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 body. Red blood cells Going through Vessels 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 and unhealthy spleen from someone An x-ray of a hand with Sickle swollen from dactylitis Cell The History of 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 Disease”’ • 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 cell. Who can get Sickle Cell? • 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 Prevalence o It is estimated the up to 80,000 people in America have Sickle Cell Disease o 1/500 African Americans have Sickle Cell Disease 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 recovered. 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 theories… 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 prominent •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 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 trait. 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 mutation. Alpha Alpha Beta S Beta S •All of this person’s beta subunits are replaced by beta S. 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 tissues. • The HBB protein is 146 amino acids long. • The HBB gene is found on chromosome 11. Location of the HBB Gene: Chromosome 11 Chromosome Map From: http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?ORG=hum&CHR=11&MAPS=ideogr%5B11pter%3A11qter%5D,loc%5B0.000000%3A142127415.000000% 5D&query=e:HBB HBB Gene Continued… • Most people receive two normal hemoglobin genes (one from the mother and another from the father). • 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 cells. Who is Tested? • Screening test is often performed when one is a newborn or a young child. • 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 history). • People of African or Caribbean descent should be tested before anesthesia. Testing •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 jaundice. – A hemoglobin electrophoresis can determine if a person is a carrier. The Blood Test • 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 S STEP 1: Wildcard gene is inserted Normal HBB Gene S STEP 2: homologous recombination 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 did. • 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 http://www.sciencenews.org/articles/20011215/fob1.asp 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 Definition • 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 stroke. • 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 Effectiveness Blood transfusion is currently the single most effective and proven treatment for severe complications of sickle cell disease. It also significantly reduces strokes. Age Blood transfusions are mostly administered to children who have severe cases of sickle cell anemia. However, persons of all age can receive this treatment. Cost 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 Penicillin • 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 flow. • 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 • 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 Hydroxyurea 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. Cost Hydroxyurea costs around $90 for 100 capsules. Blood and Marrow Stem Cell Transplantation Bone marrow transplants are the closest things possible to a cure for sickle cell anemia. Process In bone marrow transplantation, the affected person’s bone marrow is replaced with cells containing genes for the non-sickle cell hemoglobin. 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 Transplantation Problem 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. Cost Bone Marrow transplantation can cost as much as $30’000 and so only certain people could afford this form of treatment. Gene Therapy Definition 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 Cost 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 cell http://video.google.com/videoplay?docid=4164 829552325284094&q=sickle+cell+anemia+tre atment&total=19&start=0&num=10&so=1&ty pe=search&plindex=0 Works Cited •"Carolina: The curriculum in genetics and molecular biology." Oliver Smithies, D Phil. 2007. 30 Oct 2007 <http://gmb.unc.edu/faculty/smithies.htm>. •"HBB: The Gene Associated with Sickle Cell Anemia." Human Genome Project Information. 16 Oct 2007 <http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/hbb.shtml>. •Seppa, Nathan . "Gene Therapy for Sickle-Cell Disease?." Science News 160.2415 Dec 2001 372. 1 Nov 2007 <http://www.sciencenews.org/articles/20011215/fob1.asp>. •"Sickle Cell Anemia." Diseases and Conditions Index. National Heart Lung and Blood Institute. 30 Oct 2007 <http://www.nhlbi.nih.gov/health/dci/Diseases/Sca/SCA_Causes.html>. • "Sickle Cell Anemia." Human Diseases and Conditions. 2007. 30 Oct 2007 <http://www.humanillnesses.com/original/Se-Sy/Sickle-cell-Anemia.html>. •"Sickle Cell Disease." Health Information. Children's Hospital of Wisconsin. 16 Oct 2007 <http://www.chw.org/display/PPF/DocID/21860/router.asp>. •"The Test." Sickle Cell Test. Lab Tests Online. 16 Oct 2007 <http://www.labtestsonline.org.uk/understanding/analytes/sickle/test.html>. •"What is Sickle Cell Anaemia?." Sickle Cell Society. Sickle Cell Society. 27 Sep 2007 <http://www.sicklecellsociety.org/education/sicklecell.htm#anchor62960>.