REVIEW–The Bioterrorist Next Door –


InSeptember, an amiable Dutchman stepped up to the podium at a scientific meeting convened on the island of Malta and announced that hehad created a form of influenza that could well be the deadliest contagiousdisease humanity has ever faced. The bombshell announcement, by virologistRon Fouchier of ErasmusMedical Center, sparked weeksof vigorous debate among the world’s experts on bioterrorism, influenza,virology, and national security over whether the research should have beenperformed or announced and whether it should ever be published.

Meanwhile,a joint Japanese-American research team led by the University ofWisconsin’s Yoshihiro Kawaoka says that it, too, has manufactured asuperflu. Additionally, a team at the U.S. Centers for Disease Control and Prevention (CDC) inAtlanta has acknowledged doing similar research, without successfully makingthe über flu. The U.S.National Science Advisory Board for Biosecurity is now deliberating whetherto censor publication of the Fouchier and Kawaoka papers, though it lacks anyactual power to do so: It could so advise scientific journals, but editors would still decide. The advisory boardis expected to release its decision on Dec. 15.

The interest in this brave newworld of biology is not limited to the scientific community. U.S. Secretary ofState Hillary Clinton made a surprise visit to Geneva on Dec. 7, addressing theBiological Weapons Convention review conference. The highest-ranking U.S. official to speakto the biological weapons group in decades, Clinton warned, “The emerging gene-synthesis industry is makinggenetic material widely available. This obviously has many benefits for research,but it could also potentially be used to assemble the components of a deadlyorganism.”

“A crude buteffective terrorist weapon can be made by using a small sample of any number ofwidely available pathogens, inexpensive equipment, and college-level chemistryand biology,” Clinton also stated. “Less than a year ago, al Qaeda inthe Arabian Peninsula made a call to arms for, and I quote, ‘brothers withdegrees in microbiology or chemistry to develop a weapon of massdestruction.'”

Noting that “Itis not possible, in our opinion, to create a verification regime” forbiological weapons compliance under the convention, Clinton called forvoluntary transparency on biological experimentation among the 165 countries thathave signed the agreement.

Officials throughoutthe U.S. government are declining to comment on the influenza experiments orelaborate on Clinton’s comments and appearance in Geneva. The influenza scientistswere politely but firmly instructed recently by U.S. officials to keep theirmouths shut and provide no data or details regarding their experiments toanybody. Sources inside the Dutch, German, and French governments say thatdiscreet agreement was reached among Western leaders to greet the influenzapronouncements with a wall of silence, pending the advisory board’s decisionand detailed analysis of the experiments by classified intelligence andscientific bodies.

Should we worry? Ifthese scientists have indeed used thetechniques that they have verballydescribed (but not yet published) to produce a highly contagious andvirulent form of the so-called “bird flu,” thefeat can at least theoretically be performed by lesser-skilled individuals withnefarious intentions. Perhaps more significantly, the evolutionary leaps might be made naturally, viaflu-infected birds, pigs, even humans. In other words, the research hasimplications for both terrorism and a catastrophic pandemic. Moreover, severalexperimental antecedents involving smallpox-like viruses and polio lendcredence to the idea that concocting or radically altering viruses to createmore lethal or transmissible germs is becoming an easier feat and an accidentalbyproduct of legitimate research.

The advisory board isdebating whether the work, as well as details on how the flu viruses weredeliberately mutated, should be published. That is the wrong question. As apractical matter, experimental results are now shared with lightning speedbetween laboratories, and I know that several leading scientists outside Fouchier’s and Kawaoka’s labs already recognize exactly how these experiments wereexecuted. The genie is out of the bottle: Eager graduate students in virologydepartments from Boston to Bangkok have convened journal-review debatesreckoning exactly how these viral Frankenstein efforts were carried out.

Thelist of attempts by governments to stifle scientific information is lengthy and markedby failure.Iwas at a 1982optical engineering meeting in San Diego that was disrupted by a censorshiporder handed down by the Ronald Reagan administration’ssecurity chief, Adm. Bobby RayInman, compelling seizure of about 100 papers. The administrationclaimed the findings in those mathematics papers would, in Soviet hands, posean existential threat to the UnitedStates –an assertion that proved laughable when the studies soon saw the light of day.In 2006, George W. Bush’s administrationtriedto block climate change–related presentations by NASA scientist James Hansen;everysingle one of Hansen’s data points swiftly appeared on the Internet.

Rather than trying to censorresearch because its inevitable release might be harmful, we ought to be havinga frank, open discussion about its implications. The correctquestions that scientists, national security and political leaders, and thepublic ought to be asking are:Howdifficult was it to perform these experiments? Could they be replicated in thehands of criminals or would-be terrorists?Whathave these experiments shown us about the likelihood that the H5N1 “birdflu” virus will naturally evolve into this terrifying form?Arewe safer, or less secure, today due to the post-2001 anthrax-inspiredproliferation of high-security biological laboratories?

What Genie HasPopped from Which Bottle?

In1997, the form ofinfluenza now dubbed H5N1, or avian flu, emerged in Hong Kong, killing six people and forcing the destruction of every chickenin the protectorate. The virus had been circulating in aquatic migratory birdsand domestic poultry flocks within mainland China for at least two years, butit was not recognized as a unique entity until the Hong Kong outbreak. Thespreadof H5N1 was temporarily halted by Hong Kong health official Margaret Chan,who ordered the mass culling of the area’s poultry. Chan now serves as directorgeneral of theWorld Health Organization (WHO).

Thevirus reappeared in Thailand in 2003, killing flocks of chickens and ducks that November and infecting humans in January 2004 in Thailand and Vietnam. TheH5N1 virus mutated in 2005 as it spread among various species of birdsmigrating through northern China, giving avian flu the capacity to infect a fargreater range of bird species, as well as mammals — includinghuman beings. That year,human and animal outbreaks of H5N1 appeared across a vast expanseof the globe,from the southernmost Indonesian islands, up to central Siberia, and as farwest as Germany.

Bymid-2011, H5N1 had becomea seasonal occurrence in a swath of the world spanning 63 countries of Asia, thePacific Islands, Eastern and Western Europe, the Middle East, and North and West Africa. Since its 2004 reappearance,H5N1 has sickened at least 565 people, killing 331, for an overall mortalityrate of 59 percent. The Ebola virus can be more lethal — as high as 90percent — but is not terribly contagious. Rabies, in the absence ofvaccination, is 100 percent lethal, but it can only be transmitted through thebite of an animal. It is estimated that in pre-vaccine days, the smallpoxvirus killed about a third of the people it infected.

Only influenzaholds the potential of both severe contagion and, in the case of H5N1,astounding mortality rates, ranging from about 35percentin Egypt (where the virus circulates widely) to more than 80percentin parts of Indonesia (where 178 confirmed cases have resulted in 146 deaths).The virulence of H5N1 is far higher than that seen with any other influenza,including the notorious 1918 flu that killed an estimated 62million people in less than two years. (Some reckonings of 1918 deathtolls in poor countries that lackedepidemic reporting systems, such as China, India, and all of Africa, put thefinal mortality at 100 million, when the world population was just 1.8 billionand commercial air travel did not exist.) Six years ago, thespread of H5N1 sparked concern in the Executive Office of the Secretary-General of theUnited Nations, the White House, and many of its counterpart centers ofgovernment worldwide. Tremendous efforts ensued to kill infected domesticpoultry, rapidly identify outbreaks, and pool scientific resources to track andscrutinize various H5N1 strains as they emerged. Some 400 million domesticbirds were killed between 2004 and 2010, at an estimated global cost of $20billion. It all seemed to work: Bythe end of 2008 the annual number of poultry outbreaks of H5N1 had shrunk from4,000 down to 300.

Infearful anticipation,health and virus experts also watched for signs that the virus was spreading fromone person to another. Although there were clusters of victims, infected families, andisolated person-to-person possible infections, the dreaded emergence of a formof humanly contagious H5N1 never occurred. By 2010,manyleading virologists concluded that H5N1 was a terrifying germ — for birds. The confident consensus, however,was that the mutations that avian flu would have to undergo to be able to spreadeasily from one human lung to another’s were so complex as to approachevolutionary impossibility.

Bymid-2011 the global response to avian flu had grown lethargic and complacent. Predictably,in the absence of vigilant bird-culling and vaccination efforts, troubleemerged as outbreaks mounted across Asia. Between January 2010 and the springof 2011 more than 800 outbreaks were dutifully logged by government officialsworldwide. In late July, a 4-year-oldgirldied of H5N1 in Cambodia, making her the seventh avian flu mortality in acountry that had been free of the microbe for a long time.

OnAug. 29, the Food andAgriculture Organization sounded a mutation alarm, notinga new strain of the virus, dubbed H5N1-,had surfaced in wild and domestic bird populations in Vietnam. Vietnam was oneof six countries (including Bangladesh, Egypt, Indonesia, China, and India) inwhich avian flu had become endemic,meaning it permanently circulated among local and migratory birds. A week later, aBoston biotech company called Replikins announced the discovery of a mutant combinationof the avian H5N1 flu and the so-called “swine flu” that spread swiftly amongpeople during the 2009 global pandemic. Replikins’sclaim implied that the highly virulent bird flu could gain the capacity tospread rapidly between people by absorbing infection genes from thecontagious-but-wimpy H1N1 swine influenza.

Althoughthese announcements sparked a minorpanic in Asia, further scrutiny of both the and Replikins’sclaim left the WHO convincedthat no new human threat loomed. In early September, acollective sigh of public-health relief was expelled.

Threedays later, the conference of the European ScientistsFighting Influenza (ESWI, the Romance-language acronym) convened in Malta,opening with scientific evidence of current pandemic potentials.The stage was set by renowned University of Hong Kong flu scientist MalikPeiris, who described with exquisite precision which genetic factors made the”swine flu,” H1N1, highly contagious between pigs, ferrets, humans, and othermammals. Peiris offered evidence that the 2009 H1N1 pandemic started amongAmerican pigs but had beencirculating in swine populations throughout North America and China for decadesbefore making the mutational steps that sparked global spread.

Fouchier, the Dutch scientist, who has tracked H5N1 avian flu outbreaks in Indonesiafor years, then suggested that vaccines used for years on chicken farms are nowfailing. Perhaps under selective evolutionary pressure, forms ofvaccine-resistant H5N1 have appeared, Fouchier told the Malta meeting, adding,”We discovered that only one to three substitutions are sufficient to cause largechanges in antigenic drift.” In otherwords, naturallyoccurring, infinitesimal changes in the flu’s geneticmaterial are sufficient to render vaccines useless.

Fouchierwent on to describe what he dubbed his “stupid“experiment of infecting ferrets in his lab sequentiallywith H5N1. One set of the animals would be infected, and then Fouchierwould withdraw nasal fluid from the ferretsanduse it to inoculation-infect a second set of animals. After 10 repeats, thesuperkiller H5N1 emerged, spreading throughthe air rapidly, killing 75 percent ofthe exposed animals. (Because Fouchier’s work has not been published,accounts of the experiment vary, based on reporting from those who werepresent to hear his Malta speech. In some accounts the superlethal bird fluresulted from only five serial passages in ferrets — anumber far more likely to occur randomly in nature.)

“Thisvirus is airborne and as efficiently transmitted as the seasonal virus,” Fouchier told theMalta crowd, adding that he had identified which specific five mutationswere necessary. Only five minute switches in RNA nucleotides — themost basic elements of genetics — wereneeded.

“Thisis very bad news, indeed,” a sober Fouchier concluded.

The five dire mutations (technically, singlenucleotide changes occurring inside two genes) have been separately found ininfluenza viruses circulating in the world. The actual mutations are not,therefore, unique. Fouchier’s only innovation was in making all five occurinside the same virus at once. The more famous flu researcher from Erasmus,Albert Osterhaus, told reporters that what is done in the lab canhappen in nature, adding, “Expect the unexpected.… Themutations are out there, but they have not gotten together yet.”

Under questioningin Malta, Fouchier said his ferret form of H5N1 would certainly spread amonghumans and is “one of the most dangerous viruses you can make.”

Shortly after Fouchier’s announcement, Kawaoka, the University of Wisconsin scientist, let itbe known that he, too, has made an airborne-transmissible H5N1 that readilyspreads among mammals. Kawaoka’s efforts were jointly executed by teams heheads at the University of Wisconsin and the University of Tokyo. Nofurther details regarding this effort are publicly available, though Kawaokahas submitted a paper detailing his techniques and discoveries for review bythe U.S. National Science Advisory Board for Biosecurity, as has Fouchier. Bothscientists wish to publish their work in major scientific journals.

Scientists are deeply divided regardingpublication. “If I were a journal editor and I received an article thatsaid how to make a bioweapon, I’d never publish it, but that would be based onself-regulation, not any government restriction,” anthrax expert andretired Harvard University professor Matt Meselson told an interviewer. “I’ve never heard of a case where thegovernment has restricted publication. I don’t think it would work.” Butfellow anthrax researcher Paul Keim, who chairs the advisory board, toldreporters, “I can’t think of another pathogenic organism that is asscary as this one. I don’t think anthrax is scary at all compared to this.”

Perhaps the mostintriguing comments came from Australian scientist Ian Ramshaw,who suggested that the Fouchier or Kawaoka papers could serve as bioterrorismblueprints: “Asa researcher you do the good thing, but in the wrong hands it could be used forevil. In this case I’m not so worried about bioterrorism. It’s the disgruntledresearcher who is dangerous — the rogue scientist,” Ramshawwarned, according to the Canberra Times.Ten years ago Ramshaw accidentally made a superkillerform of mousepox, the rodent version of smallpox, in his AustralianNational University laboratory. He injected lab mice with the pox virus to testout a completely unrelated contraceptive vaccine, but the experimenttransformed the virus into a deadly monster with a 100 percent fatality rate.In 2001 Ramshaw’s work spurred high-level concern about the use of geneticallymodified smallpox by a rogue nation or terrorist group, launchingthe vigorous, multibillion-dollar post-9/11American smallpox vaccine effort, as detailed in my new book, I Heard the Sirens Scream.

Within two years of Ramshaw’s accidentalmousepox creation, separate labs deliberately created viruses. In 2002,researchers at the State University of New York in Stony Brook built a poliovirus from its genetic blueprint. This constituted a proof of principle,demonstrating that in a sufficiently skilled laboratory, all that is requiredto make a deadly virus is its nucleotide sequence — details of which are nowroutinely published for everything from anthrax to the Ebola virus. At the time, Eckard Wimmer, the lead scientist on theproject, warned: “The worldhad better be prepared. This shows you can re-create a virus from writteninformation.”

Thefollowing year another scientific team deliberately mimicked Ramshaw’s mousepoxaccident, not only with the rodent form of pox but also with pox viruses thatinfect rabbits and cows. And in 2005 the CDC famously joined fragments of RNAfrom thawed tissue of victims of the 1918 flu, re-creating the originalsuperkiller.

The Genie Is Out of the Bioterrorism and Pandemic Bottles:How Scared Should We Be?

This April, a team of CDC scientists publishedword that it had tried to manipulateH5N1 genes to render the avian virus a human-to-human spreader, but couldnot make it work. The team used a different method from the one apparently deployed byFouchier and Kawaoka’s team: The CDC group directly altered the genes ofviruses, rather than sequentially infecting ferret after ferret. The CDCconcluded, “An improvement intransmission efficiency was not observed with any of the mutants compared tothe parental viruses, indicating that alternative molecular changes arerequired for H5N1 viruses to fully adapt to humans and to acquire pandemiccapability.”

Thatseemed comforting.

Butin 2007 a differentCDC team did to the SARS virus what Fouchier apparently has done to H5N1, with lethalresults. Just as Fouchier produced highly infectious bird flu in ferrets bysequentially infecting one group of animals after another, the CDC group passedthe SARS virus through one group of mice after another. Mice are normallyharmlessly infected by SARS, which cannot cause disease in the rodents. But after 15 such passages, the team got a 100percent fatal form of the virus. Moreover, it was an airbornekiller, sniffed out the air. (SARS, or severe acute respiratory syndrome, killed more than 900 peopleworldwide in 2002 and 2003, mostly in China.)

TheUniversity of Minnesota’s Michael Osterholm, an expert on both bioterrorismand pandemics, thinks that understanding how animals might pass a virus likeSARS or H5N1 among themselves, in a fashion in nature that mimics thelaboratory experiments, may hold a vital key to predicting future epidemics. “Wedon’t want to give bad guys a road map on how to make bad bugs reallybad,” he recently told Sciencereporter MartinEnserink. Health experts, however, do applaud the controversial research becauseit shows which mutations are necessary and at least one way they might arise.

There is no way to put a number on theprobability of such natural mutational events. Are the odds 50-50 that a deadly,contagious form of H5N1 will wreak havoc across the world in the next 10 years?Anybody who claims to answer such a question, or pooh-pooh the asking of it, isa fool or a charlatan. It is an unknown.

WhatAbout the Proliferation of High-Security Biology Labs: Good or Dangerous?

Before the anthrax mailings terrorizedAmerica in 2001, there were only a handful of top security Biosafety Level 4(BSL-4) labs in the world and a few dozen of the next-level BSL-3 facilities.The CDC and U.S. Army had the two largest pre-2001 BSL-4 labs, which nestedlike matryoshka dolls, with one layer of security inside another and another. Theinnermost labs required identity clearance, scientists wore protective spacesuits, and all air and water were specially cleansed and filtered to preventaccidental escape of Ebola, smallpox, and dozens of other superlethalorganisms. The world’s most dangerous known microbes were carefully kept underlock and key in a clearly identified handful of BSL-4 labs.

Even the less-secure BSL-3 labs requiredthat scientists undergo security checks, wear spacesuits, and breathe throughspecial respirators. Their numbers were finite and known, and researchersworking on influenza, anthrax, or other deadly-but-treatable microbesrepresented a fairly small pool of scientists.

Since the 9/11 terrorist attacks, however, the number of suchlaboratories has proliferated spectacularly, not only inside the United States, but allover the world. In 2001 the United States had five “centers of excellence,” asthey were called, devoted to bioterrorism. By the end of 2002, more than 100such centers were named, amid a record-breaking expansion in the numbers oflaboratories and scientists studying anthrax, smallpox, Ebola, botulism, andevery other germ somebody thought could be weaponized. After 9/11, the EuropeanUnion saw the number of BSL-4 labs grow from six to 15. In the United States: from seven to 13. Canada built a BSL-4 complex inWinnipeg. Just as possession of rockets in the 1950s or nuclear power plants inthe 1960s seemed the marks of a serious state power, so having BSL-3 and BSL-4 labssuddenly became a mark of national significance in the world — an achievement towhich countries should aspire. This year India opened its first BSL-4 facility,and it is rumored that Pakistan is now building one.

The proliferation of high-securitylabs means a great deal more than the mere construction of physical buildings. Where 10 yearsago a finite pool of predominantly senior scientists toiled in such facilities,today thousands of graduate students, postdoctoral fellows, technicians, andsenior researchers work in facilities stocked with humankind’s worst microbialfoes. Accidents have occurred with alarming regularity since the labproliferation commenced, as I have detailed in my book. The facilities also constitutelocations wherein individuals could theoretically execute experiments toproduce supergerms without risking harm to themselves or others, regardless ofwhether the intent were noble, as appears to be the case for Fouchier and Kawaoka, or whether the intent were evil, as was the case withthose responsible for the anthrax mailings.

Since 2005, several flu experimentsconducted under BSL-3 conditions have raised eyebrows, as critics have chargedthe work should have been done inside the far more difficult but secure BSL-4conditions. The original 1918 virus was “revived” from a long-frozen human bodyand grown inside a BSL-3 lab. Experiments were done on the 1918 virus in aneffort to discover what genes made it so lethal. And the research that the CDCteam, Fouchier, and Kawaoka performed on the H5N1 virus was all done in BSL-3labs.

In September, when news of the Fouchierwork started to appear in science magazines, Thomas Inglesby of theCenter for Biosecurity at the University of Pittsburgh told New Scientist, “Small mistakesin biosafety could have terrible global consequences.” His Pittsburghcolleague D.A. Henderson concurred: “The potential for escape of thatvirus is staggering.”

According to the FBI, the culprit behindthe 2001 anthrax mailings was Bruce Ivins, who worked in the U.S. Army’sBSL-3 and BSL-4 labs in Maryland. Whether or not the FBI caught the right man — apoint of controversy among scientists — it remains extraordinary that theresponse to what the agency calls “Amerithrax” is the creation of moresuch facilities in which more “Ivins” might toil.

The questions that arise from these H5N1experiments have nothing to do with publication of the Fouchier and Kawaokapapers. We should be asking what we can do to ensure that such terrible man-madeviruses never accidentally escape their laboratory confines or are deliberatelyreleased. And we should heed the question posed in the recently released Hollywood thrillerContagion when a HomelandSecurity character queries a CDC scientist:

“Isthere any way someone could weaponize the bird flu? Is that what we’re lookingat?”

“Someonedoesn’t have to weaponize the bird flu,” the CDC scientist responds, “The birdsare doing that.”

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