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BIOCHEMISTRY
DNA SYNTHESIZED FROM TNA TEMPLATE First step could lead to polymerase that works with simpler nucleic acids
C
ERTAIN DNA POLYMERASES
can synthesize D N A from a template composed of threonucleic acid (TNA), which contains the sugar threose instead of deoxyribose in its backbone, according to researchers at Harvard Medical School. Their goal is to find a DNApolymerase that can serve as the starting point for directed evolution of a polymerase that will work with TNA. "TNA is a pretty interesting molecule that was discovered by Albert Eschenmoser {see page 48} in a search for possible progenitors of RNA or DNA, the kinds ofmolecules that might have been the early genetic molecules in the origin oflife," says team leader Jack W. Szostak, a Howard Hughes Medical Institute investigator and professor of genetics in the molecular biology department at Harvard Medical School. 'We're very interested in learning anything we can about the capabilities of TNA. Basically the question is, 'Could there have been a T N A world before the RNA world?'" Szostak, postdocJohn C. Chaput, and graduate student Justin K. Ichida used an assay to find D N A polymerases that would work with a T N A template that consisted of a primer, a six-base D N A "running start," and aninebase T N A region. Most of the polymerases were able to catalyze the synthesis ofDNAone to three nucleotides into the T N A region of the template, and some of the polymerases showed traces of the full-length D N A product [J.Am. Chem. Soc, published online Dec. 28, 2 0 0 2 , http://dx.doi.org/10. 1021/ja028589k}. "There's quite abit ofvariation between polymerases," Szostak HTTP://WWW.CEN-ONLINE.ORG
ON T H E H U N T Harvard researchers Chaput (left), Szostak, and Ichida seek DNA polymerases that can be evolved to replicate TNA.
says. "Some really don't like to work on T N A at all. Others were surprisinglygood."The results encourage Szostak to believe that evolving a suitable polymerase will be easier than he had originally thought.
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So far, Szostak has demonstrated halfof what's needed to replicate TNA. In other work, his group is looking for enzymes that can make TNAfromaDNAtemplate. "It would be nice ifwe had a single enzyme that could do both reactions," Szostak says. "That requires modifying an existing D N A polymerase in two ways: It has to recognize theTNAtemplate, TNA and it also has to be able to synthesize TNA. We've decided to simplify things by breaking it down into the two separate steps." Leslie E. Orgel, a profesOH sor at the Salk Institute for I 0 = P —0 Biological Studies in La JolI la, Calif., says that the work "maybe the first step in the o0 development of an artificial I replicating system that, though still dependent on RNA protein enzymes, is capable B = nucleotide base of evolving under selection." In addition, "in the context of the origin of life," Szostak's work also "supports the idea that a simpler genetic polymer could be taken over by a more complicated polymer," Orgel says.—CELIA
OH
HENRY
BIOWEAPON
Deadly Toxin Ricin Found In London Apartment , ritish antiterrorism police and security service agents have arrested seven North African men after recovering small amounts of ricin and the equipment to make the highly toxic poison from their north London apartment. Scientists at the Defence Science & Technology Labs at Porton Down have positively identified the toxin. Ricin is banned under chemical and biological weapons treaties. But small amounts of the poison—consisting of two 30,000molecular-weight chains connected by a disulfide bond—can be extracted from seeds of the widely available castor bean plant. The laxative castor oil is also derived from this plant. Ricin is a cytotoxin and has been studied as a possible anticancer agent. The molecule's B
B!
chain binds to the cell wall to facilitate transport of the A chain into the cell. Once in the cell, the A chain kills the cell by inhibiting protein synthesis. By injection, the fatal dose in an adult is 1 |xg per kg of body weight, but ricin is also lethal at slightly higher doses when inhaled or ingested. Initial symptoms are flulike, and death occurs within days from multiple organ failure. There is as yet no antidote, but Ellen S. Vitetta, a cancer researcher at the University of Texas Southwestern Medical Center, Dallas, and colleagues have developed a recombinant DNA vaccine that "works well in mice and is very safe." She has applied for an NIH grant for eventual testing in humans and is working with a drug company to develop an oral formulation.-LOIS EMBER
C&EN
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13,
2003
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