Definition:

• Sickle cell diseases-one of the commonest genetic diseases,comprises a group of disorders characterized by the presence of at least one hemoglobin S allele (an alternative form of a gene).
• It causes  the red blood cells to deform and become sickle/crescent shaped.
• Sickle cell diseases are caused by a mutation in the hemoglobin subunit gene(HBB).
• Sickle hemoglobin(HbS) is as a result of a single base-pair point mutation in the beta globin gene resulting in the substitution of the amino acid valine for glutamic acid in the beta globin chain.
• The misshapen red blood cells clump together and  get stuck in blood vessels,blocking blood flow and depriving tissues and organs of oxygen-rich blood.
• The commonest type of SCD occurs in individuals homozygous for the HbS allele.
• The most common sickle cell disease is sickle cell anemia

How does one inherit sickle cell disease?

 Sickle cell disease is inherited in an autosomal recessive pattern. This means a child will not inherit the disease unless both parents pass down a defective copy of the gene. People who inherit one good copy of the gene and one mutated copy are carriers. They are clinically normal, but can still pass the defective gene to their children. 

What is sickle cell trait? 

1. Dehydration
2. Low oxygen  in the air
3. High altitudes
4. High pressure in the atmosphere

Symptoms of Sickle Cell Anemia

Acute symptoms

• Sepsis
• Hypersplenism
• Dactylitis
• Acute Chest Syndrome
• Pain Crisis
• Osteomyelitis
• Stroke
• Splenic sequestration
• Priapism

Chronic symptoms

• AVN of  the hip joint
• Infertility
• Hyposthenuria
• Cholelthiasis
• Infertility

Demographic mostly affected

Sickle Cell Diseases primarily affect people with African,Hispanic and Mediterranean ancestry.

The main focus of this research is the demographic in Africa specifically sub-Saharan Africa where malaria prevalence is highest.

Why is Sickle Cell Prevalent in some demographics than others?

The evolution of the disease in Malaria prone regions-this mutation was to help people tolerate malaria.

The frequency of Sickle Cell Anemia is highest in equatorial  low altitude regions of Africa.

Sickle Cell Anemia has a low prevalence in southern and northern parts of Africa as malaria has a low prevalence in these regions.

Evidence shows that about 90% of the world’s sickle cell disease population lives in Nigeria,DRC and India.

Sub-Saharan Africa

This is the region in Africa below the Sahara Desert and consists of 47 countries.

The countries in Sub-Saharan Africa with the highest prevalence of SCD cases are:

1. Cameroon
2. Democratic Republic of Congo
3. Gabon
4. Ghana
5. Nigeria-globally has the  highest cases of SCD
6. Uganda – about 45% prevalence in some parts

Statistics. 

The impact of Sickle Cell Diseases(SCD) is global and increasing. In the USA an estimated 100,000 individuals have the disease and in Sub-Saharan Africa  about 300,000 children are born with SCD annually and face a 75-90% mortality rate by the age of five due to infectious diseases.

Sub-Saharan Africa comprises all the countries below the Sahara desert in Africa.

Effects of SCD on individuals

The individuals  who survive premature death due to the disease are forced to live in constant pain, weak immune systems that make them susceptible to all types of infections, dehydration and shortness of breath. Most children growing up with sickle have a constant fear of not reaching adulthood  and when they do, most of them succumb to the severe symptoms and end up helpless and jobless as their symptoms do not permit them to hold a demanding job. They are told that they should not let their condition limit their life. But how can they not; when it is what determines how they live because, any wrong move and they end up in the hospital, the repercussions are a high hospital bill that leaves a huge dent in their finances and those of their guardians.

Treatments for SCD

The available treatments for sickle cell that can be used to manage the symptoms of  the disease are: 

1. hydroxyurea
2. L-glutamine
3. Voxelator
4. Crizanlizumab 

These medications aid in alleviating the pain  and managing the other symptoms which enable the patients to manage their suffering. The downside of these available treatments is that  they are not available to all patients with sickle cell.Most of these patients have low incomes  and meeting the high cost of the medications becomes impossible, most are left in crippling debt where they are forced to obtain loans so that they can get the medication they need. 

Approved Cures for Sickle Cell Diseases

1. Hematopoietic stem cell transplant
2. Gene therapy comprises of gene editing and gene addition

Patients who can afford the stem cell transplantation are faced with a challenge of obtaining a donor .Finding a compatible donor is not guaranteed thus most patients are left with crushed dreams of getting cured of the disease that limits them. The procedure involves risk of  graft vs host disease where the patient’s body may reject the transplanted cells. The mortality rate after transplantation is about 5% which is high as no one wants to take such a risk on their lives. These shortcomings coupled with the inability of the medications to get rid of the symptoms of sickle cell prompted the revolutionary discovery of CRISPR, a gene editing technique that involves transplantation of genetically edited cells and gets rid of the sickle cell symptoms. 

 CRISPR is  an acronym for clustered regularly interspaced short palindromic repeats(CRISPR) ; a gene editing technique that is used to correct the mutation in the hemoglobin that results in the production of mutated  red blood cells. The application of this technique is meticulous and occurs in distinct phases, which are:

1. Identifying the mutated cells and extracting hematopoietic stem Cells: In sickle cell disease, a specific mutation in the HBB gene results in the production of abnormal hemoglobin (HbS). Scientists first identify the precise location of this mutation in the patient’s genome then the cells are extracted from the patient’s bone marrow
2. Designing CRISPR Components: Researchers design the guide RNA (gRNA) to specifically target the mutated sequence in the HBB gene. They also prepare the CRISPR-associated protein 9 (Cas9) enzyme that will cut the DNA at the targeted location.
3. Delivery into Cells: The CRISPR components (gRNA and Cas9) are delivered into the patient’s hematopoietic stem cells, which are the cells responsible for producing blood cells, including red blood cells.
4. Editing the Genome: The guide RNA guides the Cas9 enzyme to the mutated region in the HBB gene, where the Cas9 makes a precise cut. The cell’s natural repair machinery then kicks in.
5. Repair Mechanism: The cell’s repair machinery may use the provided template or the non-homologous end joining (NHEJ) repair pathway to fix the cut in the DNA. Ideally, if a template is provided, the corrected sequence from the template is incorporated into the genome, replacing the mutated sequence.
6. Production of Healthy Hemoglobin: The corrected cells, now with a properly functioning HBB gene, can produce normal hemoglobin instead of the abnormal hemoglobin characteristic of sickle cell disease.
7. Transplantation: The edited hematopoietic stem cells are then reintroduced into the patient through a stem cell transplant. The hope is that these edited cells will give rise to healthy blood cells, including red blood cells with normal hemoglobin

The treatment has worked for the majority of the patients that have undergone the trial and there are no short term negative implications on the patients. The first patients of this treatment claim that it has positively changed their lives. Victoria Gray, age 38 is among the first patients to receive CRISPR treatment and she claims that it completely changed her life for the better. Prior to the treatment Victoria’s life had become a series of unfinished chapters as she  could barely finish school, take care of her children and hold a stable job because her symptoms crippled her. After the treatment all her symptoms disappeared and it was as if she had never  been sick and she now  champions for the approval of the CRISPR treatment as it will help change the lives of many sickle cell patients just as it changed hers.

This technique provides a  solution for many patients and it is advantageous in that there will be no worry over compatibility with donors because the bone marrow will be extracted from the patient to obtain the cells that need editing so as to eradicate the disease. There will be no need to give the patients immunosuppressants because these are detrimental to patients as they weaken their immune systems making them susceptible to infections,moreover, the risk of graft vs host diseases is greatly decreased as the graft is obtained from the patients themselves. This disease is common in stem cell transplants where the immune cells from the donor attack the tissues of the recipient causing them immense pain.

References

1. Mburu, Joy, and Isaac Odame. 2019. “Sickle Cell Disease: Reducing the Global Disease Burden.” International Journal of Laboratory Hematology 41 Suppl 1: 82–88. https://doi.org/10.1111/ijlh.13023.
2. Kuznik, Andreas, Abdulrazaq G Habib, Deogratias Munube, and Mohammed Lamorde. 2016. “Newborn Screening and Prophylactic Interventions for Sickle Cell Disease in 47 Countries in Sub-Saharan Africa: A Cost-Effectiveness Analysis.” BMC Health Services Research 16: 304. https://doi.org/10.1186/s12913-016-1572-6.
3. McGann, Patrick T, Léon Tshilolo, Brigida Santos, George A Tomlinson, Susan Stuber, Teresa Latham, Banu Aygun, et al. 2016. “Hydroxyurea Therapy for Children with Sickle Cell Anemia in Sub-Saharan Africa: Rationale and Design of the REACH Trial.” Pediatric Blood & Cancer 63 (1): 98–104. https://doi.org/10.1002/pbc.25705.
4. Zhou, Albert E, and Mark A Travassos. 2022. “Bringing Sickle-Cell Treatments to Children in Sub-Saharan Africa.” The New England Journal of Medicine 387 (6): 488–91. https://doi.org/10.1056/NEJMp2201763.
5. Le Page, Michael. 2023. “Sickle Cell CRISPR ‘Cure’ Is the Start of a Revolution in Medicine.” New Scientist 260 (3466): 16. https://doi.org/10.1016/S0262-4079(23)02182-6.
6. Shyr, David C, Robert Lowsky, Weston Miller, Mark A. Schroeder, Tonia Buchholz, Kirstin Dougall, Allison Intondi, et al. 2023. “One Year Follow-up on the First Patient Treated with Nula-Cel: An Autologous CRISPR/Cas9 Gene Corrected CD34+ Cell Product to Treat Sickle Cell Disease.” Blood 142: 5000. https://doi.org/10.1182/blood-2023-188963.
7. Vida  Ebrahimi, and Atieh Hashemi. 2021. “The Fabulous Impact of CRISPR Method in Sickle Cell Disease Treatment.” Trends in Peptide and Protein Sciences 6: 1–8. https://doi.org/10.22037/tpps.v6i.34202.
8. Anitra Persaud, Stacy Desine, Katherine Blizinsky, and Vence L. Bonham. 2018. “A CRISPR Focus on Attitudes and Beliefs toward Somatic Genome Editing from Stakeholders within the Sickle Cell Disease Community.” Genetics in Medicine. https://doi.org/10.1038/s41436-018-0409-6.
9. Camille Castelyn. 2021. “Shifting Perceptions of CRISPR.” Voices in Bioethics 7. https://doi.org/10.52214/vib.v7i.8595.

  To do list

• Write down project goals and the scope
• What is not the scope of the project
• Go through the sources/evidences
• Decide which tool to use for my research-Considering storymaps/wordpress
• The order of pages on the website-will decide over time
• Have a glossary for the vocabulary-to be continually updated
• Find images – only got one
• Find other sources
• Find more information about the available treatments

Research Goals:

1. Creating awareness of the Sickle Cell Diseases/Symptoms and available treatments and *accessibility in Sub Saharan Africa.
2. The reason why sickle cell is prevalent in Sub Saharan Africa-(SSA)
3. Create awareness of the new treatment CRISPR by focusing on the pros and cons of the treatment and the concerns about the gene editing technique
4. How CRISPR is administered
5. How to decrease the burden of Sickle Cell Diseases
6. Compare the economic data from the SSA countries with projected CRISPR prices to determine accessibility-average household income and the cost of the treatment.
7. CRISPR is a cure while the available treatment -difference is that CRISPR is a cure

Question I’m trying to answer/The scope of my topic

If CRISPR  is fruitful, then can it be made available to the demographic that mostly needs it i.e the demographic in SSA

Research topic(up for consideration):

The efficacy of CRISPR in treating SCD and the feasibility of its accessibility by patients in SSA

Not in scope:

1. Sickle Cell Diseases prevalence in other parts of the world
2. How the available treatments are administered- as this may detract from the main focus of the research which is CRISPR
3. The timeline of CRISPR 
4. The Science behind Sickle Cell-try to keep the content simple for easier understanding

Background

Sickle Disease

• Sickle cell disease (SCD) is a hereditary disorder of hemoglobin (Hb) characterized by inheritance of two abnormal Hb genes, at least one of which is responsible for the production of HbS is the gene that is responsible for sickle cell diseases.
• SCD is as a result of a point mutation in the gene of an individual
• The sickling of red blood cells  damages its membrane and causes them to become dehydrated and more rigid than normal. Furthermore, these cells tend to become abnormally adherent to the endothelial lining of blood vessels.
• It has been universally invisible because of the lack of awareness about the disease among the local health policy makers and the public that is mostly affected by SCD
• The most common is sickle cell anemia-resulting from homozygous Hb-SS
• SCD is most prevalent in Sub-Saharan Africa(SSA)-the region in Africa below the Sahara Desert
• SSA has 47 countries some with a higher prevalence of SCD than others
• Fun fact! Sickle cell Disease was first discovered by Dr. James  Herrick

Symptoms of SCD

1. Hypercoagulability-high thrombin generation,platelet activation
2. Vaso-occlusion- due to hypercoagulability
3. Increased susceptibility to invasive pneumococcal infections
4. Acute chest syndrome
5. Stroke
6. Splenic sequestration-when sickle red blood cells block the blood vessels in the spleen causing it to swell and become painful.
7. Priapism- a condition of prolonged erection for males of all ages

Timeline for SCD

(the source of the dates os from the internet-hope to get a journal with better chronology)

• 1910: James B. Herrick first described SCD in Western medical literature in an article about a West Indian student with unusual red blood cells. 
• Verne Mason, a medical resident at Johns Hopkins Hospital, named the disease sickle cell anemia in 1922.
• 1956: The SCD gene mutation was discovered.
• 1960s: Blood transfusions began to be used as a treatment for SCD.
• 1972: Federal programs for SCD were established.
• 1995: A study published in The New England Journal of Medicine showed that the anticancer drug hydroxyurea could reduce the painful complications of SCD. The FDA approved hydroxyurea for treating adults with SCD in 1998.
• 1997: Periodic blood transfusions were shown to reduce the risk of stroke by 90% in children with SCD who are at risk for stroke.
• 2012: Researchers showed that bone marrow transplants could cure some SCD patients. However, bone marrow transplants have challenges, such as donor availability and potential complications.
• 2017–2021: Additional medications were approved to treat SCD, including L-glutamine, crizanlizumab, and voxelotor.
• 2019: Gene-editing therapy was first used to treat SCD.
• December 2023: The FDA approved two new genetic therapies to treat SCD

Available Treatments

The available treatments for sickle cell manage the symptoms of  sickle cell diseases but they are not cures.

The available treatments increase the lifespan of individuals suffering 

Glossary:

SCD-sickle Cell Diseases

CRISPR-Clustered Regularly Interspaced  Short Palindromic Repeats – a gene editing technique for treating sickle cell

Allele-alternative form of a gene

Polymerization

Homozygous

Heterozygous

Hb-hemoglobin

SCD-sickle cell diseases

I am interested in the Digital Scholarship Student Research Fellowship because being part of this Fellowship provides ample opportunities to interact with students from diverse academic backgrounds on a more personal level and the opportunity to explore topics of mutual and eclectic interest in the presence of cross-disciplinary perspectives. Interacting with other students during the Fellowship will enable me to improve my communication skills, learn new skills from my teammates, improve my creativity, and develop a sense of accountability. Interacting with fellow scholars from different disciplines will strengthen my social skills. Working collaboratively with peer scholars will help me accomplish my research and group goals more quickly than working individually. The first week has been splendid as my interactions with other fellows and the fellowship coordinators have encompassed cheerful banter to informative sessions that have left me expectant and anticipating our meetings.

My project is on Clustered, Regularly Interspaced Short Palindromic Repeats, abbreviated CRISPR. It is a gene editing technique that has revolutionized the field of medicine. I will begin by describing what sickle cell disease entails, its symptoms, and its effects on individuals, families, and friends, followed by a vivid description of CRISPR, how the treatment is administered, and the statistics of its success. The project focuses on the pros, cons, and ethical concerns about gene editing. This project is dear to my heart as in my country, Kenya, many children die young and do not get to reach adulthood as they succumb to the adverse symptoms of this disease. CRISPR technology provides a cure for these children, giving them a fighting chance and an opportunity to grow into adults. CRISPR is, however, very expensive because it is a gene therapy technique that makes it impossible for most sickle cell patients to afford it, and the majority are in the dark about a potential cure for sickle cell. As a fellow, I  will have ample time to delve into the research of how CRISPR  will be made available to the public and its downside, thus the efficacy of CRISPR in treating Sickle Cell Diseases and whether it is feasible for this treatment to be made available to the demographic that mainly needs it, is among the main focuses of the project.

I have learned how to write and post a weekly blog in WordPress. I hope to learn how to narrow my research topic to the scope of questions that I need to answer about my research topic. I look forward to learning about mapping tools, timelines, tableau, and project management tools.