Have you ever wondered why people look different from each other? Why do some people have blue eyes, have brown hair, or have a tall height? These physical traits are encoded in something called the genome, which carries information for our “body’s form and function” and makes us who we are (Gene, 2017).
Our genome is found inside every cell of the body and is like an instruction manual that decides almost everything that happens in the cell, ranging from controlling cell division to regulating how the cell behaves and any interactions with other cells or substances (Genes, 2021). A person’s genome is also inherited from their parents, with half from the mother and half from the father.
Our genome is made of DNA that contains information in the form of a long chain of nucleotides, and a gene is a segment of the genome. Genes are used as a template for creating mRNA during transcription, which is then read by ribosomes during translation to create an amino acid chain that folds into a protein. This is the central dogma of molecular biology, which essentially means the genes contain information that encodes for a protein. These proteins are what determines the cell’s function or behavior.
But, there could be mistakes in the instruction manual. A gene might mutate and change the sequence of nucleotides, due to things like UV light, radiation, or an error when replicating DNA. These mutations could be passed down from parents, or be developed when a person grows, and lead to defective or missing genes. These mutations could alter the amino acid chain produced and in turn, result in proteins becoming misfunctioning or possibly missing.
These proteins might be crucial for a cell, so a mutation could cause devastating consequences. For example, the P53 gene is widely known for being associated with cancer (The, 1998). This gene codes for a protein that regulates how often a cell replicates, but a mutation would result in this protein failing to function or being missing. So, the cell would grow uncontrollably and lead to cancer. Another example is cystic fibrosis, a fatal condition that damages the lungs (About, 2021). It is caused by misfunctioning or absent CFTR proteins due to mutations in the gene that codes for it (Basics, 2021).
A Solution
How could scientists resolve these problems with our genes? One method is gene therapy, which involves editing the genes in cells, like replacing misfunctioning genes with healthy ones or introducing new genes. This would restore functioning proteins or introduce new helpful proteins in the cell, which has a promising potential to treat diseases, like cancer and cystic fibrosis as mentioned, but also others like muscular dystrophy (Adminstrator, 2021).
Genes cannot just be injected into cells, but need to be carried into the nucleus by something called vectors (Gene, 2020). One common vector is a virus, like adenoviruses or retroviruses, as they have evolved to be very skillful in inserting their genome into the nucleus, so the virus can hijack the cell and replicate (How, 2020). The virus could be modified to remove all its disease-causing genes.
Then, the desired gene could be genetically edited into the genome of the virus with CRISPR, so after the virus genome enters the nucleus, the desired gene can be introduced and perform its function (How, 2020).
For some viruses like retroviruses, the desired gene can integrate with the cell’s genome, allowing it to replace broken genes and replicate along with the cell (How, 2020).
But, for other viruses like adenoviruses, the desired gene cannot integrate, so even though the protein encoded by the desired gene would be made, the gene would not be present in the cell’s offspring (How, 2020).
Sickle Cell Anemia
One of the very fascinating uses of gene therapy would be treating sickle cell anemia, a genetic hereditary disease due to a mutation in the HBB gene, which encodes for a protein that is part of hemoglobin (Walker, 2018). If a parent has sickle cell anemia, there is a chance for their children to also have it because the child might inherit the HBB mutation from their parents (About, 2020). If both parents have anemia, there is roughly a 25% chance that their children have the disease (About, 2020).
Hemoglobin is a crucial protein in Red Blood Cells that enables them to carry oxygen around the body, which is essential because oxygen is needed for all cells to function (About, 2020). Red Blood Cells with normal hemoglobin are “round and smooth”, able to move through blood vessels and carry oxygen effectively (About, 2020). But, for those with the HBB mutation, it would cause proteins made that form abnormal hemoglobin, which makes red blood cells have a “rod-like” sickle shape (About, 2020).
This shape causes the cells to carry oxygen less effectively and more likely to be destroyed in the body by the spleen, as this organ filters blood for pathogens but sickle cells could get stuck and die (Sickle, 2021). As such, oxygen cannot be carried effectively around the body, causing anemia and its symptoms like fatigue or weakness (Anemia, 2019). Moreover, the sickle cell shape more easily piles up together, potentially causing blockages that could damage organs and cause strokes (About, 2020). It also damages the filter in the spleen and increases the risk of infections (About, 2020).
Bone Marrow Transplants?
Clearly, sickle cell anemia is a devastating disease, but is there a cure? One solution could be bone marrow transplantation, as red blood cells are made in the bone marrow. Healthy bone marrow cells could be transplanted into the patient, so normal and healthy red blood cells would be created (About, 2020). Sadly, it is very rare and difficult for finding a matching donor, because many conditions need to be met to prevent rejection, like the cells needing to be genetically compatible with those in the patient (About, 2020).
If they are not, the immune system might attack the donor’s cells and cause major complications. Donors typically have a close genetic relationship with the patient, like siblings or parents, but even so, there is only a 18% chance that the donated cells work (About, 2020). The transplantation process is also very risky and physically demanding for both the donor and patient, so if the donor is unhealthy or unfit, the transplantation might fail.
A New Hope?
Fortunately, gene therapy offers a potential solution, as it can replace the defective HBB gene with a healthy one. After extracting stem cells in the bone marrow, which are cells that can both replicate and turn into red blood cells, from the patients, scientists can fix the HBB gene through virus vectors in a lab (CRISPR, 2021). Then, the edited stem cells with a normal HBB gene can be placed back into the bone marrow, where they can replicate and produce normal red blood cells (CRISPR, 2021).
The offspring of the stem cells would also have the normal HBB gene, so normal red blood cells would be produced throughout the patient’s lifetime (CRISPR, 2021). Essentially, the patient’s sickle cell anemia would be cured. Such trials have been conducted already on humans and improved dozens of lives (Davies, 2019).
For example, Evie Jones suffered from sickle cell anemia and could not live a normal life from it, like being unable to run (Tiare, 2020. He also had to remove his “spleen” due to the disease (Tiare, 2020). But, after gene therapy treatment, he was able to recover and live a more fulfilling life (Tiare, 2020).
There are many advantages to this kind of treatment. Primarily, because the bone marrow cells inserted are from the patient, there is no risk of genetic incompatibility and the immune system attacking those cells (About, 2020). Also, there is no need to find a matching donor, which allows this treatment to be used by far more patients than bone marrow transplants. Due to the many restrictions and challenges with transplantation, many suffering from sickle cell anemia could never have had a chance to be cured. But, with gene therapy already been proven successful and safe for this disease in numerous trials, gene therapy offers new hope for these patients.
Other than sickle cell anemia, gene therapy has the potential to also treat diseases that were deemed incurable, like the severe combined immunodeficiency syndrome or muscular dystrophy (Bloomberg, 2021), which gives a life-saving opportunity for patients to live a normal life.
But, there are many disadvantages and challenges with gene therapy. Even when disease-causing genes in viruses are being edited out, it is very difficult to edit out all the antigens or proteins on the surface of the virus. The body’s immune system could identify these foreign antigens and spark a strong immune response, causing inflammation, fever, and more (Challenges, 2021).
In severe cases, fatal problems like organ failure could occur as a result (Disorders, 2021). For example, in 1999, a patient testing gene therapy for a liver condition died from the unwanted immune response caused by the vector (Challenges, 2021). Even if this response is treated, the immune system could recognize the virus and kill it before it delivers the genes.
This would prevent repeating the treatment many times, which is a major problem because most forms of gene therapy require multiple doses (Gene, 2017). While there are possible solutions, like immunosuppressing drugs or choosing viruses that trigger the immune system less, they have many shortcomings like an increased risk of infection or less flexibility with genes (Challenges, 2021).
Apart from that, gene therapy involves a lot of testing and trials before it can be used to ensure that the treatment is safe and works. Some forms of gene therapy might also need to be tailored for a person so it to be effective (Chief, 2019). These aspects make gene therapy very costly, ranging from hundreds of thousands to millions of dollars (Chief, 2019).
For sickle cell anemia, gene therapy could cost around $600,000 (Gene, 2018). This would make the procedure inaccessible to most people. Also, the treatment only alters the cells in the bond marrow and not the germline, so the patient’s children might still have a chance of getting sickle cell anemia and need to pay the hefty fee for treatment. All these financial costs are a major burden for a family.
Moreover, there is no guarantee that it works perfectly all the time. There is a chance that the new gene does not replace the broken HBB gene, but an important gene like one that suppresses cancer (Gene, 2018). These unforeseen complications might take a long time to appear and would not appear in testing, so it is very difficult to avoid them (Gene, 2018).
Ethics
There are many more challenges with gene therapy, like a limited gene capacity in the virus that prevents using long genes, or many ethical considerations, especially if gene therapy is performed on the germline. It is can be justified to use gene therapy for severe and incurable genetic diseases, and avoid it for any sort of cosmetic enhancements.
Yet, there are many matters in between, like having poor skin due to genetics. Who draws the line that separates what gene therapy should and should not treat? If gene therapy is done on an embryo, the baby has no choice to refuse it. What if the baby does not consent to the treatment?
All in all, gene therapy is a very promising form of treatment that has immense potential in the field of medicine, like curing sickle cell anemia. But, there are still many hurdles that need to be overcome, like its costs, risks, and ethics. Hopefully, innovations in the future could solve these problems to make gene therapy a reliable solution that is accessible for everyone.
For more reading (if you are interested):
About Cystic Fibrosis. (n.d.). Retrieved January 17, 2021, from https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/
About Sickle Cell Disease. (2020b, May 26). Retrieved January 16, 2021, from https://www.genome.gov/Genetic-Disorders/Sickle-Cell-Disease
Administrator. (n.d.). Diseases Treated by Gene Therapy. Retrieved January 16, 2021, from http://www.genetherapynet.com/JoomlaTest2/index.php?option=com_content&view=article&id=164:diseases-treated-with-gene-therapy-&catid=97:patient-information&Itemid=14
Anemia — Symptoms and causes. (2019, August 16). Retrieved January 16, 2021, from https://www.mayoclinic.org/diseases-conditions/anemia/symptoms-causes/syc-20351360
Basics of the CFTR Protein. (n.d.). Retrieved January 17, 2021, from https://www.cff.org/Research/Research-Into-the-Disease/Restore-CFTR-Function/Basics-of-the-CFTR-Protein/
Bloomberg — Are you a robot? (n.d.). Retrieved January 17, 2021, from https://www.bloomberg.com/tosv2.html?vid=&uuid=4addde00-5859-11eb-96da-8f02d1bea331&url=L25ld3MvZmVhdHVyZXMvMjAxOS0wNi0wNS9nZW5lLXRoZXJhcHktYXBwZWFycy10by1iZS1iZWF0aW5nLW9uY2UtaW5jdXJhYmxlLWRpc2Vhc2Vz
Challenges In Gene Therapy. (n.d.). Retrieved January 17, 2021, from https://learn.genetics.utah.edu/content/genetherapy/challenges/
Chief, E. (2019, February 26). 14 Advantages and Disadvantages of Gene Therapy. Retrieved January 17, 2021, from https://connectusfund.org/14-advantages-and-disadvantages-of-gene-therapy
CRISPR gene therapy shows promise against blood diseases. (2020, December 8). Retrieved January 16, 2021, from https://www.nature.com/articles/d41586-020-03476-x
Davies, K. (2019, April 2). CRISPR and Beyond: Advances in Gene Therapy. Retrieved January 16, 2021, from https://www.genengnews.com/insights/crispr-a-powerful-lab-tool-and-a-boon-to-gene-therapy/
Disorders of the Immune System. (n.d.). Retrieved January 17, 2021, from https://www.hopkinsmedicine.org/health/conditions-and-diseases/disorders-of-the-immune-system
Gene therapy — Mayo Clinic. (2017, December 29). Retrieved January 16, 2021, from https://www.mayoclinic.org/tests-procedures/gene-therapy/about/pac-20384619
Gene Therapy Basics | ASGCT — American Society of Gene & Cell Therapy |. (2020, October 22). Retrieved January 16, 2021, from https://patienteducation.asgct.org/gene-therapy-101/gene-therapy-basics
Gene therapy targets sickle-cell disease. (2018, December 12). Retrieved January 17, 2021, from https://www.nature.com/articles/d41586-018-07646-w
Genes: Function, makeup, Human Genome Project, and research. (n.d.). Retrieved January 16, 2021, from https://www.medicalnewstoday.com/articles/120574
How does gene therapy work?: MedlinePlus Genetics. (2020, September 17). Retrieved January 16, 2021, from https://medlineplus.gov/genetics/understanding/therapy/procedures/
Sickle Cell Disease. (n.d.). Retrieved January 16, 2021, from https://www.hopkinsmedicine.org/health/conditions-and-diseases/sickle-cell-disease
The p53 tumor suppressor protein — Genes and Disease — NCBI Bookshelf. (1998, January 1). Retrieved January 17, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK22268/
Tiare. (2020, November 30). Gene therapy gives man with sickle cell disease the chance for a better future. Retrieved January 17, 2021, from https://newsroom.ucla.edu/releases/gene-therapy-sickle-cell-disease-better-future
Walker, M. (2018, January 15). Gene Therapy. Retrieved January 16, 2021, from https://sicklecellanemianews.com/gene-therapy/
