In February 2011, the National Human Genome Research Institute (NHGRI) published a Strategic Plan for translating the advances made in genomic science since the Human Genome Project (HGP) into improved methods and practices for diagnosis and treatment of human diseases. CCV research directly supports two key objectives developed in the Strategic Plan: Understanding the Biology of Genomes and Understanding the Biology of Disease:
By developing methods that directly analyze the causality between human genetic variation and phenotype, the CCV will help take the catalogs of human variation and disease associations that have been collected since the HGP to the next logical step by providing generally applicable experimental methods for distinguishing which variations make real differences to biology vs. which are incidental to it.
These CCV methods will apply to non-coding as well as coding variations in the human genome, a key need identified in the Strategic Plan because there is vastly more variation in non-coding vs. coding DNA in humans and it is much more difficult to understand. The methods will also be applicable to newly discovered and rare variations, such as those being identified by the 1000 Genomes Project and other genome and exome sequencing efforts (e.g., PubMed).
CCV’s aim of extending these methods to induced Pluripotent Stem Cells and cell types that can be derived from them will provide a way of understanding the ways in which the causality of variations may operate differently in different human cell types or tissues. This again promises to take catalogs of human variation and disease associations to a next logical step, as these catalogs usually offer only limited abilities to analyze the impact of variations on different cell types.
Similarly, CCV-developed methods for highly parallel in situ single-cell RNA transcription analysis will enable single cell resolution of different behaviors of cells in complex tissues or cell populations. Since non-coding variations are generally conceived to influence transcription patterns, highly parallel single cell transcription analysis will provide ways of tracking the impacts of different combinations of non-coding variations, or of non-coding variations in multiple cell types, in single experiments.
In addition to supporting the two strategic objectives of Understanding the Biology of Genomes and Disease, CCV research also contributes to other elements of the Strategic Plan, including:
All of the CCV’s technology development efforts focus on developing methods that will work with high efficiency, can be run in highly parallel manners, and which will work with small samples and small amounts of reagents. As these features all contribute to lowering the economic costs of applying these methods, these features will support their translation into clinical practice where the scale-up costs of using new technology can be a critical barrier.
By developing methods for routinely engineering changes to the genomes of human induced Pluripotent Stem Cells, will provide tools that will have direct application to Gene Therapy and will thus contribute to development of new therapeutics.
Centers for Excellence in Genomics Sciences (CEGS) are a class of Centers funded by the NHGRI to develop potentially game-changing capabilities that could change the course of biological research. CEGS bring together multi-investigator, multi-disciplinary teams to work out novel approaches to biological and technological problems, or to generate and analyze new forms of ‘omics’-level biological data, that will enable researchers to overcome barriers to understanding and control of biology critical to improving human health and reducing the burden of disease. CEGS are expected to explore approaches that are high-risk but have high potential, and, while they focus on specific important biological problem areas, are expected to develop methods that can be generally applied to other biological problems. CEGS must deliver innovative research products that could not have been achieved without the ability to pursue high-risk, multi-disciplinary science provided by the CEGS program. The CCV meets these CEGS critera in the following ways:
As described above, the CCV addresses a critical need for general methods for engineering human genomes in ways that can be used to analyze the causal consequences of human genetic variations in many human cell types. These methods will overcome present-day limits to understanding and applying the wealth of information on human variation collected by genome sequencing and Genome Wide Association Studies.
The CCV brings together researchers with proven track records in genetic engineering, stem cell technology and biology, and development of high-throughput ‘omics’ methods and automation, with the goal of developing genome engineering methods that can be applied generally, inexpensively, and, ultimately, routinely throughout biology and medicine. While many labs and companies have developed methods for modifying genetic loci, the engineering of human cells remains a difficult problem characterized by low efficiencies and cumbersome, biology-specific screening and selection systems. By setting itself the higher target of developing general, high-efficiency, and highly parallelizable methods, the CCV explores high-risk, high-potential approaches that could not be pursued outside of a CEGS.
In addition to these scientific criteria for a CEGS, the CCV also meets CEGS’ commitments to increasing the representation of underrepresented minority communities in genomics sciences careers by maintaining a diversity program.