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
- “Chemotherapy for Non-Hodgkin Lymphoma.” American Cancer Society, www.cancer.org/cancer/non-hodgkin-lymphoma/treating/chemotherapy.html.
- 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.
- 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/.
- Schwab, M., Schaeffeler, E. Pharmacogenomics: a key component of personalized therapy. Genome Med 4, 93 (2012). https://doi.org/10.1186/gm394
- Adams, J. (2008) Pharmacogenomics and personalized medicine. Nature Education 1(1):194
- 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
- “About Cystic Fibrosis.” CF Foundation, www.cff.org/What-is-CF/About-Cystic-Fibrosis/.
- 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.
- 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.
- Adams, J. (2008) Pharmacogenomics and personalized medicine. Nature Education 1(1):194
- 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.
- 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.