CCFA Launches IBD Genetics Initiative
Recent studies have demonstrated that specific organisms in the gut can cause IBD in the presence of specific genes, and that specific genes only cause disease in the presence of specific organisms. Understanding the genes and their functions is the next big step in clarifying what can go wrong and result in a chain of biological events referred to as the pathogenesis of IBD – and with advanced study of human genetic variants that correlate to IBD risk or protection, scientists believe we can make dramatic advances in the fight against IBD. We will be able to connect the dots of discovery and uncover new opportunities for curing or preventing the onset of Crohn's disease and ulcerative colitis.
Building a Launch Team for IBD Genetics
To capture this opportunity, CCFA has embarked on a campaign to raise six to ten million dollars targeted at a unique IBD Genetics Initiative spanning the next three to five years. Like its sister project, the CCFA Microbiome Consortium, the new initiative will involve the best scientists in multiple disciplines and locations who will work in a coordinated fashion to reap the benefits of knowledge we can build from today’s science and technology.
To succeed, this ambitious program requires superlative leadership. Through the eyes of its leaders, the daunting work can be described, categorized and prioritized. Through the resources and knowledge of its leadership, six or seven of the best and brightest researchers in this field will be selected to join a multidisciplinary "dream team," poised to launch this next phase of genomic-era progress in IBD. Significantly, the study of Crohn's disease and ulcerative colitis has already been a pace setter for understanding the role of genes in human disease.
Initiative Leadership: A Clear Choice
When CCFA collected proposals from IBD researchers this spring to compare their strategic visions and tactical approaches, there was a clear choice of leadership for this initiative. Ramnik Xavier, M.D., Ph.D., who serves as chairman of the department of gastroenterology at Massachusetts General Hospital (MGH) in Boston, has taken a commanding role in the dynamic field of IBD genetics. However, Dr. Xavier is much more than a legendary hunter of IBD genes.
Dr. Xavier directs research laboratories at MGH, Harvard Medical School, and the Broad Institute of Harvard and MIT and is a leader in developing the tools and technology that facilitate genetic discoveries. His laboratory is associated with identification and validation of the largest number of genes associated with IBD risk. He is a founding member of the Center for Computational and Integrative Biology, currently one of the top-ranked centers of bioinformatics and systems biology approaches to deciphering the biology of human disease.
At the Broad Institute, he co-directs the "Learning from Human Genetics" program. Their goal is to create a cohesive and coordinated framework around functional genomics capabilities that can be applied to gene and pathway validation in human disease. He also serves as the director for the Center for the Study of Inflammatory Bowel Disease, under an NIH center grant. The Center has a membership of over 100 investigators. All this experience qualifies Dr. Xavier to lead a multi-disciplinary, multi-investigator, multi-institutional program focusing on IBD functional genetics.
Because of his laboratory's accomplishments, Dr. Xavier was invited to write review articles for the prestigious journal Nature in 2007 and 2011 to outline the astonishing breadth of IBD gene discoveries of the past ten years. These studies have highlighted the significance of the relationship between intracellular responses to microbes and the regulation of adaptive immunity in the pathogenesis of IBD.
However, Dr. Xavier is most enthusiastic about his publications in the past five years. They exemplify the spirit of teamwork that drives progress. All have resulted from collaborative efforts between biologists and computational biologists—a crossroads of science, engineering, and mathematics. As the research ramps up, there will be reams of data to analyze. This will be no problem for the Genetics Initiative. Dr. Xavier comments, "In addition to wet labs for our experiments, we have computer scientists, mathematicians, engineers, and experts in analytical genetics, who are very good at taking multiple data points and reducing the space to simple models. We will be able to use what we are calling computational genomics, with up-to-date computational tools, to simplify the models."
Gene Hunters Take Aim at Cracking the Code of IBD
Although many of the details of the new initiative are only now being finalized, Dr. Xavier has already established a co-leadership with another researcher of exceptional and complementary skills. Herbert "Skip" Virgin, M.D., Ph.D., of Washington University Medical Center in St. Louis, is chairman of its pathology and immunology department and director of the MRCE, Biodefense Institute at Washington University. He is also a member of the CCFA Microbiome Consortium. Drs. Xavier and Virgin, a virologist and immunologist, have collaborated for a number of years on multidisciplinary IBD research projects.
Dr. Virgin observes how times have changed in science, "Previously, you could be an expert on a particular gene or an organism and make substantial progress in understanding a disease. In complex diseases, like IBD, that model is really not very effective. When you have 100 loci that in some way contribute to risk and when complex populations of microbes contribute to disease, studying 'one thing' rather than the interactions between things does not work effectively. A matrix-like research organization is the only way to go. Interactions between genes make the difference. We need to work in an integrated scientific structure that brings together experts with different expertise rather than a 'one gene, one lab' environment. Those involved in the study of complex diseases have realized this, as has CCFA, which is facilitating a transition in its sponsored research."
Dr. Virgin continues, "CCFA and NIH have put a lot of work and resources into identifying genetic risk factors for IBD. It is a startling discovery that there are so many genes and yet, in aggregate, they do not explain everything. Many have unknown functions or function in pathways that were not previously thought to play a role in these diseases. The playing field is completely different now than it was before. It is not rocket science to figure out that something integrative is required; the challenge is how to do it successfully with the right interactions between the right people to effectively address a complex problem."
Dr. Xavier agrees that the timing could not be better for a consortium approach to IBD genetics. He elaborates, "A lot of the human genetic mapping of the disease is done with about 100 genetic loci associated with risk of Crohn's disease, ulcerative colitis, or common to both. At the same time, technologies that are required to understand gene function at a human disease level have been developed. We also have come to appreciate that to tackle large problems, you need something similar to what NIH has done with its cancer initiative – to bring together multiple disciplines like molecular biology, genetics, immunology, and computational biology to work as a team. In this way, we hope to try to 'crack the code' as fast as possible."
Dr. Xavier comments on the goal of enabling drug discovery, "Normally, when you make a drug, it is based on how the gene works, so once you know how it works, you define a pathway. Genetics defines genes that are aberrant in patients and pathways that contribute to disease, like autophagy (a first line of defense against infection by which cells engulf foreign invaders). Then you design a small molecule that interferes or enhances the function of the defective pathway. For example, the pathway may be hyperactive in Crohn's disease, so we want to find a small molecule that down regulates or interferes with this pathway; if the pathway is sub-optimal or less than ideal, we want to find a small molecule to enhance it and have full, normal pathway function. A developer of therapeutic drugs needs to understand the complexity of gene functions and how to reverse or block genetic function in some way."
Therapeutic and Diagnostic Implications
The vision of Dr. Xavier and Dr. Virgin also extends to diagnostics where they are already converging on Paneth cell research findings. Paneth cells in the intestine produce antibacterial proteins that control intestinal microbes. These cells are controlled by several IBD-associated genes. Alterations in Paneth cells may provide a basis for better diagnostics, ability to predict when a patient is predisposed to a flare of their IBD, or to indicate what therapy might best be used.
Dr. Virgin emphasizes that genetic research will also have a huge application to diagnostics and pharmacogenomics. The burgeoning field of pharmacogenomics correlates the patient's gene expression with responsiveness to a drug and its safety. Researchers can develop companion diagnostics to match the patient with the most likely therapy to succeed. Dr. Virgin comments, "Maybe too little attention has been paid to diagnostics. These are heterogeneous diseases. If you could define subtypes clearly, and genetics combined with pathology and biomarkers is the way to accomplish this, you could recruit patients who are more likely to respond to a given therapy in a clinical trial, improving the speed and decreasing the cost of testing new therapies. It is likely that new therapies will be needed for subgroups. There may well be no 'one size fits all' treatment. To identify therapy targets in complex diseases, effective diagnostics are critical."
When one considers the 100 non-overlapping IBD genes, including 28 shared by Crohn’s disease and ulcerative colitis, 71 for Crohn's, and 47 for colitis, along with the previously observed relevance to many mechanisms of the immune response in the cells of our bodies, it seems overwhelming to sort it all out. We know however that both Crohn's and colitis have common genetic pathways impacting various functions of our immune system such as microbial defense, barrier function, autophagy, and altered T cell programs. Dr. Xavier is confident that this is manageable. He points out that 50 percent of the discovered genes actually are clustered in areas of interest with shared impact or function. Dr. Xavier comments: "Despite 100 loci or genes, what is emerging is that 100 loci work in about a dozen pathways so we may be able to reduce the complexity to a few candidate pathways."
Patients Will Make the Difference
Dr. Xavier wants supporters of CCFA to understand how unique and far-reaching the goals of the Genetics Initiative are. It is patient based, and the protocol will call for looking at samples of thousands of individuals, with Crohn's disease, ulcerative colitis, and healthy control subjects. The Initiative will sequence the genes that have been identified in patients and know quickly what is wrong with the gene. The technology that enables us to read genetic code, called DNA sequencing, has undergone huge and continual upgrades.
Faster and more cost-effective technology offers a compelling opportunity to ask more questions and to get answers. Dr. Xavier explains the value of resequencing candidate genes: "For example, we have a paper that has been accepted in Nature Genetics where we have sequenced genes in genetic loci associated with risk for Crohn's and colitis and found additional mutations in those genes. When you identify a mutation in the gene, it becomes the culprit. It took forever to sequence these genes in the past and now we can do it quickly, from diagnosed patients."
"Many people think of research as being performed in test tubes or animal models," continues Dr. Xavier. "We will base this research on samples from patients with Crohn's and colitis as well as healthy controls. We will build animal models only based on what our scientists observe in human samples. This is translational research, still very basic, but very essential in moving the field to the next level."
Dr. Xavier is a strong believer in the synergies of collaborative research among multiple laboratories. He sees this model as an accelerator of progress in genetics. Synergies are already popping up. Thanks to his involvement with the Broad Institute, he is already looking at FDA-approved drugs or molecules of known structure to determine if they may have function in the pathways that contain Crohn's or colitis genes. He adds, "The big advantage is that we already know existing drugs are safe in patients and our ability to move to testing patients is going to be a lot faster." The Broad Institute has developed cost-effective applications of new technology for determining the gene expression profile of individuals, such that they can obtain genetic signatures for an individual patient at an accessible cost per test. This technology will be applied to the goals of the CCFA Genetics Initiative. And it can help connect the dots.
CCFA is on a mission to win the war against IBD. As Dr. Virgin says, "We are off and running. We are making lists of genes. We are taking names and identifying prisoners." The Foundation is taking the understanding of IBD to a new level by sponsoring organized, collaborative research into IBD genetics. The vision for a CCFA Genetics Initiative is in place. The funding needs to follow to make it a real hope for all patients and families in search of a better future. Dr. Xavier reminds us, "Every dollar counts." We are funding high-impact genetic research that will be synergistic with CCFA’s existing research in the microbiome. There could not be a better time to give generously.
This article originally appeared in the Fall 2011 issue of Under the Microscope, CCFA's bi-annual research and news bulletin. To receive Under the Microscope, become a member of CCFA today.