2002

Mouse Genome Sequenced - The international Mouse Genome Sequencing Consortium, jointly funded by several NIH Institutes along with the Wellcome Trust, published a high quality draft sequence of the mouse genome - the genetic blueprint of a mouse - together with a comparative analysis of the mouse and human genomes. This is the first time scientists have compared the human genome with another mammal's. Because the mouse carries a very similar set of genes, this information will allow scientists to learn more about human genes and the proteins they encode, leading to a better understanding of human disease and improved treatments and cures. The sequence is posted on the Internet, where it is freely available.

2001

­found that the DASH (Dietary Approaches to Stop Hypertension) diet combined with reduced intake of sodium lowered blood pressure for all groups of people, not just those with high blood pressure. The diet is rich in fruits, vegetables and low-fat dairy foods but low in fats, cholesterol and sweets. Middle-aged Americans face a 90 percent chance of developing high blood pressure at some time during the rest of their lives, according to NIH's National Heart, Lung and Blood Institute (NHLBI). The condition can lead to stroke, heart disease and kidney failure. (Intramural and Extramural)

­an international team including NIH scientists found a new, "hidden" influenza virus protein scientists hadn't previously known about that proved toxic to human cells. This new protein may be key to the mystery of what makes some influenza strains so deadly. (Intramural)

­discovered that HIV, the virus that causes AIDS, must attach to cholesterol-rich regions of a cell's membrane in order to enter and infect the cell. The finding provides a more detailed picture of how HIV travels into and out of cells and points to possible ways to block that travel. (Intramural)

­designed an antibody to recognize and directly deliver a toxin to cancer cells using recombinant DNA technology. This "immunotoxin" induced complete remission in 11 of 13 patients with hairy-cell leukemia that was resistant to previous chemotherapy. The compound, BL22, has been licensed to AlbaPharm, Inc., of Rockville, Md. The company, in collaboration with NCI scientists, will conduct a larger clinical trial that will involve patients with this cancer of the immune system from throughout the country. (Intramural)

­found a gene encoding a cell-destroying toxin that enables certain strains of the bacterium Chlamydia trachomatis to cause blindness and debilitating genital tract infections. (Intramural)

­found that a program to train health care providers to diagnose and treat depression can significantly reduce the time that patients spend clinically depressed for a cost of less than $500 per depressed patient. Over a two-year period, the program reduced the length of patients' depression by well over a month and increased the time they spent employed by about four work weeks. (Extramural)

­found that the shape of a man's sperm appears to be the best way to know if he is fertile. Sperm concentration and motility (how well they move) are also important. However, none of these measures can completely predict fertility. (Intramural and Extramural)

­identified the genetic basis of two rare disorders, familial cold autoinflammatory syndrome (FCAS), in which affected people develop rashes and other symptoms when exposed to cold air, and Muckle-Wells syndrome (MWS), which causes deafness as well as periodic fevers. Symptoms of both syndromes are caused by an altered immune system protein named cryopyrin. The scientists believe that cryopyrin is part of the innate immune system — an evolutionarily ancient defense system that is present in plants and other lower organisms. The identification of the gene underlying FCAS and MWS will help researchers understand the origin of these rare conditions and may point them in new directions for treatments. (Extramural)

­showed that people at high risk of developing advanced stages of age-related macular degeneration (AMD) significantly lowered that risk by taking a high-dose combination of zinc and the antioxidants vitamin C, vitamin E and beta-carotene. These nutrients are the first effective treatment to slow the progression of AMD, a leading cause of visual impairment and blindness in Americans 65 years of age and older. (Intramural and Extramural)

­established scientifically-based selection criteria for identifying emphysema patients that would receive little benefit from a new treatment called lung volume reduction surgery (LVRS) and are at high risk of death from the procedure. Emphysema is a disabling condition in which the fine architecture of the lung is destroyed, leading to large holes in the lung, obstruction of the airways, trapping of air, and difficulty exchanging oxygen. Typically caused by cigarettes, the disease affects approximately 2 million Americans and kills more than 17,000 people in the U.S. each year. This research will let doctors identify which patients would do better receiving medical treatments such as medications, exercise rehabilitation, and nutritional supplementation rather than LVRS. (Extramural)

­discovered the receptor on the outside of cells that protective antigen (PA), one of the three toxic proteins produced by anthrax bacteria, uses to get inside. Part of the receptor was used by the scientists to overwhelm the toxins and protect cells in a culture from being killed by anthrax toxins. This approach might eventually lead to a similar therapy in people. The receptor can also now be used as a tool to find potential medicines that block anthrax toxin from binding to it. (Extramural)

­solved the crystal structure of one of the three toxic proteins produced by anthrax bacteria, lethal factor (LF), and discovered how it interacts with the specific proteins it destroys inside the cell. LF kills macrophages, a key cell of the human immune system. This structural information can now be used to look for therapeutic agents to block LF's deadly activity. (Intramural and Extramural)

­designed an inhibitor of anthrax toxin by looking for random peptides (portions of proteins) that blocked the three anthrax toxic proteins from binding to each other. The scientists tested the inhibitor in rats that are highly sensitive to anthrax toxin and found that an injection could completely protect the rats from anthrax toxin without any noticeable side effects. This, or another inhibitor developed with a similar approach, might now be developed as a medicine to combat anthrax toxin when antibiotic treatment is too late. (Extramural)

­sequenced the genome of a virulent strain of Streptococcus pneumoniae. S. pneumoniae kills millions of people, especially the elderly, worldwide each year with pneumonia, blood stream infections and meningitis, and many strains have become resistant to common antibiotics. The examination of this sequence and comparison with other strains should provide targets for the development of new drugs and vaccines. (Extramural)

­found that a small change in the genetic sequence of one of influenza virus's 10 genes (known as PB2) was key to one strain's virulence, a significant advance toward understanding the molecular basis of why some strains kill so many people while others are relatively benign. The influenza virus constantly changes, and new strains emerge each year, thus requiring new vaccines each year. In order to prepare effective vaccines or design more effective antiviral drugs, it is critical to understand what makes some strains of the virus so deadly. (Extramural)

­sequenced the genome of Porphyromonas gingivalis, a bacterium thought to play a major role in gum disease. It is the first oral disease-causing microbe to be completely sequenced. This data should help researchers develop better ways to prevent or eradicate gum disease. (Extramural)

­deciphered how a variant form of a gene called COMT affects the prefrontal cortex of the brain to slightly increase the risk for schizophrenia. This is one of the first studies to show how a specific gene contributes to a mental illness. (Intramural and Extramural)

­developed a method that, by combining microarray (or gene chip) technology with a form of artificial intelligence called an artificial neural network (ANN), can tell the difference between four childhood cancers that often look alike. Using traditional diagnostic technologies, the tumors caused by these four unique types of cancer — neuroblastoma, rhabdomyosarcoma, non-Hodgkin's lymphoma (Burkitt's lymphoma) and Ewing's sarcoma — are difficult to tell apart. Gene chip technology was used to analyze the pattern of activity of thousands of genes at once while an ANN "learned" how to recognize the genetic patterns produced by each type of cancer. As a result of this work, the different cancers can now be classified with much greater accuracy. An accurate diagnosis can be critical for a child's survival, as the treatments for these tumors are quite different. This study should also help lead to the discovery of genes that are altered in these tumors, and ultimately to the development of effective new treatments. (Intramural)

­funded the lion's share of the basic research that eventually led to the discovery and development by the drug company Novartis of a new drug known as Gleevec. It is the first anti-cancer drug specifically developed to target a molecular problem that causes a particular type of cancer, in this case, chronic myelogenous leukemia (CML). In this disease, too many white blood cells are made in the bone marrow. In a clinical trial, Gleevec restored normal blood counts in 53 out of 54 patients with CML. Side effects thus far seem very mild. NCI and Novartis are conducting clinical trials to determine the long-term effectiveness of this drug. (Intramural and Extramural)

­turned mouse embryonic stem cells into cells that produced insulin and showed other characteristics of pancreatic islet cells. Diabetes, which affects 16 million people in the US, results from abnormal function of pancreatic islets. This research may be an important step toward a diabetes treatment, as stem cells may enable doctors to overcome the problems of availability and tissue rejection seen in transplants. (Intramural and Extramural)

­completed sequencing the 1.8 million DNA base pairs of Streptococcus pyogenes, a bacterium that causes a wide variety of human diseases including strep throat, scarlet fever, the skin infection impetigo, pneumonia, acute kidney inflammation, toxic shock syndrome, blood "poisoning," acute rheumatic fever, rheumatic heart disease, and the flesh-eating disease known as necrotizing fasciitis. Having this bacterium's genome will help in the development of new prevention and treatment attempts such as creating vaccines. (Extramural)

­developed a new genetic test that can distinguish between two types of hereditary breast cancer — caused by BRCA1 and BRCA2 mutations — and sporadic breast cancer. The new approach, using microarray technology to analyze the activity of over 5300 genes at once, was developed by a team of international researchers that included NIH scientists. This advance should ultimately help physicians quickly and accurately diagnose the cause of a woman's breast cancer and guide decisions about the most effective treatment. (Intramural)

­discovered the gene that codes for sweet taste receptors in the mouth. NIDCD scientists were among three separate research groups reporting the discovery of this gene. Taste receptor cells contain molecular receptors that respond to chemicals in food and drink to create the sensation of taste. The discovery of this receptor may help in the development of better artificial sweeteners, and in learning why some people seem to have more of a sweet tooth than others. Taste defects are also associated with many health problems such as obesity, diabetes, hypertension and malnutrition. (Intramural and Extramural)

­developed and tested the first vaccine capable of protecting children ages 2 to 5 against typhoid fever. Seemingly the most effective typhoid vaccine ever developed, it is also virtually free of side effects. Spread by fecal contamination of drinking water or food, or by person to person contact, typhoid fever is common in developing countries without adequate sewage and sanitation. Symptoms include fever, stomach pains, weight loss, loss of appetite, delirium, severe diarrhea (in children), and constipation (in adults). About 16 million people worldwide develop typhoid each year, and 600,000 die from it. (Intramural and Extramural)

­found, using rats, that craving for cocaine seems to increase, rather than decrease, in the days and months after drug use has stopped. This phenomenon helps explain why cocaine addiction is a chronic, relapsing disease. (Intramural)

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–assembled a working draft of the sequence of the entire human genome, the genetic blueprint for a human being. This draft contains overlapping fragments of DNA sequence–the order of the four chemical bases that make up DNA&#150covering approximately 90 percent of the genome, with some gaps and ambiguities. Sequence information from this public project has been continuously, immediately and freely available with no restrictions on its use or redistribution. Already, many tens of thousands of genes have been identified and dozens of disease genes pinpointed by access to the working draft. The international Human Genome Sequencing consortium responsible for this working draft includes scientists at 16 institutions in the United States, France, Germany, Japan, China, and Great Britain. The project is funded by grants from government agencies and public charities in these various countries. (Intramural and Extramural)

–reversed advanced kidney cancer in some patients using blood stem cell transplants from a healthy sibling. Advanced kidney cancer is often resistant to therapy and is usually fatal in less than a year. Of 19 patients who did not respond to prior therapy, three had total regression of the disease after the stem cell transplantation and seven had partial regression. Although this was a small study with a relatively short follow-up, the high response rate is very encouraging. (Intramural)

–identified a gene, BMPR2, associated with primary pulmonary hypertension (PPH), a rare but devastating lung disease that causes an uncontrolled build-up of cells in blood vessels in the lungs. The resulting blockages in the blood vessels force the heart to pump harder and increase blood pressure. With current treatments, life expectancy for people with PPH is on average less than three years. Now that a gene has been identified, scientists can focus on learning how it works so that they can better devise treatments. (Extramural)

–identified the protein in Ebola virus which causes the massive internal bleeding that kills people with the disease. The protein destroys endothelial cells­the cells that line blood vessel walls. Ebola virus, depending on the strain, can kill up to 90 percent of the people it infects. Now that scientists have found the responsible protein and gained insight into how it works, they can focus on new drugs or vaccines to combat its deadly effects. (Intramural and Extramural)

–found that treating the worm C. elegans with antioxidants increased the worms' life spans by approximately 44%. Although these worms are far from human, these experiments further a growing body of evidence supporting the theory that oxidative stress plays a major role in aging. (Extramural)

–found differences in the expression of nearly 80 different genes between the blood vessels of human colon cancers and normal colon tissue. This accomplishment gives scientists a host of new targets in their attempts to shut off the growth of the blood vessels that growing tumors in the colon need to survive. (Extramural)

–identified a gene that makes the malaria parasite resistant to chloroquine, the former mainstay, low-cost anti-malarial drug. Malaria strikes 300 to 500 million people each year, and kills 1 million. Chloroquine has been losing its effectiveness against the parasite, and no alternative approaching its affordability and effectiveness has yet emerged. This gene discovery will help scientists explore ways to overcome the parasite's resistance to chloroquine, and also help them detect chloroquine-resistant parasites in people living in areas where malaria is endemic. (Intramural and Extramural)

–discovered pore-like holes in the membranes of red blood cells infected by the malaria parasite. Made by the parasites, these channels allow them to get extra nutrients from outside the cells to support their explosive growth and multiplication within. Searching for drugs that block this channel may lead to new ways to combat this parasite. (Intramural)

–determined the complete genomic sequence of the bacteria that causes cholera. Cholera causes severe diarrhea, killing nearly 8,500 people worldwide last year and striking another 223,000. This accomplishment should speed the development of vaccines and drugs to fight the disease. (Extramural)

–identified several genes that can be used to predict particularly aggressive malignant melanomas. Scientists used gene chips to look at the activity of thousands of genes in 31 different melanomas and seven normal tissue samples. They found that the patterns of genes expressed could predict the melanomas' progression. This discovery will help doctors separate tumors that look the same under the microscope into clinically significant groups. It will also help scientists focus in on new targets for drugs to combat the disease. (Intramural and Extramural)

–identified a protein called RhoC that can cause metastasis in melanoma cells. Metastasis, the spread of cancer cells to other parts of the body, is perhaps the biggest threat to survival in patients with solid tumors. (Extramural)

–identified several genes in a bacterium that allow it to persist as a chronic tuberculosis (TB)-like infection in leopard frogs. These bacteria are related to that causing TB in humans, and follow the same pattern of infection as TB when they infect frogs. Two of the genes with very similar counterparts in TB bacteria were found to be necessary for the bacterial infection to persist. They may, therefore, be good targets for new drugs against TB, which kills an estimated 2 million people each year and persists in approximately one-third of the world's population. (Extramural)

–completed sequencing the genome of the fruitfly Drosophila melanogaster, one of the most intensely studied creatures in biology. Fruitflies are used to study a host of basic biological questions related to aging, development, learning, memory and more. This milestone, which proved the speed and value of a new technique called whole-genome shotgun sequencing, was accomplished through the combined effort of public and private laboratories. (Extramural)

–used microarray technology to show that there are actually two subtypes of diffuse large B-cell lymphoma (DLBCL). Until this work, which used the new technology to look at approximately 1.8 million measurements of gene expression from 96 different samples, scientists had been unable to account for the fact that 40% of DLBCL patients respond well to therapy, yet the remainder succumb to the disease. Microarray technology allows scientists to look at how thousands of genes are expressed at once, a scale previously unimaginable. This is just the first demonstration of a technique that promises to revolutionize cancer diagnosis as well as many other areas of scientific research. (Intramural and Extramural)

–found that mice genetically engineered to remove the receptor that responds to hot peppers developed an amazing tolerance for hot sauce, and surprisingly also showed less sensitivity to other types of pain. The mice tolerated heat better, and their cells weren't as affected by an acidic solution designed to mimic internal inflammation. This hot pepper receptor is an important new potential target molecule for developing drugs for pain relief. (Extramural)

–created the most detailed maps yet of the developing human brain, using high-resolution three-dimensional magnetic resonance imaging to show that the human brain is constantly growing and changing well into puberty. By repeatedly scanning the brains of children three to 15 years old over a four year period, scientists were able to see huge growth between the ages of three and six in the area of the brain that helps sustain attention and regulates the organization and planning of new actions. Between six and 13, the highest growth rates were in the region specialized for language. Somewhere between 11 and 15, growth in this region slows down, reflecting the difficulty most people have in learning new languages after the age of 12. (Intramural and Extramural)

–discovered a mutation that causes one form of early-onset hypertension, a condition that is particularly dangerous during pregnancy. Hypertension during pregnancy raises the risk of pre-eclampsia, which can be fatal for mother and fetus. Identifying women at risk for the condition can help doctors intervene early to prevent it. (Extramural)

–identified a protein, C-reactive protein, that predicts the risk of a woman having a heart attack better than cholesterol. It can be detected with a simple, inexpensive blood test. People who know they are at risk for heart attacks can take aggressive steps to try to prevent them. (Extramural)

–demonstrated that a simple and inexpensive change in basic surgical procedures–giving patients more oxygen during and immediately after surgery&#150can cut the rate of wound infections in half, thus saving millions of dollars in hospital costs by helping to prevent post-surgical wound infection, nausea and vomiting. (Extramural)

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1995-1999

–completed first sequence of a human chromosome, chromosome 22. Genes on chromosome 22 have been implicated in immune system function, congenital heart disease, schizophrenia, mental retardation, birth defects, and several cancers, including leukemia. The 33.4 million nucleotides that make up chromosome 22 comprise the longest continuous stretch of DNA ever deciphered. (Extramural)

–demonstrated an affordable and practical strategy for preventing transmission of the HIV virus from mother to infant. A single oral dose of the antiretroviral drug nevirapine given to an HIV-infected woman in labor and another to her baby within three days of birth reduced the transmission of virus by half compared with a similar short course of AZT. If used in developing countries, this treatment might prevent some 300,000 to 400,000 newborns per year from becoming infected and eventually developing AIDS. (Extramural)

–the risk of pregnant women infected with HIV transmitting the virus to their infants was reduced by about 50 percent if they delivered by cesarean section before they went into labor and before their membranes ruptured. (Intramural and Extramural)

–found "master" gene that makes Salmonella a deadly bacteria. Without the gene for an enzyme called Dam, Salmonella bacteria not only did not kill the mice they were injected into, but also served as a vaccine against future infection by deadly Salmonella. Because Dam is found in many other dangerous bacteria, this discovery opens possibilities for a whole new generation of antibiotics and vaccines against virulent bacteria. (Extramural)

–first demonstration that sleep deprivation may have a harmful effect on the body, not just the mind. The bodies of men whose sleep was severely restricted for one week had characteristics that mimicked some of the hallmarks of aging, including lowered glucose tolerance, which is a risk factor for diabetes, obesity and hypertension; and raised cortisol levels, a condition thought to be involved in insulin resistance and memory problems. The negative effects of sleep deprivation could be corrected by normal sleep. (Extramural)

–completed the sequence and gene map of a region essential to the immune system, the human major histocompatibility complex (MHC). The MHC is associated with more diseases than any other region of the human genome. One group of proteins encoded by the genes of the MHC are the markers of self that appear on almost all body cells and thus play a critical role in rejection of organ transplants as well as in autoimmune diseases like rheumatoid arthritis. A second group of proteins which the MHC codes for helps fight foreign invaders like viruses and bacteria. (Extramural)

–completed the first high-resolution genetic map of Plasmodium falciparum, the deadliest malaria parasite. This accomplishment will help scientists find new targets for improved diagnostic tools, therapies and vaccines. Each year P. falciparum malaria affects up to 500 million people worldwide and kills more than 2 million, primarily young children in sub-Saharan Africa. (Intramural and Extramural)

–women with preeclampsia, a potentially fatal complication of pregnancy, were found to have an imbalance of two key chemical compounds that control blood pressure, prostacyclin and thromboxane, months before the symptoms of preeclampsia appeared. The discovery suggests strategies for designing new treatments for the condition. There is currently no cure for preeclampsia. Characterized by high blood pressure, excessive weight gain, headaches and other symptoms, preeclampsia may progress to convulsions and bring about a variety of other birth complications. About 5 percent of first-time mothers develop preeclampsia. (Intramural)

–children born to mothers with untreated hypothyroidism during pregnancy were found to score lower on IQ tests than children of healthy mothers, suggesting that early detection and treatment of hypothyroidism in pregnant women may be a critical part of prenatal care. Hypothyroidism is a condition in which the thyroid gland does not produce enough hormone, leading to fatigue and a lack of energy; coarse, brittle hair; thick, coarse skin; and a lowering of the metabolic rate. About 3% of women of childbearing age develop the condition, but hypothyroidism often goes undetected because the women do not yet have obvious physical signs or symptoms. (Extramural)

–created transgenic mice that showed enhanced performance in six different memory tests. Scientists achieved the result by getting adult mice to express a juvenile form of one brain receptor. This research is a major advance in understanding memory and learning. (Extramural)

–a single gene was found to make laboratory mice more friendly and affectionate toward their cage mates. Receptors for the hormone vasopressin were taken from the sociable prairie vole and put into laboratory mice. When the mice were injected with vasopressin, they became more affectionate. This study is the first to show that even complex social behavior can be radically affected by a single gene. (Extramural)

–between 1992 and 1996, the rate of Sudden Infant Death Syndrome (SIDS) dropped by 38 percent. Much of that drop was likely due to a 66 percent decrease during the same period in the number of U.S. infants being placed to sleep on their stomachs. The Back to Sleep Campaign, a national campaign that encourages infants to be placed to sleep on their backs, was launched by NICHD in partnership with several other organizations in 1994. (Intramural and Extramural)

–developed promising new strategy for treating cancer in a mouse model. Rather than directly attacking cancerous cells, which can develop resistance to chemotherapeutic drugs, researchers starved them by targeting drugs to the new blood vessels that nourish the tumors. This method spares other tissues in the body, and proved to be effective in mice. Human trials are currently underway. (Extramural)

–demonstrated that the human circadian clock can be reset by applying light to the back of the knees. Scientists had previously assumed that the body's internal timekeeping clock was set exclusively by light reaching the eyes. This discovery was a surprising step in understanding how the body's biological rhythm is set. (Extramural)

–identified a particular molecule involved in nicotine addiction, a subunit of a known nicotine receptor. Mice lacking this molecule don't self-administer nicotine like normal mice. This discovery uncovers a potential target for developing medications to treat nicotine addiction. (Extramural)

–losing weight and cutting down on salt were found to lessen and sometimes eliminate the need for blood pressure-lowering medications in elderly people with high blood pressure. The study showed that lifestyle modifications can be used to control high blood pressure. About 50 million Americans have high blood pressure, and it is one of the most important risk factors for cardiovascular disease. (Extramural)

– vitamin E supplements were found to substantially reduce the incidence of prostate cancer and death in male smokers. Men of 50-69 years old who took a moderate dose of vitamin E daily for five to eight years had 32 percent fewer diagnoses of prostate cancer and 41 percent fewer prostate cancer deaths compared to men who did not receive the vitamin. (Extramural)

–developed a safe and effective method of screening for Down syndrome in the first trimester of pregnancy. Previous methods of screening for fetuses with Down syndrome during the first trimester carried significant risks of miscarriage. (Extramural)

–showed for the first time that an edible vaccine can safely trigger significant immune responses in people. Volunteers developed the responses after eating bite-sized pieces of raw potato that had been genetically engineered to produce part of the toxin secreted by the Escherichia coli bacterium, which can cause diarrhea. This accomplishment is a significant milestone on the road to developing inexpensive vaccination programs, and is of particular importance to developing countries. (Extramural)

–identified mutations in a newly discovered gene, MYO15, that can cause one of the most common forms of inherited deafness, nonsyndromic recessive deafness. Research on a similar protein in mice leads scientists to speculate that MYO15 plays an important role in the functioning of the inner ear hair cells. (Intramural and Extramural)

–sequenced the complete genome of Treponema pallidum, the bacterium that causes syphilis. This accomplishment will help advance the development of vaccines and diagnostic tests. Syphilis is a sexually transmitted disease that can cause serious heart abnormalities, mental disorders, blindness, other neurologic problems, and death. (Extramural)

–resolved the three-dimensional structure of gp120, the surface protein that the HIV virus uses to attach itself to immune system cells. The discovery allows scientists to identify important target sites for developing new drugs and vaccines. (Extramural)

–showed that women at high risk of developing breast cancer who took tamoxifen had 49% fewer cases of breast cancer than those who didn't. Tamoxifen was hailed as the first drug to prevent breast cancer in women at high-risk for the disease. Because of the incidence of side effects from the drug, it may be most beneficial for women at high risk for breast cancer. (Extramural)

–completed the sequence of the Chlamydia trachomatis genome, providing new insights into chlamydial infections and ways to combat them. Chlamydia is the most prevalent bacterial sexually transmitted disease in the United States, leading to infertility, tubal pregnancy and chronic pelvic pain. The same bacterium can also infect the eye, causing trachoma, the leading cause of preventable blindness in the developing world. (Extramural)

–sequenced the complete genome of the tiny roundworm Caenorhabditis elegans in 1998, representing the first time that scientists have spelled out the genetic instructions for a complete animal that, like humans, has a nervous system, digests food, and has a sexual reproductive system. (Extramural)

–three-dimensional structure of the tubulin molecule solved by electron crystallography. Tubulin, a major part of every cell's skeleton, is the target of taxol, a potent anti-cancer drug. Knowing the three-dimensional structure of tubulin will aid attempts to find and design new anti-cancer drugs. (Extramural)

–identified a defective gene that causes some inherited cases of Parkinson's disease. The discovery provides clues to how nerve cells are killed in the disease and suggests possible new therapeutic strategies. Parkinson's disease, characterized by trembling and a loss of muscular control, afflicts about 500,000 people in the United States. (Intramural and Extramural)

–identified the Clock gene, which controls circadian rhythm in mammals. Biological clocks are disturbed in problems ranging from jet lag to manic depressive illness. (Extramural)

–discovered that people blind from birth actually rewire their brains to use the primary "visual" areas of the cerebral cortex to read Braille. This discovery shows that even basic aspects of brain organization can change, at least in the very young. (Intramural and Extramural)

–pinpointed the area of the brain involved in seeing and storing working, short-term memories of a face or a series of letters. A time course of brain activity was observed for the first time with high resolution using an advanced technology called functional magnetic resonance imaging (fMRI). (Extramural)

–developed the laser capture microdissection (LCM) technique, which allows scientists for the first time to pinpoint and remove targets as small as one cell from a sample without damaging either the target or the surrounding tissue. Earlier extraction methods either fragmented the sampled cells or destroyed the surrounding tissues. The precision of LCM is invaluable in analyzing cells from patients with diseases such as cancer. (Intramural)

–identified the protein that causes red blood cells to clump together and block blood flow during an infection by the malaria parasite. This discovery provides a new target for anti-malarial therapies. Malaria is one of the most serious and complex health problems facing humanity in the 20th century. Worldwide, between 300 and 500 million people are infected and between 1.5 and 2.7 million die of malaria each year. (Intramural and Extramural)

–discovered a gene, STGD1, involved in age-related macular degeneration, the leading cause of blindness in older Americans. The scientists found mutations in this gene in 16 percent of the 167 cases of age-related macular degeneration they studied. (Intramural and Extramural)

–genes for two different forms of glaucoma, juvenile angle glaucoma and primary congenital glaucoma, identified. These discoveries advance the understanding of the causes of glaucoma and may lead to early detection and improved treatments. Glaucoma, a condition where pressure builds up in the eye and damages the optic nerve, blinds almost 12,000 people in the United States each year, and accounts for 15% of blindness worldwide. (Extramural)

–complete sequence of Escherichia coli genome published. E. coli is a laboratory workhorse with a long and rich history, and was the largest and most complex bacterial genome to be completely sequenced at the time (1997). This accomplishment gives researchers a powerful new tool for understanding fundamental questions of biological evolution and function. (Extramural)

–nationwide "Dietary Approaches to Stop Hypertension" (DASH) trial showed that a diet low in fat and high in vegetable, fruit, and low fat dairy foods significantly and quickly lowered blood pressure. A DASH diet could reduce some people's need for medication to control their hypertension. High blood pressure affects about one in four Americans, and can lead to coronary heart disease and strokes. (Extramural)

–identified the gene which causes Werner's syndrome, a rare and ultimately fatal genetic disease with symptoms resembling premature aging. People with Werner's syndrome get gray hair, lose elasticity in their skin, and develop cataracts while in their twenties, and most die before age 50. They can also develop several age-related diseases at a young age, including atherosclerosis, cancer, diabetes, and osteoporosis. Scientists think that the genetic defect causing Werner's syndrome allows DNA damage to accumulate, thus leading to the premature development of age-related diseases. This discovery is important not only for understanding the biological processes involved in aging, but also in understanding the array of rare tumors and other age-related diseases associated with Werner's syndrome. (Extramural)

–identified two key molecules on the surface of immune cells that the HIV-1 virus needs in order to enter immune cells and begin its attack. People with two mutant copies of one of these molecules were found to resist HIV infection. These findings suggest new strategies for combating AIDS. (Intramural and Extramural)

–identified a gene, HPC1, that when mutated predisposes men to prostate cancer. The researchers estimate that 1 in 500 men have an altered version of this gene, and that it is responsible for at least a third of familial prostate cancer. (Extramural)

–found the first direct biological link between cigarette smoking and lung cancer. DNA mutations caused by the cigarette smoke byproduct benzo[a]pyrene in the tumor suppressor gene p53 were found to be the same as those found in lung cancer cells. Scientists have long associated cigarette smoking with lung cancer, but this discovery uncovers the molecular basis for how smoking leads to lung cancer. (Extramural)

–identified mutations in a gene that lead to an inherited form of epilepsy. While inherited epilepsy is rare, understanding how the defects in this gene lead to epilepsy may give scientists insight into how epilepsy develops in other people. Epilepsy is estimated to affect more than 2.5 million Americans, about 1 percent of the population. (Extramural)

–DNA sequence completed of the brewer's yeast Saccharomyces cerevisiae, a simple model system for understanding complex problems in cell biology. This was the largest genome to be completely sequenced at the time (1996), and will aid greatly in the analysis of yeast genes and their products. (Extramural)

–discovered that the cerebellum is involved in perceiving sensory input, challenging the prevailing view that it serves only in controlling muscles. (Extramural)

–a new class of anti-HIV drugs called protease inhibitors shown to help significantly prolong the lives of AIDS patients. NIH-supported basic research paved the way for the development of this new class of drugs, from discovering the HIV protease enzyme to determining its three-dimensional structure in order to design drugs to block its action, to conducting drug-screening efforts and clinical trials. (Extramural)

–a 5-year clinical trial funded by NINDS led to a rapid decision by the Food and Drug Administration (FDA) to approve the clot-dissolving drug t-PA1 for the emergency treatment of stroke. Those treated with t-PA1 within 3 hours of their initial stroke symptoms were at least 30 percent more likely than untreated patients to recover from their stroke with little or no disability. (Extramural)

–"PEPI" trial changed the course of hormone replacement therapy (HRT) for postmenopausal women. The study found that including progestin in HRT substantially reduced the increased risk of cancer of the endometrium (lining of the uterus) associated with taking estrogen alone. HRT is used to counteract the symptoms many women experience as their body adjusts to the fall in their body's estrogen levels during menopause: hot flashes and flushes, sweats, sleep disturbances and an increased rate of bone loss that may result in osteoporosis and bone fractures. Progestin seems to counteract estrogen's deleterious effect on the uterus by preventing overgrowth of the endometrial lining. (Intramural and Extramural)

–the cancer mortality rate fell nearly 3 percent between 1991 and 1995, the first sustained decline since national record keeping started in the 1930's.

–an "immortality" enzyme, telomerase, was found to be active in many types of cancers, but is not generally detectable in cells that age and die normally. Telomerase is thought to reverse the cell's aging process. Bestowing immortality on the cell, however, leads to the uncontrolled growth that characterizes tumors. This robust telomerase activity has been detected in 80-90% of human tumors, providing important insight into the events that lead to cancer. (Extramural)

–treating HIV-infected pregnant women and their newborns with zidovudine (AZT) was found to reduce the risk of HIV transmission from mother to infant by approximately two thirds. Maternal-infant transmission is the primary means by which young children become infected with HIV. This finding opened the door to a major preventive effort. (Extramural)

–discovered the obese gene, which causes gross obesity in mice when not produced properly, along with its human counterpart. The protein for which obese codes, leptin, is now the subject of clinical trials attempting to combat human obesity. (Extramural)

–first discovery of a gene involved in Usher syndrome (US), the most common cause of combined hearing and vision problems in the United States. More than half of the estimated 16,000 people in this country who are deaf and blind are believed to have US. People with this form of Usher Syndrome, Type 1B, are profoundly deaf from birth and have severe balance problems. They often begin to develop vision problems by the time they are ten, and tend to progress rapidly until they are completely blind. This discovery is a major step forward in understanding the causes of Usher Syndrome and pinpointing potential targets for therapy. (Extramural)

–discovery of the gene and mutations responsible for ataxia telangiectasia (A-T), a complex inherited childhood disorder characterized by weakened muscle control, a sensitivity to x rays, an unusually high risk of diabetes, lung infections, dilated blood vessels in the eyes and other parts of the face, and a predisposition to many different types of cancer. People with A-T usually die of respiratory failure or cancer by their early twenties. Researchers are particularly interested in A-T because it affects so many different systems in the body. The A-T protein was found to communicate with the tumor suppressor gene p53, which normally helps to halt cell growth and allow DNA damage to be repaired. Scientists believe it also communicates with other important proteins in the cell. (Intramural and Extramural)

–a clinical trial of treatment for sickle cell anemia was halted early due to its overwhelming success. Daily administration of the drug hydroxyurea reduced the frequency of painful episodes and related hospital visits by about 50%; reduced the frequency of acute chest syndrome, a life-threatening complication of sickle cell anemia characterized by chest pain, fever, prostration, and an abnormal chest X-ray; and reduced the number of blood transfusions for patients in the study. Sickle cell anemia is an often fatal disease that affects millions throughout the world. Approximately 2 million Americans carry the sickle cell trait, and about 72,000 are affected by the disease. (Intramural and Extramural)

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1990-1994

–identified two breast cancer susceptibility genes, BRCA1 and BRCA2, that together account for up to 70% of all hereditary breast cancers (between 5% and 10% of all breast cancer is hereditary). Mutations in BRCA1 and BRCA2 have also been implicated in ovarian cancers, and BRCA2 mutations have now been associated with increased risks of cancers of the prostate, pancreas, gallbladder, bile duct, and stomach as well as malignant melanoma. (Extramural and Intramural)

–identified four genes that may be involved in over 13% of colon cancers. These genes code for proteins engaged in DNA "mismatch repair", a form of genetic spell-checking. Once scientists linked one mismatch repair protein to human colon cancer, previous research using bacteria pointed them to the other three human genes. (Extramural and Intramural)

–identified the gene responsible for the most common type of kidney cancer, sporadic (nonfamilial) clear cell carcinoma, which accounts for about 85 % of all kidney cancers. This gene had been previously identified as the cause of the inherited cancer syndrome von Hippel-Lindau (VHL) disease, which leads to tumors in the adrenal glands, the kidneys, the pancreas, and parts of the nervous system including the brain, eye and spinal cord. (Intramural)

–discovered the most frequently mutated gene in human cancer, which codes for the p53 protein. This protein acts like an emergency brake in the cell cycle. Mutations in p53 lead to uncontrolled cell growth and tumor formation. (Extramural)

–first trial of gene therapy in humans, in which infusions of genetically altered cells were used to treat adenosine deaminase deficiency, a rare genetic disease that cripples the immune system. (Intramural)

–discovered the gene involved in fragile X syndrome, the most common inherited form of mental retardation in males. In 1980s, discovered the fragile X syndrome. (Extramural)

–proved the safety and effectiveness of methotrexate for treating rheumatoid arthritis and juvenile rheumatoid arthritis. (Extramural)

–found for the first time a gene that causes a form of osteoarthritis. (Extramural)

–determined an effective treatment for lupus kidney disease. This work has been going on since the 1970s. (Intramural)

–determined mechanisms by which estrogen is effective against bone loss. (Extramural)

–determined the three-dimensional structure of myosin, a protein critical to generating force and motion in nearly all living things. (Extramural)

–developed new methods for growing sheets of skin to treat people with burns and blistering diseases. (Extramural)

–determined the gene and structural defect in the skin responsible for a form of ichthyosis. (Intramural and extramural)

–showed that tight control of blood glucose levels effectively delays the onset and slows the progression of long-term diabetes complications including diabetic retinopathy, nephropathy, and neuropathy in patients with insulin-dependent diabetes. (Extramural)

–showed that people who already have some form of heart disease can benefit from cholesterol reduction. (Extramural and National Cholesterol Education Program; work also done during the 1980s but became clear in the 1990s)

–discovered and characterized the genetic abnormality of a second form of familial hypercholesterolemia. (Extramural)

–demonstrated the first effective treatment for spinal cord injury. Patients treated with methylprednisolone within the first 8 hours of a spinal cord injury recovered more motor and sensory function than patients who did not receive this drug. (Extramural)

–found a new drug that, when added to the standard levodopa/carbidopa treatment, prolongs by more than 60 percent the relief of symptoms in patients with Parkinson's disease. (Intramural)

–found that valium, given at times of fever, safely reduces the risk of febrile seizure recurrences in infants and children. (Extramural)

–helped to develop a major new drug for epilepsy, felbamate, that is safe at high doses and does not have side effects commonly associated with other antiepileptic drugs. (Intramural)

–showed that the gene dose of apolipoprotein E type 4 is a major risk factor for late-onset Alzheimer's disease. (Extramural)

–discovered that a calcium intake by children that is higher than the recommended daily allowance significantly increased their gain in bone mass. (Extramural)

–found that drug treatment can help prevent strokes in older people with isolated systolic hypertension. (Extramural)

–showed that treatment with aspirin or warfarin dramatically lowers the risk of stroke in patients with atrial fibrillation. Widespread application of this finding could result in prevention of 20,000 to 30,000 strokes per year in the United States. (Extramural)

–developed taxol as a therapy for ovarian and breast cancer. (Extramural; also during the late 1980s)

–supported the development of limb-sparing surgery for cancer patients and lumpectomy plus radiation rather than mastectomy for breast cancer. (Extramural; this work has been done since the 1970s.)

–developed and disseminated methods of hypertension control. In 1972, based on scientific evidence of the importance of detecting and treating hypertension, NHLBI established the National High Blood Pressure Education Program. During the term of the program, deaths due to stroke declined by more than 57 percent and deaths due to heart attacks declined by about 50 percent. The association of these dramatic declines with the NHLBI program suggests that the hypertension research and education efforts of NHLBI have contributed substantially to a major advance in the nation's health. (This effort has been under way since 1970s.)

–improved treatment for CMV retinitis, a potentially blinding retinal disease that affects about one of every four people with AIDS. (Intramural and extramural)

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1980's

–first transfer of a foreign gene into humans. (Intramural)

–identified the cystic fibrosis gene, thus allowing for improved diagnosis and early treatment. This discovery also laid the groundwork for attempts to cure the disease through gene therapy. (Extramural)

–identification of the first drug to show any efficacy against HIV in laboratory tests and the first administration of the drug to a patient with AIDS. (Intramural)

–development of successful treatments for several formerly fatal diseases–such as Wegener's granulomatosis–that are characterized by inflammation of the walls of blood vessels. (Intramural; work started in 1970s)

–provided indisputable evidence that 90% of post-transfusion hepatitis still being seen after development of the screening test for hepatitis B was due to one or more previously unrecognized human hepatitis viruses. Showed that the first of these, the hepatitis C virus, was a transmissible agent. (Intramural)

–determined the complete structure of the IgE receptor that is involved in triggering allergic reactions. (Intramural)

–demonstrated that continual use of the antiviral drug acyclovir was safe and effective in preventing recurrences of oral and genital herpes infections. (Intramural)

–proved the effectiveness of estrogen replacement for stopping the bone loss of osteoporosis. (Extramural)

–developed a mouse model that verified the relationship between prenatal exposure to diethylstilbestrol (DES) and reproductive tract abnormalities in male and female children of mothers who were prescribed the drug during pregnancy. (Intramural)

–determined the sequence of reactions triggered by the enzyme aldose reductase (AR) that underlie the development of diabetic complications such as sugar cataracts and nerve damage. This finding resulted in studies of AR inhibitors as a new treatment for these problems. (Intramural)

–developed a long-acting androgen contraceptive, as well as safer and more effective short- and long-acting estrogens and progestogens for oral contraceptives. (Extramural; the estrogen work was done in late 1980s and early 1990s)

–used recombinant erythropoietin to correct anemia in patients with end-stage renal disease. (Extramural)

–discovered cholesterol's role in heart disease and the effects of lowering cholesterol. Discovery of the LDL receptor and the regulation of cholesterol metabolism. (Extramural; Nobel prize in 1985)

–provided the first definitive proof in humans that lowering blood cholesterol reduces the risk of coronary heart disease. The study showed that dietary restriction of cholesterol and fat along with a cholesterol-lowering drug reduced cholesterol levels and caused a 19 percent reduction in definite coronary heart disease death or nonfatal heart attacks. Moreover, the degree of reduction in coronary heart disease risk was found to be related to the degree of cholesterol lowering, with a 2-percent reduction in risk observed for every 1-percent reduction in serum cholesterol. (Extramural)

–provided the guidelines for physicians on cholesterol screening and, in the 1990s, for the public on how to lower their cholesterol levels.

–pioneered the angiographic studies that showed that decreasing one's cholesterol levels does slow the progression of fatty deposits and can shrink them in the coronary arteries. (Extramural)

–revised the understanding of which coronary lesions are really important in angiography by showing that lipid-rich plaques can be more dangerous than advanced lesions and that these dangerous lesions can be treated through cholesterol reduction methods.
(Extramural; also during the 1990s)

–conducted observational studies that showed that women who took estrogen supplementation had a markedly reduced death rate from heart attacks. (Extramural)

–developed a surfactant to prevent or treat respiratory distress syndrome. (Extramural)

–developed the new conjugate technology for making vaccines and developed one for H. influenzae type b that is effective in infants. (Intramural)

–developed supportive treatments for patients with leukemia who are prone to infections after chemotherapy. (Extramural and Intramural; also during the 1970s)

–conducted studies of sickle cell disease leading to the development of clinically useful therapies to elevate fetal hemoglobin as a treatment for sickle cell and thalassemia syndromes. (Intramural; work done since the 1960s)

–helped to establish the scientific basis for retinal cell transplantation that could have huge treatment ramifications for blinding diseases such as macular degeneration and retinitis pigmentosa. (Extramural)

–showed that briefly freezing the outer part of the retina with a probe can protect the vision of many premature infants with retinopathy of prematurity. This research could save the Federal government as much as $20 million annually. (Extramural)

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1970s

–discovered that oncogenes have normal cellular functions, thus laying the cornerstone for understanding the genetic origin of cancer and widening the insight into the complicated signal systems that govern the normal growth of cells. (Extramural; Nobel prize in 1989)

–development of the first successful cure for a childhood cancer (leukemia). This played a major role in establishing chemotherapy as a standard cancer treatment. (Intramural; work was done during the 1950s and 1960s)

–discovered Lyme disease and developed treatment for it. (Extramural and intramural)

–developed a treatment (PUVA) for the skin disorder psoriasis. (Extramural)

–identified or isolated the agents responsible for a number of infectious diseases including hepatitis A and intestinal infections, particularly infant diarrhea. (Intramural)

–established the importance of distinguishing between the normal processes of aging and the changes produced by diseases in later life. Also, developed the ability to make such distinctions. (Intramural; this work continues through today.)

–provided the first comprehensive description of the sequence of hormonal interactions during the menstrual cycle. This laid the foundation for modern reproductive endocrinology and new approaches to contraception and infertility. (Intramural)

–developed the assay for human chorionic gonadotropin that evolved into the home pregnancy tests. (Intramural)

–developed a microassay for thyroid hormone that made simultaneous screening of newborns for both congenital hypothyroidism and PKU possible. Studies showed the effectiveness of this screening and thyroid hormone replacement in preventing mental retardation; screening for both disorders is now mandatory in all 50 states. (Extramural; also during early 1980s)

–demonstrated the safety and accuracy of prenatal diagnosis of congenital disorders associated with mental retardation by means of amniocentesis. (Extramural)

–elucidated the role of asbestos in cancer especially when smoking is a risk factor. (Intramural and extramural)

–identified the specific carcinogens in tobacco smoke and their mechanisms of action, as well as the hazards of smokeless tobacco. (Intramural and extramural)

–discovery of cisplatin as a cure for testicular cancer. (Extramural)

–established laser surgery as a safe and effective treatment for diabetic retinopathy. It is estimated that laser surgery for this disease will save the Federal government up to $2.8 million over the next 20 years. (Extramural)

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1960s

–demonstrated that the information required to fold the polypeptide chain of ribonuclease into the specific three-dimensional form of the active enzyme resides in the sequence of amino acids. Thus it became clear that this protein could be synthesized in the laboratory by joining the proper amino acids in the correct order and allowing the chain of amino acids to spontaneously fold. (Intramural; Nobel prize in 1972)

–recognized the first human slow virus disease, kuru, which is a degenerative, fatal infection of the central nervous system. This discovery of a new mechanism for infectious diseases revolutionized thinking in microbiology and neurology. (Intramural; Nobel prize in 1976)

–cracked the genetic code, deciphering how nature uses the order of DNA bases to produce proteins that determine the nature and characteristics of all living things. (Nobel prize in 1968) This has led to major advances in our understanding of genes and their roles in health and disease as well as to revolutionary new ways to treat or prevent diseases through the use of recombinant DNA technology (the development of which was supported by NIH) and gene therapy (which was first done by NIH intramural scientists).

–defined the mechanisms that regulate noradrenaline, one of the most important neurotransmitters in the brain. This discovery provided a clearer understanding of the chemistry of the brain and its effect on human behavior, which, in turn, has led to the development of better drugs for treating mental disorders. (Intramural; Nobel prize in 1970)

–discovered the Australian antigen, later identified as the surface antigen of the hepatitis B virus and principal diagnostic indicator of serum hepatitis. This led to a test to screen donated blood for the presence of hepatitis B, greatly reducing the risk of transfusion hepatitis. (Intramural and extramural; Nobel prize in 1976)

–developed the first licensed rubella vaccine and the first test for rubella antibodies that was practical for large scale testing (rubella hemagglutination inhibition test). (Intramural)

–discovered an effective combination drug therapy for Hodgkin's lymphoma. (Intramural)

–discovered that tooth decay is caused by bacteria. (Intramural)

–clarified the safety and effectiveness of using lights rather than exchange transfusion for jaundice in newborn infants. (Extramural)

–documented the effectiveness of neonatal screening and dietary restriction in preventing mental retardation due to phenylketonuria. (Extramural)

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1950s

–first complete removal and successful replacement of a patient's diseased mitral valve with an artificial one, which was developed at NIH. (Intramural)

–identified or isolated a number of agents responsible for respiratory infections ranging from croup to pneumonia. (Intramural)

–discovered the cure for choriocarcinoma. (Intramural)

–created a system of mouse plasma cell tumors that made possible the development in 1975 of hybridomas, cells that produce monoclonal antibodies. These antibodies have revolutionized biomedical research. (Intramural)

–discovered that low levels of fluoride in drinking water could prevent tooth decay. This work began in the 1930s, continued through the 1940s and culminated in the 1950s. (Intramural)

Advances for the period 1950-present were prepared by: Harrison Wein, Ph.D.
Email: weinh@od.nih.gov

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1887-1950