6 Genome Technology Development Grants for the Human Genome Project and Beyond

1.1. Technology Development Research and a Focus on Multidisciplinary Research Teams Needed to Be Nurtured, Because These Were Uncharacteristic for NIH Grants and Funding in the Early 1990s

The emphases on technology development and on multidisciplinary teams were unusual for the NIH. This assertion is substantiated by the fact that planning workshops, as described above, found it necessary to recommend the formation of special review panels. This became a focus for implementation as demonstrated by insights from early participants. For example, years later, Dr. Elke Jordan, originally the Director of the Office of Human Genome Research at the NIGMS and subsequently the Deputy Director of NHGRI, described how peer review had to be tuned so that appropriate grant applications could be successful. “Peer review as it was operating at NIH at the time was really not prepared for genomic kind of research, which was large scale, moving towards completion, and all those characteristics. So we really had to train reviewers, or convince reviewers, to take a different kind of look at applications. And the weeding out of centers really was in large part a peer review issue. Staff worked with the peer reviewers to get the criteria right. The peer reviewers eventually got it. And they were able to distinguish those that might be successful from those that were not” (Jordan 2015). Dr. Jordan’s comments were with regard to the review of center grants, but they pertain as well to technology development (a central goal of those centers as well as of other grants).

Similarly, Dr. Cheryl Corsaro, working in the Division of Research Grants (later renamed the Center for Scientific Review), was the Scientific Review Administrator for a series of Special Emphasis Panels for genomics grants beginning in March 1988 and of the chartered Genome Study Section, which began reviewing grant applications in 1990. Dr. Corsaro recalled, “There was concern at some higher level that regular study sections would not appreciate grant applications involving technology development or those involving genetic and/or physical mapping, which were just seen as large data gathering exercises, that is, non-hypothesis driven research. There was also an attitude that technology development was something that could be carried out on a back burner in a lab and it wasn’t something you got a whole grant for. So it was decided that the only way around these issues was to have a separate study section for the HGP. It was called the Genome Study Section, as opposed to the Human Genome Study Section, to be more inclusive” (Dr. Cheryl Corsaro, Personal Communication).

To reinforce this imperative to support technology-directed research, funding announcements incorporated explicit language to alert applicants, reviewers, and the institute’s National Advisory Council that ambitious technology research would be a central factor in grant application evaluation and funding decisions. This language sent the important message that applicants should take seriously that it was worth their effort to submit ambitious technology development projects, that reviewers were expected to be open-minded about projects proposing technology development and evaluate them for what they propose to accomplish, and that advisors should support the funding of high-quality, ambitious technology projects. Both of the initial NHGRI announcements for R01 and R21 grants (NIH Guide 1990a, 1990b) included language promoting high-risk/high-payoff projects. The GESTEC program introduced the award criterion: “Value of the proposed research and of the proposed technology development for achieving the goals of the Human Genome Program” (NIH Guide 1994a). And the first RFA directed exclusively at DNA sequencing technology (NIH Guide 1994d) introduced additional scientific and technical merit review criteria, including:

• likelihood that the proposed technology will serve as a technology that can support the completion of the goals of the Human Genome Project for sequencing of genomic DNA.
• degree to which the project contributes to a fully integrated, automated, modular system for the sequencing of genomic DNA;
• degree to which the proposed technology considers and effectively overcomes existing bottlenecks in large-scale sequencing of genomic DNA;
• degree to which the proposed system addresses data acquisition and handling issues;
• degree to which the proposal considers exportation and support of the ensuing technology.

All of these factors together—formation of special review panels, increasingly direct language in funding calls, and vigilance by institute staff—contributed to building and sustaining a grants culture that was enthusiastic about supporting the development and application of new technology toward meeting challenging goals in genomic science.

Allied with calls for grant support for technology development research projects, NHGRI supported career awards for “training in the biological sciences (of) individuals with doctoral degrees in scientific disciplines that have the potential to further the technological developments essential to the success of the Human Genome Program, such as mathematics, engineering, computer sciences, chemistry, and physics, in order to enable such individuals to pursue a career in genomic research” (NIH Guide 1991). Of nine principal investigators receiving awards under this career awards program between 1992 and 1995, four had backgrounds in physics, math, and engineering and have had successful careers contributing to development of genomic technologies, each one winning numerous other grants and several honors.

1.2. NHGRI Grants Supported, and Continue to Support, Technology Development in Various Contexts

As described above, projects whose main goal was to produce large genomic datasets provided an essential setting for genomic technology development. A strong motivator, continuing in such grants today, has been the imperative to produce ever more and better data at decreasing cost. Generally speaking, such production projects do not develop entirely novel methods. Instead, they adapt methods that work only acceptably well into robust, cost-effective methods that can be used at scale to produce high-quality data—an activity that is clearly critical to the success of projects such as the HGP and its follow-ons. Data production grants form an outstanding setting in which to improve recipes for molecular biology and biochemistry preparations, to “harden” those preparations (e.g., standardizing and streamlining of protocols), and to apply automation to reduce costs and errors.

Data production projects also import technologies from vendors and, as early adopters, they provide critical feedback to those vendors about system weaknesses or shortcomings; they then help the rest of the community to adopt the improved commercial systems. They are able to do this in part because, given the consistent NHGRI investment in technology at data production centers, the centers are able to employ dedicated staff who are experienced in such activities and bring expertise (e.g., quantitative science and engineering) different from that of typical biologists. The work these center staff do is critical to the operation because they pursue technology development in collaboration with the data production staff who are intimately familiar with the processes and challenges of real-world data generation.

Dr. Richard Myers described some of these challenges, along with the importance of this activity for successful data production, in an interview (Myers 2015): “Technology development was and continues to be a critical part of all of this. And while you want to do technology development when you’re generating large amounts of (data)—and it actually helps to have large amounts of data—it’s really hard to combine production with development. You have a pipeline that’s working and if you want to change something in that, you mess up your production. So most groups—and this is where these grants came in, and I don’t remember when they started calling them GESTEC grants, it was early on, it wasn’t the very first ones—where you would really need to have a development arm almost separate from your production arm, but not too far away, because you don’t want to develop something that doesn’t need to be done. The production environment and the people doing that truly understand what the problems are. This step is the rate limiting one, for instance. So that was actually a hard lesson and in fact, I think we early on tried to learn something from industry. A bunch of us from NHGRI went to the Motorola cell phone factory in Illinois and learned how they did their assembly line and one of the lessons there is that every step of a 30 or 40 step process, every step had some kind of QC, some kind of quality analysis and quality control. And you would stop it if it didn’t fit the quality control. . . . So that’s part of technology development, too, is making a start-to-finish pathway, pipeline. It’s not very glamorous, it’s pretty boring in some ways. It’s not some new, shiny technology. It’s putting the pieces together.”

A second “flavor” of technology development activity is exemplified by the approach taken by the ENCODE (Encyclopedia of DNA Elements) project (see chapter 4). The ENCODE pilot project’s mandate was to apply state-of-the-art methods to data production. However, available methods could assay only a subset of functional elements, and technologies for better-studied elements were not very efficient or accurate. Therefore, alongside the data production RFA, a parallel RFA (NIH Guide 2003 and subsequently reissued) offered funding to develop novel methods to enable assay of additional functional elements beyond those for which assays existed at the time, and to improve efficiency and accuracy of assays for elements that could already be studied. These projects were awarded as R01 grants and were not part of the ENCODE data production collaboration. Interestingly, even though the ENCODE technology grants were awarded independent of the production activities, the RFA included language to remind applicants of the importance of factors that would be required soon (assuming that the ENCODE pilot would expand in a few years to the full genome, as ultimately occurred). The RFA noted: “The ‘process’ of technology development can be considered to span a spectrum of stages. Initially, it involves the development of an entirely new methodology (or the significant improvement of an existing methodology) to the point of proof of principle. The method must then be reduced to practice. For such a new method to have a significant impact for genomic studies, it also must be shown that it can be used efficiently on a large-scale, or genomic basis, which requires another level of technology development. This RFA is intended to solicit applications that address any of these phases of technology development.”

A related example of this second type of technology development grant opportunity at about the same time as the ENCODE RFA was an RFA for improving clone libraries for physical mapping (NIH Guide 2002a). When this RFA was published, the human genome draft sequence and the sequences of the official HGP model organisms had been published, so production center activity had shifted away from mapping. The shotgun genome sequencing approach (without underlying maps) was ascendant. Yet there remained several potential uses for genome-wide clone maps for genomes for which such a resource did not exist, and if clone maps could be generated quickly and cost-effectively, genomics projects could be expanded to those organisms. Given that a 2002 state-of-the-art bacterial artificial chromosome map for a mammalian genome cost $1.5–$2 million, which was more than most projects could afford, the RFA called for increase in throughput and decrease in cost of clone mapping, either by improving current methods or developing new ones. It emphasized the need for developing the technology and for proof of principle of its scalability, demonstration of map quality, and for a commitment from a production center to consider putting the method into use.

The third “flavor” of NHGRI-supported technology development projects has been independent of any explicit data generation project. These calls were open-ended, listing a wide range of types of genomic data for which technology should be developed. NHGRI has maintained active FOAs of this type (e.g., NIH Guide 1990a, 1990b, 1992, 1994a, 1994b, and subsequent similar program announcements every few years) to encourage investigator-initiated grant applications. While the ultimate goal was to create technology to enable efficient, high-quality, low-cost data production and analysis tools, most of these calls for applications did not require demonstration of those characteristics within the period of any particular grant. This approach allowed investigators to explore truly novel methods, even though the methods might not be reduced to practice within a two-to-five-year grant duration.

This approach to technology development has been very important. First, the approval of data production centers has been highly selective, using criteria focused on many factors beyond the quality of technology development plans. NHGRI wished to engage a wider community of investigators in the development of genomics technologies than could possibly be associated with the small number of production centers. Second, a center that was required to report several times per year on its data production milestones might not enthusiastically support developing entirely novel methods for which the demonstration of proof of principle might take several years. And third, the wider community that the NHGRI hoped to attract included investigators not necessarily focused on genomics but with physical science or engineering expertise—for example, surface chemistry, analytical chemistry, materials science, electrical engineering—that those investigators believed, and that indeed the HGP planners believed, would have potential to produce genomics tools.

This was a two-edged sword, because while some of these investigators were correct about genomic potential of the technology, per se, they could easily have gone off in directions that would not prove useful even if the technology itself worked, because, for example, the field had solved the problem in another way, or the experiments they proposed to aid were not of great interest to biologists. Therefore, program directors encouraged investigators from fields outside of biology to collaborate with users—biologists who might benefit if the technology project succeeded. Specifically, program directors suggested that a grant application might be stronger if it could include the statement from a biologist-collaborator, such as, “If this method works, I’ll be able to do important biology experiments that I either can’t do at all today, or that are too laborious or for which data quality is tenuous.” Such a collaboration would also keep the physical science collaborator focused on the needs of the biology. This practice helped numerous investigators to prepare grants applications that otherwise might not have succeeded in peer review.

NHGRI issued and continues to issue FOAs to encourage grant applications focused on technology development. These convey the intent of the institute to fund such research and provide parameters to investigators to better understand that intent. It should be noted, however, that many technology development grant applications were submitted to the NHGRI and funded outside of those specific FOAs. These include investigator-initiated grant applications; the NIH, unlike some other federal granting agencies, invites investigators to submit their project ideas without waiting for specific topical requests. Similarly, the majority of NHGRI’s small business grants have been focused on technology development, and most of these were submitted in response to the omnibus small business grant opportunities, in which all of the NIH institutes and centers participate by including broad descriptions of the research topics they support. A wide range of technology development projects similar to those that might be submitted through technology development FOAs are handled through these generic grant applications, enabled by the technology development culture fostered in the early days.

Given the primacy of DNA sequencing as a genomic technology critical to the HGP and subsequent genomics projects, its development was aggressively pursued, both in association with and independent of data production. Clearly, underdeveloped (inefficient, costly, poor quality) DNA sequencing technology would either devour vast sums of money if it were scaled up, or severely limit the biology that could be pursued because it was too expensive to scale up. Prior to the scale-up of sequencing for the HGP, the focus of RFAs was on increasing throughput and decreasing cost using existing methods, by the application of automation, miniaturization, and reagent and process improvement (NIH Guide 1994d, 1995). The generic technology development FOAs and investigator-initiated applications brought in similar projects to those supported by the RFAs, and also attracted pursuit of entirely novel sequencing methods, such as atomic force/scanning probe microscopy, mass spectrometry, sequencing by hybridization and nanopore sequencing, expanding the scope of the program to less-well-demonstrated methods.

Subsequent to completion of the HGP, NHGRI issued, again with support from a planning process, RFAs for a ten-year program of revolutionary improvements in sequencing technology, with ambitious goals to reduce costs by one-hundred-fold in five years and another one-hundred-fold five years later (NIH Guide 2004a, 2004b and subsequent). This Advanced Sequencing Technology Program supported a wide range of projects spanning a spectrum of risk, with further miniaturization and automation of methods used for HGP sequencing at the low-risk end and approaches such as nanopore sequencing near the high-risk end. The program incorporated features such as explicit and ambitious goals, acceptance of risk, use of timelines and milestones, grants of varying sizes to investigators having a variety of backgrounds, to academics and private companies, grantee meetings, data sharing, and active, flexible management of grants, all of which had been hallmarks of the successful management of the HGP (Schloss et al. 2020). The program is generally considered to have been highly successful (Hayden 2014), having contributed funding to versions of virtually all of the current commercial next-generation and next-next generation sequencing technologies that are enabling biomedical research in ways that could not rationally have been proposed when the original RFAs were issued. These successes notwithstanding, NHGRI continues to aggressively support sequencing technology development.

An important factor in achieving progress in genomic technology development has been the recruitment of investigators who bring a range of disciplinary experience as discussed above. It is interesting to analyze the number of investigators who had not previously been funded by the NIH and then received NHGRI technology development grants. We tallied grants made in response to technology development funding calls from 1988 to 1995 (NIH Guide 1988b, 1990a, 1990b, 1992, 1994b, 1994c, 1994d, 1995). Sixty-eight unique investigators received awards from this collection of FOAs. Of these, twenty-eight, or 41 percent, had not previously received NIH funding. The proportion of investigators without prior NIH support from individual FOAs in this list ranged annually from 20 percent to 60 percent. For the collection of FOAs that comprised the Advanced Sequencing Technology Development Program ($100,000 genome and $1,000 genome technology), awards were made from 2004 to 2013 to sixty-seven unique investigators of whom thirty-five, or 52 percent, had not received previous NIH support.

[Method: The publicly available NIH RePORTER system was searched with the program announcement and RFA codes.2 Only type 1 awards (first year of a new grant) were counted (so that if the name of the principal investigator was changed during the award, this was not registered; a renewal of a previously existing grant, even if from outside of the FOA, would not be counted). Investigators who received multiple awards were counted only once. If investigators had received training grants (e.g., career awards or fellowships) but not research grants, they were considered to be already within the NIH system and so they were counted among unique investigators but not as having received no prior NIH support. No attempt was made to determine whether an investigator might be at the beginning of her or his career and that was the reason why they had not received prior NIH support.]

Practices put in place to stimulate technology development for the HGP had impact beyond genomics. Practices such as encouraging grants to pursue technology development and design- and discovery-driven (and not exclusively hypothesis-driven) research, and expanding the background of investigators who may apply to conduct that research—multidisciplinary, interdisciplinary, physical scientists, mathematicians and engineers—subsequently became central to other highly visible NIH programs. These included bioengineering grants (NIH Guide 1998a and 1998b) and grants under the National Nanotechnology Initiative (NIH Guide 1999 and 2002b).

NHGRI’s broadest-ranging experiment in supporting novel genomic technologies has been the Centers of Excellence in Genomic Science (CEGS), a program that was developed through discussions with members of the National Advisory Council for Human Genome Research at the end of the 1990s as HGP DNA sequencing was scaling up. Part of the motivation was to provide investigators with a center grant vehicle for novel, investigator-initiated research projects that could bring together complementary expertise with sufficient funding and time to try to meet a very challenging goal, to significantly advance the genomics field. In contrast to previous NHGRI centers that had focused on technology development and data production to meet near-term goals, CEGS would develop genomics tools and concepts to enable the research community to ask new questions about biology (NIH Guide 2000). The program sets out parameters with respect to a high bar for novelty, a ten-year time limit, and certain budgetary guidelines, but is open-ended with respect to genomic technology topic, promoting investigator-initiated creativity. As the CEGS program has matured since its initiation twenty years ago, it has supported a small number of relatively high-risk/high-reward projects, several of which have been remarkably successful (National Human Genome Research Institute 2020).

1.3. Planting Technology Seeds and Harvesting Their Bounty

Numerous stories could be told of positive and sometimes serendipitous outcomes of NHGRI-supported technology development grants. Continuing the theme of NHGRI support for grant applications submitted outside of any focused program, this section provides anecdotes on three such projects. Examples of value creation as a result of funding under the Advanced Sequencing Technology Program are presented in Schloss et al. (2020).

• Bakajin, O., T. A. Duke, J. Tegenfeldt, et al. 2001. “Separation of 100-Kilobase DNA Molecules in 10 Seconds.” Analytical Chemistry 73:6053–56.
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• Chou, C. F., O. Bakajin, S. W. Turner, et al. 1999. “Sorting by Diffusion: An Asymmetric Obstacle Course for Continuous Molecular Separation.” Proceedings of the National Academy of Sciences USA, no. 96 (Nov):13762–65.
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• Das, S. K., M. D. Austin, M. C. Akana, P. Deshpande, H. Cao, and M. Xiao. 2010. “Single Molecule Linear Analysis of DNA in Nano-Channel Labeled with Sequence Specific Fluorescent Probes.” 2010. Nucleic Acids Research, no. 38 (Oct): e177.

• Hayden, Erika Check. 2014. “The $1,000 Genome.” Nature, no. 507 (Mar): 294–95.

• Jordan, Elke. 2015. A Quarter Century After the Human Genome Project’s Launch: Lessons Beyond the Base Pairs. Introductory Talk Discussants: Elke Jordan and Mark Guyer. December 3. Accessed February 1, 2020. https://www.genome.gov/event-calendar/after-Human-Genome-Project-Launch-Lessons.

• Kasianowicz, J. J., E. Brandin, D. Branton, and D. W. Deamer. 1996. “Characterization of Individual Polynucleotide Molecules Using a Membrane Channel.” Proceedings of the National Academy of Sciences USA, no. 93 (Nov): 13770–73.

• Levene, M. J., J. Korlach, S. W. Turner, M. Foquet, H. G. Craighead, and W. W. Webb. 2003. “Zero-Mode Waveguides for Single-Molecule Analysis at High Concentrations.” Science, no. 299 (Jan): 682–86.

• Myers, Richard. March 2015. NHGRI’s Oral History Collection: Interview with Richard Myers. Accessed February 1, 2020. https://www.genome.gov/leadership-initiatives/History-of-Genomics-Program/oral-history.

• National Center for Human Genome Research. 1990. “Understanding Our Genetic Inheritance. The U.S. Human Genome Project: The First Five Years, FY 1991–1995.” NIH Publication No. 90–1580. DOE/ER-0452P. US Department of Health and Human Services. US Department of Energy.
• National Human Genome Research Institute. 2020. Centers of Excellence in Genomic Science. Accessed February 1, 2020. https://www.genome.gov/Funded-Programs-Projects/Centers-of-Excellence-in-Genomic-Science.
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• NIH Guide. 1994d. RFA-HG-95–001. “Improved Electrophoretic DNA Sequencing Technology.” 23, no. 42 (December 2).
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• NIH Guide. 1998a. PAR-99–009. “Bioengineering Research Grants.” (October 29). https://grants.nih.gov/grants/guide/pa-files/par-99-009.html.
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• NIH Guide. 2002b. PAR-03–045. “Nanoscience and Nanotechnology in Biology and Medicine.” (December 12). https://grants.nih.gov/grants/guide/pa-files/PAR-03-045.html.
• NIH Guide. 2003. RFA-HG-03–004. “Technologies to Find Functional Elements in Genomic DNA.” (February 21). https://grants.nih.gov/grants/guide/rfa-files/RFA-HG-03-004.html.
• NIH Guide. 2004a. RFA-HG-04–002. “Near-Term Technology Development for Genome Sequencing.” (February 12). https://grants.nih.gov/grants/guide/rfa-files/rfa-hg-04-002.html.
• NIH Guide. 2004b. RFA-HG-04–003. “Revolutionary Genome Sequencing Technologies—The $1000 Genome.” (February 12).

• Schloss, J. A., R. A. Gibbs, V. B. Makhijani, and A. Marziali. 2020. “Cultivating DNA Sequencing Technology After the Human Genome Project.” Annual Review of Genomics and Human Genetics 21:117–38.
• Schwartz, D. C., X. Li, L. I. Hernandez, S. P. Ramnarain, E. J. Huff, and Y. K. Wang. 1993. “Ordered Restriction Maps of Saccharomyces cerevisiae Chromosomes Constructed by Optical Mapping.” Science, no. 262 (Oct): 110–14.

• Tegenfeldt, J. O., C. Prinz, H. Cao, et al. 2004. “From the Cover: The Dynamics of Genomic-Length DNA Molecules in 100-nm Channels.” Proceedings of the National Academy of Sciences USA, no. 101 (Jul):10979–83.

• US Congress, Office of Technology Assessment. 1988. “Mapping Our Genes—Genome Projects: How Big, How Fast?” OTA-BA-373. US Government Printing Office.