Lethal Cascade

The neurologic manifestations ofAIDS are a particularly terrifyingaspect of the disease. As many

as 60 percent of those who have AIDSsuÝer memory loss, motor and behav-ioral diÛculties and cognitive impair-ment. In some cases, nearly half of theneurons in areas of the cortex die. Yetthe mechanisms of human immunode-Þciency virus (HIV) infection in the brainhave remained, in large part, elusive.

Now, however, scientists say a pic-ture is emerging from disparate Þnd-ings, many of them previously consid-ered to be at odds. ÒEven last summerthere was a fair amount of contentious-ness between this personÕs factor andthat personÕs factor,Ó comments Rich-ard T. Johnson, chief neurologist at theJohns Hopkins University School of Med-icine. ÒIt was chaos until a couple ofmonths ago. Now it may all Þt together.Ó

Despite the optimism, the story ofhow HIV damages the brain remainscomplicated and incomplete. Recent ev-idence suggests that certain strains ofHIV preferentially aÝect the organ. Butno one knows how the virus initiallygets in. One theory posits that infectedwhite blood cells serve as Trojan hors-es, covertly ferrying the virus acrossthe blood-brain barrier. Another main-tains the blood-brain barrier is some-how disrupted, permitting the entry ofviral particles or infected cells.

Once there, the virus appears to in-fect and replicate in scavenger cells:brain macrophages and macrophage-like cells, called microglia. Although neu-rons die in the course of the disease,they do not, in general, seem to be in-fectedÑbut Òit is still an open question,Ósays Janice E. Clements, a neuroscientistat Johns Hopkins.

Researchers have proposed manyroutes by which the infected cells couldbring about neuronal death, explainsRichard W. Price, a neurologist at theUniversity of Minnesota. One possibili-ty is that HIV-laden macrophages andmicroglia release cytokines and othercellular compounds that can be toxic.

A second theory suggests that prod-ucts made by the virus itself cause neu-rotoxicity. For example, HIV and HIV-in-fected cells can shed a protein calledgp120, which is found on the surfaceof the virus. This protein binds with amolecule on a form of immune systemcellÑT4 cellsÑthat allows the virus toenter them. Gp120 has also been shownto bring about the production of cyto-

Lethal CascadeA model for the neurologicdamage found in AIDS

Even disregarding what Blankenshipcalls the Òwild cardÓ of volcanism, re-searchers may be hard-pressed to fore-cast AntarcticaÕs future. One commonbelief is that increased precipitation in-duced by global warming over the pastcentury is causing the ice sheet to grow.That claim is unsubstantiated, accord-ing to Stanley S. Jacobs of Lamont-Do-herty. In a recent Nature article entitledÒIs the Antarctic Ice Sheet Growing?,ÓJacobs concluded that there are notenough data for a deÞnitive answer: ÒItis too early to say how the Antarctic icesheet will behave in a warmer world.Ó

Ellen S. Mosley-Thompson of OhioState agrees. She notes that ice coresprovide only rough estimates of theamount of precipitation in a given year,and real-time measurements of precipi-tation around the continent have beenspotty. This season, Mosley-Thompsonßew to the South Pole to set up equip-ment for long-term measurements ofprecipitation, but she says it could takemany years to provide data good enoughto constrain models predicting Antarc-ticaÕs future. ÒWe canÕt even predict theweather for Columbus, Ohio,Ó she says,Òand this is an entire continent.Ó

In the meantime, scientists can onlyspeculate. David R. Marchant, a geolo-gist at the University of Edinburgh, isasked to do just that by journalists vis-iting him at his camp on Ross Island,where he is spending the austral sum-mer. Marchant, his skin reddened bythe wind and 24-hour sunlight, says hefavors the stablist position in what hasbeen called the stablists-versus-dynam-icists debate. Yet even he acknowledg-es that, if the past is any guide, greatchanges could be in store for Antarctica.

During the peak of the last ice age18,000 years ago, he points out, the shelfof ice covering the Ross Sea slumped tothe seaßoor, causing the ice streamsfeeding it to back up. The ice shelf burstits seams, ßowing upward into sur-rounding valleys and burying this sootyspit where Marchant and his two stu-dents have pitched their canary-yellowtents. On the other hand, ice cores andother evidence indicate that the EastAntarctic ice sheet shrank during thatperiod, starved of precipitation.

If global warming persistsÑa possibil-ity Marchant actually doubtsÑthis sce-nario could happen in reverse. Within acentury or two, the West Antarctic icesheet could disintegrate, triggering asurge in sea levels. Eventually, over thou-sands of years, sea levels might dropagain as increased snowfall caused bythe warmer weather builds up the EastAntarctic ice. ÒThis is just arm waving,ÓMarchant says. ÒBut itÕs one possibilitythat should be out there.ÓÑJohn Horgan

28 SCIENTIFIC AMERICAN March 1993 Copyright 1993 Scientific American, Inc.

kines and to alter calcium channels. Thelatter change, either independently or inconjunction with the neurotransmitterglutamate, can damage neurons.

The promise of synthesis was prompt-ed by ongoing discoveries about cyto-kines and astrocytes, a type of glial cellthat sustains neurons. Although prolif-eration of astrocytes is a characteristicof AIDS, the reason for their unnaturalgrowth was not clear. But Howard E.Gendelman, a virologist at the Universi-ty of Nebraska Medical Center, and hiscolleagues may have an answer. Theysuggest that interplay between infectedmacrophages and astrocytes causes themacrophages to make tumor necrosisfactor and interleukin-1. These cyto-kines, in turn, spur the astrocytes to pro-liferate. The researchers found that with-out this interaction cultured, HIV-infect-ed macrophages were unable to do theirdeadly work. This fact Òis important be-cause macrophages require astrocytes,Ósays Leon G. Epstein, a neurovirologistat the University of Rochester.

The team also discovered what ap-pears to be a positive feedback loop.The cytokines are regulated by arachi-donic acid metabolites and platelet-ac-tivating factor, which have been impli-cated in studies of neurologic AIDS andwhich may be released by macrophagesand astrocytes. These compounds pro-mote the production of more cytokines.ÒAstrocytes may serve as an ampliÞer,ÓEpstein notes. He adds that these Þnd-ings may help explain one commonlyobserved phenomenon of AIDS infec-tion: very few HIV-infected cells bringabout extensive damage.

The astrocyte-macrophage interac-tion model appears to dovetail with ageneral theory of neuronal impairment.In many forms of brain injuryÑinclud-ing strokeÑdamage or death is broughtabout by glutamate. This messenger, op-erating through a receptor called NMDA,can cause neurons to become too ex-cited: like overloaded fuses, they burnout. Some of the cytokines and the com-pounds produced by infected macro-phages and by astrocytes may sensitizethe neurons to the deleterious eÝects ofglutamate. ÒThere may be a Þnal com-mon pathway with many initiating fac-tors,Ó Gendelman says. ÒThe NMDA re-ceptor could be that pathway.Ó

And gp120 has a role in this activi-ty as well. Not only does the viral pro-tein stimulate the synthesis of toxic cy-tokines, it appears that it, too, interactswith astrocytes. Dale J. Benos of the Uni-versity of Alabama at Birmingham andothers have found that gp120 can alterastrocytes, interfering with their normalfunction of glutamate uptake. The glu-tamate stimulates additional NMDA re-

SCIENTIFIC AMERICAN March 1993 29Copyright 1993 Scientific American, Inc.

ceptors, increasing the potential for neu-rotoxicity, Benos explains.

Taken together, these Þndings Òbringup some really nice possibilities for ther-apeutics,Ó Johnson notes. ÒIf you couldÞgure out what the cascade is, youcould treat aspects of it.Ó To this end, re-searchers, including Stuart A. Lipton, aneurologist at Harvard University, havebeen studying NMDA antagonists, com-

pounds that prevent glutamate frombinding to the receptor, and calciumchannel blockersÑmany of which areapproved for other uses. Lipton hasbeen able to prevent cell damage in cul-tures, and one NMDA antagonist is al-ready in clinical trials. ÒThe chance ofaÝecting this disease is much more pos-itive than I thought it was a year ago,ÓEpstein says. ÑMarguerite Holloway

NoahÕs Freezerhen Gregory Benford heard biologists discussing the rates at whichspecies are disappearing, he was struck by the resignation in theirvoices. “They were uniformly gloom and doom,” he recalls. “They all

believe we are going to lose a big piece of biodiversity.”So Benford, a physicist at the University of California at Irvine and a popu-

lar author of science fiction, decided some action was in order. “It occurredto me that if we think we’re going to lose it, we have a moral obligation totry to save some samples,” he says. Last November in the Proceedings of theNational Academy of Sciences, Benford proposed doing just that—not only inzoos, gardens and refuges but also flash-frozen in liquid nitrogen.

“Admitting your ignorance about the number and dispersal of species,you should just sample randomly in a threatened region,” Benford says. Smallplants and insects might be frozen whole; other animals and trees might berepresented by embryos or tissue samples. “A plausible estimate is that youcould get representatives of a few percent of the total species.”

A few percent may not sound like much, which is why Benford calls the ef-fort “an emergency salvaging operation” rather than a species inventory. La-bels on the samples would state only their place of origin. No effort wouldbe made to identify or describe the specimens. “The main thing,” he says, “isto get the data and to process them as little as possible.”

Indeed, any attempt to identify the species en route to the freezer wouldprobably make the project impossible. Benford argues that there are notenough taxonomists to catalogue a broad sample from the endangered re-gions. Yet nonspecialists could easily be trained to collect and freeze speci-mens. The project could therefore be conducted fairly inexpensively with lo-cal labor anywhere in the world. Liquid nitrogen would be the refrigerant ofchoice because it offers the best combination of low cost (about 25 centsper liter) and high reliability.

By Benford’s estimate, it would cost less than $2 billion for biologists tocollect samples from all the tropical rain forests and store them for a century.“You can do something on the cheap,” he says. “It’s not like the Supercon-ducting Super Collider.” Independent groups could each tackle a habitat. Ben-ford has suggested, for example, that the Sierra Club might consider sam-pling and freezing the species from the endangered redwood forests.

But what will anyone ever do with the frozen compendium? “That’s depen-dent on future technology,” Benford says. Some simple organisms might stillbe alive after they were defrosted, but most would not. The DNA inside thecells, however, would be largely intact. Benford believes the genetic infor-mation in the DNA could be analyzed for its secrets. The DNA might even beinserted into living cells to re-create an extinct species, à la Jurassic Park.

According to Benford, one reviewer of his paper had asked why he did notpropose storing just the DNA. “The reason is that it’s more expensive to pullthe DNA out of a beetle than it is to put the beetle in a bag,” Benford ex-plains. “And you get much more information out of a whole beetle.”

At the urging of the National Science Foundation, Benford says, he plansto organize a small conference later this year to discuss the idea. Critics willundoubtedly find weaknesses in it. The sampling of any habitat will almostcertainly be biased in some way: soil microorganisms, for example, may besampled less thoroughly than larger animals or plants. It is hard to guesshow much information about an entire species could be deduced from a sin-gle frozen individual. But even if Benford’s freezing plan is imperfect, thequestion remains: What are the alternatives? —John Rennie

W

Ameeting of the American Astro-nomical Society may seem anunlikely place to be confronted

with a proud coupleÕs baby pictures.But that did not discourage Stephen E.and Karen M. Strom of the Universityof Massachusetts at Amherst. And theinterest expressed was more than po-lite, perhaps because the pictures por-trayed newborn stars, still swaddled inthick clouds of gas and dust.

In collaboration with K. Michael Mer-rill of Kitt Peak National Observatory,the Stroms have produced images thatreveal aspects of star formation neverbefore seen. The observations also pro-vide information about the disks of mat-ter that seem to surround young stars.Such disks, which are thought to formthe raw material of planetary systemssuch as the solar system, are the subjectof provocative new observations by theHubble Space Telescope.

One of the primary obstacles to watch-ing stars being born is that the birthstake place deep within dense nebulae.Enshrouding dust scatters visible light,obscuring the earliest stages of stellarformation. Infrared rays have a longerwavelength than does light and so areable to penetrate the thick clouds andto supply information about what ishappening within. Only for the past fewyears, however, have detectors existedthat can generate high-resolution imagesof the infrared sky.

Using these detectors, which StephenStrom says Òhave revolutionized proto-stellar astronomy,Ó Merrill and theStroms inspected Lynds 1641, an in-terstellar cloud lying on the outskirtsof the Orion Nebula. (The Orion Nebulais visible to the naked eye as a fuzzyÒstarÓ in OrionÕs sword.) They capturedunprecedentedly clear views of star-forming regions that include some ofthe youngest stars ever seenÑabout500,000 years old; the sun is 4.6 billionyears old, for comparison.

As the researchers peered deep intothe stellar nursery, they observed starsclustered into eight small gatherings,each about one light-year wide and con-taining anywhere from a few dozen to150 members. Previously, astronomershad observed stars forming either aloneor in vast congregations, which made itimpossible to see the details. The newresults Òshow that the most commonpath of stellar formation may be insmall groups,Ó Stephen Strom says. Thehuge, spectacular associations of youth-

Young SunsTelescope technology pullsthe veil from infant stars

30 SCIENTIFIC AMERICAN March 1993 Copyright 1993 Scientific American, Inc.