YEAR IN REVIEW 1999

Molecular Biology A Promising Cancer Therapy. The sprouting and growth of new blood vessels is essential during embryonic development so that developing tissues can be supplied with oxygen, nutrients, and waste-disposal services provided by blood flow. At the same time, blood-vessel growth, or angiogenesis, must be limited so that an inordinate fraction of the mass of the organs will not be devoted to blood vessels. It follows that angiogenesis must be under the control of both natural stimulators and inhibitors such that the balance between them produces the proper degree of vascularity. This same reasoning applies to the growth of a tumour as well as to the growth of an embryo. A solid cancer, or tumour, derives from a single cell that has mutated in a way that permits it to escape from the biochemical controls that limit the multiplication of normal cells. Once that cell fails to respond normally to growth inhibitors, it starts to proliferate. When the growing tumour reaches a diameter of about two millimetres (less than one-tenth of an inch), however, simple diffusion in and out of the tumour tissue no longer suffices to supply oxygen and nutrients and remove waste. Further growth depends on angiogenesis, and the small tumour must produce factors that stimulate the ingrowth of blood vessels. In the early 1960s such considerations led Judah Folkman (see BIOGRAPHIES), then a U.S. Navy surgeon, to begin a search for angiogenic factors, a task he subsequently continued at Harvard University. An assay was essential to allow the detection of these factors and then to guide their purification, and over the years Folkman and his collaborators devised two assays that used living animal tissues to test the ability of a given substance to stimulate blood vessel growth. Painstaking work over several decades resulted in the isolation of not one but several angiogenic factors, including angiogenin, vascular endothelial growth factor, vascular permeability factor, and basic fibroblast g rowth factor. Once these were available, it was easier to search for inhibitors of angiogenesis. That such inhibitors existed was surmised from the ability of a primary solid tumour to inhibit the growth of small offspring, or metastatic, tumours. During the past few years, a number of antiangiogenesis compounds were identified, and by 1998 some of them had been given clinical trials, the goal being a generally applicable treatment for solid cancers. Moreover, because factors that stimulate the growth of cells must bind to specific molecular receptors on the cell surface in order to function, a compound that can block those receptors will prevent the action of the growth stimulators. Several such blockers, or antagonists, of angiogenic factors were also under study. During the year two recently isolated natural inhibitors of angiogenesis, called angiostatin and endostatin, were attracting particular attention. Folkman and his collaborators at Harvard showed that angiostatin given to mice prevented the growth of carcinoma in the lung. In a second approach they used genetic means in mice to cause their cells to overproduce angiostatin, which in turn resulted in long-lasting suppression of fibrosarcoma, ordinarily a fast-growing cancer. Importantly, there was no indication that the cancers could develop resistance to angiostatin. Researchers looked forward to conducting clinical trials of angiostatin and endostatin in cancer patients in the next year or two and, if these proved positive, to the widespread availability of this highly promising treatment. Antifreeze Proteins. Certain species of fish routinely live in seawater cold enough to freeze their blood. Ocean water does not freeze at such temperatures because of its high salt concentration, but the fish blood has only a third the salinity of seawater. Why does it not freeze? The answer lies in antifreeze proteins present in the fish blood. It is well known that highly purified water can be cooled below its freezing point (0 C, or 32 F) without freezing. If one adds the smallest crystal of ice to such supercooled water, it rapidly freezes. Water ordinarily freezes at 0 C because it contains minute particles that initiate, or nucleate, the growth of ice crystals. The antifreeze proteins bind to ice crystals in the blood while they are still microscopic in size and prevent their further growth. In work extending back to the 1960s, scientists identified several types of antifreeze proteins from fish and determined their structures. Although all share the ability to bind to ice crystals, comparative study of their amino-acid sequences carried out in the past two years indicated that they can be grouped into four distinct families. It thus appeared that these antifreeze proteins, which have similar ice-binding functions and mechanisms, have independent evolutionary origins. Adults 'Toon In By 1998 television cartoons aimed primarily at adults had reached an unprecedented popularity. Fox Broadcasting's "The Simpsons" not only was the longest-running animated program on TV but, after the show's ninth season on the air, had become the longest continually running prime-time series still releasing new episodes. The Cartoon Network was perhaps the most successful new cable channel. Another cable network, Comedy Central, attracted huge audiences and wowed critics with such animated hits as "South Park," "Dr. Katz, Professional Therapist," and the British-made "Bob and Margaret." At a time when the preponderance of television sitcoms featured generic characters, canned laughter, and pat story lines, adult viewers in search of intelligent humour and genuine, compelling characters were, ironically, turning increasingly to cartoons. Adult-oriented TV cartoons had come a long way since 1960, when "The Flintstones" and "Mr. Magoo," the first prime-time animated programs, made their debuts. "The Flintstones" was based in part on Jackie Gleason's classic sitcom "The Honeymooners," and the antics of the nearsighted, crotchety Mr. Magoo recalled the comedy of W.C. Fields. These and other early animated shows, such as the popular "Peanuts" television specials, could be enjoyed equally by children and adults. By and large they avoided social and political criticism and, some would say, reflected a more wholesome era than today. The cartoon landscape changed dramatically in 1990 with the appearance of "The Simpsons," the first animated prime-time series in two decades. Created by comic-strip artist Matt Groening, the show depicted the misadventures of the Simpson family, focusing particularly on Homer, the bickering, ineffectual husband and father, and Bart, the sly, sarcastic 10-year-old son. A de facto revolt against idealized images of the American family promulgated by such well-known sitcoms as "Father Knows Best" and "The Cosby Show," "The Simpsons" instantly struck a chord with viewers and cleared the way for other adult-oriented cartoons. "King of the Hill," developed by Fox as a companion show to "The Simpsons," debuted in 1997. Set in a Texas suburb and featuring another beleaguered working-class family, the cartoon was one of television's most successful new shows. Other prime-time cartoons stirred controversy. MTV's "Beavis and Butt-head" and Nickelodeon's "Ren and Stimpy" tried hard to be obnoxious, but perhaps the most outrageous cartoon of all was "South Park." Although the series centred on the lives of four young boys, it carried a "mature audiences" rating for its liberal doses of profane language, gross humour, and graphic violence (one character, Kenny, was killed in almost every episode, sometimes more than once). Described by one critic as "Peanuts on acid," the cartoon's deadly satire helped it become the highest-rated show on cable. Like "The Simpsons," "South Park" also strove for an element of realism. "Most kids on TV are just projections of what adults think kids should be like," observed "South Park" cocreator Matt Stone. "Kids are not sweet and innocent. They're mean and vindictive . . . and that's what makes them so funny." Although satire was sure to remain their emphasis, adult-oriented cartoons promised to continue breaking new ground. At year's end Groening was hard at work on "Futurama," an animated science-fiction series, scheduled to air in January 1999.