When Aunt Flo Brings Extra Baggage: The Menstrual Cycle’s Link to Sickle Cell Flare-Ups

    A significant connection between the menstrual cycle and an increase in pain episodes in women with sickle cell disease (SCD) is clarified by new research from the University of Pennsylvania. The study, which was published in Blood Vessels, Thrombosis & Hemostasis, shows that in women with sickle cell disease (SCD), levels of C-reactive protein (CRP), a measure of inflammation, sharply increase during the follicular phase of the menstrual cycle. Painful vaso-occlusive events (VOEs) are more common in these individuals during this phase, which takes place in the early half of the cycle. ​

    The results imply that changes in hormones during the menstrual cycle worsen inflammation, which raises the risk of VOEs. This realization creates opportunities for focused interventions. Hormonal contraceptives that control or suppress menstruation, for example, may lessen these uncomfortable episodes. The authors of the study warn that larger, prospective research is required to confirm these results and investigate efficient management techniques.

    While previous studies have noted a temporal association between menstruation and VOEs, this research is pioneering in identifying a biological mechanism—elevated CRP levels—that may underpin this relationship .​

Sickle Cell Gene Therapy

 FDA approves two gene cell therapies to treat the disorder of sickle cell anemia. Of these two treatments, the gene-editing CRISPR technology is utilized. In this technology the patient's blood cell's DNA is permanently changed. The CRISPR technology will knock out a gene that triggers the defective blood cells, while medication will kill off the flawed cells. The second approved therapy is called Lyfgenia, which utilizes a common virus that delivers genetic modifications to the patient's blood stem cells in the bone marrow. These modifications cause the blood cells to start producing healthy blood cells. Both therapies involve stem cells being removed from a patient's blood for treatment. 

These new found treatments and technologies are a huge advancement in the medical world. Having these treatments available will helps many have the chance at a life without the pain of the disease. However, the concerns lie with the costs of these treatments. It is likely that these will not be affordable and very expensive. This would mean that many will not be able to receive this treatment and likely will still have to live with the pain from the disease. 

CRISPR Gene Therapy Approved

 CRISPR-Cas9 has been one of the most pivotal developments in 21st Century Genetics. To put it simply, CRISPR technology uses a "Guide RNA" to bind to a specific site of DNA. That RNA-DNA pair is then cleaved with an Endonuclease and a cut in the DNA chain is made. Selected/Desired genes can then be inserted into the cleaved portion of DNA allowing for novel protein expression. For agriculture this has been particularly well studied as it allows botanists to insert genes that make crops resistant to pathogens, tolerate droughts better, or grow uniquely colored/flavored products. The same pattern of applications have been used in animal agriculture, making many disease resistant breeds of fish, poultry, etc. 

A Red Blood Cell with Sickle Cell Anemia

In medicine, gene therapy is becoming one of the hot topics. Recently, CRISPR-Cas9 was approved by the FDA for human trials to treat Sickle Cell Anemia. Sickle Cell Anemia is caused by a genetic mutation that inhibits the formation of hemoglobin. By manipulating the genomes of those with sickle cell anemia, scientists could theoretically let those afflicted produce normal hemoglobin, and in turn be cured of their condition. 

A diagram on how CRISPR-Cas9 works

One worry I have is whether or not mutations associated with sickle cell anemia are pleiotropic. If they are there is a potential for patients to produce healthy hemoglobin but could potentially express other currently unknown problematic proteins. However, given the thoroughness of modern medical trials, this worry seems highly unlikely. 

Link to article here

Sickle Cell Gene Therapy May Cause Cancer Linked Mutations

 There are forms of gene therapy that has the potential to benefit patients with genetic blood disorders. There is a study on individuals in a trial for sickle cell disease that suggests  key process within giving out the treatment might cause mutation that turn blood stem cells cancerous. In a very recent study that was lead by the University of York reported that  six patients involved in treatment for sickle cell gene therapy had showed signs of mutations that are linked with the development of cancer. Scientists responsible for the study says that this case needs more of a long-term study so they can understand and determine how the cells continue to evolve. Sickle Cell disease is where an inherited disorder in which causes pathological changes to an individual's hemoglobin. This is where the disease causes red blood cells to harden and obtain the "sickle" shape and die. With this, gene therapy can alter an individual's genes in a certain way that corrects the mutation or makes they can express a different, healthy form of hemoglobin. 

    Researchers paired whole-genome sequencing with new methods to follow and compare the DNA of blood stem cells in patients before and also after they undergo their treatment. After the study they were able to find that there were numerous driver mutations that have been linked to blood cancer. The researchers also describe that the treatment itself is not causing the mutations, but they say it appears to come from one of the earlier parts of the process. As described in the beginning they would need to undergo further research and study and identify how the cells evolve like that. 

Links:

https://www.fiercebiotech.com/research/sickle-cell-gene-therapy-process-may-cause-cancer-linked-mutations-blood-stem-cells

https://www.hopkinsmedicine.org/health/conditions-and-diseases/sickle-cell-disease#:~:text=Sickle%20cell%20disease%20is%20an%20inherited%20blood%20disorder%20marked%20by,causing%20painful%20and%20damaging%20complications.

Sickle Cell Anemia Presence in Africa

    The inspiration of this article comes from a conversation I had today with a co-worker whose ancestry descends from Nigeria. We work in an emergency room together, our experiences today is what initiated this conversation. Sickle Cell Anemia (SCA) is a homozygous recessive trait that causes an abnormality amongst red blood cells, hemoglobin is the protein in your red blood cells that is responsible for carrying oxygen. Sickle cell anemia is common in places where malaria amongst mosquitoes is prominent, natural selection promotes family pedigree who are resistant to the malaria disease. In turn, if a person is immune malaria they unfortunately carry the sickle cell trait. This immune population can either be heterozygous or homozygous recessive. Being diagnosed with sickle cell anemia brings many potential health risks including sickle cell crisis, vaso-occlusion blood clots to digits in infants, the spleen, lungs, etc. If someone has sickle cell anemia, they are immune-compromised, if their body were to come in contact with common bacterias that cause pneumonia, or common colds, without proper medical attention these bacterias can yield fatal results. The first link of my article is a video that gives insight on the pathophysiology, potential health risks, and treatment methods of sickle cell anemia. I recommend giving it a watch, as it is quite fascinating. 

    Reflecting back on the conversation with my co-worker, she began to explain some methods countries in Africa and South-East Asia use to try to mitigate the presence of this brutal disease in their countries. In her home country, it has gotten to the point where churches will not conduct a marriage unless the genotype of the parents is confirmed. If the engaged couple runs the risk of producing offspring who can suffer from SCA, the church will not conduct the marriage. While some may regard this as unethical, the prevalence of sickle cell in their country is alarming. It is estimated about 150,000 children in Nigeria have SCA, and nearly 25% of the country are heterozygous carriers of the trait. Since there is no cure for the disease, the only way to lower these numbers is to try to prevent it from being passed on. This was a very interesting topic to me, if anyone has more insight on this please leave a comment as I would like to learn more. 

Link: https://www.youtube.com/watch?v=fIIJmg_1hv0

Link: https://bmcmedethics.biomedcentral.com/articles/10.1186/s12910-019-0376-8

Link: https://www.cdc.gov/ncbddd/sicklecell/data.html 

SIckle Cell Treatment Is Not Cancer Relted

 Sickle Cell Treatment Shows It Is Not Linked To Cancer

 

  An article named "Sickle Cell Treatment Not Linked to Cancer, Researchers Say" talks about how just after a few weeks of working on gene therapy researchers have already proven that it is not linked to cancer. Throughout this article in The New York Times, they also describe the treatment and study methods that they used.

    There was also a separate sickle cell trial held at Bostons Children's Hospital but it was soon shut down when Bluebird Bio stated that two cancers were found but they were being funded/ getting the study paid for by the National Institute of Health. The researchers in this study were asking the National Institute of Health to resume their work but they were not allowed to.

Article: Sickle Cell Treatment Not Linked to Cancer, Researchers Say - The New York Times (nytimes.com)

About Sickle Cell Treatment: ADAKVEO® (crizanlizumab-tmca) | Health Care Providers (novartis.com)

Promising treatment for sickle cell disease and beta-thalassemia

All over the world, people are affected, and doctors hope one treatment that promises to alter the DNA in blood cells can be the tool to help cure sickle cell diseases and beta-thalassemia. In addition to the alternation of the blood cells, they need the help of CRISPR. I believe it can help because with both sickle cell and beta-thalassemia, they have issues within the body that can be fixed by the treatment. With sickle cell, many have blood that clots up and causes a lack of blood flow and oxygen to the body. While beta-thalassemia has no normal hemoglobin, which causes suffering of breathing issues making the patients get transfusions every so often to help them. I believe if they find a way to have CRISPR and blood cells mixed correctly, it can help many people get better and have less pain.

https://abcnews.go.com/Health/wireStory/gene-editing-treatment-shows-promise-sickle-cell-disease-74558189

https://www.mayoclinic.org/diseases-conditions/sickle-cell-anemia/symptoms-causes/syc-20355876#:~:text=Sickle%20cell%20anemia%20is%20an,like%20sickles%20or%20crescent%20moons.

https://medlineplus.gov/genetics/condition/beta-thalassemia/#:~:text=Beta%20thalassemia%20is%20a%20blood,many%20parts%20of%20the%20body.

Sickle Cell Against Malaria

Sickle Cell is a recessive inherited trait caused by a mutation in the hemoglobin-beta gene on chromosome 11. The disease causes red blood cells, to be abnormal (crescent shaped). 

Normal and Sickle red blood cells

An article published by ScienceDirect notes that Sickle human hemoglobin (Hb) can actually protect against malaria. The article notes that people that are heterozygous for the sickle cell gene, show a survival advantage in areas where malaria is prevalent. The disease in fact does not prevent the host from developing the parasite, but makes it tolerant to it. Individuals with sickle cell accumulate cell free hb and heme (non-protein part of hb) in the plasma which induces the expression of heme oxygenase-1. This enzyme catalyzes heme into other molecules including carbon monoxide, which binds to sickle hb and prevents it from releasing more heme and hence the pathogenesis of experimental malaria. 

Specialists think that the mechanism involving sickle hb is similar to other genetic blood diseases that also seem to provide  a type of protection to the host. These findings provide a great advantage and open ways to new therapeutic inventions against malaria.

Early clinical trial data show gene therapy reversing sickle cell anemia

The Cincinnati Children's Cancer and Blood Diseases Institute has been researching and developing a new gene therapy to combat the horribly inherited disease, sickle-cell anemia. After finally being able to treat two patients, and now a year and six months after treatment, both patients are seeing "remarkable improvement in the quality of life due to remarkable reduction in disease symptoms."

This therapy developed in Cincinnati uses "modified gamma globin lentivirus vector to transfer healthy fetal hemoglobin (HbF) gene into a patient's blood stem cells." If sufficient amounts of HbF are present in the human body, the blood cells cannot "sickle" and therefore are able to properly transport oxygen through the blood. First, cells are collected from the sickle-cell patient and genetically modified with the lentivirus. Then after a low dose of chemotherapy to the patient's bone marrow, the newly corrected cells are placed back into the body. The goal of such gene therapy is to make it most accessible and affordable in Central Africa, where sickle-cell is rampant. However, some 90,000 people in the United States are still plagued with the disease.

As mentioned, the patients who received gene therapy have been experience a better life after their treatment. After only 15 and 12 months, patient one had only one acute sickle event and the second has had no issue with blood cells becoming stuck in the bloodstream. Cincinnati Children's hopes to be able to further their research and continue to treat more patients with less harmful treatments so the quality of life for genetically sickle-cell patients continues to improve.

The research done in Cincinnati seems to have been successful for the sickle-cell community. I am sure that those who suffer from or have family members that suffer from this horrible disease would be glad to see treatment option soon available, with little harm and to their health, and seemingly quick relief of past symptoms.
https://www.sciencedaily.com/releases/2018/12/181204095344.htm
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3139383/
https://www.cincinnatichildrens.org/service/c/cancer-blood/cancer

Genetic Treatments for Sickle Cell

        

     Sickle cell is a condition that causes life-threatening problems in childhood. The inheritance of just one copy of the mutation somehow protected people against a different threat to survival while having two copies is lethal. It was found that sickle cell is common for people who lived in areas where malaria is present. Children born with a single mutated hemoglobin gene does not cause major problems were somehow better able than their peers to fight off malaria and would survive to deliver the gene to their future children.

A molecule of hemoglobin is made up of four subunits: most commonly two identical proteins called alpha-globins and another pair of proteins known as beta-globins. Each of these subunits contains an iron-bearing structure which can grab on to or release a molecule of oxygen. Each hemoglobin can carry up to four oxygen molecules. Individuals who inherit a single sickle-cell mutation produce one defective and one normal beta-globin; those who inherit sickle-cell genes from both parents produce only defective beta-globins.

      The only known cure for sickle-cell disease is bone marrow transplantation to provide a new circulatory system. There is another situation during development in the womb.

A fetus has a distinct kind of hemoglobin that binds very tightly to oxygen, allowing it to compete successfully with its mother's hemoglobin for oxygen in the placenta. The production of this fetal hemoglobin usually drops off, decreasing the amount of oxygen found in red blood cells. In a child who inherits the sickle-cell flaw from each parent, cells usually start to sickle several months after birth.

https://www.scientificamerican.com/article/genetic-treatments-for-sickle-cell/

https://www.nhlbi.nih.gov/health/health-topics/topics/sca