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iPSCs for personalized medicine: what will it take for Africa?
Forum: Science & Society
Trends in Molecular Medicine December 2012, Vol. 18, No. 12
iPSCs for personalized medicine: what will it take for Africa? Eyitayo S. Fakunle1,2 1 2
Department of Chemical Physiology, Center for Regenerative Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA CalAsia Pharmaceuticals, Nancy Ridge Technology Center, San Diego, CA 92121, USA
Induced pluripotent stem cells (iPSCs) are cutting edge biotechnology that may revolutionize medicine, and creating iPSCs from ethnically diverse individuals would generate valuable therapeutic and drug development tools. However, challenges must be overcome in creating the infrastructure and scientific capacity needed to pursue innovative, leapfrogging strategies to make iPSCs available in Africa.
Why iPSCs and Africa? While participating in a recent workshop on ‘Personalized Stem Cell Medicine’, I was struck by the potential of the field to impact human health by providing a renewable resource of cells that can potentially be used for drug discovery and regenerative therapies. I was left asking the question ‘What would it take to have this technology widely available in Africa?’ The workshop discussion was focused on applying stem cells to the practice of medicine in the United States, but the differences in research culture and resources makes it difficult to simply apply the same methods to the African continent. In this article, I discuss the factors that make iPSCs a particularly attractive technology for medical applications in Africa and lay out many of the fundamental changes that need to occur before iPSC technology can be widely available (Box 1). Not only are there social considerations for research design and community outreach but also practical issues of laboratory and protocol design that need to be addressed. Genetic diversity in African populations: implications for disease and drug response Sub-Saharan Africa (SSA) has the highest burden in the world for infectious diseases, and chronic diseases have rapidly taken hold. Consequently, health status in Africa is in dire straits. SSA has the highest prevalence of HIV/ AIDS on the planet, where at least 22.9 million people live with the disease [1]. The World Health Organization (WHO) predicts that in the next decade SSA will have the greatest increase in death rate from cardiovascular disease, cancer, respiratory diseases, and type 2 diabetes mellitus [1]. Moreover, many African countries will be unable to meet the Millennium Development Goal (MDG) targets for infant and maternal mortality; currently, 1 in 8 children die before age Corresponding author: Fakunle, E.S. ([email protected]) Keywords: ethnic diversity; genetic ancestry; personalized medicine; induced pluripotent stem cells (iPSCs); public–private partnerships; biorepositories; umbilical cord blood; Africa.
five [1]. To further complicate these dire statistics, social factors such as brain drain, poor scientific capacity, and poor infrastructure make it challenging for the continent to address its own scientific and medical problems [2]. As the birthplace of modern humans, the population of Africa has a very rich cultural, linguistic, ethnic, and genetic diversity, exemplified by the presence of more than 2000 ethno-linguistic groups [3]. As a result of the age and demographic history of the population, the genetic structure of African populations is unique compared with other populations worldwide. Africans have more haplotypes, shorter linkage disequilibrium (LD) blocks, and more varied patterns of LD [3]. Understanding these features are essential for reconstructing human evolution, comprehending the expansion of populations out of Africa, as well as fine mapping complex disease [3]. SSA has the greatest structural genetic diversity, including single nucleotide polymorphisms (SNPs), when compared with non-African populations, as well the highest within population genetic diversity [3,4]. For example, a comparison of sequencing data between two Bushmen from South Africa showed more differences between those two genomes than the average number of differences between genomes from individuals of Asian and European (Caucasian) origin [4]. Genetic variation worldwide has very practical implications for personalized medicine. Information such as individual genetic variation, family history, and environmental and lifestyle factors are used to personalize medical approaches for preventing, diagnosing, or treating disease. Despite the wealth of information African genomes have to offer, these populations remain understudied. Only a few African populations, such as the Yoruba, have genome information included in projects such as HapMap or 1000 genomes. A Yoruba genome has been fully sequenced [5] and is used to represent the ‘African’ genome; however, a recent study shows that the extent of genetic diversity among African genomes, even those within close geographic proximity, implies that there is no representative African genome [4]. African genomic diversity has important implications for dissecting the genetic risk of both complex and infectious diseases. Different populations have varied risk and disease prevalence, and genetic factors contribute to both [3]. For example, sickle cell disease is largely limited to populations of African heritage [3], and the CCR5-D32 deletion mutation, which protects against HIV infection when homozygous in an individual genome and delays 695
Forum: Science & Society Box 1. What it will take for Africa Widespread collection of suitable biospecimens, including blood, hair, and skin. Leapfrogging innovations in laboratory technology – such as room temperature storage and low volume microfluidic technologies – to reduce the resources required for implementation. Cooperation between nations to establish public-oriented biorepositories with representation of diverse genetic backgrounds. Strong collaborations should be fostered on both sides of the ocean between Africa and other continents to aid capacity building, technology transfer, and advocacy for African biomedical research needs.
death from AIDS when heterozygous, is prevalent in Caucasian, but not African, populations [3,5]. iPSCs for dissecting complex disease mechanisms and studying genetics Current models for dissecting the genetics underlying complex diseases rely on genome wide association studies (GWAS) performed on human samples from populations with or without the disease of interest [3,6]. Typically, these GWAS involve sample collections of blood, from which DNA is extracted for SNP genotyping analysis. Although numerous risk variants have been determined using such samples, DNA alone is static and finite in nature and does not allow phenotypic or functional studies, such as gene expression profiling. However, a renewable source of DNA for future studies can be created by Epstein–Barr virus (EBV) transformation of the blood lymphocytes to generate renewable lymphoblastoid cell lines (LCLs) that can continuously undergo mitotic cell divisions. LCLs allow phenotypic studies on the genetic backgrounds of individuals or populations from which the primary blood source was obtained [6]. Despite the utility of LCLs for numerous genetic studies, there are several limitations, including the fact that they do not represent a natural cell type in the body. Furthermore, LCLs cannot be differentiated into other tissue types and are not useful for future therapeutic purposes. iPSCs could be a more powerful, dynamic, and renewable tool for dissecting complex diseases and accelerating translational research and personalized medicine. iPSCs are generally derived by reprogramming somatic cells to pluripotency by forced expression of transcription factors involved in embryonic development [7]. iPSCs are uniquely capable of both selfrenewal and pluripotency. Self-renewal is the ability to proliferate indefinitely in culture by mitosis while retaining normal properties, whereas pluripotency is the ability to be converted into all types of specialized cells within the body while maintaining normal properties. This technology has opened up new avenues to study human development, disease risk, and pharmacogenomics and has the potential to be used for transplantation and to treat debilitating diseases such as neurological diseases and HIV/ AIDS. In addition, iPSCs can be created from diverse sample types, including, but not limited to, blood [8], skin [7,9], and the outer root sheath of hair [10]. In fact, even LCLs can be reprogrammed into EBV-free cell lines that have the normal properties of iPSCs, potentially expanding the current utility of LCLs [6]. LCLs as a source of 696
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iPSCs is of great interest because well-characterized LCL biorepository samples are available from genetically diverse populations, such as the HapMap collections in which African populations are represented, providing a potentially comprehensive catalog of cells lines representing human genetic variation [3,6]. The ability to generate iPSCs from adult somatic tissues circumvents many of the ethical concerns involved in deriving human embryonic stem cells (hESCs), which involves the destruction of embryos. We propose that innovative iPSCs techniques should be implemented in Africa within the larger context of existing disease priorities and emerging science and development initiatives on the continent [2] (Table 1). Furthermore, studies using iPSCs should focus on translation towards personalized medicine and therapy development. The first iPSCs have been generated from an African individual, of Yoruba ethnicity [11], thus leading the way for larger studies on the iPSC-based genomics of African populations. Creating large-scale biorepositories on the African continent will enable personalized medicine New initiatives are underway on the African continent to create large-scale biorepositories that can function to collect, process, store, and catalog biological samples, all of which will be an important part of building greater scientific capacity [2]. These facilities will harmonize sample collection efforts, support large-scale genomic studies, and be a centralized point for disseminating samples for collaborative research. African biorepositories will be a critical piece of infrastructure that will enable high-throughput approaches for biomarker discovery, drug development, and personalized medicine, as well as provide potential samples for regenerative therapies. We suggest that the generation of renewable cell lines via iPSCs should be included in the agenda for biorepositories on the continent. Moreover, sample collection efforts should include cell types from which iPSCs can be generated, such as the outer root sheath of hair, skin, adult blood, as well as umbilical cord blood (UCB) and associated tissue. Samples such as outer root sheath of hair are especially desirable because they can be easily obtained by non-medical personnel, which facilitates collection in low-resource settings. Sources such as UCB are typically disposed of at birth as medical waste but can be easily obtained without risk to the donors and are a rich source of cell types for reprogramming [12]. In addition, there are many current applications of UCB for regenerative therapy that do not require reprogramming, including treatments for leukemia and thalassemia. Furthermore, UCB collection efforts could stimulate further access to patients for interventions that support maternal, fetal, and infant health. Given that Africa is falling behind on MDG targets, innovative interventions are desirable [1]. There are currently only three UCB banks in Africa, all of which are private cord blood banks located in South Africa. There is a need for other African countries to create UCB banks and save these valuable specimens that not only represent African genomes but could also be useful for both prospective cohort studies and therapeutic purposes. Public UCB banks that are for community benefit rather
Forum: Science & Society
Trends in Molecular Medicine December 2012, Vol. 18, No. 12
Table 1. Resources for more information on the variety of initiatives, programs, and tools that could be harnessed to further the use of iPSCs and other research agendas on the African continent Initiatives, organizations, programs, and resources with a presence in Africa The Human Heredity and Health in Africa (H3Africa) Initiative Bill and Melinda Gates Foundation World Health Organization USAID PEPFAR UNICEF eHealth Nigeria Seeding labs LabCap – Global laboratory capacity strengthening program Medshare Engineers without borders Beyond Traditional Borders Friends of the Poor-Africa IFASEMB Stem cell resources, biorepositories, and personalized medicine services The National Institutes of Health resource for stem cell research California Institute for Regenerative Medicine International Society for Stem Cell Research (ISSCR) International Society for Biological and Environmental Repositories (ISBER) Rutgers University Cell and DNA Repository (RUCDR) Global directory of biobanks Parents guide to cord blood Hixton group international consortium on stem cell ethics and law International Stem Cell Registry Bone marrow donors worldwide Be the match bone marrow registry 23andMe Navigenics PharmGKB Open source tools and resources National Center for Biotechnology information (NCBI) International HapMap Project Pluritest Multi experiment viewer (MEV) Bioconductor Quartz BikaLims Openfiler Educational tools MIT Open Courseware Journal of Visualized Experiments eFront EasyCampus Select biotechnology companies with products and services of interest for Africa Inqababiotec Biomatrica CalAsia Pharmaceuticals Illumina Life technologies Qiagen Bio-Rad Thermo Scientific Lonza
than private family use should be created to provide more equitable opportunities for the entire population, and innovative models such as the public–private partnership model pioneered by Virgin Health in the UK [13] should be considered in Africa. The Virgin Health hybrid model takes
http://h3africa.org/ http://www.gatesfoundation.org/Pages/home.aspx http://www.who.int/en/ http://www.usaid.gov/ http://www.pepfar.gov/ http://www.unicef.org/ http://ehealthnigeria.org/ http://seedinglabs.org/ https://www.labcap.org/index.cfm http://www.medshare.org/ http://www.ewb-usa.org/ http://beyondtraditionalborders.rice.edu/ http://www.friendsofthepoor-africa.org/projects.html http://www.ifasemb.org http://stemcells.nih.gov/ http://www.cirm.ca.gov/ http://www.isscr.org//AM/Template.cfm?Section=Home http://www.isber.org/index.cfm http://www.rucdr.org/ http://www.specimencentral.com/biobank-directory.aspx http://www.parentsguidecordblood.org http://www.hinxtongroup.org/wp_mea_map.html http://www.umassmed.edu/iscr/lawsandpolicies.aspx http://www.bmdw.org/index.php?id=hla_info http://marrow.org/Home.aspx https://www.23andme.com/ http://www.navigenics.com/ http://www.pharmgkb.org/ http://www.ncbi.nlm.nih.gov/ http://hapmap.ncbi.nlm.nih.gov/ http://www.pluritest.org/ http://www.tm4.org/mev/ http://www.bioconductor.org/ http://www.quartzy.com/ http://bika.sourceforge.net/ http://www.openfiler.com/ http://ocw.mit.edu/index.htm http://www.jove.com/ http://www.efrontlearning.net/download http://www.educadium.com/easycampus.html http://www.inqababiotec.co.za/ http://www.biomatrica.com/ http://www.calasiapharma.com/index.html http://www.illumina.com/ http://www.lifetechnologies.com/us/en/home.html http://www.qiagen.com/default.aspx http://www.bio-rad.com/ http://www.thermoscientific.com/ http://www.lonza.com/
advantage of benefits from both public and private UCB banking [13]. In public banking, parents altruistically donate UCB at birth for potential use as transplant material in unrelated recipients. In private UCB banking, parents save the samples of their newborns in the event 697
Forum: Science & Society that their child would need for future therapy [13]. In the Virgin model, 20% of the samples are stored for private use and the remaining 80% are for public use, with the public cord blood being listed in the international bone marrow database. Private UCB bankers also have access to the public bank for their future needs, an added benefit because it is likely that if a child requires a future transplant, they would need allogeneic, rather than autologous, tissues [13]. In addition, the Virgin biobank uses its resources to make charitable contributions to stem cell research, enabling further development of the field [13]. There are several reasons why a similar model should be adopted in Africa. First, a public–private model would promote sustainability and benefit sharing; income generated from private UCB banking could support, at least in part, maintenance of the overall infrastructure. In addition, the dual model will help to coalesce stakeholders and build critical scientific capacity. Thirdly, logistically combining both types of facilities together expands access to donors and samples. Existing infrastructure and expertise obtained from establishing bone marrow banks and blood banks should be synergized when creating new biorepositories on the continent. As with UCB banks, samples from bone marrow and blood sources could potentially be expanded from their current therapeutic applications by reprogramming them into iPSCs [12]. The recent opening of a bone marrow registry in Nigeria makes it only the third on the African continent. This development has not arrived too soon considering the dire need to increase the repertoire of donors of African origin to find suitable matches for patients requiring bone marrow stem cell transplants. Furthermore, only three countries in Africa can harvest and transplant bone marrow: South Africa, Nigeria, and Egypt. The capacity for this therapy on the continent needs to be improved. In addition to including UCB banks, blood banks, and bone marrow registries, African biorepositories should be compatible with electronic medical records (EMRs) and disease registries that store patient data, such as medical and family history. This will enable integration of phenotype information with genetic data from all kinds of patients and samples, including iPSCs, speeding the rate at which personalized medicine is possible. Furthermore, as biorepositories, genomics, and biomedical technologies become widespread in Africa, public and stakeholder engagement will be important to promote equity in access to biotechnology and to evaluate the social and ethical implications of adopting the new technologies [2]. Infrastructure and scientific capacity in Africa: challenges and potential solutions Poor infrastructure and scientific capacity in many areas of SSA is a major bottleneck to implementing all types of biomedical research. Basic centralized services such as water, electricity, and telecommunications are unreliable in many countries. Many highly trained physicians and scientists leave for better opportunities in the developed world, contributing to ‘brain drain’ and aggravating the problems on the continent. To address the infrastructure challenges, sustainable, leapfrogging approaches should be adopted. Leapfrogging technologies skip first-generation technologies and instead use the most advanced, more 698
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robust and more sustainable, next-generation technologies. For example, landline telephones preceded cell phones, but in Africa cell phone use has significantly overtaken the installation of landline telephones and requires less infrastructure. Solar and wind power would provide leapfrogging sources of electricity to run critical infrastructure. In addition, the potential use of room temperature storage products to preserve nucleic acids, blood, and other biological specimens without the need for cryogenic storage or electricity will enable more biomedical research in low-resource settings [14]. Finally, much traditional laboratory research equipment can be replaced with microfluidic technologies that require low volumes and are potentially automated, easy-to-use systems [15]. African scientists should also take advantage of software resources such as open source laboratory information management systems (LIMS), medical record systems (MRS), and genomic tools such as those provided by the National Center for Biotechnology Information (NCBI). These would provide accessible and affordable resources for biotechnology development on the continent. To accelerate capacity building in the region, a sustainable strategy for technology transfer should be developed with all of the critical stakeholders within a socio-ecological framework fully engaged in this process. The socio-ecological framework summarizes the dynamic interaction between the individual and society though the ascending layers of the individual, networks of individuals, organizations, communities, and public policy. African scientists in the diaspora should be engaged in research on the continent to mitigate or reverse the current brain drain. Ministries of health in African countries should be engaged to create new policies that enable science, stem cell research, and personalized medicine. What is more, existing resources provided by non-governmental organizations such as The WHO, United States Agency for International Development (USAID), and Engineers without Borders (EWB) to build capacity in the continent should be engaged and incorporated wherever possible. Innovative modes of distance learning, knowledge transfer, and dissemination of findings via social media, podcasting, Skype, YouTube, and wireless applications should be widely adopted. Furthermore, strong collaborations should be promoted on both sides of the ocean to aid capacity building, technology transfer, and advocacy for African biomedical research needs. Of particular interest towards enhancing stem cell research on the African continent are potential collaborations between scientists in California and Africa. The California Institute of Regenerative Medicine (CIRM) is the largest funder of stem cell research in the world with three billion dollars of committed state funding over 10 years to sponsor the development of stem cell science and technology in California. Collaboration between African scientists and individual research groups in California, the establishment of training centers in California, and the development of exchange programs for students and scientists will not only enable technology transfer but will raise awareness and promote the African agenda in California and help rally support for African initiatives. CIRM has recently established funding partnerships and memorandums of understanding with governments of several countries in Europe, Asia, and South America, making it an
Forum: Science & Society excellent resource to extend these collaborations around the world. The possibility of potential partnerships between CIRM and African governments will further accelerate biomedical research on the continent and make personalized therapies, including those developed from iPSCs, a reality in Africa. Acknowledgments This work was supported by funding from the Bill and Melinda Gates Foundation, UNCF-Merck Postdoctoral Fellowship, the National Institutes of Health (NIH), California Institute for Regenerative Medicine (CIRM), The Ester O’Keeffe Foundation, and the Millipore Foundation. The author would like to thank Dr Jeanne Loring for mentorship and support, Dr Adeyemo Adebowale for useful comments, and Dr Akinola Abayomi for collaborations on scientific and capacity building opportunities in Africa. The author would like to acknowledge the Canada–California–Japan discussion workshop on Personalized Stem Cell Medicine, held at The Gladstone Institutes, San Francisco, CA, USA, which inspired the question ‘Now what will this take for Africa?’ and the content of this article.
References 1 World Health Organization Department of Health Statistics (2012) World Health Statistics 2012, World Health Organization (http:// www.who.int/gho/publications/world_health_statistics/2012/en/) 2 H3Africa Working Group (2011) Harnessing Genomic Technologies Toward Improving Health in Africa: Opportunities and Challenges, Human Heredity and Health in Africa (http://h3africa.org/h3africa_ whitepaper.pdf) 3 Sirugo, G. et al. (2008) Genetic studies of African populations: an overview on disease susceptibility and response to vaccines and therapeutics. Hum. Genet. 123, 557–598 4 Schuster, S.C. et al. (2010) Complete Khoisan and Bantu genomes from southern Africa. Nature 463, 943–947
Trends in Molecular Medicine December 2012, Vol. 18, No. 12 5 Bentley, D.R. et al. (2008) Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 6 Rajesh, D. et al. (2011) Human lymphoblastoid B-cell lines reprogrammed to EBV-free induced pluripotent stem cells. Blood 118, 1797–1800 7 Takahashi, K. et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 8 Loh, Y.H. et al. (2009) Generation of induced pluripotent stem cells from human blood. Blood 113, 5476–5479 9 Glenn, V.L. et al. (2012) Isolation of human dermal fibroblasts from biopsies, In Human Stem Cell Manual: A Laboratory Guide (2nd edn) (Loring, J. and Peterson, S.E., eds), pp. 129–141, Elsevier 10 Aasen, T. et al. (2008) Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat. Biotechnol. 26, 1276–1284 11 Laurent, L.C. et al. (2010) Restricted ethnic diversity in human embryonic stem cell lines. Nat. Methods 7, 6–7 12 Hu, K. et al. (2011) Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood 117, e109–e119 13 Fisk, N.M. and Atun, R. (2008) Public–private partnership in cord blood banking. BMJ 336, 642–644 14 Biomatrica (2011) Scientific Evaluations of Biomatrica’s Technologies for Room Temperature Storage and Stabilization of Biological Samples, Biomatrica 15 Fakunle, E.S. and Fritsch, I. (2010) Low-temperature co-fired ceramic microchannels with individually addressable screen-printed gold electrodes on four walls for self-contained electrochemical immunoassays. Anal. Bioanal. Chem. 398, 2605–2615
1471-4914/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2012.10.005 Trends in Molecular Medicine, December 2012, Vol. 18, No. 12
Taking diversity programs to the next level Laina King Director, Diversity in Life Science Programs and Mentor, Keystone Symposia Fellows Program, Keystone Symposia on Molecular and Cellular Biology, Silverthorne, Colorado, USA 80498
The Keystone Symposia Fellows Program is a unique and diverse research mentoring and positioning program tailored for ‘end of the pipeline’ scientists and can successfully enhance career advancement. Major program components include mentoring by wellestablished global science leaders and exposure to high-level discussions and decision making on future research priorities. During the past decade, discussions at annual conferences on diversity in life science programs and activities have often raised the question ‘What design should be used in the next stage of evidence-based mentoring programs for advanced level underrepresented minority (URM) scientists?’ Specifically, what mentoring activities and positioning programs that focus on early career scientists (i.e., postdoctoral fellows, assistant professors, and industry Corresponding author: King, L. ([email protected]) Keywords: life science; diversity; mentoring; underrepresented minority populations; career advancement.
scientists at equivalent levels) are indicated? The overwhelming majority of life science and STEM diversity program activities in the recent past have focused on earlier stages: high school and undergraduate mentoring and experience activities, programs that promote enrollment and retention of students in undergraduate and doctoral level degree programs, scholarships to scientific conferences for undergraduate and graduate students, and mentoring at these early stages [1]. The Keystone Symposia Fellows Program was conceived and initiated to address the need for a program focused on the early career development of life scientists from both underrepresented and majority backgrounds. Keystone Symposia Fellows Program Keystone Symposia on Molecular and Cellular Biology is a life science research and education conference organization committed to accelerating life science discovery and connecting the life science community, primarily by organizing life science research and education conferences. It 699
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iPSCs for personalized medicine: what will it take for Africa? Eyitayo S. Fakunle1,2 1 2
Department of Chemical Physiology, Center for Regenerative Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA CalAsia Pharmaceuticals, Nancy Ridge Technology Center, San Diego, CA 92121, USA
Induced pluripotent stem cells (iPSCs) are cutting edge biotechnology that may revolutionize medicine, and creating iPSCs from ethnically diverse individuals would generate valuable therapeutic and drug development tools. However, challenges must be overcome in creating the infrastructure and scientific capacity needed to pursue innovative, leapfrogging strategies to make iPSCs available in Africa.
Why iPSCs and Africa? While participating in a recent workshop on ‘Personalized Stem Cell Medicine’, I was struck by the potential of the field to impact human health by providing a renewable resource of cells that can potentially be used for drug discovery and regenerative therapies. I was left asking the question ‘What would it take to have this technology widely available in Africa?’ The workshop discussion was focused on applying stem cells to the practice of medicine in the United States, but the differences in research culture and resources makes it difficult to simply apply the same methods to the African continent. In this article, I discuss the factors that make iPSCs a particularly attractive technology for medical applications in Africa and lay out many of the fundamental changes that need to occur before iPSC technology can be widely available (Box 1). Not only are there social considerations for research design and community outreach but also practical issues of laboratory and protocol design that need to be addressed. Genetic diversity in African populations: implications for disease and drug response Sub-Saharan Africa (SSA) has the highest burden in the world for infectious diseases, and chronic diseases have rapidly taken hold. Consequently, health status in Africa is in dire straits. SSA has the highest prevalence of HIV/ AIDS on the planet, where at least 22.9 million people live with the disease [1]. The World Health Organization (WHO) predicts that in the next decade SSA will have the greatest increase in death rate from cardiovascular disease, cancer, respiratory diseases, and type 2 diabetes mellitus [1]. Moreover, many African countries will be unable to meet the Millennium Development Goal (MDG) targets for infant and maternal mortality; currently, 1 in 8 children die before age Corresponding author: Fakunle, E.S. ([email protected]) Keywords: ethnic diversity; genetic ancestry; personalized medicine; induced pluripotent stem cells (iPSCs); public–private partnerships; biorepositories; umbilical cord blood; Africa.
five [1]. To further complicate these dire statistics, social factors such as brain drain, poor scientific capacity, and poor infrastructure make it challenging for the continent to address its own scientific and medical problems [2]. As the birthplace of modern humans, the population of Africa has a very rich cultural, linguistic, ethnic, and genetic diversity, exemplified by the presence of more than 2000 ethno-linguistic groups [3]. As a result of the age and demographic history of the population, the genetic structure of African populations is unique compared with other populations worldwide. Africans have more haplotypes, shorter linkage disequilibrium (LD) blocks, and more varied patterns of LD [3]. Understanding these features are essential for reconstructing human evolution, comprehending the expansion of populations out of Africa, as well as fine mapping complex disease [3]. SSA has the greatest structural genetic diversity, including single nucleotide polymorphisms (SNPs), when compared with non-African populations, as well the highest within population genetic diversity [3,4]. For example, a comparison of sequencing data between two Bushmen from South Africa showed more differences between those two genomes than the average number of differences between genomes from individuals of Asian and European (Caucasian) origin [4]. Genetic variation worldwide has very practical implications for personalized medicine. Information such as individual genetic variation, family history, and environmental and lifestyle factors are used to personalize medical approaches for preventing, diagnosing, or treating disease. Despite the wealth of information African genomes have to offer, these populations remain understudied. Only a few African populations, such as the Yoruba, have genome information included in projects such as HapMap or 1000 genomes. A Yoruba genome has been fully sequenced [5] and is used to represent the ‘African’ genome; however, a recent study shows that the extent of genetic diversity among African genomes, even those within close geographic proximity, implies that there is no representative African genome [4]. African genomic diversity has important implications for dissecting the genetic risk of both complex and infectious diseases. Different populations have varied risk and disease prevalence, and genetic factors contribute to both [3]. For example, sickle cell disease is largely limited to populations of African heritage [3], and the CCR5-D32 deletion mutation, which protects against HIV infection when homozygous in an individual genome and delays 695
Forum: Science & Society Box 1. What it will take for Africa Widespread collection of suitable biospecimens, including blood, hair, and skin. Leapfrogging innovations in laboratory technology – such as room temperature storage and low volume microfluidic technologies – to reduce the resources required for implementation. Cooperation between nations to establish public-oriented biorepositories with representation of diverse genetic backgrounds. Strong collaborations should be fostered on both sides of the ocean between Africa and other continents to aid capacity building, technology transfer, and advocacy for African biomedical research needs.
death from AIDS when heterozygous, is prevalent in Caucasian, but not African, populations [3,5]. iPSCs for dissecting complex disease mechanisms and studying genetics Current models for dissecting the genetics underlying complex diseases rely on genome wide association studies (GWAS) performed on human samples from populations with or without the disease of interest [3,6]. Typically, these GWAS involve sample collections of blood, from which DNA is extracted for SNP genotyping analysis. Although numerous risk variants have been determined using such samples, DNA alone is static and finite in nature and does not allow phenotypic or functional studies, such as gene expression profiling. However, a renewable source of DNA for future studies can be created by Epstein–Barr virus (EBV) transformation of the blood lymphocytes to generate renewable lymphoblastoid cell lines (LCLs) that can continuously undergo mitotic cell divisions. LCLs allow phenotypic studies on the genetic backgrounds of individuals or populations from which the primary blood source was obtained [6]. Despite the utility of LCLs for numerous genetic studies, there are several limitations, including the fact that they do not represent a natural cell type in the body. Furthermore, LCLs cannot be differentiated into other tissue types and are not useful for future therapeutic purposes. iPSCs could be a more powerful, dynamic, and renewable tool for dissecting complex diseases and accelerating translational research and personalized medicine. iPSCs are generally derived by reprogramming somatic cells to pluripotency by forced expression of transcription factors involved in embryonic development [7]. iPSCs are uniquely capable of both selfrenewal and pluripotency. Self-renewal is the ability to proliferate indefinitely in culture by mitosis while retaining normal properties, whereas pluripotency is the ability to be converted into all types of specialized cells within the body while maintaining normal properties. This technology has opened up new avenues to study human development, disease risk, and pharmacogenomics and has the potential to be used for transplantation and to treat debilitating diseases such as neurological diseases and HIV/ AIDS. In addition, iPSCs can be created from diverse sample types, including, but not limited to, blood [8], skin [7,9], and the outer root sheath of hair [10]. In fact, even LCLs can be reprogrammed into EBV-free cell lines that have the normal properties of iPSCs, potentially expanding the current utility of LCLs [6]. LCLs as a source of 696
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iPSCs is of great interest because well-characterized LCL biorepository samples are available from genetically diverse populations, such as the HapMap collections in which African populations are represented, providing a potentially comprehensive catalog of cells lines representing human genetic variation [3,6]. The ability to generate iPSCs from adult somatic tissues circumvents many of the ethical concerns involved in deriving human embryonic stem cells (hESCs), which involves the destruction of embryos. We propose that innovative iPSCs techniques should be implemented in Africa within the larger context of existing disease priorities and emerging science and development initiatives on the continent [2] (Table 1). Furthermore, studies using iPSCs should focus on translation towards personalized medicine and therapy development. The first iPSCs have been generated from an African individual, of Yoruba ethnicity [11], thus leading the way for larger studies on the iPSC-based genomics of African populations. Creating large-scale biorepositories on the African continent will enable personalized medicine New initiatives are underway on the African continent to create large-scale biorepositories that can function to collect, process, store, and catalog biological samples, all of which will be an important part of building greater scientific capacity [2]. These facilities will harmonize sample collection efforts, support large-scale genomic studies, and be a centralized point for disseminating samples for collaborative research. African biorepositories will be a critical piece of infrastructure that will enable high-throughput approaches for biomarker discovery, drug development, and personalized medicine, as well as provide potential samples for regenerative therapies. We suggest that the generation of renewable cell lines via iPSCs should be included in the agenda for biorepositories on the continent. Moreover, sample collection efforts should include cell types from which iPSCs can be generated, such as the outer root sheath of hair, skin, adult blood, as well as umbilical cord blood (UCB) and associated tissue. Samples such as outer root sheath of hair are especially desirable because they can be easily obtained by non-medical personnel, which facilitates collection in low-resource settings. Sources such as UCB are typically disposed of at birth as medical waste but can be easily obtained without risk to the donors and are a rich source of cell types for reprogramming [12]. In addition, there are many current applications of UCB for regenerative therapy that do not require reprogramming, including treatments for leukemia and thalassemia. Furthermore, UCB collection efforts could stimulate further access to patients for interventions that support maternal, fetal, and infant health. Given that Africa is falling behind on MDG targets, innovative interventions are desirable [1]. There are currently only three UCB banks in Africa, all of which are private cord blood banks located in South Africa. There is a need for other African countries to create UCB banks and save these valuable specimens that not only represent African genomes but could also be useful for both prospective cohort studies and therapeutic purposes. Public UCB banks that are for community benefit rather
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Table 1. Resources for more information on the variety of initiatives, programs, and tools that could be harnessed to further the use of iPSCs and other research agendas on the African continent Initiatives, organizations, programs, and resources with a presence in Africa The Human Heredity and Health in Africa (H3Africa) Initiative Bill and Melinda Gates Foundation World Health Organization USAID PEPFAR UNICEF eHealth Nigeria Seeding labs LabCap – Global laboratory capacity strengthening program Medshare Engineers without borders Beyond Traditional Borders Friends of the Poor-Africa IFASEMB Stem cell resources, biorepositories, and personalized medicine services The National Institutes of Health resource for stem cell research California Institute for Regenerative Medicine International Society for Stem Cell Research (ISSCR) International Society for Biological and Environmental Repositories (ISBER) Rutgers University Cell and DNA Repository (RUCDR) Global directory of biobanks Parents guide to cord blood Hixton group international consortium on stem cell ethics and law International Stem Cell Registry Bone marrow donors worldwide Be the match bone marrow registry 23andMe Navigenics PharmGKB Open source tools and resources National Center for Biotechnology information (NCBI) International HapMap Project Pluritest Multi experiment viewer (MEV) Bioconductor Quartz BikaLims Openfiler Educational tools MIT Open Courseware Journal of Visualized Experiments eFront EasyCampus Select biotechnology companies with products and services of interest for Africa Inqababiotec Biomatrica CalAsia Pharmaceuticals Illumina Life technologies Qiagen Bio-Rad Thermo Scientific Lonza
than private family use should be created to provide more equitable opportunities for the entire population, and innovative models such as the public–private partnership model pioneered by Virgin Health in the UK [13] should be considered in Africa. The Virgin Health hybrid model takes
http://h3africa.org/ http://www.gatesfoundation.org/Pages/home.aspx http://www.who.int/en/ http://www.usaid.gov/ http://www.pepfar.gov/ http://www.unicef.org/ http://ehealthnigeria.org/ http://seedinglabs.org/ https://www.labcap.org/index.cfm http://www.medshare.org/ http://www.ewb-usa.org/ http://beyondtraditionalborders.rice.edu/ http://www.friendsofthepoor-africa.org/projects.html http://www.ifasemb.org http://stemcells.nih.gov/ http://www.cirm.ca.gov/ http://www.isscr.org//AM/Template.cfm?Section=Home http://www.isber.org/index.cfm http://www.rucdr.org/ http://www.specimencentral.com/biobank-directory.aspx http://www.parentsguidecordblood.org http://www.hinxtongroup.org/wp_mea_map.html http://www.umassmed.edu/iscr/lawsandpolicies.aspx http://www.bmdw.org/index.php?id=hla_info http://marrow.org/Home.aspx https://www.23andme.com/ http://www.navigenics.com/ http://www.pharmgkb.org/ http://www.ncbi.nlm.nih.gov/ http://hapmap.ncbi.nlm.nih.gov/ http://www.pluritest.org/ http://www.tm4.org/mev/ http://www.bioconductor.org/ http://www.quartzy.com/ http://bika.sourceforge.net/ http://www.openfiler.com/ http://ocw.mit.edu/index.htm http://www.jove.com/ http://www.efrontlearning.net/download http://www.educadium.com/easycampus.html http://www.inqababiotec.co.za/ http://www.biomatrica.com/ http://www.calasiapharma.com/index.html http://www.illumina.com/ http://www.lifetechnologies.com/us/en/home.html http://www.qiagen.com/default.aspx http://www.bio-rad.com/ http://www.thermoscientific.com/ http://www.lonza.com/
advantage of benefits from both public and private UCB banking [13]. In public banking, parents altruistically donate UCB at birth for potential use as transplant material in unrelated recipients. In private UCB banking, parents save the samples of their newborns in the event 697
Forum: Science & Society that their child would need for future therapy [13]. In the Virgin model, 20% of the samples are stored for private use and the remaining 80% are for public use, with the public cord blood being listed in the international bone marrow database. Private UCB bankers also have access to the public bank for their future needs, an added benefit because it is likely that if a child requires a future transplant, they would need allogeneic, rather than autologous, tissues [13]. In addition, the Virgin biobank uses its resources to make charitable contributions to stem cell research, enabling further development of the field [13]. There are several reasons why a similar model should be adopted in Africa. First, a public–private model would promote sustainability and benefit sharing; income generated from private UCB banking could support, at least in part, maintenance of the overall infrastructure. In addition, the dual model will help to coalesce stakeholders and build critical scientific capacity. Thirdly, logistically combining both types of facilities together expands access to donors and samples. Existing infrastructure and expertise obtained from establishing bone marrow banks and blood banks should be synergized when creating new biorepositories on the continent. As with UCB banks, samples from bone marrow and blood sources could potentially be expanded from their current therapeutic applications by reprogramming them into iPSCs [12]. The recent opening of a bone marrow registry in Nigeria makes it only the third on the African continent. This development has not arrived too soon considering the dire need to increase the repertoire of donors of African origin to find suitable matches for patients requiring bone marrow stem cell transplants. Furthermore, only three countries in Africa can harvest and transplant bone marrow: South Africa, Nigeria, and Egypt. The capacity for this therapy on the continent needs to be improved. In addition to including UCB banks, blood banks, and bone marrow registries, African biorepositories should be compatible with electronic medical records (EMRs) and disease registries that store patient data, such as medical and family history. This will enable integration of phenotype information with genetic data from all kinds of patients and samples, including iPSCs, speeding the rate at which personalized medicine is possible. Furthermore, as biorepositories, genomics, and biomedical technologies become widespread in Africa, public and stakeholder engagement will be important to promote equity in access to biotechnology and to evaluate the social and ethical implications of adopting the new technologies [2]. Infrastructure and scientific capacity in Africa: challenges and potential solutions Poor infrastructure and scientific capacity in many areas of SSA is a major bottleneck to implementing all types of biomedical research. Basic centralized services such as water, electricity, and telecommunications are unreliable in many countries. Many highly trained physicians and scientists leave for better opportunities in the developed world, contributing to ‘brain drain’ and aggravating the problems on the continent. To address the infrastructure challenges, sustainable, leapfrogging approaches should be adopted. Leapfrogging technologies skip first-generation technologies and instead use the most advanced, more 698
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robust and more sustainable, next-generation technologies. For example, landline telephones preceded cell phones, but in Africa cell phone use has significantly overtaken the installation of landline telephones and requires less infrastructure. Solar and wind power would provide leapfrogging sources of electricity to run critical infrastructure. In addition, the potential use of room temperature storage products to preserve nucleic acids, blood, and other biological specimens without the need for cryogenic storage or electricity will enable more biomedical research in low-resource settings [14]. Finally, much traditional laboratory research equipment can be replaced with microfluidic technologies that require low volumes and are potentially automated, easy-to-use systems [15]. African scientists should also take advantage of software resources such as open source laboratory information management systems (LIMS), medical record systems (MRS), and genomic tools such as those provided by the National Center for Biotechnology Information (NCBI). These would provide accessible and affordable resources for biotechnology development on the continent. To accelerate capacity building in the region, a sustainable strategy for technology transfer should be developed with all of the critical stakeholders within a socio-ecological framework fully engaged in this process. The socio-ecological framework summarizes the dynamic interaction between the individual and society though the ascending layers of the individual, networks of individuals, organizations, communities, and public policy. African scientists in the diaspora should be engaged in research on the continent to mitigate or reverse the current brain drain. Ministries of health in African countries should be engaged to create new policies that enable science, stem cell research, and personalized medicine. What is more, existing resources provided by non-governmental organizations such as The WHO, United States Agency for International Development (USAID), and Engineers without Borders (EWB) to build capacity in the continent should be engaged and incorporated wherever possible. Innovative modes of distance learning, knowledge transfer, and dissemination of findings via social media, podcasting, Skype, YouTube, and wireless applications should be widely adopted. Furthermore, strong collaborations should be promoted on both sides of the ocean to aid capacity building, technology transfer, and advocacy for African biomedical research needs. Of particular interest towards enhancing stem cell research on the African continent are potential collaborations between scientists in California and Africa. The California Institute of Regenerative Medicine (CIRM) is the largest funder of stem cell research in the world with three billion dollars of committed state funding over 10 years to sponsor the development of stem cell science and technology in California. Collaboration between African scientists and individual research groups in California, the establishment of training centers in California, and the development of exchange programs for students and scientists will not only enable technology transfer but will raise awareness and promote the African agenda in California and help rally support for African initiatives. CIRM has recently established funding partnerships and memorandums of understanding with governments of several countries in Europe, Asia, and South America, making it an
Forum: Science & Society excellent resource to extend these collaborations around the world. The possibility of potential partnerships between CIRM and African governments will further accelerate biomedical research on the continent and make personalized therapies, including those developed from iPSCs, a reality in Africa. Acknowledgments This work was supported by funding from the Bill and Melinda Gates Foundation, UNCF-Merck Postdoctoral Fellowship, the National Institutes of Health (NIH), California Institute for Regenerative Medicine (CIRM), The Ester O’Keeffe Foundation, and the Millipore Foundation. The author would like to thank Dr Jeanne Loring for mentorship and support, Dr Adeyemo Adebowale for useful comments, and Dr Akinola Abayomi for collaborations on scientific and capacity building opportunities in Africa. The author would like to acknowledge the Canada–California–Japan discussion workshop on Personalized Stem Cell Medicine, held at The Gladstone Institutes, San Francisco, CA, USA, which inspired the question ‘Now what will this take for Africa?’ and the content of this article.
References 1 World Health Organization Department of Health Statistics (2012) World Health Statistics 2012, World Health Organization (http:// www.who.int/gho/publications/world_health_statistics/2012/en/) 2 H3Africa Working Group (2011) Harnessing Genomic Technologies Toward Improving Health in Africa: Opportunities and Challenges, Human Heredity and Health in Africa (http://h3africa.org/h3africa_ whitepaper.pdf) 3 Sirugo, G. et al. (2008) Genetic studies of African populations: an overview on disease susceptibility and response to vaccines and therapeutics. Hum. Genet. 123, 557–598 4 Schuster, S.C. et al. (2010) Complete Khoisan and Bantu genomes from southern Africa. Nature 463, 943–947
Trends in Molecular Medicine December 2012, Vol. 18, No. 12 5 Bentley, D.R. et al. (2008) Accurate whole human genome sequencing using reversible terminator chemistry. Nature 456, 53–59 6 Rajesh, D. et al. (2011) Human lymphoblastoid B-cell lines reprogrammed to EBV-free induced pluripotent stem cells. Blood 118, 1797–1800 7 Takahashi, K. et al. (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 8 Loh, Y.H. et al. (2009) Generation of induced pluripotent stem cells from human blood. Blood 113, 5476–5479 9 Glenn, V.L. et al. (2012) Isolation of human dermal fibroblasts from biopsies, In Human Stem Cell Manual: A Laboratory Guide (2nd edn) (Loring, J. and Peterson, S.E., eds), pp. 129–141, Elsevier 10 Aasen, T. et al. (2008) Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat. Biotechnol. 26, 1276–1284 11 Laurent, L.C. et al. (2010) Restricted ethnic diversity in human embryonic stem cell lines. Nat. Methods 7, 6–7 12 Hu, K. et al. (2011) Efficient generation of transgene-free induced pluripotent stem cells from normal and neoplastic bone marrow and cord blood mononuclear cells. Blood 117, e109–e119 13 Fisk, N.M. and Atun, R. (2008) Public–private partnership in cord blood banking. BMJ 336, 642–644 14 Biomatrica (2011) Scientific Evaluations of Biomatrica’s Technologies for Room Temperature Storage and Stabilization of Biological Samples, Biomatrica 15 Fakunle, E.S. and Fritsch, I. (2010) Low-temperature co-fired ceramic microchannels with individually addressable screen-printed gold electrodes on four walls for self-contained electrochemical immunoassays. Anal. Bioanal. Chem. 398, 2605–2615
1471-4914/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2012.10.005 Trends in Molecular Medicine, December 2012, Vol. 18, No. 12
Taking diversity programs to the next level Laina King Director, Diversity in Life Science Programs and Mentor, Keystone Symposia Fellows Program, Keystone Symposia on Molecular and Cellular Biology, Silverthorne, Colorado, USA 80498
The Keystone Symposia Fellows Program is a unique and diverse research mentoring and positioning program tailored for ‘end of the pipeline’ scientists and can successfully enhance career advancement. Major program components include mentoring by wellestablished global science leaders and exposure to high-level discussions and decision making on future research priorities. During the past decade, discussions at annual conferences on diversity in life science programs and activities have often raised the question ‘What design should be used in the next stage of evidence-based mentoring programs for advanced level underrepresented minority (URM) scientists?’ Specifically, what mentoring activities and positioning programs that focus on early career scientists (i.e., postdoctoral fellows, assistant professors, and industry Corresponding author: King, L. ([email protected]) Keywords: life science; diversity; mentoring; underrepresented minority populations; career advancement.
scientists at equivalent levels) are indicated? The overwhelming majority of life science and STEM diversity program activities in the recent past have focused on earlier stages: high school and undergraduate mentoring and experience activities, programs that promote enrollment and retention of students in undergraduate and doctoral level degree programs, scholarships to scientific conferences for undergraduate and graduate students, and mentoring at these early stages [1]. The Keystone Symposia Fellows Program was conceived and initiated to address the need for a program focused on the early career development of life scientists from both underrepresented and majority backgrounds. Keystone Symposia Fellows Program Keystone Symposia on Molecular and Cellular Biology is a life science research and education conference organization committed to accelerating life science discovery and connecting the life science community, primarily by organizing life science research and education conferences. It 699