(Circulation. 2000;101:468.)
© 2000 American Heart Association, Inc.
Editorials |
NHLBI Genomics Initiatives
Looking Beyond the Human Genome Project
From the Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, Md.
Correspondence to Claude Lenfant, MD, Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD 20892.
Key Words: Editorials • genomics
The US Human Genome Project has already produced a vast abundance of data, technologies, and resources. With its anticipated completion of the sequencing of human genomic DNA by the year 2003 come many exciting challenges and opportunities for the National Heart, Lung, and Blood Institute (NHLBI).
With this groundwork placed before us, the next essential step is to
successfully correlate these data, technologies, and resources with the
physiology and pathophysiology that define health and disorders. Of the
100 000 human genes, the NHLBI is particularly concerned with the
subset that is linked to heart, lung, blood, and sleep health and
disorders. Our challenge is to clearly identify these genes, then to
build on this knowledge to develop better methods for prevention,
diagnosis, and therapy. Let me provide some examples of approaches we
are taking to meet this challenge.
The NHLBI has already developed several important initiatives in gene discovery. The Family Blood Pressure Program, for instance, seeks to uncover the multiple genes and interacting factors that contribute to blood pressure regulation and dysfunction. Our asthma program has shown a linkage of asthma and its associated traits to multiple genomic regions and is now moving forward to apply positional candidate gene approaches. For sickle-cell disease, we seek to identify and characterize those genes that modulate disease severity in the hope of designing more individualized strategies to manage this devastating illness. In thrombosis, we are about to fund a new program to elucidate the molecular genetic mechanisms of thrombosis in the arterial and cerebral vasculature. Cutting across all of these disease-specific efforts is pharmacogenetic research aimed at correlating genetic variations with individual responses to drugs, both favorable and adverse.
But to make continued meaningful progress in these and other areas, it is necessary to develop the tools and resources needed for future discoveries. Accordingly, the NHLBI has taken the lead role in the National Institutes of Health (NIH) rat genomic efforts, which have provided important information and reagents for gene discovery and function and established the Rat Genome Database (http://www.nih.gov/science/models/rat/). We are partners in the NIH mouse genomics effort, including the establishment of a facility for large-scale mutagenesis and phenotyping for developmental defects in the mouse. We are part of the NIH Mammalian Gene Collection, which supports the generation and sequencing of full-length human and other mammalian cDNAs. And we are part of the Single-Nucleotide Polymorphism program to develop and apply the appropriate technologies to identify and detect this next generation of DNA markers. We stand firmly committed to providing the tools needed for the future in genetics research to study genes as well as their interactions with other genes and with the environment.
Although these individual programs provide the hope of continued discovery, they are merely part of a broader picture. Our goal should be a complete understanding of the influences, both positive and negative, that each element of our vast genome contributes to our well-being. To foster this understanding, the NHLBI is initiating one of its most ambitious, wide-ranging efforts to date, the Programs for Genomic Applications (PGAs). Our objectives are straightforward: to link genes to function on a genomic scale; to establish targeted training and education programs to disseminate information and technologies; and to enhance the development of the technologies, biological models, methodologies, reagents, and software that will be necessary for investigators to better understand the biology and pathobiology associated with heart, lung, and blood function and disease. The themes of the PGAs will address the biological processes and systems required for cardiovascular, pulmonary, and hematological function and dysfunction.
The PGAs will represent a significant step forward in the support of genomics-based investigation into biological function. The NHLBI intends to commit up to $35 million in fiscal year 2000 to fund as many as 10 new PGAs, each at up to $3.5 million. The PGAs will be supported for a period of 4 years, with the possibility, based on productivity and funding availability, of a second 4-year award. As is customary, the initial PGA awards will be made on the basis of superior scientific and technical merit. The subsequent renewal will also be based on successful competitive peer review. The NHLBI will give its most favorable consideration to those applications that have broadly based themes of scientific relevance to heart, lung, blood, and sleep disorders; that encompass multiple tissue or organ systems; and that are integrated and interactive.
Program awards will be made as cooperative agreements in which the NHLBI assists the recipients by supporting and stimulating their activities, while still giving principal investigators the dominant role in and primary responsibility for their research studies. The Institute will take an active role in program coordination between awardees, encouraging strong collaborations among the various PGAs and convening subcommittees to cover such cross-discipline areas as quality control, molecular biology strategies, phenotypic measurements, genotyping and sequencing, data collection and analysis, computation biology, training and education, sharing of data and materials, intellectual property rights, publication policies and procedures, rights of authorship, and ethical, legal, and social implications.
A central principle of the PGAs is that information and reagents developed as part of the program will be made immediately and freely available to the research community, thereby allowing those not directly involved in the programs to develop their own relevant studies. The PGAs will create usable subsets of the vast amount of data generated by the Human Genome Project and other allied efforts that will benefit all areas of heart, lung, and blood research, from epidemiology and prevention to cellular and molecular studies, by coupling genomic technologies and resources with the biology and pathophysiology that define health and disease. Furthermore, the PGAs will serve as a springboard for the development of investigator-initiated, hypothesis-driven research and will make available critical resources that are difficult or too expensive to develop in most individual laboratories.
These goals are in harmony with other NHLBI efforts to provide resources for genetic studies. These now include the NHLBI Mammalian Genotyping Service, which provides genotyping aimed at identifying genes in all disease areas; the Stored Genetics Sample Inventory Database (http://irtpdev.nhlbi.nih.gov/genetics/), which provides a means to foster collaborative genetic studies; and the Genetically Altered Animal Models Database (http://www.nhlbi.nih.gov/resources/medres/transgen.htm), which provides information on crucial animal models and prevents wasteful duplication of effort.
As we pause to reflect on the magnitude of what we hope to achieve with these programs, we can see that there is clearly much work before us. But as we begin to reap the dividends of our national investment in the Human Genome Project, these genomics initiatives presented by NHLBI should provide the impetus to stir our creativity and thereby bring new light and new hope to the prevention, diagnosis, and treatment for disorders of the heart, lungs, and blood.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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  C. Lenfant Cardiovascular Research : A Look Into Tomorrow Circ. Res., February 16, 2001; 88(3): 253 - 255. [Full Text] [PDF]
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