The problem I have researched that biologists have had success in curing is X-Linked Severe Combined Immunodeficiency, a recessively inherited disease caused by a mutation of the gene IL2RG which primarily affects the immune system. The problem is that children with the disease who are not treated in a prompt manner fail to survive past their first birthday due to the infections and other diseases which they are essentially defenceless to. The gene IL2RG codes for the common gamma chain protein, and its mutation is caused by large deletions in the chain, which result in a lack of white blood cells known as lymphocytes. All 3 lymphocytes are vital in protecting the body from infections. The B cells make antibodies, whilst the T-cells direct the B cells to create antibodies against foreign cells. The natural killer cells destroy infected and cancerous cells. Children with the disease have absent, defective or low levels of T Lymphocytes, which cause them to have non-functioning B-cells (1). Natural killer cells are usually not present. X-Linked SCID only affects males, however females can be silent carriers but will not be affected by the disease as their second X chromosome compensates and is dominant over the defected chromosome. Contrarily, if a male inherits the defected X chromosome they will be affected by the disease. X-Linked SCID is the most common case of SCID and is estimated to be present in around 45% of all SCID cases (2).
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The pie chart (3) shows the relative frequencies of the various types of SCID found in 174 consecutive human cases evaluated at Duke University Medical Centre over the past 3 decades. It shows that X-Linked SCID is the most common case with 46% of the cases being X-Linked.
The symptoms of SCID are very recognisable as children are likely to suffer infections in very early life before they are 3 months old. The infections are usually followed by pneumonitis where lung inflammation occurs and common symptoms become present such as coughing, shortness of breath and fever. Common features such as rashes, diarrhoea, congestion, pneumonia, sepsis, meningitis along with bloodstream infections and other severe bacterial infections are likely to occur in children with SCID. Infants rarely have tonsils, have undetectable peripheral nymph nodes and a small thymus gland.
The disease can be diagnosed most simply through observation of the immune system. Lymphocyte counts in children with X-SCID are usually observed and found to be much lower than that of a typical child of the same age who would be likely to have large amounts of lymphocytes. Small amounts of T-cells are usually observed, along with non-functional B cells and no absent natural killer cells. Along with counting the lymphocytes, tests to see the function of a child's lymphocytes can be used to identify X-SCID. The antibody responses of the B-cells are absent when vaccines or infections are introduced, whilst the usual T-cell response to the chemical substance mitogen is deficient in children with the disease (4). Mitogen is a chemical substance that stimulates cell division and causes mitosis, and the chemical helps to stimulate the transformation of lymphocytes. In addition to this, immunoglobulin levels will be identified as below average in a child with X-SCID. Immunoglobulin (better known as antibodies) are gamma globulin proteins found in the blood or other body fluids that are essential to the immune system, their function being the identification and neutralization of foreign objects such as viruses and bacteria. Without them, children with X-SCID are at risk to fatal infections. The Thymic Shadow usually present in chest X-rays is also a process of seeing if a child has X-SCID as it is usually absent in those with the disease. Genetic testing would be another method of diagnosis by looking for carriers in an X-SCID pedigree. If the Mother is a heterozygous carrier, there would be a 50% chance of transmitting the mutation which causes the tragic disease. Biologists have been trying to find a cure for X-SCID and have been successful with certain methods, which could essentially decrease the mortality rate of children with X-SCID.
Main Solution - Stem Cell treatment (Bone Marrow Transplantation)
A Bone Marrow Transplant (BMT) is the main solution to curing and treating X-Linked Severe Combined Immunodeficiency, and hopes to help children with SCID acquire immune reconstitution. The stem cells that are present in healthy bone marrow are multipotent, thus meaning they can give rise to a few different cells. The treatment is an allogeneic process, which means the stems cells are gathered from a donor rather than the patient. In the case of X-SCID the absent necessity of the type of white blood cells known as lymphocytes are hoped to become present and functioning. The transplant needs to be carried out promptly after birth, as earlier transplants have proven to be much more successful due to the fact that they are much less likely to have had severe infections or the failure to thrive in comparison to an older child with X-SCID who is likely to have had numerous infections.
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BMT is usually performed with the use of "HLA-matched bone marrow from a relative or haploidentical parental bone marrow depleted of mature T cells" (5). The term "haploid" means half the genetic information, I other words, children receiving transplants are likely to receive bone marrow that contains genetic information that is half identical to that of their parents. Children with X-SCID can receive BMT even if there is no suitable donor, providing that the bone marrow is first depleted of its mature T-cells. This is important as failure to do this will result in a reaction in the child due to mismatched T-cells, which would consequently cause Graft-versus-host disease (GVHD). GVHD is a common complication in Bone Marrow Transplants and is caused by the functional immune cells of the transplanted marrow recognising the recipient of the transplant as foreign which causes them to immunologically attack. Younger infants are less likely to suffer frequent post-transplant infections, along with a minor degree of GVHD and a more rapid engraftment.
The aim of the BMT is to create the ability for a child with X-SCID to develop their own T and B cells. This would result in a child with X-SCID having the ability of their stem cells dividing to create pre-B lymphocytes in the red bone marrow eventually forming into B cells. Likewise, their pre-T lymphocytes would develop in both the red bone marrow and also migrate to the thymus until they are fully developed (6). Once their T-cell and B-cell lymphocytes are fully developed, they circulate to the lymph nodes and spleen, as shown in the diagram on the next page (7).
The diagram shows how the B and T lymphocytes develop in the bone marrow and also the thymus for the T-cells, along with illustrating their circulation of the spleen and lymph nodes and their deaths. The process of creating sufficient amounts of lymphocytes is the expected and hoped for results after a child has received a bone marrow transplant.
Bone marrow is usually removed from the hip bone (iliac crest) of the donor and then filtered, treated and transplanted immediately, although it is sometimes frozen and kept for later use.
The diagram (8) shows how the bone marrow is transfused into the patient intravenously through the use of an IV line. The new bone marrow transports itself to the intended bone cavities, where it is hoped that it will grow rapidly to replace the old bone marrow.
Bone marrow transplantation is by far the most ideal method to treat children with X linked Severe Combined Immunodeficiency. The procedure has high success rates, and therefore it is arguably an appropriate approach to curing the devastating cellular and humoral disease. The treatment can solve the issue of children dying young due to their deficiency of their immune systems, as the treatment restores their deficit of lymphocytes and allows them to live normal lives without bearing the plight of suffering back-to-back infections which consequently kill them. The treatment has proven that it can cure sufferers of X-SCID and provide them with the ability to independently produce functional B and T cell lymphocytes along with sufficient Natural killer cells to create a sufficient immune system.
There is evidence for the success of BMT from a study into the survival rate of infants given a transplant in a neonatal period within the first 28 days of life. The study was made at the Duke University Medical Centre and the children with various types of SCID were able to receive a BMT early in life due to early diagnosis (nine in the uterus and twelve at birth) made available because of family history with the disease. The graph (9) shows the extent of success within the 21 infants with SCID. The percentage of survival was 95% for those receiving stem cell transplants in the first 28 days of life. Only one patient died at 4 months due to CMV encephalitis, despite the successful engraftment. The others survive at varying ages, and have developed normally with little limitations in life. This corroborates with the suggestion that "bone marrow transplants, which replace the defective stem cells with healthy donor cells have proven effective in treating some cases of SCID" (10).
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Although the graph shows the success rate of children being cured of cases with SCID, it must be remembered that the patients in this study were diagnosed in a neonatal period within the first 28 days of life. The success rate for children with cases of SCID receiving a BMT after the neonatal period, although still relatively high, proved to be less successful than children given treatment in early life. The study's results concluded that SCID children given treatment before 28 days of life had a 95% surviving rate, with the patients surviving ranging from the relatively short time of 8 months to the amazing 19.2 years after the transplantation. In comparison, the success for those given treatment after the neonatal period was not as high, with a 76% survival rate of 96 patients receiving a transplant after 28 days of life (9).
This is clearly a limitation of the solution, as diagnosis for the disease usually occurs in later life and by then SCID children would most likely have suffered recurrent infections and had failure to thrive, limiting their chances of a successful BMT. In addition to this limitation, there are further limitations, such as the risk of graft-versus-host disease, which occurs because of mismatching T-cells as previously mentioned. A major limitation of the BMT treatment is the fact that quite often, even in early transplantations; the B-cells functioning are still not improved. Consequently, there is a failure to produce sufficient antibodies to protect the body from recurrent infections. This results in the need for the majority of X-SCID patients to receive long term periodic (usually monthly) administration of immunoglobulin/gamma globulin. "Temporary immunity can be imparted to children with SCID by injecting them with a preparation of antibodies (gamma globulin)" (10).
Implications of stem cell treatment for children with X-SCID
There are various implications of bone marrow transplants which stress both the positive and the negative impacts of the treatment. Economic implications are present in the treatment, as the procedure will be costly for either the patient or the economy. The treatment will be very expensive to a patient without health insurance of some kind, and therefore many people will not be able to afford the treatment for their child to have a bone marrow transplant which could possibly save their life. Another implication which supports the treatment is the ethical framework of maximising the amount of good in the world. The approach is known as utilitarianism, and using this framework in association with BMT suggests that the treatment should be used, as it presents the opportunity for their to be less suffering and the chance to live for children with X-SCID, which as a result creates a greater amount of good in the world.
Benefits/advantages of treatment for children with X-SCID
The solutions that biologists are using are beneficial to children that are affected by X-SCID, and they set out to either cure the disease or prevent X-SCID children from suffering persistent infections. The solutions prove to be advantageous to sufferers of the disease as when successful it gives them sufficient amounts of lymphocytes which give them a functional immune system of which they previously were deficient of. This gifts children with X-SCID the ability to life with hopefully no side effects or problems. It also benefits the economy as although it costs money to carry out the treatment, it allows children to grow up healthfully and work in jobs which in turn beneficially contribute back to the economy.
Risks/Disadvantages of stem cell treatment for children with X-SCID
The risks of BMT involve the side-effect of graft-versus-host disease (GVHD). This happens when T-cells of both bone marrows are mismatched causing the functioning cells of the donor's marrow to attack the recipient's marrow due to recognition of them being foreign. This is a disadvantage of the solution as it slows down the engraftment process or causes it to be unsuccessful, which can result in the disease being uncured. Another disadvantage of the main solution is that it can prove to be unsuccessful in creating sufficient B-cell lymphocytes which create antibodies to protect the body, which means the immune system will still be deficient of vital and necessary defence lymphocytes. This results in the need for regular immunoglobulin administration, which is a disadvantage of the solution as it means it is not fully cured and there is also a reliance on medicine to keep the patient protected from infection. In addition to this, the medicine will be economically disadvantageous as it will cost money to produce and transact it into the patient.
An alternate solution for treating X-SCID could be gene therapy. Gene therapy has had some success in curing infants of SCID conditions and it is still being worked on currently, so it is very much a futuristic approach which biologists are optimistic about. The success has been achieved by using autologous stem cells from the bone marrow and inserting it as a retrovirus with a therapeutic gene, which replaces the mutant allele. This has succeeded in rebuilding the faulty immune system of children with X-SCID. This treatment is seen a purely a secondary treatment for patients that have had unsuccessful bone marrow transplants. The treatment is autologous, which means the stem cells have been extracted from the patient and genetically changed before re-inserting it. This contrasts the main solution where the stem cells are gathered from a donor, therefore making it allogeneic (11). "The aspirated bone marrow had been enriched for CD34+ cells, activated with cytokines, and exposed repeatedly to a supernatant containing high-titers of IL2RG retroviral vector, before re-infusion into the patients" (12). The source describes the process of how the therapy is carried out before the retrovirus is infused back into the patient.
The source above (13) shows the strategies for delivering therapeutic genes into patients through a retrovirus.
Gene therapy could be more successful if coupled with pre-natal testing of embryos that are suspected to have a chance of inheriting X-SCID due to a pedigree of the disease in the family. Amniocentesis or Chorionic Villus Sampling would succeed in giving reliable results to identify the mutant IL2RG gene, and allow time for preparation of gene therapy in the early stages of life before they have encountered infections which lower their chances of success. The same process would increase the chances of a successful BMT. In addition to this, pre-natal testing in the future would allow children diagnosed with the disease in the embryo to receive germ-line therapy, which involves repairing the mutant allele before the child is born. However, germ-line therapy is unlikely to become available because of its ethical issues as the embryo has no choice in the matter and the therapy could lead to the ability to change the characteristics of people before they are born, which is commonly known from the phrase "designer-baby".
Despite gene therapy's large success and its appeal as an adequate solution to the problem, there have been links with the therapy causing cured children with X-SCID to develop cases of leukaemia after treatment, making it a disfavoured treatment to the BMT. Therefore, gene therapy is still a futuristic treatment and is currently undergoing trials now.
Another possible treatment to the problem would be regular transactions of immunoglobulin/gamma globulin on a regular basis from birth. The gamma globulin proteins found in the blood can be administered to the patient intravenously. The treatment is known as Intravenous Immunoglobulin (IVIG), and would need to be administered to the patient every 2-3 weeks. The treatment would increase the antibody levels of the patient and restore parts of their immune system, giving them protection from infections. However, this treatment would not be considered as a primary treatment of X-SCID, and it would usually be used to supplement and assist the immune reconstruction from either a bone marrow transplant or gene therapy, or as a temporary protection whilst searching for a suitable donor for BMT or preparation of gene therapy. This is because the immunoglobulin would not fully protect patients from infections and would not create a fully functioning immune system.
Reference 6 and 10 are both derived from the same source. It is a non-web based source called "Anatomy and Physiology" 5th Edition Mosby. The authors are Gary A. Thibodeau and Kevin T. Patton, two people who are experienced in the topics they teach and professors in differing biological topics. It is unlikely that the source contains any bias towards the matter, as its purpose is to give accurate information about anatomy and physiology. As the writers are both professors in medical areas it is likely that they would be accurate about the topics included in the book, and they have no particular reason to be bias as they aren't trying to advertise the treatments that are discussed within the texts for their own profit. It is highly likely the source is reliable, as the book lists many references and contributors, proving that information was gathered from a wide range of areas. It is fair to assume that the information included within the book would be found elsewhere in other sources. The text lists many reviewers of the book who have checked it before it was published, and they are likely to be experts in their chosen areas of study as each reviewer is named and associated with their teaching position in areas of studies such as universities and colleges across the world. This makes the text highly accurate and valid as it has been peer reviewed by many people from universities and colleges related to the topics included to check that the information produced is accurate.
Source 5 is used in the report as a quote which helps to describe the method of the main solution. The authors are Joie Davis and Jennifer M Puck, and they are both involved in the National Human Genome Research Institute. This means they are likely to be experts in the topics they are informing of in the source, so the source is likely to contain reliable and valid information. The source is also extremely likely to be reliable as it contains references of numerous literature pieces which have been studied to produce the information. Numerous references mean that the information is from a wide range of areas and viewpoints which makes the source even more reliable. At first glance it is arguable that the information may be invalid, as it is not a recent report, so its information may be dated and consequently incorrect. However, the source has been revised since its original submission date of April 2003 in December 2005, which means it is relatively up to date with its information. The information was developed by the University of Washington in Seattle, so therefore the details provided in the source are likely to be accurate and reliable due to the fact the information is produced from an area of academic excellence. The source does not state if it has been peer-reviewed to ensure accuracy, however, it is likely it has checked as it is of a scientific origin and it is probable that the University has checked it.