- Email: [email protected]
Genomic Medicine in Emerging Economies
CHAPTER
GENOMIC MEDICINE IN EMERGING ECONOMIES
21 Catalina Lopez Correa
Genome British Columbia, Vancouver, BC, Canada
21.1 INTRODUCTION Advances in genomics, and all other “omic”-related technologies, are revolutionizing the practice of medicine around the world. Genomic analysis is being used to provide a much more precise diagnosis to help guide treatments and to indicate the prognosis of several human diseases, in particular in rare diseases, cancer, and infectious diseases.1 Genomic analysis is gradually being adopted by diagnostic laboratories and hospitals in the United States, Canada, and Europe, and guidelines from US Food and Drug Administration (http://www.fda.gov) and the European Medicines Agency (http://www.ema.europa.eu) are being developed to provide a regulated framework for the clinical implementation of these new technologies.2 However, the adoption of genomic technologies in clinical practice in resource-limited countries and regions has been much slower. In this chapter, we will describe the advances in genomic technologies, the challenges emerging economies are facing in implementing these technologies, and also the opportunities that should be explored in order to democratize the use of genomics.
21.2 FROM SANGER SEQUENCING TO NEXT-GENERATION SEQUENCING AND NATION-WIDE GENOMIC PROGRAMS Genomic analysis, and genome sequencing in particular, has been the key innovation that has allowed scientist to analyze the genetic information contained in the DNA of every living organism. Genome sequencing technologies are the key drivers of precision (personalized) medicine approaches. The first generation of genome sequencing was introduced in the 1970s3 and was distributed more widely and industrialized during the 1980s. The first generation of sequencing technologies was recognized by its high accuracy but was expensive and had a very low throughput, which limited its use at a large scale. Even with its limitations, Sanger sequencing was the technology used to sequence the first human genome. In fact, the cost of sequencing the first human genome was about $3 billion, and it took several international institutes, hundreds of researchers, and 13 years to complete.4 Given the high cost of the first sequencing machines, only research institutions in developed countries could afford to adopt this technology when it was introduced in the market. Applied Genomics and Public Health. DOI: https://doi.org/10.1016/B978-0-12-813695-9.00021-2 © 2020 Elsevier Inc. All rights reserved.
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Luckily, in the past few years the cost of sequencing has declined exponentially thanks to a series of next-generation sequencing (NGS) technologies that have been developed and marked a new era in genomics, because they allowed to analyze very large amounts of DNA at a much more reasonable cost.5,6 Following the development of NGS technologies, in 2014 the US government launched a unique program to drive the cost of genome sequencing down to $1000 per genome. This dramatic decrease in the cost of sequencing has been often compared to Moore’s law who observed that computing power tends to double—and that its price therefore halves—every 2 years, but it is now clear that sequencing technologies have outpaced Moore’s law. As personal computers changed the world, the great advances in genome sequencing technologies are now revolutionizing the biomedical field.7 The genomic revolution is allowing scientist to sequence genomes much faster and at a much lower cost, leading to a more decentralized and democratized access to genomic data.8 All these advances in sequencing and genomic technologies together with an increasing number of results that are having an impact in patient care, going from disease prevention to more accurate diagnosis and personalized treatment decisions, have led to the development of a series of cuttingedge genomic medicine or precision medicine programs in various countries. Most of these programs are using local expertise and are aligning their efforts according to their cultural, political, and social backgrounds. On one hand, these programs are helping advance the use and application of genomics in clinical practice, and on the other the challenge remains that most of these programs are being developed in isolation. Organizations such as the National Human Genome Research Institute and the Global Genomic Medicine Collaborative (G2MC) are now fostering connections between different global initiatives and are also working on capturing and disseminating research outcomes, best practices, policies, and health economic analysis to help develop international standards in order to advance the global implementation of genomics medicine.9 However, the pace of implementation of genomic medicine practices is not always equally met in developing and resource-limited countries or emerging economies, where significant barriers exist, often related to lack of resources, lack of technology and knowledge transfer, and lack of training. Some of the barriers that these regions are encountering when trying to implement clinical genomic initiative are described more in detailed here.
21.3 CAPACITY BUILDING AND COST OF SETTING UP SEQUENCING CENTERS Even with the dramatic increase in sequencing speed and the decrease in sequencing cost, establishing a genome sequencing facility with NGS remains a very costly endeavor. It has been estimated that the cost of establishing a sequencing facility varies from $100,000 to $700,000. The costs are higher when establishing a sequencing facility in developing countries (shipment, customs, reagents, maintenance, etc.), and the challenge is to maintain these facilities up a running at a costeffective manner.10 Also, laboratories in developing countries have great difficulty to cover contract services and to buy consumables and reagents that will ensure a fully operational high-throughput sequencing facility, at a cost that is affordable and that can compete with sequencing facilities in developed countries. The cost needed to develop and maintain these types of sequencing facilities
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far exceeds the funds that scientist in developing countries can access through local grants. Given these limitations, in many cases, scientists in developing countries are outsourcing genome sequencing services to private companies (e.g., Genotypic, Macrogen, Eurofins, and BGI) located in different regions of the world. However, it is important to invest in building capacity around genomic technologies in low- and middle-income countries to ensure the training of local scientists and the development of local initiatives. Investing in infrastructure not only for sequencing but more importantly in bioinformatics is one of the crucial steps to ensure emerging economies benefit from the genomics revolution.11
21.4 LACK OF DIVERSITY ON INTERNATIONAL DATABASES Many thousands of whole genomes have been sequenced after the first human genome sequence was published in 2001. However, most of these genomes have been sequenced in Europe or in the United States and belong, in the majority of the cases, to individuals of Caucasian origin. Despite the general agreement regarding the need to increase diversity on the human genomic data that are being generated and the need for a more democratized and equitable access to genomic technologies, genomics research remains largely focused on populations of European descent. A 2009 study indicated that 96% of all genomics studies were done on populations of European descent.12 An updated analysis done in 2016 indicated that non-European participants represented 19% of individuals studied in Genome-Wide Association Studies analysis.13,14 Most of this increase was associated to genomic data generated from Asian populations with other ethnic groups showing only a minimal increase15 even though over three-fourths of the world population live in Africa.16
21.5 PARACHUTE RESEARCH Lots of the research work around genomics in developing countries and emerging economies has been done in collaboration with northern and more developed countries. In recent years the term “parachute research” has emerged to describe initiatives where the results of these collaborations only, or mostly, benefit one side of the group. There is an increasing resistance against parachute researchers: the ones who go to another country (particularly low- and middle-income countries), use the local infrastructure, take samples of patients and populations, and then go back home to write an academic paper for a high-ranking journal without even acknowledging the participation of the local scientists and without ever returning results or data to the patients or populations used in the study.17 It is clear that North South collaborations are of great value, but these collaborations should be performed on equal and respectful bases where all contributions are fully recognized, and most importantly, these collaborations should be based on needs and priorities defined by the low- and middle-income countries. This mutual beneficial collaboration model has been suggested in 2013 by the Genomic Medicine Alliance (www.genomicmedicinealliance.org), and several collaborations have emerged based on this model.18 Some groups have initiated pilot studies that analyze the
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FIGURE 21.1 Model for productive North South collaborations. This figure illustrates the need for a more interactive collaboration where the exchange is initiated based on local needs, and the results will benefit emerging economies directly.
development of demand-driven and locally led research (Fig. 21.1) where countries from the South fully benefit from collaborations with northern countries.19
21.6 EDUCATION AND CAPACITY BUILDING The public health benefits from genetic and genomic innovations can only be realized when we fully understand how to best implement innovations in clinical practice. Several groups have studied the barriers for clinical implementation in Europe and the United States and have determined that clinician’s knowledge and understanding of the uses and applications of genomics in medicine
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is one of the key barriers that have slow down the adoption of genomic technologies in clinical practice.20 Several programs are now being set up in England and United States to help educate health-care providers on the use of genomics. In low- and middle-income countries the problem is even larger. The challenge is not only that the health-care provider are not informed and not trained to be able to fully understand and benefit from genomic innovations, the largest challenge is the lack of bioinformatics and computational expertise, and also the lack of a critical mass of scientists that are trained in cutting-edge genomic technologies.21 If we think about the patient’s journey, from the moment that a patient visits a doctor and the doctor decides to prescribe a test to the moment the patient gets the report with the results of the genomic or genetic test (Fig. 21.2), there are many professionals involved. All these professionals (doctors, nurses, pharmacists, lab technicians, bioinformaticians, etc.) need to be trained in order to fully implement clinical genomics to help improve patient’s health and outcomes. Biomedical scientists and health-care professionals in low- and middle-income countries frequently fail to fully appreciate the potential that this new technologies offer to improve medical diagnosis and treatment. Investing in training genomics scientist and informing health-care providers and patients about genomics is highly recommended to ensure these new technologies are adopted.
FIGURE 21.2 The patient journey. This figure illustrates the different professionals that are involved in ordering, performing, analyzing, and providing the results of a genomic test.
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Aside from these barriers, there are also growing opportunities to advance the implementation of genomics in emerging economy settings. Developing countries may be resource-limited but are also potentially rich in producing data in various genomic medicine-related disciplines, from the perspective of public health genomics. Even though the pace of implementation of genomic medicine varies from country to country, depending on a number of different parameters, in recent years, we have observed a series of success stories that are indicating the great potential genomic medicine has to help solve some of the most pressing health challenges present in low- and middleincome countries. Some of the opportunities for the implementation of genomic medicine in these countries are described next.
21.7 FAST-SECOND WINNER MODEL Most of the developed countries follow a very linear path to innovation. This path includes large investments in fundamental research to advance some initiatives into translation and application that could led to concrete return on investment and commercial opportunities.22 Instead of this linear innovation model used in developed countries, which goes from discovery science toward application and translational, a new innovation model for emerging economies has been proposed.23 The new approach has been called “Fast-Second Winner” model of innovation. This model offers multiple entry points into the global genomics innovation ecosystem for developing countries, whether or not extensive discovery projects and infrastructure is already in place. Some low- and middleincome countries have already been using this model of innovation and have advanced the implementation of genomic medicine at a public health level. One of these examples is the implementation of pharmacogenomics testing in some Asian countries. Whereas some European countries are heavily investing on large whole-genome sequencing initiatives similar to the one developed by Genomics England,24 scientists from Thailand proposed a simple pharmacogenomics test that could be used to avoid severe adverse drug events such as Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Adverse drug events such as SJS/TEN can occur in patients who take carbamazepine and have a particular gene variant; even though the events are rare, the burden on the patients and the cost to the health-care system are high due to the clinical severity. The scientist from Thailand then developed a simple pharmacogenomics ID card that is cost-effective and easy to use and that can indicate when an individual has the genetic variants associated with the severe adverse drug event. This pharmacogenomics ID card is now being covered by the public healthcare system in Thailand and is being implemented in other Asian countries such as Taiwan.25 Other countries have used different strategies to implement pharmacogenomics in clinical practice and have successfully aligned the local expertise with specific regional needs to advance the use and implementation of genomics.26
21.8 HEALTH BIOTECHNOLOGY IN LATIN AMERICA As described before, emerging economies as well as low- and medium-income countries are starting to use genomics and health biotechnology in many different ways. A study published in 2018
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analyzed the patterns of health biotechnology publications in six Latin American countries (Argentina, Brazil, Chile, Colombia, Cuba, and Mexico) from 2001 to 2015. They found that many of these countries had a publication growth patter higher than some industrialized nations, but the visibility of their research (measured by the number of citations) did not reach the world average, with the only exception of Colombia.27 Some of the examples cited in the paper are the development of an immune-enzymatic assay for the detection of serum antibodies against Trypanosoma cruzi (Chagas disease) in Chile and a diagnostic assay that uses biomarkers for tuberculosis detection in Colombia. The article also indicates that Latin American countries are active in international research collaboration with Colombia being the most active (64% of papers coauthored internationally), whereas Brazil was the least active (35% of papers). Data published in this and other papers indicate that emerging economies are embracing genomics and biotechnology and are also developing international collaborations on areas of key priorities for the regions such as infectious diseases.
21.9 GENOMICS IN AFRICA One of the key barriers and bottlenecks to advance the use of genomics in emerging economies is the lack of bioinformatics and computational biology expertise and the lack of local datasets. In most of low- and middle-income countries the use and analysis of large-scale genomics datasets have been limited by the availability of scientific expertise, the lack of infrastructure, and the lack of data generated from local populations. The African continent, with funding support from the National Institute of Health and the Welcome Trust, developed a new initiative called the Human Heredity and Health in Africa (H3Africa; https://h3africa.org). This initiative was created to help advance research of the genomic and environmental aspects of diseases prevalent in Africa, to build capacity around bioinformatics and around genomics research, and to generate reference datasets arising from African populations.28 As part of the H3Africa initiative, a specific bioinformatics network (H3ABioNet) was created to enable scientist to analyze their own data.29 The network has significantly contributed to create new infrastructure and to develop human capacity that will allow the continent to be more self-sufficient without having to always rely on the expertise and infrastructure available in developed countries.
21.10 GLOBAL INITIATIVES There are several global initiatives around genomics that have emerged in the last few years. Two worth noting are the Global Alliance for Genomics and Health (GA4GH; https://www.ga4gh.org) and the G2MC (https://g2mc.org). On the one hand the GA4GH has focused mainly on the research aspects of genomics by developing a policy framework and technical standards to enable responsible sharing and aggregation of genomic data. One of the initial GA4GH driver projects is the Clinical Genome Resource initiative (ClinGen) aiming at developing a knowledge base to support the understanding of genes and variants for use in precision medicine.30 ClinGen has been used as
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a reference dataset to help advance phenotype genotype correlations that can have an impact on patient diagnosis. On the other hand, the G2MC group is focusing on the clinical application and implementation of genomic medicine by fostering collaboration and engaging multiple stakeholders across the globe. The G2MC group is focusing on enabling the demonstration of value and supporting the effective use of genomics in medicine. The G2MC started as a discussion group where participants from many different regions (mostly developed countries) joined forces to develop standards for clinical implementation of genomics.9 The organization is now an independent entity that is embracing and attracting several members of low- and middle-income countries. It is clear that many advances have been made in the last 5 6 years and that we can now whiteness several success stories on the use and implementation of clinical genomics in emerging economies. These success stories will continue to grow, but the speed and impact will fully depend of the capacity emerging economies will have to invest in science and technology in order to build local capacity and expertise.
REFERENCES 1. McCarthy JJ, McLeod HL, Ginsburg GS. Genomic medicine: a decade of successes, challenges, and opportunities. Sci Transl Med. 12. 2013;5(189):189sr4. 2. Knowles L, Luth W, Bubela T. Paving the road to personalized medicine: recommendations on regulatory, intellectual property and reimbursement challenges. J Law Biosci. 2017;4(3):453 506. 3. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA. 1977;74(12):5463 5467. 4. Sboner A, Mu XJ, Greenbaum D, Auerbach RK, Gerstein MK. The real cost of sequencing: higher than you think!. Genome Biol. 2011;12(8):125. 5. Shendure J, Ji H. Next-generation DNA sequencing. Nat Biotechnol. 2008;26(10):1135 1145. 6. Mardis ER. A decade’s perspective on DNA sequencing technology. Nature. 2011;470(7333):198 203. 7. Check HE. Technology: the $1,000 genome. Nature. 2014;507(7492):294 295. 8. Li PE, Lo CC, Anderson JJ, et al. Enabling the democratization of the genomics revolution with a fully integrated web-based bioinformatics platform. Nucleic Acids Res. 9. 2017;45(1):67 80. 9. Manolio TA, Abramowicz M, Al-Mulla F, et al. Global implementation of genomic medicine: we are not alone. Sci Transl Med. 2015;7(290):290ps13. 10. Helmy M, Awad M, Mosab KA. Limited resources of genome sequencing in developing countries: challenges and solutions. Appl Transl Genom. 2016;9:15 19. 11. Forero DA, Wonkam A, Wang W, et al. Current needs for human and medical genomics research infrastructure in low and middle income countries. J Med Genet. 2016;53(7):438 440. Available from: https://doi.org/10.1136/jmedgenet-2015-103631. 12. Bentley AR, Callier S, Rotimi CN. Diversity and inclusion in genomic research: why the uneven progress? J Community Genet. 2017;8(4):255 266. 13. Hindorff LA, Bonham VL, Brody LC, et al. Prioritizing diversity in human genomics research. Nat Rev Genet. 2018;19(3):175 185. Available from: https://doi.org/10.1038/nrg.2017.89. Epub 2017 Nov 20. 14. Hindorff LA, Bonham VL, Ohno-Machado L. Enhancing diversity to reduce health information disparities and build an evidence base for genomic medicine. Per Med. 2018;15(5):403 412. Available from: https://doi.org/10.2217/pme-2018-0037. Epub 2018 Sep 13. 15. Popejoy AB, Fullerton SM. Genomics is failing on diversity. Nature. 2016;538(7624):161 164.
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16. Nordling L. How the genomics revolution could finally help Africa. Nature. 2017;544(7648):20 22. 17. Bockarie M, Machingaidze S, Nyirenda T, Olesen OF, Makanga M. Parasitic and parachute research in global health. Lancet Glob Health. 2018;6(9):e964. 18. Cooper DN, Brand A, Dolzan V, et al. Bridging genomics research between developed and developing countries: the Genomic Medicine Alliance. Per Med. 2014;11(7):615 623. 19. Kok MO, Gyapong JO, Wolffers I, Ofori-Adjei D, Ruitenberg EJ. Towards fair and effective North-South collaboration: realising a programme for demand-driven and locally led research. Health Res Policy Syst. 2017;15(1):96. 20. Sperber NR, Carpenter JS, Cavallari LH, et al. Challenges and strategies for implementing genomic services in diverse settings: experiences from the Implementing GeNomics In pracTicE (IGNITE) network. BMC Med Genomics. 2017;10(1):35. Available from: https://doi.org/10.1186/s12920-017-0273-2. 21. Isaacson Barash C. Translating translational medicine into global health equity: what is needed? Appl Transl Genom. 2016;9:37 39. Available from: https://doi.org/10.1016/j.atg.2016.03.004. Published2016 Mar 10. 22. Wiechers IR, Perin NC, Cook-Deegan R. The emergence of commercial genomics: analysis of the rise of a biotechnology subsector during the Human Genome Project, 1990 to 2004. Genome Med. 2013;5(9):83. Available from: https://doi.org/10.1186/gm487. Published 2013 Sep 20. 23. Mitropoulos K, Cooper DN, Mitropoulou C, et al. Genomic medicine without borders: which strategies should developing countries employ to invest in precision medicine? A new “Fast-Second Winner” strategy. OMICS. 2017;21(11):647 657. Available from: https://doi.org/10.1089/omi.2017.0141. PubMed PMID: 29140767. 24. Turnbull C, Scott RH, Thomas E, et al. 100 000 Genomes Project. The 100 000 Genomes Project: bringing whole genome sequencing to the NHS. BMJ. 2018;361:k1687. Available from: https://doi.org/ 10.1136/bmj.k1687. Erratum in: BMJ. 2018 May 2;361:k1952. PubMed PMID:29691228. 25. Sukasem C, Chantratita W. A success story in pharmacogenomics: genetic ID card for SJS/TEN. Pharmacogenomics. 2016;17(5):455 458. Available from: https://doi.org/10.2217/pgs-2015-0009. Epub 2016 Mar 30. PubMed PMID: 27027537. 26. Mitropoulos K, Al Jaibeji H, Forero DA, et al. Success stories in genomic medicine from resourcelimited countries. Hum Genomics. 2015;9:11. Available from: https://doi.org/10.1186/s40246-015-0033-3. PubMed PMID: 26081768. 27. Leo´n-de la ODI, Thorsteinsdo´ttir H, Caldero´n-Salinas JV. The rise of health biotechnology research in Latin America: a scientometric analysis of health biotechnology production and impact in Argentina, Brazil, Chile, Colombia, Cuba and Mexico. PLoS One. 2018;13(2):e0191267. Available from: https://doi. org/10.1371/journal.pone.0191267. 28. Mulder N, Abimiku A, Adebamowo SN, et al. H3Africa: current perspectives. Pharmgenomics Pers Med. 2018;11:59 66. Available from: https://doi.org/10.2147/PGPM.S141546. Published 2018 Apr 10. 29. Mulder NJ, Adebiyi E, Adebiyi M, et al. H3ABioNet Consortium, as members of the H3Africa Consortium Development of bioinformatics infrastructure for genomics research. Global Heart. 2017;12 (2):91 98. 30. Dolman L, Page A, Babb L, et al. ClinGen advancing genomic data-sharing standards as a GA4GH driver project. Hum Mutat. 2018;39(11):1686 1689. Available from: https://doi.org/10.1002/humu.23625. PubMed PMID: 30311379.
GENOMIC MEDICINE IN EMERGING ECONOMIES
21 Catalina Lopez Correa
Genome British Columbia, Vancouver, BC, Canada
21.1 INTRODUCTION Advances in genomics, and all other “omic”-related technologies, are revolutionizing the practice of medicine around the world. Genomic analysis is being used to provide a much more precise diagnosis to help guide treatments and to indicate the prognosis of several human diseases, in particular in rare diseases, cancer, and infectious diseases.1 Genomic analysis is gradually being adopted by diagnostic laboratories and hospitals in the United States, Canada, and Europe, and guidelines from US Food and Drug Administration (http://www.fda.gov) and the European Medicines Agency (http://www.ema.europa.eu) are being developed to provide a regulated framework for the clinical implementation of these new technologies.2 However, the adoption of genomic technologies in clinical practice in resource-limited countries and regions has been much slower. In this chapter, we will describe the advances in genomic technologies, the challenges emerging economies are facing in implementing these technologies, and also the opportunities that should be explored in order to democratize the use of genomics.
21.2 FROM SANGER SEQUENCING TO NEXT-GENERATION SEQUENCING AND NATION-WIDE GENOMIC PROGRAMS Genomic analysis, and genome sequencing in particular, has been the key innovation that has allowed scientist to analyze the genetic information contained in the DNA of every living organism. Genome sequencing technologies are the key drivers of precision (personalized) medicine approaches. The first generation of genome sequencing was introduced in the 1970s3 and was distributed more widely and industrialized during the 1980s. The first generation of sequencing technologies was recognized by its high accuracy but was expensive and had a very low throughput, which limited its use at a large scale. Even with its limitations, Sanger sequencing was the technology used to sequence the first human genome. In fact, the cost of sequencing the first human genome was about $3 billion, and it took several international institutes, hundreds of researchers, and 13 years to complete.4 Given the high cost of the first sequencing machines, only research institutions in developed countries could afford to adopt this technology when it was introduced in the market. Applied Genomics and Public Health. DOI: https://doi.org/10.1016/B978-0-12-813695-9.00021-2 © 2020 Elsevier Inc. All rights reserved.
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Luckily, in the past few years the cost of sequencing has declined exponentially thanks to a series of next-generation sequencing (NGS) technologies that have been developed and marked a new era in genomics, because they allowed to analyze very large amounts of DNA at a much more reasonable cost.5,6 Following the development of NGS technologies, in 2014 the US government launched a unique program to drive the cost of genome sequencing down to $1000 per genome. This dramatic decrease in the cost of sequencing has been often compared to Moore’s law who observed that computing power tends to double—and that its price therefore halves—every 2 years, but it is now clear that sequencing technologies have outpaced Moore’s law. As personal computers changed the world, the great advances in genome sequencing technologies are now revolutionizing the biomedical field.7 The genomic revolution is allowing scientist to sequence genomes much faster and at a much lower cost, leading to a more decentralized and democratized access to genomic data.8 All these advances in sequencing and genomic technologies together with an increasing number of results that are having an impact in patient care, going from disease prevention to more accurate diagnosis and personalized treatment decisions, have led to the development of a series of cuttingedge genomic medicine or precision medicine programs in various countries. Most of these programs are using local expertise and are aligning their efforts according to their cultural, political, and social backgrounds. On one hand, these programs are helping advance the use and application of genomics in clinical practice, and on the other the challenge remains that most of these programs are being developed in isolation. Organizations such as the National Human Genome Research Institute and the Global Genomic Medicine Collaborative (G2MC) are now fostering connections between different global initiatives and are also working on capturing and disseminating research outcomes, best practices, policies, and health economic analysis to help develop international standards in order to advance the global implementation of genomics medicine.9 However, the pace of implementation of genomic medicine practices is not always equally met in developing and resource-limited countries or emerging economies, where significant barriers exist, often related to lack of resources, lack of technology and knowledge transfer, and lack of training. Some of the barriers that these regions are encountering when trying to implement clinical genomic initiative are described more in detailed here.
21.3 CAPACITY BUILDING AND COST OF SETTING UP SEQUENCING CENTERS Even with the dramatic increase in sequencing speed and the decrease in sequencing cost, establishing a genome sequencing facility with NGS remains a very costly endeavor. It has been estimated that the cost of establishing a sequencing facility varies from $100,000 to $700,000. The costs are higher when establishing a sequencing facility in developing countries (shipment, customs, reagents, maintenance, etc.), and the challenge is to maintain these facilities up a running at a costeffective manner.10 Also, laboratories in developing countries have great difficulty to cover contract services and to buy consumables and reagents that will ensure a fully operational high-throughput sequencing facility, at a cost that is affordable and that can compete with sequencing facilities in developed countries. The cost needed to develop and maintain these types of sequencing facilities
21.5 PARACHUTE RESEARCH
363
far exceeds the funds that scientist in developing countries can access through local grants. Given these limitations, in many cases, scientists in developing countries are outsourcing genome sequencing services to private companies (e.g., Genotypic, Macrogen, Eurofins, and BGI) located in different regions of the world. However, it is important to invest in building capacity around genomic technologies in low- and middle-income countries to ensure the training of local scientists and the development of local initiatives. Investing in infrastructure not only for sequencing but more importantly in bioinformatics is one of the crucial steps to ensure emerging economies benefit from the genomics revolution.11
21.4 LACK OF DIVERSITY ON INTERNATIONAL DATABASES Many thousands of whole genomes have been sequenced after the first human genome sequence was published in 2001. However, most of these genomes have been sequenced in Europe or in the United States and belong, in the majority of the cases, to individuals of Caucasian origin. Despite the general agreement regarding the need to increase diversity on the human genomic data that are being generated and the need for a more democratized and equitable access to genomic technologies, genomics research remains largely focused on populations of European descent. A 2009 study indicated that 96% of all genomics studies were done on populations of European descent.12 An updated analysis done in 2016 indicated that non-European participants represented 19% of individuals studied in Genome-Wide Association Studies analysis.13,14 Most of this increase was associated to genomic data generated from Asian populations with other ethnic groups showing only a minimal increase15 even though over three-fourths of the world population live in Africa.16
21.5 PARACHUTE RESEARCH Lots of the research work around genomics in developing countries and emerging economies has been done in collaboration with northern and more developed countries. In recent years the term “parachute research” has emerged to describe initiatives where the results of these collaborations only, or mostly, benefit one side of the group. There is an increasing resistance against parachute researchers: the ones who go to another country (particularly low- and middle-income countries), use the local infrastructure, take samples of patients and populations, and then go back home to write an academic paper for a high-ranking journal without even acknowledging the participation of the local scientists and without ever returning results or data to the patients or populations used in the study.17 It is clear that North South collaborations are of great value, but these collaborations should be performed on equal and respectful bases where all contributions are fully recognized, and most importantly, these collaborations should be based on needs and priorities defined by the low- and middle-income countries. This mutual beneficial collaboration model has been suggested in 2013 by the Genomic Medicine Alliance (www.genomicmedicinealliance.org), and several collaborations have emerged based on this model.18 Some groups have initiated pilot studies that analyze the
364
CHAPTER 21 GENOMIC MEDICINE IN EMERGING
FIGURE 21.1 Model for productive North South collaborations. This figure illustrates the need for a more interactive collaboration where the exchange is initiated based on local needs, and the results will benefit emerging economies directly.
development of demand-driven and locally led research (Fig. 21.1) where countries from the South fully benefit from collaborations with northern countries.19
21.6 EDUCATION AND CAPACITY BUILDING The public health benefits from genetic and genomic innovations can only be realized when we fully understand how to best implement innovations in clinical practice. Several groups have studied the barriers for clinical implementation in Europe and the United States and have determined that clinician’s knowledge and understanding of the uses and applications of genomics in medicine
21.6 EDUCATION AND CAPACITY BUILDING
365
is one of the key barriers that have slow down the adoption of genomic technologies in clinical practice.20 Several programs are now being set up in England and United States to help educate health-care providers on the use of genomics. In low- and middle-income countries the problem is even larger. The challenge is not only that the health-care provider are not informed and not trained to be able to fully understand and benefit from genomic innovations, the largest challenge is the lack of bioinformatics and computational expertise, and also the lack of a critical mass of scientists that are trained in cutting-edge genomic technologies.21 If we think about the patient’s journey, from the moment that a patient visits a doctor and the doctor decides to prescribe a test to the moment the patient gets the report with the results of the genomic or genetic test (Fig. 21.2), there are many professionals involved. All these professionals (doctors, nurses, pharmacists, lab technicians, bioinformaticians, etc.) need to be trained in order to fully implement clinical genomics to help improve patient’s health and outcomes. Biomedical scientists and health-care professionals in low- and middle-income countries frequently fail to fully appreciate the potential that this new technologies offer to improve medical diagnosis and treatment. Investing in training genomics scientist and informing health-care providers and patients about genomics is highly recommended to ensure these new technologies are adopted.
FIGURE 21.2 The patient journey. This figure illustrates the different professionals that are involved in ordering, performing, analyzing, and providing the results of a genomic test.
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Aside from these barriers, there are also growing opportunities to advance the implementation of genomics in emerging economy settings. Developing countries may be resource-limited but are also potentially rich in producing data in various genomic medicine-related disciplines, from the perspective of public health genomics. Even though the pace of implementation of genomic medicine varies from country to country, depending on a number of different parameters, in recent years, we have observed a series of success stories that are indicating the great potential genomic medicine has to help solve some of the most pressing health challenges present in low- and middleincome countries. Some of the opportunities for the implementation of genomic medicine in these countries are described next.
21.7 FAST-SECOND WINNER MODEL Most of the developed countries follow a very linear path to innovation. This path includes large investments in fundamental research to advance some initiatives into translation and application that could led to concrete return on investment and commercial opportunities.22 Instead of this linear innovation model used in developed countries, which goes from discovery science toward application and translational, a new innovation model for emerging economies has been proposed.23 The new approach has been called “Fast-Second Winner” model of innovation. This model offers multiple entry points into the global genomics innovation ecosystem for developing countries, whether or not extensive discovery projects and infrastructure is already in place. Some low- and middleincome countries have already been using this model of innovation and have advanced the implementation of genomic medicine at a public health level. One of these examples is the implementation of pharmacogenomics testing in some Asian countries. Whereas some European countries are heavily investing on large whole-genome sequencing initiatives similar to the one developed by Genomics England,24 scientists from Thailand proposed a simple pharmacogenomics test that could be used to avoid severe adverse drug events such as Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Adverse drug events such as SJS/TEN can occur in patients who take carbamazepine and have a particular gene variant; even though the events are rare, the burden on the patients and the cost to the health-care system are high due to the clinical severity. The scientist from Thailand then developed a simple pharmacogenomics ID card that is cost-effective and easy to use and that can indicate when an individual has the genetic variants associated with the severe adverse drug event. This pharmacogenomics ID card is now being covered by the public healthcare system in Thailand and is being implemented in other Asian countries such as Taiwan.25 Other countries have used different strategies to implement pharmacogenomics in clinical practice and have successfully aligned the local expertise with specific regional needs to advance the use and implementation of genomics.26
21.8 HEALTH BIOTECHNOLOGY IN LATIN AMERICA As described before, emerging economies as well as low- and medium-income countries are starting to use genomics and health biotechnology in many different ways. A study published in 2018
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analyzed the patterns of health biotechnology publications in six Latin American countries (Argentina, Brazil, Chile, Colombia, Cuba, and Mexico) from 2001 to 2015. They found that many of these countries had a publication growth patter higher than some industrialized nations, but the visibility of their research (measured by the number of citations) did not reach the world average, with the only exception of Colombia.27 Some of the examples cited in the paper are the development of an immune-enzymatic assay for the detection of serum antibodies against Trypanosoma cruzi (Chagas disease) in Chile and a diagnostic assay that uses biomarkers for tuberculosis detection in Colombia. The article also indicates that Latin American countries are active in international research collaboration with Colombia being the most active (64% of papers coauthored internationally), whereas Brazil was the least active (35% of papers). Data published in this and other papers indicate that emerging economies are embracing genomics and biotechnology and are also developing international collaborations on areas of key priorities for the regions such as infectious diseases.
21.9 GENOMICS IN AFRICA One of the key barriers and bottlenecks to advance the use of genomics in emerging economies is the lack of bioinformatics and computational biology expertise and the lack of local datasets. In most of low- and middle-income countries the use and analysis of large-scale genomics datasets have been limited by the availability of scientific expertise, the lack of infrastructure, and the lack of data generated from local populations. The African continent, with funding support from the National Institute of Health and the Welcome Trust, developed a new initiative called the Human Heredity and Health in Africa (H3Africa; https://h3africa.org). This initiative was created to help advance research of the genomic and environmental aspects of diseases prevalent in Africa, to build capacity around bioinformatics and around genomics research, and to generate reference datasets arising from African populations.28 As part of the H3Africa initiative, a specific bioinformatics network (H3ABioNet) was created to enable scientist to analyze their own data.29 The network has significantly contributed to create new infrastructure and to develop human capacity that will allow the continent to be more self-sufficient without having to always rely on the expertise and infrastructure available in developed countries.
21.10 GLOBAL INITIATIVES There are several global initiatives around genomics that have emerged in the last few years. Two worth noting are the Global Alliance for Genomics and Health (GA4GH; https://www.ga4gh.org) and the G2MC (https://g2mc.org). On the one hand the GA4GH has focused mainly on the research aspects of genomics by developing a policy framework and technical standards to enable responsible sharing and aggregation of genomic data. One of the initial GA4GH driver projects is the Clinical Genome Resource initiative (ClinGen) aiming at developing a knowledge base to support the understanding of genes and variants for use in precision medicine.30 ClinGen has been used as
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a reference dataset to help advance phenotype genotype correlations that can have an impact on patient diagnosis. On the other hand, the G2MC group is focusing on the clinical application and implementation of genomic medicine by fostering collaboration and engaging multiple stakeholders across the globe. The G2MC group is focusing on enabling the demonstration of value and supporting the effective use of genomics in medicine. The G2MC started as a discussion group where participants from many different regions (mostly developed countries) joined forces to develop standards for clinical implementation of genomics.9 The organization is now an independent entity that is embracing and attracting several members of low- and middle-income countries. It is clear that many advances have been made in the last 5 6 years and that we can now whiteness several success stories on the use and implementation of clinical genomics in emerging economies. These success stories will continue to grow, but the speed and impact will fully depend of the capacity emerging economies will have to invest in science and technology in order to build local capacity and expertise.
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