Xplaining X-Inactivation: How this untapped genetic landmine could lead to a cure for cancer
Hand holding DNA.
Have you ever thought that the human body could be the best doctor in the world? No scientist, pharmacist, or doctor could think some of the cures that the human body prescribes itself on a daily basis. The microscopic processes going on in your body as you read this are some of the most complex and sophisticated regulatory measures that exist in the world.
One process in particular, called X inactivation, involves the silencing of an entire X chromosome in a female cell. Since females have two X chromosomes and males have only one, the human body silences one X chromosome in females to make the genes equal between the sexes. How does the body achieve such a massive feat? The answer is epigenetics.
Epigenetics, the process of changing DNA’s physical shape and not its genetic information, is the main mechanism by which these X chromosomes are silenced. By changing the shape of DNA through proteins and chemicals, the human body’s genetic “on/off” switch is triggered. By adding chemicals to DNA, certain genes, such as cancerous ones, are turned off and cancer is never initiated. Conversely, chemicals can be added to turn on certain genes, such as cancer-killing genes, which enables the body to kill cancer cells after they have developed. If scientists harnessed this mechanism and created drugs that added chemicals to DNA, many illnesses would be nipped in the bud and a cure for cancer could possibly be in mainstream healthcare in the near future.
X inactivation occurs by the same processes of epigenetics: DNA modification. Put simply, the body takes chemicals that you consume through activities such as eating, drinking, or smoking and adds it to your DNA. Depending on how coiled up or spread out your DNA is, your genes will be more or less expressed. We want good genes to be more expressed and bad or mutated genes to be less expressed. An X chromosome is silenced by making it as coiled up as possible, rendering it practically useless.
DNA with various modifications.
X inactivation has inspired many scientists to study epigenetics in other contexts. Researchers have examined the mechanisms of the human body’s ability to inactivate an entire chromosome and are seeking to synthetically mimic that in pharmaceutical drugs.
Epigenetics is the human body’s way of editing your genes if things go awry. The best thing about it is that it is reversible. This key factor, as well as its versatility, is what makes epigenetic drugs, or epidrugs, the perfect medicine for serious illnesses and cancer. Epidrugs can add chemicals to your DNA and be reversed by other epidrugs that remove chemicals from your DNA.
Epidrug clinical trials are currently still in their elementary stages. Scientists have yet to figure out the correct dosage and delivery of epidrugs in regards to cancer and other serious diseases. According to medical journal Breast Cancer Research, epidrugs against breast cancer are in phase I and II trials, but are proving to be only mildly effective against reducing tumors. When used in combination with other drugs, however, the tumors were significantly reduced. 3% of patients responded to epidrugs alone, whereas 20% of patients responded to epidrugs used along with other chemotherapies. The good news is that Phase II trials are exploring ways to make epidrugs effective on their own. Scientists are studying how to make epidrugs more specific to each disease. Medical journal Cancer Management and Research reports that the International Human Epigenome Consortium (IHEC) is making an effort to sequence thousands of genomes that contain cancerous mutations. The information that the IHEC gains through mapping out as many variations in the human genome as possible contributes to the ability to make epidrugs as specific to its target as possible.
Examples of drugs that have shown success rates are Vidaza and Zebularine, as reported by scientific journal Genetics and Epigenetics. Both epidrugs use the same mechanism, in which the drug edits the DNA and turns on a certain gene. These drugs turn on genes that cause cell death, so it becomes useful in killing rapidly dividing cancer cells. The more this cancer-killing gene is expressed, the more likely it will stop cancer from spreading. Vidaza has been FDA-approved and is injected into the patient by needle. Zebularine, however, is not FDA-approved yet and is taken by mouth, which makes it the first epidrug of its kind that is administered orally. Zebularine is just one example of the many epidrugs that can lead to effective anticancer drugs in the future.
More money needs to be placed in the research of epidrugs. There are only 6 FDA-approved epidrugs, many of which have low efficacy due to their limited funding. By allotting more money into projects such as the IHEC’s efforts to sequence genomes, we can learn more about epigenetics. By studying more biological phenomena like X inactivation, scientists can add to their knowledge of epigenetics and create effective drugs that imitate the human body’s internal processes. Also, more specialized research studies need to be done on humans with varying illnesses to see the results of epidrugs in a broad range of diseases. If epidrugs are given more research and funding, then a more advance version of Zebularine can be produced and cancer could quite possibly be cured by a single pill. The future of medicine depends on unique and innovative treatments, most of which reside within the human body itself.
By: R. Ammanamanchi
Dueñas-González, Alfonso, et al. “Introduction of Epigenetic Targets in Drug Discovery and Current Status of Epi-Drugs and Epi-Probes.” Epi-Informatics, Academic Press, 25 Mar. 2016, www.sciencedirect.com/science/article/pii/B9780128028087000010.
Falahi, Fahimeh, et al. “Current and Upcoming Approaches to Exploit the Reversibility of Epigenetic Mutations in Breast Cancer.” Breast Cancer Research : BCR, BioMed Central, 29 July 2014, www.ncbi.nlm.nih.gov/pmc/articles/PMC4303227/.
Heerboth, Sarah, et al. “Use of Epigenetic Drugs in Disease: an Overview.” Genetics & Epigenetics, Libertas Academica, 27 May 2014, www.ncbi.nlm.nih.gov/pmc/articles/PMC4251063/.
Roberti, A., Valdes, A.F., Torrecillas, R. et al. Epigenetics in cancer therapy and nanomedicine. Clin Epigenet 11, 81 (2019). https://doi.org/10.1186/s13148-019-0675-4
Valdespino, Victor, and Patricia M Valdespino. “Potential of Epigenetic Therapies in the Management of Solid Tumors.” Cancer Management and Research, Dove Medical Press, 31 July 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4529253/.
- “Hand Holding DNA.” What Is Epigenetics?, 30 July 2018, https://www.whatisepigenetics.com/what-is-epigenetics/.
- “Methylated DNA .” Flickr, Flickr, 23 Aug. 2010, https://www.flickr.com/photos/ajc1/4920090582/in/photolist-8uLKvY-bk42PS-a3Xwxb-2eknUHg-nm7TGS-rzwAKk-oQpGgT-5o66kM-e6dK6V-UWdG1b-WaausU-7LzR9U-W23J6x-WaatbA-VCnAxA-UWfsFS-UZ6gbX-Bm9RGd-WaaqHQ-VCnyYy-TDkF8n-5gYb7X-Mtsp4n-VCnytA-VCp6FU-UZ6eRH-WdxMjB-UZ6e2B-VXGchs-gHkeCk-7LzR3S-xaFrRz-d1w1a9-gnZ1gz-uHzsug-nGH9aZ-dvTywo-nGYqfY-qzx5W1-eEPXa7-nEXpWs-mpgEMX-nqvuiT-nC3V6Q-7YW1A9-2in23So-hmingS-bzZ5sm-qWinea-YxsCUg.