The enormous amount of scientific and technological advancements in the field of healthcare which includes diagnosis, prognosis and treatments has proven to benefit disease management on a large scale. One such advancement includes ‘precision medicine’ which is an alternative or an advanced treatment option opted due to less efficiency of the conventional treatments for most of the diseases. Personalized or precision medicine is not a brand-new notion in the medical field. It in a way started back in 1901 with the “Identification of the ABO blood group system”, by Karl Landsteiner which explained the variability in each patient’s Biology which paved the way for accurate blood transfusion procedures [1].
An article published in Oncologist in 1999 entitled “New Era of Personalized Medicine: Targeting Drugs for Each Unique Genetic Profile” by Robert Langreth and Michael Waldholz, stated that the current Pharmacotherapy was a “one‐size‐fits‐all” approach, with only 50-70% efficacy even for the best drugs. The article also shed light on the existence of disease heterogeneity and variability among different patients which may lead towards ineffectiveness of the drugs and imposed importance to understand the variability of diseases for each patient [2].
Over the last 20 years, various names have been used to characterise the term Individualized (or) Comprehensive therapy, with the term "precision medicine" becoming the favoured term in the last 8–10 years, replacing the term "personalised medicine." In fact, the term precision medicine had first been proposed by Prawase Wasi in 1997, during a discussion of the prospects for the future of genomic medicine [3].
The Human Genome Project (HGP), which was finished in 2003, with its first clinical interpretation in 2010 can be credited as a stepping stone that contributed to the majority of the work that has been done to develop the field of precision medicine. Since the mapping of the total human genome, abundant studies are conducted to find the potential biomarkers (i.e., the genes responsible) for various health ailments including cancer, cardiovascular diseases, diabetes mellitus, nephrotic disorders, heritable genetic disorders, etc. HGP also aided in the advancement of the subject by allowing researchers to go beyond the genome and into the complete spectrum of molecular medicine.
Consequences of these discoveries, investments were made by the National Institutes of Health (NIH) under the leadership of Francis S. Collins, who hoped to use this new information to advance genetic medicine beyond the study of already known mutations and chromosomal aberrations. In 2015, US President Barack Obama, started the “Precision Medicine Initiative” a new milestone to study the genomic health of 1 million volunteers with funding of $215B.
Precision Medicine defines as “medical treatments tailored according to the individual’s genetic and physiological characteristics by prescribing comprehensive medications/drugs specific to the mutations observed through sequencing of the individual’s genome which provides the genomic data of the individual”, Figure 1. The National Cancer Institute (NCI) describes personalized medicine as follows:
“A form of medicine that uses information about a person's genes, proteins, and environment to prevent, diagnose, and treat disease. In cancer, personalized medicine uses specific information about a person's tumour to help diagnose, plan treatment, find out how well treatment is working, or make a prognosis.” Examples of personalized medicine include - using targeted therapies to treat specific types of cancer cells, such as HER2‐positive breast cancer cells [4].
Figure 1: How genetic diagnosis helps provide precise treatments for patients with variable mutations for the same cancer type.
To study the genome of an individual, the DNA samples are first extracted from the patient’s test samples (blood, hair, biopsy samples, etc.) followed by Polymerase Chain Reaction (PCR), Fragmentation and Sequencing. The sequencing includes Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES) & RNA Sequencing. The raw data after sequencing is then analysed using Bioinformatics tools to proceed with the identification of the mutated genes/sites. The patient’s genome is mapped with the reference genome obtained through the Human Genome Project (HGP) to identify the Genetic variations, chromosomal aberrations and Single-nucleotide Polymorphisms (SNPs) associated with a particular disease. Over the years, a considerable number of genetic biomarkers have been identified for several diseases through genetic sequencing. Some of the biomarkers associated with diseases are given in Table 1. In precision medicine, molecular information improves the accuracy with which patients are classified and treated, i.e., we have an endotype (or phenotypic variant) of a disease that results from the interaction of a gene or collection of genes with environmental factors and lifestyle [5].
Table 1: Some biomarkers associated with diseases
Disease | Key Genetic Biomarker | Reference |
Cancer | BRCA1, BRCA2, P53, MDM2, EGFR, HOXB13, ATM, KRAS, etc. | [6] |
Cardiovascular Diseases | ABCA1, ANGPTL4, FADS1, LDLR, PCSK9, ANGPTL3, APOB, ASGPR, MTHFR | [7] |
Diabetes Mellitus | GAD65, SLC30A8, HLA‐DQA1, HLA-DQB1, HLA-DRB1, ACAA, TCF3, WDR5, etc. | [8, 9] |
Alzheimer’s Disease | PSEN1, PSEN2, APP, APOE | [10] |
Cystic Fibrosis | CF Gene | [11] |
Sickle Cell Anaemia | βS-globin (HBB) gene | [12] |
Thalassemia | HBB Gene | [13] |
Down Syndrome | D21S11, IFNAR | [14] |
"The theory of precision medicine is exciting and clear — deliver the right medicine, at the right time, to the right patient. But, in practice, it can be quite challenging—identifying how to develop a medicine with the right biomarker is actually really tough," says Thomas Hudson, Vice President of Oncology Discovery at AbbVie, with enormous interest in cancer research.
During the inauguration of the Precision Medicine Initiative, President Barack Obama had pointed that “In some patients with cystic fibrosis, this approach has reversed a disease once thought unstoppable.” Later the president also declared that precision medicine “gives us one of the greatest opportunities for new medical breakthroughs that we have ever seen.”
Commenting on the contribution of the Human Genome Project (HGP) "The Genome Project has significantly improved our ability to learn how tumour cells work at the molecular level — the more we learn their inner workings, the better we're able to develop effective therapies," says Andrea Califano, Chairman of the Department of Systems Biology, Columbia University.
According to Carol Bult, a professor at The Jackson Laboratory, “Research on precision is improving the odds that the patient will receive the right therapy at the get-go, rather than having them undergo other therapies that won’t work.” Developing specific drugs that have an inhibitory effect for a particular mutation has been very fruitful to both the medical and pharmaceutical fields. "Now we understand the genetic architecture of each cancer. Sometimes it is better to know the genetic basis of cancer rather than its location. Drugs are being developed based on cancer's genetic vulnerability rather than [on] tissue of origin," said Chris Boshoff, Chief Development Officer at Pfizer Oncology in New York City.
Precision treatment of the diseases for the identified biomarkers potentially treats the disease at the genetic level, thus eliminating the need for continuous conventional treatments like Chemotherapy, Radiotherapy, Dialysis, Angioplasty, Open heart surgeries and medications for some of the common but life-consuming diseases like Cancer, Chronic Kidney Disease, Cardiovascular Diseases, Diabetes, Alzheimer's Disease and also Genetic Disorders like Cystic Fibrosis, Sickle cell Anaemia, Thalassemia, Haemophilia, Down Syndrome, etc. Appropriate FDA approved drugs are prescribed to correct the mutations at the genetic level and treat the diseases.
Because of genetic and translational investigations, precision medicine has aided the discovery of better actionable gene targets, as well as the revitalization of the pharmaceutical sector, which is now capable of generating safer and more effective medications. When taken together, these advancements fulfil the promise of the Human Genome Project (HGP) by providing each patient with the option to receive the appropriate medication at the appropriate dosage at the appropriate time in the most convenient manner.
References
[1] Schwarz, H. P., & Dorner, F. (2003). Karl Landsteiner and his major contributions to haematology. British journal of haematology, 121(4), 556-565.
[2] Langreth R, Waldholz M. New era of personalized medicine: targeting drugs for each unique genetic profile. Oncologist. 1999;4(5):426-427.
[3] Wasi P. Human genomics: implications for health. Southeast Asian J Trop Med Public Health. 1997;28 Suppl 2:19-24.
[4] NCI Dictionary of Cancer Terms. Personalized Medicine. National Cancer Institute. Available at https://www.cancer.gov/publications/dictionaries/cancer‐terms/def/personalized‐medicine. Accessed December 1, 2018.
[5] Perlman, R. L., and Govindaraju, D. R. (2016). Archibald E. Garrod: the father of precision medicine. Genet. Med. 18, 1088–1089. DOI: 10.1038/gim.2016.5
[6] Khailany RA, Aziz SA, Najjar SM, Safdar M, Ozaslan M. Genetic biomarkers: Potential roles in cancer diagnosis. Cell Mol Biol (Noisy-le-grand). 2020;66(3):1-7. Published 2020 Jun 5.
[7] Shukla H, Mason JL, Sabyah A. Identifying genetic markers associated with susceptibility to cardiovascular diseases. Future Sci OA. 2018;5(1):FSO350. Published 2018 Oct 26. DOI: 10.4155/fsoa-2018-0031
[8] Zhang, X., Gao, L., Liu, ZP. et al. Identifying module biomarker in type 2 diabetes mellitus by discriminative area of functional activity. BMC Bioinformatics 16, 92 (2015). https://doi.org/10.1186/s12859-015-0519-y
[9] Ze-Jun Ma, Pei Sun, Gang Guo, Rui Zhang, Li-Ming Chen, "Association of the HLA-DQA1 and HLA-DQB1 Alleles in Type 2 Diabetes Mellitus and Diabetic Nephropathy in the Han Ethnicity of China", Journal of Diabetes Research, vol. 2013, Article ID 452537, 5 pages, 2013. https://doi.org/10.1155/2013/452537
[10] Basavaraju M, de Lencastre A. Alzheimer's disease: presence and role of microRNAs. Biomol Concepts. 2016;7(4):241-252. DOI: 10.1515/bmc-2016-0014
[11] White R, Woodward S, Leppert M, et al. A closely linked genetic marker for cystic fibrosis. Nature. 1985;318(6044):382-384. DOI: 10.1038/318382a0
[12] Powars D, Hiti A. Sickle cell anemia. Beta s gene cluster haplotypes as genetic markers for severe disease expression. Am J Dis Child. 1993;147(11):1197-1202. DOI: 10.1001/archpedi.1993.02160350071011
[13] Origa, R. β-Thalassemia. Genet Med 19, 609–619 (2017). https://doi.org/10.1038/gim.2016.173
[14] Liou JD, Chu DC, Cheng PJ, et al. Human chromosome 21-specific DNA markers are useful in prenatal detection of Down syndrome. Ann Clin Lab Sci. 2004; 34(3): 319-323.
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