40 YEARS OF DISCOVERY: FROM MOLECULES TO MEDICINES

THE NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES GOT ITS START in 1962 as the "basic research institute" of the National Institutes of Health. Forty years later, the Institute's investments have paid off in major advances in many fields of science, including genetics, cell biology, structural biology, chemistry, biochemistry, pharmacology, and physiology. Breakthrough discoveries made by NIGMS-funded scientists have led to 51 Nobel Prizes and countless other prominent scientific honors. Institute training programs continue to produce investigators who do cutting-edge science that spans many different areas of biomedicine, and NIGMS maintains its steadfast commitment to increasing the number of minority biomedical researchers. Looking to the future, the Institute is helping to support and develop areas that will likely dominate 21st-century science, such as bioinformatics, computational biology, and proteomics. To commemorate NIGMS' first 40 years, here are 40 ways we say "NIGMS."

DESPITE THE FACT THAT general anesthesia is a routine part of many types of surgery, exactly how many anesthetic medicines work has remained a mystery to scientists for more than 150 years. NIGMS-funded scientists supported by individual and multi-investigator grants have been trying to answer this important question. Today, researchers are closing in on the molecular targets of an important class of medicines used to anesthetize surgical patients. These medicines, inhaled gases called volatile general anesthetics, work by somehow interacting with the oily membranes that encase cells. Scientists have not yet determined precisely how this happens, partly because inhaled anesthetics appear to interact with many types of molecules in cells, including so-called channel proteins, molecules that snake their way through cell membranes. Studies using model organisms like electric fish and roundworms are beginning to uncover pathways of signaling molecules involved in the anesthesia response. In addition to revealing how anesthesia works and providing critical information for designing future anesthetic medicines, these fundamental studies will also lead to a better understanding of the brain and central nervous system, and perhaps even of consciousness itself.

	Courtesy of Terry Gaasterland

IN MAY 2001, NIGMS established the Center for Bioinformatics and Computational Biology (CBCB) to support research and training in areas that join biology with the computer sciences, engineering, mathematics, and physics. The goal of the fields of bioinformatics and computational biology is to use computer technologies to solve enormously complex biomedical research problems, such as how cells move around and communicate or how organs and embryos develop. A flood of data generated by the Human Genome Project and by an ongoing explosion of recent advances in genomics has created an urgent need for researchers to use sophisticated and powerful computer techniques to sift through the reams of new data. The Institute's CBCB encourages biomedical scientists and so-called quantitative (mathematically based) researchers to work together to assemble mathematical models of biological networks, develop modeling and simulation tools, conduct basic theoretical studies related to the organization of biological networks, and develop software tools for analyzing and storing data. CBCB is NIGMS' focal point for this important new area of science.

RECOMBINANT DNA technology, making bread, and brewing beer all have something in common: Each of these pursuits is an example of biotechnology, the science of using biology to create things that people use. In the last few decades, biotechnologists, some of whom are trained formally as bioengineers, have created a variety of useful products, including living organisms like genetically modified bacteria. Other creations born of biotechnology include biological catalysts that speed the production of useful chemical compounds, medicines and diagnostic tools, and biological probes that scientists use to examine the inner workings of cells. While many different NIH components--including NIGMS--have contributed to the development of techniques and concepts used in biotechnology, NIGMS has been the central point for research training in this area. In 1988, at the urging of Congress, the Institute established a program of biotechnology training grants. Over the years, these grants have supported university-based programs that produce broadly trained scientists who have the knowledge and orientation to combine basic and applied research. Graduate students sponsored by NIGMS biotechnology training grants do coursework and extensive research as they pursue a Ph.D. in a discipline related to biotechnology. To give them a meaningful research experience in industry, these graduate students are also required to perform a summer internship in a biotechnology or pharmaceutical firm. Related fields of research that benefit from an investment in biotechnology include molecular biology, biochemical engineering and bioprocessing, metabolic engineering, drug delivery, and a burgeoning area of science called tissue engineering.

	Courtesy of Laura Kiessling

IN OUR BODIES, CELLS "talk" to each other constantly. Often, this cellular conversation hinges on carbohydrates-sugar molecules that blanket every cell in our bodies. Carbohydrates and proteins associated with them permit cells to transmit and receive chemical, electrical, and mechanical messages that underlie everything from growth to movement to thought. Scientists know very little about how our cells use sugars to communicate, but NIGMS-funded research is helping to uncover new information in this area. As noted by one prominent scientist in the field, carbohydrates are "the most information-dense molecules Mother Nature makes." But because they are notoriously diffi- cult to work with, carbohydrates are not nearly as well understood as DNA and proteins. Scientists have had great difficulty in determining how long, complicated carbohydrate pieces are hooked together, and making carbohydrate precursors in the lab has also been challenging. However, new methods recently developed by NIGMS-supported scientists to untangle the structure of highly branched sugar molecules, along with clever approaches to piecing together the constituent individual parts of sugar molecules, are providing opportunities for rapid progress on this blazing research frontier. The study of carbohydrates could pay off in improved knowledge of-and better treatments for-a host of conditions ranging from cancer to inflammation and a variety of immune system disorders.

THE CELL IS THE UNIT of life in all living things. In many ways, NIGMS could be considered the "cell institute." Since the Institute's beginnings, NIGMS-funded scientists have worked to identify and understand what's inside cells and how cells function. These researchers have found millions of critical molecules that govern cell behavior. Studies have shown how cells contend with changing conditions, such as new environmental stimuli, while continuing to carry out a huge array of everyday activities. Research on cell growth and division, using cells from humans and model organisms, has produced a wealth of knowledge that has improved understanding of diseases like cancer, in which the basic process of cell division gets terribly out of kilter. Important information about developmental processes, such as the formation of body parts and the assembly of cells into organs and tissues, has come from NIGMS support of the study of cells. Cell studies have also revealed how cellular parts called organelles work together to produce cell components and how these components interact. In years to come, a full understanding of the normal functioning of a healthy cell will include a complete catalog of all of the molecules in a cell, as well as the structure and function of each molecule. This level of organization, sort of like a periodic table or parts list of cellular components, will be a crucial step in understanding how healthy cells work and subsequently in understanding how cells malfunction in disease.

	Courtesy of April Robbins

EVERY CELL ON THE planet has an unbroken lineage that goes back three and a half billion years. A cell divides into two daughter cells, which also divide, establishing the ongoing cycle of life. A cell's life is itself cyclic, consisting of distinct phases in which key events take place, such as the copying of the genetic material DNA. Scientists recognized these phases more than 50 years ago, and since then, NIGMS-supported basic researchers have delved deeper into investigating cell cycle transitions and the elements that control them. Unraveling the intricacies of these cellular events holds the key to understanding how errant cell cycle transitions cause birth defects and diseases like cancer. The past 10 years alone have witnessed a remarkable burst of knowledge in how cells make important decisions during their cycles, and with clockwork precision. As a result, on the horizon may be a new generation of drugs to target cancer cells dividing out of control. Fundamental advances in cell cycle research are also yielding powerful molecular diagnostic tools that some clinical researchers are using to tailor cancer therapy. Currently in the clinical trials pipeline are scores of potential drugs targeted to either beef up or tone down levels of key cell cycle molecules.

	Courtesy of K. Donais, D. Webb

IT SHOULD COME AS NO surprise that nearly all of the topics in this booklet somehow relate to the study of cells. To understand cells, it is critical to understand how cells interact with one another and how their activities are regulated. How do cells talk to each other? How do cells move around in the body? What makes cells form organs and tissues? As simple as these questions sound, they remain major unanswered questions in biology. The first two of these scientific puzzles are the subjects of recent NIGMS-funded glue grants, which bring together large, multidisciplinary teams of scientists to attack big and complicated problems in biomedicine. In additional projects that center on the multitude of ways cells interact with each other, NIGMS-funded chemists and biologists examine how cell "stickiness," or adhesion, is involved in a range of physiological processes such as inflammation or the spread of cancer cells throughout the body. Other scientists probe how cell behavior significantly impacts fundamental processes such as the formation of body parts. Nearly all of these studies are performed using model organisms, underscoring the importance of the Institute's unwavering support for research using worms, fruit flies, mice, and other animals to understand human biology.

	Courtesy of Coriell Institute for Medical Research

TEN YEARS INTO ITS existence, NIGMS created an extremely useful research resource called the NIGMS Human Genetic Cell Repository. This facility operates via a contract to the Coriell Institute for Medical Research in Camden, New Jersey. A nonprofit organization, the Coriell Institute maintains the world's largest collection of human cells for research. Carefully kept within the NIGMS cell repository are many highly characterized, contaminant-free cell cultures and high-quality, well-characterized DNA samples derived from these cell cultures, both subjected to rigorous quality control. The repository collects and distributes to researchers cell lines from people with genetic disorders as well as from unaffected people, whose cells can be used as controls. Cell donors are not identified. Resources housed in the cell repository speed the pace of genetic and genomic research by scientists around the world. Basic researchers have used repository cell lines and DNA information to map and identify genes linked to a variety of diseases and conditions, such as Huntington's disease and cystic fibrosis.

IT HAS BEEN SAID THAT as scientists seek to understand biology at the level of molecules, the language spoken must be that of chemistry. Since 1962, 22 scientists who received research funding from NIGMS have been awarded the Nobel Prize in chemistry. The Institute supports the lion's share of chemistry research at NIH, funding studies in areas ranging from medicinal chemistry to enzymes, bioenergetics, and the myriad roles played by carbohydrates (sugar molecules) in the body. NIGMS-supported chemistry research areas also include the synthesis of natural products made by plants, animals, and microorganisms; analytical chemistry; and spectroscopy and biophysical chemistry. During NIGMS' 40 years, the use of chemistry to explore biology has grown markedly. Reflecting this trend, several major chemistry departments across the country have changed their names to include "chemical biology," and in 1992 the Institute launched the Chemistry-Biology Interface predoctoral training program. In the future, NIGMS-funded chemistry and biochemistry research will continue to have an impact on many areas of biomedical science, including drug discovery and metabolic engineering, a field in which scientists harness the tools of biology to create new chemicals that, in many cases, never existed before in nature.

NATURE MAKES TWO, mirror-image versions of most molecules on the planet, not too unlike pairs of gloves. Of course these molecules are millions of times smaller than gloves, so it may not be easy to imagine two "hands" of a molecule like an amino acid, the basic building block of proteins. Yet not only do the two forms (called enantiomers) really exist, but it matters a lot that they do. For decades, NIGMS has supported groundbreaking research in this area, which is called chiral chemistry. Enantiomers have different enough spatial conformations that they can perform completely different functions. They can also have very distinct properties, such as odor or taste. Spearmint and caraway, for instance, are enantiomers. In the laboratory, synthetic reactions nearly always yield a mixed pool of both "left-" and "right-handed" enantiomers. However, the active part of many medicines consists of a single hand of a molecule. A mixture that includes the "wrong" hand of a molecule can be ineffective or even harmful to the body. In 2001, long-time NIGMS grantee Dr. K. Barry Sharpless won the Nobel Prize in chemistry for developing chemical tools called chiral catalysts, molecules that enable researchers to selectively control chemical reactions. The use of chiral catalysts has streamlined the production of a wide array of important chemicals, including certain antibiotics, heart medicines, and antidepressants.

EXCEPT FOR EGGS, sperm, and red blood cells, every cell in our bodies has 23 pairs of chromosomes, the keepers of much of our past and future health: our genes. Years ago, scientists believed that chromosomes were merely DNA packaging systems consisting of a mix of proteins and the genetic material. For over 30 years, NIGMS-funded research on chromosomes has created a deeper understanding of these cellular fixtures, which scientists now know do a whole lot more than just hold DNA. Elaborate cellular orchestration assures that each time a cell divides, the chromosomes double and move apart at just the right time, distributing 23 pairs of new chromosomes to each daughter cell. Over the last decade, NIGMS-supported scientists have unveiled heretofore unknown roles performed by structures at the tips of chromosomes called telomeres. NIGMS-funded basic research in this area has recently suggested that telomere length may be linked to aging and cancer. With new research findings emerging constantly, the chromosome story is not likely to end anytime soon.

IT ALL STARTED NEARLY 30 years ago, when scientists first stumbled upon mutant fruit flies with a permanent case of jet lag. Since then, NIGMS-sponsored basic research has fueled an explosion of discoveries in the field of circadian rhythms, or "biological clocks." Researchers working in this area now appreciate a striking evolutionary parsimony in the molecules and pathways used by seemingly every organism on the planet--including bacteria, fungi, plants, silk moths, mice, and humans--to establish a 24-hour physiologic day. NIGMS-funded researchers working with these various model organisms have discovered that many of the protein parts of biological clocks in such widely diverse life forms appear remarkably alike, although in many cases the individual parts perform varying functions in different species. Such conservation of function has scientists who study circadian rhythms confident that they will be able to use fruit flies and other genetically tractable model organisms to dissect the biological clock of mammals. This research will likely lead to a better understanding of a host of human afflictions, including not only jet lag but also a variety of sleep disorders and mental illnesses. Recent NIGMS-funded circadian rhythm studies with fruit flies have shown that other surprising phenomena are linked to genes controlling biological clocks. One example is sensitivity to repeated cocaine exposure, which occurs in both fruit flies and vertebrates and has been linked to drug addiction in humans.

WHILE THE SCIENTIFIC resources maintained in the NIGMS Human Genetic Cell Repository have been extremely useful to researchers over the years, this NIGMS-managed repository stands out in another important way. Over the past few years, NIGMS has worked to establish ethically sound procedures surrounding the use of repository-held cell and DNA samples from individuals representing identified populations. A recent policy at the repository requires that any researcher wishing to submit samples from individuals from a recognizable ethnic or racial group must take steps to consult with members and leaders of that community before collecting the samples for his or her research studies. NIGMS' efforts to consult communities whose members participate in genetic research have prompted the Institute to take the lead in preparing an NIH "Points to Consider" document to help geneticists decide when and how to consult with communities before conducting research with identified populations. NIGMS also organized and led a 2-day meeting in September 2000, the "First Community Consultation on the Responsible Collection and Use of Samples for Genetic Research." Several other consultations have been held since then.

	Courtesy of FlyBase/ Rudi Turner

DECADES OF NIGMS-funded basic research using model organisms like fruit flies and mice have shown that the development of embryos is exquisitely controlled by genes. Fruit flies, for example, have body plans and basic features--arms, legs, even a primitive brain--quite similar to those of humans. "Nobody would have predicted that an arcane fruit fly that had a leg sticking out of its head would have revealed fundamental secrets about the development of human embryos," says one scientist who uses the flies to study basic developmental processes. The leg-in-the-head fly taught researchers a valuable lesson: that genes can act as switches. Certain genes choreograph the proper embryonic development of an entire organism, exerting control messages such as "make a leg." Signature stretches of DNA, such as sequences called homeoboxes, are so important for development that nearly every creature ever examined--frogs, worms, beetles, chickens, mice, yeast, plants, and people--has been found to contain these DNA-based switches.

	Courtesy of Robert Langer

SCIENTISTS GENERATE a wealth of great ideas for new medicines, but many of these potential medicines fail because they cannot get to their target sites in the body. One of the biggest challenges is getting medicines, most of which are foreign substances, past the body's protective armor--the stomach, intestines, and immune system. To help find ways to target drugs appropriately and minimize unwanted side effects, NIGMS supports research in drug delivery that blends approaches from chemistry, biology, and engineering. Drug delivery research has yielded clever devices to get medicines where they need to go as quickly as possible, sometimes purposefully keeping them out of places like the intestines, where medicines can be chewed up rapidly by digestive enzymes. Drug-impregnated skin patches, inhalers, and implantable pumps are just a few examples of drug delivery products already in wide use. On the horizon are coin-sized silicon wafers containing small reservoirs for liquid or powder forms of medicines. The contents of such chips would be released in a controlled way to provide the right dose of a medicine at the right time. To improve understanding of how drugs are handled in the body, NIGMS also supports research aimed at understanding drug transporters, proteins that control the movement of natural and foreign molecules into and out of cells.

NIGMS-FUNDED RESEARCH in chemistry and biology underpins the process of discovering new medicines. A solid investment in basic research in these areas lays the foundation for future applied research done by other NIH components and biotechnology or pharmaceutical companies. One area of research pioneered by NIGMS-supported scientists is structure-based drug design, an approach that has yielded many important medicines including the anti-HIV class of drugs called protease inhibitors. Although another time-honored approach to drug discovery begins with plants and other natural products, scientists predict that many of tomorrow's medicines will likely result from a detailed knowledge of biology that is gained through the use of novel chemical tools. An example is the automated screening of so-called "libraries" of chemical compounds, which is now a routine method used to search for new medicines. NIGMS supports cutting-edge research that merges chemistry and biology in ways that will speed the discovery of new medicines. One example is "chemical genetics," a new area of research that uses small molecules in a systematic way to explore biology. Clever methods that enable chemists to force chemical reactions to produce a single desired product, rather than a mix of desired and undesired products, are also helping researchers in the search for new ways to make medicines more efficiently (see Chirality). Yet other new angles in drug discovery hinge on biology. Proteomics, a field dedicated to identifying all of the protein products of human and animal genomes, is poised to deliver thousands of useful drug targets for chemical investigation. And pharmacogenetics, the science of understanding how people's genes affect the way they react to medicines, will also be an important element of future drug discovery efforts.

	Courtesy of Mary Jo Ondrechen

WHEN YOU THINK OF cells, tissues, and organs, biology usually comes to mind. But biology has its roots in chemistry--biochemistry, to be exact. Cells are buzzing chemical factories filled with worker molecules called enzymes. Enzymes, which typically are proteins, keep cells healthy and running by mediating almost all of the processes upon which life depends. Because of the crucial biochemical role of enzymes, NIGMS has a longstanding interest in understanding the principles by which enzymes function. The Institute has supported studies on what enzymes are made of, how enzymes work chemically, and how the body switches enzymes on and off--sometimes incorrectly, in various diseases. Every minute of every day, enzymes speed up the chemical reactions that occur in our bodies, making it possible for us to think, move, eat, and perform countless other activities. Decades of NIGMS-funded basic research have been critical to building the foundation of knowledge about how sequentially linked enzymes underlie hundreds of key physiological processes.

	Courtesy of Varian NMR Systems

WHILE THE MAIN FOCUS of the Institute is to support research, the investigators doing this research need tools, and sometimes these tools are extremely expensive. Synchrotrons, nuclear magnetic resonance (NMR) machines, and various types of high-powered microscopes are among the scientific instruments that have unveiled an impressive amount of biological data in the areas of cell biology and structural biology. NIGMS has done its part to be sure that scientists working in these exciting areas have ample resources to perform their research. An example is access to synchrotrons, the enormous machines that produce X-ray beams used by structural biology researchers to tease apart the three-dimensional structures of molecules. Typically, scientists must schedule their data-collection visits to synchrotrons months in advance. They must then work feverishly before and during these few days to make the best use of their scarce synchrotron "beam time." NIGMS, along with the National Cancer Institute, has recently responded to this need by supporting the design and construction of a user station consisting of three new beamlines at Argonne National Laboratory's Advanced Photon Source, the newest and most advanced synchrotron in the country. In recent years, NIGMS has also issued a call for research proposals to develop collaborations to test the capabilities of powerful 900 MHz NMR machines. These novel pieces of equipment, massive in size and price, are especially useful to scientists trying to determine the threedimensional structures of proteins in motion as well as the structures of carbohydrate molecules.

NIGMS-SPONSORED research advances arising from the use of model organisms all over the branches of life's evolutionary tree continue to underscore the value of looking to ancestral life forms to reveal information about health and disease. The theory of evolution is the underlying principle that explains the differences, similarities, and relationships of all living things. Take the case of HIV, the virus that causes AIDS. Without an understanding of evolution, researchers would have been stumped to explain why HIV drugs become resistant to medicines so alarmingly fast. As with all microorganisms, the deadly HIV evolves in minutes to hours, outpacing the evolution of the human species by millions of years. As this and countless other examples illustrate, evolution is much more than a historical scientific framework--it is an integral part of life. NIGMS has encouraged research to understand how evolution impacts the relationships among microorganisms, their hosts, and their environment. The Institute has also stimulated research on how these interactions can lead to serious health consequences such as the development of resistance to antibiotic medicines. In the future, NIGMS plans to support studies of genetic variation on a large scale, addressing how genomes change over time and how genes interact with each other and the environment.

	Courtesy of Protein Data Bank (http://www.rcsb.org/pdb/)

CELLS ARE HARDLY THE bags of constituents pictured simplistically in many textbooks. Rather, cells are bustling centers of activity, teeming with messages rushing in and out. Key switches that convey many of these messages are signaling molecules called G proteins. NIGMS-supported research on cellular communication and cell behavior nearly always includes some element of study of this vast group of molecules, which join up with cell surface receptors and convey messages to the cell interior. Hormones, neurotransmitters, and countless other molecules rely on G proteins to relay information within or between cells. The 1994 Nobel Prize in physiology or medicine was awarded for work on G proteins to long-time NIGMS grantee Dr. Alfred Gilman and the late NIH scientist Dr. Martin Rodbell. With funding from NIGMS, Dr. Gilman has taken the study of cell communication and G protein signaling to a new level, forming a large consortium of scientists called the Alliance for Cellular Signaling. This ambitious, collaborative effort to map the entire circuitry of two cell types was made possible by an NIGMS "glue" grant. The glue grant initiative, which brings together biomedical researchers from a variety of disciplines to tackle major scientific problems, is winning high praise from the research community.

	Courtesy of NCBI/NLM/NIH

IN 1982, RESPONDING to prevalent concerns from the scientific community about the mounting difficulty of keeping track of emerging DNA sequence information, NIGMS staff established GenBank^�, an extensive computerized collection of DNA and RNA sequence information. During its early years, GenBank was supported through research contracts to private companies, first Bolt Beranek and Newman and later Intelligenetics, Inc. In both instances, subcontracts were awarded to Los Alamos National Laboratory for data collection. In late 1992, the National Library of Medicine's National Center for Biotechnology Information took over responsibility for the sequence repository, including all phases of data validation, production, support, and distribution of sequence information. Now 20 years old, GenBank is an essential tool for biomedical research scientists worldwide, nearly 50,000 of whom access GenBank each day via the World Wide Web. In 1997, GenBank celebrated a significant milestone in adding the one billionth nucleotide base to the DNA sequence portion of its database collection. Today, GenBank contains nearly 98 percent of the entire human genome and some 14 billion nucleotide bases from over 100,000 organisms. GenBank is a member of the International Nucleotide Sequence Database Collaboration, which includes the DNA DataBank of Japan and the European Molecular Biology Laboratory. The three organizations exchange data daily.

IN 2003, THE FEDERALLY funded Human Genome Project will have determined the entire "letter-by-letter" sequence of the 3 billion nucleotides that make up the human genetic material. Few people realize that this history-making project got its start at NIGMS, following a 1987 call for grant proposals in this area of science. In fiscal year 1988, Congress provided money to NIGMS for the project, which was managed by what was then the Institute's Genetics Program. In 1989, a few NIGMS staff members left to join the newly formed Office of Human Genome Research. This office grew into today's National Human Genome Research Institute. Over the years, NIGMS has maintained a significant involvement in genome research, mostly related to the genomes of model organisms. The Institute also has a strong investment in helping bring genomic information to biology through its bioinformatics and computational biology efforts.

THE FREEDOM TO EXPLORE. The independence to pursue a curious laboratory observation. The chance to test an unpopular hypothesis. From the beginning, NIGMS has championed the efforts and ideas of the individual investigator. That's the basic scientist with a good idea who needs the autonomy and resources to explore its plausibility. This scientific latitude has made possible a wide array of important, and in many cases unexpected, discoveries. The Institute's staff maintains close ties to the scientific community, and over its 40-year history, NIGMS has anticipated and adjusted to the changing needs of investigators. Recently, with enhanced budgets, this had led to large-scale commitments to certain defined emerging areas of science, such as bioinformatics and computational biology, structural genomics, pharmacogenetics, and complex biological systems. However, NIGMS' major focus of support continues to be on individual ideas crafted by scientists either new to or experienced in the NIH funding process. To foster healthy growth of the next generation of scientists, NIGMS makes special efforts to provide research support to first-time grant applicants.

	Courtesy of http://www. pharmacology.ucla.edu

PROPER AMOUNTS OF important biological molecules such as fats, sugars, and proteins are crucial to the formation and proper functioning of membranes, the oily envelopes that encase our cells and all of their vital contents. A membrane is by no means a simple barricade, but rather a remarkable cellular engineering feat--an orderly arrangement of lipid (fat)-containing molecules, proteins, and carbohydrates. Proteins embedded in the plasma membrane transmit messages and molecules into and out of cells. NIGMS-supported studies on membranes are a valuable part of the biomedical research enterprise, since membrane proteins are the targets of many medicines and are responsible, in part, for the uptake, metabolism, and clearance of medicines and other substances. In part because of the nature of the construction of membranes, these structures are notoriously difficult to study. In recent years, NIGMS has lent a helping hand by providing scientists with funds to determine the three-dimensional structures of membrane proteins. Recent spectacular successes in solving the structures of some of these proteins suggest that the study of membrane proteins by techniques such as X-ray crystallography, electron microscopy, and nuclear magnetic resonance spectroscopy is indeed feasible, albeit laborious and difficult. The hard work should pay off, however, giving way to a better understanding of known membrane protein structures that will reveal many of the basic features underlying cellular functions essential to human health.

METALS SOMETIMES suffer a tarnished reputation when it comes to human health. While some toxic metals--such as lead, arsenic, and mercury--aren't good for the body in any amount, many other metals perform vital functions in the body. Iron, zinc, and copper, for example, play important roles in the myriad enzymatic reactions that fuel metabolism. Iron helps ferry oxygen through the blood. Many other metals, such as zinc, copper, and magnesium, help keep proteins folded into their proper shapes. Longstanding NIGMS support of the study of metals in biology has led researchers to discover molecules called metal "chaperones" that escort metals like copper safely to where they need to go in the body. A recent NIGMS-led initiative, "Metals in Medicine," was created to help build bridges between inorganic chemistry and medicine. Metals in Medicine has a dual focus: on the basics of how metals cooperate with other molecules such as proteins in the body, and on the use of metals in designing new drugs. The program, which NIGMS initiated after ongoing communications with scientists who study the biology of metals, has been enthusiastically received by the scientific community. One recently funded project seeks to scan the cellular landscape for zinc, using tailor-made fluorescent grabbers called chelators.

A LARGE AMOUNT OF what researchers know about cells has been learned from studies using microscopes. Not surprisingly, NIGMS has made a huge investment in microscopy and its applications to biomedicine. Scientists use microscopes to view a cell's landscape, to take an inventory of various molecules at the scene, and then to observe what happens under various conditions. Stunning advances in the field of microscopy over the years now permit researchers to view cell parts with remarkable clarity. Biologists can watch cellular "movies" and craft testable ideas based upon what they see. Other sophisticated techniques, such as electron microscopy, have the power to resolve with precision the three-dimensional arrangement of individual cell components. Emerging techniques include high-resolution electron microscopy, which may help scientists examine large, interlocked assemblies of proteins inside cells. Other promising technologies currently under development will give researchers the ability to manipulate single molecules, which has the power to enhance understanding of the behavior of biological molecules in living cells. Such techniques should also give scientists a window into how cells work in real time, allowing the monitoring of molecules and pathways under changing environmental conditions.

	Courtesy of Jeri Muller

A CORE MISSION OF NIGMS is to increase the number of scientists who are members of underrepresented minority groups. The NIGMS Division of Minority Opportunities in Research (MORE) supports many innovative activities to meet this important need. In 2002, two flagship MORE programs, Minority Access to Research Careers (MARC) and Minority Biomedical Research Support (MBRS), celebrate their 30th anniversaries. MARC, which got its start at NIGMS, offers research training support to 4-year colleges, universities, and other minority-serving institutions to increase the number of minority biomedical scientists and their competitiveness for research grants. MBRS provides grants to minority institutions to support investigator-initiated research and to enhance faculty, student, and institutional development. The Bridges to the Future program supports the transition of students from associate degree programs to bachelor's degree programs, and from master's degree programs to Ph.D. programs. Another MORE program combines a traditional postdoctoral research fellowship with a teaching experience at a minority institution. In addition to creating and administering programs like these, MORE Division staff work to motivate, guide, and assist minority institutions, faculty members, and other prospective grantees who are new to the NIH funding system.

WHAT DO RATS, FROGS, plants, microbes, and zebrafish all have in common? Each of these organisms looks very different on the outside, but contains a remarkably similar genetic make-up on the inside. Scientists rely heavily on these so-called "model organisms" to study human health and other fundamental issues of basic biology. With its primary focus on basic research, NIGMS supports a vast number of studies using model organisms. In addition to the list above, other models include mice, baker's yeast, fruit flies, roundworms, viruses, and primitive organisms called Archaea, which thrive in hot springs and other harsh environments. Among the characteristics that make these life forms especially suitable for laboratory study are rapid development with short life cycles, small adult size, and general ease and economy of use. Over the years, NIGMS-supported scientists have accumulated valuable information from studies with these organisms, providing explanations about normal human development, gene regulation, genetic diseases, and evolutionary processes. NIGMS also participates in an NIH-wide effort to foster collaboration and data sharing between individual research groups working with various model organisms.

	Courtesy of Edgar Fahs Smith Collection, University of Pennsylvania Library

NIGMS-FUNDED RESEARCH has fortified the biomedical research knowledge base by providing many fundamental, paradigm-shifting insights. In recognition of the importance of these basic advances, 51 NIGMS grantees have received the Nobel Prize in chemistry or in physiology or medicine. The discovery of the role of the genetic code in protein synthesis, the restriction enzymes that make recombinant DNA techniques possible, cell signaling, cell cycle regulation, organic chemical synthesis, and the structural and functional organization of cells are all examples of NIGMS-funded, Nobel Prize-winning research. These and other important breakthroughs in chemistry and biology often "prime the pump," leading to more focused, applied research that culminates years later in important medical advances. On many occasions, basic research begun with NIGMS support has matured into clinically useful research findings or commercial products such as medicines or biotechnology tools.

	Courtesy of Alison Davis

AS THEIR NAME IMPLIES, organelles are like miniature organs inside cells. NIGMS' major emphasis on understanding cells, often through visual methods such as microscopy, inevitably encompasses the study of organelles--the nucleus, the mitochondrion, the endoplasmic reticulum, the Golgi apparatus, and others. Each organelle is a vital cell component, so gaining a fundamental understanding of these structures contributes to health by providing researchers with information about how cells fail during disease. In a way, each organelle is like a tiny factory station. All of a cell's components work together, performing the many steps involved in reading our genetic code, manufacturing proteins, ferrying important cell components about by attaching "address labels" to them, making essential sugars and fats, and breaking down or recycling used materials. Each organelle must also cooperate with the others to perform the communication tasks of the cell--getting messages in and out and knowing when to grow or to stop growing and die, which in many cell types is a necessary part of life. Learning how cells work means understanding how organelles work, and NIGMS-supported scientists are working hard to figure that out.

THE SAYING "ONE SIZE does not fit all" could not be more true when it comes to taking medicines. Pharmacogenetics is the study of how genes affect the way people respond to medicines, including antidepressants, chemotherapy treatments, asthma drugs, and many others. The ultimate goal of pharmacogenetics research is to help doctors tailor doses of medicines to a person's unique genetic make-up. This will inevitably make medicines safer and more effective for everyone. Because pharmacogenetics marries several areas of basic research, NIGMS has become a focal point at NIH for this area of science. In 2000, NIGMS took the lead in recruiting several other NIH components to join the Institute in sponsoring a nationwide research effort in pharmacogenetics. At the heart of the resulting network of scientists, which in 2002 consists of 13 research teams across the country, is a shared information library, called "PharmGKB," into which network researchers deposit results they collect. Research data, which does not identify study participants, is accessible to scientists worldwide, with the goal of forging new links between gene variation and drug response.

THE ACADEMIC DISCIPLINE of pharmacology has been a staple of the medical school curriculum for decades, but over the years this field has undergone phenomenal growth in its scope. Simply said, pharmacology is the study of how drugs work in the body. But since medicines work in so many different ways in so many different organs, pharmacology research spans just about every area of biomedicine. Because by nature pharmacology research is not limited to an organ or a disease, NIGMS is a major supporter of studies in this field. The intestinal tract, the brain, the muscles, and the liver are a few representative areas in the body in which pharmacologists focus their studies on how medicines work. Of course, inside each of these organs are cells, and inside the cells are genes, so many pharmacologists study the molecular actions of, and cellular and gene responses to, a huge array of medicines. NIGMS-supported pharmacology projects range widely, from investigating the genetic underpinnings of people's responses to medicines to teasing apart the complexity of drug-drug interactions in the human body. For years, NIGMS has funded postdoctoral training programs in clinical pharmacology. These programs aim to produce a cadre of physician-scientists well-versed to perform either basic or more clinically related pharmacology research. NIGMS also funds predoctoral training programs in the pharmacological sciences; currently, there are 27 such programs at academic centers across the nation. Pharmacology is the focus of NIGMS' only intramural activity, the Pharmacology Research Associate program, a 2-year postdoctoral research training fellowship in the pharmacological sciences in a laboratory at NIH or the Food and Drug Administration.

	Courtesy of Jacob Keller

NIGMS' EMPHASIS ON structural biology takes vivid form in the NIGMS Protein Structure Initiative (PSI). Proteins control many biological processes in organisms ranging from bacteria to plants and humans. One way to understand proteins--and perhaps find ways to control their actions--is to decipher their three-dimensional structures. The PSI is divided into two phases: a 5-year pilot stage that began in 2000 and a subsequent, full-scale production phase. To date, the PSI consists of a network of nine research groups, each of which is developing tools to improve methods for solving the structures of a wide array of proteins as well as methods for high-throughput structure determination. The PSI's second phase will use results from pilot phase studies, and NIGMS organizers of the project hope ultimately to produce an inventory of representatives of all protein structure families in nature, a remarkable 10,000 protein structures. Using the tools of structural genomics and computer modeling to relate gene sequences to protein structures and functions, scientists expect to be able to rapidly predict any protein's structure from its gene sequence. The Institute anticipates spending a total of around $200 million on projects in the pilot phase alone, making NIGMS one of the world's largest funders of structural genomics. Over time, it is likely that the PSI will yield major biological findings that will improve understanding of health and disease.

NIGMS' EXTREMELY broad scope spans basic biomedical research in a wealth of different areas. To educate the public about these areas of science, the Institute produces science education materials on an ongoing basis. Thousands of high school and college science students and teachers across the nation have requested free copies of NIGMS' award-winning science education publications. The publications cover numerous topics, including chemistry and biochemistry, structural biology, genetics, cell biology, pharmacology, and pharmacogenetics. In its 40th anniversary year, NIGMS is excited to embark on another educational pursuit. Together with the NIH Office of Science Education, NIGMS will produce a middle school curriculum supplement, tentatively entitled "Doing Science." This educational tool on the process of scientific inquiry, which will be available free of charge to educators, will emphasize the process of thinking about and doing science. Major concepts to be conveyed include the importance of critical thinking in scientific pursuits and in everyday life; the continual, revisionistic nature of scientific inquiry; generating and testing hypotheses; and the importance of sample size and using controls.

BASIC RESEARCH PAYS off by contributing incrementally to the foundation of knowledge about biology. Rewards from past basic studies can also be more applied, yielding tools that are indispensable to today's researchers. Recombinant DNA technology is a great example. This technology is the result of fundamental, Nobel Prize-winning work in the early 1970s by several different groups of NIGMS-funded scientists. Also called genetic engineering, recombinant DNA technology has had dramatic practical applications in medicine, such as the manufacture of human hormones and therapeutic proteins with the help of bacteria. The research that led to recombinant DNA technology began with basic studies on how DNA as the carrier of our genetic traits drives the chemistry inside our cells. This knowledge, combined with the discovery that restriction enzymes found in bacteria can act as "chemical knives" to cut DNA into defined pieces, provided the basis for the modern-day biotechnology industry. Recombinant DNA technology is also used to study the genetics of a wide array of biological processes, ranging from normal embryonic development to disease.

WELL-TRAINED SCIENTISTS are necessary to conduct the quality research that yields the fundamental advances, medical insights, and useful research tools described throughout this booklet. Today, NIGMS supports nearly half of the predoctoral trainees and just over one-quarter of all the trainees who receive assistance from NIH. Research training programs funded by NIGMS recognize the interdisciplinary nature of biomedical research, and these programs stress approaches that cut across disciplinary and departmental lines. Such experience prepares trainees to pursue creative research careers in a wide variety of areas. Certain NIGMS training programs address areas in which there is a particularly serious need for well-prepared scientists. One of these, the Medical Scientist Training Program, trains investigators to bridge the gap between basic and clinical research by supporting research training leading to a combined M.D.-Ph.D. degree. Other NIGMS programs train scientists to do research in the rapidly growing fields of biotechnology, bioinformatics, and computational biology. In keeping with its commitment to training a diverse research workforce, NIGMS is continually vigilant to how institutions recruit and retain trainees who are members of underrepresented minority populations.

	Courtesy of V. Hornak, C. Simmerling

RIBONUCLEIC ACID, or RNA, tends to get less attention than its better known molecular cousin, DNA. But RNA is a master performer in the cell. The job RNA is best known for, serving as an intermediate molecule in the process of turning a DNA sequence into a protein, is only one of RNA's many skills. The 1989 Nobel Prize in chemistry was awarded to two NIGMS-funded scientists, Drs. Thomas Cech and Sidney Altman, who discovered that RNA can act as an enzyme. This discovery rocked the biological paradigm of the times, which was that enzymes could only be made of protein. NIGMS-supported research on this fundamental molecule of life continues to yield surprises. Recent findings have expanded understanding of a trick that RNA has been performing for millions of years--a gene activity-controlling operation called RNA interference. This process, nicknamed RNAi, was first found to occur in plants and then in roundworms, but in the last few years scientists have discovered that RNAi takes place in nearly all species in which they have looked, including in human cells. In the future, researchers may be able to develop new, gene-based treatments by using RNAi to purposefully manipulate gene activity.

	Courtesy of Argonne National Laboratory

JUST AS SURGEONS carefully pry open a body to see inside, many cell biologists use tools like microscopes to visualize the innards of cells. Delving deeper still, specialized biologists who focus on individual proteins inside cells are fascinated by how the many different atoms that make up a protein actually fit together in three-dimensional space. These scientists yearn to understand the shapes of proteins, which are major determinants of how the proteins work in a healthy cell and how they don't work in a diseased one. Because of its fundamental research focus, NIGMS is a major supporter of the field of structural biology. The tools of the structural biology endeavor--biophysical techniques called X-ray crystallography and nuclear magnetic resonance spectroscopy--require sophisticated machines that can cost millions of dollars and therefore are often shared by many researchers from both the physical and life sciences. But the payoffs hold great value. Understanding how biology works in three dimensions offers important clues about multidimensional cell processes. As reported recently in an obituary in the journal Nature, the late crystallographer extraordinaire and former NIGMS grantee Dr. Don Wiley expressed the doctrine of crystallography succinctly. When asked to expand on an unspecified question about biology, Dr. Wiley replied, "I'm sorry, but I just don't understand anything in biology unless I know what it looks like."

	Courtesy of Woody Machalek

IF YOU ASK THOSE WHO have been associated with NIGMS to cite what first comes to mind about the Institute, a consistent response is the people. NIGMS staff are a close-knit, collaborative, and productive group. The Institute began with two dozen people; it now has 179 staff members who manage a budget of $1.7 billion in fiscal year 2002. By and large, people stay awhile- it is not unusual to find employees who have been working at NIGMS for 20, 30, or more years. Seven directors have steered the course of NIGMS and its predecessor, and the Institute remembers its third director every year in October with the annual DeWitt Stetten, Jr. Lecture. NIGMS established this named lecture series on its 20th anniversary in 1982 to honor the late Dr. Stetten's strong commitment to basic science, especially research in genetics, cellular and molecular biology, and chemistry. Dr. Ruth Kirschstein had the longest tenure at the helm of NIGMS, for 19 years from 1974 to 1993. She left NIGMS to become the acting director of NIH. Dr. Kirschstein views NIGMS as "a special organization with a very special place in my heart because of the wonderful people. They combine a real interest in and dedication to their tasks with a complete knowledge of how to perform those tasks effectively, efficiently, and with the loftiest of scientific and intellectual goals, yet with warmth, friendliness, and an outpouring of goodwill. There is no comparable group of people anywhere else."

INJURY IS THE LEADING cause of death for Americans under the age of 44. For burn injuries alone, 1.1 million incidents demand medical attention each year in the United States. NIGMS-supported basic and clinical research on injuries caused by burns and trauma has driven survival statistics for serious burns upward dramatically. Twenty years ago, burns covering half the body were routinely fatal. Today, patients with burns encompassing 90 percent of their body surface can survive, albeit sometimes with permanent impairments. Among the significant research advances sponsored by NIGMS' trauma and burn injury research program is work leading to the development of an artificial skin system called Integra^� Dermal Regeneration Template�, a product that is now widely used in burn wards across the country. Other NIGMS-funded developments include new treatments for complications common to the post-burn healing process, such as bone and muscle loss and smoke inhalation injury. In addition to its significant investment in funding research on burns and traumatic injury, NIGMS also funds research on some aspects of surgery--often referred to as "controlled trauma"--and various aspects of the recovery process for both burns and trauma, such as wound healing.