It’s the second to last day of the conference and the chemists are starting to head home. The hallways are quieter, the rooms less full, the Metro less forested by rolled up posters, the Power Bar options in the press room more limited. So I decided to give myself a little treat today: biological chemistry. As a life scientist by training, I’ve been rather out of my element the past week.

First Justin Gallivan from Emory in Georgia gave an entertaining talk about programming bacteria “to seek and destroy small molecules”. To control the cells, he’s using riboswitches — fragments of RNA which, when bound to certain small molecules, will bind to DNA and control gene expression. He’s now engineered riboswitches to respond to the molecules and regulate the genes of his choosing.

To do this, he scrambled portions of a well-studied riboswitch and screened for mutants that would 1) reliably bind DNA when not bound to the small molecule (real riboswitches are leaky), 2) recognize the herbicide atrazine but not its degradation product hydroxyatrazine, and 3) move toward atrazine.

The “movement” part was my favorite (and made for some cute videos of scurrying E. coli). E. coli naturally explore their environment via a “random walk”, where they alternate between swimming in more or less a straight line and “tumbling” before changing directions, steering towards tasty chemicals when they sense them. But E. coli lacking the gene cheZ just tumble around the whole time. Gallivan engineered his riboswitch to bind to cheZ, blocking its transcription and leaving the poor little bacteria spinning around aimlessly. But when atrazine was around, it would bind the riboswitch, permit transcription of cheZ, and the bacteria would swim right for it. When engineered with an enzyme that breaks down atrazine, the bugs could both seek and destroy.

Dennis Dougherty then gave a great talk about nicotinic acetylcholine receptors to explain why smokers don’t paralyze themselves everytime they take a drag. The receptors, which are activated by nicotine and acetylcholine, are located on our muscles and in our brains. This is fine — some would argue euphoric — in the brain, but if nicotine activated the receptors in muscles, one puff of a cigarette would cause every skeletal muscle to contract.

For better or worse, this doesn’t happen, so Dougherty brought his chemistry into the mix to figure out why. He discovered that the nicotinic acetylcholine receptors in the brain and on the muscle are made of different types of subunits, which he published a few months ago in Nature. As a result of a subtle change in the binding site, the receptors in the brain make a tight bond, called a cation-π bond, with nicotine and acetylcholine, but those on the muscle only make this bond with acetylchonline.

Finally, Lilly Award winner Scott Silverman talked about making DNA catalysts, which don’t occur in nature (the only naturally-occurring catalysts are protein enzymes and RNA enzymes (ribozymes)). Silverman’s been taking a random pool of DNA sequences and selecting for catalytic activity. He’s discovered deoxyribozymes that can ligate RNA — even forming “lariats” and “branched” RNA — and is now trying to find deoxyribozymes that will work with small molecules, proteins and sugars. It’s all well and cool, but it’s not clear to me what lariats and branched RNA are good for, or why DNA catalysts are superior in any way to ribozymes or protein enzymes. Maybe time will tell.

Image: NIH.gov

It’s the second to last day of the conference and the chemists are starting to head home. The hallways are quieter, the rooms less full, the Metro less forested by rolled up posters, the Power Bar options in the press room more limited. So I decided to give myself a little treat today: biological chemistry. As a life scientist by training, I’ve been rather out of my element the past week.

First Justin Gallivan from Emory in Georgia gave an entertaining talk about programming bacteria “to seek and destroy small molecules”. To control the cells, he’s using riboswitches — fragments of RNA which, when bound to certain small molecules, will bind to DNA and control gene expression. He’s now engineered riboswitches to respond to the molecules and regulate the genes of his choosing.

To do this, he scrambled portions of a well-studied riboswitch and screened for mutants that would 1) reliably bind DNA when not bound to the small molecule (real riboswitches are leaky), 2) recognize the herbicide atrazine but not its degradation product hydroxyatrazine, and 3) move toward atrazine.

The “movement” part was my favorite (and made for some cute videos of scurrying E. coli). E. coli naturally explore their environment via a “random walk”, where they alternate between swimming in more or less a straight line and “tumbling” before changing directions, steering towards tasty chemicals when they sense them. But E. coli lacking the gene cheZ just tumble around the whole time. Gallivan engineered his riboswitch to bind to cheZ, blocking its transcription and leaving the poor little bacteria spinning around aimlessly. But when atrazine was around, it would bind the riboswitch, permit transcription of cheZ, and the bacteria would swim right for it. When engineered with an enzyme that breaks down atrazine, the bugs could both seek and destroy.

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