Sufficient Complexity And Combinatorial Chemistry In Stars, Planets And Life

How did life begin, anyway?



I am a research professor at the University of California, Santa Cruz, and over the past 30 years my students and I have been working to understand how cellular life arose. The unit of all life today is the cell, a molecular system of functional polymers (proteins and nucleic acids) that is bounded by a membrane composed of lipid.



We and others have discovered ways to fabricate what we call protocells, artificial molecular systems that have some of the properties of life. In the next few years I am reasonably confidant that artificial cells will be assembled with virtually all of the properties of life, and that this breakthrough will lead to a deeper understanding of how life began. These are very exciting times! I want to share some of the excitement with readers of this column, and invite them to share their own views and comments.



To get some idea of the scope of the question of life’s origins, let’s consider for a moment what a planetary surface in our solar system was like four billion years ago, before life began. There were no genes to tell a living organism what proteins to make. There were no enzymatic catalysts, no photosynthesis, no metabolism. Instead, on Mars and the Earth, there were hot, sterile surfaces, salty oceans containing a dilute solution of thousands of organic compounds, volcanic land masses rising from boiling seas, and tidal wet-dry cycles where seas met land. Water continuously evaporated from the interface between sea and atmosphere, condensed as rain and fell on the lava of volcanic islands where it formed small pools containing organic solutes, then evaporated again. From this unpromising chaos of land, sea and atmosphere, the first life somehow emerged, certainly on the Earth, perhaps on Mars.



I want to tell this story in a new way. Because life today is so much a phenomenon of chemistry, it has been mostly chemists who are attracted to the question of how life began. Chemists see this question through their perception that the origin of life is best understood as a chemical process. And of course, this is true, at least in part. When the first organisms began to grow and reproduce on the early Earth, chemical reactions associated with growth, metabolism and replication were central to much of what we call the living state.



But how could the chemistry begin?



I believe that the answer will be found in the realm of physics, and more specifically biophysics, defined as the physical processes that we now associate with the living state. The chemistry of life became possible after physical processes permitted specific chemical reactions to occur in molecular assemblages that emerge when the laws of physics and chemistry intersect. On the early Earth, over a period of time measured in tens to hundreds of millions of years, countless microscopic compartments were produced when dilute solutions of organic solutes were mixed, baked to dryness on mineral surfaces, dispersed by rain or tides, then cycled again.



This is where chemistry takes over. I will argue that three chemical concepts must work together for life to begin. Furthermore, these concepts should help guide present and future research on the origins of life.



Here are the three concepts:



• The principle of sufficient complexity



• The advantage of cycling reactions



• The power of combinatorial chemistry



Sufficient complexity means just what it says. When Stanley Miller produced amino acids from simple gas mixtures, it was essential to have water, ammonia, methane and hydrogen present. If any one of these components had been absent, the mixture would be insufficiently complex and the experiment would have failed.



The origin of life also required components of sufficient complexity. We, as scientists, tend to keep our experimental conditions as simple as possible, to rule out confounding complexities so that the results are clear. This is simply good research technique, because it forces us to limit the scope of our research. Most recently the emphasis has been on replicating and catalytic systems involving RNA and DNA which are studied in small plastic test tubes. My point is that such systems may be insufficiently complex, and that we need to take the next bold step into interacting systems of nucleic acids and peptides, for instance, in order to more closely simulate the reactions that led to the origin of life.



The advantage of cycling reactions is also obvious, but it is rarely applied. Studies of chemical reactions related to the origin of life typically produce a mixture of products that need to be analyzed. For this reason they are usually run just once, over periods of minutes to days, and the products are analyzed after the reaction reaches equilibrium.



This approach simplifies the analysis, which is important for an investigator who has a limited time to do experiments and publish the results. However, a single run negates the potential for evolution within the mixture. Furthermore, a single run is not a plausible simulation of what would happen on the early Earth where organic mixtures would be exposed to cycling conditions over many years of time.



I will argue that we need to dig deeper into the possibilities of cycling reactions and design experiments that will take advantage of possible evolutionary steps toward increased complexity within chemical mixtures.



A standard approach used by chemists is to run a given reaction in a single container, again for experimental convenience and simplicity. However, in recent years the technique of combinatorial chemistry has developed, which is used in the pharmaceutical industry to study large numbers of compounds and conditions 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.



A lipid-encapsulated systems of molecules can also be a version of combinatorial chemistry. In my lab, I often make liposomes by adding water to a flask containing a few milligrams of a dry phospholipid such as lecithin. If I shake the flask for a few seconds, a milky suspension of liposomes is produced that contains trillions of individual microscopic vesicles in the size range of small bacteria, half a micrometer in diameter. And if the vesicles are prepared in a solution containing small peptides and short nucleic acids such as RNA, each of the trillion vesicles will contain a different set of components.



Now let’s think about the early Earth. Instead of milligrams of lipid in a flask, the early Earth would have had trillions of tons of organic material assembling into enormous numbers of microscopic compartmentalized molecules, and half a billion years of time to do the experiment. I think the origin of life is best understood as a version of combinatorial chemistry, but at a level far beyond what we can do in the laboratory.



Will we ever discover the combination of ingredients that gave rise to life? I hope so, of course. Our only hope is to apply what we know about the chemistry and physics of living systems to reduce the odds, then be brave enough to actually try the experiments.