--President Bill Clinton

• In health care, major shifts are occurring in the age distribution of the U.S. population. For example, in 1990, 12.5 percent of our citizens were age 65 and older. In 2030 half of the baby boomers will reach 65, resulting in over 20 percent of the nation falling in the 65 and older age category. (U.S. Census Bureau projections). This will increase the prevalence of diseases that are associated primarily with the elderly, such as some types of cancer, Alzheimer's disease, and osteoporosis. Shifts also are occurring in how healthcare is financed, with more and more people participating in managed care programs. We must determine the impact this will have on basic and clinical research that underlies future medical advances. In an attempt to keep down costs of long-term care, as well as improve the overall quality of life, greater attention is now being given to research leading to better methods of preventing diseases.
• In agriculture, growing environmental and human health concerns coupled with new trade agreements and commodity price support policies require the federal government to reassess its science and technology priorities and strengthen its partnerships with the states and private sector. In order to keep agribusiness strong and to ensure a safe and reliable food supply, the Federal government must maintain its research investments that produce new knowledge to improve environmental and human health and expand economic opportunities.

In February 1996, President Clinton released a report of the National Science and Technology Council entitled, Meeting the Challenge: A Research Agenda for America's Health, Safety, and Food. This report takes into account the numerous changes that we are experiencing in both health care and agriculture. It offers research strategies to contain health care costs while preserving access to high quality health care services, to develop sustainable agriculture and environmental management, and to contribute to our national security by enhancing international disease surveillance and access to food.
The breadth and diversity of our Federally supported research activities related to improving health range from fundamental research in molecular biology to crop breeding programs for improved pest resistance. This chapter highlights a number of the Administration's accomplishments spanning the breadth of our health-related research portfolio, and describes key areas of opportunity that merit enhanced support consistent with the strategic goals articulated in Meeting the Challenge.

This Administration has strongly backed biomedical research investments. Since 1993, the NIH budget has been increased by $2.4 billion (23 percent), representing significant new investment in biomedical research, in an era of constrained budgets. This commitment recognizes the need for stability to protect our long-term investment in the biomedical sciences. Living cultures or animal strains must continue to be fed, patients enrolled in clinical trials must be cared for, and the search must be continued for better methods for preventing, diagnosing, and treating disease. The Administration continues to sustain this critical investment in order to reap the benefits of better health and quality of life.

Scientific and technological breakthroughs are providing new approaches to solving many of the long-standing mysteries of life and its damaging diseases. We now have very powerful tools, developed through advances in computing, instrumentation, and recombinant DNA techniques, to help us understand what happens when normal biological processes go awry. We are beginning to apply this knowledge to developing ambitious strategies to bolster our natural protection systems and speed recovery. These tools have myriad applications that may lead to new disease treatments and new methods of disease prevention. Learning how healthy cells, organs, and organ systems operate when they are fully functional allows us to attempt to replicate, or add back defective pieces when necessary. For example, radiation or the sun's rays can damage DNA within the cell's nucleus, sometimes leading to skin and other cancers. If we can recreate DNA repair mechanisms, perhaps we may be able to prevent such damage in the future.

p.96.JPGUsing tools emerging from the Human Genome Project, an international team tracked the gene for hereditary nonpolyposis colon cancer to a region of chromosome 2. Gene-based therapies may be designed to augment the immune system's response to cancer or to boost the effectiveness of chemotherapeutic agents.

Although disease has always been part of life, certain behaviors and activities associated with the modern world present numerous new health challenges. For example, greater use of modern transportation can rapidly spread infectious disease, unhealthy diets can led to osteoporosis and other diet-related diseases, and smoking can result in cancer and heart disease. A greater understanding of the behavioral factors and related activities underlying many conditions may lead to more effective methods of intervention and prevention.

Acquired immunodeficiency syndrome (AIDS) is now the leading cause of death among Americans aged 25-44. As of June 1995, more than 500,000 cases of AIDS had been reported in the United States. It is estimated that over 20 million people world wide might be infected with the human immunodeficiency virus (HIV). Researchers must answer some very basic questions about how the virus behaves within the context of the human immune system before they can hope to design effective therapeutic and protective measures.
HIV infection is so different from the majority of infectious diseases that scientists must develop innovative and diverse approaches to learning how the virus functions and how the body responds to it. In most cases of infection, the immune system recognizes that a microorganism has invaded or damaged body cells and quickly destroys the intruder. In the case of HIV, however, the target of the virus is a type of cell known as CD4; a part of the immune system itself. CD4 cells are named for a protein receptor on the cell surface which is used by HIV to bind to the cell. Researchers have recently confirmed that the CD4 receptor is not sufficient for the virus to fuse with and infect the immune cells. NIH-supported scientists and others have recently discovered two cell surface proteins, fusin and CCR5, that act as "cofactors," or coreceptors, with CD4 that assist HIV in binding to and infecting immune cells.
These discoveries are important for developing new anti-HIV drugs to block or interfere with the binding of HIV to the receptors. At the same time, they may also explain why some people are seemingly immune to HIV, despite repeated exposure. Scientists have determined that two such individuals had inherited defective genes for a fusion cofactor; in effect, the defect was a lifesaver. HIV was unable to gain entry into the immune system because the cells lacked the needed receptor protein.
NIH-supported basic biomedical research on HIV has allowed researchers to elucidate the viral life cycle and identify three specific enzymes critical to HIV replication. One of these critical enzymes is HIV protease. This enzyme is involved late in the HIV replication process at the stage of viral particle formation, release, and maturation.
X-ray crystallography and structure-based drug design programs have been used to determine both the structure of HIV protease and other molecules that might inhibit its activity. Preventing viral replication would potentially stop the spread of infection from HIV-infected cells to uninfected cells, ultimately halting disease progression in the patient. HIV protease inhibitors are achieving dramatic results in some AIDS patients.

Alzheimer's disease (AD) already affects four million Americans and that number will increase dramatically as the baby boomers reach the age of highest risk. NIH scientists have identified four genes that play a role in this devastating illness. Defects in either of two of these genes, PS1 and PS2, may be responsible for up to 80 percent of a subtype of AD that strikes before age 65. Recent progress in the field of protein structural biology is being applied to better understand neurodegeneration and other diseases of the aging nervous system, including AD. Sophisticated imaging technologies are being used to develop structural maps and to visualize molecular interactions in the aging brain. Understanding the functional consequences of changes in the 3-D structure of brain proteins has the potential to identify new treatments for AD and other neurodegenerative disorders.

It is obvious that preventing disease is preferable to treating it after it occurs. Disease and disability prevention offer the patient and the community-at-large better quality of life and the economic benefits attendant to higher productivity. Ideally, prevention measures also incur lower health care costs, as in the case of vaccines. Some prevention measures, such as education, may be more costly or involve greater effort, but the scales are tipped in their favor in terms of societal benefits. For these reasons, prevention research is a high priority and spans the full range of biomedical and behavioral research. The latest technologies, such as protein engineering and recombinant vaccine development as well as social and behavioral sciences, are being put to good use in erecting effective barriers against disease and disability.
Rising health care costs increase the importance of research to prevent disease and minimize the impact of illness and injury. New preventive strategies against disease involve investigations of emerging infections, as well as the prevention and treatment of drug and alcohol abuse. Vaccines against cancer and infectious diseases such as HIV, otitis media (earaches), herpes, chicken pox, pneumococcus, Shigella and Salmonella, are being studied. Prevention also entails the behavioral, genetic, and environmental aspects of risk assessment. The control of transmission of infectious disease by, for example, microbicide or behavioral changes, is an important aspect of prevention research. Prevention research across all stages of life includes reducing and early diagnosis of osteoporosis. In addition, bionutrition, including the genetic basis of eating disorders and pathological consequences of particular diets, has become an important area for study in prevention of disease.

To ward off pathogenic microbes, we are critically dependent on research to identify infectious diseases and to provide improved drugs and new vaccines. Both basic and clinical research are key, as the speed with which we develop the new antibiotics, new vaccines, and effective treatments will depend upon our understanding of the human immune system and the ever-growing number of pathogens that threaten human health. Research must also focus on the relationships and linkages among disease and climate, eco logical change, population growth, and human behavior.
Since Vice President Gore announced the President's policy directive on emerging infectious diseases (EID) in July 1996 (see vignette on Combating Ebola Hemorrhagic Fever, Chapter 3), the National Science and Technology Council launched a number of new research initiatives. To expand EID research, for example, NIH has funded ten internati onal EID training awards and provided funding to expand four ongoing research and training efforts related to EIDs. The VA and DOD are investing jointly in research on emerging pathogens. NASA is supporting an NIH effort to study emerging viral diseases u sing remote sensing, and the Centers for Disease Control and Prevention are cooperating with NIH on epidemiologic surveys. NIH also has initiated long-term programs to study hepatitis C, hantavirus, the infectious origins of gastric ulcers, and Lyme disea se. NIH and DOD are cooperating on the synthesis and testing of a new drug against the Ebola virus.

New recombinant DNA tools, advanced gene transfer techniques, and monoclonal antibody production are greatly improving public vaccination efforts. Vaccines now in development will provide greater protection for our nation's children against a wide range o f infections and will lead to reduced disease and lower health care costs. For example, development of a vaccine against otitis media is under way. Such a vaccine would benefit millions of American children who suffer from this often chronic disease, whic h is responsible for more than $3.5 billion worth of visits to doctors' offices, clinics, and emergency rooms annually.

p.99.JPGVaccines are our strongest form of preventive medicine. Scientists supported by the National Institutes of Health have develope d new vaccines for pertussis, rotavirus, and Hemophilus influenzae type b. The latter vaccine provides the means to completely eliminate this disease from the United States in the next few years.

In response to a comprehensive evaluation of the NIH AIDS research program, NIH has established an AIDS Vaccine Research C ommittee, a highly distinguished group of outside advisors in immunology, virology, and vaccinology. The committee, chaired by Nobel Laureate David Baltimore, will address key scientific questions in vaccine development, including new vaccine designs, eff orts to understand the mechanisms of protection in animal models, and potential new targets for vaccines.

Rotavirus Vaccine - NIH intramural scientists recently developed and patented the first vaccine against rotavirus, the cause of infections that annually result in an estimated 130 million cases of diarrhea in infants and children. Moderate to sever e dehydration occurs in 18 million of these episodes, and more than 870,000 children world-wide die as a consequence. In the United States alone, rotaviral infections incur costs of $500 million annually in doctor visits and hospitalizations. The new vacc ine protects against four different strains of human rotavirus. Clinical trials have shown the vaccine to safely achieve significant reductions in the incidence of rotavirus diarrhea. It is 80 percent protective against severe rotaviral disease and comple tely effective in preventing dehydrating illness. Routine childhood vaccination against rotavirus could quickly alleviate this major public health problem.

Hemophilus influenzae type b Vaccine - The vaccine against Hemophilus influenzae type b (Hib) meningitis provides t he means to completely eliminate this disease from the United States within the next few years. For years, this disease had devastated our children, affecting 15 to 20 thousand of them each year, almost as many as polio at its peak. Hib killed 10 percent a nd left one third deaf and another one third mentally retarded, making it this country's leading cause of acquired mental retardation. Fortunately, two NIH scientists were instrumental in developing a safe and effective vaccine which, together with three other licensed Hib vaccines, has reduced the incidence of Hib by 95 percent since their use began in 1988. With greater use across the country, we have the hope of completely eliminating Hib meningitis.

PREVENTING DISABILITY AMONG OLDER AMERICANS

Preventive health care for older Americans has a high payoff. More than $108 billion is spent annually on long-term care for the elderly in the United States. Researchers are studying risk factors for disability, improving screening processes to identify at-risk populations, and designing and evaluating interventions specifically targeted to at-risk individuals. The research is paying off:

• Three short tests of physical performance abilities can strongly predict the occurrence of disability as much as four years in advance.
• Older persons with three selected risk factors - such as mental impairment, low physical activity, and foot problems - are nearly 8-fold more likely to be involved in automobile accidents or traffic violations compared to those with no risk factors.
• Research showed a 44 percent reduction in serious falls among older persons through the use of interventions focused on physical risk factors, such as bone fragility, muscle weakness, use of sedatives or multiple medications, and balance and walking p roblems.
• Elderly patients who were cared for in a special hospital unit that focused on rehabilitation, prevention of disability, and preparation for the patient's return to home were significantly more able to perform basic activities of daily living and less likely to need institutionalized long-term care than individuals who received standard hospital care. This was accomplished without increasing in-hospital or post-discharge costs.

Genetic medicine is the application of DNA technologies to the diagnosis, treatment, and prevention of disease. It also includes analysis of complex diseases such as diabetes and assessment of genetic risk. The mapping and sequencing of entire genomes (hu man, as well as yeast, worm, fruit fly, and mouse) are critical components of genetic medicine. The technological tools developed in recent years - mapping techniques, various methods for sequencing the genome, and others - have accelerated the discovery of human disease genes and are now widely used by researchers. For example, obesity genes, genes for aging, neurological disease genes, and cancer genes, such as BRCA-1 and 2, are being identified and characterized. Once the consequences of altered genes are understood, rational therapies may be able to be designed. Gene therapy to replace missing or defective genes, is one such approach that is under investigation. It has proven difficult to insert genes that operate properly and produce adequate protein products.
Most complicated diseases of modern life - cancer, heart disease, diabetes, arthritis, and a host of neuropsychiatric disorders - seem to result from the activities of several genes and the interact ions between the human body and its environment. The direct causes of these disorders have been difficult to discover. Research at the NIH Center for Inherited Disease Research wi ll specialize in applying computer-based technology and robotics to conduct large-scale, rapid genetic analysis of these diseases, leading to the identification of the genes involved. Developments are currently under way to enable simultaneous analysis of thousands of DNA strands on a single silicon chip. These micro-machines greatly speed up research and lower its cost.

December 1996 marked the twenty-fifth anniversary of the war on cancer. Since 1971, scientists have discovered the causes of many cancers and have proven that cancer can be cured. Today, more than ten million of our family members, friends, neighbors and coworkers owe their lives to cancer research. Cancer survivors are alive today and enjoy a better quality of life because the years of research in prevention, diagnosis, and treatment methods have given doctors better information and more accurate tools. America's youth have received the greatest benefit from this country's investment in cancer research. For example, most cases of childhood leukemia are now curable. Death rates from children's cancers have declined by more than 62 percent. Cancer research has also brought about dramatic improvements in the survival rates for adults. The death rate for testicular cancer, for example, has declined 66 percent and five-year survival is now 95 percent. Today, most Hodgkin's disease patients can be cured.
Gene-based therapies are one class of exciting new approaches under investigation in cancer treatment. These methods are designed to augment the immune system's response to cancer or to boost the ef fectiveness of chemotherapeutic agents. They may involve administration of genes for immune factors, either in the patient or in cells taken from the patient and then returned. Another method is to give the patient genes that will increase the tumor's sen sitivity to an anticancer drug, thus reducing harmful side effects on normal cells. Yet another technique involves the use of drug-resistance genes that protect the vulnerable bone marrow from highly toxic chemotherapy. Important goals for the future incl ude the development of better viral vectors for delivering genes to their intended target cells and regulating production of the introduced genes' protein products.
A new project of the National Cancer Institute (NCI) provides another exciting example of the application of this technology to the u nderstanding of disease. The Cancer Genome Anatomy Project seeks to define all the genes that play a critical role in the development of cancer. The project will d evelop high volume, cost effective technologies to analyze the molecular mechanics of cancer cells and put those technologies in the hands of clinical researchers. Coupling these technologies with clinical investigation will provide a better understanding of the basis of disease, as well its detection, diagnosis, prognosis, development of treatments, and selection of therapy.

OBESITY

In the United States, obesity is second only to tobacco as a risk factor for disease and accounts for about 300,000 deaths per year and an economic cost of $50-$100 billion. Obese individuals suffer increased risk for numerous chronic diseases, such as di abetes mellitus, cardiovascular disease, hypertension, gallbladder disease, and certain cancers. Fortunately, opportunities to attack obesity at the molecular level have multiplied. NIH-supported scientists have made important new discoveries regarding th e obese (ob) gene, its protein product (leptin), its receptors, and its interactions with other regulators of energy expenditure and food intake.
This year, the diabetes (db) genetic mutation in the mouse and the fatty (fa) mutation in the rat (which cause diabetes in these animals) have been shown to be mutations of the leptin receptor gene. This is crucial evidence of the link between diabetes and obesity.
Although it appears unlikely that leptin deficiency causes obesity in most humans, the discovery of leptin and its receptor has already deepened our understanding of metabolism, and will continue to lead to fundamental research in the relationship between food intake, energy expenditure, and the regulation of body weight.

As we are past the midway point in the Decade of the Brain, it is appropriate to highlight research and progress in the neurosciences. This discipline recently joined other areas in reaping the benefits of modern biology by coming one step closer to deciphering the molecular basis of memory and behavior. Two NIH-funded groups, using different but related genetic techniques, reported advances in understanding how mice create a mental map of a new environment. Using sophisticated monitoring equipment, researchers are able to detect activity in individual brain cells as the mice investigate their surroundings. From these data, a map of the cells responsible for forming memory about spac e and time can be constructed. This work illustrates the interdisciplinary nature of neurobiology, marrying genetics with electronics to analyze cellular and biochemical processes as they occur in living organisms.
The biology of brain disorders encompasses studies of the basic biology, chemistry, and anatomy of the brain, including the physiology of the neuron, its receptors and the neurotransmitters that are responsible for relaying messages between cells. This area of research extends studies that seek to understand the development of the normal brain and the changes in development which may underlie brain disorders. The research employs animal models, neur o-imaging, and clinical studies in an effort to understand many disorders, such as pain, addiction, mental illness, neurodevelopmental disorders of children, neurodegenerative disease, diseases of the aging brain, and damage to the sensory system.
New or expanded NIH-supported research programs within this area include studies on the development of the nervous system, which have implications for the ability of the adult brain to repair and re organize itself following injury from stroke, trauma, or degenerative processes such as Parkinson's disease; and studies related to spinal cord injury and neuroregeneration. Studies related to Alzheimer's disease in addition to those in genetics will focu s on:

• different aspects of the theory that components of the amyloid plaques that characterize AD trigger an inflammatory immune response that is the actual cause of neurodegeneration;
• different approaches to determine whether proteins known as kinases, which have an important role in normal cell function, also contribute to the formation of the abnormal protein filaments and plaques seen in Alzheimer's; and
• understanding of the process by which amyloid is deposited in brain blood vessels, as a part of AD or the normal aging process.

ACADEMIC HEALTH CENTERS AND THE
CHANGING HEALTH CARE ENVIRONMENT

Academic health centers (AHCs), medical schools, affiliated hospitals, and schools of allied health professions are the principal places in the United States for combining medical t echnological development, basic and clinical biomedical research, and clinical education. In AHCs, education, research, and patient care are inextricably intertwined; patients are able to receive innovative medical care using the most modern techniques an d can participate in research activities, and medical education is conducted. AHCs also provide a disproportionately large share of this country's care of the indigent and uninsured.
System-wide changes in the financing and delivery of health care are having substantial effects on basic and clinical research and medical education in AHCs. Patient care costs historically have bee n higher at AHCs because of the added research and education missions. Yet, the latter are clearly an important and broadly distributed public good for the future of quality health care in this country. The marketplace changes are raising important issues with respect to the ability of AHCs to attract the patient base needed to support their research and education missions:

• A decrease in the ability of AHCs to attract research subjects would affect the rate at which new treatments are developed, tested, and applied.
• A decrease in the ability of AHCs to subsidize research and teaching costs would have a negative impact on the nation's research infrastructure and on the training of the next generation of researchers and clinicians.

In November 1995, the President's Committee of Advisors on Science and Technology wrote to the President relaying their con cerns about the future vitality of our AHCs. The research and educational capacity of our AHCs will continue to be a factor in the Administration's efforts to improve our health care system. It is important to continue to evaluate data to determine what i mpact recent changes in the health care system are having on AHCs.

There is a direct link between our health and the food we eat. Poor diet is a significant underlying contributor to illnesses that lead to death. In addition to the critical relationship between diet and health, it is estimated that each year millions of individuals become ill and that thousands of people die from eating food contaminated with microbial pathogens such as Salmonella and E. coli O157:H7. Research supported by the federal government in the area of diet and nutrition and foo d safety has greatly improved the overall health of our nation's citizens. However, additional research is needed to guide efforts to improve the diets of Americans and to ensure that our food supply is free from harmful pathogenic microorganisms.

Nutrition plays a pivotal role in optimizing health and productivity, while reducing the risk of diet-related diseases. The annual cost in the United States of treatment and care for individuals with diseases linked strongly to diet, such as cardiovascula r disease, obesity, osteoporosis, and cataracts, exceeds $200 billion. Fortunately, over the last half of this century, we have witnessed remarkable improvements in the dietary patterns of the U.S. population and those of several other western industriali zed nations. Most notably these changes have brought about a decline in deaths from coronary heart disease, the leading cause of death in the United States. However, poor diet continues to be a leading contributing factor to numerous illnesses.
We still have much to learn about the prevention or management of diet-related diseases. In particular, we need to develop a better understanding of nutrient-gene interactions so that we can produce healthier food and better detect and prevent nutrition-related disease. An expanded human nutrition knowledge base will lower health care costs and raise the effectiveness of federal food assistance programs, such as food stamps. Since the causes of maln utrition and nutrition-related disease within the United States are complex, it is important that nutrition-related research include a multidisciplinary perspective.
The development of science-based programs that promote healthier eating habits will remain a high priority for the Administration. One such effort, based on a three-year trial involving 96 elementar y schools in four states, has shown that children can be taught behaviors that may protect them against heart disease. Schools successfully lowered the fat content of school lunches, and physical education instructors increased the amount of vigorous exer cise. Students reported lower daily caloric intake from fat at home. This program worked equally well among ethnically diverse populations and represents a cost-effective, easily implemented program that can have profound positive effects on children's ea ting habits and activity levels.

FOOD SAFETY

The Centers for Disease Control and Prevention estimate that as many as 6.5 million cases of food-borne illnesses occur annually in the United States, and that these illnesses contribute to appr oximately 9,000 deaths. USDA's Economic Research Service estimates that the annual overall economic impact of food-borne illnesses in this country is $6 - 9 billion. The safety of the wide v ariety of food we consume each day starts with its production on farms, ranches, ponds, lakes, and oceans, and ends at the table. Further research into food production, harvesting, and handling practices that will reduce human exposure to microbial pathog ens, chemicals, and biotoxins - as well as into improved methods to detect and survey these hazards - can eliminate or significantly reduce an important cause of illness in the United States.
Enhancing our strong research program in food safety will further ensure public health and safety and reduce the prevalence of food-borne diseases. However, we also need a system that integrates pre vention, detection, and intervention throughout the food production cycle, making use of technological advances in food processing and packaging, and pest control. Such a research program will build the scientific foundation for sound food safety regulati on and policy, spur innovation in food safety and production, and help educate consumers to improve their food safety practices and increase their understanding of the relative risks and benefits.
Scientists are developing new ways to reduce the microbial contamination of food products. Hazard Analysis and Critical Control Point (HACCP) systems are one such approach. HACCP is based on the premise that for overall reduction of microbial pathogen contamination of food, it is better to reduce the level of pathogen contamination at key points in the food production , slaughter, and processing pathways rather than to simply inspect the finished processed product. The Administration has established over the last two years new regulations that require the implementation of HACCP principles for meat, poultry, fish, and shellfish. Research and disease surveillance are needed to guide the implementation of HACCP. In particular, research must be conducted that generates data needed to conduct quantitative risk assessments.
The Departments of Agriculture, Health and Human Services, and the Environmental Protection Agency have begun a comprehensive food safety initiative which will provide an integrated federal strategy to help ensure the microbiological safety of our nation's food supply. Key elements to this initiative are improved research, surveillance, risk assessment, and education, all done in full cooperation with state governments and the private sector.

Agricultural productivity in the United States has grown dramatically at a rate of nearly 2 percent per year. Production has more than doubled since 1950 while total input use (use of energy, water, fertilizers, etc.) has actually fallen slightly over thi s same period. However, due to the new economic, environmental, and health demands being placed on our food and fiber production systems, we need to reassess our science and technology investments in agricultural research. Maintaining and enhancing rates of growth in food and fiber productivity in this new environment will be the major science and technology challenge for agricultural and natural resource scientists in the twenty first century.
Global food security remains a challenge for the next century. Significant uncertainties, however, remain in projections of future world food requirements and the ability of poor countries to achiev e sustainable economic and agricultural development. Scientific and technical advances that improve agricultural productivity can help combat the human and social deterioration associated with hunger and poverty. In addition to traditional aid programs, U .S. support for international agricultural research centers helps build the research infrastructure in many regions of the world with persistent food production problems. U.S. land grant universities train significant numbers of agricultural scientists fr om the developing world, who in turn contribute to their national research programs. Working with other nations to develop the scientific tools and infrastructure they need to provide for the nutritional needs of their own people, the United States can he lp alleviate the pain of hunger that afflicts 800 million people daily.

Our nation's farms, rangelands, forests, and coastal waters must be managed in a fashion that allows for their long-term, sustainable use for production purposes while preserving other vital functions, such as habitat for wildlife, watershed protection, a nd recreation. To achieve sustainable production practices, we should view our farms and forests as integrated systems with a variety of inputs and outputs. Scientific knowledge, generated through research, has been and will continue to be the most import ant factor in any sustainable production system. Greater scientific understanding of the inter-relatedness of the multiple components of our nation's food and fiber production systems, ranging from geochemical and biological to social and economic interac tions, will help farmers and natural resource managers understand what is necessary to maintain or restore the economic, social, and natural attributes of the system.
An excellent example of an integrated approach to natural resource management is the USDA Forest Service's Wine Spring Basin demonstrat ion project in North Carolina's Nantahala National Forest. It encompasses about 4,500 acres and contains a mix of hardwood forest types, streams with native brook trout, and old growth timber stands. The purpose of the project is to develop, test, and dem onstrate ecologically based concepts and technologies to restore the native mixed pine forest, its diverse understory, and stream habitats, as well as to achieve a sustainable forest community. Early project development has centered on reintroduction of f ire under prescribed conditions, testing improved regeneration techniques for oak forest, restoring stream habitats with addition of woody debris, and a socioeconomic assessment of public attitudes and values.
Our coastal waters are as productive as the richest American farmland. Significant strides have been made in restoring the living marine resource habitat value to areas that have been degraded throu gh catastrophic events such as oil spills or ship groundings, or as a result of cumulative human activities, such as water diversions or land use changes. Projects eventually benefiting upwards of 48,000 acres of coastal wetlands were initiated or under w ay by the end of 1996. As part of the efforts to recover Pacific salmon populations, removal of barriers to fish migration and restoration of historic spawning streams have been undertaken, in many cases by members of the fishing industry displaced as a r esult of reduced harvest levels due to habitat losses and other factors. These restorations generally represented partnerships among Federal, state, and local governments, tribes, industry, and non-governmental organizations.

Reducing negative impacts on the environment or even improving its overall health is now a major consideration for American food and fiber producers. This is a significant shift from our traditional approach to farming and forestry in past decades. Since the end of World War II, farming was geared toward optimizing production using chemical pesticides and fertilizers or through management techniques that may have solved one problem but often created other, more serious ones. Excessive tillage to control w eeds, for example, often led to unacceptable rates of erosion of valuable topsoil. Forestry was practiced in many cases with little regard for endangered species or the water quality of streams and rivers. Today we are investing in science and technology to produce more from our food and fiber production systems while protecting our environment.

Tillage and Global Change: Keeping organic matter tucked away in soil - where it is needed most for agricultural productivity - benefits the earth and the atmosphere. As organic matter is plowed up, carbon dioxide loss from the soil into the air dr amatically increases. Measurements of a range of soil types, tillage methods, and climatic conditions indicate that deep plowing results in a much greater loss of carbon dioxide than all other forms of tillage. Such information is vital in quantifying the effects of tillage on soil quality and productivity and provides data for validating agriculture's role in global warming. These findings offer agricultural producers a way to help counteract global change by altering their cultivation practices.

Water Quality - Water pollution from agricultural chemicals must also be prevented. Combining wetlands, ponds, and underground irrigation could result in water conservation and bigger yields for farmers. USDA scientists built such a system in Ohio to demonstrate the benefits of recycling runoff and drainage water from fields. It reduces sediment and agricultural chemical flow to streams, improves water quality, enhances wildlife habitat, increases wetland acreage, and improves crop yields. The wetl ands remove sediment and agricultural chemicals from field runoff. The water is then stored in a pond until it is needed to irrigate a field. Finally, it is pumped back through underground pipes to reduce water stress in crops. The overall result is that less pesticide and fertilizer runs off into surface waters.

p.109.JPGProtecting surface and ground water from contamination by agricultural activities requires knowledge of land use, soil proper ties and hydrogeology as exemplified by the Mahantango Creek watershed near Klingerstown, Pennsylvania.

New biotechnology-derived crops also have the capability to improve management practices. For example, plants are being developed that require fewer applications of pesticides, that require less til lage (therefore reducing soil erosion), and that require less irrigation. While new genetic traits and the use of genetically engineered crops may be environmentally beneficial in many circumstances, a continuing strong research program is important to id entify and minimize any potential long-term negative impact this technology may have on the environment.

Recent trade agreements such as GATT and NAFTA are creating significant opportunities to ex pand international markets for U.S. agricultural products. However, with the increased trade liberalization, U.S. agriculture faces a transition away from a system of commodity price supports to market-driven pricing. To succeed in this new environment, U .S. farmers will have to rely on the latest information and newest technology. Economic research also is needed to support decision-making at multiple levels from what to plant on the family farm to negotiations of international trade agreements.
Where are the most promising growth markets for U.S. agricultural products? Will developing countries achieve sustainable agricultural practices or economic development that allows them to participa te in world trade markets? Or will they stumble, fostering conditions for hunger, malnutrition, and political unrest? How can we overcome unfair trade barriers to U.S. agricultural products? These questions must be addressed if agriculture and its related activities are to continue to be major contributors to our nation's economy. Only through scientific and technological advances, coupled with sound economic decision-making, can our nation's farmers successfully compete in global markets.
USDA has developed new models to aid in assessing complex trade interactions. These models effectively measure and evaluate tariff barriers to trade and estimate the economic consequences of freer t rade for U.S. agricultural producers and consumers. This allows economists to identify such key growth markets for U.S. agriculture as China, Korea, Indonesia, Mexico, and Saudi Arabia. Further, USDA research shows that growth in demand for U.S. exports i s likely to be greater for high-valued products, such as processed foods and meats, than for bulk commodities. Such analysis not only identifies opportunities for U.S. agricultural exporters, but provides forward-looking information that can smooth out wo rld prices when unexpected events disrupt world markets.

Animal diseases cost the United States billions of dollars each year, which is why the USDA supports research addressing the health concerns of important livestock, poultry, and aquatic species. Much of the research conducted by the biomedical programs of the NIH, DOD, and VA is directly relevant to improving animal health. New vaccines, drugs, and other approaches to disease prevention need to be continuously added to the veterinarian's disease fighting arsenal.
Production practices that result in healthy food animals not only improve agricultural profitability and the well-being of the animals, but also improve human health. Animal pathogens may play a lar ger role in human health than previously thought. Some human health concerns, such as E. coli O157:H7 or Salmonella infection, can be drastically reduced through improved animal health. Recent data indicate a degenerative disease of the human nervous syst em may have been transmitted from cattle infected with bovine spongiform encephalopathy (BSE), also known as "mad cow disease." Unknown in the United States, it has had a devastating effect on the British beef industry. USDA scientists have developed a new test for the prion protein believed by some to be linked to BSE. This test may be a promising tool to test live animals for the presence of scrapie (a related disease of sheep) or BSE. Scientists at the National Institute of Neurological Disorders and Stroke have also developed an assay for transmissible spongiform encephalopathies for use in humans an d non-human mammals. Ensuring the safety of the American beef supply will help keep U.S. agriculture competitive in world markets.

Farmers generally lose 10 to 30 percent of their crops to pests, costing them nearly a third of their production. In addition to existing pests, farmers are continually challenged by new pests such as the Karnal bunt fungus, new races of the fungus causin g potato late blight, sweet potato whitefly with associated gemini viruses, and the brown citrus aphid with the associated citrus tristeza virus. These and other pests not only reduce profitability but often threaten export markets. The sweet potato white fly has become a devastating pest of cotton, vegetables, melons and ornamentals in the United States, causing an estimated $500 million in crop losses annually in this country. In Imperial County, California, alone, crop losses to sweet potato whitefly ha ve been estimated at $100 million. USDA scientists have teamed with USDA's Animal and Plant Health Inspection Service, Texas A&M University, and private industry to develop an EPA-approve d fungal pathogen that kills up to 90 percent of whiteflies in vegetables and melons. Large-scale cooperative field tests have begun to refine pest management strategies that use the pathogen in conjunction with other biological controls. The fungal patho gen reduces producers' dependence on chemical pesticides and contributes to USDA's target of 75 percent of U.S. agricultural acreage being under integrated pest management (IPM) practice s by the year 2000.

p.110.JPGUsing science and technology to control pests is one goal of the Department of Agriculture's integrated pest management research. The brown citrus aphid is just one example of a new pest that is threatening U.S. agricultural production.

The goal of USDA's IPM research is to reduce the use of synthetic pesticides by placing greater emphasis on natural controls, host resistance, cultural practices, biological controls, and biopestici des. The aim is to produce high-quality food and agricultural products, while maintaining farmers' profitability and protecting human health and the environment. Research at Texas A&M University has saved the economy $1.5 billion per year and spared the e nvironment from 17.3 million pounds of insecticides alone. At the same time, 20,000 new jobs in Texas are associated with IPM. One IPM program in the Rio Grande Valley for carrots destined for baby food, soup, and frozen foods reduced insecticide use by 6 6 percent while increasing individual farmer profits by $22,000.
More than 40,000 farmers have significantly reduced their use of chemical pesticides on row crops, fruits, and vegetables. USDA scientists, working with their counterparts in the Land Grant universi ty system, have provided farmers with science-based information on new pest management practices that meet agricultural production, human health, and environmental goals. Fortunately, recent scientific advances, such as in molecular biology and computer s cience, hold great promise for further improvements in approaches to pest management. Where effective tactics have been developed, they are widely and rapidly implemented by farmers. IPM methods are used on about half of all fruit and nut, vegetable, and major field crop acreage in the United States.

IPM in Oregon has been proven to reduce greatly the amount of pesticides applied to crops. Twenty thousand acres of Oregon apples have gone from a maximum of three miticide applications per year to less than one under IPM. Each application costs gr owers $3 per acre. Determining the pest status on a regular basis of 6,000 acres of pears in southern Oregon has helped eliminate 18 pounds of active pesticide ingredient per acre for a savings of more than $600,000 per year. An Oregon mint IPM program ad ds $500,000 to the value of the crop, since processors will not buy peppermint oil with pesticide residues.

GENETIC RESOURCES

Over a century of genetics research and breeding has led to many successful improvements in plants and animals. Virtually every foodstuff and many forest species have benefited from such improvements. Recent developments in genetic manipulation and the ra pid mapping of genes are opening new possibilities, from improved disease resistance, to better taste, to longer shelf life. Access to genetic resources, such as gene sequencing and mapping data, and genetic material, such as cloned genes, novel strains, wild relatives and other plant, animal and microbial germplasm, are vital to the future health of American agriculture and forestry. The development of economically, environmentally, and nutritionally important traits will be possible only if the scientif ic community has ready access to needed genetic resources.
The majority of agriculturally important species produced in the United States did not originate in North America. Therefore, we need to continue to rely on other countries for valuable germplasm, w hich underpins our nation's crop and livestock improvement efforts. We must preserve the incredibly diverse gene pool of all plants and animals now in existence, or we risk missing important future opportunities for progress. Preservation of existing gene tic diversity is integral to improving our crops and livestock. Future work in germplasm preservation and maintenance must focus on improving access to existing worldwide collections and identifying gaps that exist in these collections.
A future challenge is to establish international agreements that ensure access to genetic resources. For example, potato germplasm maintained in one country should be accessible to the global resear ch community so that new traits, such as resistance to the fungus that causes late blight, can be incorporated into potato cultivars in areas threatened by this pathogen. Although countries have rights over genetic resources within their borders, the Admi nistration believes that open access to such resources is important to improve agricultural species critical to global food security.
Research leading to improved storage and regeneration of germplasm in a manner that ensures its genetic integrity is of paramount importance. We must also continue to develop appropriate databases t hat document germplasm availability, quality, and traits. To enhance germplasm traits that contribute to improved productivity and environmental sustainability, we should encourage multidisciplinary research approaches that combine the traditional tools o f breeding and selection with the new tools of molecular genetics. The public and private sectors need to collaborate on research, development, and technology transfer to ensure an adequate flow of improved germplasm for major food and fiber species.
The genetic base of some important food species is dangerously narrow. This is particularly true of fish and shellfish stocks used in aquaculture farming, including catfish, shrimp, oysters, and sal monids. For example, the ancestry of most of the farmed catfish stocks in the southern United States can be traced to a single source of fish in Oklahoma. This greatly increases the chance of susceptibility to new or reemerging diseases and limits the pos sibility of genetic improvements through breeding.

In 1995, the National Plant Germplasm System, under the auspices of USDA's Agricultural Research Service, distributed approximately 120,000 samples of seed and clonal germplasm to both U.S. (85,000 samples) and foreign (35,000 samples) requestors.

GENOMICS

Gene maps are powerful tools with which to genetically improve plants, livestock, and other beneficial organisms. Such maps and their associated DNA markers are useful for improving the accuracy of selection of desirable new genotypes, moving new genes in to populations, and characterizing potentially valuable germplasm populations. USDA scientists, working in collaboration with researchers from State Agricultural Experiment Stations, have produced genetic maps of important animals (cattle, swine, sheep, a nd poultry) and plants (corn, soybean, loblolly pine, wheat and others), which can be accessed electronically.
In general, the quality of these maps must be improved before their full potential can be brought to bear on new crop and breed development. The focus of USDA research in the area of animal genome m apping for the next five years will be on the development of markers for use in selection schemes for each of the livestock species. For plant gene mapping efforts, continued work is needed on improving the resolution of various maps and on the isolation of genes that confer desirable traits. In addition, considerable effort needs to be given to database development and the development of libraries of large genome fragments to facilitate gene identification and isolation.
Intellectual property rights associated with genetic resources need to be addressed. While promoting technology transfer and application in major crops, such as corn and wheat, patenting genetic res ources and methods of genetic modification may actually impede the commercialization of biotechnology-derived minor crops, such as vegetables. Companies holding patents on enabling biotechnologies and genes may not be inclined to issue licenses for minor uses. We need to ensure that breeders of minor crops have access to the genetic resources and techniques needed to maintain the competitiveness of the minor crops industry.

The livestock gene maps developed at the U.S. Meat Animal Research Center in Clay Center Nebraska, have over 1,300 markers for cattle, 1,100 for swine, and 500 for sheep. The poultr y map developed in cooperation with Michigan State University has over 600 markers, and is being integrated with the United Kingdom's poultry map.

USDA is supporting research, through the National Research Initiative and the Agricultural Research Service, o n gene mapping, identification, and characterization of over 40 crop species.

INVESTING IN A BALANCED
AGRICULTURAL RESEARCH PORTFOLIO

Agricultural research supported by the federal government requires a balanced science and technology portfolio that encompasses a broad range of activities from fundamental to applied and developmental research. Private sector research spending in agricul ture has grown more rapidly than that of the public sector and now accounts for more than the combined level of federal and state funding. While private sector research spending has taken over an increasing share of the developmental research (that portio n of research that promises adequate economic returns to investors), the opportunities for developmental research and continuing technology advances depend on advances in research funded by the Federal government and primarily conducted by the USDA's Agri cultural Research Service and State Agricultural Experiment Stations.
As in other research areas, the Administration has made a clear commitment to enhancing the quality and accountability of Federally funded agricultural research. Rigorous peer-review, the hallmark o f American science, has been promoted annually by the Administration through the budget-setting process; science programs that are based on merit review with peer evaluation are a priority. The new Fund for Rural America, supported by the President and established in the Federal Agriculture Improvement and Reform Act of 1996, has strong merit-review provisions. Th ese provisions are written into the program's authorizing language and will be implemented through peer evaluation. The National Research Initiative (NRI) utilizes excellent competitive peer-review procedures. Peer review procedures used by other USDA res earch programs (intramural and formula funds) are being assessed to determine how they can be improved.

Increased support for fundamental research programs in molecular and cellular biology, physiology, and ecology has expanded our understanding of fundamental processes such as pathogenesis, genetic disorders, nutrition, photosynthesis, nitrogen fixation, a nd evolution. Better understanding of these and other biological processes leads directly to a more secure and economically competitive food and fiber supply. In addition to basic research in the biological sciences, it is important to recognize the impor tant contributions that research in chemistry, physics, engineering, and social sciences make in agriculture through the development and adoption of new enabling technologies and instrumentation. There is a clear need to maintain our Federal investment in the full range of agriculture-related science and technology activities, but investments in fundamental research are expected to generate the highest yield. Therefore, the Administration will continue to provide strong support for the NRI and other progr ams supporting fundamental agriculture research.

Agricultural problems often are based on specific soil, climate, or production systems that are unique to a particular region of the country. Therefore, much applied agricultural research needs to be conducted at the local or regional level, and funding s hould be based on priorities set regionally or locally. In addition to USDA's geographically dispersed intramural programs, support of applied research has been achieved primarily through state support and through various formula programs where Federal fu nds are distributed directly to State Agricultural Experiment Stations. Although this system of Federal support for applied research has substantially leveraged Federal investments, it has come under growing stress because Federal formula funds have not g rown as fast as research costs and because research funds have declined in some states.
Several steps could be taken, and in some cases are under way, to improve the effectiveness of the current formula-based funding programs. State Agricultural Experiment Stations are downsizing. Down sizing requires careful attention to priorities, with most institutions supporting existing specific areas of excellence. Severe reduction or elimination of programs is forcing institutions to take a more regional approach to addressing the needs of their clientele. Often, they rely on expertise found in a neighboring state. In addition to downsizing, experiment stations are improving their use of formula funds through creative local funding mechanisms. For example, some experiment stations have establish ed competitive peer-reviewed funding programs with their formula funds. Others use these funds to support young investigators or special projects.
As in other research areas, the Administration has made a clear commitment to enhancing the quality and accountability of Federally funded agricultural research. Rigorous peer-review, the hallmark o f American science, has been promoted annually by the Administration through the budget setting process; science programs that are based on merit review with peer evaluation are a priority. The new Fund for Rural America, supported by the President and es tablished in the Federal Agriculture Improvement and Reform Act of 1996, has strong merit-review provisions written into the program's authorizing language, which will be implemented through peer evaluation. The National Research Initiative (NRI) utilizes excellent competitive peer-review procedures. Peer review procedures used by other USDA research programs (intramural and formula funds) are being assessed to determine how they can be improved.

Urea is widely applied as a nitrogen fertilizer because of its cost-effectiveness, ease in handling, and high nitrogen content. However, it is not efficiently used by plants. Most of what is applied to fields is degraded by soilborne microorganisms into volatile ammonia, which is often toxic to plants. USDA's National Research Initiative has supported research on the enzyme responsible for the degradation, urease, to determine how the enzyme works as well as its molecular structure. A better unders tanding of urease sets the stage for developing safe, effective inhibitors of the enzyme to improve the efficient use of urea by plants.

Ethylene is a chemically simple gas that acts as a plant hormone, regulating multiple plant processes ranging from stem elongation to root growth and fruit ripening. Work on the ethylene signal transduction pathway supported by the Department of En ergy's Division of Energy Bio-sciences has led to the first isolation of a plant hormone receptor. These studies show that plants sense this gaseous hormone throug h a combination of proteins that resemble signal transduction pathways previously described in bacteria and yeast. Genetic manipulation of these proteins will provide new tools for modifying plant growth and development for increased crop and biomass prod uctivity.

The Departments of Energy and Agriculture and the National Science Foundation have cooperated to fund the effort to sequence the entire genome of the flowering plant Arabi dopsisthaliana. When completed, this will be the first complete DNA sequence for any flowering plant. Arabidopsis is the leading model organism for the study of genetic traits that relate to plant growth and development and therefore to traits related to crop productivity. The goal is to complete the sequence by the year 2004.

Nearly 60 years after Dorothy left grey Kansas for the vibrant land of Oz, wizards of a different sort have concocted a powerful new way to visualize the full set of human chromosomes in a rainbow of colors. The new technique, called "spectral karyotypin g," translates comptuer-gathered light waves into a full-color palette and assigns each chromosome its own distinct hue. With all 23 pairs of human chromosomes identified by a different color, scientists can more easily examine the entire set of chromoso mes for changes that could lead to a disease, such as missing or extra pieces, or parts from different chromosomes that have swapped places. The technique could prove to be extremely valuable in diagnosis of disease based on chromosomal alterations.
"The value of chromosome examination in understanding the changes that take place during disease progression could be greatly enhanced if we could study the entire genome at once, and clearly distin guish genetic material belonging to one chromosome from that of another," said National Human Genome Research Institute scientist Thomas Ried, who led one of two groups that developed the technique. David Ward led a Yale University team in creating a different method that reachedthe same endpoint in chromosome analysis.

p.100.JPGThis image shows the full complement of 23 pairs of human chromosomes, each painted a different color using the new labeling t echnique called "spectral karyotyping."

The power of the current diagnostic techniques is limited in examining whole chromosome sets, called karyotypes, for changes, because the methods rely on chemical stains that reveal only shades of g ray. Pieces moved from one chromosome to another -a process called "translocation" that is often associated with disease -cannot easily be detected. And in diseased cells containing several badly distorted chromosomes, tracking the multiplication or exc hange of genetic material is often impossible with conventional black-and-white banding.
Chromosome banding ws first developed in the early 1970s, when it was observed that each human chromosome portrayed a characteristic pattern of bands when exposed to chemical stains. This allowed r esearchers to identify and sort out human chromosomes under the microscope not only by their size but also by their characteristic staining patterns.
As staining techniques evolved, scientists used them to link chromosome changes to disease; missing bands indicated a deletion of genetic material, as in some inherited diseases, whereas extra bands , or translocations, indicated altered or additional genetic material, as is the case in many cancers.
Higher-resolution molecular techniques for visualizing chromosome regions, particularly fluorescence in situ hybridization, or FISH, later improved the process. FISH used DNA probes labeled with fluorescent dyes to identify specific chromosomal regions. Spectral karyotyping is a new way to interpret data from FISH experiments and has distinct advantages over conventional micro scopy.

p.101.JPGThis technique highlights broken and rearranged chromosomes in a breast cancer cell line, a method that may lead to early dia gnosis of disease.

Ried and his coworkers applied spectral imaging, a technology used in remote sensing devices, to chromosomes isolated from cells. First, they applied different molecular "paints" to the chromosomes . The wavelengths of light, or emission spectra, emitted by each painted chromosome provided a unique "thumbprint" for that chromosome. Although to the eye, the thumbprints are difficult to distinguish from one chromosome to the next, computers rapidly detect differences in emission spectra and assign each chromosome its own easy-to-see color. In a spectral karyotype from a healthy cell, for example, computers translate the emission spectrum for chromosome 1 into yellow, chromosome 2 red, 3 gray, 4 tur quoise, and so on.
Spectral karyotyping has already been applied successfully to analysis of cells from leukemia patients. Ried collaborated with Janet Rowley from the University of Chicago to locate a predicted chro mosomal abnormality. In the process, several additional translocations were identified. These types of studies will improve scientists' understanding of the genetic basis of cancer and may ultimately assist the development of new methods for cancer trea tment and prevention.
In addition to its role in identifying chromosome changes related to the progression of disease, the authors report that spectral karyotyping may be valuable in comparing genomes from different species to determine how genetic composition evolved over hundreds of thousands of years.

Cancer patients may soon receive dramatically more effective radiation therapy as researchers refine and test a revolutionary new tool for analyzing and planning treatments. The program, known as Peregrine, draws on technologies originally developed by the national laboratories for military applications - and turns them to life-saving use.
Peregrine addresses a straight-forward problem: Doctors have had no accurate means with which to assess how radiation travels through the body. Each year, roughly one third of the 300,000 cancer pat ients doctors hope to cure by radiation therapy die because the radiation failed to kill the original tumor. Improving the success of radiation therapy is exceedingly difficult because without reliable, detailed information showing how radiation is transp orted through tissues of different type and density, such as bone and lung, a physician trying to cure cancer tumors with radiation is like a surgeon operating in a dimly lit theater.
The Peregrine program takes advantage of increases in the speed and performance of computers, sophisticated computational techniques, and comprehensive nuclear and atomic physics databases residing in the national laboratories. It is being developed by scientists at the Lawrence Livermore National Laboratory, in collaboration with colleagues in medical physics and radiation oncology, and is expected to be commercially available within two years. It will provide doctors better information about where radiation is directed in the body, greatly improving the therapy's effectiveness, raising the prospect of saving as many as 100,000 lives each year in the United States alone.
Treatment planning based on Peregrine begins with a computer-aided three-dimensional (CT) scan that provides information about the exact location, composition, and density of the tumor and sensitive organs. These data are subjected to a sophisticated computational technique known as Monte Carlo that calculates the probabilities of random molecular interactions. The method enables doctors to track the path of an x-ray as it moves through the body, in teracting with atoms much as balls in a pinball machine bounce randomly as they encounter obstacles in their path. The result is a detailed three-dimensional model that simulates the physical processes involved in radiation transport.
Current methods of calculation only approximate radiation dose distribution to the patient, which can result in underdosing of the tumor. In the tumor shown here, for example, current methods of cal culation assured the radiation oncologist that the entire tumor would be treated. But Peregrine calculations show that the prescribed radiation targeted only a fraction of the tumor, making the treatment less effective.
Inaccurate dose calculations can have other unintended consequences, causing radiation to be directed where it is not needed, potentially damaging healthy cells. Peregrine will allow clinicians to a dminister more precisely targeted beams of radiation, giving them the confidence they need to treat tumors more aggressively, while minimizing risk to healthy cells.
Monte Carlo techniques have long been recognized as the best way to calculate dose distributions for radiation therapy, but such calculations often took hundreds of hours. Recent advances in computa tional techniques and computer architecture mean dose calculations now take only minutes, not days. Peregrine brings high-speed, highly accurate, and high resolution Monte Carlo treatment planning to desktop computers through simple network connections, m uch like file servers in an office environment. Cost should thus not be a limiting factor for hospitals who want to utilize the new treatment planning approach.
Researchers currently are examining Peregrine's application to a variety of patients and tumor types, including tumors of the lung, head and neck, larynx, and breast. So far, researchers have assess ed how well the method would work using data only from patients who have already completed their radiation treatment. Once cleared by the Food and Drug Administration, physicians will be able to use it for patients preparing to undergo treatment, raising the odds of survival for hundreds of thousands of cancer patients, while reducing harmful side effects.

p.105.JPGCancer patients may soon receive dramatically more effective treatment through Peregrine. This revolutionary new technique is used to target radiation on tumors more precisely than current methods, and raises the odds of survival of the hundreds of thousands of cancer patients treated every year, while reducing harmful side effects. In a planned lung tumor treatment using current techniques, the Peregrine calculation (right panel) shows that the intended dose misses much of the tumor. The Peregrine program will allow more precise planning of radia tion therapy.

In July 1996, President Clinton announced sweeping reform of the nation's food safety rules, for the first time bringing science to the task of meat and poultry inspection. The new sanitation standards and requirements for scientific tests are designed to reveal the presence of deadly bacteria, and to maintain food safety from "farm to table." While previous methods for inspecting meat and poultry were based on how the food looks, feels, or smells, the new methods rely on technology to detect the bacteria E. coli and Salmonella, which are invisible without a microscope. A similar program for seafood inspection was adopted a year earlier.
The heart of the reform is a Hazard Analysis and Critical Control Points, or HACCP (pronounced "hazup"), system. Un like many federal regulations, the new rules do not dictate specific steps industry must take. Instead, packers and slaughterhouses are required to identify points in the process, such as cutting and grinding, where contamination can occur, and then come up with remedies that prevent the contamination. To verify that the preventive steps are effective, slaughterhouses and plants that produce raw, ground meat and poultry are required to meet standards for Salmonella, and also to conduct microbial testing f or generic E. coli (a form of E. coli that is common in the intestinal tracts of food animals). E. coli often indicates fecal contamination, which is the main pathway for contamination of meat and poultry.
The inspection reforms reflect recommendations during the past decade by external bodies including the National Academy of Sciences, the General Accounting Office, and the National Advisory Committee on Microbiological Criteria for Foods. Like many observ ers, they urged modernizing the inspection system to address the growing hazards presented by microbial pathogens. For all our technological advances, the inspection system was virtually unchanged for nearly a century, since muckrakers in the early 1900s exposed filthy conditions in the nation's meat packing plants. In response, the government set up a manual system that relied on the senses of federal inspectors to protect the public from unsafe food.
Over the years, only incremental changes were made. Then, in 1993 tragedy struck people who ate undercooked fast food hamburgers at a restaurant in the western United States. Four children died from the outbreak, and hundreds became ill. The nation's - and the President's - attention was riveted on the threat posed by deadly strains of E. coli, in this case E. coli O157:H7. It was clear that the inspection procedures needed to be r evamped, and government and industry began to work together in earnest to devise an effective system.

p.106.JPGNew scientific technology reforms meat and poultry inspection. Microbial testing will be implemented in the Hazard Analysis and Critical Control Points program that requires the development and implementation of rapid tests to detect microorganisms. The two light areas are a deadly strain of E. c oli O157:H7 among colonies on non-pathogenic strains.

As the changes are phased in over the next few years, industry and scientists will continue to need additional, and more reliable, information, and faster, more accurate test results. Advances in biotechnology promise to provide earlier detection of conta mination. Scientists from the U.S. Department of Agriculture have trimmed the time required to detect disease-causing bacteria on meat from the typical 48 hours to just five minutes. They have also developed tests specifically to detect hemorrhagic E. coli O157:H7 in less than eight hours, compared to the traditional three-day test.
None of this negates personal responsibility for handling raw meat and poultry safely, and for making sure it is well-cooked before it is served. But the progress is real. As President Clinton obser ved in announcing the inspection reforms, "Parents should know that when a teenager borrows the car to get a fast food hamburger, the hamburger should be the least of their worries. Our new food safety initiative will give families the security to know th at the food they eat is as safe as it can be."

• Established focused research initiatives in response to pressing public health needs, including initiatives
  for pediatric research, spinal cord injury, and drug abuse and addiction
• Strengthened communication of medical research results to the public
• Supported the development of advanced instrumentation and computer technologies for research and education
• Published the Surgeon General report, "Preventing Tobacco Use Among Young People"
• Collaborated with industry, through technology transfer agreements, on research into therapeutics and other health care products
• Improved data collection system for family and intimate violence
• Established the NIH Center for Inherited Disease Research
• Proposed guidelines for organ transplantation between species (xenotransplantation)
• Merged research and extension agencies in USDA
• Improved food labeling
• Developed Hazard Analysis and Critical Control Point (HACCP) food safety regulations
• Set new integrated pest management goals
• Established Fund for Rural America
• Streamlined FDA and USDA biotechnology regulations
• Promoted sustainable agriculture
• Integrated competing forestry interests
• Promoted new uses of agricultural commodities

• Identified and isolated many genes involved in important human diseases
• Developed animal models that will facilitate the study of human diseases
• Discovered hepatitis G virus, assessed incidence of transfusion-associated hepatitis G
• Launched human gene map containing 16,354 genes on World Wide Web
• Developed first vaccine against hepatitis A
• Reported that estrogen treatment improves memory in women with Alzheimer's disease
• Identified brain areas involved in drug craving
• Elucidated biological basis for how cigarette smoking causes lung cancer
• Found new insights on the link between obesity and diabetes
• Progress made in understanding HIV infection:
  Immune system factors that suppress HIV replication identified
  Receptors that act as cofactors for HIV-1 infection of immune cells discovered
  Role of CKR5 gene in HIV infection elucidated
• Advances in HIV/AIDS therapies:
  Combination anti-retroviral therapy slows HIV disease progression
  Interleukin-2 reverses immune system damage in HIV-infected patients
  Determination that blood level of HIV genetic material is a reliable predictor of disease prognosis
• Launched sequencing project for the flowering plant Arabidopsis
• Insect pest populations better understood through chaos theory
• Isolated plant disease resistance genes
• Identified chemical responsible for communication between nitrogen-fixing bacteria and roots
• Elucidated ion movement across bacterial membranes
• Unraveled genetics of flower development
• Developed new gene mapping techniques for trees
• Generated new economic models to assist in trade analysis
• Improved animal waste management techniques
• Produced new hybrid catfish for aquaculture
• Developed tests for microbial food pathogens
• Genetically engineered bacteria for ethanol production
• Produced microorganisms to degrade pesticides
• Developed vaccine for important swine disease
• Established biological control for gypsy moths
• Created nutritious food supplements
• Constructed livestock and crop gene maps