TRMOME-1051; No. of Pages 2
Forum
Personalized medicine going precise: from genomics to microbiomics Sanjay K. Shukla1, Narayana S. Murali2, and Murray H. Brilliant1 1 2
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA Department of Nephrology, Marshfield Clinic, Marshfield, WI, USA
Practicing medicine has always been an art dependent upon the judgment of a physician. This art relies on listening, caring, and empathizing for the patient, and on judgment applied to every patient under their own unique circumstances in the backdrop of optimum medical care. Thus, medical treatment and disease management has always been personalized. However, practicing modern medicine is increasingly more complex in the era of genomics and microbiomics, as physicians and their patients have much more information to consider about the disease, and more treatment options are becoming available. In this context, the ‘Precision Medicine’ initiative (http://www. whitehouse.gov/precisionmedicine) is exciting because it will be based on recognizing individual differences in genes, environment, and lifestyle. The five objectives of the ‘Precision Medicine’ initiatives include: (i) more (and better) treatments for cancer; (ii) creation of a voluntary national research cohort; (iii) commitment to protecting privacy; (iv) regulatory modernization; and (v) public– private partnerships (http://www.whitehouse.gov/thepress-office/2015/01/30/fact-sheet). This initiative could not be more timely because years of basic, clinical, and translational research in biology (e.g., genetics, genomics, microbiome), chemistry (e.g., synthetic), physics (e.g., imaging), bioinformatics (e.g., management of big data, machine learning, and analytical software), and engineering (e.g., nanotechnology) have resulted in a better understanding of the complexities and pathophysiology of many complex traits and diseases. The human genome project conceived in the 1990s revealed approximately 20 000–25 000 genes in the human genome [1], but geneticists soon realized that a single human genome sequence did not, and could not, capture the whole gamut of human genetic variations. The HapMap project followed, with aims to describe common genetic variation and haplotypes across human populations [2]. The concept of ‘Personalized Medicine’ in its current avatar was born from these initiatives and revolves around the ability to exploit an individual’s known genetic variation that causes disease to customize their treatment. While ongoing research in genomics has continued to tease apart and explain the genetic susceptibilities of diseases, the role of the microbiome as a powerful modulator of human health and disease [3,4] emerged from the human Corresponding author: Shukla, S.K. ([email protected]). Keywords: personalized medicine; precise medicine; genomic medicine; genetics and health; microbiome. 1471-4914/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2015.06.002
microbiome project, which was launched in 2008 (http:// commonfund.nih.gov/hmp/index). The human microbiome, also referred to as the ‘second (human) genome’, consists of trillions of microbes that inhabit the human body and are ecologically and immunologically integrated with their host [5]. The microbiome is more complex than the human genome. The Human Microbiome revealed that commensal microbial genes exceed the total number of human genes by 100:1, and an adult human gut can harbor up to 100 trillion microbial cells; ten times higher than the total number of somatic and germ cells [5]. Indeed, experts of the International Human Microbiome Consortium have recommended that determining human metagenome and its variation with human population, genotypes, disease, age, nutrition, medication, and environment should be the goal of the Human Metagenome project (http://www. human-microbiome.org/index.php?id=243). Further, the metabolic contribution of the microbiome to host health is expected to be as large and significant as their gene pool. It will continue to be a mammoth task to fully understand the potential of how this vast amount of non-human genetic material, or at minimum the ‘functional core set’ of microbial genes conserved in each of us necessary to maintain gut functions [6], modulates pathophysiology of their human host. For ‘Personalized Medicine’ to succeed, researchers need biobanks of patient DNA, serum, and tissue blocks to probe genetic abnormalities. In addition, samples such as fecal and oral materials to determine the microbial composition will be crucial to see if and how the microbiome is shaped by disease phenotypes or vice versa. Analysis may also reveal cases where the microbiome creates disease susceptibilities or maintains chronic disease status. The ‘Precision Medicine’ initiative envisions implementing what we know as ‘actionable’ now, while continuing the discovery of new actionable variants learned from large cohorts. For example, we know the effects of certain variants on drug metabolizing genes, but the effect of other rare variants is currently unknown. Banking and genotyping the DNA of large numbers of people will enable new clinical recommendations for specific individual variants. Similarly, we are only beginning to know the consequences of individual microbiomes on health. Larger sets of data will result in new clinically actionable recommendations. The National Institutes of Health (NIH) has helped to create large biobanks of usable clinical samples, data sharing plans for large DNA and protein datasets, and bioinformatics tools. The NIH-funded Electronic Medical Trends in Molecular Medicine xx (2015) 1–2
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TRMOME-1051; No. of Pages 2
Forum Records and Genomics (eMERGE) Network developed and applied approaches to combine DNA biobanks with corresponding medical records to assess relationships between genetic variants and diseases of interest by genome-wide association studies (GWAS) [7]. GWAS have identified genetic variants associated with many heritable disorders including age-related macular degeneration, Crohn’s disease, and Alzheimer’s disease. The eMERGE-PGx project, a partnership of the electronic medical record (EMR), Genomics Network, and Pharmacogenomics Research Network is assessing clinically actionable variants in 84 pharmacogenes in thousands of patients with exposure to prescribed drugs of interest (such as clopidogrel, simvastatin, and warfarin). This project employs clinical decision support tools to deliver point-of-care recommendations for the drugs. The knowledge of the specific variant is made available and is tied to clinical recommendations that have enabled the acceptance and utility of PGx testing [8]. While genomic medicine has matured, the role of microbiomics in diagnostic and precision medicine is still in its nascent stage. It is important that metagenome data generated using different methodologies and from different laboratories should be optimally comparable. Nevertheless, evidence from rodent models of microbiome studies suggest that thousands of microbial species in the gut can contribute to obesity, leanness, stress, and emotional behavior through endocrine and neuroendocrine pathways [9]. The significance for human health is now being revealed through observations such as how exercise and diet promote gut microbial diversity in athletes [10], intestinal dysbiosis is associated with liver diseases [3], and that elderly people living in long-term stay care [who also have significantly higher levels of inflammatory markers such as tumor necrosis factor a (TNF-a) and interleukin 6 (IL-6)] have less diverse microbiota [4]. These findings need to be replicated in other populations and from larger multicenter-based investigations. One example of translational success from microbiome research is the duodenal infusion of donor feces for recurrent Clostridium difficile infection [11]. Future results of ongoing clinical trials to assess the effect of microbiome, metabolome, and microbiome modulators on clinical gingivitis, celiac disease, and diabetes may lead to new therapeutic approaches. The human proteome and metabolome are additional pieces of the puzzle that will help advance precision medicine [12].
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Trends in Molecular Medicine xxx xxxx, Vol. xxx, No. x
In simple terms, genetics, the environment, and the human microbiome are at constant interplay to modulate health and disease. Biomedical research has arrived at an era where we have the capability to understand the genomics and microbiome of both healthy and diseased states of our body. The epoch of precision medicine began with treatments for monogenic diseases, and with modern approaches we will soon be able to diagnose complicated and refractory diseases and prescribe treatment or microbiome modulators that will be precise and based on the genetic and microbiological makeup of a person. This field will continue to evolve and be refined as our understanding of complexities of true systems biology is improved. The ‘Precision Medicine’ initiative will surely expedite the goal of evidence-based personalized medicine. Acknowledgments M.H.B. acknowledges support from NIH grants UL1TR000427 and 1U01HG006389 and S.K.S. from the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427, and Marshfield Clinic Research Foundation.
References 1 International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431, 931–945 2 International HapMap Consortium (2004) The International HapMap Project. Nature 426, 789–796 3 Schnabl, B. and Brenner, D.A. (2014) Interactions between the intestinal microbiome and liver diseases. Gastroenterology 146, 1513–1524 4 Claesson, M.J. et al. (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178–184 5 Ba¨ckhed, F. et al. (2005) Host–bacterial mutualism in the human intestine. Science 307, 1915–1920 6 Qin, J. et al. (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–67 7 Gottesman, O. et al. (2013) The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future. Genet. Med. 15, 761–771 8 Rasmussen-Torvik, L.J. et al. (2014) Design and anticipated outcomes of the eMERGE-PGx project: a multicenter pilot for preemptive pharmacogenomics in electronic health record systems. Clin. Pharmacol. Ther. 96, 482–489 9 Mayer, E.A. et al. (2015) Gut/brain axis and the microbiota. J. Clin. Invest. 125, 926–938 10 Clarke, S.F. et al. (2014) Exercise and associated dietary extremes impact on gut microbial diversity. Gut 63, 1838–1839 11 van Nood, E. et al. (2013) Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 12 Uhlen, M. et al. (2015) Tissue-based map of the human proteome. Science 347, 1260419
Forum
Personalized medicine going precise: from genomics to microbiomics Sanjay K. Shukla1, Narayana S. Murali2, and Murray H. Brilliant1 1 2
Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield, WI, USA Department of Nephrology, Marshfield Clinic, Marshfield, WI, USA
Practicing medicine has always been an art dependent upon the judgment of a physician. This art relies on listening, caring, and empathizing for the patient, and on judgment applied to every patient under their own unique circumstances in the backdrop of optimum medical care. Thus, medical treatment and disease management has always been personalized. However, practicing modern medicine is increasingly more complex in the era of genomics and microbiomics, as physicians and their patients have much more information to consider about the disease, and more treatment options are becoming available. In this context, the ‘Precision Medicine’ initiative (http://www. whitehouse.gov/precisionmedicine) is exciting because it will be based on recognizing individual differences in genes, environment, and lifestyle. The five objectives of the ‘Precision Medicine’ initiatives include: (i) more (and better) treatments for cancer; (ii) creation of a voluntary national research cohort; (iii) commitment to protecting privacy; (iv) regulatory modernization; and (v) public– private partnerships (http://www.whitehouse.gov/thepress-office/2015/01/30/fact-sheet). This initiative could not be more timely because years of basic, clinical, and translational research in biology (e.g., genetics, genomics, microbiome), chemistry (e.g., synthetic), physics (e.g., imaging), bioinformatics (e.g., management of big data, machine learning, and analytical software), and engineering (e.g., nanotechnology) have resulted in a better understanding of the complexities and pathophysiology of many complex traits and diseases. The human genome project conceived in the 1990s revealed approximately 20 000–25 000 genes in the human genome [1], but geneticists soon realized that a single human genome sequence did not, and could not, capture the whole gamut of human genetic variations. The HapMap project followed, with aims to describe common genetic variation and haplotypes across human populations [2]. The concept of ‘Personalized Medicine’ in its current avatar was born from these initiatives and revolves around the ability to exploit an individual’s known genetic variation that causes disease to customize their treatment. While ongoing research in genomics has continued to tease apart and explain the genetic susceptibilities of diseases, the role of the microbiome as a powerful modulator of human health and disease [3,4] emerged from the human Corresponding author: Shukla, S.K. ([email protected]). Keywords: personalized medicine; precise medicine; genomic medicine; genetics and health; microbiome. 1471-4914/ ß 2015 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.molmed.2015.06.002
microbiome project, which was launched in 2008 (http:// commonfund.nih.gov/hmp/index). The human microbiome, also referred to as the ‘second (human) genome’, consists of trillions of microbes that inhabit the human body and are ecologically and immunologically integrated with their host [5]. The microbiome is more complex than the human genome. The Human Microbiome revealed that commensal microbial genes exceed the total number of human genes by 100:1, and an adult human gut can harbor up to 100 trillion microbial cells; ten times higher than the total number of somatic and germ cells [5]. Indeed, experts of the International Human Microbiome Consortium have recommended that determining human metagenome and its variation with human population, genotypes, disease, age, nutrition, medication, and environment should be the goal of the Human Metagenome project (http://www. human-microbiome.org/index.php?id=243). Further, the metabolic contribution of the microbiome to host health is expected to be as large and significant as their gene pool. It will continue to be a mammoth task to fully understand the potential of how this vast amount of non-human genetic material, or at minimum the ‘functional core set’ of microbial genes conserved in each of us necessary to maintain gut functions [6], modulates pathophysiology of their human host. For ‘Personalized Medicine’ to succeed, researchers need biobanks of patient DNA, serum, and tissue blocks to probe genetic abnormalities. In addition, samples such as fecal and oral materials to determine the microbial composition will be crucial to see if and how the microbiome is shaped by disease phenotypes or vice versa. Analysis may also reveal cases where the microbiome creates disease susceptibilities or maintains chronic disease status. The ‘Precision Medicine’ initiative envisions implementing what we know as ‘actionable’ now, while continuing the discovery of new actionable variants learned from large cohorts. For example, we know the effects of certain variants on drug metabolizing genes, but the effect of other rare variants is currently unknown. Banking and genotyping the DNA of large numbers of people will enable new clinical recommendations for specific individual variants. Similarly, we are only beginning to know the consequences of individual microbiomes on health. Larger sets of data will result in new clinically actionable recommendations. The National Institutes of Health (NIH) has helped to create large biobanks of usable clinical samples, data sharing plans for large DNA and protein datasets, and bioinformatics tools. The NIH-funded Electronic Medical Trends in Molecular Medicine xx (2015) 1–2
1
TRMOME-1051; No. of Pages 2
Forum Records and Genomics (eMERGE) Network developed and applied approaches to combine DNA biobanks with corresponding medical records to assess relationships between genetic variants and diseases of interest by genome-wide association studies (GWAS) [7]. GWAS have identified genetic variants associated with many heritable disorders including age-related macular degeneration, Crohn’s disease, and Alzheimer’s disease. The eMERGE-PGx project, a partnership of the electronic medical record (EMR), Genomics Network, and Pharmacogenomics Research Network is assessing clinically actionable variants in 84 pharmacogenes in thousands of patients with exposure to prescribed drugs of interest (such as clopidogrel, simvastatin, and warfarin). This project employs clinical decision support tools to deliver point-of-care recommendations for the drugs. The knowledge of the specific variant is made available and is tied to clinical recommendations that have enabled the acceptance and utility of PGx testing [8]. While genomic medicine has matured, the role of microbiomics in diagnostic and precision medicine is still in its nascent stage. It is important that metagenome data generated using different methodologies and from different laboratories should be optimally comparable. Nevertheless, evidence from rodent models of microbiome studies suggest that thousands of microbial species in the gut can contribute to obesity, leanness, stress, and emotional behavior through endocrine and neuroendocrine pathways [9]. The significance for human health is now being revealed through observations such as how exercise and diet promote gut microbial diversity in athletes [10], intestinal dysbiosis is associated with liver diseases [3], and that elderly people living in long-term stay care [who also have significantly higher levels of inflammatory markers such as tumor necrosis factor a (TNF-a) and interleukin 6 (IL-6)] have less diverse microbiota [4]. These findings need to be replicated in other populations and from larger multicenter-based investigations. One example of translational success from microbiome research is the duodenal infusion of donor feces for recurrent Clostridium difficile infection [11]. Future results of ongoing clinical trials to assess the effect of microbiome, metabolome, and microbiome modulators on clinical gingivitis, celiac disease, and diabetes may lead to new therapeutic approaches. The human proteome and metabolome are additional pieces of the puzzle that will help advance precision medicine [12].
2
Trends in Molecular Medicine xxx xxxx, Vol. xxx, No. x
In simple terms, genetics, the environment, and the human microbiome are at constant interplay to modulate health and disease. Biomedical research has arrived at an era where we have the capability to understand the genomics and microbiome of both healthy and diseased states of our body. The epoch of precision medicine began with treatments for monogenic diseases, and with modern approaches we will soon be able to diagnose complicated and refractory diseases and prescribe treatment or microbiome modulators that will be precise and based on the genetic and microbiological makeup of a person. This field will continue to evolve and be refined as our understanding of complexities of true systems biology is improved. The ‘Precision Medicine’ initiative will surely expedite the goal of evidence-based personalized medicine. Acknowledgments M.H.B. acknowledges support from NIH grants UL1TR000427 and 1U01HG006389 and S.K.S. from the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427, and Marshfield Clinic Research Foundation.
References 1 International Human Genome Sequencing Consortium (2004) Finishing the euchromatic sequence of the human genome. Nature 431, 931–945 2 International HapMap Consortium (2004) The International HapMap Project. Nature 426, 789–796 3 Schnabl, B. and Brenner, D.A. (2014) Interactions between the intestinal microbiome and liver diseases. Gastroenterology 146, 1513–1524 4 Claesson, M.J. et al. (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488, 178–184 5 Ba¨ckhed, F. et al. (2005) Host–bacterial mutualism in the human intestine. Science 307, 1915–1920 6 Qin, J. et al. (2010) A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–67 7 Gottesman, O. et al. (2013) The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future. Genet. Med. 15, 761–771 8 Rasmussen-Torvik, L.J. et al. (2014) Design and anticipated outcomes of the eMERGE-PGx project: a multicenter pilot for preemptive pharmacogenomics in electronic health record systems. Clin. Pharmacol. Ther. 96, 482–489 9 Mayer, E.A. et al. (2015) Gut/brain axis and the microbiota. J. Clin. Invest. 125, 926–938 10 Clarke, S.F. et al. (2014) Exercise and associated dietary extremes impact on gut microbial diversity. Gut 63, 1838–1839 11 van Nood, E. et al. (2013) Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 12 Uhlen, M. et al. (2015) Tissue-based map of the human proteome. Science 347, 1260419
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