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Pharmacogenomics in Personalized Medicine: How Medicine Can Be Tailored To Your Genes

By: Anushka Gupta, Genetics and Genomics, ‘20

Author’s Note: Modern medicine relies on technologies that have barely changed over the past 50 years, despite all of the research that has been conducted on new drugs and therapies. Although medications save millions of lives every year, any one of these might not work for one person even if it works for someone else. With this paper, I hope to shed light on this new rising field and the lasting effects it can have on the human population.

 

Future of Modern Medicine

Take the following scenario: You’re experiencing a persistent cough, a loss of appetite, and unexplained weight loss to only then find an egg-like swelling under your arm. Today, a doctor would determine your diagnosis by taking a biopsy of your arm and analyzing the cells using the microscope, a 400-year-old technology. You have non-Hodgkins lymphoma. Today’s treatment plan for this condition is a generic one-size-fits-all chemotherapy with some combination of alkylating agents, anti-metabolites, and corticosteroids (just to name a few) that would be injected intravenously to target fast-dividing cells that can harm both cancer cells and healthy cells [1]. This approach may be effective, but if it doesn’t work, your doctor tells you not to despair – there are some other possible drug combinations that might be able to save you. 

Flash forward to the future. Your doctor will now instead scan your arm with a DNA array, a computer chip-like device that can register the activity patterns of thousands of different genes in your cells. It will then tell you that your case of lymphoma is actually one of six distinguishable types of T-cell cancer, each of which is known to respond best to different drugs. Your doctor will then use a SNP chip to flag medicines that won’t work in your case since your liver enzymes break them down too fast. 

 

Tailoring Treatment to the Individual 

The latter case is one that we all wish to encounter if we were in this scenario. Luckily, this may be the case one day with the implementation of pharmacogenomics in personalized medicine. This new field takes advantage of the fact that new medications typically require extensive trials and testing to ensure its safety, thus holding the potential as a new solution to bypass the traditional testing process of pharmaceuticals. 

Even though only the average response is reported, if the drug is shown to have adverse side effects to any fraction of the population, the drug is immediately rejected. “Many drugs fail in clinical trials because they turn out to be toxic to just 1% or 2% of the population,” says Mark Levin, CEO of Millennium Pharmaceuticals [2]. With genotyping, drug companies will be able to identify specific gene variants underlying severe side effects, allowing the occasional toxic reports to be accepted, as gene tests will determine who should and shouldn’t get them. Such pharmacogenomic advances will more than double the FDA approval rate of drugs that can reach the clinic. In the past, fast-tracking was only reserved for medications that were to treat untreatable illnesses. However, pharmacogenomics allows for medications to undergo an expedited process, regardless of the severity of the disease. There would be fewer guidelines to follow because the entire population would not need to produce a desirable outcome. As long as the cause of the adverse reaction can be attributed to a specific genetic variant, the drug will be approved by the FDA [3]. 

Certain treatments already exist using this current model, such as for those who are afflicted with a certain genetic variant of cystic fibrosis. Additionally, this will contribute to reducing the number of yearly cases of adverse drug reactions. As with any field, pharmacogenomics is still a rising field and is not without its challenges, but new research is still being conducted to test its viability. 

With pharmacogenomic informed personalized medicine, individualized treatment can be designed according to one’s genomic profile to predict the clinical outcome of different treatments in different patients [4]. Normally, drugs would be tested on a large population, where the average response would be reported. While this method of medicine relies on the law of averages, personalized medicine, on the other hand, recognizes that no two patients are alike [5]. 

 

Genetic Variants

By doubling the approval rate, there will be a larger variety of drugs available to patients with unique circumstances where the generic treatment fails. In pharmacogenomics, genomic information is used to study individual responses to drugs. Experiments can be designed to determine the correlation between particular gene variants with exact drug responses. Specifically, modern approaches, including multigene analysis or whole-genome single nucleotide polymorphism (SNP) profiles, will assist in clinical trials for drug discovery and development [5]. SNPs are especially useful as they are genetically unique to each individual and are responsible for many variable characteristics, such as appearance and personality. A strong grasp of SNPs is fundamental to understand why an individual may have a specific reaction to a drug. Furthermore, SNPs can also be applied so that these genetic markers can be mapped to certain drug responses. 

Research regarding specific genetic variants and their association with a varying drug response will be fundamental in prescribing a drug to a patient. The design and implementation of personalized medical therapy will not only improve the outcome of treatments but also reduce the risk of toxicity and other adverse effects. A better understanding of individual variations and their effect on drug response, metabolism excretion, and toxicity has the potential to replace the trial-and-error approach of treatment. Evidence of the clinical utility of pharmacogenetic testing is only available for a few medications, and the Food and Drug Administration (FDA) labels only require pharmacogenetics testing for a small number of drugs [6].

 

Cystic Fibrosis: Case Study

While this concept may seem far-fetched, a few select treatments have been approved by the FDA for certain populations, as this field of study promotes the development of targeted therapies. For example, the drug Ivacaftor was approved for patients with cystic fibrosis (CF), a genetic disease that causes persistent lung infections and limits the ability to breathe. Those diagnosed with CF have a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, rendering the resulting CFTR protein defective. This protein is responsible for moving chloride to the cell surface, attracting water that will then generate mucus. However, those with the mutation have thick and sticky mucus, leaving the patient susceptible to germs and other infections as the bacteria that would normally be cleared [7]. Ivacaftor is only approved for CF patients who bear the specific G551D genetic variant, a specific mutation in the CFTR gene. This drug can then target the CFTR protein, increase its activity, and consequently improve lung function [8]. It’s important to note that the G551D is only just one genetic variant out of 1,700 currently known mutations that can cause CF.  

 

Adverse Drug Reactions

Pharmacogenomics also addresses the unknown adverse effects of drugs, especially for medications that are taken too often or too long. These adverse drug reactions (ADRs) are estimated to cost $136 billion annually. Additionally, within the United States itself, serious side effects from pharmaceutical drugs occur in 2 million people each year and may cause as many as 100,000 deaths, making it the fourth most common cause of death according to the FDA [9]. 

The mysterious and unpredictable side effects of various drugs have been chalked up to individual variation encoded in the genome and not drug dosage. Genetics also determines hypersensitivity reactions in patients who may be allergic to certain drugs. In these cases, the body will initiate a rapid and aggressive immune response that can hinder breathing and may even lead to a cardiovascular collapse [5]. This is just one of the countless cases where unknown patient hypersensitivity to drugs can lead to extreme outcomes. However, some new research in pharmacogenomics has shown that 80% of the variability in drugs can be reduced. The implications of this new research could mean that a significant amount of these ADRs could be significantly decreased inpatient management, leading to better outcomes [11].  

 

Challenges

Pharmacogenomic informed medicine may suggest the ultimate demise of the traditional model of drug development, but the concept of targeted therapy is still in its early stages. One reason that this may be the case is due to the fact that most pharmacogenetic traits involve more than one gene, making it even more difficult to understand or even predict the different variations of a complex phenotype like a drug response. Through genome-wide approaches, there is evidence of drugs having multiple targets and numerous off-target results [4]. 

Even though this is a promising field, there are challenges that must be overcome. There is a large gap between integrating the primary care workforce with genomic information for various diseases and conditions as many healthcare workers are not prepared to integrate genomics into their daily practice. Medical school curriculums would need to be updated in order to implement information and knowledge regarding pharmacogenomics incorporated personalized medicine. This would also create a barrier in presenting this new research to broader audiences including medical personnel due to the complexity of the field and its inherently interdisciplinary nature [12]. 

 

Conclusion

The field has made important strides over the past decade, but clinical trials are still needed to not only identify the various links between genes and treatment outcome, but also to clarify the meaning of these associations and translate them into prescribing guidelines [4]. Despite its potential, there are not many examples where pharmacogenomics impacts clinical utility, especially since many genetic variants have not been studied yet. Nonetheless, progress in the field gives us a glimpse of a time where pharmacogenomics and personalized medicine will be a part of regular patient care.

 

Sources

  1. “Chemotherapy for Non-Hodgkin Lymphoma.” American Cancer Society, www.cancer.org/cancer/non-hodgkin-lymphoma/treating/chemotherapy.html.
  2. Greek, Jean Swingle., and C. Ray. Greek. What Will We Do If We Don’t Experiment on Animals?: Medical Research for the Twenty-First Century. Trafford, 2004, Google Books, books.google.com/books?id=mB3t1MTpZLUC&pg=PA153&lpg=PA153&dq=mark+levin+drugs+fail+in+clinical+trials&source=bl&ots=ugdZPtcAFU&sig=ACfU3U12d-BQF1v67T3WCK8-J4SZS9aMPg&hl=en&sa=X&ved=2ahUKEwjVn6KfypboAhUDM6wKHWw1BrQQ6AEwBXoECAkQAQ#v=onepage&q=mark%20levin%20drugs%20fail%20in%20clinical%20trials&f=false.
  3. Chary, Krishnan Vengadaraga. “Expedited Drug Review Process: Fast, but Flawed.” Journal of Pharmacology & Pharmacotherapeutics, Medknow Publications & Media Pvt Ltd, 2016, www.ncbi.nlm.nih.gov/pmc/articles/PMC4936080/.
  4. Schwab, M., Schaeffeler, E. Pharmacogenomics: a key component of personalized therapy. Genome Med 4, 93 (2012). https://doi.org/10.1186/gm394
  5. Adams, J. (2008) Pharmacogenomics and personalized medicine. Nature Education 1(1):194
  6. Singh D.B. (2019) The Impact of Pharmacogenomics in Personalized Medicine. In: Silva A., Moreira J., Lobo J., Almeida H. (eds) Current Applications of Pharmaceutical Biotechnology. Advances in Biochemical Engineering/Biotechnology, vol 171. Springer, Cham
  7. “About Cystic Fibrosis.” CF Foundation, www.cff.org/What-is-CF/About-Cystic-Fibrosis/.
  8. Eckford PD, Li C, Ramjeesingh M, Bear CE: CFTR potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner. J Biol Chem. 2012, 287: 36639-36649. 10.1074/jbc.M112.393637.
  9. Pirmohamed, Munir, and B.kevin Park. “Genetic Susceptibility to Adverse Drug Reactions.” Trends in Pharmacological Sciences, vol. 22, no. 6, 2001, pp. 298–305., doi:10.1016/s0165-6147(00)01717-x.
  10. Adams, J. (2008) Pharmacogenomics and personalized medicine. Nature Education 1(1):194
  11. Cacabelos, Ramón, et al. “The Role of Pharmacogenomics in Adverse Drug Reactions.” Expert Review of Clinical Pharmacology, U.S. National Library of Medicine, May 2019, www.ncbi.nlm.nih.gov/pubmed/30916581.
  12. Roden, Dan M, et al. “Pharmacogenomics: Challenges and Opportunities.” Annals of Internal Medicine, U.S. National Library of Medicine, 21 Nov. 2006, www.ncbi.nlm.nih.gov/pmc/articles/PMC5006954/#idm140518217413328title.

New Drug “Sponge” Absorbs Chemo Side Effects

By Brooke B., Neurology, Physiology, and Behavior, ‘22

Author’s Note: I heard about this device on the news, and I was immediately intrigued by the concept. I decided to research it further, upon which I was surprised how logical and efficient the device worked with such substantial results. I wanted to share what I believe to be a huge breakthrough in cancer research.

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Christianson Syndrome

By Madison Dougherty, Biochemistry and Molecular Biology ‘18

Author’s Note:

“I wrote this paper as a supplement to a presentation in my genetics class. I believe it is important to inform people about mental disabilities other than the most commonly seen disorders, such as Down Syndrome or autism. This paper serves to educate readers about Christianson Syndrome, an X-linked genetic disorder that, although phenotypically similar to more widely-known disorders, is actually quite different at the genetic level.”

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“Let’s Take a Deep Breath”: Managing Hypertension by Bridging the Clinic-Home Healthcare Gap

Independent Project Findings

By Harsh Sharma,  Neurobiology, Physiology, and Behavior, ’13

Author’s Note:

“I wrote this paper to share my independent project takeaways with everyone who is interested in, or a part of, the healthcare field. This project taught me a lot about what we can do to help our patients get the most out of the clinic they go to. As you gain experiences in the medical field, think about the services your organization offers and how you can use your skills to enhance those services to the next level!”

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Critical Factors Involved in the Relationship Between Cannabis and Schizophrenia

By Carly Cheung, Microbiology, ’17

Author’s Note:

“I wrote this piece for my UWP 104F: ‘Writing in the Health Professions’ class with Professor Walsh in Winter 2016. Our assignment was to examine a health related research question and explore the subject in a quarter-long research and synthesis process. I decided to write about Schizophrenia because I realized that I knew close to nothing accurate about people with mental health illnesses. Lack of understanding of the disease can contribute to stigmatization of these patients and cause further psychological harm. On my way to demystifying Schizophrenia, one of the most researched relationship I found was that of Marijuana and Schizophrenia. Throughout this process, I not only gained valuable knowledge on this topic, but I also learned to appreciate the various methods scientists developed to study the mechanism of this multi-layered and abstract disease.”

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Zika Virus

By Nicole Strossman, Biochemistry and Molecular Biology, ’17

Author’s Note:

“I chose to write about this topic in an effort to gain a better understanding of Zika virus. While the topic is frequently in the news, the specifics of the virus are not always discussed in depth. As ongoing research is demonstrating the virus’ possible links to human health disorders, it is important for the general public to be informed about the facts of the virus, in an effort to minimize its spread.”

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An Overview of Tension-Type Headache

By Lo Tuan, Neurobiology, Physiology, and Behavior and Managerial Economics, ’17

Author’s Note:

“I chose to write this paper because I have a family member who suffers from TTH and expanding my knowledge of the topic through researching and writing empowered me to play a more active role in assisting my family with addressing such medical condition.”

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The Future of Surgery

By Nicole Strossman, Biochemistry and Molecular Biology, ’17

What do you picture when you think about surgery? Most likely, you imagine a person having their body cut open, and then a surgeon performing what is necessary to fix the problem, whether that be removing a damaged organ or tissue, repairing damages internally, or performing some other procedure. In all of these cases, it is expected that the doctor makes a cut large enough so that he or she can see what is inside of the body and operates. However, a new method of surgery takes a radically different approach. Laparoscopic surgery, also called minimally invasive surgery, Band-Aid surgery, or keyhole surgery, is a relatively new surgical technique that is revolutionizing the surgical field. Traditionally, surgery is performed by making a large incision in order to directly view and operate on the tissues, organs, and other structures of interest inside of the body. In contrast, with laparoscopic surgery, a series of small incisions, typically of .5 cm to 1.5 cm, are made along the abdomen. (more…)

What is LASIK?

By David Ivanov, Biochemistry and Molecular Biology, 2015

LASIK, or laser-assisted in situ keratomileusis, is a surgical procedure commonly used to correct for visual defects or lack of visual clarity. Commonly referred to as laser eye surgery, LASIK is a type of surgery that is used to alleviate visual loss associated with common defects of the eye, such as myopia (nearsightedness), hypermetropia (farsightedness), and astigmatism. Astigmatism, like near and far-sightedness, can be caused by the irregularity in shape of the cornea that leads to blurred vision. For all three cases, corneal remodeling via LASIK can be performed (Thomson, 2015).

The cornea is the outermost layer of the eye, the transparent part that one can touch, and upon which contact lenses are placed. It is responsible for most of the focusing power, and thus is a common culprit in visual defects of the eye. The cornea focuses the light reflected into the eye, through the lens and onto the the retina at the back of the eye, which senses light and converts it to nerve impulses, and transmits the resulting image to the brain for processing. This then produces the image that we ‘see’. While the retina is the part of the eye that is light-sensitive and is responsible for transmitting the image to the brain, the cornea, along with the lens, must focus light reflecting off of three dimensional surfaces so that they strike onto the anterior, or front part of the retina. Without this precise focusing of light rays directly onto the retina, the brain generates a blurred image (NKCF 2014).

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Can Polio Cure Cancer?

By Briga Mullin, Biochemistry and Molecular Biology, ’15

The human body’s immune system has been developed to successfully battle foreign invaders including bacteria, parasites, and viruses. Immunotherapy is the idea that the power of the immune system can be utilized against diseases such as cancer. Typically, the immune system does not harm the body’s own cells, preventing it from being extremely effective against cancer. However with different medical interventions to strengthen the body’s immune response, it is possible to get an effective treatment (Cancer Immunotherapy 2015).

A unique and exciting branch of immunotherapy involves oncolytic viruses, genetically modified viruses that are used to infect tumor cells and fight cancer (Vile, Ando, and Kirn 2002). One example of an oncolytic virus is Oncolytic Polio/Rhinovirus Recombinant (PVS-RIPO), a genetic combination of poliovirus and a strain of the common cold. (more…)