Sickle cell anemia Sickle Cell Disease anaemia

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					Sickle Cell Disease

    By: Cecil, Caitlin, and Kerri
         What is Sickle Cell?
• People who have Sickle
  Cell have sickle shaped
  red blood cells, which
  causes complications
  because the blood cells
  are not able to reach
  certain parts of the
Red blood cells Going through
Symptoms of Sickle Cell

                  * About 30% of Jamaican
                   patients with Sickle Cell
                develop ulcers in comparison
                     to 1% of Americans
Diseases and Conditions people with Sickle
         Cell are likely to develop:
                          • Acute chest syndrome
                          • Aplastic crisis
                          • Dactylitis – swelling of the hands and feet
                          • Painful crises: really painful episodes when blood cells
                            are blocked from going to certain parts of the body – pain
                            can occur anywhere, but it is usually in the chest, arms,
                            and legs
                          • Enlarged spleen – sickle cells pool in the spleen, and in
                            some cases there is no spleen in the body.
                          • Stroke
                          • Hematuria

                                                                        An enlarged
                                                                        spleen from
  An x-ray of a hand                                                     with Sickle
swollen from dactylitis                                                     Cell
                                     The History
                                     Sickle Cell

• Many people of African tribes were
  the first to develop sickle cell disease
• Most of the names they had for it had
  multiple syllables – maybe to account
  for the many painful episodes
• The tribes thought that there were
  evil spirits and the babies that died
  from sickle cell were sacrificing their
  lives for the family
 More History…
•1846: In the US, a scientist wrote
a paper called “Case of Absence
of the Spleen,” which talked
about a runaway slave whose
body was autopsied and they
found he did not have a spleen.
•1904: A hospital intern
discovered the sickle shaped cells
in a patient at a hospital.
•1910: The first formal report
came out that gave details about
the strange disease
•1922: The disease was finally
named “Sickle Cell”
Who would you think has Sickle Cell?

   Indian girl         Hispanic boy

    Black boy           White girl
   “‘Sickle Cell Anemia: It's Not a “Black

• One of the common
  misconceptions is that only
  black people get sickle cell,
  but this is not the case.
• There are many different
  ethnicities that can have sickle
                   Who can get Sickle
•                 ANYONE can get Sickle Cell Disease.

• It is most common in the following ancestries:
    o African
    o Central or South American
    o Cuban
    o Indian
    o Saudi Arabian
    o Mediterranean
    o Hispanics

o It is estimated the up to 80,000 people
  in America have Sickle Cell Disease
o 1/500 African Americans have Sickle Cell
o 1/1000 -4000 Hispanics have Sickle Cell
o 1/12 African Americans are carriers for
  Sickle Cell
o 1/50 Asians are carriers for Sickle Cell
o 1/100 Greeks are carriers for Sickle Cell
        Diary of a Man with Sickle Cell
       “In the  mid 60's, my family moved to the suburbs. For a black
family in those days, that was a big thing. We moved into a three
bedroom house complete with a bath and a half, and a pool! Yeah,
we were living large. The summer that we moved, my brother, sister
and I were ecstatic over having a pool. As soon as the weather
permitted, we jumped into our swimming suits and bounded for the
cement pond …About a week or two after we started all this
frolicking in the water, I became very ill. Confined to my bed, I
writhed in pain, suffering one of my worst crisis ever. Like always, I
basically had to brave the pain out sans pain medicine. My parents
were convinced that the day they gave me even the mildest aspirin
would be the day I'd become a junky. Exhausted and weak, I finally
         Not long after that, I rejoined my brother and sister in our
never-ending party around the pool…After another day or so of
exposure to the cold water, I took ill again. This one wasn't as bad
and my mother just figured this was what having a sickly child meant.
        It wasn't until about the third time I got sick that my parents began to get
concerned. "Why does this boy keep getting sick?" my father inquired. He usually held
my mother accountable for our condition and when I got sick, he demanded an
explanation. When my mom couldn't supply one, my dad decreed that I was to go see
the doctor.
        The doctor was as clueless as my parents, however. Sickle Cell was a disease that
doctors knew little about in those days, and each doctor practically formed his own
protocol. The doctor started asking if my routine had changed.
        "Has he had any colds of flu lately?" My mom answered no.
        "Has he been doing something different? Less rest, or anything?" My mom thought
for a little while and then finally she offered,
        "Well he's been playing in the pool a lot."
        "The pool!" The doctor was startled. He explained to my mother that there were
certain things a child with Sickle Cell should avoid, number one of them being extreme
cold temperatures. He immediately wanted to know if the pool was heated and when he
found out it wasn't he instructed my mother to limit my time in the pool.
        I was sorely disappointed once I understood the full implications of this new ruling.
While I didn't want to experience another of those excruciatingly painful crisis, it felt like
someone had dealt me a bad hand when I watched my sister play in the water all day. I
would dabble in the water and then get out as soon as I felt myself getting a little cold.
        Although it never was the same for me with the pool, I eventually learned a
balance that allowed me to enjoy as much fun possible. In turn, I'd sit on the side of the
pool and vicariously enjoy the fun my siblings had until it was safe for me to go back in.
Even to this day, I rarely spend more than 30 minutes at a time in a pool. It was a hard
lessen, learned by too many times suffering, but it came along with the territory for a kid
living with Sickle Cell.”
    Sickle cell and malaria

Distribution of the sickle cell allele   Distribution of Malaria

    As you can see, the areas where Malaria is present and
        the Sickle Cell allele is present are overlapping.
     It is Unknown why people with the Sickle Cell Trait
         are resistant to Malaria, but there are several
1.  The carriers of Sickle Cell have some abnormal
    Hemoglobin, and when they come in contact
    with the Malaria parasite they become sickled.
    Then those cells go through the spleen, which
    eliminates the cells because of their sickle shape,
    so the Malaria would be eliminated as well.
2. The Sickle Cell trait causes the malaria to stay in
    the body for an extended period of time, so it is
    able to build up a defense to it.
 3. Because oxygen concentration is low in the spleen, and because infected
     cells often get trapped in the spleen, it is possible that they are destroyed
     in the spleen
 4. The Malaria parasite produces an acid when it is inside of the red blood
     cells. This causes the red blood cells to polymerize, and the cells will
     sickle. These sickled cells are then destroyed when the blood cells go
     through the spleen.
   An Experiment on Sickle Cell
      and Malaria in 2005
•There were over 1000 people
chosen from Kenya, which is a
place where Malaria is very
•The doctor performing the
study, Dr. Tom Williams, found
that the protection to Malaria
from having the Sickle Cell trait
rose from 20% in the first two
years of life to 50% and over by
the age of 10.
•His theory of the resistance of
people with sickle cell trait
results from the immune system
building a defense.
People can live a relatively normal
life with Sickle Cell if they have the
         proper treatment.

  The average life expectancy for
          males is 42.

  The average life expectancy for
          females is 48.

In 2003 the oldest patient to have
  Sickle cell was an 85 year old
         Jamaican woman.
 Genetics of Sickle Cell

• Sickle cell is an autosomal recessive disease.
• Therefore, the child can only get Sickle cell if both
  parents are carriers, not if only one is and the
  other is normal. They have a 25% chance of
  getting it if both are carriers
 The Proteins of Hemoglobin A
• There are 4 protein subunits of Hemoglobin A


          Alpha       Alpha                Beta   Beta

 There will be different forms of Hemoglobin when there is a
                   mutation in the beta subunit.
 A carrier for Sickle Cell Will have…
•An S mutation
in one copy of                  Hemoglobin
the hemoglobin
beta gene.
•Half of the beta   Alpha   Alpha
                                             Beta   Beta S
subunits are
replaced with
Beta S.
•This person has
the Sickle Cell
When a person is a carrier, they will have:
 25 % normal HbA               50 % HbS

                   25 % HbSS
 Sickle Cell Disease: HbSS
•This results
when both
copies of the                  Hemoglobin
hemoglobin beta
gene have an S
                   Alpha   Alpha            Beta S   Beta S
•All of this
person’s beta
subunits are
replaced by beta
       Hemoglobin C
• This results when
  one of the beta
  subunits is replaced
  with beta C and
  one is replaced
  with beta S.
• If a person has
  Hemoglobin C, they     The mutation that causes this
  have sickle cell       change in the beta happens
  hemoglobin C.          because a glutamic acid residue
                         replaces a lysine residue at the sixth
                         position of the beta globin chain.
  Hemoglobin Gene
• The gene related to sickle cell anemia is
  the hemoglobin gene (HBB).
• Hemoglobin contains iron and transports
  oxygen from the lungs to the peripheral
• The HBB protein is 146 amino acids long.
• The HBB gene is found on chromosome
                    Location of the HBB Gene:
                        Chromosome 11

                                                       Chromosome Map From:,loc%5B0.000000%3A142127415.000000%
HBB Gene Continued…
       • Most people receive two normal
         hemoglobin genes (one from the
         mother and another from the
       • Carriers, or people exhibiting the
         sickle-cell trait have only one
         normal hemoglobin gene.
         Carriers rarely exhibit symptoms
         and are almost always
         completely normal.
       • People that have Sickle-Cell
         Disease have two abnormal
         hemoglobin genes.
HBB Gene – Hb S Variant
       • Sickle cell is most commonly caused
         by the Hb S variant
          – Valine, a hydrophobic amino acid
            replaces glutamic, a hydrophilic amino
            acid at the sixth amino acid position in
            the HBB polypeptide chain.
          – This causes the new hydrophobic spot
            on the outside of the protein to be
            attracted to the hydrophobic spot on
            the hemoglobin’s beta chain.
            Subsequently, the cell experiences a loss
            of plasticity due to change in surface
            tension as the Hb S molecules clump
            together, causing the “sickling” of the
      Who is Tested?
• Screening test is often performed
  when one is a newborn or a young
• As the disease is more prominent
  with African ancestry, many people
  of this descent choose to be tested
  before having children (as one can
  be a carrier).
• Prenatal testing can also be
  performed with amniocentesis and
  Chorionic Villus Sampling.
  However, one must request testing
  for sickle cell anemia when these
  procedures are done if they are of
  increased risk (such as family
• People of African or Caribbean
  descent should be tested before
•How is sickle cell
disease diagnosed?
– Many states now use hemoglobinopathy testing (looking at
  the blood for abnormalities of testing) as part of the newborn
  screening blood tests between 2 and 7 days of age.
– Careful examination of family history.
– Physical examination – some symptoms are visible, such as
– A hemoglobin electrophoresis can determine if a person is a
                  The Blood

• A chemical that reduces the amount of oxygen the
  blood carries is added to the patient’s blood.
• If the patient carries the sickle cell gene, then the
  lowered oxygen level will cause crystals to form.
• These crystals alter the shape of the red blood cell,
  giving it the “sickle shape”
• The different types of hemoglobin are separated, so
  the number of hemoglobin S can be identified and a
  diagnosis can be made.
                 The Results…

• In people without the trait, no Hb S is present.
• In carriers, Hb S constitutes 20% to 40% of the
  hemoglobin – many carriers never exhibit
  symptoms, although they may be present to a
  small degree.
• In people with the disease, 80% to 100% of
  the hemoglobin may be Hb S
   Tests may not be accurate if…
• You have had a blood transfusion within the
  past four months.
• You have polycythaemia (increased red blood
  cell production).
• If you are on certain medications – talk to
  your doctor!
                   Ethical Issues
• Testing for sickle cell is not very controversial
  aside from the controversy associated with
  genetic testing in general.
   – Pre-natal screening and terminations of pregnancy
   – Playing God
   – Discrimination in the workplace
                    Oliver Smithies

• He is exploring the possibility of gene targeting as a possible cure for
  sickle cell anemia and beta-globin thalassemia (thalassemia is when
  normal hemoglobin protein is produced in smaller quantities).
• Gene targeting uses homologous recombination – DNA is broken
  and then joined to the end of a different DNA molecule – between
  exogenous DNA and a specific chromosomal gene.
• Right now, they are attempting to correct a specific type of beta-
  globin thalassemia which is caused by a deletion.
• They are injecting mice stem cells, corrected genes are identified
  using a specific protocol designed especially for the corrected gene,
  and the corrected genes are then observed.
• They are planning to carry out similar experiments with the sickle
  cell beta-globin gene.
       Oliver Smithies Continued…
•Smithies and his team are also able to duplicate the embryonic stem cells
from mice and then restore or demolish the specific function of a gene. The
modified cells are then reintroduced into a normal blastocysts, and the
animals then exhibit the modified genes. In some cases, they have even been
able to transmit the modified gene to the animal’s offspring.

•They are hoping to use this method in order to make animal models of sickle
cell anemia.
              Oliver Smithies Continued…
Chromosome 11                  HBB

 HBB Gene                                 S
 Enlarged: Shows
 Hb S variant
STEP 1: Wildcard
gene is inserted
                                               Normal HBB Gene
occurs                                        Normal HBB Gene
As the two genes are similar, the part of the normal HBB gene between the two X’s is able to take
the place of the part of the gene between the two X’s of the gene exhibiting the Hb S variant

THE RESULT:                                   Normal HBB Gene
    Philippe Leboulch Attempts to Cure Sickle-Cell
            through Gene Therapy (2001)
•   Known (from earlier studies) that the protein gamma globin stops polymerization
    (the sticking together of hemoglobin). If a gamma globin gene is added to a beta
    globin gene, then the hemoglobin can resist polymerization.
•   Bone marrow was taken from mice infected with sickle-cell, and the modified gene
    was added to it.
•   But did this prevent the sickling of cells?
      – The modified marrow was injected into healthy mice (whose marrow had
        been taken out) to see if they developed sickle-cell.
      – These mice didn’t get sick, however, those injected with non-treated marrow
•   How did they do it?
      – The beta globin gene was delivered to the marrow by putting it with a gene
        usually found in HIV. Other DNA was also added to assist with the production
        of the beta globin.
•   After 10 months, all treated mice were making their own beta globin as a result of
    the altered gene, and therefore, there were few sickling cells.
•   The Problem?
      – Who wants to use genes associated with HIV?
      – Destroying all bone marrow is dangerous.
Philippe Leboulch Continued…

Before Gene Therapy               After Gene Therapy
Treatment Options For Sickle
       Cell Anemia
Main Treatment Methods
There is no known cure for sickle cell anemia.

The four main treatment options are:
• Blood Transfusions
• Drug Treatment
• Blood and Marrow Stem Cell Transplantation
• Gene Therapy

 These main treatment options for the painful crisis involves heavy
  reliance on painkilling drugs and oral and intravenous fluids whose
  main functions are to reduce pain and prevent complications.
Blood Transfusions
• Blood transfusion involves transferring healthy blood from one person
  into the circulatory system of another person.

• Blood transfusions are mostly known for their life-saving use in
  situations involving massive blood loss due to trauma, however its use
  in treatment of sickle cell anemia is increasing.
Blood Transfusion
What does it do?
• In sickle cell anemia red blood cells become sickle shaped.
• Painful crises as tissues become depleted of oxygen
• Useless red blood cells build up in blood vessels leading to
• Blood transfusions reduces this pain by increasing the number of
  functioning red blood cells in the body and hence increasing the
  oxygen carrying capacity of the blood. These transfusions can
  also improve conditions such as an enlarged spleen and strokes,
  which sickle cell patients are especially at risk for.
Blood Transfusions
 Blood transfusion is currently the single most effective and proven
   treatment for severe complications of sickle cell disease. It also
   significantly reduces strokes.
 Blood transfusions are mostly administered to children who have severe
   cases of sickle cell anemia. However, persons of all age can receive
   this treatment.
  The cost for one blood transfusion is around $450, and they should be
   administered once a month in children for its positive effects to be
   really seen.
Drug Treatment
• Persons with sickle cell anemia are especially susceptible to infection.

• The two main drugs used in treatment of sickle cell anemia are
  penicillin and hydroxyurea.
Drug Treatment
 • Persons with sickle cell anemia have an increased
   susceptibility to infection due to damage to one of our major
   defenses against infection, the spleen, due to restricted blood
 • Penicillin is an antibiotic which would attack these infections
   helping in quick healing and protection.
 • Folic acid, which aids in the formation of healthy blood cells
   could also be taken daily in large quantities as well.
Drug Treatment
Penicillin                          Cost
                                    • $ 54.90 for 30 Tablets
Penicillin should be taken once a
   day everyday so that effective
   protection against possible
   infection could happen.
Drug Treatment
 • Hydroxyurea was the first effective drug treatment for adults
   with severe sickle cell anemia.
 • A study showed that daily doses of the anticancer drug
   hydroxyurea reduced the frequency of painful crises and acute
   chest syndrome in sickle cell anemia. In addition, patients taking
   the drug needed fewer blood transfusions.
  Drug Treatment
How does it work?
  Higher doses results in large increases in fetal
  hemoglobin concentrations; as little as a four percent
  increase in HbF concentrations was needed to help
  prevent some sickling of cells.
  Hence, if less cells are sickled the symptoms of the
  disease are reduced.
Hydroxyurea costs around $90 for 100 capsules.
Blood and Marrow Stem Cell
  Bone marrow transplants are the closest things possible to a cure for
  sickle cell anemia.

 In bone marrow transplantation, the affected person’s bone marrow
   is replaced with cells containing genes for the non-sickle cell
 Production of healthy red blood cells starts and the sickle shaped cells
   are prevented. If the transplant is performed when the affected person
   is still young then success rates can be as high as 90-95%.(Sickle Cell
   Society 2005)
Bone Marrow and Stem Cell
  An obstacle with this kind of treatment finding enough donors for such
   an invasive and painful procedure, as well as finding specific
   donor/patient matches.
 Bone Marrow transplantation can cost as much as $30’000 and so only
   certain people could afford this form of treatment.
Gene Therapy
Gene therapy is the relatively new idea of inserting genes into the cells of
  an individual’s tissues and cells in order to treat a hereditary disease,
  such as sickle cell anemia, in which a defective mutant allele is
  replaced with a functional one.

 Gene Therapy would be the best cure for sickle cell anemia, but work
  in this method of treatment is still very new.
Gene Therapy
 What It Involves
 Two methods of gene therapy are being explored.
 1) Correction of Gene
 2) Turning Off Gene

 Correction of Gene
        Scientists are looking at whether correcting the defective gene
      in sickle cell anemia and inserting it into the bone marrow of
      people with sickle cell anemia will result in the production of
      normal adult hemoglobin.
 Turning Off Gene
      Some other scientists are looking at the possibility of turning off
    the defective gene and simultaneously reactivating another gene
    that turns on the production of fetal hemoglobin.
Gene Therapy
 The cost of gene therapy is very high at this point in time. However,
  Gene therapy will probably be cheaper in the long run since it is a
  one time only procedure. It will eliminate suffering for the
  individual and possibly their children.
 Video Newscast- Treatment of sickle
                                   Works Cited
•"Carolina: The curriculum in genetics and molecular biology." Oliver Smithies, D Phil. 2007. 30 Oct 2007

•"HBB: The Gene Associated with Sickle Cell Anemia." Human Genome Project Information. 16 Oct 2007

•Seppa, Nathan . "Gene Therapy for Sickle-Cell Disease?." Science News 160.2415 Dec 2001 372. 1 Nov
            2007 <>.

•"Sickle Cell Anemia." Diseases and Conditions Index. National Heart Lung and Blood Institute. 30 Oct
              2007 <>.

• "Sickle Cell Anemia." Human Diseases and Conditions. 2007. 30 Oct 2007

•"Sickle Cell Disease." Health Information. Children's Hospital of Wisconsin. 16 Oct 2007

•"The Test." Sickle Cell Test. Lab Tests Online. 16 Oct 2007

•"What is Sickle Cell Anaemia?." Sickle Cell Society. Sickle Cell Society. 27 Sep 2007