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Older than earth!: When the author extracted certain molecules from a five-billion-year-old meteorite and let them get wet, they self-assembled into cell-like vesicles (left). He also found that decanoic acid, a fatty acid present in the meteorite, readily forms similar vesicles—ones capable of encapsulating DNA (glowing, right).

Fourth Milestone: Evolution of Catalysts
Can genetic information somehow emerge in random mixtures, essentially by chance? If the answer is no, then we’re in trouble, because those of us who work on the origin of life claim that this is exactly what happened four billion years ago, when the first forms of life emerged from a sterile mixture of minerals, atmospheric gases, and dilute solutions of organic compounds. To address that question, I will revisit a classic experiment that David Bartel and Jack Szostak published in 1993, while Bartel was a graduate student in Szostak’s lab. Their experiment is moderately complicated, but the result is so important that it is worth explaining here. The goal was to see if a completely random system of molecules could undergo evolutionary selection in such a way that molecules with catalytic properties could evolve. The first step was to synthesize trillions of different RNA molecules consisting of approximately 300 nucleotides, arranged in random sequences. Bartel and Szostak reasoned that buried in those trillions were a few ribozymes that happened to catalyze a ligation reaction, in which one strand of RNA is linked to a second strand. They developed a procedure that captured those rare molecules even if they only weakly catalyzed the reaction. Then they used enzymes to amplify them. The amplified sequences were put through another round of selection and amplification, and the process was repeated for 10 cycles.

The results were stunning. Increased catalytic activity began to appear after four cycles, and after 10 rounds the rate of catalysis was seven million times the uncatalyzed rate! It was even possible to watch the RNA evolve. Nucleic acids can be labeled with radioactive phosphate, then separated and visualized through a technique called gel electrophoresis. A mixture of RNA molecules is placed at the top of a gel and a voltage of several hundred volts is applied, which causes the molecules to migrate downward through the gel. Larger molecules don’t move very far, so they appear as bands near the top of the gel; smaller, faster-moving molecules form bands near the middle and bottom. At the start of the experiment, nothing could be seen in the gels, because the RNA molecules were all different. But after three cycles, distinct bands appeared, meaning that certain catalytic species were already being selected. With further cycling, other species appeared for a few cycles and then went extinct. After 10 cycles, two distinct RNA species survived, representing those RNA molecules that were most efficient in catalyzing the ligation reaction.

These results demonstrate a fundamental principle of evolution at the molecular level. At the start of the experiment, every molecule of RNA was different from all the rest, but then a selective hurdle was imposed in the form of a ligation reaction that allowed only certain molecules to survive and reproduce. The result was that specific catalytic molecules emerged by a process closely reflecting Darwinian natural selection. The conclusion: genetic information can in fact appear in random mixtures, as long as the mixtures begin with large numbers of polymers defined by a variety of nucleotide sequences from which specific sequences having a catalytic property can be selected and amplified. It seems reasonable to propose that similar selective processes could have occurred on the prebiotic Earth when the first forms of life self-assembled in a mixture of organic compounds and then began to evolve.

Fifth Milestone: Combinatorial Chemistry & Garbage Bags
Most chemists learn to do their experiments in series, one per day. But experiments can also be done in parallel with a technique called combinatorial chemistry. This approach is particularly useful in the pharmaceutical industry, in which it is often necessary to experiment with large numbers of compounds in order to optimize a reaction or test a new drug. A robotic device loads hundreds or even thousands of small reaction chambers with the desired mixtures, each chamber containing a droplet that is slightly different from the rest. After the reaction is completed, the chambers are individually tested for activity.

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Credits: Chris Buzelli, David Deamer

Tagged: Biomedicine

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