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Cover Story Genomics on High Alert

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Since September 11, genomics technology development suddenly seems crucial to national security.

By Adrienne J. Burke

 

Within days of the September 11 terrorist attacks on the US, genomics labs and technology companies were being called to action. As an emergency response, the Bush administration had appropriated $40 billion for “defense, rescue and recovery, and antiterrorist spending,” and the possibility that terrorists would employ biological weapons next was on every security official’s mind, not to mention every newspaper’s front page.

Money quickly began trickling down to the genomics industry: The director of a DOE-funded university laboratory that analyzes the genomes of pathogens most likely to be used as biological weapons received an e-mail from the DOD asking how quickly he could ramp up his work; the Army put a Silicon Valley microarray manufacturer on standby and then gave it the go-ahead on a $10 million feasibility study of microarrays that could be worn by soldiers and civilians in high-risk jobs to sense biowarfare agents; and Cepheid saw government orders of its PCR biodetection platforms (and, consequently, its stock price) take a leap. During a 30-minute phone interview with GT, Cepheid COO Kurt Petersen was interrupted with the news that another DOD purchase order had just come in.

Under intensified security restrictions, government officials declined to comment on what percentage of the $40 billion emergency fund would go to biological defense research. In fact, security clampdowns stood in the way of GT obtaining many current details on biological defense initiatives for this article.

For instance, a bacteriology researcher at the US Army Medical Research Institute of Infectious Diseases in Frederick, Md., wouldn’t disclose even so much as which bioinformatics software he uses, saying he’s been “in lockdown since September 11.” Nearby, at the Aberdeen Proving Grounds, where armed guards have patrolled the facilities since the terrorist attacks, a scientist conducting genomics and proteomics research into the toxicologic effects of low-level biological exposures was eager to get publicity for his lab’s work, but was advised by superiors that, in the interest of national security, a magazine interview was prohibited. Even many private companies that spoke to GT for this article had been ordered by the government to keep mum about the details of their defense-related projects. One executive explained, “The concern is that we may become a target [for terrorists].”

Nevertheless, it is clear that in the wake of the attacks biological defense research, and inherently genomics, has quickly become a top US defense priority.

Evolving Systems

To be sure, molecular biologists are not strangers to defense work. Geneticist and Nobel laureate Joshua Lederberg has been urging life scientists since the 1960s to be vigilant about biological weapons, which he has described as “an absolute perversion of medical science.” And, of course, the human genome project got its beginnings at the DOE’s Department of Biological and Environmental Research, which pursues defense research.

But as Tara O’Toole, deputy director of Johns Hopkins’ Center for Civilian Biodefense Studies, pointed out to a national symposium on bioterrorism last year, the sad byproduct of science’s improved understanding of molecular biology is the increased risk of bioweapons. Indeed, since 1994 the National Nuclear Security Administration’s nonproliferation program has helped Russian scientists who were once engaged in developing biological weapons to find non-weapons-related work to prevent them from taking their expertise to nations that wish to employ those skills.

The fear that terrorists could get their hands on genetically engineered varieties of known pathogens is one reason genomics has become a crucial component of defense efforts in recent years. DARPA has become a significant supporter of technology development in the genomics industry. And many genomic technology companies (see sidebar, “Genomics Technologies for Defense,” p. 35) have customers within the DOD.

In his position as chair of DOD’s Task Force on Bioterrorism, genomics thought-leader and former SmithKline Beecham CSO George Poste has argued for the development of speedy and accurate diagnostics tools and for the creation of a national repository of genetic profiles of diseases that could enable public health officials to differentiate intentional outbreaks from naturally occurring ones.

Across several government agencies, funding for genomics in bioweapons defense research has been climbing. An executive at one genomics instrument company says he started noticing that the government was fast-tracking biological defense programs last spring. “We’ve been very busy with DOD the past couple of weeks, but even before that we were seeing a pulling up in the time schedules in various programs,” he says.

Sequencing for Security

Sequencing of pathogens suspected of use in biological weapons — lists range in number from 20 to 130 — has also been sped up (see box, “Critical Agents,” p. 36).

CDC’s Bioterrorism Preparedness and Response Program, which got underway in January 1999, dedicates a portion of its $180 million annual funding to pathogen genome sequencing and to using genomics to develop real-time PCR diagnostics. Stephen Morse, the program’s associate director for science, says, “We’ve been working full bore for the last two years.”

Agencies including DOE, USDA, and NIH’s National Institute for Allergy and Infectious Diseases have funded work at the Institute for Genomic Research, University of Illinois, and the University of Wisconsin to sequence pathogens on the list.

DOD’s DARPA arm, which had a budget of $124 million in FY2000 and $167 million in 2001 to support development of “underlying technologies associated with pathogen detection and remediation,” spent $11 million between 2000 and 2001 on a project to sequence biological warfare agent pathogens.

HHS’s Anti-Bioterrorism Initiative, funded at close to $2 million annually, also supports pathogen genome sequencing. In May, HHS Secretary Tommy Thompson announced that he would appoint a special assistant charged specifically with handling all of the department’s bioterrorism activities and said that bioterrorism would become “a top priority for me and my entire department.”

In addition, technologies such as a miniaturized time-of-flight mass spectrometer, a bacterial biochip that would identify genus and species of organisms without PCR, and advanced diagnostics such as rapid, single-molecule DNA sequencing are all on DARPA’s to-do list.

In 1998, DOE’s Argonne National Laboratory began a five-year program to use the human genome to develop biological agent detection systems, and the same chip maker that got the $10 million contract to develop wearable arrays had earlier developed, with the Walter Reed Army Hospital, chips carrying 200 human gene sequences linked to pathways through which biological agents would move.

But in spite of the apparent full-court press for technology development, two weeks after the September 11 attacks, Anna Johnson-Winegar, DOD’s deputy assistant for chemical and biological defense, told an audience in Williamsburg, Va., that the department is far from its goal to develop a single, universal tool for quickly detecting any biological threat.

Chris Aston, a genomics researcher at NYU Medical School with a hobbyist’s interest in biological defense technologies, says, “The goal for the military is to develop some kind of sensor that every soldier could carry. All sensors could be networked by some radio modem and results would network back to commanders who can coordinate what’s going on.” Aston calls the idea “a dream solution” that is “in no way ready to be deployed.”

Warns Johnson-Winegar: “We are making progress, but time is a-wasting. We have got to significantly accelerate our R&D.”

Batten Down, Gear Up

Now, with legislators stunned by recent events and the US on bioterrorism alert, chances for acceleration seem greatly improved. In addition to whatever slice of the $40 billion emergency budget will go toward genome analysis and related instrument development, the President’s FY2002 budget request for combating terrorism is $10.3 billion. About $1.8 billion of that is earmarked for defense against weapons of mass destruction and would be dispersed among more than 20 federal agencies. Among those, DOE is slated for $792.5 million and HHS is slated for $348.3 million — all monies to go specifically for biological defense research.

Asked whether government initiatives in genomics defense are coordinated and interdependent, one DOD higher-up says, “Who’s doing what, and how much have we done already? We’re in the process of coordinating that and should know in the next few months.”

Says a CDC researcher who works with pathogen sequences, “No, the efforts aren’t coordinated. A lot of them are classified. It’s hard to coordinate things you don’t know about.”

Overlapping or not, several funding initiatives with the potential to influence genomics technology R&D as well as sales of existing analytical tools such as sequencing machines, microarray chips, PCR instruments, and mass spectrometers, were on the table at numerous government agencies as this magazine went to press:

• The DOE announced that it had recruited a senior manager from DOD’s Chemical and Biological Defense Program to manage the $12 million Biological Threat Reduction Program at Los Alamos National Lab, and rumors swirled that the department would get a budget hike for pathogen genomics research. DOE-funded labs participating in a $40 million-per-year program to analyze genomes of bioweapon threats had earlier been warned that the 2002 budget would impose a 25 percent cutback. “We thought we were going to take a hit,” says one lab director, “but now we’re talking about bump-ups.” (See sidebar, “Pathogen Genome Labs Primed for Push,” p.34.)

• An appropriations bill that was passed out of a House subcommittee on October 3 would give the CDC and the NIH $393 million for bioterrorism preparedness funding — a nearly $50 million increase over the Bush administration’s budget request. On the same day, HHS Secretary Thompson told the corresponding Senate subcommittee that he could use an additional $1.4 billion. Among priorities for those funds would be vaccine development and enhancing the ability of regional health labs to respond to a bioterrorism event by equipping them with instruments such as thermal cyclers and sequencing machines.

• The Food and Drug Administration revealed plans to create a bioterrorism unit in its Clinical Proteomics Program to look at the applications of proteomic technologies to potential biological and chemical agents.

• The Pentagon was pushing for an additional $17 billion for defense technology procurement.

Defense Business

In the short term, heightened interest in biological defense has been good for the business of some genomics companies. Cepheid’s stock soared more than 50 percent and was experiencing as much trading activity per day as it typically did in a month due to investors’ interest in its sales of biodetectors to the DOD. “We’re seeing a huge acceptance from DOD, CDC, DOE, FBI, and municipalities,” says Cepheid COO Kurt Petersen. Since Cepheid launched its first PCR-based detection platform last year, the company has shipped 500 systems. “A large fraction of those are for bio threats,” Petersen says. Still, he says, overall, military contracts will be just a small part of his business.

Bruker Daltonics, which announced a $10 million deal to provide ion trap mass spec instruments to the DOD one week after the terrorist attacks, also experienced a stock surge. Shares were up 23 percent in early October. “For Bruker as a whole, defense contracts are not that large — I don’t think it’s more than 20 percent of our business,” says business development manager Frank Thibodeau. “But who can tell what it will be in the future?”

Government support for the development of diagnostics, mass spec, and other instruments could, of course, be translated into commercial value for non-military uses. But analysts say the flurry of defense-related activity probably won’t have any significant effect on the genomics industry in the long term.

Scott Greenstone, a genomics technologies analyst at Thomas Weisel Partners, has seen this kind of thing before: he once followed companies that make bomb-detection equipment. After an airplane crash, interest would always spike, he says. But it never lasted.

— with additional reporting by Marian Moser Jones and John S. MacNeil

 

Pathogen Genome Labs Primed for Push

 

In the aftermath of the recent terrorist attacks on the US, public labs are optimistic that they’ll be receiving additional funding for detecting, characterizing, and sequencing biological pathogens.

The US Department of Energy’s Chemical and Biological National Security Program had a budget last year of $40 million. But a bigger budget for FY2002 “certainly has been discussed” in the past month, says Jill Trewhella, bioscience division director at Los Alamos National Laboratory, which carries out research for the program.

Paul Keim, whose work on high-resolution DNA fingerprinting and sequencing of pathogens at Northern Arizona University is funded by DOE, says he has worked on “all the major players on the bacterial pathogen list” including strains of Bacillus anthracis, Brucella, Burkholderia, Francisella tularensis, and Yersinia pestis. Having been warned earlier in the year that he would have to get by on 25 percent less funding next year, Keim has been prepared to take a hit to his budget. Now, he says, indications are that his lab will get a funding boost.

Because 97 percent of the microbial world has not yet been cultured or studied, Trewhella notes, these labs have plenty of work ahead to profile unknown biological pathogens that enter the environment. Not only are most microbes not cultured, but the differences, for example, between the pathogenic and non-pathogenic strains of the anthrax microbe are not obvious.

Trewhella’s division has been comparing sets of genes from different nonpathogenic B. anthracis species to identify genes that are unique to the pathogenic strains. The division also is creating databases to investigate the interaction between pathogens and human cells.

Though its work is hardly complete, the division has created a library of genetic profiles for hundreds of different B. anthracis strains. The library has demonstrated that both Iraq and the former Soviet Union engaged in biological warfare programs to deploy B. anthracis. More recently, the library explained why a French soldier wounded in Bosnia was infected with a strain of anthrax instead of a B. thuringiensis strain used in biopesticides.

Another Los Alamos program involves development of a decoy molecule, or receptor-mimicking molecule, that stops the spread of a bacterium’s toxin by preferentially binding to the toxin, thereby inhibiting it from attaching to cells in the immune system. Early testing of the decoy molecule was in Staphylococcus aureus infections, but the molecule could be used for anthrax or plague.

Meanwhile, at Lawrence Livermore National Laboratory, various strains of plague have been sequenced, as have the genomes of other biological pathogens.

Both Los Alamos and Lawrence Livermore are part of the US Department of Energy’s Joint Genome Institute, based in Walnut Creek, Calif. JGI Director Trevor Hawkins says the Walnut Creek facility has sequenced drafts of “neighbor” genomes of biological pathogens for Los Alamos and Lawrence Livermore. The drafts provide researchers with a 95 percent complete genome sequence in just days. Hawkins too anticipates JGI could receive more funds for microbial sequencing next year.

— William Langbein

 

Genomics Technologies for Defense

The following is just a sampling of defense-related work that genomics technology companies and laboratories are engaged in:

Bruker Daltonics, which has been a defense contractor since the Gulf War, has a new $10 million DOD contract to supply ion trap mass spectrometers for chemical and biological defense. The systems will be used to sample air on battlefields, identify the properties of ions, and compare them to what is already known about the environment. The instruments will be carried in the Army’s BIDS (Biological Integrated Detection System) mobile units — Humvees equipped with a lightweight multipurpose shelter that carries a biological detection suite. Frank Thibodeau, who recently left his post as an operational specialist in nuclear, chemical, and biological warfare with the US Army to become Bruker’s business development manager, says the instruments are already in use in Tokyo’s subways.

The Center for Applied Genomics in Newark, NJ, and the New Jersey Medical School Center for Emerging and Reemerging Pathogens won an Army contract in September to develop microarray-based molecular diagnostics for first-, second-, and third-tier biological warfare agents. A study aims to come up with molecular signatures of host responses that are specific for individual agents that a terrorist might use. The groups will conduct expression profiling in human high-density arrays and then, once specific signatures are isolated, will design low-density arrays with the key genes involved in signature responses.

Cepheid and Environmental Technologies Group have a DOD contract to deliver hand-held biological detection devices that would provide early warning to troops and emergency response civil servants of the presence of biological weapons including anthrax. Cepheid is using its I-Core and microfluidic technologies to capture, purify, and amplify DNA.

In addition, Cepheid has supplied PCR technology for the DOD’s BIDS vehicle since 1996, and has a method for conducting five-minute sample prep for anthrax. “There’s a fair amount of work you have to do to adapt instruments [to military use],” says COO Kurt Petersen. “They want a global positioning system built in, a rugged casing, special electronics for communication, and extended temperature ranges.” Prototypes of its GeneXpert that Cepheid is sending to the DOD now are in black boxes. The real ones, Petersen says, will be in camouflage boxes.

Motorola has a $5 million contract under DARPA’s Bio-flips program to develop its microfluidic Multi-Chip-Module genetic analysis sample preparation systems. Motorola scientists are collaborating with Jed Harrison from the University of Alberta and Mark Hayes of Arizona State University to develop plastic microfluidics devices that would allow experiments, including sample preparation and detection, to take place on a soldier’s wrist. DARPA’s Bio-flips program funds research aimed at developing miniaturized analytical devices.

Nanogen is in a two-year, $1.1 million contract with the US Army Medical Research Acquisition Activity to develop an arrayable electronic system for the identification of biological warfare or infectious disease agents. Nanogen says it will deliver devices, including one miniaturized system, and protocols for performing a nucleic acid amplification and hybridization approach for detection of four biological agents.

Orchid Biosciences has a three-year, $4.8 million contract from DARPA’s Office of Special Technology to develop technology for microfluidic-enabled DNA synthesis that could yield “significant quantities” of long oligos. The technology will contain a “micro device” that can be integrated with electronic components to form subsystems within future bioassay systems for integrated DNA analysis.

Transgenomic’s nucleic acid fragment analysis system, called Wave, has been in use by various DOD contractors for more than a year. The company’s HPLC-based instrument allows for DNA separation for identification purposes. Explains Marty Hensley, executive vice president for global sales and marketing, “Once we can take a DNA fingerprint, we can establish what agent you’re looking for. Once you have that DNA fingerprint recorded, then you can take very small samples with our device to see if a suspected body has dangerous agents in it.” In a matter of minutes, the Transgenomic instrument runs a test that would once have taken at least 24 hours.

— AB

 

CRITICAL AGENTS

The following biological agents are deemed by the US Centers for Disease Control to pose a risk to national security. Where noted, the genome sequence has been completed or is under way.

 

High priority

Variola major (smallpox)

Bacillus anthracis (anthrax) In progress at TIGR

Yersinia pestis (plague) Done by Sanger Centre

Clostridium botulinum toxin (botulism)

Francisella tularensis (tularemia) In progress by Europe/North America Consortium

Filoviruses (Ebola hemorrhagic fever and Marburg hemorrhagic fever)

Arenaviruses (Lassa fever and Argentine hemorrhagic fever)

 

Second Priority

Coxiella burnetti (Q fever)

Brucella species (brucellosis) In progress at TIGR

Burkholderia mallei (glanders) In progress at TIGR, USAMRIID

Alphaviruses (venezualan encephalomyelitis, eastern and western equine encephalomyelitis)

Ricin toxin from Ricinus communis (castor beans)

Epsilon toxin of Clostridium pefringens

Staphylococcus enterotoxin B

 

Food or waterborne pathogens

Salmonella species In progresss at University of Illinois

Shigella dysenteriae

Escherichia coli Done by University of Wisconsin

Vibrio cholerae

Cryptosporidium parvum

 

Third Priority

Nipah virus

Hantaviruses

Tickborne hemorrhagic fever viruses

Tickborne encephalitis viruses

Yellow fever

Multidrug-resistant tuberculosis

 

Source: CDC

The Scan

For Better Odds

Bloomberg reports that a child has been born following polygenic risk score screening as an embryo.

Booster Decision Expected

The New York Times reports the US Food and Drug Administration is expected to authorize a booster dose of the Pfizer-BioNTech SARS-CoV-2 vaccine this week for individuals over 65 or at high risk.

Snipping HIV Out

The Philadelphia Inquirer reports Temple University researchers are to test a gene-editing approach for treating HIV.

PLOS Papers on Cancer Risk Scores, Typhoid Fever in Colombia, Streptococcus Protection

In PLOS this week: application of cancer polygenic risk scores across ancestries, genetic diversity of typhoid fever-causing Salmonella, and more.