66 Scientific American September 2000 Edible Vaccines

Vaccines have accomplished near miracles inthe fight against infectious disease. They haveconsigned smallpox to history and should soondo the same for polio. By the late 1990s an internationalcampaign to immunize all the world’s children againstsix devastating diseases was reportedly reaching 80 per-cent of infants (up from about 5 percent in the mid-1970s) and was reducing the annual death toll fromthose infections by roughly three million.

Yet these victories mask tragic gaps in delivery. The 20percent of infants still missed by the six vaccines—againstdiphtheria, pertussis (whooping cough), polio, measles,tetanus and tuberculosis—account for about two millionunnecessary deaths each year, especially in the most re-mote and impoverished parts of the globe. Upheavals inmany developing nations now threaten to erode the ad-vances of the recent past, and millions still die from infec-tious diseases for which immunizations are nonexistent,unreliable or too costly.

This situation is worrisome not only for the places thatlack health care but for the entire world. Regions harbor-ing infections that have faded from other areas are likebombs ready to explode. When environmental or socialdisasters undermine sanitation systems or displace com-munities—bringing people with little immunity into con-tact with carriers—infections that have been long gonefrom a population can come roaring back. Further, as in-ternational travel and trade make the earth a smallerplace, diseases that arise in one locale are increasinglypopping up continents away. Until everyone has routineaccess to vaccines, no one will be entirely safe.

In the early 1990s Charles J. Arntzen, then at TexasA&M University, conceived of a way to solve many ofthe problems that bar vaccines from reaching all toomany children in developing nations. Soon after learningof a World Health Organization call for inexpensive,oral vaccines that needed no refrigeration, Arntzen visit-ed Bangkok, where he saw a mother soothe a crying

by William H. R. Langridge

Edible Vaccines

FOODS UNDER STUDY as alternatives to injectable vac-

cines include bananas, potatoes and tomatoes, as well as

lettuce, rice, wheat, soybeans and corn.

One day children may get immunized by munchingon foods instead of enduring shots. More

important, food vaccines might save millions whonow die for lack of access to traditional inoculants

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baby by offering a piece of banana. Plant biologists had al-ready devised ways of introducing selected genes (the blue-prints for proteins) into plants and inducing the altered, or“transgenic,” plants to manufacture the encoded proteins.Perhaps, he mused, food could be genetically engineered toproduce vaccines in their edible parts, which could then beeaten when inoculations were needed.

The advantages would be enormous. The plants could begrown locally, and cheaply, using the standard growingmethods of a given region. Because many food plants can beregenerated readily, the crops could potentially be producedindefinitely without the growers having to purchase moreseeds or plants year after year. Homegrown vaccines wouldalso avoid the logistical and economic problems posed byhaving to transport traditional preparations over long dis-tances, keeping them cold en route and at their destination.And, being edible, the vaccines would require no syringes—which, aside from costing something, can lead to infectionsif they become contaminated.

Efforts to make Arntzen’s inspired vision a reality are stillquite preliminary. Yet studies carried out in animals over thepast 10 years, and small tests in people, encourage hope thatedible vaccines can work. The research has also fueled spec-ulation that certain food vaccines might help suppress au-toimmunity—in which the body’s defenses mistakenly attacknormal, uninfected tissues. Among the autoimmune disor-ders that might be prevented or eased are type I diabetes (thekind that commonly arises during childhood), multiple scle-rosis and rheumatoid arthritis.

By Any Other Name …

Regardless of how vaccines for infectious diseases are de- livered, they all have the same aim: priming the immunesystem to swiftly destroy specific disease-causing agents, orpathogens, before the agents can multiply enough to causesymptoms. Classically, this priming has been achieved by pre-senting the immune system with whole viruses or bacteriathat have been killed or made too weak to proliferate much.

On detecting the presence of a foreign organism in a vac-cine, the immune system behaves as if the body were underattack by a fully potent antagonist. It mobilizes its variousforces to root out and destroy the apparent invader—target-ing the campaign to specific antigens (proteins recognized asforeign). The acute response soon abates, but it leaves be-hind sentries, known as “memory” cells, that remain onalert, ready to unleash whole armies of defenders if the realpathogen ever finds its way into the body. Some vaccines

provide lifelong protection; others (such as those for choleraand tetanus) must be readministered periodically.

Classic vaccines pose a small but troubling risk that thevaccine microorganisms will somehow spring back to life,causing the diseases they were meant to forestall. For thatreason, vaccine makers today favor so-called subunit prepa-rations, composed primarily of antigenic proteins divorcedfrom a pathogen’s genes. On their own, the proteins have noway of establishing an infection. Subunit vaccines, however,are expensive, in part because they are produced in culturesof bacteria or animal cells and have to be purified out; theyalso need to be refrigerated.

Food vaccines are like subunit preparations in that they areengineered to contain antigens but bear no genes that wouldenable whole pathogens to form. Ten years ago Arntzen un-derstood that edible vaccines would therefore be as safe assubunit preparations while sidestepping their costs and de-mands for purification and refrigeration. But before he andothers could study the effects of food vaccines in people, theyhad to obtain positive answers to a number of questions.Would plants engineered to carry antigen genes producefunctional copies of the specified proteins? When the foodplants were fed to test animals, would the antigens be de-graded in the stomach before having a chance to act? (Typi-cal subunit vaccines have to be delivered by injection precise-ly because of such degradation.) If the antigens did survive,would they, in fact, attract the immune system’s attention?And would the response be strong enough to defend the ani-mals against infection?

Additionally, researchers wanted to know whether ediblevaccines would elicit what is known as mucosal immunity.Many pathogens enter the body through the nose, mouth orother openings. Hence, the first defenses they encounter arethose in the mucous membranes that line the airways, the di-gestive tract and the reproductive tract; these membranesconstitute the biggest pathogen-deterring surface in the body.When the mucosal immune response is effective, it generatesmolecules known as secretory antibodies that dash into the

Edible Vaccines Scientific American September 2000 67

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BANANA TREES AND TOMATO PLANTS growing at the

Boyce Thompson Institute for Plant Research at Cornell Uni-

versity have been genetically engineered to produce vaccines in

their fruit. Bananas are particularly appealing as vaccines be-

cause they grow widely in many parts of the developing world,

can be eaten raw and are liked by most children.

Copyright 2000 Scientific American, Inc.

cavities of those passageways, neutraliz-ing any pathogens they find. An effec-tive reaction also activates a systemic re-sponse, in which circulating cells of theimmune system help to destroy invadersat distant sites.

Injected vaccines initially bypass mu-cous membranes and typically do a poorjob of stimulating mucosal immune re-sponses. But edible vaccines come intocontact with the lining of the digestivetract. In theory, then, they would activateboth mucosal and systemic immunity.That dual effect should, in turn, help im-prove protection against many danger-ous microorganisms, including, impor-tantly, the kinds that cause diarrhea.

Those of us attempting to developfood vaccines place a high priority oncombating diarrhea. Together the maincauses—the Norwalk virus, rotavirus,Vibrio cholerae (the cause of cholera)and enterotoxigenic Escherichia coli (atoxin-producing source of “traveler’sdiarrhea”)—account for some threemillion infant deaths a year, mainly indeveloping nations. These pathogensdisrupt cells of the small intestine inways that cause water to flow from theblood and tissues into the intestine. Theresulting dehydration may be combatedby delivering an intravenous or oral so-lution of electrolytes, but it often turnsdeadly when rehydration therapy is notan option. No vaccine practical forwide distribution in the developing na-

tions is yet available to prevent these ills.By 1995 researchers attempting to an-

swer the many questions before themhad established that plants could indeedmanufacture foreign antigens in theirproper conformations. For instance,Arntzen and his colleagues had intro-duced into tobacco plants the gene fora protein derived from the hepatitis Bvirus and had gotten the plants to syn-thesize the protein. When they injectedthe antigen into mice, it activated thesame immune system components thatare activated by the virus itself. (Hep-atitis B can damage the liver and con-tribute to liver cancer.)

Green Lights on Many Fronts

But injection is not the aim; feedingis. In the past five years experimentsconducted by Arntzen (who moved tothe Boyce Thompson Institute for PlantResearch at Cornell University in 1995)and his collaborators and by my groupat Loma Linda University have demon-strated that tomato or potato plantscan synthesize antigens from the Nor-walk virus, enterotoxigenic E. coli, V.cholerae and the hepatitis B virus. More-over, feeding antigen-laced tubers orfruits to test animals can evoke mucosaland systemic immune responses that ful-ly or partly protect animals from subse-quent exposure to the real pathogens or,in the case of V. cholerae and enterotox-

igenic E. coli, to microbial toxins. Edi-ble vaccines have also provided laborato-ry animals with some protection againstchallenge by the rabies virus, Helicobac-ter pylori (a bacterial cause of ulcers)and the mink enteric virus (which doesnot affect humans).

It is not entirely surprising that anti-gens delivered in plant foods survive thetrip through the stomach well enoughto reach and activate the immune sys-tem. The tough outer wall of plant cellsapparently serves as temporary armorfor the antigens, keeping them relativelysafe from gastric secretions. When thewall finally begins to break up in the in-testines, the cells gradually release theirantigenic cargo.

Of course, the key question is whetherfood vaccines can be useful in people.The era of clinical trials for this technol-ogy is just beginning. Nevertheless, Arnt-zen and his collaborators obtained reas-suring results in the first published hu-man trial, involving about a dozensubjects. In 1997 volunteers who atepieces of peeled, raw potatoes contain-ing a benign segment of the E. coli toxin(the part called the B subunit) displayedboth mucosal and systemic immune re-sponses. Since then, the group has alsoseen immune reactivity in 19 of 20 peo-ple who ate a potato vaccine aimed atthe Norwalk virus. Similarly, after Hil-ary Koprowski of Thomas JeffersonUniversity fed transgenic lettuce carrying

68 Scientific American September 2000 Edible Vaccines

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IGN1 Cut leaf. 2 Expose leaf to bacte-

ria carrying an antigengene and an antibiotic-resistance gene.Allowbacteria to deliver thegenes into leaf cells.

3 Expose leaf to an anti-biotic to kill cells that lackthe new genes. Wait forsurviving (gene-altered)cells to multiply and forma clump (callus).

4 Allow callus to sproutshoots and roots.

5 Put in soil. Within three months, the plantlets will grow into plants bearing antigen-laden vaccine potatoes.

BACTERIAL CELL PLANT CELL

PLASMID

GENE TRANSFER

ANTIGEN GENEDNA

ANTIBIOTIC-RESISTANCE

GENEBACTERIAL SUSPENSION

ANTIBIOTIC MEDIUM

DEAD CELL CALLUS

VACCINEPOTATOES

One way of generating edible vaccines relies on thebacterium Agrobacterium tumefaciens to deliver intoplant cells the genetic blueprints for viral or bacterial

“antigens”—proteins that elicit a targeted immuneresponse in the recipient.The diagram illustrates theproduction of vaccine potatoes.

HOW TO MAKE AN EDIBLE VACCINE

Copyright 2000 Scientific American, Inc.

Edible Vaccines Scientific American September 2000 69

a hepatitis B antigen to three volunteers,two of the subjects displayed a good sys-temic response. Whether edible vaccinescan actually protect against human dis-ease remains to be determined, however.

Still to Be Accomplished

In short, the studies completed so farin animals and people have provideda proof of principle; they indicate thatthe strategy is feasible. Yet many issuesmust still be addressed. For one, theamount of vaccine made by a plant islow. Production can be increased in dif-ferent ways—for instance, by linkingantigen genes with regulatory elementsknown to help switch on the genes morereadily. As researchers solve that chal-lenge, they will also have to ensure thatany given amount of a vaccine food pro-vides a predictable dose of antigen.

Additionally, workers could try to en-hance the odds that antigens will activatethe immune system instead of passingout of the body unused. General stimula-tors (adjuvants) and better targeting tothe immune system might compensate inpart for low antigen production.

One targeting strategy involves linkingantigens to molecules that bind well toimmune system components known asM cells in the intestinal lining. M cellstake in samples of materials that haveentered the small intestine (includingpathogens) and pass them to other cellsof the immune system, such as antigen-presenting cells. Macrophages and oth-er antigen-presenting cells chop up theiracquisitions and display the resultingprotein fragments on the cell surface. Ifwhite blood cells called helper T lym-phocytes recognize the fragments asforeign, they may induce B lympho-cytes (B cells) to secrete neutralizing an-tibodies and may also help initiate abroader attack on the perceived enemy.

It turns out that an innocuous seg-ment of the V. cholerae toxin—the Bsubunit—binds readily to a molecule onM cells that ushers foreign material intothose cells. By fusing antigens from oth-er pathogens to this subunit, it shouldbe possible to improve the uptake ofantigens by M cells and to enhance im-mune responses to the added antigens.The B subunit also tends to associatewith copies of itself, forming a dough-

nut-shaped, five-membered ring with ahole in the middle. These features raisethe prospect of producing a vaccinethat brings several different antigens toM cells at once—thus potentially ful-fulling an urgent need for a single vac-cine that can protect against multiplediseases simultaneously.

Researchers are also grappling withthe reality that plants sometimes growpoorly when they start producing largeamounts of a foreign protein. One solu-tion would be to equip plants with reg-ulatory elements that cause antigen genesto turn on—that is, give rise to the encod-ed antigens—only at selected times (suchas after a plant is nearly fully grown oris exposed to some outside activator mol-ecule) or only in its edible regions. Thiswork is progressing.

Further, each type of plant poses itsown challenges. Potatoes are ideal inmany ways because they can be propa-gated from “eyes” and can be stored forlong periods without refrigeration. Butpotatoes usually have to be cooked to bepalatable, and heating can denature pro-teins. Indeed, as is true of tobacco plants,potatoes were not initially intended to be

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1 M cells pass the antigen tomacrophages

and B cells

2 Macrophages display

pieces of the antigen

to helperT cells

3 T cells stimulate B cells and seek out antigens at distant sites

4 Activated B cells make and release antibodies

able toneutralize

the antigen

1 Memoryhelper T cellsprod cytotoxic T cells to attackinfected cells

3 Antibodiesquickly neutralize the invader

2 Memory helper T cells swiftly stimulate antibody secretion

HELPER T CELL

MACROPHAGE CYTOTOXICT CELL

MEMORYHELPER T CELL

MEMORY B CELL

INFECTEDCELL

WHEN A DISEASE AGENT APPEARSINITIAL RESPONSE

STIMULATORY SECRETIONS

M CELL ANTIBODY

B CELL

ANTIGEN FROMVACCINE

ARRIVING VIRUS

Copyright 2000 Scientific American, Inc.

used as vaccine vehicles; they were stud-ied because they were easy to manipu-late. Surprisingly, though, some kinds ofpotatoes are actually eaten raw in SouthAmerica. Also, contrary to expectations,cooking of potatoes does not always de-stroy the full complement of antigen. Sopotatoes may have more practical meritthan most of us expected.

Bananas need no cooking and aregrown widely in developing nations, butbanana trees take a few years to mature,and the fruit spoils fairly rapidly afterripening. Tomatoes grow more quicklyand are cultivated broadly, but they toomay rot readily. Inexpensive methodsof preserving these foods—such as dry-ing—might overcome the spoilage prob-

lem. Among the other foods under con-sideration are lettuce, carrots, peanuts,rice, wheat, corn and soybeans.

In another concern, scientists need tobe sure that vaccines meant to enhanceimmune responses do not backfire andsuppress immunity instead. Researchinto a phenomenon called oral tolerancehas shown that ingesting certain pro-teins can at times cause the body to shutdown its responses to those proteins. Todetermine safe, effective doses and feed-ing schedules for edible vaccines, manu-facturers will need to gain a better han-dle on the manipulations that influencewhether an orally delivered antigen willstimulate or depress immunity.

A final issue worth studying is whetherfood vaccines ingested by mothers canindirectly vaccinate their babies. In the-ory, a mother could eat a banana or twoand thus trigger production of antibod-ies that would travel to her fetus via theplacenta or to her infant via breast milk.

Nonscientific challenges accompanythe technical ones. Not many pharma-ceutical manufacturers are eager to sup-port research for products targeted pri-marily to markets outside the lucrativeWest. International aid organizations andsome national governments and philan-thropies are striving to fill the gap, butthe effort to develop edible vaccines re-mains underfunded.

In addition, edible vaccines fall underthe increasingly unpopular rubric of “ge-netically modified” plants. Recently aBritish company (Axis Genetics) thatwas supporting studies of edible vaccinesfailed; one of its leaders lays at leastpart of the blame on investor worryabout companies involved with geneti-cally engineered foods. I hope, however,that these vaccines will avoid seriouscontroversy, because they are intendedto save lives and would probably beplanted over much less acreage than oth-er food plants (if they are raised outsideof greenhouses at all). Also, as drugs,they would be subjected to closer scruti-ny by regulatory bodies.

Fighting Autoimmunity

Consideration of one of the chal-lenges detailed here—the risk of in-ducing oral tolerance—has recently ledmy group and others to pursue ediblevaccines as tools for quashing autoim-munity. Although oral delivery of anti-gens derived from infectious agents of-ten stimulates the immune system, oraldelivery of “autoantigens” (proteins de-

Edible Vaccines

As research into edible vaccines is progressing,so too are efforts to make foodsmore nutritious.A much publicized example,“golden rice,”takes aim at vita-min A deficiency, rampant in many parts of Asia, Africa and Latin America. Thiscondition can lead to blindness and to immune impairment,which contributes tothe death of more than a million children each year.

Rice would be a convenient way to deliver the needed vitamin, because thegrain is a daily staple for a third or more of all people on the earth. But natural va-rieties do not supply vitamin A. Golden rice, though, has been genetically alteredto make beta-carotene,a pigment the body converts to vitamin A.

A team led by Ingo Potrykus of the Swiss Federal Institute of Technology andPeter Beyer of the University of Freiburg in Germany formally reported its creationthis past January in Science. In May an agribusiness—Zeneca—bought the rightsand agreed to allow the rice to be donated to facilities that will cross the beta-carotene trait into rice species popular in impoverished areas and will distributethe resulting products to farmers at no charge. (Zeneca is hoping to make itsmoney from sales of the improved rice in richer countries, where beta-carotene’santioxidant properties are likely to have appeal.)

Golden rice is not yet ready to be commercialized, however. Much testing stilllies ahead, including analyses of whether the human body can efficiently absorbthe beta-carotene in the rice.Testing is expected to last at least until 2003.

Meanwhile scientists are trying to enrichrice with still more beta-carotene,with othervitamins and with minerals. At a conferencelast year Potrykus announced success withiron; more than two billion people world-wide are iron deficient.

Investigators are attempting to enhanceother foods as well. In June, for instance, agroup of British and Japanese investigatorsreported the creation of a tomato contain-ing a gene able to supply three times theusual amount of beta-carotene. Conven-tional breeding methods are being used,too, such as in an international project fo-cused on increasing the vitamin and miner-al content of rice and four other staples—wheat,corn,beans and cassava.

Not everyone is thrilled by the recent ge-netic coups.Genetically modified (GM) foodsin general remain controversial.Some oppo-nents contend that malnutrition can be com-bated right now in other ways—say, by con-

structing supply roads. And they fear that companies will tout the benefits of thenew foods to deflect attention from worries over other GM crops, most of which(such as plants designed to resist damage from pesticides) offer fewer clear advan-tages for consumers.High on the list of concerns are risk to the environment and topeople.Supporters of the nutritionally improved foods hope,however,that the ricewon’t be thrown out with the rinse water. —Ricki Rusting, staff writer

“GOLDEN RICE” contains beta-

carotene, which adds color as well

as nutrition to the grain.

Moving against Malnutrition

70 Scientific American September 2000

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SUPPRESSIVESECRETIONS

SUPPRESSORT CELL

AUTO-ANTIGENDELIVEREDIN FOOD

M CELL

INTESTINALCAVITY

CYTOTOXICT CELL

NATURALKILLER

CELL

DESTRUCTIVESECRETIONS

STIMULATORYSECRETIONS

HELPERT CELL

B CELL

ANTIBODY

MACROPHAGE

DAMAGEDAREA

rived from uninfected tis-sue in a treated individ-ual) can sometimes sup-press immune activity—aphenomenon seen fre-quently in test animals. Noone fully understands thereasons for this difference.

Some of the evidencethat ingesting autoanti-gens, or “self-antigens,”might suppress autoimmu-nity comes from studiesof type I diabetes, whichresults from autoimmunedestruction of the insulin-producing cells (beta cells)of the pancreas. This de-struction progresses si-lently for a time. Eventu-ally, though, the loss ofbeta cells leads to a dras-tic shortage of insulin, ahormone needed to helpcells take up sugar fromthe blood for energy. Theloss results in high bloodsugar levels. Insulin injec-tions help to control dia-betes, but they are by nomeans a cure; diabeticsface an elevated risk of se-vere complications.

In the past 15 years, investigators haveidentified several beta cell proteins thatcan elicit autoimmunity in people pre-disposed to type I diabetes. The mainculprits, however, are insulin and a pro-tein called GAD (glutamic acid decar-boxylase). Researchers have also madeprogress in detecting when diabetes is“brewing.” The next step, then, is to findways of stopping the underground pro-cess before any symptoms arise.

To that end, my colleagues and I, aswell as other groups, have developed

plant-based diabetes vaccines, such aspotatoes containing insulin or GADlinked to the innocuous B subunit of theV. cholerae toxin (to enhance uptake ofthe antigens by M cells). Feeding of thevaccines to a mouse strain that becomesdiabetic helped to suppress the immuneattack and to prevent or delay the onsetof high blood sugar.

Transgenic plants cannot yet producethe amounts of self-antigens that wouldbe needed for a viable vaccine againsthuman diabetes or other autoimmune

diseases. But, as is true for infectious dis-eases, investigators are exploring a num-ber of promising schemes to overcomethat and other challenges.

Edible vaccines for combating au-toimmunity and infectious diseases havea long way to go before they will beready for large-scale testing in people.The technical obstacles, though, all seemsurmountable. Nothing would be moresatisfying than to protect the health ofmany millions of now defenseless chil-dren around the globe.

Edible Vaccines Scientific American September 2000 71

The Author

WILLIAM H. R. LANGRIDGE, a leader in the ef-fort to develop edible vaccines for infectious and au-toimmune diseases, is professor in the department ofbiochemistry and at the Center for Molecular Biolo-gy and Gene Therapy at the Loma Linda UniversitySchool of Medicine. After receiving his Ph.D. in bio-chemistry from the University of Massachusetts atAmherst in 1973, he conducted genetic research oninsect viruses and plants at the Boyce Thompson In-stitute for Plant Research at Cornell University. In1987 he moved to the Plant Biotechnology Center ofthe University of Alberta in Edmonton, and hejoined Loma Linda in 1993.

Further Information

Oral Immunization with a Recombinant Bacterial Antigen Produced inTransgenic Plants. Charles J. Arntzen in Science, Vol. 268, No. 5211, pages714–716; May 5, 1995.

Immunogenicity in Humans of a Recombinant Bacterial Antigen Deliv-ered in a Transgenic Potato. C. O. Tacket et al. in Nature Medicine, Vol. 4,No. 5, pages 607–609; May 1998.

A Plant-Based Cholera Toxin B Subunit-Insulin Fusion Protein Protectsagainst the Development of Autoimmune Diabetes. Takeshi Arakawa, JieYu, D. K. Chong, John Hough, Paul C. Engen and William H. R. Langridge inNature Biotechnology, Vol. 16, No. 10, pages 934–938; October 1998.

Plant-Based Vaccines for Protection against Infectious and Autoim-mune Diseases. James E. Carter and William H. R. Langridge in Critical Re-views in Plant Sciences (in press).

SA

The autoimmune reaction responsible for type I diabetesarises when the immune system mistakes proteins that aremade by pancreatic beta cells (the insulin producers) for for-eign invaders.The resulting attack, targeted to the offendingproteins, or “autoantigens,” destroys the beta cells (below,left). Eating small amounts of autoantigens quiets the pro-cess in diabetic mice, for unclear reasons. The autoantigensmight act in part by switching on “suppressor” cells of theimmune system (inset), which then block the destructive ac-tivities of their cousins (below, right).

STOPPING AUTOIMMUNITY

AFTER TREATMENT

Activated suppressor cellsgo to pancreas

PRESERVEDBETA CELL

AUTOANTIGEN

BETA CELL UNDER ATTACK

IN PANCREAS

BEFORE TREATMENT

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Copyright 2000 Scientific American, Inc.