Unprecedented developments in genomics research and ancillary technologies are creating the potential for astonishing changes in both the healthcare field and the life sciences sector. The innovative genomics applications include the following: (1) embracing next generation sequencing (NGS) in clinical diagnostics setting (applying both whole genome and exome sequencing), (2) single cell sequencing studies, (3) quantifying gene expression changes (including whole transcriptome sequencing), (4) pharmacogenomics, and (5) cell-free DNA blood-based testing. This minireview describes the impact of clinical genomics disruptive innovations on the healthcare system in order to provide better diagnosis and treatment. The observed evolution is not limited to the point-of-care services. Genomics technological breakthroughs are pushing the healthcare environment towards personalized healthcare with the real potential to attain better wellbeing. In this article, we will briefly discuss the Gulf region population-based genome initiatives that intend to improve personalized healthcare by offering better prevention, diagnosis, and therapy for the individual (precision medicine). Qatar’s endeavor in genomics medicine will be underscored including the private Applied Biomedicine Initiative (ABI).
Genomic testing has ushered in a new period in medicine triggering a medical revolution that is evidence-based whereby medicine is personalized, predictive, preventive, and participatory [
Clinical genomics utilizes sequencing technologies to support patient diagnosis and care [
Healthcare delivery is being transformed by clinical genomics. Currently, the techniques are primarily applied in medical genetics and cancer to improve diagnosis and patient care. In Qatar, the burden of chronic diseases in the society is astounding [
Next generation sequencing (NGS) technology is progressing at a very rapid pace making it faster and more accurate than before. The cost of DNA sequencing is continuously declining. Today’s human genome sequencing cost is merely few thousand dollars ($3-5K), and it continues to drop [
Recently, the different high throughput DNA sequencing technologies and their application have been reviewed [ Whole genome sequencing (WGS) Clinical exome sequencing (CES) or aka Whole Exome Sequencing (WES) Whole transcriptome sequencing (WTS) Single cell sequencing
To recap briefly, WGS has evolved from being a research tool to being applied in the clinics [
Therapeutic failure of drugs as well as serious adverse events of drugs on individuals or subpopulations of patients can have a genetic component. PGx is the science of understanding the genetic variations influencing the biological effects of drugs (drug response and adverse drug reactions). PGx combines pharmacology and genomics to develop effective, safe medications and doses that will be tailored to a person’s genetic makeup, as drug-gene interaction may lead to enzymatic inhibition and induction that may alter drugs’ metabolism.
Individuals respond differently to a drug and this wide individuals’ variation in response to treatments could be attributed to the presence of several interindividual genetic variations/polymorphisms, i.e., single polynucleotide polymorphism (SNPs) in drugs’ metabolic and action pathways, for instance, CYO450 2C19+, CYP450 2C9-, VKORC1, CYP2D6, CYP450 3A4/3A5, Factor II, Factor V Leiden, MTHFR, OPRM1, UGT1A1, and UGT2B7c, to the most commonly prescribed drugs such as selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), opioid pain medications, beta blockers, type I antiarrhythmic, and Warfarin.
Drug action studies focus on two major factors: (1) pharmacokinetic and (2) pharmacodynamic. Pharmacokinetics defines how much of a drug is needed to reach its target in the body and involves four processes: absorption, distribution, metabolism, and excretion. Pharmacodynamics, on the other hand, defines how well the target cells such as cancer cells, heart cells, and neurons respond to the drug via their receptors, ion channels, enzymes, and immune system components.
Thus, one of the benefits of PGx is to provide an entirely novel approach to therapeutics, i.e., actionable information to pinpoint which treatments will work best and avoid drugs that may cause adverse effects via individually personalized therapies’ dosage to the specific biochemical networks of the patient. Furthermore, to classify specific metabolizing gene variants into their slow, intermediate, normal, and ultrafast metabolizing forms as appropriate for each drug and group patients into poor metabolizers (PMs), intermediate metabolizer (IMs), extensive metabolizers (EMs), and a ultrarapid metabolizers (UMs) [
Cell-free nucleic acid is a broader term which describes small DNA fragments, i.e., cfDNA, mRNA, and microRNA, that are freely circulating in the bloodstream as a consequence of normal body physiology or under various clinical conditions such as cardiovascular, metabolic, and fetal disorders [
CTCs are considered molecular signatures for cancer cells that are shed from the primary tumor site and then enter the body circulation system. As such, they are seeds for subsequent growth of additional tumors in vital distant organs (metastasis). CTCs importance in current cancer research started from the mid-1990s with the observation that tumors shedding cells at less than 1.0% per day occurring early on in the course of disease are detectable in blood. The demonstration was facilitated by superbly sensitive magnetic separation technology employing ferrofluids, i.e., colloidal magnetic nanoparticles and high gradient magnetic separators. A variety of other technologies have been applied to CTC enumeration and identification since that time [
CTCs’ are deemed a “liquid biopsy” revealing metastasis in action by harnessing information about the patient’s disease status. CTC analysis has been used instead of tissue biopsies that are poor, invasive in nature, and cannot be used repeatedly and are considered ineffective in understanding metastatic risk, disease progression, and treatment effectiveness.
To date, a variety of research methods have been developed to isolate and enumerate CTCs [
Nuclear DNA is packaged in chromosomes within the cell; however, mitochondria also has a small amount of their own DNA termed mitochondrial DNA (mtDNA). In humans, mtDNA is about 16,500 base pairs, representing a small fraction of the total DNA in cells. Mutations in mtDNA can lead to several illnesses including cancers such as breast, colon, stomach, liver, and kidney cancers [
Recently, a mutation in mtDNA has been used to achieve the diagnosis of unsolved cases of prostate, ovarian, lung, and pancreatic cancers and endometriosis. Genomic deletions within mitochondria begin to happen long before traditional histology methods can identify disease. Biochemical signatures can identify genomic deletions associated with a disease and predict its onset much earlier than a pathologist can observe a problem, thus creating a greater window of time for treatment possibilities [
To amplify diagnosis probability, CTCs and cfDNA combined analysis in a single system is being tackled. The advantage of doing this is the ability to confirm that a reported mutation is real and is not a false positive.
The era of precision medicine stratifies patients into groups and subgroups. This division is an important strategy during the clinical phases of drug development. It also offers healthcare customization that reflects either disease susceptibility or response to drug/therapy, henceforth a tailored medical treatment for individual patients or subpopulations. Obviously, the catalysts for this progress have been genomics and their application in the clinics [
The human genome sequencing completion in 2003 at a cost of USD $3.0 billion has had far reaching impact. It opened the door to revolutionize molecular diagnostics and point-of-care tests (POCT). The HGP sweeping effects range from novel biomarkers and diagnostic development to cost advantage, therefore driving innovation in terms of patient outcomes improvement, process/quality of care, etc. [
The GCC genome projects were introduced in an earlier publication [
Recently, the UAE Ministry of Health and Prevention has announced the UAE Human Genome Project during the “
Genomics research is not only relevant but also a wise investment, since genomic medicine has the potential to affect people’s lives now and in the future. Only 5% of the 7,000 inherited rare diseases identified worldwide have treatments today. Rare inherited monogenic diseases epitomize the healthcare burden in the Gulf region and more specifically Qatar. By one estimate, 8% of babies in the Gulf region are born with some type of a genetic disease, compared with 5% in most high-income countries [
Personal genomics is ranked #1 within healthcare trends. Steve Jobs, Founder of Apple, said “
Indeed, personal genomics analysis is a conundrum. There are ethical ramifications of genetic testing that are not clear at all levels. It presents a dilemma in terms of What to report? How to report it and when to report it? Undoubtedly, there are still issues that need to be contended with such as personal privacy and data management security, not to mention the educational component of conveying information as the subject needs to be well informed and learn how to deal with the results. Moreover, from a scientific standpoint the predictive value for the vast majority of common health conditions is weak. We are still a distance from resolving these matters at the individual, societal, and regulatory levels. For instance, the FDA imposed restrictions and dictated regulations on 23andMe data/information sharing [
NGS scalability, speed, and resolution permit multiple genes assessment across many samples in parallel. Targeted sequencing panels have broad appeal as a diagnostic tool. Targeted gene sequencing offers the following: (1) higher depth and coverage, (2) detection of low allele frequencies, (3) digestible results, and (4) effectiveness and efficiency [
There is a tendency towards moving away from the “one test, one drug” model that has defined companion diagnostics. For instance, Quest Diagnostics and ThermoFisher partnership offer Oncomine Dx Target Test, an NGS-based companion diagnostic panel for non-small cell lung cancer that was approved by the FDA in June 2017. The panel measures alterations in 23 genes in total to define whether patients have ROS1, EGFR, and BRAF variations linked to three FDA-approved drugs plus the presence or absence of variants in other genes. It is a companion diagnostic for AstraZeneca’s EGFR inhibitor Iressa (gefitinib), Pfizer’s ALK and ROS1 inhibitor Xalkori (crizotinib), and the combination of Novartis’ MEK inhibitor Mekinist (trametinib) and RAF inhibitor Tafinlar (dabrafenib). FoundationOne CDx (F1CDx) is another NGS-based test, detecting changes in 324 genes relevant to non-small cell lung cancer, breast cancer, colorectal cancer, ovarian cancer, and melanoma that gained FDA approval as well. F1CDx also provides information on microsatellite instability and tumor mutational burden.
The forthcoming discussion was reported on earlier in a general sense [
Myeloproliferative neoplasms (MPNs), blood cancers, are a diverse group of clonal hematopoietic stem cell (HSC) disorders associated with the expansion of one or more mature cell lineages such as myeloid cells, erythrocytes, and megakaryocytes. MPNs classification includes polycythemia vera (PV), essential thrombocythemia, (ET) and myelofibrosis (MF). Several clinical complications could conceivably develop like thrombosis and/or hemorrhage acute myeloid leukemia [
The first description of MPNs pathogenesis was in 2005, when the first mutation related to MPNs in the Janus kinase 2 (JAK2) was identified [
So far, no specific molecular marker has been identified in the remaining 30 to 45% of ET or PMF patients [
In sum, all the CALR mutations were indels in exon 9 generating a +1 base-pair frameshift and had a remarkable association with the disease. These two novel CALR somatic mutations represent the second most commonly altered genes in ET and PMF patients that are JAK2 -ve and MPL -ve. CALR mutations account for about 20-30% of MPN patients. The COSMIC database has the most updated release (v87, released 13-NOV-18).
Intriguingly, a cluster of 5-tribal Qatari ET familial cases has been discovered. Since it is socially accepted and a tribal norm to marry first cousins we anticipate the preservation of a limited genetic pool engendering founder effects. This presents an opportunity to investigate the mechanisms behind MPNs phenotypic diversity [
Nutrigenomics investigates the influence of nutrients on genes to understand molecular interactions between dietary intakes with the genome. An individual’s response is tied to one's genetic makeup markedly affecting the person’s chronic disease status. This genotype nutritious optimization “personalized nutrition” facilitates personalized dietary advice [
Qatar is among the top 10 countries in diabetes prevalence and impaired glucose tolerance. Lifestyle and environmental interactions have long-lasting even generational genomic impression (epigenomic effect). It is projected that diabetes prevalence could increase by 130% demanding a new lens to assess the risk factors [
The high incidence rate of inherited monogenic inborn metabolic errors among Qatari (Qatar ~1:1,800 versus international incidence 1:100,000) is largely attributed to excessive consanguinity marriages. For example, the classical homocystinuria caused by pan tribal autosomal receives founder mutation R336C in the cystathionine
A CES study revealed a high diagnostic yield of 60% for a set of 149 Middle Eastern (ME) patients with Mendelian disorders primarily by virtue of consanguinity. Furthermore, the ME population is highly endogamous; hence, it is expected that Mendelian disorders particularly those recessively inherited are more prevalent. Other studies in the ME region revealed similar results [
A follow-up molecular study was carried out by Al-Dewik and associates [
Reanalysis of “negative” cases revealed 30/124 (24%) being positive. Most families opted not to receive ACMG secondary findings but among those 20 cases who agreed, only one had such a finding. The high diagnostic rate that was observed in this study was attributed to the high rate of consanguinity and our reanalysis of “negative” cases in light of newly published literature. The data corroborate a growing body of evidence in support of considering CES as a first-tier molecular test in patients with suspected Mendelian phenotypes. [
Qatar Science and Technology Park (QSTP) is an initiative chartered to promote innovation and entrepreneurship to facilitate a knowledge-based economy, commercialize research, and build capacity. The private biomedical ABI initiative exploits Qatar’s genomics efforts. The ABI MDx invention was hosted by QSTP accelerator program for the development of an MDx kit for CALR types 1 and 2 mutations for essential thrombocythemia (ET) and primary myelofibrosis (PMF) patients [
Synthesis of CALR genes: the CALR synthetic genes were assembled from oligonucleotides and/or PCR products. The fragment was inserted into pMA-RQ
Here, the synthetic gene CALR wild type, CALR type 2 Ins_5bp, and CALR type1 Del_52bp were assembled from synthetic oligonucleotides and/or PCR products. The fragment was inserted into pMA-RQ
In the CALR type 2 assay (K385fs
In December 2013, Her Highness Sheikha Moza bint Nasser, Qatar Foundation Chairperson, launched the Qatar Genome Project (QGP), which would “
Precision medicine: Qatar personalized genomics and healthcare initiative (Qatar Genome Project-QGP, Qatar Biobank-QBB, Sidra Medicine, Hamad Medical Corporation-HMC, WISH, and other stakeholders).
Another driving force is developing regional reference laboratory necessitating overseas lab validation. ABI long-standing goal is to establish a local, reliable reference genomics laboratory to enable physicians to make informed patients decisions in a timely, cost-effective manner.
Broadly, the ABI development programs are as follows: Blood cancers, e.g., myeloproliferative neoplasms (MPNs). Here, MPNs are presented as a case study to develop an MDx kit Metabolic syndromes and nutrigenomics Inherited genetic disorders
The scientific rational for the selection of these development programs has been described above based on the Qatari context. The marketing rational for MDx is explained below.
There is a strong demand for precise clinical diagnostic tests. Largely the nature of current clinical testing is conventional, routine, and high-volume tests such as clinical chemistry. With the tests increased difficulty and complexity like RT-PCR, NGS panels, the use of saliva in lieu of blood work, and microchips, the capable labs performing these tests decreases significantly. When complicated, low volume specialty tests introducing the number of proficient laboratories becomes considerably less. The sophisticated realms of
Applied Biomedicine intends to be a leader in developing cutting-edge molecular assay technologies based kits.
Cancer rates are rising fast in Qatar plus other GCC countries. Data from 1998 to 2007 show that there were 95,183 newly diagnosed cancer cases in the GCC [
Despite cancer prevalence increase, the vast majority of medical labs around the world still rely on routine, basic technology for diagnosis such as hematology, histopathology, cytogenetics, and some molecular techniques. These basic MDx methods are not sufficient to ascertain mutations (changes at multibase level). Regionally, the current state-of-the-art methods to diagnose cancer like NGS and other MDx are under development. NGS gene panels, whole exome sequencing, and whole genomics sequencing provide advanced tools to investigate anomalies at multigene level. Notably, existing cancer testing techniques only furnish a positive/negative end result that is a yes or no answer. This is by far a hindrance for two reasons: (1) the inability to ascertain cancer severity/burden and (2) the failure to assess patients’ response to selected therapy; therefore, cancer patients experience undue encumbrances during the course of their treatment; moreover, it puts financial constraints on the healthcare system instead of investing the money in other important care areas. Accordingly, these sophisticated NGS type testing services are needed to reduce patients’ inconvenience. The ABI MDx kit provides the solution.
ABI developed a novel cancer MDx test that quantifies the cancer burden severity in the patient and simultaneously permits therapy monitoring. A first in class highly specific and sensitive test offers the following criteria and values: Determining precisely the severity of cancer Endorsing effective treatments to alleviate patients pain and suffering Cost-savings to the healthcare system
While an RUO kit label bypasses regulatory approval, it is imperative to understand the regulatory requirements especially when considering market expansion. The US Food and Drug Administration (FDA) is a regulatory agency with broad authority. It is responsible for consumers’ protection and wellbeing from food products, to drugs/biologics to medical devices, and cosmetics, tobacco, and veterinary products. The ABI kit classification falls into Class II Device denoting market clearance through a 510(k) process.
GCC countries do not have a formal rigorous US FDA type processes in place. It is reasonable to assume that US FDA requirements, international standards and mechanisms will be adopted. Saudi Arabia has US FDA equivalent; however, it does not appear that they have approved a diagnostics kit in the past. In Qatar, the Ministry of Public Health regulates diagnostics laboratories and diagnostics kit approvals.
A variety of business and industry parameters may impact successful product launch. Many of these factors are beyond the innovator control. There are also risk factors pertaining to commercialization and regulatory approval as indicated above. Risk of failure is minimized through identifying appropriate mitigations steps.
Diagnostics device development in particular is a very complex and variable process with threats to success emerging at many points along the way. However, there are components one can put in place to ensure the smoothest path possible. Utilizing well developed or mature technology Choosing the right team Using a systems approach to product development Using a risk-based approach to product development Dedicated resources and project management
Genotype–phenotype associations have been a central dogma in biology for a century now. Advancements in nucleic acid sequencing technologies have created an extraordinary momentum in translational medicine that amplified our basic understanding of chronic, metabolic, and genetic diseases. Genomic technologies and molecular diagnostics have enabled the vision of precision medicine and are drivers for healthcare evolution. The impact of these technologies will positively affect the continuum of healthcare from prevention to diagnosis to therapy. The next applied phase is critical as it requires these technologies to be integrated into the clinics and hospitals to guide healthcare decisions toward the most effective prevention of disease and targeted therapies for individuals based on their genetic make-up. Hence, translational genomics approaches from bench to bedside will fulfill the promise of P4 medicine [
Some of the personalized healthcare emerging trends that are impacting market dynamics are as follows: Molecular diagnostics (MDx): MDx technologies are evolving rapidly and are being deployed in the clinics from diagnosis to therapy in a personalized fashion (e.g., breast cancer testing). The direct-to-consumer (DTC) diagnostic: the DTC genetic-testing industry is predicted to grow to US $340 million in the next five years. This is considered a fraction of the overall DNA testing market, which is estimated to reach $10 billion by that time. Fast-moving consumer goods (FMCG): these companies are nowadays engaged in the development of personalized healthcare products for their customer segments taking advantage of their marketing power. Information communication technology (ICT): genetic information and other healthcare data are not restricted to the domain of a physician. Practically, they are now for sale (e.g., DIY testing). They are being exploited even by non-healthcare providers in order to deliver solutions to the healthcare sector.
The QIPA1-0908-1403 USD $100K award for lead innovator and ABI founder Nader Al-Dewik is entitled “Development of absolute quantification kit for CALR types 1 and 2 mutations for essential thrombocythemia and primary myelofibrosis patients” [
The authors declare no conflicts of interest.
The Applied Biomedicine Initiative (ABI) was supported by the Qatar Science and Technology Park (QSTP) Accelerator Program on March