Report and Recommendations from the Future of Structural Biology Committees

NIGMS Advisory Council Meeting: Report of the NIGMS Future of Structural Biology Committees

Dr. Leemor Joshua-Tor’s presentation of the report begins at 00:36:22 on the archived videocast of the National Advisory General Medical Sciences Council meeting.

I previously told you about the formation of two committees focused on Protein Structure Initiative (PSI) transition planning. These committees were charged with identifying high priorities for future NIGMS investments in structural biology and determining what unique resources and capabilities developed during the PSI should be preserved to address the needs of the scientific community. Dr. Leemor Joshua-Tor, one of the committee co-chairs, presented the groups’ report at the National Advisory General Medical Sciences Council meeting on January 23.

The committees’ recommendations for preserving PSI resources that the committees felt will be important for the community in the future include:

  • Support for a modest number of protein expression resources to serve the needs of the community.
  • Continued support for a materials repository Exit icon similar to the one that has been supported through PSI.
  • Possible continued support for a structural biology knowledgebase Exit icon.

The committees identified these areas as high priorities for the future of structural biology:

  • Continued support for synchrotron beamlines for crystallography.
  • Support for modern cryo-EM resource centers.
  • Continued support for NMR resources for structural biology.
  • Support for the integration of structural biology methods.
  • Support for collaborative, multi-investigator efforts in membrane protein and large macromolecular assembly structure determination.

We’re now developing plans for implementing the report’s recommendations.

Judith Greenberg Named Deputy Director of NIGMS

Photo of Dr. Judith GreenbergI’m delighted to tell you that Judith Greenberg is NIGMS’ new deputy director.

Judith has been a vital member of the NIGMS leadership team for many years, including serving as acting director for two extended periods, as acting deputy director since shortly after I arrived and as director of our Division of Genetics and Developmental Biology since 1988. Her many significant contributions have included leading the development of two strategic plans, spearheading the establishment of important new policies and streamlining a number of internal processes.

Judith has a long record of outstanding leadership and dedication to NIGMS and NIH, and we can all look forward to continuing to benefit from her wisdom, expertise and perspective.

New NIGMS Guidelines for Funding Investigators with Substantial Unrestricted Research Support

Jon Lorsch recently posted a message about the responsibility that our grantee community shares with us to help the research enterprise thrive. One way that we have addressed this is by taking a hard look at the funding of investigators who are already well supported. As most of you know, in an effort to increase efficiency and to support as many outstanding scientists as possible, we have long required special advisory council approval  for any grant that, in combination with the principal investigator’s (PI’s) other research support, would provide over $750,000 in direct costs.

We have now developed guidelines that we will use in awarding R01s and other research grants to investigators with substantial levels of long-term, unrestricted research funding from any source. Unrestricted funding means that it is not project-based and may be used to conduct research on a broad topic at the PI’s discretion. We consider such support substantial and long-term if it is over $400,000 in direct costs (excluding the PI’s salary and direct support of widely shared institutional resources) and extends for at least 2 years from the time the NIGMS grant would be funded.

Abiding by these new guidelines will enable us to fund additional labs, increasing the likelihood of making significant scientific advances. The guidelines will take effect for applications submitted on or after January 2, 2016. If you might be affected by the new guidelines, I encourage you to discuss your plans with your program director.

NIGMS Grantee to Share 2014 Nobel Prize for High-Resolution Cellular Imaging

Cellular skeleton showing the calculated 3D location of the protein tubulin.

Using a technique made possible by super-resolved fluorescence microscopy, scientists captured this image of a cellular skeleton. More details

We were excited to learn this morning that our grantee William E. Moerner will share the 2014 Nobel Prize in chemistry Exit icon with Eric Betzig and Stefan W. Hell "for the development of super-resolved fluorescence microscopy." We congratulate them on this well-deserved recognition of their pioneering work, which has provided an unprecedented window into the cell and paved the way for understanding a range of biological processes.

I’m particularly thrilled with today’s news because it highlights an NIGMS-supported field that I’ve been closely involved in for more than 15 years. I remember my first conversation with W.E. on moving single-cell spectroscopy into biology, which led to a 2000 workshop we held to explore the state of the art in—and potential for—research in single molecule detection and manipulation. The recommendations from that workshop informed the development of a number of initiatives to apply the tools and approaches of the physical sciences to biological problems. The initiatives include our single molecule detection and manipulation program announcement and an NIH Roadmap for Medical Research program on the development of high-resolution probes for cellular imaging.

Since then, we have witnessed an explosion in the use of optical methods to look at single molecules at the nanoscale level and are gaining a wealth of insights as a result.

A statement from NIGMS on the prize is at http://www.nigms.nih.gov/news/results/pages/20141008.aspx. More information about our support of Nobel Prize winners is at http://www.nigms.nih.gov/education/pages/factsheet_NIGMSNobelists.aspx and at http://www.nigms.nih.gov/pages/GMNobelists.aspx.

Ensuring Synchrotron Beamline Access for Biomedical Researchers

The National Synchrotron Light Source (NSLS) at Brookhaven National Laboratory (BNL) closed earlier this week as a newer, more advanced facility, NSLS-II Exit icon, began to come online.

Thousands of NIH researchers have used beamlines at NSLS over the last 30 years to collect data to characterize biological macromolecules including drug targets, ion pumps and enzymes. Because the beamlines for biological research Exit icon at NSLS-II will not be available until 2016, other synchrotron facilities are temporarily expanding their capacity to address the beamline reduction.

Here are some sources that will help you identify and access beamlines at other U.S. synchrotrons:

If you have questions about NIH-funded synchrotron resources, please contact me or Ward Smith.

Update on the National Centers for Systems Biology Program

As part of the ongoing examination of our large-scale research initiatives and centers, we’re in the process of evaluating the NIGMS National Centers for Systems Biology program. This includes conducting quantitative analyses of the program’s contributions to systems biology research, training and outreach as well as gathering qualitative input from a panel of external scientific experts.

We expect the evaluation to be complete by early 2015. The results and recommendations will help us determine a future path for supporting this field in the most effective and efficient way and in the context of competing research funding priorities and opportunities. In the meantime, we’re only accepting renewal applications for projects seeking their second, and final, 5 years of funding.

Over the 10-year course of the program Exit icon, we’ve funded 21 centers covering a broad range of areas, from structural and cell biology to physiology and pharmacology. To learn more about the current and past centers, visit the Centers Web site.

Lasker Award Recognizes Question-Driven Research on Protein Folding

We congratulate long-time NIGMS grantee Peter Walter of the University of California, San Francisco, on being recognized with the 2014 Albert Lasker Basic Medical Research Award Exit icon for his elegant and insightful work on the signal that activates the unfolded protein response (UPR). He shares the honor with Kazutoshi Mori of Kyoto University in Japan.

For more than 30 years, we have funded the Walter lab to investigate how yeast cells control the quality of their proteins and organelles to maintain homeostasis. In the 1990s, at the time Walter was conducting the research that led to this award, we supported his studies of protein translocation and the signal recognition particle, which links the nascent protein chain to the endoplasmic reticulum, where folding then occurs. This work led, in part, to his research on the downstream events associated with protein misfolding and his identification of the key signal that activates the UPR.

The UPR mechanism adjusts as needed to maintain normal cellular function and prevent disease. Sustained overactivation of the UPR has been implicated in cancer, diabetes, autoimmune conditions, liver disorders and neurodegenerative diseases. Additional studies have shown that the UPR is highly conserved and present in every cell.

The Lasker Award to Walter, who’s also an HHMI investigator, is a strong endorsement of question-driven basic research and its role in revealing unpredicted, medically important pathways.

Challenge Contest: Tracing Basic Research to Medical Advances

Challenge.gov LogoThe basic biomedical research NIGMS supports is essential for the groundbreaking advances that enhance human health, but drawing a connection between an NIGMS-funded research project and a specific medical advance can be difficult. First, it can be decades between the study of a scientific question and the application of the resulting knowledge to improving human health. Second, in most cases, it’s not a single project or experiment that leads to a “eureka moment” with tangible benefits, but rather the combination of many projects. Third, the projects may be supported by different funding sources (various NIH institutes, other federal agencies, private organizations and foundations), and these sources often change during the decades of development. What started as an NIGMS project may later get funded by an NIH institute whose mission is disease-specific, followed by private funding as the advance becomes commercialized.

We’re always looking for new ways to identify these connections, and we think you can help. We’re soliciting stories that make a clear association between NIGMS-funded research and improvements in health, well-being or other tangible benefits to the public and/or economy. We’re also interested in applications in medicine, industry, technology or elsewhere that have their roots in NIGMS-funded research projects. We especially encourage our long-time grantees to share their stories of discovery.

We’re not looking for “Nobel Prize”-type stories or scientific breakthroughs that might in the future lead to improvements in the human condition. Rather, we want complete stories that can trace current treatments, therapeutics or diagnostics back to knowledge or insights gained from one or more NIGMS-funded projects. These examples will augment our own staff’s efforts to identify such stories and help us further fill out the historical context of breakthroughs in basic research and their impacts.

We’re using the Challenge.gov mechanism Exit icon for this purpose, which enables us to give monetary awards of $500 to winning entries. We’ll also post the winning stories on our Web site. Submissions are due by October 20, 2014, and we look forward to seeing what you send in!

Comment on Proposed Pilot to Support NIGMS Investigators’ Overall Research Programs

We’re planning an experiment in how we fund research, and we want your input. As outlined in the Request for Information (RFI) included below, we propose to create a pilot program called Maximizing Investigators’ Research Award (MIRA) that would support all of the projects in an investigator’s lab that are relevant to the NIGMS mission.

We expect that the MIRA program will offer a number of benefits. For instance, investigators would not have to break their work into smaller, strictly prescribed increments. In addition, the program could improve funding stability and enhance grantees’ flexibility to follow new research directions as opportunities and ideas arise.

It’s important to note that MIRAs are not intended to be a method for supporting only a perceived elite group of investigators or promoting only high-risk, high-potential-reward research.

Our intent is to pilot a program that might transform how we support fundamental biomedical research, creating a more productive, efficient and sustainable enterprise. I encourage you to read the proposal and share your comments using the RFI input form by the August 15 deadline. We welcome responses from both individuals and organizations.


Request for Information (RFI): Soliciting Comments on a Potential New Program for Research Funding by the National Institute of General Medical Sciences

Notice Number: NOT-GM-14-122

Key Dates

Release Date: July 17, 2014

Response Date: August 15, 2014

Related Announcements

None

Issued by

National Institute of General Medical Sciences (NIGMS)

Purpose

This is a time-sensitive Request for Information (RFI) directed at obtaining input to assist the National Institute of General Medical Sciences (NIGMS) in its planning for a potential new program tentatively named Maximizing Investigators’ Research Award (MIRA). This award would be a grant in support of all of the research supported by NIGMS in an investigator’s laboratory.

Background

Supporting basic research by funding individual projects has a number of consequences for the efficiency and effectiveness of the basic biomedical research enterprise in the U.S. (Alberts, 1985; Ioannidis, 2011;  Vale, 2012; Bourne, 2013; Alberts et al., 2014). To address these issues and increase the efficiency and efficacy of its funding mechanisms, NIGMS is considering a pilot program to fund investigators’ overall research programs, which represents a compilation of the investigator’s research projects. It is hoped that this new funding mechanism will achieve the following:

  • Increase the stability of funding for NIGMS-supported investigators, which could enhance their ability to take on ambitious scientific projects and approach problems creatively.
  • Increase flexibility for investigators to follow important new research directions as opportunities arise, rather than being bound to specific aims proposed in advance of the studies.
  • Improve the distribution of funding among the nation’s highly talented and promising investigators to increase overall scientific productivity and the chances for important breakthroughs.
  • In the long term, reduce the time spent by researchers writing and reviewing grant applications, allowing them to spend more time conducting research.

Overview of the proposed NIGMS MIRA program

  • An NIGMS MIRA would provide support for a lab’s research program, which represents a compilation of the investigator’s NIGMS research projects (research areas supported by NIGMS are outlined at our website). Researchers would have the freedom to explore new avenues of inquiry that arise during the course of their work as long as those avenues are relevant to the mission of the Institute and do not require additional review for regulatory compliance (e.g., new human subjects research).
  • An NIGMS MIRA would be renewable.
  • Funding would range from $150,000-$750,000 (direct costs/year), depending on recommendations of the study section and the National Advisory General Medical Sciences Council as well as staff evaluation of the needs and expected productivity and impact of the program. Support for the investigator from sources other than NIGMS would be taken into consideration when deciding on funding levels for an NIGMS MIRA.
  • Up to $150,000 in administrative supplement support for the purchase of new equipment could be requested by an NIGMS MIRA grantee per grant cycle. Decisions on these requests would be made by NIGMS staff and the National Advisory General Medical Sciences Council based on an assessment of need and the potential impact of the new equipment on the research. The number of supplements given would depend on the available funds.
  • The median direct costs for NIGMS MIRAs would be higher than the current median R01 direct costs at NIGMS.
  • The length of an NIGMS MIRA would be 5 years, which is longer than the current average for an NIGMS R01 of close to 4 years.
  • A researcher funded by an NIGMS MIRA would not be given any other sources of NIGMS funding with the following exceptions:
  • Grants supporting research resources
  • Grants supporting training, workforce development or diversity building
  • Funding for clinical trials
  • SBIR/STTR grants
  • Conference grant
  • The Program Director/Principal Investigator (PD/PI) would be expected to commit at least 50 percent research effort to the NIGMS MIRA.
  • Revision applications to allow new collaborative work might be included as part of this program.
  • Review of the application would emphasize a holistic evaluation of the investigator’s track record and the overall potential importance of the proposed research program, without focusing on specific project details. Specific aims would not be required. The process would include peer review using existing criteria and processes but would be tailored to address the particular features of the MIRA (see the section below on the Possible Peer Review Process).
  • To avoid the abrupt termination of research groups from an adverse round of peer review, NIGMS MIRAs could be ramped down from one funding level to a lower one that is more consistent with the recent and perceived future productivity of the group and the importance of the work, as assessed by the study section. Conversely, a renewing program could have its budget increased if the perceived productivity, impact and needs merited it. As per standard grants policy, NIGMS program staff would make decisions on funding levels, guided by the recommendations from study sections and the National General Medical Sciences Council.

Possible Peer Review Process

In addition to the standard review criteria, among the considerations reviewers would be asked to address in reviewing MIRA applications are whether:

  • The proposed research effort is substantive, broad and ambitious.
  • A PD/PI’s record shows evidence of productivity, creativity, adaptability, service and excellence in mentoring.
  • For Early stage Investigators (ESIs), there is evidence of productivity, independent research and contributions to the design and direction of past research efforts.
  • The proposed research includes evidence of creativity and the incorporation of novel approaches as appropriate.
  • There are sound bases and generally well-thought-through and reasoned approaches for the proposed research effort.
  • There is evidence that the PD/PI has considered alternative approaches, outcomes, models and directions that might inform the scientific questions being posed.
  • The work will be conducted carefully and cost-effectively, with good stewardship of the data generated.
  • For ESIs, there is evidence of institutional support and mentoring.

Possible Implementation Plan

Because this is a pilot program, implementation must be carefully phased in and outcomes and unintended consequences assessed along the way. One possible implementation plan, consisting initially of two paths, is outlined below.

  • In lieu of a competitive renewal (Type 2), PDs/PIs who currently have two or more NIGMS R01s could apply for an NIGMS MIRA. Application for a MIRA would be evidence of a willingness to relinquish all other NIGMS research grants upon award. Award of the MIRA would be contingent on relinquishing other current NIGMS research grants in favor of the MIRA. Applicants proposing to consolidate their NIGMS awards would have to submit a MIRA application that would undergo peer review. The budget would be higher than that for any of the individual awards the PD/PI has, but usually less than the total of all of his or her NIGMS support. The length of the NIGMS MIRA would be 5 years.
  • The program could be open to applications from ESIs. This would bring a cadre of ESIs into the system who could be directly compared to other NIH-supported ESIs funded through traditional mechanisms. MIRA would be considered a substantial, independent NIH research award that disqualifies an individual from classification as an ESI.

The MIRA Funding Opportunity Announcement, when ultimately published, will include metrics that will be used to evaluate the success of the program. Once the program is established and indications of success have been measured, additional groups of investigators would be invited to apply for NIGMS MIRAs. If the program becomes successful, it would ultimately be open to applications from all investigators working on topics relevant to the mission of NIGMS and could become the primary research funding mechanism used by the Institute.

Information Requested

NIGMS is planning to issue a Funding Opportunity Announcement (FOA) to test this new program on a pilot scale. To aid in planning, the Institute is seeking feedback from the scientific community. NIGMS invites comments on the topics below; however, comments are not limited to these topics.

  1. The merits of this funding program for established and early stage investigators.
  2. The likelihood that established and early stage investigators would apply for NIGMS MIRAs.
  3. Concerns about the NIGMS MIRA proposal.
  4. Suggestions for changes to improve the NIGMS MIRA proposal or associated processes.

Submitting a Response

All responses must be submitted to https://www.research.net/s/NewGrantProgram_gov by August 15, 2014. Responses are limited to 500 words per topic.

This RFI is for planning purposes only and should not be construed as a solicitation for applications or an obligation on the part of the government. The government will not pay for the preparation of any information submitted or for the government’s use of that information.

The NIH will use the information submitted in response to this RFI at its discretion and will not provide comments to any responder’s submission. However, responses to the RFI may be reflected in future funding opportunity announcements. The information provided will be analyzed and may appear in reports. Respondents are advised that the Government is under no obligation to acknowledge receipt of the information or provide feedback to respondents with respect to any information submitted. No proprietary, classified, confidential, or sensitive information should be included in your response. The Government reserves the right to use any non-proprietary technical information in any resultant solicitation(s).

Inquiries

Please direct all inquiries to:

Peter C. Preusch, Ph.D.
National Institute of General Medical Sciences (NIGMS)
Telephone: 301-594-0827

Helen R. Sunshine, Ph.D.
National Institutes of General Medical Sciences (NIGMS)
Telephone: 301-594-2881

Protein Data Bank Passes 100,000-Structure Mark

Protein Data Bank (PDB) counter showing 100,147 total number of entries.
The latest update brings the total number of PDB entries to 100,147.

The Protein Data Bank (PDB) Exit icon just passed a major threshold—the release of its 100,000th entry. This free online repository of experimentally determined protein and nucleic acid structures, which NIGMS and other parts of NIH have helped fund since 1978, facilitates atomic-level insight into protein structure and function. PDB is widely used by the scientific community to study basic biological processes like transcription, translation, enzymology, bioenergetics and metabolism and also for more medically oriented investigations into disease mechanisms and drug design.

In addition to scientists, students and educators use the digital resource for their own explorations of protein structure, function and interactions as well as to gain greater knowledge about biology.

Number of structures available in the PDB per year, with selected examples. For details, see http://www.eurekalert.org/multimedia/pub/73206.php?from=267554 Exit icon.

Approximately 260,000 visitors access PDB each month. Scientists around the world currently deposit about 200 structures per week, which PDB staff review, annotate and augment with links to other relevant biological data. To meet the challenges posed by large structures, complex chemistry and use of multiple experimental methods, the repository recently launched a software tool for structure deposition and annotation Exit icon.

If you aren’t already a PDB user, I encourage you to check out its resources to see if they could help advance your research.