IT鈥橲 such an obvious idea, it鈥檚 surprising no one thought of it before. Everybody knows that microorganisms can be genetically altered to pump out virtually any human protein to order. And it鈥檚 also clear that lots of diseases could be treated with proteins, if only it were possible to get the right dose to the right place at the right time. Up to now, that鈥檚 been the stumbling block. But perhaps there鈥檚 a way. Just swallow some genetically altered bugs and let them make a home in your gut. Hey presto: a cheap and steady supply of home-made medication, for life, perhaps.
It鈥檚 a medical revolution already waiting in the wings. Researchers in Belgium and the Netherlands are poised for the first trials in humans. If the tests get the go-ahead, it will be the first step towards a radically new kind of therapy: using GM bacteria to deliver therapeutic proteins just where they鈥檙e needed.
Sounds promising. But before anyone swallows a single GM bug, the researchers will have to prove that it鈥檚 safe. And not just for the patients who鈥檒l be asked to turn their intestines into GM bioreactors. Once the modified bacteria are released into the environment, there鈥檚 no recalling them, and no way of knowing if they鈥檒l stay benign. Is that a risk we鈥檙e prepared to take?
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Molecular biologist Lothar Steidler of the Flanders Interuniversity Institute for Biotechnology in Belgium thinks it should be. He heads the team that鈥檚 pioneering the new approach with a GM bacterium designed to cure inflammatory bowel disease. IBD embraces a range of debilitating and sometimes fatal chronic conditions, including Crohn鈥檚 disease and ulcerative colitis. It鈥檚 a major health problem, particularly in the West, where as many as 1 in 1000 people suffers from one form or another.
Bowel disease is just the start. If the new strategy works, it could be deployed against a host of other diseases. 鈥淭he panorama of applications is huge,鈥� says Steidler. He鈥檚 reluctant to be more specific for fear that patients will ring his lab hoping for miracle cures. But in theory, any protein drug that can be absorbed through the gut wall into the bloodstream could be delivered in this way. One obvious candidate is insulin, which can鈥檛 be taken orally because the stomach digests it before it can be absorbed.
First, though, Steidler wants to see whether his bacteria will behave as expected in people. The first human trials, which are awaiting the nod from the Dutch government, will take place in Amsterdam. The plan is to give a dozen or so volunteers a strain of Lactococcus engineered to manufacture a human protein called interleukin-10. IL-10 is a potent 鈥渋mmune modulator鈥�, capable of dampening down excessive immune reactions. The hope is that a steady trickle of IL-10, delivered straight to the gut wall by the GM bacteria, is just what is needed to suppress the abnormal immune response that gastroenterologists believe underlies IBD.
Steidler鈥檚 group originally set out to use bacteria as a cheap way to produce IL-10 for other researchers. In the process, they stumbled across Lactococcus. 鈥淪uddenly it struck us: perhaps we could use this bacterium directly as a therapy,鈥� he says. 鈥淭he conventional approach is simply not economic. To produce and purify enough IL-10 to treat one patient costs something like 拢10,000 per annum, and a patient might need life-long therapy. By contrast, our approach seems very cost effective.鈥�
Therapies for IBD already exist, and the most effective is probably repeated treatment with corticosteroid drugs, which also suppress the immune response. But because steroids bludgeon the entire immune system, they can have undesirable long-term side effects. The promise of the GM bug approach is precision engineering. All you have to do is drink a liquid suspension of the bacteria once a day and they colonise your bowel, releasing the requisite protein all the while.
It鈥檚 an ingenious solution. All the same, the prospect of GM organisms setting up home in your colon isn鈥檛 particularly enticing. By way of reassurance, Steidler first points out that the notion of eating therapeutic bacteria is not new. As early as 1907, the Russian microbiologist Elie Metchnikoff claimed that such 鈥減robiotics鈥� have many health-giving properties and could even prolong life. Modernresearch has largely substantiated his arguments (New 杏吧原创, 17 November 2001, p 40), and probiotic foods such as Actimel and Yakult are now mainstream.
Steidler鈥檚 starting point, Lactococcus lactis, is a 鈥渇ood-grade鈥� bacterium routinely grown in huge vats by cheese and yogurt manufacturers. Lactococcus is part of your normal intestinal flora and, along with other bacterial groups such as lactobacilli and bifidobacteria, is the not-so-secret ingredient in a vast range of fermented foods including yogurt. Every time you down a 鈥渓ive鈥� yogurt, you are bolstering the indigenous Lactococcus population of your intestines.
These microbial allies contribute to a healthy gut by binding to its lining, making it harder for hostile microbes to attack. What鈥檚 more, the friendly organisms also obligingly release compounds that we now know are potent anti-cancer agents.
But even if undoctored Lactococci are so beneficial, will the same be true if they are genetically engineered? There are obvious safety concerns. What might be the outcome of person-to-person transmission of such organisms? And what might happen if the gene for IL-10 escaped from the modified Lactococci and spread into some other bug?
Sue Mayer of the British campaign group GeneWatch agrees there鈥檚 a need for caution. 鈥淲e know so little about the behaviour of microorganisms generally,鈥� she says, 鈥渢hat it is particularly difficult to know whether genetically modified strains are going to pose any particular threat.鈥� Doug Parr, chief scientific adviser to Greenpeace UK, adds: 鈥淚f this leads to the deliberate release of a GM organism into the environment then there are potentially big issues.鈥�
And the campaign groups are not alone in their concerns. 鈥淭here is an awful lot that goes on in our guts that we鈥檙e still totally in the dark about,鈥� says geneticist Michael Antoniou of Middlesex University. The prospect of genes for powerful immune-system modulators breaking loose and spreading out of control is frightening indeed.
The trouble is, it鈥檚 impossible to predict exactly what risks are associated with a release of this kind. Up to now, the only application that has involved the deliberate release of GM microorganisms has been in bioremediation, using modified soil bacteria to digest pollution. The only existing medical application that comes close is gene therapy, ferrying missing genes into patients with inherited diseases such as cystic fibrosis using modified viruses, for instance.
Steidler鈥檚 approach is distinctly different from either of these. His team鈥檚 proposed trials would be the first time a GM bacterium with an inserted human gene was released into a human body, and potentially into the environment at large. Aware of the problems this might cause, Steidler and his colleagues have done all they can to ensure that their bacterium poses no threat. For starters, the human IL-10 gene has been integrated into the bacterial genome, rather than being left floating on a separate 鈥減lasmid鈥� loop of DNA within the body of the bacterium. Steidler say this should eliminate the risk of the gene jumping to another species. Plasmids are notoriously promiscuous, but genes within the main genome rarely play the field.
In addition, the modified organism is an 鈥渁ttenuated strain鈥� that can鈥檛 survive without a particular nutrient included in the growth medium. Without a steady supply the bugs die within a couple of hours. Steidler won鈥檛 say what the nutrient is except that it鈥檚 an ordinary food supplement that patients would swallow along with the bacteria.
As a result, any patient who wanted to evict the GM bacteria could simply stop taking the supplement, and the bacteria would quickly die. What鈥檚 more, says Steidler, the supplement has been fine-tuned so that very little reaches the end of the colon. This precaution ensures that the engineered bacteria die soon after being expelled in faeces, and so can鈥檛 spread to the environment or other people.
Of course, there is always the danger that the modified bacterium could acquire a gene that allows it to live without the supplement. Bacteria are remarkably good at swapping genes with their fellows, even across species barriers. But such an event is generally regarded as so unlikely as to be negligible.
And in any case, it may well be worth the risk. Extensive trials in mice suggest that the therapy really makes a difference. Almost two years ago, Steidler鈥檚 group published encouraging results. Mice with a condition similar to human inflammatory bowel disease showed up to a 50 per cent reduction in gut inflammation, making the approach just as effective as steroid treatment but with potentially fewer side effects (Science, vol 289, p 1352).
Yet worryingly, perhaps, the researchers still have no clear idea how the GM bacteria exert their beneficial influence. They might simply attach themselves to the gut wall and secrete IL-10 which influences the target immune cells. But another possibility is that the bacteria are actually taken up by specialised immune cells called 鈥淢 cells鈥� in the gut lining. In this case, the bacteria would be incorporated into the immune system itself, releasing IL-10 from the M cell. It might make a big difference which mechanism is at work, so shouldn鈥檛 we find the answer before we start any human trials?
Steidler says that his team is setting up a series of research projects to find out. All the same, he鈥檚 convinced that human studies should start immediately. The first step, he says, is a small-scale trial to see whether the experimental system is safe and effective.
The 鈥減hase I鈥� trial in humans is being planned by Steidler鈥檚 medical collaborators at the Academic Medical Center in Amsterdam. The researchers want to make sure that neither the bacterium nor the IL-10 has unexpected side effects. They also want to see whether the bacteria colonise the right part of the colon. Gastroenterologist Henre Braat of the AMC says that if they get the go-ahead, they鈥檒l feed the GM bug to 12 patients with Crohn鈥檚 disease.
During the trial, the patients will be admitted to hospital, but won鈥檛 have to stay in a special environment 鈥淥ur main concern is to ensure they use a chemical toilet,鈥� Braat says. All their faeces will be collected and destroyed so no modified bacteria escape.
On 21 May, the Dutch scientific advisory committee on genetic modification gave 鈥渄raft鈥� approval to the trial. The publication of the draft licence in newspapers and on a government website will be followed by a four-week consultation period 鈥渋n which there is time to answer any objections the public might have鈥�, says Birgit Loos, the head of the Dutch civil service office in charge of GM organisms. If there are no objections, then the licence will be finalised and there will be a further six-week period for public objections. If all disagreements are resolved within that time then the trial will go ahead.
The outcome of the public consultation period is hard to predict. Loos says she expects the licence to stand, based on past experience: medical biotechnology applications always go smoothly, she points out. But this isn鈥檛 any old medical biotechnology trial. It is officially classed as an environmental release of a GM organism, and setting GM organisms loose is widely unpopular. We can only wait and see how this one plays out.
What is clear, though, is that the Dutch trial is just the tip of the iceberg. Steidler鈥檚 group is already looking for other potentially therapeutic proteins that could be manufactured by obliging bacteria. For instance, 鈥渢refoil鈥� peptides might do for acute immune reactions what IL-10 promises to do for the chronic sort.
And we might one day send drugs to different regions of the digestive tract. Just as Lactococcus settles in the colon, perhaps it鈥檒l be possible to engineer a bacterium to deliver drugs to the stomach or small intestine.
Many research groups are now convinced that one way or another, GM bugs, perhaps in the form of live foods such as yogurt, will eventually be used as living drugs couriers. Steidler has put his money on Lactococcus as the vehicle, not least because it can easily be engineered to churn out proteins continuously and in large quantities. Meanwhile a French team led by Monique Alric of the University of Auvergne in Clermont-Ferrand is backing gut-dwelling yeasts.
Yeasts are bigger, and in some ways trickier to work with than bacteria. In yeast, human genes usually need to be switched on by some other compound, and often yield tiny amounts of the product. On the other hand, because yeasts are much more closely related to mammals than bacteria are, they can make a wider range of human proteins.
So far the French team have concentrated on creating experimental yeasts and testing them in a lab model of the human gut. The group already has yeasts capable of secreting compounds such as a plant protein called cytochrome P450, and others that can biochemically convert one compound into another. At the moment the team is negotiating contracts with commercial firms to insert genes for therapeutic proteins into yeast.
The French approach might also help assess the level of risk before human trials begin. 鈥淥ne advantage of our system is the possibility to see if gene transfer takes place between the yeast and different populations of gut bacteria,鈥� says Alric.
Another intriguing possibility is using GM bugs to mop up toxic waste products such as uric acid and creatinine, which build up in the blood of kidney patients and currently have to be removed by dialysis. Researchers at the Artificial Cells and Organs Research Center at McGill University in Quebec have already reported that artificial cells containing a GM strain of the gut bacterium E. coli can lower levels of uric acid and creatinine in rats.
It might be risky, but if the new approach makes curing serious illnesses such as Crohn鈥檚 disease and kidney failure as easy as making yogurt, surely it鈥檚 worth a shot.
