Why is resistance to antibiotics escalating? (13/3/2008)

Canada: Outbreak!
Why is our resistance to antibiotics escalating? The villains may be different than we think. Some scientists say the cause could be the genetically modified E. coli casually used in industrial labs and high-school classrooms
By Alex Roslin This Magazine (Canada), March - April 2008

Four high-school students from the tony Ridley College boarding school walked among the science teachers, offering pointers. Decked out in lab coats, the teens were helping attendees of the Science Teachers Association of Ontario's conference in Toronto to create a new life form.

Students and teachers started with familiar bacteria, Escherichia coli, the same bug that killed seven people in Walkerton, Ontario, in 2000 and made 2,000 sick, genetically modifying it by inserting a green fluorescent protein from a jellyfish. They were using a strain of E. coli rendered harmlessó although how harmless it would remain after the experiment is another question.

The reason for the role reversal at this conference was the pGLO kit, which kids at Ridley have been employing for six years to learn about genetics with their biology teacher Bob Malyk. Ridley, located in St. Catharines, Ontario, is just one of dozens of high schools and colleges where Canadian adolescents are being encouraged to try their hand at genetic engineering. 'Any biology teacher who doesn't get involved with this stuff is behind the times,' Malyk says.

Sales of educational kits that allow students to work with genetically modifi ed E. coli are hot. Made by Bio-Rad Canada, a subsidiary of Hercules, California-based biotech giant Bio-Rad Laboratories Inc., whose revenues last year were $2.4-billion, 110 of the kits were sold in Canada in 2006. Each one is good for a classroom of 36 or more students, says Bio-Rad Canada's marketing manager Avi Wener. That means potentially 4,000 Canadian youngsters have used the kits. Sales in 2006 were up 32 percent from the previous year. 'The teachers like it,' says Wener. 'It's pretty engaging for the students.'

Malyk is a convert to the pGLO kit, and enthusiastically proselytizes on its behalf. He volunteered to lead the workshop in Toronto, and led four other presentations for teachers on Bio- Rad's kits in Toronto, Ottawa and Winnipeg, sometimes bringing his privileged young charges along. 'It's great for the teachers to see the students there and see how enthused they get,' he says.

It's all good fun and, Bio-Rad says, gives the kids a vivid, hands-on education about genetics. But there's one other thing. The teens are inserting something else into their E. coli: a gene that makes the E. coli resistant to an antibiotic called ampicillin. It's called a 'marker gene,' and it's used to help mark which of the little guys has taken up the genetic transformation. If doused with the antibiotic, only the engineered bacteria will survive.

Malyk says pGLO is '100 percent safe' for his students so safe, in fact, that he's never asked students' parents for approval for the experiments. 'I can't see why parental consent would be needed. There's no way it causes disease. It's totally non-pathogenic.'

Bio-Rad's Tumay Basar, who has a Ph.D. in microbiology, agrees. 'There are no major safety issues,' she says. 'If you are in a classroom, it's good to use gloves, but it's not necessary.'

This all leaves Joe Cummins stunned. A professor emeritus at the University of Western Ontario, Cummins is one of Canada's most prominent geneticists. He thinks letting teens create drug-resistant bacteria is a very bad idea. 'It just makes my skin crawl,' he says from his home in London, Ontario. 'Regardless of even the best controls you have on kids, there are still bound to be problems.'

Cummins says it's not the strain of E. coli used in the kit that is the problem - the risk comes from making the E. coli antibiotic-resistant. If students come into contact with the ampicillin-resistant gene, there is a possibility the resistance trait could be transferred to them as well, he says. Additionally, if a student inadvertently carried the drug-resistant bacteria out of the classroom, it's possible the trait could be passed to bacteria in the environment.

And it's not just the kids we have to worry about. Grown-up scientists make mistakes in labs, too. Cummins cites a landmark Dutch study from 1991 that surprised the scientific ccommunity by discovering lab coats were routinely contaminated by genetically modified bacteria, often penetrating to the clothes underneath. The idea that drug resistance could be carried into the environment is troubling, as the antibiotic ampicillin is commonly used to treat bacterial infections and as a last-resort drug against bacterial meningitis and the deadly strain of E. coli that struck Walkerton. If you are resistant to ampicillin, the antibiotic won't help you.

Cummins says high-school biotech experiments also point to a much wider problem of lax attitudes toward trillions of genetically modified bacteria and viruses being engineered with little outside scrutiny in labs around the world: 'They tend to be wildly careless.'

So far in the debate about genetic engineering, teeny-tiny germs have gone pretty much ignored. The focus has been on big, visible stuff like GM-food labels and the ethics of designer babies or cloned pets. Yet the single most frequently genetically transformed organism isn't canola, sheep or GloFish. It is the minuscule E. coli bacterium, which lives by the billions in every person's guts.

E. coli and other GM microbes have completely transformed the pharmaceutical industry and other microbiological research, including the fast-expanding field of biowarfare experimentation. E. coli is the love machine of the living world. It multiplies so fast that a single organism's offspring could weigh as much as the earth in two days if they didn't run out of food or space. Researchers in corporate, academic and military labs harness this awesome sexual power to study everything from new drugs to biological warfare agents.

New species of E. coli are created every day after being chopped up or reshuffled with genes from people, pigs, jellyfish and even viruses such as HIV. The E. coli is so prolific at passing on its genes, in fact, that it can do so even after it is dead.

So, how do labs make sure the engineered microbes don't escape into the environment and pass on their traits in an unpredicted way? Surprisingly, both Canada and the United States have very few special legal or regulatory requirements for the safety of labs that work with GM bacteria and viruses.

The main confinement and disposal guidelines are voluntary. The hundreds of Canadian and U.S. labs that make GM microbes are for the most part on the honour system. Regulators in neither country know how many such labs exist or what they are creating. And neither country requires labs to report any but the most serious GM lab accidents.

All but the most secure labs that deal with pathogenic microbes are essentially self-policing. What monitoring there is falls to a hodgepodge of agencies and departments that don't seem to communicate with each other, much less exercise any special monitoring for genetically engineered bugs. In Canada, those bodies include the Public Health Agency of Canada, which issues guidelines on lab safety and monitors importation of microbiological material to Canadian labs and Human Resources and Social Development Canada, which monitors worker safety at the labs. Provincially, environment ministries are supposed to monitor discharges from labs, and occupational health and safety bureaus keep tabs on lab work conditions for staff.

Retired in January 2008, Suzanne Wuerthele was a veteran risk-assessment expert at the U.S. Environmental Protection Agency and the EPA's regional toxicologist for six western states. She is also one of a handful of experts worldwide who studies contamination involving genetically engineered microbes.

'There has been a lot of hype about GM plants and salmon,' she says, speaking from her office at the agency's regional headquarters in Denver, Colorado. 'But microorganisms have much more potential to do things we would not be happy with and to do it without us even knowing about it. There are no [government] inspections, to my knowledge, of the facilities that do this, and we don't even know who they are.'

She is especially concerned about how GM microbes are disposed of. It is typical, she says, for labs to flush them down the drain or toss them in the trash after they are autoclaved or sterilized. The goal is, typically, to kill 99.9999 percent of microbes. But Wuerthele says that still means survivors are common because of the huge numbers of germs created. 'If you make 50 tonnes of something, you may still wind up with a fairly large number of organisms still alive.'

Canadian universities confirm much of the GM microbiological material generated at their labs winds up in municipal landfills. Biology professor Margo Moore, head of the biosafety committee at Simon Fraser University, says Biosafety Level 1 microbesóthose that are considered non-pathogenic, like the E. coli in the pGLO kitóare first autoclaved, 'then it goes into the regular garbage. It poses no risk to individuals and the community.' She says SFU has 82 active permits for work with GM microbes.

What would happen if GM drug-resistant microbes were released into the environment? Cummins believes this has already happened, thanks to the lack of government oversight. As for the effects, he believes the escapes that have already occurred to be one reason for the rise of drug-resistant supergerms around the world over the past 30 years. Supergerms are the monster bugs that are frightening the lab coats off doctors and scientists because they are resistant to most medicines of last resort, and the numbers of such germs are increasing fast.

Cummins' claim is controversial and runs counter to orthodox scientific opinion. Although no one really knows for sure why superviruses are proliferating, the common explanation holds that the main culprit is the overuse of antibiotics in hospitals and cattle feed. But Cummins says antibiotics have been widespread since World War II, while supergerms started appearing in huge numbers only in the 1970sóthree decades after the mass use of antibiotics began, but coinciding neatly with the rise of genetic engineering.

This alternative theory was first comprehensively spelled out in a seminal study in the journal Microbial Ecology in Health and Disease back in 1998. The paper was co-authored by several European scientists, including geneticist Mae-Wan Ho, director of the Institute of Science in Society, based in London, England. (Cummins sits on the institute's advisory council.)

Ho's study called for an independent public inquiry into how biotechnology has contributed to the rise of supergerms, and said government regulations on GM bugs were 'grossly inadequate' worldwide.

The notion that GM food or microorganisms can pass their traits on to other creatures was flatly rejected for years by biotech proponents. But in 2002, British scientists confirmed that resistance genes present in many GM foods do, indeed, pass their traits on to human gut bacteria. The researchers, commissioned by the British Food Standards Agency, found that DNA genetically modified to be resistant to a herbicide had survived passage to the small intestine, where the herbicide-resistant trait was adopted by existing bacteria in the gut.

'Everyone used to deny that this was possible,' British geneticist Michael Antonio told the Guardian newspaper at the time. 'It suggests that you can get antibiotic marker genes spreading around the stomach which would compromise antibiotic resistance. They have shown that this can happen even at very low levels after just one meal.' This logic also applies to genetically modified bacteria, Cummins says. They, too, can pass on their resistance traits to other germs living hitherto benignly in our bowels or the environment. The same is true, he says, for the vast masses of GM microbiological material being dumped into landfills; they, too, could pass on their traits.

The stakes behind all this are pretty high. The first major study of one of the fastest-spreading drug-resistant microbes, methicillin-resistant Staphylococcus aureus (MRSA), found it causes over 94,000 serious infections and nearly 19,000 deaths in the U.S. each year. In the study published last October, the U.S. Centers for Disease Control and Prevention said also that African Americans had two times more chance of catching the bug than the average person, while those older than 65 are four times more at risk. In February, the Canadian government launched a national campaign to reduce MRSA after estimates the superbug now hits 6,400 Canadians each yearóan infection rate six times the 1995 level.

Perhaps not surprisingly, no inquiry followed Mae-Wan Ho's 1998 study. In fact, while biotech products have become ubiquitous in the decade since, the last regulatory debate about the safety of GM research took place more than 30 years ago.

The setting was the rustic Asilomar Conference Center at the tip of California's scenic Monterey Peninsula. Here, 140 biologists and regulators gathered in 1975 amid grazing deer and barking seals to debate the safety of the fledgling technology of genetic engineering.

Asilomar was provoked by worries that Frankenstein-type genetic monsters would wreak havoc if they got into nature. The participants formulated strict guidelines that were adopted in 1976 by the National Institutes of Health. They required tight physical confinement of many biotech experiments and forbade genetic research with cancer viruses.

Just a few years later, however, scientists bristling at the controls and eyeing the lucrative new technology started lobbying the NIH to loosen its guidelines. In the early 1980s, under the Reagan administration, the NIH finally gave in to pressure from industry and the scientific community, agreeing to gut its rules and allow genetic engineering to be performed under loose voluntary safety guidelines. The ban was dropped on research on cancer viruses.

Canada adopted similar voluntary guidelines at the same time. Then in 1998 the federal auditor general's office expressed concerns about Canada's lax biosafety standards. It called on federal authorities to do a review of every lab in the country to verify if the safety guidelines were being respected. The review has yet to be done 10 years later.

The lack of controls has remained essentially unchanged worldwide since the 1980s, and the lackadaisical attitude is so pervasive that GM bugs with antibiotic resistance are now actually entering the environment with the U.S. Environmental Protection Agency's stamp of approval.

In the mid-'90s, Becker Underwood, an Iowa-based agrifood giant, wanted approval for a genetically modified soil bacteria called Rhizobium meliloti. Rhizobium is a naturally occurring soil bacterium that lives on the roots of legumes. The company had engineered it to allow farmers to increase alfalfa yields. The bacteria were also engineered with marker genes that made them resistant to two antibiotics used against tuberculosis, tularemia and the plague. Wuerthele was asked to look at her agency's risk assessment of the new product.

She was flabbergasted when she saw the EPA's risk assessment. 'It was a jokeóthree or four pagesóand it didn't ask any questions,' she says. Wuerthele discovered that 2,000 species of legumes growing in North America also have Rhizobium on their roots. No one had studied how the product might affect them. To make matters worse, it wasn't even clear the bacteria actually helped increase alfalfa yieldsóthe product's main purpose.

The product was referred to an outside advisory panel, and only one of its six scientist members gave it the thumbs-up. When it became clear the EPA would move to approve the bacteria anyway, one member, Conrad Istock, resigned in protest. 'It's just good practice not to leave antibiotic resistance in organisms that you are going to release,' Istock said in an interview. 'According to risk-benefit analysis, if it has no benefit why take the risk?'

The EPA approved the Rhizobium for sale in 1997. 'Nobody's followed up on it or even asked the farmers to see if it improved yields,' Wuerthele says. 'The EPA has no idea whatsoever what has happened as a result. It was completely irresponsible.' While the effects of the first planned release of GM bacteria may not ever be known, a series of lab accidents has made it impossible for the dangers of poor containment of microbes to go unnoticed.

One of the worst cases came in 1977, when lab contamination in Russia is believed by many to have led to the reemergence of the Spanish influenza virus, which killed 20 to 50 million people in 1918 and 1919. In 1979, an accidental release of anthrax at a Soviet military lab in the Ural Mountains killed 64. In 2003 and 2004, SARS escaped high-security labs in Singapore, Taiwan and China, prompting a World Health Organization probe that found few countries have adequate biosafety practices.

And since 9/11, concerns about lab biosafety have heightened, thanks, ironically, to over $45 billion in U.S. and Canadian funding for biowarfare research, much of it involving genetically engineered bugs. As an example of the risks, the Sunshine Project, an Austin, Texas-based watchdog group, reported in 2002 that the U.S. Special Forces had invited scientists to propose ways to create GM bacteria that could be placed on an enemy building and later activated to destroy it through corrosion or to illuminate it for attack planes. The research is part of a U.S. program of studying so-called Genetically Engineered Anti-Material Agents, which have been under study since the early 1990s. The research has continued even though the U.S. Navy Judge Advocate General has ruled it violates the 1972 multilateral Biological and Toxin Weapons Convention, which prohibits biological weapons that deteriorate enemy equipment and supplies.

Even the top-security labs doing much of this research have sloppy practices, and the chances of an accident have shot up with all the new research, says the Sunshine Project's Edward Hammond. 'The most likely source of some sort of horrible biological incident in the U.S. is not a terrorist, but our own labs,' he says.

In 2004, Hammond's group released a troubling survey of 400 high-security GM labs at U.S. universities, private companies and government institutions that received grants for biowar research. Only four percent had fully complied with government guidelines.

'Disregard for federal recommendations is rampant,' the study said. 'The root of the problem lies in the fact that the United States does not have comprehensive laboratory safety law. The system does not even have comprehensive reporting requirements for accidental releases.'

In a follow-up study in 2005, the group found only three percent of scientists studying biowar germs had received a grant to work with such bugs before. 'Too many scientists with too little training are handling agents that are too dangerous for their experience,' the study noted. The Canadian story is all too similar. The federal government's top-security virology lab in Winnipeg is a veritable Three Stooges performance of what can go wrong at even the safest facilities. The lab was built to study the world's most lethal diseases, like Ebola and SARS. Three weeks after it opened in 1999, the $172-million federal complex, one of only 15 Biosafety Level 4 labs in the world, equipped to handle the deadliest microbes known, accidentally spilled 2,000 litres of unsterilized waste water into the Winnipeg sewer system. The lab didn't disclose the accident for two weeks, prompting angry Winnipeggers to hold a meeting to demand independent oversight of the sprawling complex, which is located in a mixed residential-industrial neighbourhood in the city centre.

The outside oversight never happenedóthough a 'community liaison committee' was formed to reassure localsóand an audit declared the lab was safe. Just months later, in January 2000, another spill released 100 litres of lab waste inside the facility. Other incidents have come to light since then. In 2005, the lab was in the news when a courier truck crashed in central Winnipeg on the way to the facility while transporting anthrax, influenza and tuberculosis. Several blocks were cordoned off before authorities announced nothing had spilled. And last April, 30 lab employees had to be given antibiotics after yet another contamination incident, this time involving material derived from anthrax. Then, in July, a sterilization unit that is used to treat waste from the lab malfunctioned. And those are only the incidents the lab has made public. A CBC inquiry in 2001 found 25 other mishaps where the lab didn't issue a press release, including two in which staff were injured. Moreover, the lab's liaison committee, which is required to issue a yearly report on its work, hasn't issued such a document since 2005.

It all makes Cummins wonder. If the world's most secure labs can have so many screw-ups, what kind of surprises lurk in less controlled environments? He wonders how the lack of regulation, accountability and public debate on genetic engineering and the patchwork approach of oversight can continue in light of everything we now know. 'It is as if workers and the public are really insignificant,' he says. 'We have grown very careless.'

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