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Thursday, Sept. 11, 2003
Putting bacteria to work in the body
By ROWAN HOOPER
Margaret Atwood's latest novel, "Oryx and Crake," is set in a future where multinational power has created a dystopia of genetically engineered organisms living in a globally warmed world.
At one point in the novel, the scientist Crake reminds his friend Jimmy about how dentists went out of business when a GM mouthwash was introduced. The GM mouthwash contained benevolent bacteria that live in the mouth and out-compete the harmful bacteria that cause tooth decay.
Like this GM mouthwash, many of Atwood's ideas are eminently plausible, and the book is all the more compelling for them. It's "speculative fiction," says Atwood. But just how plausible her ideas are, and how likely to occur, is confirmed this week in a leading U.S. science journal.
Peter Lee and colleagues, of the department of medicine at Stanford University, Calif., have modified bacteria that may soon be used in humans. But not in the mouth. This is lactobacilli bacteria that are naturally present in the vagina, and Lee's group has engineered them to protect against HIV. The work is published in the Proceeding of the National Academy of Sciences.
HIV is mainly spread by heterosexual sex, with by far the greater risk of transfer from male to female. More than 19 million women are currently infected worldwide. The new research offers women a unique ability to protect themselves against HIV transmission.
"At present, females have little control over protecting themselves from STDs like HIV," said Lee in an e-mail interview. "A particularly innovative feature of our product is that it might be used on an intermittent basis, for instance, maybe once weekly. In this way it would be self-administered by a woman in a discrete, completely female-controlled, manner."
The mucous membranes of a woman's reproductive tract are naturally colonized by a number of bacterial species, which form an ecosystem that acts as a barrier against HIV.
"The reproductive tract of healthy women is colonized by specific species of lactobacilli," said Lee. "A deficiency of these lactobacilli is known to be associated with recurrences of conditions such as urinary-tract infection and bacterial vaginosis and perhaps, an increased rate of HIV transmission."
Lee decided to increase the protection that lactobacilli offer by getting the bacteria to specifically target HIV. Lee's team gave one species of bacteria (Lactobacillus jensenii) an extra boost by adding the gene for CD4, a protein that specifically latches on to HIV. The modified bacteria secretes CD4 and binds HIV.
Lee envisions the virus being "mopped up" by a CD4-carrying bacterium before it has a chance to infect the body. But will the new bacteria be able to persist in the tough vaginal ecosystem?
"One of the key unknowns is whether lactobacilli that have been genetically modified can compete similarly [with unmodified bacteria in the vagina]," agreed Lee. "To this end, we have done extensive testing on our genetically modified bacteria and are encouraged that these bacteria behave similarly to the wild-type strain in vitro."
Testing has so far been limited to lab studies in the Petri dish ("in vitro"), where Lee's team found that the bacteria reduced the rate of HIV infection in susceptible epithelial cells by at least half. Preliminary studies using monkeys showed that the engineered bacteria grew well and proved to be safe.
"We will be interfacing with regulatory agencies to develop a clinical strategy which ensures rigorous clinical studies and appropriate safety testing," said Lee. "I'm hesitant to attach a specific time frame to this, but the product could be available for testing in the not very distant future."
It remains to be seen how those opposed to genetic modification will react.
"I know anti-GMO lobbyists will have concerns," said Lee. "At the same time, we are pursuing a concept that offers the potential to prevent HIV transmission in regions of the world where HIV is rampant and thousands are dying per day. From my standpoint, this appears to be a critically important cause."
The research is seen as eventually leading to the creation of a small vaginal suppository that a woman could use on a regular basis to provide ongoing protection. Such a product would be inexpensive to manufacture and distribute, making it suitable for developed and developing nations.
Lee, not surprisingly, has a more positive view of genetic modification than Atwood (a view that cynics might say comes from that fact his company, Osel, stands to make a lot of money from his product. Then again, Atwood has made a lot of money from her book).
"We believe lactobacilli can be used in a number of different ways to trap and inactivate viruses or other pathogens [our present MucoCept approach], display vaccine antigens, locally deliver therapeutic proteins," said Lee. "In fact, we are aware of groups that are pursuing genetically modified bacteria for prevention of dental caries -- possibly where Atwood got the idea. There appears to be a lot of emerging interest in using these safe, nonpathogenic, lactobacilli for delivery of a range of proteins."
Finally, for the homosexual men out there wondering if there will be any GM bacteria that can help protect them, there is good news.
"Lactobacilli colonize the vaginal cavity, as well as the rectum," said Lee. "Thus, this approach may also prove to be applicable to men."
"Oryx and Crake" by Margaret Atwood is published by Bloomsbury. The Web site of Peter Lee's bacterial therapeutics company, Osel, is at www.oselinc.com Rowan Hooper is a researcher at Trinity College, Dublin. He welcomes comments at email@example.com