Last in a five-part Global Security Newswire series on emerging technologies and scientific advances that might pose new proliferation risks.
WASHINGTON --The newfound ability of scientists to produce disease materials from scratch has led to concerns that extremists might seek the same capabilities to carry out acts of bioterrorism (see GSN, Aug. 11).
Synthetic pathogens are man-made infectious agents that are produced either from the manufacture or adaptation of DNA, cells and other biological structures.
While scientists have been engineering genetic sequences for decades and commercial gene sequencing has been around for years, the field continues to move into uncharted territory. This year, researchers for the first time were able to design and produce cells that do not exist in nature without using pre-existing biological matter -- marking the latest evolution in the rapidly advancing field of synthetic biology.
Additionally, recent technological advances and lower equipment costs now allow amateur scientists to conduct complex biological experiments such as DNA duplication outside of institutional settings and with machinery purchased online.
The developments could pave the way for advancements in medicine, energy and agriculture, but also could put sensitive materials in the wrong hands, analysts warn (see GSN, May 21).
"With the advent of DNA synthesis technology, simply restricting access to the actual pathogen no longer provides the security that it once did. Since the gene sequence is a blueprint, once an organism has been sequenced it can be synthesized without using samples of existing cultures or stock DNA," issue specialists Ethel Machi and Jena Baker McNeill wrote for the Heritage Foundation in an August memo on the issue.
The federal government classifies 82 pathogens and biological toxins such as anthrax and smallpox as "select agents" that pose an extreme threat to public health. Access to those materials is strictly regulated. However, the complete genetic sequences, known as the genome, for many of these select agents are now available through the Internet.
"The problem is that now you can make DNA. For a number of these, you really don’t need to have access to the sample. The genome of these pathogens are in publicly available databases," said Jean Peccoud, an associate professor at the Virginia Bioinformatics Institute at Virginia Tech. "For a few thousand dollars you can get the Ebola genome."
The genetic sequence is not harmful in itself. It must be inserted into a recipient cell and begin replicating to pose a physical threat. "I could have the entire genome of the Ebola virus and eat it with my breakfast," said Gigi Kwik Gronvall, a senior associate with the University of Pittsburgh's Center for Biosecurity. "In order to have a pathogen, the sequence needs to be processed by a cell."
A scenario presently exists in which terrorists could place an Internet order for the DNA sequence of a select agent and then use the sequence and synthetic biology techniques to recreate or even genetically modify the pathogen in a laboratory.
The likelihood of success in this area, however, is considered very small for anyone working without at least a graduate level of education in the field and years of practice synthesizing sequences, according to a September 2009 University of California, Berkeley working paper on biosecurity concerns by synthetic genomic industry experts.
Still, multiple scientists and security experts interviewed for this article by Global Security Newswire declined to describe in detail the bioterrorism possibilities of synthetic biology for fear of giving extremists insights on how to create or adapt lethal disease agents.
"There has not been an incident yet but the technology is very cheap. I think there is definitely a risk. The question is trying to figure out where is the risk," Peccoud said.
Under the auspices of researching and combating infectious agents, scientists in 2008 used synthetic biology to recreate the SARS virus. Three years earlier, researchers successfully reconstructed the 1918 flu virus, which caused a worldwide pandemic estimated to have killed 50 million people.
"Eventually, it will almost certainly be possible to recreate bacterial pathogens like smallpox. We might also be able to enhance these pathogens. Some work in Australia on mousepox suggests ways of making smallpox more potent, for example. In theory, entirely new pathogens could be created," Hastings Center Report Editor Gregory Kaebnick said in congressional testimony during a May hearing on Capitol Hill.
At a 2003 closed seminar hosted by the National Academy of Sciences, scientists discussed the possibility that new "designer" biological weapons could be engineered. Possibilities include genetically modifying two innocuous agents to become lethal when combined or engineering viruses to cause low-level symptoms that become deadly when the infected person takes a common treatment such as aspirin (see GSN, Nov. 17, 2003).
Machi and McNeill speculated that malicious actors could acquire the capability to re-engineer organisms to create novel biological weapons by 2020.
"If a lab has an ordinary strain of influenza, you could engineer it into the 1918 strain. If you have a bacterium that is resistant to six drugs, it isn’t too hard to make it resistant to eight drugs," said George Church, a genetics professor at Harvard University and the founder of the Personal Genome Project.
There is today very limited federal oversight on the sale of genetic sequences. While large scientific institutions that receive federal funding must follow reporting requirements on the type of research they are doing, there are no such rules for the growing number of amateur biologists who are now performing genetic experiments on their own, Church said.
"I think most of my colleagues would [say] that it requires a great deal of education to do just about anything [in the synthetic biology field]. I am less certain of that," Church said. "The 9/11 guys didn’t need a lot of education in flying planes."
Even if terrorists are unable to weaponize select agents for widespread dissemination, their ability to produce a lethal pathogen could have dire ramifications if, for example, they unintentionally infect themselves and then proceed to infect others, he said.
Though the intellectual expertise required to perform synthetic bioengineering should not be underestimated, the increasing accessibility of sensitive technology must also be recognized, said James LeDuc, director of the Galveston National Laboratory at the University of Texas Medical Branch.
Guarding Against the Threat
Commercial gene synthesis companies, working in the United States and abroad sell their products to a range of buyers including pharmaceutical firms, nonprofit laboratories and unaffiliated hobbyist biologists.
The gene synthesis firms begin their work by manufacturing the short building blocks of DNA known as "oligonucleotides." These "oligos" are then assembled into a full gene, the gene is inserted onto a plasmid and the plasmid is injected into a bacterium. Lastly, genes are grown and withdrawn from the cloned bacteria, according to the Berkeley working paper.
"None of the foregoing steps is beyond a well-trained microbiologist who routinely performs cloning experiments. For this reason, attempts to deny commercial gene synthesis services to nation states like Russia or even Iran have only limited value," states the paper. "Terrorists, on the other hand, have notoriously small budgets ... and are very sensitive to cost and technical risk. For this reason, barriers that add even modestly to cost ($100,000) or failure risk (10 percent) are typically worth considering."
In November 2009, the U.S. Health and Human Services Department released screening guidance for the gene synthesis industry. The voluntary guidance recommends sellers know their customers for genomic products and be aware if the product constitutes a theoretical public hazard.
The guidelines advise sellers to do background checks on their customers for warning signs such as evasiveness about a buyer's identity or affiliations, information that cannot be verified, an exceptionally large order of DNA sequences or several orders of the same sequence placed in a short amount of time.
Requested sequences should also be checked to see if they match select agents or "sequences of concern," according to Washington. If flags are raised from the customer or sequence screening, follow-up checks should be carried out. If security concerns persist, sequence manufacturers should contact the FBI or Commerce Department.
Researchers with the American Association for the Advancement of Science stated in a January report that many individual gene synthesis providers have already begun to screen their orders for select agent sequences and report that it is "very rare" for a customer or DNA request to raise security concerns.
However, there is presently no framework for DNA suppliers to trade information on buyers and sequence requests so fellow providers can be alerted about denied orders. This creates the possibility that requests rejected by one supplier could be filled by another.
The AAAS report recommends the scientific community build a curated database of harmful sequences that dealers could check for sequences that might "confer pathogenicity" -- the ability to produce infectious agents in a host organism.
"The important thing is to make sure that the database that companies check has the capability of evolving with new information," Gronvall said. The system should be managed by the private sector, which is more adaptive to change than the federal government, she added.
Machi and McNeill concurred in their paper: "Further advances in gene sequencing and synthesis would be severely hindered by government regulation of these databases." They recommended that Washington commission risk assessments to develop regulations that fit the present realities of genomic technologies.
President Barack Obama has assigned his bioethics commission to study potential applications and risks in synthetic biology and to report back to him with recommendations by November. According to the Hasting Center’s Kaebnick, the FBI and the National Institutes of Health’s National Science Advisory Board for Biosecurity are also developing a policy to regulate purchases of synthetic DNA sequences that could represent biosecurity threats.
The U.S. government lists select agents by their names and categorizes them by whether they pose a threat to humans, the agricultural sector or both. Last month, the National Academy of Sciences issued a report that recommends moving from that name-based system to a classification scheme in which pathogens are defined by their gene sequences.
Under the present classification system, natural variation among pathogens and the deliberate modification of DNA sequences could allow malicious actors to skirt biosecurity regulations and obtain select agent sequences by purchasing them from companies that are unaware the order matches a dangerous pathogenic sequence, according to the report (see GSN, Aug. 4).
LeDuc, who chaired the NAS committee that wrote the report, said a sequence-based definition would provide a more precise classification of the disease agents and would also boost scientists’ ability to recognize if subtle changes have been made to pathogen sequences. This could be done using computer analysis to compare customer sequence orders to the genetic sequences of select agents.
Harvard’s Church has developed his own proposal for regulating the synthetic biology industry. It focuses on restricting access to the machines needed to synthesize DNA fragments to only licensed government, nonprofit and commercial entities.
Gronvall, however, said she believes it is too late to try to limit access to gene synthesis equipment: "The technology … it is everywhere. It’s exquisitely dual use."
An Overblown Danger?
There are some in the scientific community who believe the biological weapons threat posed by synthetic pathogens is being exaggerated and risks strangling a promising new industry which has the potential to lead to many positive advancement like the engineering of microbes capable of digesting waste or producing fuel.
"We in the community debated long and hard about this. There’s lots and lots of good things happening [in the field]. We didn’t want to overburden the fledgling biosynthesis industry," LeDuc said. "On the other hand, we did recognize that there’s the potential for some abuse of the system, for some activities that could be very threatening to public health and national security."
University of Illinois international law professor Francis Boyle, however, believes the U.S. government is wrong to spend money researching the bioterror possibilities of synthetic biology.
"We need no more money allocated to biowarfare research. It’s a joke and a fraud," said Boyle, a longtime opponent of U.S. biodefense work and the author of the 1989 Biological Weapons Antiterrorism Act, which made it illegal for anyone in the United States to develop or possess biological weapons.
"The real danger is that scientists in the United States, working for and with and the United States government, want to either get rid of my act or to amend it out of meaningful existence so that they can go right ahead and pursue so-called synthetic biology to their heart’s content with no regulation," he asserted.
Boyle said the real public health danger lies in biodefense research conducted in laboratories at the behest of the federal government in which scientists recreate, modify and test disease agents for the stated purpose of improving medical treatments to these biological threats (see GSN, Sept. 8).
"It’s the Wild West out there," he said. "It’s literally a catastrophe waiting to happen when you have all these laboratories out there and all of these researchers out there with all of this access to deadly pathogens and many of them trying to make up new ones themselves."
In contrast, Church said he thinks Washington should spend enough money to ensure the right kind of regulations are developed that guard against bioterror risks while not suffocating legitimate scientific research.
"A few regulations don’t cost that much money and if you spend a little more money you get more intelligent regulations," Church said. "If you try to do regulations on a shoe string without anyone paying attention then you’re going to get something like our tax code."
Church also supports regular electronic surveillance of laboratories conducting synthetic biology experiments with dangerous pathogens. Regulation without monitoring is not enough, he said. "You have to explicitly say there should be surveillance. Electronic monitoring at the minimum."
Gronvall argued the federal government should divide its energies between studying the bioterrorism possibilities in synthetic biology and improving its ability to respond to a biological attack.
"You don’t want to put every egg in one basket but where I think the majority of eggs should be is the ability to respond to diseases whether they are accidental, natural or deliberate," she said (see GSN, Aug. 27).
Others point out that the U.S. government, by commissioning studies and holding public hearings, could be drawing extremist attention to the bioterrorism possibilities in synthetic genomics where they had previously been unaware.
"The process of dreaming itself is dangerous," Church said. "We don’t need to come up with hypothetical plans."
Peccoud, though, pointed out that if the "white hats" do not start thinking about the biowarfare implications of synthetic biology, then they will be leaving "someone with a black hat" to do all of the planning.
Last in a five-part Global Security Newswire series on emerging technologies and scientific advances that might pose new proliferation risks.