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LETTERS TO THE EDITOR

Answer to comments regarding the article “Genomics in medicine”

Ruth Ruiz Esparza-Garrido,^a Miguel Angel Velázquez-Flores,^a Diego Julio Arenas-Aranda,^a† Fabio Salamanca-Gómez^a,b

^aUnidad de Investigación Médica en Genética Humana, Hospital de Pediatría

^bCoordinación de Investigación en Salud

^†In memoriam

Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Distrito Federal, México

Communication with: Fabio Salamanca-Gómez

Email: fasalam@prodigy.net.mx

We thank Dr. Victor Manuel Gomez Valdespino for his comments on our article “La Genómica en la Medicina” ("The genome in medicine").¹ As Dr. Valdespino mentioned, the goal of our article was to analyze in a simple and didactic way the major developments that have occurred in recent decades in the genomic study of complex diseases such as cancer. As the article notes, for a disease to develop, it is necessary for different cellular alterations to join: mutations, single nucleotide polymorphisms (SNP) and copy number variations (CNV), chemical modifications in the expression of DNA sequences (epigenetic alterations), posttranslational modifications of the protein, and changes in expression of gene expression regulators such as small noncoding RNA (microRNA, siRNA, piRNA) and long noncoding RNA (lncARN), which induce changes in complex signaling networks and affect the proper functioning of the organism.
Personalized predictive medicine is a new and complex field that uses the technology available to try to choose the best treatment and makes models to individualize diseases.^2-4 Genetic information obtained from each patient can be used to explain the success or failure of a drug in the treatment of a disease in patients with identified genetic alterations; however, personalized medicine remains a challenge for the daily practice of applied clinical medicine.3 This is important, because in order to individualize treatments it is necessary to carry out a large number of population studies, because "the system" needs feedback.3-5 This process consists of different phases:

 

1. Phase I: Knowledge generation.
2. Phase II: Application of technology, which in turn includes:
   • Genomic sequencing.
   • Marker database.
   • Therapeutic target: suggestions about therapies and prescriptions.

Personalized medicine is gradually becoming a field of transformation. So far, seven diagnostic and drug combinations have been approved; however, it is not possible to say that the ideal scenario or solution to complex diseases have been reached, because these are remarkably heterogeneous.^2-5 That is to say, a signaling or metabolic pathway may have different levels of regulation: transcriptional, epigenetic, and post- transcriptional, which can generate the "aberrant mechanism” cell phenotype. Also, although a great effort has been made to create algorithms that allow us to store and analyze the vast amount of data obtained daily from various types of mass analysis, it is not an easy task to identify useful biomarkers for disease treatment. Consequently, the application of individual treatment must now be taken with some reserve.^2-6

Both human gene engineering and therapy are techniques that allow one to insert a functional gene into a cell to try to correct a genetic defect or to give the cell a new function.⁷ As with personalized medicine, these techniques are very powerful instruments whose potential is still limited.⁷ That is, the use of these techniques has been applied only in certain hereditary genetic diseases.^8-14 In this sense, it is essential to take into account factors such as:

 

1. What type of cell or tissue the "new gene" shall be inserted into.
2. It should be known whether this amendment will only affect the cells or tissue of our choosing.
3. Which vector will be used to perform the insertion of genetic material; and finally.
4. It is necessary to evaluate the efficiency of the introduced gene and its response in the cell, tissue, or organ in which was lodged.¹⁰

 

While these technologies have proven effective in particular cases, it is essential to bear in mind the complexity of regulation and interaction networks that exist in cells.¹⁴ This is because the introduction of genetic material into an organism by vectors is a process that must be approached from a holistic point of view; that is, one must know and take into account all factors that may influence the response to be obtained, which is complex and difficult.¹⁰ Experiments in animals form a key part in the study of any gene therapy application, as well as safety analysis, determination of efficiency of gene transfer, and the effects and duration of dose.¹²

All of these tools, along with systems biology, have unlimited potential for the development of new drugs and therapeutic targets, which can be very beneficial for the treatment of various human diseases. This is, thankfully, a very dynamic field. Consider the recent breakthrough in the prevention of mitochondrial diseases of matrilineal transmission, for which the British Parliament has authorized the development of human beings with the genomic contribution of three different individuals.¹⁵ However, one should never lose sight of the implications and levels of complexity that are permanently generated in the cells to harmoniously carry out the regulation of genes and their multiple and intricate processes. 

References

1. Ruiz R, Velázquez MA, Arenas D, Salamanca F. La genómica en la Medicina. Rev Med Inst Mex Seguro Soc. 2014; 52(5):566-73.
2. Cohen JP, Felix AE. Personalized Medicine’s Bottleneck: Diagnostic Test Evidence and Reimbursement. J Pers Med. 2014;4(2):163-75.
3. Bowdin S, Ray PN, Cohn RD, Meyn MS. The genome clinic: a multidisciplinary approach to assessing the opportunities and challenges of integrating genomic analysis into clinical care. Hum Mutat. 2014;35(5):513-9.
4. Ginsburg GS, Willard HF. Genomic and personalized medicine: foundations and applications. Transl Res. 2009;154(6):277-87.
5. Berkman BE, Hull SC, Eckstein L. The unintended implications of blurring the line between research and clinical care in a genomic age. Per Med. 2014;11(3):285-95.
6. Okimoto RA, Bivona TG. Recent advances in personalized lung cancer medicine. Per Med. 2014;11(3):309-21.
7. Jekunen A. Clinicians’ expectations for gene-driven cancer therapy. Clin Med Insights Oncol. 2014;8:159-64.
8. Liu M, Maurano MT, Wang H, Qi H, Song CZ, Navas PA, et al. Genomic discovery of potent chromatin insulators for human gene therapy. Nat Biotechnol. 2015 Jan 12. doi: 10.1038/nbt.3062. [Epub ahead of print]
9. Le Du F, Ueno NT. Targeted therapies in triple-negative breast cancer: failure and future. Womens Health (Lond Engl). 2015;11(1):1-5.
10. Sugawara K, Koushima Y, Inao M, Nakayama N, Nagoshi S, Yakabi K, et al. Multicenter Prospective Study to Optimize the Efficacy of Triple Therapy with Telaprevir in Patients with Genotype 1b HCV Infection According to an Algorithm Based on the Drug Adherence, IL28B Gene Allele and Viral Response: the AG & RGT Trial. Hepatol Res. 2015 Jan 9. doi: 10.1111/hepr.12475. [Epub ahead of print]
11. DiGiusto DL. Stem Cell Gene Therapy for HIV: Strategies to Inhibit Viral Entry and Replication. Curr HIV/AIDS Rep. 2015 Jan 13. [Epub ahead of print]
12. Smith SN, Paige C, Velazquez KT, Smith TP, Raja SN, Wilson SP, et al. Injury-specific promoters enhance herpes simplex virus mediated gene therapy for treating neuropathic pain in rodents. J Pain. 2015; 7. pii: S1526-5900.
13. Muthiah M, Che HL, Klash S, Jo J, Choi SY, Kim WJ, et al. Formulation of glutathione responsive anti-proliferative nanoparticles from thiolated Akt1 siRNA and disulfide-crosslinked PEI for efficient anti-cancer gene therapy. Colloids Surf B Biointerfaces. 2014; 126C:322-7.
14. Ruiz Esparza-Garrido R, Velázquez-Flores MÁ, Diegopérez-Ramírez J, López-Aguilar E, Siordia-Reyes G, Hernández-Ortiz M, et al. A proteomic approach of pediatric astrocytomas: MiRNAs and network insight. J Proteomics. 2013;94:162-75.
15. Castle S. Britain Set to Approve Technique to Create Babies From 3 People. NY Times. Feb. 3, 2015.

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