 7 sickle cell. This heterozygous

upcoming individuals were demonstrates an Sickle Cell had

studies. diagnosed with increase in the severe Malaria

M2B1. 14 days younger while 54% of

after the study generation. non-sickle cell

began, 25 people Another example patients had

were diagnosed of this is shown severe Malaria.

with the strain. with generations Another example

16 days after the (age groups) 35- of this exists

study began, 50 44 and 15-24. with fatal cases

individuals were With 35-44, of Cerebral

diagnosed with 20.8% were Malaria. 2% of

the strain. On the diagnosed by heterozygous

other hand, heterozygous Sickle Cell

Patients with Sickle Cell. In patients had fatal

Sickle Cell 15-24, 21.1% cases of Cerebral

experienced were diagnosed Malaria while

significantly low by heterozygous 12% of non-


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diagnosis of Sickle Cell. This Sickle Cell

different shows an patients had fatal

versions of the increase in the cases of Cerebral

Malaria younger Malaria.

Plasmodium. generation.

With M2B1,

throughout the

whole

experiment (40

days) no

individuals were

diagnosed with

the strain.

Another example

with people

without Sickle

Cell is present

with the strain

B4. In 8 days, 2

people were

diagnosed with

this strain. In 10

days, 50 people
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were diagnosed

with this strain.

In 12 days, 100

people were

diagnosed with

this strain. On

contrary, with

people with

Sickle Cell, with

the strain B4, no

one was

diagnosed with

the strain during

the duration of

the study

Beginning with results, results from study 1 demonstrate the idea that individuals

diagnosed with a heterozygous sickle cell genotype experience increased sickling in cells

infested with the Malaria Parasite. This data is not surprising as the mechanism in which cells

sickle support the results of this data. The results were caused by this mechanism. Upon

stimulation through Malaria infiltration, for heterozygous individuals, hormone proteins are

released that interact with the cellular membrane of cells with detected plasmodium infiltration.

The interaction acts as a promoter and causes sickling. This supports the data. Alone, the results
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mean nearly nothing to my research question. Support with the upcoming studies alongside the

results of this study demonstrate how Sickle Cell is a superior solution to the Malaria argument.

Continuing on with the results from study 2, the results from study 2 demonstrate that Sickle Cell

provides near perfect immunity to all strains of Malaria as demonstrated through non induced

sickle cell patients being diagnosed for Malaria much more than sickle cell patients. This is also

demonstrated through study 4 with different severities of Malaria. In general, sickle cell patients

demonstrate almost perfect immunity to all severities of Malaria. Study 4 and 2 were not

surprising as the scientific mechanism with Sickle Cell Disease supports these findings. The

results are as a result of the characteristics of Sickle Cell. As a result of the shape of sickled cells,

less oxygen is provided to these cells. In Malaria infected cells, this decrease in oxygen causes

the death of the plasmodium. This results in immunity as demonstrated in the data. Here is where

the results of study 1 come into play. As the results of study 2 and 4 determined that sickling of a

patient’s cells provide immunity and study 1 determined that malaria induced cells are sickled at

a greater degree, the conclusion from these 3 studies is that Sickle Cell focuses Malaria induced

cells with increased sickling, kills these cells with decreased oxygen, and provides almost perfect

immunity to the Plasmodium. This supports the thesis and the argument that stimulating a

heterozygous sickle cell environment is the superior solution. Finally, the results of study 3

determine that younger generations when compared with older generations exhibit increase

genotypic features incorporating heterozygous sickle cell traits. This was not surprising as it

makes sense according to the mechanism of evolution and natural selection. A trait that makes an

organism better fit for an environment will result in the more fit organism surviving at a greater

rate than the less fit organisms. This will eventually result in the population with this fit trait

increasing due to the increased rate of survival. Based on this reasoning, since those with
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heterozygous sickle cell are surviving at greater rates than those that do not have heterozygous

sickle cell and therefore increasing in population, heterozygous sickle cell must make the human

organism more fit for a Malaria environment. This supports the thesis and the argument through

demonstrating stimulating Sickle Cell is an effective method to dealing with Malaria. Study 3’s

results ultimately combine with the results of study 1,2, and 4 and ultimately, support the

argument.

The limitations of the data collection, meta-analysis, derive from the point that articles

are not specifically suited for each other and are distinctive in their own manner. This makes it

difficult to connect all of them. If this were to be done again, articles would be found that were

even better suited for each other in order to connect them even more.

These results ultimately support the thesis and argument which states implementing a

Sickle Cell environment would be the superior way to deal with Malaria. This may warrant

future research into the topic and allow for a possible cure to the disease through genome editing.

The new knowledge that can be extrapolated from the results include implementing a Sickle Cell

environment would be the superior way to deal with Malaria.

Conclusions

Throughout the years, possible solutions have arrived to solve the argument of the

Malaria endemic. Ultimately, they are not as viable for use as a solution to the Plasmodium as

Sickle Cell immunity is, due to the negative effects they result in. Studies have also

demonstrated heterozygous Sickle Cell as a near perfect method for immunity to Malaria.

Simulating a heterozygous Sickle Cell environment is the superior method to deal with Malaria

and a practical one with implementation through bacterial plasmids and the Cas9 CRISPR
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mechanism. Now that there is a method, the people can make the world a Malaria free place.

Now, the people must voice their opinion and change public policy.
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