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Letting the Bedside Inform the Bench

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  • Title: Research Assistant, MIT
  • Education: PhD, Harvard-MIT Division of Health Sciences and Technology, 2008; currently pursuing MD at Harvard Medical School
  • Recommended by: James Collins

Tim Lu is in the relatively rare position of having first-hand experience at the bedside and bringing his own research efforts to bear on real-life problems in the clinic. As a researcher also pursuing his MD, Lu uses synthetic biology to combat bacterial infections, with a specific focus on engineered bacteriophages.

The initial inspiration for this came to him while fulfilling his med school duties: examining dialysis patients with indwelling catheters, many of whom suffer from severe bacterial infections caused by biofilms. "There are a lot of biofilms in all sorts of medical devices, such as indwelling catheters. You can get a bacteria that sticks to the catheter surfaces that are really hard to eradicate with any conventional antibiotics," Lu says. "So you have to rip out the catheter and insert a new one, which causes morbidity in a lot of patients."

Instead of inventing a nuclear-powered can of Lysol, Lu saw an opportunity to use his synthetic biology skills to engineer a bacteriophage capable of destroying the biofilm by penetrating the extracellular wall and attacking the bacteria inside. Last year, Lu and Boston University's Jim Collins demonstrated that this was possible using an engineered E. coli-specific phage expressing dispersin B, an enzyme capable of breaking down several different types of biofilms. According to their initial experiments using E. coli biofilms on a plastic surface, the engineered bacteriophage was capable of killing 99.997 percent of the biofilm cells.

But the US Food and Drug Administration has not yet approved bacteriophages for use in humans, although the medical community has been aware of their potential for some time. "The biggest hurdle for us going forward is acceptance of the medical community and the FDA. We're using engineered bacteriophage, which are virus, even though they only affect bacteria," he says. "People are becoming increasingly interested in using bacteriophage, so I don't think this is going to be a problem in the next 10 or 20 years — but there's obviously a lot of work that needs to be done to prove to [the] medical community that this is something that's viable."

In addition to fighting biofilms, engineered bacteriophages can also be used to fight antibiotic-resistant bacteria, another issue with which Lu is familiar from his experience as a physician-in-training. Lu says that by inserting bacteriophages that knock out networks of bacteria responsible for the resistance mutation in combination with prescribing currently available antibiotics, he and Collins have demonstrated that it is possible to reduce the mutation rate 1,000-fold and kill bacteria 30,000 times more effectively than with just the antibiotic alone.

Looking ahead

The long-term vision for the bacteriophage that can eliminate antibiotic-resistant bacteria is to use it first against the most serious types of infections such as MRSA, which can't easily be eradicated. At present, Lu and Collins are using mouse trials and hope to eventually work with the Centers for Disease Control and Prevention to start gaining more clinical acceptance. In the future, Lu says, they would like to engineer their bacteriophage to work around a particular resistance to offer a more rational approach to fighting bugs that are constantly evolving.

Publications of note

In a 2007 paper published in PNAS entitled "Dispersing biofilms with engineered enzymatic bacteriophage," Lu and Collins showed that engineered biofilm-destroying bacteriophage were several orders of magnitude better than wild-type bacteriophage at eliminating biofilms.

And the Nobel goes to …

Lu says he would like to receive the Nobel for creating a long-term, sustainable solution to treating antibiotic-resistant bacteria.

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