~MOLECU LE OF THE YEAR

NO News Is Good News A startlingly simple molecule unites neuroscience, physiology, and immunology and revises scientists' understanding of how cells communicate and defend themselves A decade ago, nitric oxide

E(NO) was just another toxic

1862

SCIENCE * VOL. 258 * 18 DECEMBER 1992

Downloaded from http://science.sciencemag.org/ on January 23, 2019

lar physiology, and carcinogenesis-suddenly realized they were studying the same molecule. Like a squirt of some powerful perfume, a puff of nitric oxide spurs different cells into an array ofdifferent activities, from communication to defense to regulation. A thousand times NO. In 1992, scientists probed the reasons behind these multiple personalities. One significant clue: the biochemistry of nitric oxide manufacture. Cells rely on various forms of an unusual enzyme called NO synthase (NOS) to do the job, and a

ing out how the enzyme works. NO cure for heartache. This year, clinical applications of NO knowledge bloomed molecule, one of a lengthy in several directions at once, but much effort list of environmental polfocused on nitric oxide's role as the body's Molecule lutants found in unsavory own blood pressure police. In blood vessels, cigarette haunts such as the of Year smoke and NO is released by endothelial cells on the smog. Destroyer inside of the vessel wall, migrates to nearby of ozone, suspected carcinogen, and precurmuscle cells, and relaxes them. This dilates sor of acid rain, this gas had a bad reputation. the vessel and lowers blood pressure. But over the past 5 years, diverse lines of Understanding this process opens the door evidence have converged to show that this to a host of new drugs. Indeed, faults in the sometime poison is a fundamental player in NO system may be the guilty parties in the everyday business ofthe human body. some familiar cardiovascular diseases, In 1992, NO was ushered into the pantheon ofmessenger molecules with a fan*X possibly even essential hypertension and atherosclerosis. In 1992, scientists raced fare of hundreds of research papers. This to develop a new class of chemicals that year scientists probed NO's activities in can release NO more controllably and the brain, arteries, immune system, liver, successfully tested them in cell cultures pancreas, uterus, peripheral nerves, and and in mammals. lungs. They found that the molecule is In a handful of extreme cases in 1992, essential to activities that range from diphysicians have used NO inhibitors to gestion and blood pressure regulation to save lives. Septic shock, a leading cause antimicrobial defense. of death in U.S. intensive-care wards, is Nitric oxide also carries important somehow related to too much NO: Lifeinformation in the nervous system: In threatening low blood pressure occurs males, it is the messenger that translates when the body pours out nitric oxide in sexual excitement into an erect penis. In NCD trace. Immunohistochemical staining tracks the pres response to a bacterial infection. This the brain, nitric oxide may be a long- enoIce of NOS and lights up NO-making macrophages. year, nitric oxide inhibitors successfully sought mystery molecule that aids in learning and remembering. single cell may have two kinds of enzyme- brought several patients' blood pressure out Yet early wariness concerning the power constitutive and inducible-that produce NO of the danger zone in a few minutes. Also this of NO was not ill-founded: This year the for different roles. Constitutive enzymes are year, Phase I clinical trials were begun to test molecule's derivatives were found to damage ever-present citizens of the cell, always avail- NO inhibitors as an adjunct to interleukin-2 DNA in human cells, and it is implicated in able to make brief puffs of NO for delicate (11-2) therapy for stubborn cancers of the tasks like neurotransmission. In contrast, in- skin and kidney. 11-2 rouses the immune sysnerve damage left by strokes. In 1992, the nitric oxide breeze wafting ducible enzymes are goaded into action more tem but also triggers a dangerous flood of through the scientific world strengthened into slowly by other cellular messengers. But over nitric oxide; physician-scientists hope NO gale force winds, stirring up potential drug a period of days they can produce at least inhibitors will keep blood pressure up while development and propeling hundreds ofhere- 1000 times more NO for cellular defense. In 11-2 helps kill the cancers. The power of NO. As a defensive weapon, tofore-unrelated scientists together into a new 1992, scientists cloned the genes for a string of these enzymatic forms, including constitu- NO appears to work in at least two ways: by research field. NO wonder. Not to be confused with its tive NOS from human and bovine endothe- inhibiting key metabolic pathways to block cousin, laughing gas or nitrous oxide (N20), lial cells, and inducible NOS from mouse growth, and by killing cells outright. In the first mode, NO attacks susceptible iron groups nitric oxide is the smallest, lightest mol- macrophages and human liver cells. ecule-and the first gas-known to act as a Understanding this unusual enzyme is cru- in certain enzymes, including those that synbiological messenger in mammals. The mol- cial to designing drugs to turn NO on and off. thesize DNA and help cells respire. When ecule has one unpaired electron, making it a For example, a handful of molecular cofactors those enzymes are crippled, cells cannot grow free radical that avidly reacts with other mol- are tightly bound to NOS and help the enzyme and divide; this may be an important part of ecules. In the presence of oxygen, NO may accomplish its task of stripping five electrons NO's antitumor function. This year it was shown that NO can also vanish a few seconds after it forms, although from one amino acid (L-arginine) to produce NO and another amino acid. This year bio- combine with oxygen to eventually produce its lifespan in the human body is unknown. No one expected such a bizarre molecule chemists discovered that one such molecular potent cellular assassins such as the hydroxl to be important in physiology, and the earli- helper is heme, the iron-containing compound radical, OH, and nitrogen dioxide. Such est research reports were greeted with disbe- that carries oxygen and makes blood red. Since pathways may be behind NO's antibacterial lief. But in the late 1980s, scientists in dis- heme is a known electron acceptor, the new properties, which are the basis of the centutinct disciplines-immunology, cardiovascu- knowledge gives biochemists a start on figur- ries-old practice of curing meat with nitrite-

OSt0z

SCIENCE

*

VOL. 258

*

18 DECEMBER 1992

ered new class of signaling molecules-gases that swiftly pass through a cluster ofcells and then vanish. Preliminary evidence hints that one candidate for such an airy messenger may be carbon monoxide, another molecule that today has a shady reputation. Stay tuned for new developments next year. Despite this year's burst of research, scientists have a long way to go before they understand nitric oxide's paradoxical nature. On page 1898 of this issue, Stamler et al. argue that the uncharged, free radical form, NO, may not be responsible for all of the myriad activities attributed to "nitric oxide." Other, intermediary compounds containing the NO group may also play a role. That view is by no means a consensus opinion, but the debate itself bespeaks a new attention to basic chemistry, especially oxidation and reduction reactions. As Stamler et al.'s paper illustrates, NO's conceptual contribution has made itself keenly felt this year. This molecule's Cinderella story-from vaguely noxious gas to powerful queen of communication and defense-offers a classic example of nature's continuing power to surprise. And the runners-up are...

In 1992, science surged forward, often in unexpected directions. Below are nine advances that deserve to share the spotlight-and remember, they may be composed of billions of molecules. Any elegant technique or unusual corner of the universe may qualify, if it has earned a place in scientific history this year. Chromosome countdown. In a landmark year for the Human Genome Project, scientists in 1992 completed high-resolution physical maps for two of the 24 human chromosomes, Y and 21. These maps demonstrate that the genome project-which celebrated its second birthday this year-is living up to

New maps. Chromosomes Y (yellow) and 21 have been completed.

its promise. The goal of mapping the entire human genome by 1995, once considered overly ambitious, is now clearly within reach. Each map is itself a scientific coup. The Y chromosome is the essence of maleness, responsible for dividing our species into two 1863

Downloaded from http://science.sciencemag.org/ on January 23, 2019

rich salts. In 1992, scientists investigated the of research in hopes of clinical applications. In addition to being found in the genitalia, possibility that NO is a primitive defense against a whole range ofmicrobes and worked nitric oxide also carries out its duties as neuto understand how host cells defend them- rotransmitter throughout the lungs and gut. For example, during digestion, the gut begins a selves against this internal killer. In the brain, NO's split personality emerges set of systematic wavelike contractions-periat full strength, as the molecule acts as either stalsis-that move food through the stomach messenger or killer depending on conditions. and intestines; NO triggers the relaxation comFor example, evidence gathered this year and ponent. This process is blocked in some inlast suggests that neurons confants with a potentially lethal taining NO synthase may ac_° condition called infantile hytually kill their neighbors durc pertrophic pyloric stenosis. ing a stroke. These NOS neu@ This year, scientists found evirons-themselves eerily resisdence that lack of NO is the tant to stroke damage-apparculprit in that disorder. ently may become overstimuLearning to say NO. Back lated by the excess neurotransin the brain, a series of exmitter released during a stroke periments done in late 1991 and throughout 1992 suggests and flood nearby cells with toxic amounts of NO. In mice that nitric oxide may help cells to store and retrieve inand cultured nerve cells, NO NO resistancet. NJOS neurons inhibitors can reduce damage (gray) live as ol)theirs (black) die. formation-the keys to learning and memory. significantly; scientists are avThe cellular basis for learning and memory idly pursuing the therapeutic implications. NO neurotransmitter. In neuroscience, is thought to rely on strengthening the constartling discoveries of NO's myriad roles are nection between sending and receiving neuemerging at a rapid pace. This year nitric rons, the presynaptic and postsynaptic cells. oxide has proven itself privy to a host of One way to do this is a process called longdelicate body functions-yet it continues to term potentiation (LTP), in which repeated firing causes postsynaptic cells to respond defy the normal rules of neurotransmission. This evanescent molecule sometimes does more strongly the next time they receive a the work of a neurotransmitter but doesn't signal. One theory for how it works invokes look or act like any other such messenger. the "retrograde messenger," a mysterious When a neuron fires, it releases neurotrans- molecule that would travel backward across mitter from special storage vesicles into a gap the synapse and enhance the release of neucalled the synapse; the receiving cell picks up rotransmitter in the presynaptic cell. Such a the neurotransmitter and is activated. But messenger would have to pass lightly from cell NO has no special storage facilities, and no to cell without benefit of either release maspecial release mechanisms. Made when and chinery or receptors-just like nitric oxide. where it's needed, it seems simply to diffuse So in the past 2 years, neuroscientists have out of the producing cell. rushed to test nitric oxide. Several labs have Most neurotransmitters are composed of now performed the crucial experiment and amino acids or a string of peptides, which gotten positive results: In rat hippocampal couple with precisely configured receptors neurons, LTP can be prevented by inhibiting on the surface of cells. Compared to this NO synthesis. Also this year, scientists inmodel, NO is positively promiscuous. It needs jected NO inhibitors into the brains of live no receptor gates, passing through membranes rats and found that the rats could no longer like a ghost. Its known targets are enzymes learn a water maze. But not everyone is ready to crown nitric deep within cells, and it carries its message to oxide as retrograde messenger. One missing any and every cell within reach. NO sex. So what makes this odd molecule piece in the puzzle: Thus far, no one has been so similar to a neurotransmitter? One of the able to detect NOS reliably in the hippocambest examples comes from sex. This year, pal neurons that are supposed to be releasing scientists proved definitively that in males, NO. A few more experimental replications NO translates sexual excitement into po- will increase everyone's confidence that the tency by causing erections. Key pelvic nerves effect is real. Expect intense, focused effortget a message from the brain and make nitric and a torrent of papers-to resolve this deoxide in response. NO dilates blood vessels bate next year. NO class? In the brain, nitric oxide scithroughout the crucial areas of the penis, blood rushes in, and the penis rises to the ence is in the discovery phase, as neuroscienoccasion. If NO synthesis is blocked-as was tists test NO in a variety of systems. It's far done in experiments in live rats this year- too soon to put all the pieces together, but those all-important blood vessels never di- NO is clearly a crucial part of our neurolate, and the penis stays limp. With 10% of chemical system. the male population suffering from impoSome scientists speculate that nitric oxtence, researchers are hotly pursuing this line ide is merely the first of a soon-to-be-discov-

uC mS 2 leaving host cells intact. many plants and sea-dwelling invertebrates sexes. Chromosome 21 MRI makes its has been linked to gevanished. In 1992, new evidence has brought C F move. Magnetic reso- one chapter of the story-the search for a netic disorders such as z nance imaging (MRI) Down's syndrome and likely impact crater-to a close. ' familial Alzheimer's. has long offered mulTwo years ago, geologists honed in on a To map the chromotiple benefits to medi- giant subterranean crater, 180 km in diamsomes, scientists cloned cine and science, beeter, near the town of Chicxulub in Mexico's overlapping pieces of cause it offers a nonYucatan peninsula. This year, using lasers DNA, each tagged with invasive way to peer inand high-resolution mass spectrometers to one or more known se*:r1 _ side the body. But in measure isotopes of argon, two groups of requences, and then put 1992, the technology searchers independently dated molten rock the tags in order. Thus leaped forward with the from the crater at 65 million years ago-right the vast stretches of undevelopment of func- at the Cretaceous-Tertiary boundary. Samples HE tional MRI, which al- from Haiti and northeastern Mexico showed known DNA that make up the chromosomes Making movies. MRI t,racks changes in lows scientists to track that tektites-beads ofglass forged in the fiery have been divided into the human visual corte:x as lights flicker. blood flow in the brain heat of an impact-were exactly the same age manageable chunks, in real time. This year as the crater and similar in chemistry. bounded on each side by known sequences. With data linking impact debris to the subjects stepped into a large magnet and Also this year, independent groups of sci- stared at lights or squeezed objects, while Chicxulub crater, and both to the pivotal entists completed two separate genetic linkage scientists made real-time movies of the $65 million date, many former skeptics now maps of the whole genome, linking molecular changes in their brains. Scientists even told admit that something big crashed to Earth at markers with inheritance of specific traits. subjects to imagine a bright light-and the end of the Cretaceous era in Mexico. All this information will speed the work watched the visual cortex light up. And so the next phase of research has begun: For years this kind of functional imag- finding out what happened after the crash, of understanding known genetic diseases, as well as the genetic components of common ing-where scientists match thought, deed, and whether more mundane processes such or disease to corresponding brain activityas climate change served as accomplices in afflictions such as cancer and heart disease. has been the domain of PET the death of the dinosaurs. There's still much to be done, of courseParallel power. Supercomthese chromosomes are charted by maps, not (Positron Emission Tomputer users are accustomed to wO by complete sequences. Those going gene ography) and SPECT (Single rapidly changing technology.y hunting must still do some searching-but Photon Emission Computer But 1992 was something special: H Tomography). Now MRI, now they know where to look. the dawn of the era of a new Resourceful ribozymes. Ribozymes- which does not require injecstyle of supercomputer, the masRNA molecules that can serve as catalytic tions of tracer elements as sivelyparallel machine. This year O enzymes-greatly expanded their known rep- these techniques do, offers a third alternative. nearly a dozen supercomputer m ertoire of activities this year, showing promise Functional MRI uses magcompanies introduced or anas therapeutic agents and spurring a flurry of netic fields and radio waves to Seeing parallel A parallel research in both companies and universities. nounced plans for massively parallel computers. Scientists used When first discovered, ribozymes' tasks trackchangesinbloodflowand machine modelsS water. these machines to tackle an arblood oxygenation. And it's bewere restricted to processing RNA molecules. But in 1992, nearly conclusive evidence sug- coming quicker and easier all the time. Fans ray of complex problems, from imaging the surface of a silicon chip to deciphering the insist functional imaging doesn't even require gests ribozymes can also build bridges bestructure of an ion channel protein. a state-of-the-art MRI machine but could be tween amino acids to form proteins, and can Most of today's supercomputers use more make and break the bonds that link amino done on the 2000 conventional machines in acids to RNA. This offers a new view of how use in hospitals worldwide. Though Hollywood than one processor-the Cray Y-MP has needn't worry about competition just yet, the eight, for example-but massively parallel proteins are made in the cellular structure machines represent a new type of computer called a ribosome. Biologists once thought age of MRI movie-making has begun. X marks the spot For more than a dearchitecture, in which a small army of proproteins themselves performed the catalytic labor, while RNA merely supplied a support- cade, circumstantial evidence has been pil- cessors can dissect and work huge problems ing up for an extra-terrestrial villain in one of at awesome speeds. Devotees foretell a thouive scaffold. This year's results suggest the reverse-the proteins are the scaffolding, geology's great whodunits: the Cretaceous- sand-fold increase in peak computer speed in Tertiary extinction, when the dinosaurs and the next few years. and the ribozymes do the work. What kinds of science will these new maAlso this year, scientists co-opted the chines solve? Any problem rich in data and power of natural selection to coax ribozymes complexity-the "grand challenges" of scito perform new chemical tricks in the test ence, including the mysteries of molecular tube (see article on page 1910). Ribozymes' interactions, protein folding and structure, ability to "evolve" new functions-as well as properties of materials, climate change, and their newly expanded catalytic talents-are the evolution of galaxies. consistent with the "RNA world," the theory Bench scientists can take heart in another that early life relied on RNA to perform many landmark this year: jumps in the speed of roles in the biological stage. computer communications. Today scientists The more practical implications of all this can communicate on Internet, with each enzymatic activity have not been lost on the other and with supercomputers, at speeds up biotechnology industry. Companies old and to 45 million bits per second, a goal achieved new have pounced on the opportunity to 1 year ahead of schedule. Next year, expect develop specific ribozymes that could slice Heavy hitter. Gravity data outlines the speeds of 155 million bits per second. the RNA of pathogens such as HIV while Yucatan's 65-million-year-old crater. z

e.

_30~ ~ ~ ~ ~

1864

SCIENCE

*

VOL. 258

*

18 DECEMBER 1992

Downloaded from http://science.sciencemag.org/ on January 23, 2019

w

CLIMERWRI

TOR

Antisense weapons have been crafted Nitrogen news. One of the triumphs to fight leukemia, AIDS, hepatitis, and of the Industrial Revolution was the f other diseases. This year scientists used a Haber process, which allows chemists virus to slip antisense RNA molecules to create ammonia, NH3, from nitrointo cells already infected with HIV. The gen gas, N2, by using strong-arm tactics results: HIV infectivity decreased by more ofhigh temperature and pressure. But scithan 99% in vitro. entists have long known that nature does it Another antisense technique relies on better. Certain bacteria in the roots of plants relatively short synthetic DNA molecules Z perform the same reaction at atmospheric pres(called oligonucleotides) that are apparently sure and temperature, in the process making Cosmic kernels. COBE found traces of the structure of the early universe. spontaneously taken up by cells, and so need nitrogen available to other life forms. no special means of delivery. This year, the How do these bacteria do it? NineteenBut Big Bang theory also suggests that 15 first human trials of these compounds began, ninety-two saw the start of the era in which chemists and biologists can begin to answer billion years ago the newborn universe was a in a patient with leukemia and in patients that question. This year, scientists revealed featureless structure, stretching out evenly in with human papilloma virus, which causes the structure of nitrogenase, the enzyme re- all directions. Today matter is clumped tightly genital warts. And in September, the Nasponsible for the enviable abilities of nitro- into galaxies like our own Milky Way, with tional Institutes of Health approved the first vast reaches of empty space in between. How antisense gene therapy trials, scheduled to gen-fixing bacteria. did galaxies and star clus- begin next year in patients with lung cancer. During the past deEmbryonic efforts. In 1992, medicine ters emerge? Cosmolocade, two independent ; gists had predicted slight marched backward to the earliest stages of groups of scientists have E) bumps in the texture of life, breaking new ground in fetal diagnosis carried out the painstakthe early universe, which and treatment and gaining greater undering work needed to deover the eons were standing of the biology of life in utero. duce the enzyme's comThis year, the healing power offetal tissue strengthened by the plex structure. Their reforce of gravity into ma- was used to treat Parkinson's disease in a sults show that nitrogejor cosmic structures. handful of studies. The results were encournase is essentially two Traces of these early ir- aging-several patients regained their abilcomplicated proteins, regularities should be ity to walk and talk. But transplanting fetal an iron protein and an preserved today as slight tissue to adults is only the beginning. Beiron-molybdenum provariations in the back- cause the fetal immune response is not yet tein, which work tofully developed, undeveloped fetuses themground radiation. gether to catalyze the reIn 1992, after many selves may be ideal recipients for transplants. action. One surprise was months of orbit, COBE In 1992, scientists continued to explore the the molybdenum: chemgot- the goods: It mea- potential for fetal medicine in animal modists had long thought this transition metal Nitrogenase unveilled. Two proteins (Fe, sured slightly cooler and els, and in some cases performed surgery to warmer spots, differing correct anatomical defects in utero. crucial to the catalytic bottom, and Mo-Fe, top) work together. In fetal diagnosis, testing was pushed back by only 30 millionths of process. But the molybdenum atoms turn out to be so thoroughly a degree, in the cosmic microwave radiation. to the first few days of life in a procedure tied up with other bonds that they seem un- Thus cosmologists' notions of the early uni- appropriately nicknamed BABI (Blastomere likely candidates for the actual site of nitro- verse have been vindicated. More good news Analysis Before Implantation). Coupled with arrived this month, when data from a balloon- in vitro fertilization and performed at the gen reduction. Finding the structure set off a flurry oftheo- borne experiment, which scanned a smaller eight-cell stage, the technique allows physirizing-and experimentation-by chemists area of sky at a different wavelength, partially cians to screen embryos for specific genetic diseases before implanting who think they can already see how electrons confirmed COBE's results. < them into the mother's might be persuaded to take the crucial steps: For cosmological explorers, uterus. In 1992, BABI profrom the iron protein, to the molybdenum- looking up has paid off. duced a healthy baby girl Common antisense. iron protein, and finally to N2. However the who does not carry the gene electrons make their journey, the structure of Scientists have long recogfor cystic fibrosis-even nitrogenase has begun a new age of explora- nized the potential power though both her parents do. of knocking out specific tion for a new generation of chemists. Scientists also opened a Space tracks. Cosmology, a field rich in genes with antisense molnew diagnostic frontier that theory but poor on experiment, this year re- ecules. This year, this may eventually allow fetal ceived a rich inoculation ofdata from a satel- benchside technique blostesting simply by screening lite seeking the seeds of galactic structure. somed into drug developCalled the Cosmic Background Explorer ment, and antisense com- The youngest ppatiients. Fetal the mother's blood. New (COBE), the National Aeronautics and pounds were used in hu- medicine forges , ahead. techniques can isolate fetal cells from maternal cells in Space Administration's probe was sent out mans for the first time. Antisense molecules prevent cells from the bloodstream, and in two cases have idento take the temperature of the early universe by measuring the faint afterglow left by the translating genetic information into proteins. tified fetuses with major genetic defects. Taken together, these developments pave Nucleic acids have two complementary Big Bang. The occurrence of that primordial explostrands, only one of which-the "sense" the way for a new kind of medicine, in which sion is backed up by pervasive microwave strand-codes for protein. The other strand patients are diagnosed-and treatedradiation, which bathes the universe at ex- is "antisense," which can bind to sense mol- months before they are born. -Elizabeth Culotta and actly the temperature predicted by Big Bang ecules and prevent them from being exDaniel E. Koshland Jr. pressed. theorists, 3 degrees above absolute zero. W

*

VOL. 258

*

18 DECEMBER 1992

1 865

Downloaded from http://science.sciencemag.org/ on January 23, 2019

SCIENCE

NO news is good news E Culotta and DE Koshland Jr

Science 258 (5090), 1862-1865. DOI: 10.1126/science.1361684

http://science.sciencemag.org/content/258/5090/1862

REFERENCES

This article cites 1 articles, 1 of which you can access for free http://science.sciencemag.org/content/258/5090/1862#BIBL

PERMISSIONS

http://www.sciencemag.org/help/reprints-and-permissions

Use of this article is subject to the Terms of Service Science (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. 2017 © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. The title Science is a registered trademark of AAAS.

Downloaded from http://science.sciencemag.org/ on January 23, 2019

ARTICLE TOOLS

NO news is good news.

A startlingly simple molecule unites neuroscience, physiology, and immunology, and revises scientists' understanding of how cells communicate and defe...
3MB Sizes 0 Downloads 0 Views