The Birth of Biological Information

You study the origin of life. Where does it come from? What is your own basic idea of the origin of life? Braun: A great deal must have happened on the Earth before living organisms – life as it is generally understood – could have emerged, even the simplest ones. Biological evolution, based on competition between organisms, was preceded by a phase of chemical evolution, of molecular evolution. The question at the center of our research is: How could molecular evolution have given rise to biological information? We approach the problem from the physicist’s perspective: How could prebiotic systems, systems that are not in equilibrium have made that possible? In the beginning, there were simple chemical building blocks, molecules that had to be linked together to form polymers, RNA or DNA – the macromolecules in whose subunit sequences biological information is encoded. Such a polymerization process cannot occur spontaneously. It must be driven by the environment. Because we have been able to recapitulate some of the necessary steps in laboratory experiments, we now have a good idea of the kind of environment in which this process took place. Hydrothermal vents or volcanic settings, where geothermically heated water emerges from vents in volcanic rock onto the seafloor, provide the basic setting. Here one finds tiny, water-filled rock pores in which temperature gradients are steep. And – from a physical point of view – we think that this is all one needs to drive such a system.

In your view, how did non-living matter make the transition to the living state? Defining what exactly distinguishes living from non-living systems, what life really is one of the goals of this research. One possible answer is that one can use the term ‘life’ only when we have a – biological – cell. Others take the view that molecules that are capable of undergoing open-ended Darwinian evolution are already alive.

And the initial steps in this molecular evolution were driven by temperature differences? Precisely. Temperature gradients enable several things to happen at once. First they allow molecules to be concentrated, because in a temperature gradient molecules move from warm to cold. In addition, they set up what are called convection currents in the water itself. Fluids rise when they are heated and sink again when they cool. If the pores are small enough, with diameters of around 0.2 mm, these two phenomena reinforce each other. The molecules, which tend to accumulate in the cold zone anyway, are also transported there by convectional flows. – And this coupling can increase the efficiency of accumulation by factors of thousands or even millions. This is important because very highly concentrated molecules are most likely to polymerize. So the basic hypothesis is that the first RNA polymers formed under such conditions, and paired up for polymerization if their subunit sequences were ‘complementary’.

And what happens next, in this scenario? The next step is the reproduction of the information. This requires the separation of paired polymers – double-stranded RNA or DNA – into their component strands, so that the complementary building-blocks can interact with the subunits of the existing ‘template’ strands to form two double-stranded molecules – in principle, this is what happens when cells divide in an organism. This process enables the sequence of subunits, and hence the genetic information, to be passed to each of the daughter molecules before the mother molecule can be degraded. Separation, or melting, of double-stranded RNA or DNA does not need enzymes. It too can be done by temperature gradients. An oscillatory process develops. Molecules can make excursions into the warm zone, where they melt, and the single strands can be returned to the cold zone, allowing each to interact with and align new subunits. With each convection cycle and the right chemistry, the number of molecules in the system can be doubled. When this works well, it is like the rice grains on the chessboard – an exponential replication of similar sequences.

Over the past several years, you have uncovered a series of mechanistic details that support your thesis. How do these elements fit together? We plan to extend this scenario further, and we have now received an advanced grant from the European Research Council (ERC). We would really like to carry out an experiment in which evolution occurs in a test-tube. We plan to begin with three sorts of molecules: two complementary bases – for example A and T – for the DNA, and a chemical cross-linker called EDC, which can link the bases to each other. Analogs of this compound may have been available in prebiotic settings. Normally, EDC can link a handful of bases together. But, in our temperature trap, in which the building blocks can be so efficiently concentrated, we expect to obtain significantly longer polymers. We have already shown that 30mer of DNA can yield veritable DNA or RNA gels with millimeter dimensions.

And where does evolution come in? The interesting point here is that gel formation represents a phase transition, like that between liquid and solid. Moreover, this phenomenon allows DNA or RNA molecules to be sorted according to their sequences. Sequences that are unable to interact with the growing network are excluded, remain single-stranded and can be rapidly degraded, while other sequences are incorporated gels by forming double-stranded regions with complementary molecules. This can be viewed as a new phenotype: the gel-former. In terms of size, the gel-former is a dinosaur relative to the other forms we find. It has fundamental survival advantages, it can get caught in pores and form far more stable complexes. Here, a physical phase transition enables certain sequences to be selected from a mixture of random sequences – in other words, we have a selection process. So EDC can trigger a chain reaction, which initiates a process of cyclical growth. Only if segments of two molecules carry complementary sequences can they interact, i.e. hybridize with each other. The molecules grow, as the thermal trap selects for increasing length, and the sequence can survive because it has a template. We therefore expect that the experiment will be the first to yield cycles of Darwinian evolution in a physical system in which temperature differences alone maintain a non-equilibrium state.

You now lead a new Research Group at LMU’s Center for Advanced Studies (CAS) , which has funding for one year, and to which you have invited experts from all over the world to contribute. How does this work, and what are you working on with the invited Fellows? Most of our guests are experimentalists, and together we want to design novel experiments. For example, they might bring a reagent with which we can set up redox gradients, in which molecules are sorted according to their readiness to accept or donate electrons during chemical reactions. But we are also interested in programmatic discussions about hypotheses that would be worth testing in the next stage of our investigation. The fact that there are now so many more scientists who are trying to integrate the experimental data available has transformed the field. Not so long ago, the general attitude was that if one can theoretically simulate something on a computer, then one can explain and understand the emergence of life. But this notion has been discarded now. But if theory and experiment are closely linked, we can frame the important questions much more precisely – and this is where international exchanges have been tremendously fruitful. With the ERC advanced grant, a new Collaborative Research Center 235 Emergence of Life (SFB/TRR) funded by the Deutsche Forschungsgemeinschaft (DFG) and involving both LMU and the Technical University of Munich, and the CAS Research Group, we hope to establish Munich as a center for the field.

The clues to how the Earth came to host life go back a very long way. LMU astrophysicist Andreas Burkert from the University Observatory recently encapsulated the story in the phrase: We are all made of stardust. Where are the links between your work and the insights that come from astronomy and related disciplines? The SFB/TRR’s remit extends to the geological aspects. We interrogate the rocks – the stardust – in search of clues. Going further back means asking different questions. What distinguishes the Earth from the millions of other planets? How might molecules have arrived here from outer space? And how relevant is all that to the origin of life? We hope to be able to study this with the Excellence cluster “Origins”. Here again, there are two schools of thought. One argues that the collision with a Mars-sized planetoid, which gave rise to the Moon, destroyed everything that might have arrived or evolved on the proto-Earth, so that the parameters were reset. The other side believes that comets and meteorites deposited considerable amounts of molecular material on our planet. But I think both models leave out a lot. The collision that preceded the formation of the Moon initiated a long period in which extreme conditions prevailed on the Earth. Could the formation of the Moon have been essential for the origin of life on Earth? Then there is the question of phosphorus. Phosphorus is indispensable for life, but how was it distributed on early Earth? It was not synthesized in the earliest stars, but much later in supernova explosions. The Earth is 4.5 billion years old. Could phosphorus have been available by that time? We hope to take up these questions with the help of particle physicists and astrophysicists in a new “Origins” project, a proposal for which has been submitted for the upcoming round of the Excellence Initiative. It was very visionary of Andreas Burkert when he asked whether we wanted to participate in the venture. So we as biophysicists can profit from the expertise of astronomers and astrophysicists who study the origins of the Universe, thus extending the project’s reach. It gives us a unique opportunity to expand the interdisciplinarity of the field so that we can cover all aspects of the question of how life emerged. If the proposal is accepted at the end of September, and we are able to organize the whole thing properly, this research consortium will be in a highly competitive, if not unparalleled position in the field.

Prof. Dr. Dieter Braun ist Professor of Systems Biophysics at LMU.