By Grace Aun, '23
Cancer is the second leading cause of death worldwide, killing 10 million people in 2021. There are 1.7 million diagnoses of cancer and 600,000 resulting deaths per year [1].
With cancer rates gradually increasing along with life expectancy, it is imperative more now than ever that we find a cure or a more effective, less strenuous treatment [2]. So why haven’t we already found a cure? We have already directed billions of dollars and decades of research towards cancer, yet we still don’t completely understand its complexity [3].
What is Cancer and How Does it Form?
Cancer isn’t a single disease. Instead, multiple types of cancer can develop in any tissue. Cancer forms unique subclones, which have different mutational profiles [4]. Every cancer starts from a mutation within a small set of your genes, which leads to uncontrolled cell division and invasion of other tissues and cells. Cancers usually originate from mutations of two genes, oncogenes, and tumor suppressors. Oncogenes start as regular genes, also known as proto-oncogenes. They code proteins that begin cell division, prevent cell differentiation, and regulate apoptosis (programmed cell death), contributing to the growth, development, and maintenance of organs and tissues [5]. A common oncogene is Ras; the Ras gene is mutated and turns into an oncogene, which changes the shape of the protein it creates. This modified protein gets permanently stuck in the “on” position to signal the cell to grow constantly. Since this protein has an altered shape, other proteins can’t recognize it and turn it off. This uncontrolled cell growth leads to the formation of a tumor.
Conversely, tumor suppressors, also known as anti-oncogenes, are supposed to stop cell division when conditions are preferable, fix DNA mistakes, and enact apoptosis. Cells in the body have two copies of the tumor suppressor if one is mutated. Usually, a tumor suppressor is mutated on one document and removed from its other composition. So, there’s no tumor suppressor left to control cell division. While oncogenes result from the turning on of proto-oncogenes, tumor suppressors cause tumors because they are turned off [6, 7].
It takes multiple mutations for a normal cell to become cancerous and cause the growth of a malignant tumor. Tumors aren’t always cancerous, as they are masses of mutated cells. Tumors fall into the two categories of benign vs. malignant. Benign tumors don’t spread or metastasize. If the Benign tumor is treated, it can grow large and lead to severe health complications. While they’re not as much of a threat as malignant tumors, they can still be very painful and dangerous [8, 9, 10]. Malignant tumors are cancerous, usually resistant to treatment, and reoccurring. Additionally, they grow quicker than benign tumors and are more likely to invade healthy tissues and organs. When one has a cancerous tumor, the bloodstream may spread cancer cells to other parts of the body, leading to new tumors.
Cancer cells communicate with each other and neighboring healthy cells in a tumor. These cells can prompt healthy cells to form blood vessels that feed the tumor with nutrients and oxygen, suppressing the immune system’s natural response to recognize or destroy the cancer. They can adapt their molecular and cellular characteristics to survive, and some can even turn on “shields” by changing their gene expression when shot with chemotherapy and radiation. Even when it seems like a tumor is completely gone, one cancer stem cell can initiate the growth of a new tumor.
Cancer Treatment Complexities
So how do we cure cancers when they’re highly complex, adaptive diseases? Producing a treatment is more intricate since it takes a series of mutations for a normal cell to become cancerous. While we do have chemotherapy and radiation treatments, they can take a significant toll on the body. Chemotherapy drugs circulate through the bloodstream, affecting the whole body. The drug targets cells in different cell cycle phases, thus regularly [12]. Examples of chemotherapy drugs include Alkylating Agents that damage the cell’s DNA; Antimetabolites that mimic RNA and DNA building blocks; and Antitumor Antibiotics that bind with DNA and impede the enzymes involved in making DNA copies.
Each chemotherapy drug prevents the cancer cells from reproducing [13]. Since chemotherapy can’t differentiate between cancer cells and healthy cells, healthy cells can also get damaged. When determining appropriate drug dosage, doctors must consider the timing of the cell cycle and make sure that they’re not killing too many normal cells while still effectively killing the cancerous ones.
Chemotherapy Side Effects
Chemotherapy can also result in many horrible side effects such as nausea, ulcers, mood changes, and hair loss [12]. Likewise, radiation can damage the DNA of normal cells. Usually, when talking about radiation for cancer treatments, people refer to Ionizing Radiation, which ionizes atoms. This radiation destroys the cancer cells’ DNA to the point where it’s unrecognizable and can’t reproduce. Doctors try to expose tiny healthy tissues and cells to the radiation and aim it directly at the tumor [6]. The side effects of the radiation depend on its type. It is directed at the body; some include swelling in the arm and leg, difficulty swallowing, and radiation fibrosis, which can cause permanent lung scars [14]. Overall, the main treatment methods for Cancer are risky and come with severe patient side effects.
Personalize Medicine: An Adaptive Treatment Plan
Thus, we need treatment plans that are as adaptive as cancers and more options to match the number of cancer varieties for personalized medicine. Personalized medicine can tailor treatment plans to a patient’s specific condition and genetic profile [15]. One example is CRISPR-Cas9, which stands for “Clustered Regularly-Interspaced Palindromic Repeats.” This technology was adapted from the bacteria’s immune system that protects them against bacteriophages. CRISPR consists of repeated palindromic nucleotide sequences separated by unique spacer DNA. These spacers match up with the bacteriophage DNA. The genes associated with CRISPR are known as cas genes and make cas proteins, usually helicases (proteins that unwind DNA) and nucleases (proteins that cut DNA). Once the virus attacks, the cas complex will transcribe and translate proteins and transcribe that DNA into crRNA (CRISPR RNA). If the virus injects DNA and does not have a matching spacer, the cas complex will create a class 1 cas protein. This protein will take in the viral DNA, destroy it, make a copy of it, and store it in the CRISPR system. Spacers within CRISPR essentially serve as a history of DNA from past viral attacks, which allow the bacteria to recognize and fight off these viruses in the future. Scientists thought they could alter this system and use it as a gene-editing tool. The CRISPR-Cas9 system was found in the labs of Jennifer Doudna and Emmanuelle Charpentier. They were working on the Streptococcus pyogenes and its Cas-CRISPR system. In this, it only had one cas protein-Cas9, which has a nuclease that can cut DNA and two long strips of RNA, the crRNA that fits into the cas, and tracrRNA (tracer RNA), which holds the crRNA in place. Scientists modified this system and turned it into one with two parts: the Cas9 protein and a new type of RNA, the trcrRNA-crRNA chimeric/gRNA (guide RNA). If we have a piece of DNA we want to cut, we can create a gRNA with a corresponding RNA piece. Once the gRNA matches up with the gene’s DNA, Cas9 cuts the DNA. This will leave us with an inactivated or broken gene. If we want to insert a new gene, the system will now have three parts, the Cas9, the gRNA, and the host RNA that we want to insert. When we break the DNA, a strand of host DNA will be added, and then the DNA will fix it and add another strand [16, 17].
Cancer researchers have used CRISPR to locate “specific targets” such as RNA from cancer cells and choose genes to target with drugs. Some concerning issues are that CRISPR may accidentally cut DNA that’s not on target and how to deliver CRISPR into someone’s body properly. CRISPR can be delivered through viral vectors. Viruses can naturally deliver genetic material into cells. Once their ability to infect disease is removed, they can be used as vectors to distribute CRISPR into cells. Certain viruses can infect multiple cells, so CRISPR would mean different editing cells than intended. Scientists are testing viruses that will only infect one organ and have created nanocapsules that are supposed to deliver CRISPR to other partitions. In the United States, one 2019 clinical trial that tested a CRISPR therapy for Cancer was partially successful. In one of the patients, their sarcoma (malignant tumor) stopped growing initially but then continued to develop later. While there were off-target edits and some side effects, these edits didn’t negatively affect the cells, and the side effects likely stemmed from prior chemotherapy [18].
The ongoing research on CRISPR therapy for Cancer and other incurable diseases is making immense progress! Ultimately, the goal of the tireless efforts to investigate CRISPR will be our ability to treat tumors and cancers in the future more effectively.
References
[1].Cancers. (2019). CDC. https://www.cdc.gov/chronicdisease/resources/publications/factsheets/cancer.htm
[2] Jones, G. (2015). Why are cancer rates increasing? Cancer Research UK - Science Blog. https://scienceblog.cancerresearchuk.org/2015/02/04/why-are-cancer-rates-increasing/
[3] News-Medical. (2009, December 2). Cancer History. News-Medical.net. https://www.news-medical.net/health/Cancer-History.aspx
[4].Ogundijo, O. E., & Wang, X. (2019). SeqClone: sequential Monte Carlo based inference of tumor subclones. BMC Bioinformatics, 20(1). https://doi.org/10.1186/s12859-018-2562-y
[5] What are Proto-Oncogenes? (2010, February 25). News-Medical.net. https://www.news-medical.net/life-sciences/What-are-Proto-Oncogenes.aspx
[6]Why We Haven’t Cured Cancer. (2015). [YouTube Video]. In YouTube. https://www.youtube.com/watch?v=7tzaWOdvGMw
[7].American Cancer Society. (2000). Oncogenes and tumor suppressor genes. Cancer.org; American Cancer Society. https://www.cancer.org/cancer/cancer-causes/genetics/genes-and-cancer/oncogenes-tumor-suppressor-genes.html
[8]. Khan Academy. (n.d.). Cancer and the cell cycle | Biology (article). Khan Academy. https://www.khanacademy.org/science/ap-biology/cell-communication-and-cell-cycle/regulation-of-cell-cycle/a/cancer
[9] Types of Tumors - Pancreatic Cancer | Johns Hopkins Pathology. (n.d.). Pathology.jhu.edu. https://pathology.jhu.edu/pancreas/types-of-tumors
[10].Cancer Treatment Centers of America. (2018, December 20). What’s the difference? Benign and malignant tumors. Cancer Treatment Centers of America. https://www.cancercenter.com/community/blog/2017/12/whats-the-difference-benign-and-malignant-tumors
[11] TED-Ed. (2017). Why is it so hard to cure cancer? - Kyuson Yun [YouTube Video]. In YouTube. https://www.youtube.com/watch?v=h2rR77VsF5c
[12] Acute Complications of Chemotherapy (side effects, adverse effects). (2018). [YouTube Video]. In YouTube. https://www.youtube.com/watch?v=p2ctcB4688s
[13].American Cancer Society. (2013). How Chemotherapy Drugs Work. Cancer.org; American Cancer Society. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/chemotherapy/how-chemotherapy-drugs-work.html
[14].Cancer.net. (2020, August). Side Effects of Radiation Therapy. Cancer.net. https://www.cancer.net/navigating-cancer-care/how-cancer-treated/radiation-therapy/side-effects-radiation-therapy
[15]Personalized Medicine. (n.d.). Genome.gov. https://www.genome.gov/genetics-glossary/Personalized-Medicine
[16]Vidyasagar, A., & Lanese, N. (2018, April 21). What Is CRISPR? Live Science. https://www.livescience.com/58790-crispr-explained.html
[17] Bozeman Science. (2016). What is CRISPR? In YouTube. https://www.youtube.com/watch?v=MnYppmstxIs
[18] NCI Staff. (2020, July 27). How CRISPR Is Changing Cancer Research and Treatment - National Cancer Institute. Www.cancer.gov. https://www.cancer.gov/news-events/cancer-currents-blog/2020/crispr-cancer-research-treatment
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