Earth biochemistry relies on DNA as the information-carrying polymer and water as the chemistry-facilitating solvent. Life on other planets, however, could leverage very different chemistry. This grant supports work by Sara Seager, Professor of Planetary Science, Physics, and Aeronautical and Astronautical Engineering at the Massachusetts Institute of Technology, that will explore an alternative to Earth biochemistry. The proposed research focuses on identifying a DNA-like molecule that is functional in concentrated sulfuric acid (CSA), the primary component of Venus’ atmosphere and a water-alternative solvent found on many planets in our galaxy.   There are several steps to establishing that a DNA-like molecule can function in CSA, and Professor Seager is tackling what is perhaps the core challenge: identifying components of a DNA-analog molecule that are structurally stable and appropriately reactive in CSA, focusing on the three primary molecular components of DNA: nucleic acid bases, so-called ‘linker’ molecules, and a ‘molecular backbone’ structure. Her project is divided into four tasks. In Task 1 Seager and her researcher team will determine the CSA reactivity of the nucleic acid bases found in DNA/RNA. While Seager has demonstrated that the core structures of these canonical bases are CSA-stable, it’s not yet known whether the bases can bond with one another in CSA; something required to form a DNA-like molecule.   Excess protons found in CSA (or in any acid) may interfere with the hydrogen bonding that holds two bases together in a DNA molecule, making base-pairing with these canonical bases impossible in CSA. Accordingly, in Task 2 the researcher team will test the CSA stability and reactivity of ‘alternative’ nucleic acid bases that do not rely on hydrogen bonding for base-pairing. In Task 3, the researchers will develop a list of linker and backbone molecule candidates that promise to be stable in CSA and in Task 4 these candidates will be subjected to CSA stability/reactivity testing.   Establishing that a replicating, information-bearing molecule can exist in CSA goes a long way to establishing CSA as a solvent that can host life. Such a finding would significantly impact exoplanet research, expand the number of planets regarded as habitable, and inform planned and proposed missions to Venus aimed at searching for signs of extraterrestrial life.

Life as we know it is primarily chemistry: all living organisms are composed of carbon-based molecules such as proteins, carbohydrates, and nucleic acids that are the result of chemical reactions between different elements like carbon, hydrogen, oxygen, nitrogen, and sulfur. Understanding the basic principles underlying chemical reactions is important to understanding life. When thinking about reactions in a chemical context, scientists typically think about reactants interacting in a homogeneous solution that’s essentially the same in any given place. But the cytoplasm, the liquid in cells where biochemical reactions take place, is a biological context that’s quite different from the simplified models of chemistry textbooks. Cytoplasm is a heterogeneous fluid that looks and functions differently across the cell and so it’s not accurately represented by simplifying assumptions of homogeneity. Precisely how these assumptions are distorting our picture of cellular chemistry, and therefore our understanding of fundamental biochemistry, is not well understood. This grant supports Lauren Zarzar and Ayusman Sen at the Pennsylvania State University who will study how solution heterogeneity influences reactivity for three important classes of biochemical reactions. First, they will study autocatalytic reactions, in which one of the reaction products facilitates (i.e. is a catalyst for) the same, or a coupled, reaction. Autocatalysis is a mechanism for chemical self-replication and is considered a key aspect of the prebiotic chemistry that gave rise to life. Next, the team will study enzyme reaction cascades, a sequence of enzyme-catalyzed reactions whereby the product of one reaction is the reactant for the next reaction. They’ll focus on chemotaxis (chemical activity that leads to motion towards or away from a higher concentration of some substance) to study how solution structure affects enzyme cascades. Finally, they will study polymerization reactions and, in doing so, address an important question in prebiotic chemistry: how polymers with specific monomer sequences arise without a specific sequence-directing mechanism. Ultimately, this project will deepen our understanding of specific reactions central to cellular chemistry and shed light on the role solution heterogeneity plays in driving the chemistry of life.

This grant supports Ben Machta at Yale University who will use tools from information theory and statistical physics to explore how bacteria process signals from their environment, and how they use this information to drive behavior. Machta will use bacteria to study one aspect of information processing: how noise (spurious signal accompanying the information-carrying signal) limits bacterial behavior. Specifically, Machta  will investigate how bacteria navigate their local chemical environment through chemotaxis (movement along a concentration gradient of a substance) and how they communicate with one another through quorum sensing (chemical signaling that reflects the density of nearby bacteria). Grant funds will allow Machta to determine the theoretical limit on the rate at which E. coli acquire behaviorally-relevant information (the concentration of so-called attractant molecules) and to measure this information-acquisition rate, to provide the first direct measurement of whether any organism’s biochemical sensory system approaches the performance limits imposed by the laws of physics. Additionally, Machta and colleagues will study how E. coli amplify signals without introducing noise via experiments that will test whether equilibrium or non-equilibrium models do a better job of describing chemotactic signal amplification. Finally, the researchers will use V. cholerae bacteria as a model organism to study the fidelity of information transmission as multiple signals propagate through the quorum sensing signal processing pathway. Collectively, these experiments will provide an important demonstration of how the tools of  information theory and statistical physics can be used to gain mechanistic insight into the information processing that drives behavior in simple living systems. 

This grant funds an ambitious plan by an international collaboration of six laboratories to achieve a milestone that science, and humanity more generally, has imagined for quite some time: building some version of life from scratch. That claim must be qualified by cautions that the effort may not succeed and by clarification that the proposed entity is probably better viewed as a minimal form of life rather than as a (much more complex) natural cell. To be clear about the version of life herein proposed, the goal of this project is to design and build a protocell from nonliving chemicals that is capable of indefinite cycles of genetic replication, growth, and division, and which—over generations—exhibits environmentally driven Darwinian evolution.The project team is led by Jack Szostak, Professor of Chemistry at the University of Chicago and includes researchers Irene Chen (UC Santa Barbara. U.S.), Sheref Mansy (University of Alberta, Canada), Arvind Murugan (University of Chicago, U.S.), John Sutherland (Medical Research Council, United Kingdom), and Anna Wang (University of New South Wales, Australia).Project activities will consist of laboratory experiments guided by theory and computation, organized along three primary research thrusts.First, the team will conduct research to achieve indefinite cycles of RNA replication by achieving high-fidelity copying of the entire RNA-based genome. The two major components of this first thrust are optimizing the chemistry for copying a given gene sequence from a template and ensuring that the entire genome is copied. The second research thrust focuses on achieving indefinite cycles of cell growth and division. Here the primary challenge is understanding and controlling membrane growth and division, and the team will experiment with several different approaches to using fatty-acid vesicles as the primary protocell container. In the third research thrust, the research team will address issues associated with making the genetic and compartmentalization systems mutually compatible. After these major goals are achieved, the team will then observe this primitive living system over several generations as it increases in complexity, adapts and evolves, and as its genome grows to encode more information about the world.

Understanding how cells cooperate to achieve new capabilities is important since cooperation underlies the transition from single-cell life to multicellularity. This grant supports a series of experiments by Karine Gibbs, a Professor of Biology at the University of California, Berkeley, aimed at improving our understanding of the mechanisms that facilitate collective migration (swarming behavior) of the model bacterial organism Proteus mirabilis (P. mirabilis). Understanding the swarming behavior of P. mirabilis may eventually reveal fundamental principles for forming and possibly manipulating biological collectives.Professor Gibbs' work focuses on studying the role kin-recognition plays in P. mirabilis swarming behavior. Kin-recognition is a form of intercellular communication that relies on direct cell-to-cell contact. A filament carrying a toxin at its tip extends through the membrane of a P. mirabilis bacterium and punctures a neighbor's membrane, thereby delivering the toxin to the neighbor. If this neighbor-cell is genetically the same as the 'attacking' cell (i.e. it's a relative, kin) then the neighbor cell encodes the toxin as well as the antidote and the cell lives. If, however, the neighbor is not kin, then it does not encode the toxin nor the antidote and the neighbor dies.Prior studies by Professor Gibbs suggest that kin-recognition plays a role in P. mirabilis swarming and here she will use this model organism to study how collective migration is modified by two loosely-related mechanisms: intentional mutations affecting kin-recognition, and random mutations acted on by fitness-guided selection. Gibbs will leverage her prior work that correlates growth conditions with bacterial colonies exhibiting different levels of collectivity. Specifically, by varying bacterial growth conditions Gibbs is able to create two types of bacterial communities corresponding to fast/cooperative collective migration on the one hand and slow/independent migration on the other. Professor Gibbs will use her recipes for creating fast and slow swarming communities to pursue a research project with three aims.Under Aim 1, she will develop quantitative, physical metrics that can be used to distinguish fast-swarming colonies from slow-swarming colonies. Experiments involving microscopy and subsequent image-analysis will establish quantitative descriptors of cell morphology, physiology, and motility for both single-cells and for the cell-groups observed to facilitate fast swarming. Quantitative descriptors will be developed both for single-cells and for cell-groups in both fast and slow colonies. Potential descriptors include cell area, curvature, instantaneous speed, location and trajectory, adjacency to other cells, and the number of interactions over time, among others.Under Aim 2, Gibbs will use the quantitative descriptors developed in Aim 1 to assess whether and how mutations affecting kin-recognition influence collective migration. Experiments will be performed for two 'environments': growth conditions that enable fast/cooperative swarming and growth conditions that inhibit fast/cooperative swarming (thereby favoring slow/independent migration). The experimental approach involves comparing 'regular', unmutated P. mirabilis to P. mirabilis strains with mutations that disrupt the toxin secretion system used in kin-selection. This will allow Gibbs to test the hypothesis that kin-recognition provides a fitness advantage in environments where efficient swarming is possible but not in environments where independent behaviors dominate (efficient swarming not possible).Under Aim 3, Professor Gibbs will perform experiments intended to identify genes that promote collective fitness; specifically, the ability to participate in efficient swarming. Random mutations arise at some frequency and if you start with a mutant P. mirabilis that can grow but not swarm, the bacterial population will increase (growth) but will largely be constrained to its initial location (no swarming migration). As the number of bacteria increases, eventually a mutant cell will arise that has acquired a mutation that restores the ability to swarm. This mutant will swarm away from the static population, identifying itself by spatial separation and thereby allowing experimenters to capture and genetically sequence this mutant. The researchers will then determine the genome-location of the swarm-enabling mutation as well as the alterations to the descriptors of collective vs. independent behavior.