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PARTI Recent Progress in Science and Technology Oncogenes How is a normal cell transformed into a cancer cell? How can diverse agents, from chemicals to radiation to viruses, cause that transformation? The answers to these questions require an un- derstanding of the molecular changes that propel a normal cell . . into ma 1gnancy. This understanding has been emerging in the last 10 years from intersecting work in several subfields of biology, among them cellular and molecular biology, pharmacology, and biochemis- try. As a result, key aspects of cancer can now be described in molecular terms: normal genes that control cell growth become slightly modified. These modified genes then encode proteins capable of changing a normal cell into a cancer cell; hence, those genes are called oncogenes. Oncogenes were first discovered through studies of animal cells infected by viruses, including the Rous sarcoma virus that 5

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THE O UTLOOK FOR SCIENCE AND TECHNOLOG Y 1985 causes cancers in chickens. The virus converts certain normal . , . amma1 genes into potent oncogenes. Human oncogenes were discovered by inserting DNA seg- ments from human cancer cells into normal cells in culture. The specific DNA sequences responsible for transforming these recipient cells into cancerous cells human oncogenes are closely related both to normal human genes and to viral oncogenes. Active oncogenes have been demonstrated in a varie- ty of human cancers. Knowledge of the structures of oncogenes, their relation to chromosomal abnormalities seen in malignancies, the proteins they encode, and the intriguing relation of some oncogenes to growth factors observed in hormonal tissue repair has expanded enormously in recent years. However, exactly how oncogenes act, the functions of the proteins they encode, and the nature of their activation by chemical carcinogens, viruses, radiation, and other agents are still unclear. Cancers are diverse; they have neither a single cause nor a single cure. Further, the transformation of normal cells into malignant ones includes many steps. Among them, the activa- tion of oncogenes is an important, perhaps necessary step, but not the only one. While efforts to prevent cancers can be directed against any of these critical stages, the discovery of some 20 human oncogenes has expanded possibilities for the treatment and prevention of cancers. There could be drugs to block the action of oncogene proteins; or immunologic agents, including antibodies, that would recognize and destroy ceils carrying oncogene proteins on their surfaces; or agents to block cellular receptors that enhance the growth of malignant cells. The di- agnosis of cancers also may be improved by identifying oncogenes activated by an environmental or other agent. Atherosclerosis Atherosclerosis causes heart attacks and strokes and accounts for halfofall ofthe deaths in the United States. In this disease, the flow of Hood through the arteries is obstructed by plaques that 6

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RECENT PROGRESS IN SCIENCE AND TECHNOLOGY have formed on the arterial walls. Eventually, a blood clot de- velops and obstructs the artery, blocking the flow of blood to the heart muscle or the brain. This disease is the product of a complex interplay between components of the blood and the ceils that line the interior walls of the blood vessels. Through interdisciplinary efforts drawing upon molecular and cellular biology, physics, chemistry, and genetics, that interplay has become better unclerstood. The new understanding applies not only to atherosclerosis but also to other illnesses characterized by abnormal interactions between blood ant! vessel wails, such as blood-clotting disorders, adult respiratory distress syndromes, and high blood pressure. Structures, molecular mechanisms, and controls involved in various components of blood-blood vessel interactions have been identified. For example, the inner lining of blood vessels is a single layer of ceils: the endothelium. Research has transformed our view of the endothelium from an apparently simple material with simple tasks to one capable of performing an impressive array of complex functions, among them the regulation of blood pressure, blood clotting, and the growth of new capillaries. The structure of the endothelium has been probed, as have the mechanisms by which materials cross it when moving from blood to tissue. At the same time, the structure and functions of the blood components that interact with the endothelium have been in- vestigated. These include platelets, essential to blood clotting; leukocytes, or white blood cells, which help to defend the body against infectious agents; and plasma lipoproteins, from which the cholesterol in atherosclerotic plaques is derived. The impetus for research into these interactions stems from new concepts and techniques. For instance, more factors affect- ing the very complex set of reactions involved in the formation and removal of blood clots have been found. Two hypotheses concerning the origins of atherosclerosis- both dealing with the deposition of fat, especially cholesterol, upon inner arterial layers have stimulated a wide range of research. New ap- proaches to slowing the onset of atherosclerosis, ones coupling modified diets with medication, are being pursued. And new

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THE O UTLOOK FOR SCIENCE AND TECHNOLOG Y 1985 instrumentation for sorting and isolating cells now makes it possible to obtain sufficient numbers of individual blood cells for study. Finally, receptors and channels, the modes by which materials pass in and out of cells and cellular organelles, can be examined using advanced techniques of cellular and molecular biology. Important clinical advances likely to emerge from this work include improved prosthetic devices, such as heart valves, vascu- lar replacements, dialyzing membranes, and artificial organs, and fresh insights into the prevention and treatment of athero- sclerosis. Parasitism Research on infections caused by parasites is driven by in- terIocking humanitarian and scientific motives. Parasitic diseases such as malaria and schistosomiasis affect more than a billion people globally. In the United States, the parasite, Giardia lamb- lia, is a common cause of epidemic diarrhea. Immigration, in- creased international travel, and the stationing of U. S. military and civilian personnel in countries where parasitic diseases are common are increasing the incidence of these diseases in Amer- ~cans. Confounding an effective attack on parasitic diseases is the very complex life cycle of parasites, which makes them extreme- ly difficult to control without harming the host. In addition, parasites have evolved novel mechanisms for eluding the usual immunological and other defenses. However, these same traits adaptability and complex life cycles make parasites attractive for the investigation of such basic biological events as cell growth and differentiation. Thus, work on parasitic diseases has led to advances in molecular biology, immunology, mem- brane and cellular biology, biochemistry, and pharmacology. In turn, parasitology has benefited from advances in these fields by exploiting new techniques such as monoclonal antibodies and the isolation and copying of specific genes. A constant theme in this field is exploration ofthe unique traits of parasites. For example, the usual response to most infections is 8

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RECENT PROGRESS IN SCIENCE AND TECHNOLOG Y the appearance of antibodies that can react with the surface antigens of the infecting agent. However, one type of parasite can change its surface coating hundreds oftimes during an infec- tion, so that the antibodies invariably attack the wrong antigen. Research on such antigen structures has influenced research on gene expression already and may be important to understanding how genes are regulated. Continuing studies of parasitic evasions of immunological defenses may clarify the nature of such de- fenses, or the reasons for their absence, in other diseases. Explor- ing how antigens and other substances traverse parasitic and cellular membranes will enhance our understanding of mem- brane biology. Finally, a better understanding ofthe basic biology of parasitic diseases should yield ways to combat them more effectively. Thus, studying the genes that modulate the transformation of parasites through their different stages may reveal new ways to interrupt their life cycles. Already, the use of monoclonal anti- bodies is leading to the development of greatly improved di- agnostic reagents. And there are new methods to generate anti- gens for use in vaccines against those diseases. Chemical and Process Engineering for Biotechnology The phenomenal progress in molecular biology, genetics, and biochemistry in the last 20 years now makes it possible to have cells manufacture products ranging from simple molecules to complex proteins. The need today is for fundamental engineer- ing knowledge-and people to translate that capacity into commercial processes. That translation faces several difficulties: living organisms can mutate or change genetically, affecting process operations; biological processes must be completely aseptic; and these processes usually occur in very dilute, aqueous solu- tions, so the products have to be separated from large volumes of water; such separations are complicated by the fact that the products are often fragile, hard to purify, and structurally com- plex. Surmounting these problems entails the design of suitable 9

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THE O UTLOOK FOR SCIENCE AND TECHNOLOG Y 1985 bioreactors for the large-scale culturing of plant and animal cells, the separation and purification of reaction mixtures in order to obtain products of sufficient purity at competitive costs, and the improvement of bioprocess instrumentation and control. Each area requires blending scientific with engineering knowledge. Bioreactor research, for example, involves the merger of such biological sciences as molecular and cellular biology, microbiol- ogy, and cell physiology with engineering skills, chemical kinet- ics, thermodynamics, fluid dynamics, heat and mass transport, and precise process control. Progress in separation and purifica- tion sciences necessitates in part adapting to large-scale processes such powerful technique of the research laboratory as elec- trophoretic and affinity separations. The control of bioprocesses poses special demands, such as the on-line monitoring of com- plex products for which no sensors are available yet. Solutions to these problems may require the use of enzymes, monoclonal antibodies, and living cells as components of electrochemical and optical detectors. Potential opportunities for applying biochemical technologies are diverse and provocative. In the area of human and animal health care, for example, a new family of products based on genetically engineered proteins may emerge that can detect quickly and accurately viral and bacterial diseases, susceptibility to autoimmune diseases, genetic defects, and neoplasms. Other proteins, such as those inhibiting the growth oftumors or those that dissolve blood clots, are being tested. In agriculture, the new technologies may yield fungicides and herbicides that are highly potent, specific, and environmentally safe. Other prospects lie in environmental protection, where biochemical engineering may provide methods of destroying or removing toxic products, and in the use of natural resources, such as the improved recovery of metals from low-grade ores. Advanced Polymeric Composites Bone, wood, and clam shells are natural composites: their structures have properties matched to specific purposes. A grow 10

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RECENT PROGRESS IN SCIENCE AND TECHNOLOGY ing array of manmade polymeric composites similarly matches properties to use, most commonly to provide materials that, on a per-weight basis, are stronger and stiffer than the best structural metals. Such advanced composites are being used already in the manufacture of aircraft and sporting equipment, and are on the verge of major applications in automobiles, heavy equipment, robotics, and other areas. The rapid technological development of advanced composites in the last decade has outpaced the underlying science. For in- stance, the understanding of the relationships between structure and properties is still primitive, as is the knowledge of why and how composite structures fail. A science of the design and pro- cessing of polymeric composites, embodying extensive computer-based modeling in design, engineering, and manufac- ture, needs to be developed. Further, the toxicity of components, their long-term environmental effects, and their reuse need to be studied and this knowledge applied to the development of new composites. Advances on these and related fronts will amplify the already substantial use of advanced composites. For example, the wider use of composites in the automobile industry will depend on attaining an acceptable balance between processing speed and product quality, a useful technology for joining and repairing composites, and their long-term dimensional stability. The re- sultant benefits may be considerable. The costs of tooling for composites are much lower than for steel and allow for greater manufacturing flexibility, quicker design turnover, and less capital investment. Composites also are less likely to corrode than metals; lower vehicle weights will save fuel. Supercomputer Architectures Supercomputers, able to respond to about 100 million instruc- tions per second, will soon be capable of executing 1,000 million instructions per second, rising to 20,000 million in the next decade. Such extreme speeds derive from the rapidly developing technology for raising the densities and hence the speed of 11

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THE OUTLOOK FOR SCIENCE AND TECHNOLOGY 1985 integrated circuit chips; they also derive from new architectures which often embody, in a limited way, parallel or concurrent computations. While further improvements in the underlying componentry are vital, attaining even faster speeds in the future will depend on implementing new computer architectures-specifically, the effective use of large-scale parallelism. This entails the develop- ment of computers that can execute many hundreds, thousands, or tens of thousands of instructions simultaneously, and of soft- ware that can orchestrate these simultaneous streams of computation effectively. Faster computers, accompanied by refinements in software, will expand dramatically the applications of computers to ever more complex scientific and technological problems. To illus- trate, computer simulation will affect aircraft design, the devel- opment of new pharmaceuticals, the design of energy storage systems and industrial products, and the testing of new genera- tions of integrated circuit chips. In science, faster computers will be applied to simulating intricate phenomena Tying beyond ob- servation and experimentation. Examples inclu(le the path taken by an electron traversing a neutron star; a chemical reaction under extreme temperatures and pressures; the forces that give protons and neutrons their structure; the optimal conditions for a fusion reactor; the neural pattern triggered when, say, a finger touches an object; and climate, weather, and other atmospheric phenomena, such as tornadoes and wind shears. Finally, faster computers are vital to national security goals, weapons design, and to assessing phenomena such as "nuclear winter." Information Technology in Prernlleoe F.durntinn ~ -<5 - ~-~ ~ ~ ~ ~ ~ _ ~ tar The cognitive sciences combining cognitive psychology, linguistics, philosophy, and biology examine how humans process information. Artificial intelligence reflects a concern with how computers process information and their emulation of intelligent action and human perception. Recent progress in the cognitive sciences and in artificial intelligence, combined with more powerful, versatile, and accessible computers, provides a 12

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RECENT PROGRESS IN SCIENCE AND TECHNOLOGY basis for new technologies to improve education. Problem- solving, hearing, and the organization of semantic memory are all areas to which the cognitive sciences have contributed sub- stantially. Similarly, expert systems have provided both an orig- inal method for organizing the knowledge of a human expert and a --vvindow into the nature of human knowledge, skilled problem- solving, and reasoning. These recent advances have occurred through a linking of the cognitive sciences, artificial intelligence, ant! educational re- search. This progress offers a major opportunity to create learn- ing systems that can help students to acquire the knowledge and cognitive skills necessary for effective work ant! citizenship. Experimental learning systems such as DEBUGGY, an expert system for diagnosing a student's procedural errors in subtrac- tion, are being tested already. Analogous efforts certainly will not solve all- or even most- of the problems of education. However, they will provide a coherent and scientific basis for designing instructional systems and for training teachers and restructuring curricula. They also may create valuable new resources in the form of mode! electron- ic learning environments, while attracting a new cadre of profes- sionals to education and to educational research. Opportunities in Physics Discoveries in physics have influenced virtually all of the sciences and have spawned industries. Observations of electrical and magnetic phenomena, starting in the eighteenth century, led to concepts the:, in the nineteenth century, spurred! a crescendo of experimental and theoretical knowledge of electromagnetism. This rich body of knowlecige is the basis of electric power, telephony, radio, radar, and television. The emergence of quan- tum mechanics in the twentieth century underlies much of phys- ics and chemistry ant! is the foundation of such technological discoveries as transistors, lasers, and solar cells. Fundamental advances in physics continue to enrich all of science, and virtually all technologies. Cosmology and astrophysics are intertwined with the subnuclear physics of 13

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THE OUTLOOK FOR SCIENCE AND TECHNOLOGY 1985 elementary particles. New discoveries in quantum mechanics have changed our knowledge of atoms and molecules dramatically and have revolutionized our understanding of solids. Semiconductors are not only the results of these dis- coveries, in the invention of the transistor and the solar cell, but also have led, in turn, to striking progress in many technologies. Two contemporary examples convey the influences of phys- ics. One is the deliberate structural design of materials through the arrangement of atoms in one or two dimensions. The result- ing materials have remarkable properties quite different from those of natural materials, thus presenting scientific puzzles and technological opportunities. The physics of these layered mate- rials is fundamentally interesting and their properties are technologically important to the computer and energy indus- tries. Another example is the contribution of physicists to biological problems, including recent work on transmembrane signaling- the transmission of information in brain, nerve, and muscle tissue. The molecular basis of such signaling is now accessible, and the perspectives of physicists joining with those of biologists are expanding upon a vast array of research questions, such as how nerves conduct information and execute commands. These few examples illustrate continuing traits of physics: enormous diversity, the search for fundamental laws, strong connections to other sciences, and technological and industrial . . app. .lcatlons. Solar-Terrestrial Plasma Physics Plasma physics studies the interactions of charged particles with each other and with electrical and magnetic fields. Its re- search areas comprise, in addition to the effort to attain fusion power, the interactions of the sun and the earth: the chain of physical processes that starts with the generation of the sun's magnetic field in the solar interior and links it to activity at the sun's surface and, ultimately, to the earth's ionosphere and atmosphere. Fundamental questions continue to drive solar-terrestrial 14

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RECENT PROGRESS IN SCIENCE AND TECHNOLOGY physics. Why does the appearance of sunspots on the sun presage magnetic storms and auroras? What roles do magnetic fields play in stars and galaxies? Rapid progress toward answering such questions has occurred in the last decade, made possible by the increasing precision of measurements, numerical modeling, and the further clevelopment of theories applied to solar-terrestrial plasma problems. Plasma phenomena in the solar system are mirrored in other stars, in the neighborhood of neutron stars and black holes, and in galaxies. The sun and the solar system have become, therefore, a laboratory in which astrophysical plasma processes can be studied in situ and with a precision attainable nowhere else. As a result, space and astrophysical plasma physicists have begun to work closely together and a new and broad research field is developing. The power of the solar-terrestrial system as an astrophysical laboratory will be enhanced by the proposed multispacecraft International Solar-Terrestrial Physics Program. Together with the Solar Optical Telescope, this program can be expected to provide the fundamental underpinning of solar-terrestrial plas- ma research for the next 10 years. The overall research goal is to synthesize growing knowledge to create a unified and quantitative model of events affecting the sun and the earth: solar wind, or the plasma connection between the sun and the earth; sources of coronal heating and solar flares; and links between solar activity and magnetic storms on earth. 15

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