The National Institute of General Medical Sciences (NIGMS) focuses on supporting fundamental or "basic" biomedical research. At its core, fundamental science seeks to elucidate and expand scientific knowledge about how living systems work, from individual molecules to cells, organs, whole organisms, and populations. A strength of fundamental science is that it is neither disease nor organ specific. Rather, fundamental science creates the very foundation upon which an understanding of normal life processes and the diseases that disrupt them are built.
Fundamental research is essential for achieving medical and technological breakthroughs. This year's Nobel Prizes in both chemistry and in physiology or medicine, for instance, were awarded to multiple NIGMS grantees.1 The Nobel Prize in chemistry was awarded to an NIGMS grantee and two others for the development of cryo-electron microscopy (cryo-EM), a technique that simplifies and improves the imaging of biomolecules.2 This improved imaging allows researchers to make unprecedented advances in understanding the dynamics of various cellular processes that can, in turn, lead to the development of new drugs and vaccines. Similarly, the Nobel Prize in physiology or medicine was awarded to three NIGMS grantees for their work on molecular mechanisms controlling circadian rhythms, more commonly known as the "biological clock."3 Biological clocks influence a variety of physiological conditions such as alertness, hunger, metabolism, fertility, and mood; clock dysfunction is associated with various disorders, including insomnia, diabetes, and depression. The award for this work serves as yet another example of how studying fundamental biological processes in model organisms such as fruit flies can reveal important principles that underlie human biology, health, and disease.
A central tenet of the 2015-2020 NIGMS Strategic Plan is to maximize investments in investigator-initiated biomedical research that advance our understanding of human health and disease.4 To help achieve this important objective, a signature program of the Institute, known as Maximizing Investigators' Research Award (MIRA), was piloted in 2015. MIRA seeks to transform how fundamental biomedical research is supported by providing investigators with a heightened level of both scientific stability and flexibility, allowing investigators to follow new research directions and insights in real-time while simultaneously providing an extra year of financial support as part of a more coordinated scientific program (versus project) focus. In addition, the peer review process for MIRA applicants considers early stage investigators (ESIs) independently from well-established investigators (EIs), thus allowing each group of applicants to be examined relative to their peers. Since the creation of the program, NIGMS has awarded 231 MIRAs to EIs and 192 MIRAs to ESIs. The MIRA program is especially beneficial for ESIs, as evidenced by the increase in the number of ESI applications from 393 in 2015 (prior to MIRA) to 649 in 2017. The mean age of an ESI MIRA awardee is 36.8 years, which is younger than that of 38.4 years for an ESI R01 awardee.5 ESI MIRA awardees are also increasingly located throughout the Nation, including in Institutional Development Award (IDeA) states.
The IDeA program administered by NIGMS helps to broaden the geographic distribution of biomedical research funding by enhancing the competitiveness of investigators located at educational institutions in states with historically low NIH funding. The program seeks to build institutional capacity within these states by supporting faculty development and research infrastructure enhancement. One of IDeA's initiatives, the Centers of Biomedical Research Excellence (COBRE) program, aims to develop thematic, multidisciplinary centers to augment and strengthen institutional biomedical research capabilities (see Program Portrait below for a detailed description of the Mt Desert Island COBRE). Another important aspect of the IDeA program is its ability to promote medical research for rural and underserved communities. The IDeA Clinical and Translational Research Network (CTR), for instance, provides support for clinical and translational research that addresses health conditions such as cancer, cardiovascular disease, substance abuse, and other conditions that are prevalent among local populations.
In 2017, NIGMS issued a Collaborative Program Grant announcement to fund highly integrated research teams of three to six investigators to tackle ambitious projects with a single, shared goal.6 This new grant program replaces the complex constellation of mechanisms the Institute previously used to support team science. The Collaborative Program grants also allow support for pilot projects for early career researchers with a goal of helping them launch their careers and obtain independent funding. NIGMS expects to award four to six collaborative program grants per year.
Supporting the development of a highly skilled, creative, diverse, and multi-talented biomedical research workforce represents a cornerstone of the NIGMS' strategic efforts.7 As NIGMS strives to reach this goal and simultaneously keep pace with the rapid evolution of biomedical research, the Institute has begun to catalyze changes in biomedical graduate education. For instance, NIGMS recently convened a symposium of stakeholders from the biomedical graduate education community to discuss modernization of graduate education and to assess the effectiveness of associated educational innovations.8 To operationalize concepts discussed and refined during this symposium, a completely revised Funding Opportunity Announcement has been issued for the Institute's T32 predoctoral training grants that emphasizes the development of research skills, heightened scientific rigor and reproducibility, responsible research conduct, and diversity/inclusion as its primary objectives.9
Because supporting a well-trained research workforce begins with early outreach and education, NIGMS was proud to welcome the NIH Science Education Partnership Award (SEPA) program to the Institute in 2017. The goal of the SEPA program is to invest in educational activities at the pre-kindergarten to grade 12 (P-12) level as an early intervention in ensuring that the nation's biomedical, behavioral, and clinical research needs continue to be met. SEPA supports diversity in the workforce by providing opportunities for students from underserved communities to consider careers in basic or clinical research. It does so by providing hands-on scientific experiences and learning opportunities for students, as well as professional development material and opportunities in biomedical sciences for teachers. It also improves community health literacy through science center and museum exhibits. Almost every state in the Nation has benefited from this program by having a SEPA-sponsored project. Ten of the 14 SEPAs in IDeA states are currently in partnerships with IDeA COBREs or IDeA Networks of Biomedical Research Excellence (INBREs). These activities and accomplishments place NIGMS within reach of its goal of having at least one SEPA in every state.
The recent explosion of computing power is propelling biomedical research into new areas. Researchers, including those with MIRA funding, are beginning to make discoveries by harnessing computers to analyze vast data sources, such as anonymized electronic health records from large clinical centers. One research group used this sort of data-mining approach to comb through 16 million electronic records of 2.9 million patients in two separate databases. The analysis uncovered a correlation between taking commonly prescribed heartburn medications, known as proton-pump inhibitors, and heart attacks. Specifically, people who take a proton-pump inhibitor appeared 16 percent to 21 percent more likely to suffer a heart attack when compared with patients who did not take that kind of medication. Although more work needs to be done to determine the mechanism of this effect, the study shows the power of "big data" to point scientists in new directions. Scientists also use computational approaches known as deep-learning algorithms to analyze features in images. With the technique, pharmaceutical scientists hope to visualize the impact of potential drugs on the shape and biochemistry of cells. Clinicians expect to use it to diagnose diseases such as diabetic retinopathy and cancer. Basic researchers plan to apply it to study patterns of gene activity in cells exposed to various chemical environments. Researchers are also leveraging computers to do the heavy lifting in drug design. One interdisciplinary team of researchers applied the power of computation to the problem of opioid overdose. Starting with a newly deciphered atomic structure of the brain's morphine receptor, the scientists designed a substance that, in mice, blocked pain as effectively as morphine, but lacked the potentially deadly side effects. In particular, the new molecule did not interfere with breathing-the main cause of death in opioid overdoses-or cause constipation, a common opioid side effect. Researchers are investigating whether this compound is less addictive than traditional opioids, and will also need to test it for safety in humans. Powerful computers are also being used to model the detailed, three-dimensional structure of disease-related molecules and to scan through databases of genomic and drug data to predict new uses for medicines that are already on the market. Using this approach, called drug repositioning, researchers are evaluating whether drugs approved by the FDA to treat one disease might be equally effective on a completely different disease. Because this approach avoids the need to re-test drugs for human safety, it promises to save billions of dollars in drug development costs. At a more fundamental level, by evaluating patterns of gene activity in various disease states, researchers hope to learn more about how certain diseases progress and how some drugs work at the molecular level.
If salamanders and starfish can regrow lost limbs, why can't we? Researchers around the globe, including several at Mount Desert Island Biological Lab in Maine, are tackling that question. Re-growing human arms and legs is unlikely anytime soon, but the research has more immediate implications for healing tissues destroyed by heart disease, chronic wounds, and musculoskeletal diseases. By studying regeneration in various organisms, scientists strive to learn which molecules and genes might help us heal and regrow lost tissues. In humans and many other animals, scars form at injury sites, hampering regeneration. As scars thicken and tighten, they can prevent normal movement and functioning. Much of the death and disability caused by heart disease, the world's top killer, is a direct result of scarring following a heart attack. Unlike humans, the adult axolotl, or Mexican salamander, can build new heart muscle. Researchers discovered that doing so requires a type of white blood cell called a macrophage. Lacking macrophages, axolotls developed permanent scar tissue that blocked regeneration. The scientists hope eventually to find a way to trigger production of macrophages and promote scar-free healing in humans. Other researchers have zeroed in on a particular molecule, dubbed MSI-1436 that promotes regrowth of heart muscle in mice. Mice are genetically similar to humans and share our problem with scarring. When administered 24 hours after an artificially induced heart attack in mice, MSI-1436 greatly increased survival, improved heart function, reduced scarring, and stimulated the production of heart muscle cells. The researchers obtained a patent and formed a company to explore MSI-1436 as a potential regenerative treatment for heart attack patients. Earlier clinical trials for unrelated conditions indicate that MSI-1436 is safe in humans, further bolstering its potential in regenerative medicine. Chronic wounds are another major public health threat-and one that is increasing in the U.S. with the rise in diabetes, obesity, and average age. Treating chronic wounds costs $50 billion a year,10 not including untold costs in lost productivity and life quality. Key to wound repair is replacing lost cells, a process typically attributed to cell division. Scientists are now learning about other healing strategies, such as polyploidy, in which cells increase their size and DNA content. In most mammalian cells, polyploidy-actually, extra genetic material-is a sign of disease. But some mammalian cells in the liver, heart, and cornea become polyploid after injury. An early-career investigator with MIRA funding and her group are studying the role polyploidy plays in wound healing using the fruit fly,11 a common research organism. They aim to find genetic or pharmacological targets that could promote healing in humans. Other scientists focus not on natural healing processes, but on developing new materials on which to grow tissue for implantation into humans. A team at Boise State University in Idaho are studying whether graphene foam-a 3D material made of carbon-is suitable for growing muscle tissue. In addition to its relevance for growing implantable tissue, such work could improve our understanding of musculoskeletal disorders.
1Lorsch, J., Four NIGMS Grantees Recognized with 2017 Nobel Prizes. NIGMS Feedback Loop Blog, October 4, 2017. https://loop.nigms.nih.gov/2017/10/four-nigms-grantees-recognized-with-2017-nobel-prizes/↵>
2NIH Grantee Wins 2017 Nobel Prize in Chemistry, NIH News Releases, October 4, 2017. https://www.nih.gov/news-events/news-releases/nih-grantee-wins-2017-nobel-prize-chemistry#overlay-context↵
3NIH Grantees Win 2017 Nobel Prize in Physiology or Medicine, NIH News Releases, October 2, 2017. https://www.nih.gov/news-events/news-releases/nih-grantees-win-2017-nobel-prize-physiology-or-medicine↵
4NIGMS 5-Year Strategic Plan, March 2015. https://publications.nigms.nih.gov/strategicplan/NIGMS-strategic-plan.pdf↵
5Early-Stage Investigator MIRA Review Analysis. Presented at the National Advisory General Medical Sciences Council, September 15, 2017. https://videocast.nih.gov/summary.asp?Live=26224&bhcp=1↵
6Collaborative Program Grant for Multidisciplinary Teams (RM1). https://grants.nih.gov/grants/guide/pa-files/PAR-17-340.html↵
7NIGMS 5-Year Strategic Plan, March 2015, Goal 2: Support the development of a highly skilled, creative and diverse biomedical research workforce. https://publications.nigms.nih.gov/strategicplan/NIGMS-strategic-plan.pdf↵
8Faupel-Badger, J., Gibbs, K. NIGMS Symposium on Catalyzing the Modernization of Graduate Education. NIGMS Feedback Loop Blog, February 26, 2016. https://loop.nigms.nih.gov/2016/02/nigms-symposium-on-catalyzing-the-modernization-of-graduate-education/↵
9NIGMS Ruth L. Kirschstein National Research Service Award (NRSA) Predoctoral Institutional Research Training Grant (T32). https://grants.nih.gov/grants/guide/pa-files/PAR-17-341.html↵