In December, Cure Alzheimer’s kicked off one of the most ambitious projects it has funded—the Collaboration to Infer Regulatory Circuits and to Uncover Innovative Therapeutic Strategies, or CIRCUITS. Following in the footsteps of the 3-D Drug Screen Consortium (3DDS), CIRCUITS tasks nine renowned researchers and their labs from six world-class institutions to address the many unanswered questions about epigenetics and Alzheimer’s disease, and to create a vast, analyzed repository of epigenetic data tied to biological and health data from patients. To meet the ambitious goals of the CIRCUITS research plan, Cure Alzheimer’s Fund will support the group with $4 million over two years.
The researchers involved in CIRCUITS are:
Lars Bertram, M.D., University of Lübeck (Germany)
Joseph Ecker, Ph.D., Salk Institute for Biological Studies
Winston Hide, Ph.D., University of Sheffield (United Kingdom)
Brad Hyman, M.D., Ph.D., Harvard Medical School/Massachusetts General Hospital
Manolis Kellis, Ph.D., Broad Institute/Massachusetts Institute of Technology
Rudolf Jaenisch, M.D., Massachusetts Institute of Technology
Andreas Pfenning, Ph.D., Carnegie Mellon University
Rudy Tanzi, Ph.D., Harvard Medical School/Massachusetts General Hospital
Li-Huei Tsai, Ph.D., Massachusetts Institute of Technology
CIRCUITS has its foundations in the Alzheimer’s Genome Project™ (AGP), headed by Rudy Tanzi, Ph.D., at Massachusetts General Hospital, and supported by Cure Alzheimer’s Fund since 2005. The AGP scanned the entire human genome from a large cohort of Alzheimer’s families for genes associated with risk for or protection against Alzheimer’s disease. The project identified dozens of risk genes, many of which currently are being investigated for therapeutic potential by CureAlz researchers.
“The AGP provided us with a wealth of genetic data,” explains Tanzi, “but to really understand how these genes are functioning in the disease, we need epigenetic data as well. That’s where CIRCUITS comes in.”
From Genetics to Epigenetics
Genes are sections of DNA that code for specific proteins. The APP gene, for instance, codes for the amyloid precursor protein. Mutations in these sections of code can lead to gain or loss of function as the mutated proteins perform differently than the typical version. Such changes can lead to dysfunction and disease in ways that, in many instances, scientists have been able to trace.
But recently, geneticists have found that genes themselves don’t tell the whole story. In addition to the genes in our DNA, there are vast sections of code that we are only just beginning to parse. Much of this DNA, which once was considered “junk,” is now thought to regulate whether and at what level genes are decoded into proteins.
“APP, APOE and other AD genes carry mutations that directly influence susceptibility to Alzheimer’s,” Tanzi explains, “but another section of DNA in the human genome might be responsible for regulating that gene. It’s just as important to understand this regulatory activity as it is to understand the gene defects themselves.”
These regulatory changes often take place through a process called DNA methylation. Molecules called methyl groups attach themselves to genes in DNA. The number and location of these groups will affect whether and how that section of DNA is made into proteins and used by the cell.
Epigenetics introduces new levels of complexity in our understanding of DNA, but also explains a great deal that our earlier concept of genetics could not. For instance, while an organism has the same DNA in each cell of its body, the location of methyl groups on the DNA can differ by cell type. This means that a neuron and a blood cell, for example, might have different patterns of methyl groups, and therefore identical genes produce different protein output in the different cell types. Additionally, evidence suggests that an organism’s life experience affects methylation, meaning how DNA is expressed can change over the course of an organism’s lifetime. As a result, two individuals born with the same gene variant impacting risk of disease still might face different levels of risk from that variant, depending on how their life experiences affect the methylation of that gene.
New Levels of Specificity
Manolis Kellis, Ph.D., of the Broad Institute and Massachusetts Institute of Technology (MIT), and Li-Huei Tsai, Ph.D., of MIT and a member of the Cure Alzheimer’s Fund Research Consortium, are leading a CIRCUITS project aimed at understanding these differences among cell types. “In the past, when researchers have looked at brain tissue for evidence of DNA changes linked to Alzheimer’s, they haven’t distinguished among cell types,” Kellis explains. “My project with Dr. Tsai will provide data specific to different cell types, so we’ll know whether the abnormal encoding is happening in neurons, glial cells or somewhere else.”
Other researchers are generating data from a variety of sources to build a comprehensive picture of changes seen in the disease. For example, Brad Hyman, M.D., Ph.D., of Harvard Medical School and Massachusetts General Hospital, will be comparing neurons grown from stem cells to actual brain tissue from the same patients. “With current stem cell technology,” explains Hyman, “we can take a patient’s skin cells, convert them back into stem cells, and then grow them into a new cell type, such as a neuron.” Hyman will be able to compare these lab-grown neurons with actual brain cells from the same patient upon autopsy. “No one has ever had the opportunity to compare stem cell models to brain cells from the very same individual,” says Hyman. “This experiment will be invaluable in telling us about possible limits of stem cell models, and if these newly generated cells differ from cells in tissue that has already lived many years.”
Analyzing and Disseminating Data
While researchers like Kellis, Tsai and Hyman are performing experiments to generate new data, other CIRCUITS researchers are working on ways to analyze that data. Winston Hide, Ph.D., of the University of Sheffield, brings his expertise as a computational biologist to the CIRCUITS team. Hide is working on the algorithms and database design needed to make sense of the volume and complexity of the experimental data produced by the other members of the consortium. Hide and Andreas Pfenning, Ph.D., of Carnegie Mellon, will employ “big data” computing and advanced biostatistics to reveal patterns and connections among the data inputs that would have gone unseen without such sophisticated tools. The end result will be a ranking of genes and epigenetic regulatory pathways based on their likely impact on Alzheimer’s disease, as well as their profile for potential drug intervention.
This data will be of vital importance to CureAlz researchers for future studies, but it also will be of great value to the Alzheimer’s field as a whole. “One of the primary goals of CIRCUITS,” Kellis explains, “is to generate data that can be widely distributed and used by any researcher. We don’t want to keep anything proprietary. We want this information to be used to get us to a cure as fast as possible.”
The Consortium Approach
While Cure Alzheimer’s Fund historically has supported smaller-scale research projects—one or two researchers working together and grants at the $100,000–$300,000 level—it was clear a different approach was needed for CIRCUITS. Generating many different types of data and analyzing that data requires expertise across several fields and a strong collaborative approach. Having seen solid results from the 3-D Drug Screening Consortium established in 2015, CureAlz wanted to apply the model in other circumstances where separate projects may never accomplish as much as a planned, coordinated effort.
“CIRCUITS has been designed very thoughtfully as a multilab consortium,” says Tim Armour, President and CEO of Cure Alzheimer’s Fund. “We have always encouraged and even required our funded researchers to share ideas and collaborate. CIRCUITS epitomizes a model where collaboration is built into the very structure of the research. The funding CureAlz provides, thanks to our donors, not only encourages, but actually enables, this kind of organized team research across institutions. We are committed to establishing additional consortia on topics vital to finding a cure.”
A consortium on APOE, the gene whose variants have the greatest impact on risk of late-onset or sporadic Alzheimer’s, is expected to launch this year. Meanwhile, Cure Alzheimer’s Fund also will continue to support individual researchers working on innovative stand-alone projects exploring promising topics in Alzheimer’s research.