Issue 2
By Joshua Nam (FOCUS ARTICLE) Eric Yoon Hugh Kang Jiwon Lee
A immune-checkpoint-inhibitor preventing a cancer cell from evading a T-Cell. (Getty Images)
Immune Checkpoint Inhibitors: The Cure to Cancer? By Joshua Nam There were 18.1 million new cases of cancer and 9.6 million deaths caused by cancer in 2018, according to the World Health Organization (WHO). From such numbers, the topic begs the question, why are we so defenseless against cancer, and can’t we do anything significant to increase our chances of survival?
Well, we certainly aren’t defenseless. Cancer isn’t a brand new threat that appeared out of nowhere and started terrorizing humans. It has been a longtime disease found in not only humans but other biological organisms (including plants, although they are slightly less vulnerable), that has only become prevalent with new factors that increase the chances of cancer with the recent advances in technology and shifts in lifestyle, such as frequent smoking. Over the years of evolution, organisms have developed ways to deal with cancerous tumors.
Our body possesses special immune cells called T cells, which are produced primarily within the thymus specializing in the recognition of foreign particles and combating them. These cells bind to other cells’ T cell receptors which are groups of proteins on the surface that present the T cell with certain molecules. Normal cells present the T cell with the proper molecules, whereas cancerous cells present the T cell with a foreign particle, also called an antigen. Once T cell recognizes an antigen and the cancerous cell fails to pass this checkpoint, it sends a message to the nucleus of the cancerous cell ordering it to kill itself.
Of course, if this method was 100% fool-proof, cancer wouldn’t be so prolific today. Cancer cells can bypass this “test” by handing the T-cell inhibitors/molecules that bind to the T-cell’s receptors and inhibit its ability to message the nucleus. Examples include PD-L1, a ligand/protein that binds to the T-cell’s PD-1 (Programmed cell Death protein 1) and prevents the T-cell from killing the cancerous cell.
To counter this, immune checkpoint inhibitors (ICIs) were developed by humans. ICI’s are important drugs for those afflicted with different types of cancers, whether it be malignant
melanoma (a cancer of pigment-carrying skin cells), lung cancer, kidney cancer, bladder cancer, and much more. ICI’s make T-Cells simply ignore the test they give cancerous cells and simply kill them. The ICI’s bind to the specific receptors of the T-Cell and prevent the cancer cells’ ligand from attaching, forcing the T-Cell to ignore this checkpoint and simply get rid of cancer cells. In a way, ICI’s are inhibitors of inhibitors. They prevent the cancerous cell’s inhibitors from binding to the T-cell’s receptors by binding itself to the T-cell beforehand and causing it to kill the cancerous cells without being inhibited.
Ipilimumab was the first approved immune checkpoint inhibitor for treating patients with advanced melanoma/skin cancer. Approved by the US Food and Drug Administration in 2011, It targets cytotoxic T-lymphocyte antigen-4 (CTLA-4), a protein immune checkpoint that can be bypassed by the cancer cells through CD80/CD86 ligands. This antibody prevents T-cell inhibition and promotes the activation and proliferation of effector T cells. Ipilimumab proved to be very effective, and earned approval as a potent solution against cancerous tumors. The success of Ipilimumab lead to the examination of other antibodies that target immune checkpoints and the creation of other effective ICIs. For example, Pembrolizumab and nivolumab, ICIs that target programmed death-1 (PD-1), showed promising results in melanoma and non-small cell lung carcinoma patients. As of now, hundreds of clinical trials for phase 1, 2, 3, and 4 cancer patients are being carried out across the globe to evaluate the efficacy of multiple ICIs, and ways to utilize such drugs efficiently (e.g. using combinations of ICI’s vs applying one at a time).
ICI’s themselves are a revolutionary advancement in the field of oncology. They make cancer cells more vulnerable to our human immune system, opening up ways for other treatment options. So are ICI’s a perfectly fine counter to cancer? Well, if you think about how death by cancer is still very prevalent today, you can infer that ICI’s aren’t a seamless barrier to cancer. Research shows that ICI’s are in fact far from being perfect.
To start off with, there are simply too many factors that determine how effective an ICI is in an individual’s body, and the ways for cancer cells to gain T-Cell Immunity are too diverse or varied for ICI’s to completely prevent cancer. ICI’s merely prevent cancer cells from bypassing immune checkpoints of t-cells. There are numerous other methods to prevent the immune system from noticing and combating the cancer. For example, some cancers are known to simply inhibit the presence of T-cells around the cancer. However, this in itself is not necessarily a disadvantage of ICI’s; cures to a disease are often never complete without the use of other complements. ICI’s are simply a piece of the larger puzzle named “The Cure to Cancer.” Developing ICI’s have brought us closer to that achievement.
Some issues of ICI’s lie in the ICI’s themselves. ICI’s have been shown to be highly toxic to the human body, and that they are able to cause severe inflammatory effects. These side-effects are designated as irAEs, which stands for immune related adverse effects. irAE’s affect practically all parts of the body, but the stomach, intestines, liver, endocrine glands, and the skin suffer the worst. The gastrointestinal tract suffers from colitis(inflammation of the large intestine), and enteritis(inflammation of the small intestine). The liver suffers from
hepatitis(inflammation of liver), causing vomiting, tiredness, poor appetite, and more. The skin develops rashes and vitiligo(loss of skin color). Besides that, there is a large plethora of symptoms ICI’s bring, varying in fatality, but all quite unpleasant.
A diagram of all the various irAE’s in the human body. (New England Journal of Medicine)
Why do irAE’s occur then? Inflammation in itself is an immune response that heats up the body to help repel foreign organisms such as bacteria. It is designed to create harsh conditions that makes it difficult for the bacteria to proliferate. When there are no foreign threats, there is no inflammation, as such conditions aren’t optimal for our cells as well.. However, ICI’s can cause a “false alarm.” Altering the immune system, as ICI’s do, can cause great increases in
the immune system’s security, one effect of which is inflammation. In essence, ICI’s are removing the checkpoints that are needed to be passed for the immune system to improve its security - and kill the cancer cells whether or not the immune system recognizes them.
However these checkpoints exist for a reason. Increasing the immune system’s security is costly in terms of energy usage, and in the case of inflammation it greatly disturbs various processes, such as enzyme activity (after all it was designed to do the same against foreign intruders), within the human body as well as cause uncomfortable side-effects.
Considering the severity of the side effects ICI’s can cause, we must take greater care and attention towards their usage. Decreasing the toxicity of the ICI’s themselves is a top priority for those in the study of immunotherapy. As for now, all we can do about irAE’s is to prescribe drugs to ameliorate the side effects of inflammation that come with the application of ICI’s. But perhaps more important is to continue with the research of ways to prevent cancer caused by different causes. After all, ICI’s only deal with one method of cancer proliferation.
While not complete counters to cancer, ICI’s themselves have proven themselves to be an effective measure. They are a taste of what’s to come with the ongoing development of oncology, and display promising results. The cure to cancer has never been about the creation of a single prescription drug, but rather the outlining of a treatment program with multiple processes that all interact together to put an end to cancer. The development of ICI’s means that we have found one of the possible processes that are crucial to the discovery of the cure, and in
the near future, we will be able to discover the remaining processes and prevent cancer from causing any more deaths in the human population.
Works Cited
Darvin, P., Toor, S. M., Nair, V. S., & Elkord, E. (2018). Immune checkpoint inhibitors: recent progress and potential biomarkers. Experimental & Molecular Medicine, 50(12). doi: 10.1038/s12276-018-0191-1
Azoury, S., Straughan, D., & Shukla, V. (2015). Immune Checkpoint Inhibitors for Cancer Therapy: Clinical Efficacy and Safety. Current Cancer Drug Targets, 15(6), 452–462. doi: 10.2174/156800961506150805145120
Immune checkpoint inhibitors to treat cancer. (2018, October 1). Retrieved from https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunothe rapy/immune-checkpoint-inhibitors.html
Eric Yoon CRISPR- Super Humans or Super Screwed? If you could protect your future child from ever becoming ill or sick with a single, painless change to their genetic code that was proven to work, would you? Unless you harbored the spirit of an anti-vaxxer mother, most likely yes. Then, let’s ask a more contentious question: if this power was extended so that all traits of your future child were alterable, what would you change? Would it be moral to change anything other than deficiencies from the average standard of human health? Would it be immoral NOT to provide your child with extra intelligence, if you as a parent came from a disadvantaged household and were in poverty, unable to give your child the same standard of intelligence as a child from a well to do family? These are the questions we have to think about with the emergence of CRISPR, a precise, cheap, safe tool to edit the genetic code of an individual. "CRISPR" stands for "clusters of regularly interspaced short palindromic repeats." It is a specialized region of DNA with two distinct characteristics: the presence of nucleotide repeats and spacers. CRISPR technology was adapted from the natural defense mechanisms of bacteria and archaea (the domain of single-celled microorganisms). These organisms use CRISPR-derived RNA and various Cas proteins, including Cas9, to foil attacks by viruses and other foreign bodies. They do so primarily by chopping up and destroying the DNA of a foreign invader. When these components are transferred into other, more complex, organisms, it allows for the manipulation of genes, or "editing." So far, scientists have used it to reduce the severity of genetic deafness in mice, suggesting it could one day be used to treat the same type of hearing loss in people. They’ve created mushrooms that don’t brown easily and edited bone marrow cells in mice to treat sickle-cell anemia. Down the road, CRISPR might help us develop drought-tolerant crops and create powerful new antibiotics. CRISPR could one day even allow us to wipe out entire populations of malaria-spreading mosquitoes or resurrect once-extinct species like the passenger pigeon. So yes, CRISPR is a powerful tool that can be used to affect not only our genome but other organisms we’ve domesticated. The ethical concerns that plague it, however are numerous: Chinese biophysicist and entrepreneur He Jiankui’s use of CRISPR gene-editing technology to alter the genetic code of two human babies rocked the international scientific community. And that’s only looking at the current state of affairs; returning to the example in the first paragraph, it isn’t infeasible to say that in the not so distant future we have to confront the possibility of true gene altering. We must keep in mind that CRISPR is a tool however, and that’s all it is- a very powerful one, albeit, but still one we have complete control over. It is up to us to what we make out of it.
The Science behind Near-Death Experiences By Hugh Kang What is your near-death experience? According to a Gallup poll, around 3 percent of the US population say that they have gone through a near-death experience. Near-death experiences, or NDEs, have gotten a lot of publicity recently in both media and in the scientific field. Books like Heaven Is For Real, Proof of Heaven, and To Heaven and Back have all been very popular in recent years. These novels often vary in the details of the experiences, but the overall tenor of the experiences is remarkably similar. For example, a striking majority of these stories often involve the sensation of floating up and viewing the scene around one’s body. Many also involve entering an otherworldly realm. Others experience a reunion with long-lost family members. However, one thing that all these NDE’s shared was that fact that their experience did not feel like a dream or hallucination, Near-death experiences are often thought of as a phenomenon, but modern science has been revealing scientific explanations behind the common features of the recorded near-death experiences. These include the sensation of being dead, a feeling that the soul left the body, a voyage through a bright tunnel, and a departure to another reality. There have been several attempts to explain the different causes of NDEs. Some have asserted that they are caused by oxygen shortages, imperfect anesthesia, or a traumatic response. However, the main reason why researchers have dismissed these reasons is that the phenomenon is too widespread and consistent for the proposed medical conditions. Recently, a series of studies have been revealed that propose potential explanations for such a mystical experience. "Many of the phenomena associated with near-death experiences can be biologically explained," says neuroscientist Dean Mobbs, at the University of Cambridge's Medical Research Council Cognition and Brain Sciences Unit. Mobbs and Caroline Watt at the University of Edinburgh. For example, Cotard syndrome, also known as “walking corpse syndrome, is a remarkably similar disease that allows patients to hold the false belief that they are deceased. Although the mechanism behind the syndrome itself is still unclear, some believe that it is caused by the patients trying to understand what is going on. The disorder commonly follows a traumatic experience and has often been linked with the parietal cortex and prefrontal cortex regions of the brain. The parietal cortex plays a function of attention in the brain and the prefrontal cortex plays the role of creating delusions when the host is under conditions such as schizophrenia. Both of these combine to potentially cause the Cotard syndrome, giving the delusional belief of post-death experiences.
What about the serene experiences that NDEers have reported to have? As mentioned previously, many NDEers have said that they have been able to meet the deceased in their experiences. One possible explanation could be Parkinson’s disease. Patients with Parkinson’s disease have most commonly reported visions of ghosts and monsters while in an unconscious state. The explanation behind this could be the fact that Parkinson’s affects the functioning of dopamine in the brain, which is a neurotransmitter that evokes hallucinations. When the brain is going through a serene experience such as an NDE, the brain releases dopamine and other stress hormones, which could possibly explain the visions that the NDEers have had. Recent studies have even discovered that experiences very similar to NDEs could be triggered artificially through drugs. Drugs such as anesthetic ketamine has been reported to be able to mirror the euphoria experiences, including experiences of leaving the body and hallucinations. Ketamine works by affecting the opioid system of the brain, which sets off trauma in the brain. What about the infamous hallucination of flying through a tunnel of bright light? Although many explanations remain unconfirmed, the tunnel vision may be caused by a sudden loss of blood and oxygen in the eye. This is highly likely to occur because of the extreme fear and loss of oxygen experienced by the patients, which both are common to dying. Although there have been a couple of proposed explanations behind these near-death experiences, it still remains a very mystical phenomenon. The biggest obstacle that we face in understanding these experiences is doing the actual research on the near-death experiences and being able to do feasible analysis on them. However, when we are able to understand the process of dying, we humans might finally be able to come to terms with the inescapable conclusion to our lives.
Trepanation: Good Riddance or an Admirable Ancient Development? BY Jiwon Lee Ever-rising healthcare prices are the subject of much criticism nowadays. However, when living in a society where medical amenities are readily available, the importance of such facilities is sometimes forgotten. By contrast, people from earlier eras did not have access to the convenient medical systems of contemporary time periods. So, then, what did our ancestors do to solve the bodily problems that arose from time to time? Were they left to merely cross their fingers and hope for the best? While scientific discoveries have shown us that rudimentary forms of medical practices did exist in earlier societies, they have generally been looked upon as a barbaric and mostly ineffective affair. Having lived in a more primitive society with limited scientific knowledge about the human anatomy and the cause of diseases, the expectation is that medical diagnosis and treatment in this age were a far cry from the advanced knowledge and tools that characterize our current medical abilities. Take trepanation, for instance. This practice, which is the oldest human operation that archeologists have found fossil evidence for, is a surgical procedure in which a hole is scraped or drilled into the human skull. Practiced as early as 5000 BC and continued into the Middle Ages – even up to Renaissance for some cultures – this surgical procedure has for a long time been viewed as an uncivilized custom possibly affiliated with ceremonial purposes. This initial interpretation of the practice does seem to make sense. At first glance, trepanation seems more like an ancient torture method than a medical operation; after all, what doctor in his right mind would present a solution of drilling a hole in your skull for some, say, headache symptoms? An analysis of trepanation holes over a data set of multiple skulls, however, has shown that there is a consistent pattern in the placement of trepanation holes that suggests that their purpose went behind that of spiritual or religious motivations. Archeologists found in 1997 and 2011 a mass of trepanated skulls distributed among multiple grave sites, with many of the individuals buried in close proximity to each other. While finding multiple human remains on the same site was not a rare happening, the fact that many of them had been trepanated was. What was even more remarkable was that all of these trepanation holes had been made just above the obelion, a particular pressure point on the skull. The consistent nature of the trepanation process and the fact that creating an opening through the obelion, which
is located above a major convergence point of blood vessels in the brain, was very risky and could possibly entail death, suggested that the trepanation procedures that had been performed on these individuals would likely have had more significance than religious reasons. Perhaps in some cultures trepanation could have been part of a ceremonial ritual of some sort – and this idea is supported by the few trepanation holes found in skulls without any signs of injury or illness – but this is likely not the case for all trepanation practices, as most trepanated skulls show some sign of physical injury or hint at possible neurological diseases that could have been the reason for the trepanation procedure. While it is known that trepanation was practiced throughout North and South America, Africa, and parts of Eurasia, the best preserved trependated human remains have been found almost exclusively in Russia. This limited pool of quality data has deterred substantial conclusions from being drawn from the investigations, although further research is being conducted. However, signs of physical and neurological trauma in most trepanated subjects, coupled with the fact that these patients were able to live for a good few years following their operations, show us that there must have been some kind of medical issues that ancient doctors had been trying to solve with trepanation––and whatever the problem was, they survived it. It is somewhat startling to think that earlier surgical interventions were much more advanced than we might have initially expected. Drilling a hole in your skull for a medical purpose, although practiced from time to time in the modern age as well, is very risky and frankly terrifying. Even without the carved portion of the skull being filled in with an artificial replacement, the aforementioned fossils show that the trepanation surgeries performed on them were largely successful, a reflection of the unexpectedly advanced anatomical knowledge these earlier doctors possessed. Modern medical treatment is inarguably expensive, and generally may be an absolute pain. Nevertheless, it is safe to assume that most people are thankful that the practice of trepanation has been replaced by the surgical advances of today.
