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2003 Annual Science Report

Scripps Research Institute Reporting  |  JUL 2002 – JUN 2003

Executive Summary

What is life, the requirements for its origins and evolution, and how living systems may be identified elsewhere in the universe are some of the most fundamental questions in astrobiology. Under the auspices of the Scripps Research Institute, a multi-institutional research team has been assembled to explore a variety of interdisciplinary experimental approaches to self-reproducing molecular systems and Darwinian chemistry. Through the design and study of diverse and novel chemical systems in the laboratory, we seek to garner a better understanding of life and its origins.

In the past year our team has continued to make significant discoveries and progress in several areas of research. Benner’s group at the University of Florida has established a multidisciplinary research program that addresses issues relevant to astrobiology from several distinct but interrelated perspectives. They have hypothesized that genetic molecules in water will contain a repeating charge, universally in the galaxy. They have completed studies on a series of molecules that test this hypothesis, a step towards developing tools to detect universal biosignatures in NASA missions. Furthermore, a key step towards a synthetic biology involves the generation of artificial genetic systems that can be copied, and then have their copies copied. They reported a six letter genetic alphabet has supported a polymerase chain reaction. A long-standing debate in the history of life asks the temperature at which primitive microorganisms live. Benner’s group have resurrected proteins from ancient bacteria, studied their behaviors at different temperatures, and concluded that these bacteria lived at temperatures between 60 and 70°C. Finally, considering that the most abundant solvent in the solar system is not water, rather supercritical mixtures of dihydrogen, helium, and molecules such as methane and ammonia, Benner and coworkers have begun exploring, from a theoretical perspective, how organic molecules might behave differently in such environments. Ellington’s laboratory at the University of Texas-Austin is interested in generating novel self-replicating biopolymers in order to better identify self-replicating molecular ensembles that may be encountered on other planets. During the past year Ellington’s group has designed a cross-catalytic amplification system based on the fast and efficient deoxyribozyme. In this system complementary deoxyribozyme cleavases are inactivated by circularization. Linearization results in activation of the deoxyribozyme and leads to the initiation of a cascade of cleavage reactions that display exponential growth kinetics. This system represents the first in vitro system capable of exponential growth in the absence of protein enzymes. Ongoing in vitro selection experiments using larger and more diverse pools are expected to allow elucidation of some of the parameters surrounding the evolution of sequence and function in exponential replicating systems. The goal of Ghadiri’s research program at the Scripps Research Institute is to design, discover, and understand the primary factors responsible for directing self-organization of inanimate molecules into the animate chemistry of living systems. Ghadiri’s and coworkers’ approach has been to rationally design and recreate various forms of autocatalytic peptide networks in the laboratory and study how the interplay of molecular information and nonlinear catalysis can lead to self-organization and expression of emergent properties. Recently they have completed the design of the first de novo “small world” synthetic chemical network based on template-directed coiled-coil peptide fragment condensation reactions. The self-organized chemical network is composed of nine nodes and 21 edges including three autocatalytic processes. Their studies indicate for the first time that relatively complex networks can be rationally designed and constructed and its properties experimentally analyzed in order to gain insights into the dynamics of complex nonlinear chemical networks. This approach is expected to allow rigorous experimental and theoretical analysis of network architecture and aid in better understanding of factors contributing to system self-organization and display of emergent phenomena in living systems. Rebek and coworkers have continued their pioneering efforts in the design of novel abiotic molecular replicators and proto-cells. They have continued to explore synthetic systems in which compartmentalization leads to nonlinear, autocatalytic behavior. The compartments are reversibly formed capsules in which small molecular guests are temporarily surrounded by larger molecular hosts. They represent an extreme form of molecular recognition — molecules within molecules. The complexes are held together by weak intermolecular forces and their lifetimes vary from milliseconds to days. This range allows their applications as nanometric reaction chambers, as means to stabilize reagents and as spaces where new forms of stereochemistry can emerge. The capsule provides a mechanical barrier that imposes restrictions on the motion of guests held inside. The primary goal of the Switzer laboratory is to synthesize Alternative Nucleic Acids (ANAs) to attempt the optimization of polymer structure subject to the constraints of prebiotic availability, template-directed reproduction, replication conservative mutation, and fitness. Switzer and coworkers have designed and successfully evaluated a novel metallo-base-pair for deoxyribonucleic acid (DNA) that has greater thermal stability than natural base-pairs. This discovery expands the bounds of environmental conditions suitable for the transfer of genetic information by increasing the fitness of nucleic acid-like molecules in thermal environments, while also adding another orthogonal base-pair to the “genetic alphabet.” In an ongoing study, Switzer’s laboratory has been studying a new peptide nucleic acid that transcends previous known shortcomings of this molecular chimera of nucleic acids and peptides, opening the way to the creation of long polymer chains and highly functional proto-biopolymers that could serve as transitional polymers on the way to the present DNA/ribonucleic acid (RNA)/protein world.