The Promise and Challenges of Biobanking in Digestive Disease Research
Article Outline
Advances in biomedical research require the use of many different model systems in the laboratory, ranging from the simplest eukaryotes, yeast, to the most complex, humans. In general, basic biological mechanisms are most efficiently studied in simple model systems where the genetic background can be controlled and manipulated, and large numbers of organisms can be quickly characterized. Profound discoveries have been made in yeast (Saccharomyces cerevisiae), nematodes (Caenorhabditis elegans), fruit flies (Drosophila melanogaster), and zebrafish (Danio rerio). Mammalian models largely focus on the use of either in vitro tissue culture or rodent models such as mice. Under certain circumstances, studies in non-human primates are performed to study disease processes such as hepatitis C virus and Simian immunodeficiency virus, as well as evaluate pharmacologic interventions that parallel the biology in humans. Here, too, basic mechanisms of normal biology and disease can be probed in experiments under carefully controlled conditions. Nevertheless, it is the application of knowledge to human biology that counts the most. Despite compelling evidence for the functional mechanisms in these model systems, direct relevance to humans is sometimes difficult to predict. For example, the efficacy of pharmacologic agents clearly useful in rodent models may not translate into meaningful results in humans. Furthermore, deleterious side effects of pharmacologic agents in rodents may not be observed in humans. Finally, just because a model of disease in a mammalian system phenotypically seems to have similar characteristics of human disease does not mean that this model is relevant to human biology. Enormous expense, hard work, and effort may be expended studying these model systems later to find out that the relevance to humans is limited.
As basic discoveries are made in simplified model systems, it seems intuitively obvious that a concerted attempt should be made to determine their relevance to humans. Many types of these studies require the collection of human tissue from healthy subjects, as well as from patients with disease processes, to perform genomic studies and characterize patterns of gene expression at the mRNA or protein level for their use in biomarker discovery. One example of biobanking blood that has been extremely successful, leading to novel discoveries relevant to gastrointestinal disease pathogenesis, are the genome-wide association studies that have identified a growing number of genes associated with the development of inflammatory bowel disease (IBD).1 These discoveries have led to new paradigms in disease pathogenesis, some of which would not have been predicted by decades of research in cell culture and various animal models. In addition, this new information has provided a strong impetus for basic science investigators to focus research projects on areas that are new to the field of mucosal immunology such as autophagy.2, 3, 4 Immediate applications of this new knowledge include genotypic–phenotypic studies that may lead to genomic tests to predict patterns of disease in patients that may help to direct therapeutic interventions. The identification of interleukin-23R as a gene associated with the development of Crohn's disease has also helped to identify a new immune regulatory pathway as a target for the generation of novel pharmaceutical agents.5
With advances in transcriptome profiling to examine patterns of gene expression at the mRNA level as well as proteomics, significant advances in biomarker discovery are now much more feasible. The identification of these markers may provide useful in clinical practice by prognosticating disease phenotype, predicting response to pharmacologic therapy (as has been demonstrated in the treatment of tumors),6 and in identifying patients that may have adverse reactions to specific medical therapies. These types of studies can be performed not only on blood, but also on tissue samples obtained from the gut, which are fortunately easily accessible. The accessibility of tissue from the luminal digestive tract has facilitated important discoveries such as the progression of adenomas to carcinomas in the pathogenesis of colorectal tumorigenesis, a paradigm for the development of many epithelial tumor types. More recently, it now seems that even biobanks of human stool samples may ultimately lead to important discoveries in the role that the gut microbiome plays in diseases such as IBD, diet-induced obesity, and diabetes. To support such initiatives, the human microbiome project, supported by a National Institutes of Heath roadmap initiative, has recently been initiated.7
Despite the promise of research based on human tissues, however, there remain significant challenges in the field. First, it is critical that procedures are in place to protect patient confidentiality as mandated by the Health Insurance Portability and Accountability Act. Careful scrutiny by institutional review boards is critical in this regard. Second, the collection of tissues requires the cooperation of clinicians, pathologists, surgeons, and basic researchers. Increasing pressure in academic medical centers to maintain high levels of revenue generation has made it difficult for clinicians to justify the additional amount of time required for the collection of these samples, either in the endoscopy suite or the operating room. One solution to this obstacle is to provide a supplement to the professional fee of the clinician as compensation for the additional amount of time required to collect these samples. It is also important that basic researchers acknowledge that clinicians play a critical role in the success of human-based studies that extend beyond the collection of tissues. Annotated clinical information provided by clinicians from the care of their patients is often critical for the success of genetic and biomarker studies. Furthermore, clinicians can provide astute observations in their patients that may provide invaluable clues to basic researchers about disease pathophysiology. Examples include the observation that nonsteroidal anti-inflammatory drugs lead to the regression of colonic polyps8 and the association between Helicobacter pylori infection and the development of gastritis and peptic ulcer disease.9 Third, institutional infrastructure must be in place to support the collection of tissues and patient-based information by clinical coordinators, as well as provide sufficient storage space and technology to archive both these samples and information. Importantly, expertise in biomedical informatics must be available to analyze the large amount of data generated by biomarker and genomic studies, especially when attempts are made to correlate gene expression and genotyping data with clinically annotated information. Finally, inherent variability between human subjects, the lack of precision in the phenotypic characterization of patients with disease, and the inability to control important variables such as diet, compliance with medications, travel, and personal habits such as tobacco and alcohol use, to name a few, means that large numbers of human subjects must be enrolled in studies to achieve the power to obtain statistically meaningful results.
Despite these challenges, investment in the infrastructure to support biobanking of human tissues will pay rich dividends in the future for institutions and investigators with the foresight and patience to undertake these initiatives in digestive disease research. Biobanks are already in place for specific disease entities. In the United States, examples include the National Cancer Institute-sponsored Cooperative Human Tissue Network, the Central National Institute of Diabetes and Digestive and Kidney Diseases Repository for Biosamples and Data, as well as the Inflammatory Bowel Disease Genetic Consortium. In addition, at least 18 countries have either initiated or are planning to develop population-based biobanks, focused primarily on the collection of DNA, ranging in size from a few thousand to half a million subjects.10 One of the largest institutionally based biobanks, which was established at the Children's Hospital of Philadelphia approximately 2 years ago, has already collected blood from half of the human subjects toward its goal of 100,000. Except for the consortia on IBD genetics, most of these biobanks are not focusing specifically on digestive disease research. Nevertheless, given the substantial impact of digestive and liver disease on both the morbidity and mortality of patients worldwide, there is no doubt that these biobanks will facilitate research that will reveal invaluable new information on disease pathogenesis, hopefully facilitating the development of novel approaches to diagnostics and therapeutics for our patients.
References
- Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet. 2008;40:955–962
- A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39:207–211
- A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008;456:259–263
- Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008;456:264–268
- A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461–1463
- EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304:1497–1500
- The human microbiome project. Nature. 2007;449:804–810
- . Sulindac for polyposis of the colon. J Surg Oncol. 1983;24:83–87
- . The pathogenesis of non-ulcer dyspepsia. Med J Aust. 1985;143:319
- . Biomedical science: betting the bank. Nature. 2008;452:926–929
PII: S0016-5085(09)00047-X
doi:10.1053/j.gastro.2009.01.017
© 2009 AGA Institute. Published by Elsevier Inc. All rights reserved.
