These personal reflections about NIGMS help mark our 50th anniversary.
Angelika Amon, Massachusetts Institute of TechnologyFunded by NIGMS for 15 yearsCauses and consequences of aneuploidy
NIGMS is special in many ways, but what makes it an invaluable partner in our research are two assets: its program officers and its commitment to basic research.
I started my independent research career as a Whitehead Institute fellow in 1996. I studied chromosome segregation in budding yeast and wrote my first grant on this topic. It was an R29 grant, designed to help young scientists launch their independent careers. At the time, I knew nothing about the U. S. granting system and so did not think much of it when NIGMS decided to fund my grant. That soon changed. I got to know Marion Zatz, who until recently was my program officer. This has changed my scientific career. Marion was and likely continues to be the champion of her grantees. She takes a personal interest in the science and lives of her every grantee and watches over them. She was always available when I needed advice and always took great interest in my science. She went the extra mile. It made a great difference to me as an established scientist and was invaluable when I started out. Thank you!
NIGMS is convinced that medical breakthroughs come from basic research. It appreciates like no other institute that a deep and detailed understanding of basic biological processes is essential to obtain an understanding of the disease state and the development of treatments. It understands that from basic research comes medically relevant discovery. In a time when the value of research, especially basic research, is ever more questioned and when an immediate impact on medicine must be part of the justification of our existence as scientists, NIGMS has held steadfast in its belief that basic research provides the foundation for medical progress. It is essential that the Institute stays true to this value. Sir Alexander Fleming did not set out to change life as we know it for humankind when he discovered that a contaminant on his plate prevented the growth of Staphylococcus colonies. More often than not, great discoveries come in unexpected ways. As we never know where the next great medical breakthrough is coming from, it is important to keep the American research landscape diverse and to allow many different scientists to participate. NIGMS’ commitment to fund R01-based basic research will hopefully ensure that this is the case.
NIGMS was instrumental to the success of my research program. Thank you for that. Happy birthday! I wish you another 50 successful years of championing basic research!
Paul M. Anderson, University of Minnesota, DuluthFunded by NIGMS for 22 yearsEnzyme structure, mechanism, function and expression related to nitrogen metabolism
Support of my work by NIGMS over 22 years reflects: 1) how basic research focusing on one project leads to promising, unrelated areas of productive research; 2) the importance of collaborations; 3) how one must keep abreast of new technologies and 4) the value of the support for training young investigators.
My initial support was for study of the regulatory properties of the enzyme carbamoyl phosphate synthetase, an amidotransferase in Escherichia coli that is important in amino acid and nucleotide biosynthesis. This work ultimately evolved directly into two major, unrelated programs. One began with observations of the interaction of cyanate with amidotransferases, but led to the clarification of the regulatory properties of CTP synthetase and the elucidation of its crystal structure, opening opportunities for drug design. It also led to the elucidation of the mechanism, crystal structure and expression of the enzyme cyanase in E. coli and the structure of its operon (linked to the lac operon), which included a carbonic anhydrase important for carbon dioxide metabolism. The other stemmed from the discovery of a new type of carbamoyl phosphate synthetase in sharks and other fish, which led to a major program supported by the National Science Foundation that resulted in the elucidation of the unique pathway of ammonia metabolism via the urea cycle in fish. This work also involved gene sequencing of this enzyme from several species, which was helpful for understanding molecular evolutionary relationships.
Our later work involved extensive use of the newer molecular tools for gene sequencing and expression, which weren't even on the drawing boards when we started. Finally, much of the work we did involved projects for graduate students, most of whom are now productive contributors to the science and medical community.
I am very grateful for the support received from NIGMS. Although the work we did supported by NIGMS was basic and did not lead directly to a useful product or solve a major problem facing society, I feel it has enduring usefulness for the next generation of scientists in these fields. For example, the gene for cyanase appears to be present in all plants and, though I am now retired, several groups in our country and Europe have become interested in plant cyanase and have been in contact with us about our comprehensive characterization of the enzyme and its expression in E. coli.
Helen M. Berman, Rutgers, The State University of New JerseyFunded by NIGMS for 44 yearsStructural biology, bioinformatics
My journey as a structural biologist began in the year that NIGMS was established. While an undergraduate at Barnard College in 1962, I had the great privilege of working as an intern in Barbara Low's laboratory. There I learned about crystallography and began my long journey in that field. NIH played a prominent role in enabling my work. After receiving my Ph.D. in 1967, I did my postdoctoral training with funding from an NIH training grant.
In 1974, as a beginning faculty member at the Institute for Cancer Research at Fox Chase, I remember the excitement I felt when I received a call from Fred Bergmann, my NIH program director, telling me that my very first grant has been funded. In those years, I was trying to understand the principles of nucleic acid conformation and interactions by determining the molecular structures of model compounds. With funding from that grant, which provided support for almost 30 years, my group determined many structures. We did analyses that led to our understanding of the hydration patterns in nucleic acids and how these were related to their interactions with proteins. In later years when I moved to Rutgers, I collaborated with Richard Ebright on the structures of complexes between catabolite activating proteins and DNA and was able to use the earlier studies to understand the interactions that we observed in those complexes. And in collaboration with Barbara Brodsky, we worked on collagen model compounds and discovered the role of hydration in those structures. Several of my students at Rutgers received their funding from a molecular biophysics training grant from NIGMS.
Over the past 50 years, NIGMS funded many, many other scientists who determined the structures of biological macromolecules. As the champion of basic research in the life sciences, NIGMS' philosophy ultimately led to important advances in biology and medicine. Powerful examples include the work on ribosomes and HIV/AIDS proteins. In recent years, NIGMS led the study of proteins on a genomic scale as part of the Protein Structure Initiative. All of this activity in structural biology presents numerous challenges in data management. As the director of the RCSB Protein Data Bank (PDB) and the Structural Biology Knowledgebase, as well as a data manager for EM DataBank, all funded by NIGMS, my groups are responsible for archiving, distributing and integrating the data and making these data available to the wider community of scientists.
In addition to being a grantee, I have served on NIH committees. In the 1980's I was part of a 4-year term on the Molecular and Cellular Biophysics (BBCA) study section, whose portfolio consisted of grants that focused on the structural biology of nucleic acids using X-ray and NMR methods. Jim Cassatt was the executive secretary for the first year, and he did a fantastic job leading us through the reviews and helping us reach consensus (his home-baked cookies also helped to get us through the day). I was devastated when he said he was stepping down, but was pleased that he then became a program director at NIGMS. Marvin Cassman was often present during the reviews, and we always appreciated his wise comments. Working with John Norvell ensured that PDB data deposition would be required for all NIGMS structural biology grantees. During that period, I had the privilege of meeting Ruth Kirschstein, whose wise leadership of NIGMS was exemplary. NIGMS has played an integral role in the entire 50 years of my scientific life. Our shared anniversary is a happy and fortuitous coincidence.
Carolyn Bertozzi, University of California, BerkeleyFunded by NIGMS for 13 yearsChemical biology, glycobiology
The two fields that I straddle in my research, chemical biology and glycobiology, have evolved so rapidly during the course of my 16-year career that there is almost no overlap between graduate course lecture notes from the late 1990s and those I wrote this past semester, a useful metric for a field's derivative. What has driven the acceleration of advances in chemical biology, in my opinion, is the increased density and depth of collaborative interactions between chemists and biologists and the shared vernacular that has arisen from these interactions. This change in the social structure of the chemistry/biology interface is represented by a proliferation of interdepartmental chemical biology graduate training programs in both basic science and medical school campuses, as well as chemical biology undergraduate majors (at UC Berkeley, the relatively new chemical biology major is now more popular than the conventional chemistry major).
Indeed, NIGMS deserves high credit for fostering training at the interface via the chemistry-biology interface T32 training grants and for supporting core facilities for small-molecule library synthesis and screening at a time when the entry barrier for biologists seeking chemical tools was prohibitively high. These days, most biologists do not see chemical tools as out of reach, nor do they see chemists as players on a different field, and many have enjoyed working with chemistry-trained postdoctoral fellows.
This last bit of social engineering reflects a very different landscape than the one I experienced looking for postdoctoral positions. Back then, it was an odd choice for a chemist to pursue postdoctoral training in a biology laboratory, and many biologists I approached were as confused by my inquiry as were my chemistry faculty advisors. Fast forward to the present day, and many Ph.D. students trained in chemistry or chemical biology find that additional training in a specific biological system of interest within the lab of a focused expert is critical as they craft problems to tackle as independent investigators. Such training is almost expected within certain academic circles. And the biologists these young chemists approach are no longer surprised at the inquiry; rather, most often they perceive a special opportunity in the chance to bring a chemically minded scientist into their midst.
This openness among chemists and biologists with respect to cross-training has dramatically influenced the directions of my laboratory, particularly those projects funded by NIGMS that seek to develop chemical tools to study glycobiology. Unlike the case in the late 1990s and even early 2000s, when most of the applicants to my lab held chemistry undergraduate or graduate degrees, now it is common for biologists to approach me for positions. This emerging theme suggests to me that the dated and, in my mind, inaccurate dogma about chemists readily learning biology while biologists struggle learning chemistry will finally be put to rest. What we are also learning from each other is that collaborative efforts among chemists and biologists are critical for progress. No single individual can command the breadth of knowledge required to pursue complex problems in the most efficient and powerful ways.
The field of glycobiology has also undergone rapid changes; when I started my career many immunologists, neuroscientists, developmental biologists and microbiologists I interacted with had no substantial appreciation of the importance of glycans in every relevant biological process. Now, those who willfully ignore glycans are in the minority but the majority still do not have access to the tools and experimental approaches needed to figure out how glycans are contributing. They cannot be faulted—many such tools are not widely available, or they require such refined expertise that only a handful of possible collaborators could help out. Meanwhile, with genome sequences raining upon us, particularly from microbial organisms, and ever-increasing molecular insights into stem cell differentiation, cancer transformation and progression, viral infection and fundamental metabolism, it is clear that to ignore glycans is to overlook a major sector of human biology.
How will we heal the ever-increasing gap between our appreciation of the significance of glycans in biology and our ability to study them experimentally? NIGMS has taken a leadership role in addressing this challenge through several avenues. First, the Consortium for Functional Glycomics, funded through the U54 mechanism, has provided much-needed access to core facilities and platform technologies, such as glycan arrays, for the scientific community. This central resource lowers the entry barrier considerably for scientists who are seeking to understand the ligand specificities of glycan-binding proteins. As well, NIGMS sponsored an initiative entitled, "Expanding the Chemical Space of Carbohydrates," that supported the development of synthetic methods for generating chemically defined glycans for biological research.
Many challenges lie ahead, to be sure. We still do not know the diversity and composition of the glycome, though bioinformatics tools (many created with NIGMS resources) have made strides toward predictions. Sequencing glycans is still a highly technical and laborious endeavor and lies outside the capabilities of the typical chemist or biologist. We still do not have the chemical methods in place to synthesize even the fraction of the glycome we do understand. And tools for studying glycans in vivo via molecular imaging techniques remain in their infancy.
This latter challenge is one that my lab has devoted considerable effort to over the last decade, funded mostly by NIGMS. Our efforts to image glycans in vivo led to forays into synthetic methodology, fundamental mechanistic studies and a lot of basic science around the concept we call "bioorthogonal chemistry." The chemical tools we developed through these efforts are now being applied to imaging studies in the areas of cancer, embryogenesis and bacterial infection. I have enjoyed the participation of chemists, biologists and a computational scientist once in a while. Many colleagues in my university enjoy cross appointments in multiple departments, and we often host jointly mentored students.
It is a different world from the one I entered into and a very exciting time to pursue science at the chemistry/biology interface, focusing on glycans or not. NIGMS deserves much credit for supporting such work financially and for fostering the positive culture that has become synonymous with chemical biology.
Barry Bochner, Biolog, Inc.Funded by NIGMS for 20 yearsCell phenotyping
My company, Biolog, Inc. received crucial seed funding from NIGMS under the SBIR program to develop Phenotype MicroArray technology. The explosion of knowledge in genes and genetics has led to enormous advances in biological research. But scientists have been constrained by the lack of tools that could allow them to see how the genetic composition of a cell ultimately impacts its biology (or its phenotypes). Phenotype MicroArray technology addresses precisely this issue by allowing scientists to test thousands of phenotypes of a cell in a single experiment. Our initial funding on this project from NIGMS allowed us to first get the technology working that could test 1,920 phenotypes of bacterial cells. In subsequent years, with additional NIH funding, we extended the technology to also work on fungal cells and most recently on mammalian cells.
Important applications in microbial cells include gene function, antibiotic mode of action, and microbial toxin production and pathogenicity. Important applications in mammalian cells include disorders of metabolism (obesity and diabetes), mitochondrial function, cancer, chemical toxicology, drug discovery and bioprocess improvement. There are now over 300 diverse publications from scientists who have gained important insights using Phenotype MicroArray technology. This development would never have come about without funding support from NIGMS. We are very grateful and appreciative. Congratulations to NIGMS and its dedicated staff on their 50th anniversary!
Holly Boyd, San Diego Mesa CollegeFunded by NIGMS for 1 yearPsychology
NIGMS played a huge role in my life by funding a grant for the Bridges to the Baccalaureate program at San Diego Mesa College. I had the opportunity to be exposed to a number of experts in my area of interest that I would have not otherwise had the ability to meet. The experience as a whole has given me so much more insight into what I would like to do. The research aspect of the lab I was placed in came to be a much more challenging task than I could have known. I have since decided to go to the more personal side of psychology, where I found my strong suit to be. The tools that I have acquired will last me a lifetime. I will forever be indebted to NIGMS and Bridges to the Baccalaureate for not only changing my life, but improving it as well. Thank you.
Donald Brown, Carnegie Institution for ScienceFunded by NIGMS for 32 yearsGenetics
I had already been doing research for 15 years at the Carnegie Institution’s department of embryology in Baltimore when in 1975 I applied for and received my first NIGMS grant. Before that time, our institution discouraged its staff members from applying for outside support. My final NIH grant ended in 2007, when I shut down my lab and retired. I have nothing but the fondest memories of my dealings for over 30 years with NIGMS. NIGMS has especially emphasized high quality. The agency is well-run and the grant administrators are knowledgeable and always available for assistance.
NIH stands as proof of the essential role of a government-run agency that supports scientific research that would surely have been ignored by private money. If one could cost-account the benefits to private enterprise from the research supported by NIGMS alone, it would be impressive indeed. In fact, isn’t it time for some NIH statistician to try to cost-account all of the government-supported research commercialized by pharmaceutical companies, biotech companies, energy companies and the like? How many new jobs were generated by the biotech revolution that was created and supported by NIH, and NIGMS in particular, at nonprofit universities and institutions? Despite the increase in large projects funded by centers and program project grants throughout NIH, I hope that NIGMS will remain devoted to the individual independent projects funded through R01 grants. This is still the most cost-effective way of supporting quality research.
University of Colorado Biofrontiers InstituteFunded by NIGMS for 32 yearsRNA
While I was finishing my postdoc at MIT, I wrote my first NIGMS grant application to study the relationship between chromatin structure and transcriptional regulation in the
Tetrahymena extrachromosomal rDNA (ribosomal RNA genes). By the time I arrived at my assistant professor position at the University of Colorado in 1978, the grant was already funded. It was ranked at about the 35th percentile. Clearly times have changed! Having an R01 at the beginning of my assistant professor career was an enormous stimulus, allowing me to focus on research and teaching rather than endless grant-writing. It was a pretty good deal for NIH as well, since the grant led to the discovery of RNA catalysis 3 years later for about $35,000 per year! The flexibility of the funding was critical as well. Although the grant was entitled "Chromatin Structure of a Transcription Unit," I never felt repressed about using the funding to move into RNA research. In fact, I considered it my responsibility to use the funds for whatever would make the greatest impact.
Although the NIH often seems to distinguish strongly between research and training, those of us doing the research know that they are of course inseparable. NIGMS should be proud that its initial funding of the Cech Lab also paid the stipends of some fabulous graduate students. My early Ph.D. students Dan Gottschling, Paula Grabowski and Brenda Bass became professors and are now leaders at, respectively, the Fred Hutchinson Cancer Center, the University of Pittsburgh and the University of Utah.
Jay Dunlap, Geisel School of Medicine at DartmouthFunded by NIGMS for 27 yearsMolecular basis of circadian rhythms
It would be hard to overestimate the magnitude of the contributions of NIGMS to my own career and, more broadly, to the development of the subfield of molecular circadian biology that eventually cracked the problem and solved the mystery of how, at the least, fungi and animals keep time. My graduate work at Harvard was supported by a training grant through NIGMS, and the Hastings lab in which I trained had had NIGMS support for some years. When I was a postdoc working to clone the first clock gene, NIGMS picked me up on a National Research Service Award after my Damon Runyon fellowship ran out, and I received my first R01 in 1985 to continue work on the cloning of
frq. This stable support has been the bedrock of my research effort, allowing me to focus on research and also to train nearly 20 postdocs who have themselves entered the circadian rhythms field.
Looking back, it is interesting to note that much of the work leading up to my own, as well as the other work in the subfield of molecular clocks, was supported by NIGMS. Although the original contemporaneous genetic screens to find clock mutants at CalTech in the Benzer (Drosophila) and Horwitz (Neurospora) labs were NSF-supported, Konopka’s later independent work on
per at CalTech was NIGMS-supported, as was the later cloning of the
per gene by Young and by the Hall and Rosbash groups. The NIGMS-supported cloning of
per and then
frq and their subsequent analyses provided the molecular bases for understanding how cells keep time. It is no exaggeration whatsoever to say that support via NIGMS was the major engine that drove the genetic and molecular dissection of circadian rhythms.
It is worth noting also that in the beginning circadian biology was not mainstream science. There were many who doubted the existence of the phenomenon, much less that one could learn information useful to human health by studying cellular rhythms in dinoflagellates, fungi, or flies. However, true to its mission of funding basic research with potential implications in many areas of human health, NIGMS did and has continued to support work on rhythms, research that has, arguably, paid off in more ways than can now be counted.
As the years passed and I became more involved with the funding process, first on study sections and later as a member of the NIGMS advisory council, I came to understand and appreciate better the care with which fields are nurtured by NIGMS staff. This is not a one-size-fits-all, by-the-numbers operation where only scores drive funding. Rather, the score emerged as just the first of many factors that include novelty and significance, and with checks and balances to be sure that good science is given every chance and that cronyism is blunted, all with the goal of driving science writ large. Areas were funded and fields nurtured by supporting investigators in the same way that a wise gardener cultivates individual plants with an eye to the beauty of the whole. Within this context, the long-term commitment to training and to diversity must be mentioned, as these were pursued by staff again with the fervor of those on a mission rather than doing a job.
NIGMS supports research in the way it should be done, not wholly democratically, not wholly autocratically, not playing to the politically driven masses or to those with a quixotic mission, but in a measured, forward-looking and altogether smart manner. NIGMS has been and remains the pinnacle of the NIH system and thus the best of the best, in all ways research support done well.
NIGMS is just a terrific operation in every imaginable way. My science is better, and I am a better scientist for having been associated with NIGMS for the past few decades. It has been a great ride and it is not yet over. Congratulations on 50 years of excellence!
Dale E. Edmondson, Emory UniversityFunded by NIGMS for 28 yearsFlavoenzymes, monoamine oxidases
Our research on the structure and function of flavoenzymes focuses on the membrane-bound monoamine oxidases and has been funded by NIGMS for the past 28 years. During this time, program directors at NIGMS have responded favorably to requests for supplemental funding to promote advances in the project. These requests included support for purchasing a fermentation system for recombinant human enzyme expression, initiating crystallographic structural studies with foreign collaborators and updating 25-year-old equipment for rapid reaction kinetic studies. This support provided by NIGMS for the project and flexibility to provide additional support where needed have been essential for the progress made in this field. Results from this supported work have received international attention from both academic and pharmaceutical sectors. The results have provided insights of medical significance and have also contributed toward the molecular understanding of flavin-dependent amine oxidases and membrane-bound enzymes.
Marlyn El-Diqran, University of Houston-DowntownFunded by NIGMS for 2 yearsNeuroscience
I'm currently a senior at the University of Houston-Downtown. I was selected as a student for the Minority Access to Research Careers Undergraduate Student Training in Academic Research (MARC U-STAR) Program, which is funded by an NIGMS grant. The program started my research career by giving me the opportunity to work at the University of Texas MD Anderson Cancer Center in Houston. I conducted research there for 2 years in Dr. Ralf Krahe's laboratory, studying myotonic dystrophy type 2. Dr. Krahe gave me my own project that first summer, and throughout those 2 years, kept mentoring me in other research projects going on in the laboratory. I began with some genetics work using the polymerase chain reaction (PCR) and reverse transcription PCR and worked on proteins my second year in the laboratory by conducting some fluorescence in situ hybridization assays.
After my first summer at MD Anderson, I attended two national conferences, the Society for Advancement of Chicanos and Native Americans in Science (SACNAS) and the Annual Biomedical Research Conference for Minority Students (ABRCMS), to give an oral and poster presentation about my summer project. I was selected as the recipient for an award in both conferences that year. That experience made me realize how much I loved talking about my research and that I wanted to continue to do it through graduate school.
In my second year as a MARC student, I applied for a summer internship at UCLA through their MARC program and was accepted! I was so excited to go to another city and learn another set of techniques and projects. The best part was that the laboratory I was accepted into at UCLA was a neuroscience laboratory. I had not taken a neuroscience class as an undergraduate, so I learned a lot of basic neuroscience terms and mechanisms. It was a once-in-a-lifetime experience that the MARC program provided.
I truly believe I was able to have such incredible experiences at UCLA and MD Anderson because I had been chosen as a MARC student. My 2 years as a MARC student just finished in May, and I miss the program so much. The amount of information I learned about research, graduate programs and science careers has been so helpful.
I am now planning to apply for graduate school this semester to start next fall and am reviewing all the notes I wrote from the seminars I attended and editing my CV and personal statement. I'm sure my experience as a graduate student will be much more arduous, but I know the passion the MARC program has ignited within me will help me succeed in the laboratory.
Kathy Giacomini, University of California, San FranciscoFunded by NIGMS for 21 yearsPharmacology
NIGMS has enabled my research career over many years. When I was an assistant professor in the 1980s, NIGMS staff “reached” for my first grant application, funding it and launching my career. As a pharmacologist with a Ph.D. from a school of pharmacy, I was interested in the cellular and molecular processes that determined drug absorption and disposition. Back then, we had only a rudimentary knowledge that drugs were eliminated and that the kidney played a role in that elimination. Though we described “carriers” in the kidney by particular measurable characteristics, e.g., saturable and inhibitable, we had no idea of their molecular identities.
Today, over 350 genes encoding human membrane transporters in the solute carrier superfamily (SLC) have been identified. Many of these transporters are important in pharmacology, either as drug targets or in mediating drug absorption, elimination and tissue-specific distribution. Transporters are polymorphic, which contributes to variation in drug response and toxicity. Common and even rare polymorphisms in human populations have been identified and functionally characterized. Their association with therapeutic and adverse responses has been discovered. This information has been obtained over the past three decades, largely as a result of NIGMS, which has been the major funding institute for research in transporter biology and pharmacology.
NIGMS has supported and encouraged pharmacological research as it transitioned from measurable phenomena to molecular identities and structure, and then to genomics and pharmacogenomics. Staff at NIGMS have championed and supported basic and clinical research in pharmacology and have encouraged their integration. Large center grants such as the Pharmacogenomics Research Network and the Protein Structure Initiative, supported and led by NIGMS, have provided a framework to stimulate collaborative research among scientists in different disciplines, which has resulted in numerous discoveries in basic sciences and basic and clinical pharmacology.
I have been fortunate to have been adopted by NIGMS at an early point in my career and to have been actively involved in NIGMS-funded research. I have been privileged to interact as a member of the advisory council with the outstanding staff at the Institute, including Mike Rogers, Rochelle Long, Peter Preusch and Dick Okita.
Without support and vision from NIGMS, pharmacology, including pharmacogenomics, would not have advanced.
Thank you, NIGMS, and happy anniversary!
Lila Gierasch, University of Massachusetts, AmherstFunded by NIGMS for 35 yearsProtein folding in the cell and molecular chaperone mechanisms
My first NIGMS funding was an R01 grant in 1977 supporting work on cyclic peptide models for reverse turns in proteins. I am forever grateful to NIGMS, because the confidence shown in me at that time, when I was a young assistant professor at a predominantly undergraduate institution, truly launched my research career.
My research path has moved from a reductionist approach exploring the sequence code for protein folding to tackling the complexities of protein folding in the cell. With NIGMS support, my laboratory was able to ride the wave of intellectual discovery in protein folding: from the Anfinsen roots, to the molecular chaperone revolution, to the current realization that protein folding errors underlie many human diseases.
The evolution of the protein folding field and its immense biomedical implications could not have been predicted in the early days of research work in this area. Yet NIGMS recognized that it was crucial to ask penetrating, fundamental questions and to recognize the significance the answers could have ... which is the litmus test NIGMS-funded investigators are all held to. Essential to the successes enjoyed by NIGMS grantees is the unswerving commitment that this institute has had to basic research. Congratulations to NIGMS on its 50th anniversary, and may the mission of NIGMS flourish for several more half centuries!!!!
Fred Grinnell, The University of Texas Southwestern Medical CenterFunded by NIGMS for 29 yearsFibronectin, collagen, cell-matrix interactions; wound repair
Support from NIGMS has been the foundation of my biomedical research career for the past ~30 years. Over that time, I always found the individuals who managed the NIGMS trauma program–most recently Scott Somers and Rick Ikeda—outstanding to work with. The novel workshops and research initiatives that they organized were important to move forward the field of wound repair.
Work on my own R01 grant in the early 1980s coincided with our initial studies on fibroblast mechanics in three-dimensional collagen matrices, as we followed the lead of Eugene Bell. At the time, the importance of 3-D matrix biology had yet to be appreciated by the field. Joining Charlie Baxter's NIGMS-supported burn research center research group a few years later resulted in the most important translational research of my career. Baxter's associate, Annette Wysocki, and I found that the biological adhesion protein fibronectin frequently was degraded in chronic wounds, which made possible our discovery that these wounds have elevated levels of proteolytic enzymes—a discovery with direct implications for how chronic wounds should be managed.
Finally, receiving a MERIT award from NIGMS in 1999 advanced indirectly a whole different aspect of my work. Anticipating 10 years of funding without the time-consuming requirement to write a competing experimental research grant application, I used the energy instead to write my book, "Everyday Practice of Science: Where Intuition and Passion Meet Objectivity and Logic," published by Oxford University Press in 2009. “Everyday Practice” describes what doing science entails and the intersection between science and society.
Thanks to NIGMS for its support of my efforts and congratulations on the 50th anniversary.
Yusuf Hannun, Medical University of South CarolinaFunded by NIGMS for 21 yearsLipid biochemistry and biology
I have held an R01 from NIGMS on sphingolipids for around 21 years now. The first submission proposed to explore the then-new and uncharted field of bioactive sphingolipids. Both the grant’s reviewers and NIGMS program staff took the risk of supporting this work. Two decades later, the connections of this field to pathobiology (e.g., cancer, neurodegeneration, diabetes and inflammation) have become widely recognized. Therapeutics are being developed (e.g., for multiple sclerosis, cancer, arthritis and metabolic syndrome). This to me illustrates the absolute significance of NIGMS for laying foundations in research upon which subsequent, more direct relevance emerges—but one has to have the long-term view (two decades in our case).
Gerald W. Hart, Johns Hopkins University School of
MedicineFunded by NIH for more than 30 yearsGlycobiology
Even though my grants are supported by other NIH institutes, I am writing to congratulate NIGMS on its 50th birthday and to thank the leadership of NIGMS for their strong support for the field of glycobiology. No other institute has so clearly recognized the importance of glycans to human health. The leadership and program officers at NIGMS have taken the lead in helping to advance this key field, which had been ignored too long. Due to their efforts, many institutes at NIH and at other agencies are now recognizing the critical importance of glycans not only to human health, but to biofuels, materials science and many other aspects of society.
A sincere thanks to all of the folks at NIGMS for their foresighted and innovative view of science.
Kendall N. Houk, University of California, Los AngelesFunded by NIGMS for 27 yearsComputational organic and biological chemistry
When I was a third-year graduate student with R. B. Woodward at Harvard in 1966, Woodward's assistant said to me, "Dr. Woodward thinks you should be on the training grant." That is the first I had heard of the (then only 4-year-old) National Institute of General Medical Sciences, which paid my stipend for the last 2 years of my graduate work.
My first research support from the NIH, in 1975, was not from NIGMS but from the National Institute on Drug Abuse, while I was a young professor at Louisiana State University and working on the electronic structures and photoelectron spectroscopy of hallucinogenic drugs. When I moved to the University of Pittsburgh in 1980, I began to work hard on NIH proposals for my cycloaddition work. Eventually, after several unsuccessful tries at landing a grant to do total synthesis based on cycloaddition reactions, I wrote a proposal that resonated with the study section and landed an NIGMS grant on stereoselectivity of synthetic organic reactions. That was in 1985, and that grant has continued since that time.
I have had other NIGMS grants for shorter periods of time, including one from 1995-1998 on the theory of dynamics and biomimetic processes of carceplexes, another from 2000-2010 on the theory of the chemistry of NO, HNO, OONO, and RSNO, and currently one since 2009 on the design of new enzyme catalysts. All of these brought vital support to what became very successful and productive projects. In 1987-1990, and then again in 2005-2008, I was a member of NIH study sections that review many NIGMS grants. The first was called Medicinal Chemistry and the newer one is called Synthesis and Biological Chemistry. Serving there gave me a chance to appreciate the importance of NIH staffers and the scientific community to the progress of science, and the dedication of the scientific community to make the peer review system work.
NIGMS, along with the National Science Foundation and the Department of Energy, approached me and Cynthia Friend to co-chair a workshop, Building Strong Chemistry Departments Through Gender Equity, that brought together chairs of the top 50 chemistry departments in January of 2006 to learn about and discuss problems of mutual interest and importance. NIGMS not only supports research, but is dedicated to improving scientific education and the quality and diversity of scientists. Later, in 2011, I spoke at the National Diversity Equity Workshop sponsored by the same three agencies.
NIGMS funds the Chemistry-Biology Interface (CBI) Training Program grants that support very important training of chemists to do serious biology and biologists to use state-of-the art chemical concepts and tools. UCLA has had one of these CBI program grants since the beginning of the program, and I was honored to be the director of UCLA's CBI from 2003-2011.
I have met and interacted at NIGMS with many excellent chemists who have devoted themselves to the research enterprise and have done a great deal for the advancement of science and graduate education as well. Most recently, Mike Rogers, John Schwab, Bob Lees and Miles Fabian are people at NIGMS who have amazed me by their devotion to science and the scientific community and have done so much to advance chemistry research that promotes our understanding of biology and human health. They have been friends and valuable advisors to me and many other scientists as we endeavor to push back the frontiers of science. Thanks to NIGMS and happy 50th anniversary!
Mark Johnston, University of Colorado, DenverFunded by NIGMS for 29 yearsGlucose sensing and signaling in yeast, comparative and functional genomics
NIGMS is our mainstay of discovery research. Over the last 50 years, the Institute has enabled much discovery: A great deal of what we know about how life works came from studies funded by grants with an identifier beginning with GM. And the investment paid off handsomely in the many times that knowledge was translated into practical applications. As the “translational science” drum beats ever louder, the mission of NIGMS—to enable discoveries that fuel innovation—becomes ever more important. Long live NIGMS!
My GM grant—initially awarded for the study of yeast GAL gene regulation—was funded the day I first inserted the key into the lock of the door to my lab in St. Louis, Mo. I remember it well: a typically hot and humid August 1, 1983. Back then, beginners were entrusted with only 3 years of funding. By the time the pipettes had arrived and I had hired some hands, less than 2 years remained until the renewal application was due. That looming deadline focused my attention sharply! I met that deadline with a paper in press in PNAS; just last week, I submitted the competitive renewal application for year 30 of the project (which has evolved into the study of glucose sensing and signaling in yeasts
Some years later, I had the unusual pleasure of having two institutes compete to fund one of my grants. The DNA sequence of the yeast (S. cerevisiae) genome had just been determined, and the (obvious) next step was to compare it to the genomes of other yeasts to find the conserved—and therefore likely functional—parts. My application for funding for such a project was well received by the study section, and I soon had offers of funding from NIGMS and the National Human Genome Research Institute (NHGRI). I took the 4-year NIGMS grant because by then I had enough experience that I didn’t need to have my attention focused by a 3-year NHGRI grant.
I can’t believe how fortunate I have been to be given the opportunity—time and again—to satisfy my curiosity and make a small contribution to our understanding of how our world works. NIGMS funded me to study what has fascinated me since I was in middle school (really!!): the workings of microscopic life. The ability of tiny, single cells to sense their environment and respond appropriately to its changes captivated me when I first learned about it while in high school; explaining that ability has been the focus of my career. It continues to fascinate me, and I hope NIGMS will soon give me yet another opportunity to satisfy my curiosity about how yeast cells can know how much glucose is available to them and how they use that information productively.
NIGMS has played an essential role in enabling the translational drum to be beaten. But if the discoveries don’t keep coming, eventually there will be nothing to translate, and the drum will be silenced. Because of NIGMS I have faith that discoveries will continue to be made, thereby sustaining our chances to meet our translational mandate.
Marc Kirschner, Harvard Medical SchoolFunded by NIGMS for 39 yearsCytoskeleton, cell cycle, vertebrate development, systems biology
There is a certain pride, nostalgia and foreboding in thinking about the great accomplishments of NIGMS in the last 50 years. When I entered science as a young faculty member almost 40 years ago, the promise of fundamental discovery to advance health was an agreed-upon tenet. Although all institutes did some basic science, NIGMS was unique in not having a large clinical constituency pushing it to solve specific, targeted problems. Yet, despite that lack of translational focus, a disproportionate number of the practical advances in medicine and most of the enabling advances in science came through NIGMS. Furthermore, NIGMS seemed tied to the scientists I most respected, who valued what I valued: the highest standards in research, respect among scientific peers, concern with the training of students and public service.
Early in my career, I got to know Ruth Kirschstein well and many of the staff at NIGMS, and they too reflected and radiated exactly the same high standards of science. As I got to be a senior scientist in my own right, I marveled at the honesty and integrity of this institution and its pride in what it has done to enable scientists to penetrate the mysteries of nature. My opinion of NIGMS still holds. True, it would not be what it was without the scientists on the outside who served the broader interests of society. But just the same, we would be a much diminished lot of scientists today without the inspired service and sacrifice of NIGMS. To have a taste of the early period, I recommend a recent biography of Ruth Kirschstein, “Always There,” by Alison Davis.
The question in all our minds is, “What about the future?” Is NIGMS, or NIH itself, another of those American institutions that seems to be a victim of deferred maintenance? The enterprise is certainly in some trouble: not enough grant funding, not enough time for thoughtful reviewing, too many funding gimmicks, too much hype about translational science and not enough thought about what we need to know, and consequently more mistakes under pressure. It is at this point that we learn to appreciate conservative institutions, those that do not bend so quickly in the wind. I think it is ever more essential that NIGMS retain its commitment to exploring fundamental questions, to the advancement of young people and to fairness. Yet at the same time, merely clinging to the memory of an ancient hallowed time will be inadequate. Fairness, though important, can be an excuse for just following rules even when you know they yield the wrong answers.
If I remember anything of the legacy of Ruth Kirschstein, it is that she always pushed for something new and was always committed to a fair outcome, not just a fair process. It is hard when an institution like NIGMS is both your partner and your judge, but the possibilities of partnership should not be lost. We in the scientific community need to work with NIGMS to get the best people to volunteer their time and to influence NIGMS on policy.
The NIGMS philosophy ultimately percolated through the whole NIH. It was based on the assumption that the best science is the best medicine and that the best science should be judged not from on high, but rather from peers. I fear that these precepts are susceptible to erosion. It was NIGMS that pioneered the support of investigations “peripheral” to medical treatment, which included work on model organisms, like yeast, worms and flies; work that was distinctly chemical or genetic or mathematical; and work on molecular mechanisms that seemed remote from human health. From restriction enzymes to Hox genes, to my own discoveries of tau protein or the secrets of the frog egg cell cycle, good science ultimately turned out to be the best medicine. Are we sure that this view must now change completely?
I will end by a brief tour of my own course in science. I could not imagine having followed such a path without the understanding of my peers in an environment nurtured and supported by NIGMS. I came from protein physical chemistry, desperately looking for a biological problem. I worked with two inspiring scientists, Howard Schachman and John Gerhart, both of whom felt rather unconstrained in their NIGMS-supported work and who encouraged me to feel that way as well. I wrote my first grant on microtubules and the cell cycle, having never published a paper on either subject, and having never worked with anyone who had published a paper on either subject. I remember the comments on my grant, that there were a lot of interesting and novel ideas, which might or might not work, but it was worth 3 years to see if anything good came out. I had a single grant for many years. I continued working in the lab for the first decade of my career. I encouraged my students and postdocs to develop their dreams. The subject of my single grant oscillated widely from subjects I knew something about to others I just barely understood. My program officers offered good advice whenever I asked. My postdocs left with their projects when they started their own jobs. Many, like me, changed directions early in their careers. I once asked for supplementary money on my grant to support a German theoretician on sabbatical, Reinhart Heinrich. An NIGMS program director found the money. Reinhart came and it launched my new interest in systems biology and ultimately a new department. I have consistently found the whole process at NIGMS to be flexible and permissive.
My fondest hope is that we can somehow bequeath to the next generation the same opportunities that I had. We, scientists, cannot do this alone. If the next half century is to be as full of success and promise in science as the last, we have to have an NIGMS as rooted as it has been in the value of wide-open inquiry. As in the past, it should support investigations that do not merely extend what we know, but that challenge basic assumptions. Thinking back on my career and so many others like it, it seems that many of the greatest accomplishments came not from highly articulated prospective research proposals, but as unanticipated byproducts of careful experiments. To recognize this historical fact and support it requires a certain indulgence among reviewers and administrators. We cannot succeed without a trusting partnership between the best and most self-sacrificing scientists and the best and most idealistic administrators at NIGMS. We should base our policies on what we know science to be and not what some wish it to be.
Terry Ann Krulwich, Mount Sinai School of MedicineFunded by NIGMS for 35 yearsBacterial bioenergetics, research education and diversity programs
The National Institute of General Medical Sciences (NIGMS) is marking its 50th anniversary! My congratulations go out to the whole NIGMS family. I have had the joy of being part of this extended family. My NIGMS "aunts," "uncles" and "cousins" have provided me with many forms of mentoring and advice. I've taken on some tasks too, when asked. I've joined discussions of possible initiatives and emerging plans around the awesome table in the Building 31 conference room or the new digs in Natcher, and done a share of committee work here and there—but that's only fair.
NIGMS has a long-standing and deep engagement with three areas that brought me and many others into planning, implementation and evaluation meetings. In each area, the efforts by NIGMS have often been innovative, often been bold, and often been experimental at the beginning, then either dropped or continually refined and re-evaluated. NIGMS has supported: research into basic biological problems as well as related behavioral science; research education and training in these same areas; and implementation and evaluation of interventions that have the goal of achieving greater diversity in the biomedical research workforce.
Research: As a faculty member at Mount Sinai School of Medicine, my own research has largely been directed at areas of bacterial physiology and bioenergetics involving ion-coupled pumps, ATP synthases and transporters. Oddly, my first NIH research grant was not from NIGMS; I think that a coding misinterpretation based on the use of the bacterial genus Arthrobacter landed me first in the National Institute of Arthritis, Metabolism and Digestive Diseases, but a Research Career Development Award 5 years later and all but one of my subsequent NIH research grants were made from NIGMS.
The helpfulness, guidance and kindness (at occasional times of disappointment) of the program officers with whom I've interacted have been tremendous. The commitment of NIGMS to R01s is crucial. And yet, NIGMS' forays into larger program projects or centers have also been worthwhile experiments from which we've gained a lot. These programs are especially helpful in emerging areas that require large time and resource commitments, e.g., for efforts such as the structural biology of membrane proteins and protein complexes, which has enhanced research in my field. Although my role in another such effort, the NIGMS-funded Systems Biology Center New York, is primarily in the outreach and education core area, being part of this center and a participant in meetings of the full group of centers has substantially impacted my research as well as my teaching.
NIGMS has also experimented with different ways to support innovative, potentially game-changing research ideas, which went under the name of "high risk/high (potential) impact" when I served on the NIGMS advisory council in the early 90s. Some recent mechanisms designed to achieve this same sort of goal will still need to be evaluated for efficacy, but the concept of taking some extra risk for exceptional impact remains as important as it is challenging.
Research Education and Training: I undertook responsibilities in the fledgling graduate school program about 4 years after I came to the still very young Mount Sinai School of Medicine. Having been impressed by one of the early Medical Scientist Training Programs (MSTPs) during my postdoctoral training at Albert Einstein College of Medicine and the beginnings of an MSTP initiative at the University of Wisconsin, I initiated a formal M.D./Ph.D. program at Mount Sinai and applied for NIGMS funding just a couple of years later. Vincent Price, M.D., an early MSTP program officer (in a series of great program officers), called me to give me advice that informed a successful re-application in 1977.
Serving as MSTP director for over two decades was a wonderful experience, but the first time I joined an MSTP directors’ meeting will forever stand out in my memories of those decades. Those meetings were chaired by the NIGMS director, Ruth Kirschstein, M.D. Ruth looked at me from the head of the table; I was the first woman MSTP director, and a rather young and green one at that. She then came over to greet me and thus began a mentoring friendship that created enormous opportunities for me to learn and to contribute to various research education efforts through service on one of the training grant review committees and, later, service on the NIGMS advisory council. The lessons learned enabled me to be much more effective with programs developed over the years in my home institution, the MSTP, additional T32 programs and the education programs in the Systems Biology Center.
The T32 programs and individual fellowship programs of NIGMS demand a lot of their grantees in terms of application, tracking, reporting, etc., but they are coveted and invaluable because they are a measure of institutional quality and success in the research education domain, success that helps justify additional investments of resources and attentiveness to increase the robustness of the research educational programs. The training grant design has also contributed significantly to ongoing rethinking of the configuration of research training programs on campuses, for example, by taking an early stance in reducing "silo" effects in training configuration that impeded creative transdisciplinary efforts.
Interventions in Support of Diversity: From early on in NIGMS history, NIGMS directors and key administrative staff leaders took on the task of promoting access to biomedical research, pursuing the goal of eliminating underrepresentation based on racial/ethnic group, gender, disadvantage or disability in the biomedical workforce as a whole and in the highest echelons of the workforce. NIGMS sponsors the acclaimed Annual Biomedical Research Conference for Minority Students (ABRCMS), and an alphabet soup of programs at different parts of the “pipeline” in various types of institutions has been added to the earlier Minority Biomedical Research Support (MBRS) and Minority Access to Research Careers (MARC) program, all of which are under the umbrella of the NIGMS Division of Minority Opportunities in Research (MORE).
For 10 years now, I have directed one of Mount Sinai's NIGMS/MORE-sponsored Postbaccalaureate Research Education Programs (PREP), a diversity program that has enriched my perspective and day-to-day activities enormously and has "graduated" a remarkable group of diverse scientists. MORE leadership has increasingly challenged all the diversity program directors to optimize and test the efficacy of their diversity programs. In order to make this possible, NIGMS has played a pivotal role in sponsoring research into the design and efficacy of interventions that broaden participation in research careers, and conferences and workshops to help new investigators to develop "interventions research projects." I admit to being somewhat skeptical about "interventions research" at first. But I have joined the choir of advocates for "rational, data-based and educational theory-based design" of diversity efforts and their program elements after seeing the kind of contribution that the insights from such research can make in expert hands.
What next, NIGMS? We hope it includes success in greatly increasing the manpower and perspectives brought to biomedical research by enhanced diversity.
Marc Lipsitch, Harvard School of Public HealthFunded by NIGMS for 6 yearsInfectious disease modeling
NIGMS founded the Models of Infectious Disease Agent Study (MIDAS) network in 2004 to build capacity in the United States for mathematical, statistical and computational modeling of infectious diseases, pushing the science in these fields forward while providing support to decision makers on key policy questions of planning and response to infectious disease threats. From three research groups at its founding, the network has grown to include 12 primary institutions, with many affiliated groups in the United States and globally. Our research group has participated in this network since 2006, first as a research group and, since 2009, as a research Center of Excellence, the
Center for Communicable Disease Dynamics at
Harvard School of Public Health .
In the last decade, dynamical approaches to infectious disease epidemiology have become central to the study of such diseases in the United States, a transformation that owes much to the success of the MIDAS network as a whole. Close contact with public health decision makers has stimulated MIDAS groups to focus on problems of practical importance and to refine analyses so that their findings can be of real value in public health. Close contact with public health data has improved the quality of many MIDAS studies, allowing them to reflect the current understanding and uncertainty of parameter values and biological assumptions. These advances reflect the creativity and curiosity of the MIDAS investigators, but also the stimulus from NIGMS program staff to focus on such questions, combined with a network-wide effort to make contacts with public health stakeholders that exceeds the abilities of any individual group. Colleagues from the Centers for Disease Control and Prevention, the Biomedical Advanced Research and Development Authority, the European Center for Disease Prevention and Control and other public health agencies regularly attend MIDAS meetings, creating a link between public health science and decision making on one hand, and dynamic modeling on the other, that for many years was rare or absent in the United States and most other countries.
As a result, MIDAS researchers and their research findings have played a prominent role in policy efforts surrounding various threats; these include a potential smallpox attack, pre-pandemic planning and 2009 pandemic response for influenza, and the 2010 Haitian cholera epidemic. MIDAS also contributes to public health efforts on seasonal influenza, drug-resistant microbes and other infectious agents.
Critical to the success of MIDAS, in my opinion, has been a healthy balance between these urgent, sometimes high-profile responses to major policy questions and an ongoing commitment to developing the basic science and methodology of infectious disease dynamics, including applications to pathogens that may be less in the spotlight (for the moment). Work on applied policy problems often stimulates the development of new methods and approaches that can be applied to future epidemics. But equally, work that may have little or no immediate application when first undertaken may lay the groundwork for a more effective response to novel challenges.
MIDAS has consistently supported innovation in statistical methods; integration of genomic, climatic, behavioral and other data into infectious disease epidemiology; and a diversity of approaches ranging from classical mathematical methods to large-scale computational models. This support for basic innovation will lay a strong foundation for future responses and helps to explain the growing sophistication of methods applied to SARS in 2003, the planning for pandemic influenza in the mid-2000s and the response to the 2009 flu pandemic. MIDAS’ recent focus on outreach, recruitment and training of students in infectious disease dynamics reflects a similar investment in the future.
Congratulations to NIGMS on its 50th anniversary! It is a privilege to participate through MIDAS in an Institute that so supports the essential work of basic life and quantitative science and methodological innovation as the foundation of effective responses to public health challenges.
John T. Lis, Cornell UniversityFunded by NIGMS for 33 yearsGene regulation
I am pleased to hear that the National Institute of General Medical Sciences is marking its 50th anniversary. The Institute, through its judicious administration and wise funding over the past 50 years, has good reason to celebrate. The advances in our understanding of fundamental processes of biology and the creation of new technologies have had a remarkable impact on biology and medicine that will continue to be exploited in the coming decades. I thank you for the invitation to contribute a firsthand account of how my NIGMS experiences and how the field and our own program have evolved during the past 33 years.
I begin by applauding NIGMS for supporting basic biological research that uses both well-established approaches as well as new, somewhat more adventurous approaches. While the conventional wisdom is that one should write proposals that are conservative, from my own experience applying for grants and serving as a study section reviewer, I appreciate that NIGMS and their study sections have been very supportive of more exploratory aims. For example, as a young assistant professor, I recall sending in a first grant renewal that included a final aim to examine protein-DNA interactions at specific loci in vivo. The preliminary data in this proposal fell short of demonstrating that the plan would work, and I worried that this part of the proposal could be dismissed by the study section. Instead, the evaluation was immensely encouraging and has forever influenced my approach to research and that of at least some of the trainees in my laboratory.
More recently, many of us appreciated the encouragement of NIGMS to embrace interdisciplinary research. This encouraged our own collaboration with labs in computational sciences, engineering, chemistry and physics, which has been extremely exciting in our efforts to investigate multiple aspects of gene regulation and chromatin structure. Clearly, this type of collaboration is widespread in the scientific community, and the current formidable level of interdisciplinary research will clearly have a strong impact in basic and applied biomedical research.
Finally, I encourage NIGMS administration and their study sections to continue to advocate science that seeks to find breakthroughs that are needed to understand basic molecular biological mechanisms. Transformative technologies being developed in the scientific community promise to deliver a full understanding of gene regulation and other basic biological processes. This, in turn, will allow the tailoring of highly sensitive and comprehensive diagnostic assays and, more importantly, specifically targeted therapies.
I am sure that many in the basic medical sciences community will join me in thanking NIGMS and the study section reviewers for their “outstanding” efforts over the past 50 years.
W. James Nelson, Stanford UniversityFunded by NIGMS for 27 yearsCell biology
NIGMS funding has enabled me to explore new areas of research, especially through a MERIT award, in developmental biology, evolution, bioengineering and biophysics. So, my sincere thanks to NIGMS for my life as a scientist.
I had the honor of serving on the NIGMS advisory council for 4 years during the time that Jeremy Berg was director. This experience provided a new perspective on the inner workings of NIGMS. I have the utmost respect and admiration for the NIGMS staff, their passion for science and their astonishingly broad knowledge and understanding of science. They work extremely hard, on a government salary, and make very difficult funding decisions. They are not just gatekeepers of the NIGMS coffers, as many may assume, but really think creatively about how science is performed, about new areas of science to support, how to help young scientists get started and ways to facilitate new collaborations and training opportunities. I wish that all NIGMS grantees and applicants could see them at work to really appreciate what goes into funding decisions.
So, happy anniversary NIGMS! I hope that our scientific grandchildren will be able to celebrate your continued support of basic science.
Thomas D. Pollard, Yale UniversityFunded by NIGMS for 40 yearsCell motility and cytokinesis
NIGMS: Fifty years of standing by basic research in cell biology
Young scientists today are amazed about how little anyone knew about cell biology in the early 1960s, when NIGMS started supporting fundamental research in biology. For example, beyond a few short oligonucleotides, no nucleic acid sequences were known. Although scientists could isolate nucleic acids from viruses and cells, they could not purify pieces of these genomes small enough to sequence with the limited available tools, since restriction enzymes, molecular cloning and PCR were in the future. Physiologists knew about the existence of membrane pumps, carriers and channels, but none had been purified or studied by single-channel recordings, so nothing was known about their structures or how they worked. Technologies were limited, since SDS polyacrylamide gel electrophoresis, affinity chromatography, expression of recombinant proteins, fluorescent antibody staining, fluorescent fusion proteins and digital cameras had not been invented! Communications were also limited without plain paper copiers, faxes, cell phones, FedEx, personal computers, e-mail, Internet, word or image processing software or electronic versions of manuscripts and published papers.
In my own field, much was known from pioneering studies of muscle contraction, but none of the protein molecules of the cytoskeleton of nonmuscle cells had been identified. In fact, Klaus Weber had not yet coined the term cytoskeleton. Some scientists in the 1960s questioned whether one could learn anything about cellular motility using biochemical approaches, a reminder that vitalism was alive and well in cell biology.
Just 50 years later, everything has changed in basic biology, thanks to the inventiveness of three generations of biologists and strong, consistent support by NIH, especially NIGMS. How did we get from our state of ignorance in the 1960s to 2012?
The pioneers in cell biology, including those who started the American Society for Cell Biology in 1960, aimed the field in productive directions when they framed the questions that defined the research agenda. They wanted to know the structures of cellular constituents including chromosomes and membranes and how cells synthesize proteins, compartmentalize metabolic processes, process and secrete proteins, take up molecules and particles by endocytosis, assemble the extracellular matrix, adhere to each other and the matrix, respond to stimuli, and move themselves, chromosomes and intracellular organelles. These powerful questions were on the mark and still stimulate research today.
Progress was slow at first, since only two methods dominated research. The primary tool was the electron microscope, which the founders of cell biology used to study thin sections of fixed and embedded materials. Their striking micrographs provided the context for thinking about how cells work and provided testable hypotheses for the investigation of mechanisms. Phase-contrast light microscopy was the primary source of information about the dynamics of these processes. Some pioneers complemented electron microscopy with biochemical methods to fractionate organelles and purify soluble proteins. No methods existed to isolate integral membrane proteins.
The pace of research in cell biology has accelerated relentlessly, driven by the introduction of new approaches that are now combined routinely to answer questions about mechanisms. First, morphologists appreciated the value of incorporating biochemistry and biophysics in their work, and vice versa. Subsequently, cell biologists welcomed those using genetic analysis of model organisms to identify the genes and gene products relevant to their scientific questions. Medical science raised new questions in cell biology and was repaid with advances in understanding the molecular basis of disease. For example, the entire field of cellular signaling had its roots in clinical endocrinology, and cell cycle studies were motivated in part by questions from oncology. Molecular biologists took the lead on understanding gene expression. Virtually all biologists benefitted from the techniques invented by molecular biologists to clone and sequence nucleic acids and to analyze and modify DNA sequences. Powerful new imaging methods, first video microscopy (from commercial television), confocal microscopy (from biologists), digital cameras (from astronomy) and recently several flavors of super-resolution microscopy have made it possible to study cellular dynamics with high temporal and spatial resolution. Although a hard sell at first, cell biologists now appreciate the importance of quantitative measurements, mathematical modeling and simulations to test their hypotheses. Reductionist approaches can take one’s daily activities far from the motivating biology, so it has been gratifying to see how theory and modeling can reconnect experimental measurements with the dynamics of living cells.
I have been fortunate to practice cell biology since its early days and have benefitted from technical and conceptual advances that allowed the field to learn more than anyone could have imagined in the 1960s. I became fascinated with cellular movements when I saw an amoeba move in a high school biology class in the 1950s. I wanted to understand the mechanism at the molecular level, so I studied both chemistry and biology in college. Summer research using time-lapse microscopy to study tissue culture cells reinforced my interest, but at the time none of the molecules responsible for cellular motility had been identified with certainty. Pioneers using very primitive methods had some hints that cells other than muscle might contain actin filaments and myosin motors, but the evidence was limited and not taken seriously.
Therefore, I started out with phase-contrast and electron microscopy. I was exceptionally fortunate to have Susumo Ito as my mentor at Harvard Medical School. Sus was working on secretion in the gastrointestinal track, but he took me into his lab and encouraged me to follow my own interest in cellular motility. I was intrigued by reports from Lewis Wolpert’s lab that they had isolated a crude cytoplasmic extract from amoebas that moved in a microscope chamber when warmed to room temperature in the presence of ATP. Fortunately, we did not know that others were skeptical because they had failed to reproduce this observation. After many failures ourselves, we got the extracts to move outside the cell and discovered that both thin filaments and thicker filaments were required for motility. Of course, we thought the filaments corresponded to the actin and myosin filaments in muscle, but when I showed my micrographs to Don Fawcett, the very distinguished chair of our department, he asked, “Do you really believe that amoebas have contractile proteins?” (In Don’s defense, he became a lifelong supporter and convinced me a few years later to give up clinical medicine for basic science.) Independently, Sadasi Hatano and Fumio Oosawa in Japan and Mark Adelman and Ed Taylor in Chicago produced convincing biochemical evidence for actin filaments and myosin in slime molds, launching the molecular analysis of cellular motility.
I followed in their footsteps with postdoctoral research with Ed Korn at NIH, where we worked on amoeba actin (including its association with the plasma membrane) and discovered
Acanthamoeba myosin-I, the first unconventional myosin. Although colleagues politely accepted our findings, years later they admitted that they thought our single-headed myosin was either a proteolytic fragment of a real myosin or simply something weird about amoebas, rather than the beginning of a new field.
To put the progress over the past 40 years into perspective, I note that in 1972 we would not have guessed that cells contain many families of myosins and dozens of different actin-binding proteins. We could only dream of knowing the three-dimensional structures of our proteins. Thanks to conceptual and technical advances, we now have highly informative crystal structures of many of the important proteins of the actin cytoskeleton and motility system, know the rate and equilibrium constants for many of the reactions, can document the effects on cells of deleting or mutating many of these proteins, can count the numbers of each protein in every pixel in a 3-D reconstruction of a live cell, routinely follow the dynamics of the proteins as cells move, and can bring all of this information together with mathematical models and simulations that rigorously test our beliefs about the mechanisms.
These advances supported by NIGMS and other agencies established that we now have tools to understand virtually any biological process at the molecular and cellular level, including the pathogenesis of most diseases. One unknown is how far reductionist approaches can take us in understanding very complicated biological process such as consciousness.
In contrast to the 1960s, progress in biology is now limited by resources rather than by ideas or technology. Hence, progress would be faster if many more investigators joined the effort. So the question is how soon does society want the information required to improve human health? Do we want these insights in our lifetimes or can society wait until future generations? We have to hope that continued support of biomedical research will enable everyone to benefit sooner from knowing more about how cells work.
I am very grateful to NIGMS for supporting the work of my laboratory since 1972. That support has allowed us to learn more than even our wildest dreams 40 years ago. I have been privileged to serve NIGMS as a member of their review group for training grants in the 1970s, as a member and chair of a study section with many NIGMS grant applications in the 1980s and as a member of the NIGMS advisory council in the 1990s.
Nicole S. Sampson, Stony Brook UniversityFunded by NIGMS for 3 yearsChemical biology, enzymology and metabolomics
First, my research has been funded by multiple institutes at NIH—the National Heart, Lung, and Blood Institute; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Cancer Institute; and the National Institute of Allergy and Infectious Diseases. However, most of these grants were supported by NIGMS as a secondary institute. That means that if the disease-oriented institute finds that the research program is no longer aligned with its mission, NIGMS will consider funding it as being important to contributing to foundational knowledge. This has been extraordinarily helpful in my own career, as research often takes you in unexpected, interesting directions. In my own case, I started out looking at a specific type of interaction between cells, and that led to developing new polymer chemistry that can be applied in many different fields—for example, antibacterials, cancer and imaging—and NIGMS supported me in this transition. So for me, NIGMS is the invisible hand of support to make sure we all have the tools needed to improve the human condition. Without the cross-fertilization between work in different disease areas, we would not uncover new knowledge as quickly and would run the risk of duplicating discoveries.
Second, NIGMS makes a direct investment in training programs. At Stony Brook, this means training across both the chemistry and biology disciplines. All students study a core curriculum that is taught by faculty from chemistry, biochemistry and cell biology, pharmacological sciences, and physiology and biophysics. In addition, students in our chemical biology training program have a mentor from the chemistry side and a mentor from the biological side of research who help the student to learn to speak two dialects of science. An additional benefit of this cross-training is that students learn early on to work and communicate with a team. This type of training is extremely attractive to business employers in the chemistry and biology industries. I might add that 33 percent of our supported trainees this year are getting both their M.D. and Ph.D. They understood that they need training in chemistry to do translational research that will have a direct impact in the clinic. Through the guidance and support of NIGMS, we have been able to shape research education to follow new paths that break down traditional educational barriers.
Vern L. Schramm, Albert Einstein College of Medicine, Yeshiva UniversityFunded by NIGMS for 35 yearsEnzymatic transition states
Support of fundamental research by NIGMS has led to new discoveries not anticipated from the original research plans. I never intended to create drugs, but NIGMS support led to a new research paradigm resulting in a drug discovery pipeline.
A National Science Foundation-National Research Council postdoctoral fellowship supported my 2-year adventure into the characterization of AMP nucleosidase from Azotobacter vinelandii at NASA Ames Research Center, Moffat Field, California. It did not occur to me that research on the kinetic mechanisms of allosteric enzymes might be of interest to NIH. Hence, early research in the Schramm lab at Temple University School of Medicine was funded by NSF in several small 2- or 3-year grants. Soon, the work included the enzymatic regulation of purine nucleotide pools.
Gerhard W.E. Plaut, the chair of biochemistry, suggested that my next proposal be submitted as a "dual-application" for funding by either NSF or NIH, a standard practice of the time. This proposal was approved for funding by both NSF and NIGMS. The NIH’s longer funding period was attractive, so I accepted it. NIGMS funding became the backbone for a lifetime of study on the catalytic mechanisms of enzymes.
By the mid-1970s, advancing computational power and kinetic isotope effect technology made it possible to imagine that a combination of experimental kinetic isotope effects and computational chemistry might provide insights into enzymatic transition state structure. Our original goal was to see if the transition state of AMP nucleosidase differed from the acid-catalyzed reaction and was changed by allosteric regulators. The three transition states were different.
This fundamental study provided the research tools to solve the transition state structures of additional enzymes, specifically, those proposed to be drug targets. These included nucleoside hydrolases from protozoa parasites and purine nucleoside phosphorylases from mammals. The former enzymes are targets in purine salvage and the latter are targets for T-cell cancers.
The response of human and bovine purine nucleoside phosphorylases to this analogue suggested that the transition states might be distinct, even in enzymes with high catalytic site similarity. Solving the transition state structure for human purine nucleoside phosphorylase confirmed the difference. New transition state analogues were designed and one of these is now in clinical trials for gout.
NIGMS support of fundamental research on enzyme mechanisms was directly responsible for developing transition state analogue drug design based on kinetic isotope effects, research directly relevant to medicine. The early work on purine nucleoside phosphorylase is now expanding to the design of transition state analogues for other cancers, malaria and bacterial antibiotic resistance.
The health of the nation's biomedical research enterprise depends on robust, continued funding of curiosity-driven fundamental research relevant to biological function. NIGMS has led this charge for the past 50 years. We look forward to the next 50 years of novel discoveries coming from curiosity-driven, NIGMS-supported research programs.
Thomas J. Silhavy, Princeton UniversityFunded by NIGMS for 29 yearsProtein targeting, signal transduction and outer membrane biogenesis
In my opinion, NIGMS is the jewel of the NIH. Unlike the other institutes, its mission is pure and unencumbered. Basically, NIGMS is charged with the goal of fostering scientific excellence in biomedical research. It pursues this goal in two ways. First, it funds basic—i.e., untargeted—research in the life sciences, and it supports the training of the next generation of scientists who will continue this quest and/or disseminate and apply this knowledge to create advances in human health. The success of this endeavor is widely recognized and undisputed.
I have been supported almost continually by NIGMS since I graduated from college. I was supported in graduate school by an NIGMS training grant. My predoctoral and postdoctoral advisors had R01 grants from NIGMS. So, except for the 5 years I spent at the Frederick Cancer Research Center, my entire adult life has been devoted to the mission of NIGMS: basic research and training. My experience in science was, and remains, very rewarding for me. It is difficult to put into words how grateful I am to the institution that has made all of this possible.
During my career I’ve been at a medical school, a research institute and a university. Consequently, I’ve seen the research enterprise from both the intramural and extramural side, and I’ve experienced both retrospective and prospective peer review. I’ve been in the classroom with undergraduates, graduate students and medical students. I’ve competed successfully for research grants for more than 30 years, and I served as the PI for the genetics training grant here at Princeton for more than a dozen years. I’ve served on study sections for both research and training grants, I have served as an
ad hoc member of the advisory council, and I chaired the committee for the Center for Scientific Review that reorganized the study sections for the Infectious Diseases and Microbiology Integrated Review Group. Thus, I have had direct experience with most of the activities of NIGMS.
Over these years, I have met a number of the people who work at the Institute and have made it what it is today. Some of these have had enormous impact on my research career. For example, I was awarded my first NIGMS R01 in 1978, and until his retirement last summer, the only program officer I ever had was Bert Shapiro. In both good times and bad, Bert’s advice was extremely valuable. Other staff members have become good friends. For example, I served on the training grant study section for 5 years and during this time I got to know the scientific review officer Arthur Zachary quite well. In fact, when my term ended he gave me one of his famous and very detailed doodles. It still hangs in my office. What has always struck me about the NIGMS staff was their sincere desire to foster the scientific enterprise. They get too little credit for all the work that they do.
I am very excited about the future of NIGMS. Because of budgetary problems, the last few years have been trying, but I am confident that the next 50 years will be even better than the last.
Peter Sorger, Harvard Medical School and Massachusetts Institute of TechnologyFunded by NIGMS for 18 yearsSystems biology and cancer
I am very pleased to congratulate NIGMS and its wonderful staff for 50 amazing years. There is no question in my mind that without the support of NIGMS, and its commitment to fundamental, investigator-initiated research, I would not be doing what I am today. Looking back, I am also struck by the help and encouragement I received from my program officers, Jim Deatherage in particular.
NIGMS has been very effective in acting as both advocate and judge for many an uncertain project and fledgling investigator. When I started as an assistant professor at MIT in 1994, securing an NIGMS R01 was the mark of early success, and it was always understood that getting such grants involved pursuing the most interesting line of inquiry possible, without worrying about specific diseases. In my case, this meant attempting to determine the composition of kinetochores, the structures that bind chromosomes to spindle microtubules. We tackled this in budding yeast, thinking that perhaps 6-10 proteins might have been involved. Some years later, this grew to over 60 proteins, and the wisdom of tackling the problem simultaneously in yeast, flies, worms and mammalian cells (all part of the NIGMS grant portfolio) became apparent.
Some years later, I was very fortunate to be awarded one of the first National Centers for Systems Biology grants by NIGMS. Our Center for Cell Decision Processes (CDP) provided me and my MIT- and Harvard-based colleagues 10 years of funding for open-ended studies of life-death decisions in mammalian cells. At the outset, only a few investigators in our center were active in computational biology and bioinformatics, but by the end, virtually all of us had labs combining experimental and mathematical biology. It is a remarkable feature of NIGMS that it was willing to gamble on a relatively young yeast cell biologist lacking experience in computational biology based on a few reasonable ideas and a plausible proposal. I will forever be grateful.
While I remain committed to investigator-initiated R01 research, I would also like to draw attention to the successes of the larger NIGMS grant mechanisms, such as the P50 grants that fund the National Centers for Systems Biology. Many investigators overestimate the size of these programs (they are less than 5 percent of the budget) and underestimate their impact. NIGMS has played the leading role in bringing systems biology into existence as a discipline in the United States. In our case, under the wise guidance of our program officers such as Jim Anderson, the CDP P50 has supported a wide variety of highly interdisciplinary projects. The papers from these projects are among the highest impact papers any of us have published, and more than a dozen of our trainees have gone on to start their own independent academic labs. Several successful companies have also been started by former postdocs and students. I am convinced that it would not have been possible to undertake the science we did in the absence of a fairly large and flexible multi-investigator grant. I can certainly attest that we worked much harder per grant dollar on our systems biology projects than on anything else.
I am optimistic that the next 50 years of NIGMS will be as storied and successful as the last 50. There is abundant evidence that the NIGMS science-first approach has had a bigger impact on our understanding of human biology and disease than many more focused and directed projects. We have many challenges, including declining funding and relentless attack from some quarters on the fabric and conduct of science. It seems remarkable that the very concept of federal support for science should be in doubt as we enter a century in which national wealth will be determined by scientific accomplishment, yet that is clearly the case. At the same time, it is important to realize that scientists themselves pose the greatest threat to the scientific enterprise. Our apathy, disillusionment and lack of participation are far more dangerous than any external threat. We must work to ensure that investigators at all levels make themselves available to assist and advise NIH and NIGMS and to participate in the demanding task of peer review. Moreover, we should recognize that a push for translational science is a threat to basic discovery only if we allow it to be. Many remarkable discoveries await the application of NIGMS-developed techniques and ideas to human physiology and disease. I have no doubt that NIGMS will lead the way in funding the best science in these areas, even as it retains its commitment to fundamental scientific questions, education, and training and the advancement of young people.
Kenneth S. Zaret, University of PennsylvaniaFunded by NIGMS for 26 yearsGene regulation
NIGMS has a special place in my heart. It has funded my laboratory continuously since its inception in 1986, and I have come to know its most excellent staff, its robust peer-review process and, most importantly, its basic science mission quite well. Of all of the National Institutes of Health, NIGMS can be said to support the most fundamental biological research. I cringe when I hear that NIH is not the “National Institutes of Your Favorite Model System.” Time and again, it has been shown that basic science discoveries in model systems fuel the greatest advances in our understanding of, and development of cures for, cancer and numerous other human health problems. In this era of translational science, we must not only safeguard the basic science goals of NIGMS, we must also be sure that they continue to grow within NIH so that future generations of researchers can apply new principles of science to human ailments.
Many years of open-ended, NIGMS-funded work in my lab led to the discovery of signals in mouse embryos that induce liver progenitors at the expense of pancreatic progenitors. Little did we know at the time that the same signals would be found to operate similarly in diverse model organisms and be useful today in programming liver fates from human embryonic stem cells. Such programming of stem cells is being used to generate new therapies for liver diseases.
Other studies by our lab on the basic mechanisms by which gene regulatory proteins bind DNA in a chromosomal context led to the discovery of pioneer transcription factors. Pioneer factors possess the special property of being able to bind their target DNA sites in highly compacted chromosomal regions where other regulatory factors cannot bind on their own. Pioneer factors also enable other factors to bind chromosomal DNA. While performing our research, we did not anticipate that pioneer factors would later be shown by others to play a role in endowing hormone responsiveness to breast and prostate cancer cells, and that they would now serve as targets in treating cancer.
Current NIGMS-funded work in my lab is to understand the limitations of pioneer factor binding to the genome; that is, what parts of the genome restrict pioneer factors from binding to DNA, and how does such restriction occur? This has led to the discovery of large chromosomal domains with particular epigenetic properties that play a role in stabilizing cell differentiation. Understanding the composition of those domains is providing clues about ways to overcome a cell’s intrinsic resistance to reprogramming to different fates. It will be interesting to see how this new finding may apply to areas we cannot yet imagine.
It has been a privilege to be funded by NIGMS and to be associated with its purpose. Particularly in this age, when the very existence of science and rational thought is being challenged by so many, we cannot take NIGMS’ mission for granted.
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12/12/2019 10:13 AM
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