![\"Colourful](\"\/\/media.nature.com\/w800\/magazine-assets\/d41586-018-05476-4\/d41586-018-05476-4_15861428.jpg\")
<\/div>\n<\/div>The\u00a0Escherichia coli<\/i>\u00a0bacteria is being developed as a vehicle for gene therapy in people.<\/span>Credit: Fernan Federici and Jim Haseloff\/Wellcome Coll.\/CC BY<\/p>\n<\/figcaption><\/figure>\n <\/p>\n <\/p>\n People often take medicines to rid themselves of problem bacteria. Now, a counterintuitive approach \u2014 turning genetically modified bacteria into medicines \u2014 is gaining ground.<\/p>\n Several companies are testing whether engineered bacteria can treat conditions that affect the brain, liver and other organs \u2014 and even kill other, harmful microbes. But although US regulators have approved trials of several types of engineered bacteria as a form of gene therapy, questions remain about\u00a0whether microbes\u2019 ability to share DNA with one another<\/a>\u00a0will create long-term safety risks.<\/p>\n The idea of using bacteria to deliver gene therapies first surfaced in the 1990s, but early clinical trials met with mixed results. Interest in the approach has increased in recent years amid mounting evidence that the bacteria that live in the body \u2014 the microbiome \u2014 can influence human health. Researchers are looking to treat disease by modifying microbes that are normally found in people or foods they consume.<\/p>\n Matthew Chang, a synthetic biologist at the National University of Singapore, says that genetically modified bacteria have the potential to treat many types of disease. His group is engineering the gut bacteria\u00a0Escherichia coli<\/i>\u00a0and\u00a0Lactobacillus<\/i>\u00a0to recognize and destroy harmful microbes1<\/a><\/sup>. \u201cIt\u2019s a rapidly growing area,\u201d says Chang, who adds that he is in talks with regulators in Singapore about starting clinical trials.<\/p>\n <\/p>\n <\/p>\n Missing piece<\/b><\/p>\n One strain of research is aimed at treating the genetic disorder phenylketonuria. People with the condition are deficient in an enzyme that breaks down the amino acid phenylalanine, which causes neurological damage if it builds up in the body. At the American Society for Microbiology\u2019s annual meeting in Atlanta, Georgia, earlier this month, researchers from the biotechnology firm Synlogic in Cambridge, Massachusetts, reported that\u00a0E. coli\u00a0<\/i>modified to produce an enzyme that degrades phenylalanine, and a protein that moves it from blood to cells, reduced levels of the amino acid in monkeys’ blood by more than half compared with animals in a control group.<\/p>\n The company started clinical trials in healthy human volunteers in April, and will begin testing the bacteria in people with phenylketonuria as soon as it concludes that the therapy is safe, says chief executive Aoife Brennan. In April, Synlogic began a trial of engineered\u00a0E. coli<\/i>\u00a0that make enzymes to clear the toxic build-up of ammonia in the blood of people with metabolic liver diseases.<\/p>\n Another firm, Intrexon of Germantown, Maryland, has altered\u00a0Lactococcus lactis,\u00a0<\/i>a bacterium used in cheese production, to make a protein that protects the outer layers of the skin. One ongoing clinical trial that has enrolled about 200 people with cancer is testing whether an\u00a0L. lactis<\/i>\u00a0mouthwash can prevent oral sores that are a side effect of chemotherapy. In July, the company will begin dosing people who have diabetes with a different form of\u00a0L. lactis\u00a0<\/i>that produces both the precursor to human insulin and an immune protein that enhances cells\u2019 ability to respond to insulin.<\/p>\n Both Intrexon and Synlogic have engineered their bacteria to make it less likely that they will establish colonies in the body. Patients would have take the modified microbes regularly to ensure consistent doses of the therapeutic molecules they produce. But other companies are pursuing treatments that would create colonies of transgenic bacteria in the body.<\/p>\n The biotechnology firm Osel in Mountain View, California, plans to seek US government approval later this year for a strain of\u00a0Lactobacillus<\/i>\u00a0that has been engineered to prevent HIV transmission. Studies have shown that naturally high levels of\u00a0Lactobacillus<\/i>\u00a0in the vagina can help to protect women against HIV.2<\/a><\/sup>\u00a0Osel is attempting to enhance the bacteria\u2019s protective properties by modifying it to carry a human protein that prevents HIV from infecting immune cells.<\/p>\n <\/p>\n <\/p>\n Safety concerns<\/b><\/p>\n Challenges remain before these engineered bacteria can enter the market. Scientists need a better understanding of how the bacteria interact with the body, Brennan says, because\u00a0their effects are less straightforward than those of drugs<\/a>.<\/p>\n Then there is the risk that the microbes could pass the human genes they carry to other bacteria in the body, with unknown consequences. Several companies have attempted to prevent this sort of exchange by altering the chromosomes of a bacterium, rather than its plasmids \u2014 tiny pieces of DNA that bacteria pass back and forth. They have also built in biological \u2018kill switches\u2019 that would prevent the microbes from surviving outside the body.<\/p>\n