Astrobiology Revealed #36: Natalia Mrnjavac

on the origins of metabolism

by Aubrey Zerkle

For this Astrobiology Revealed, we asked Natalia Mrnjavac about her recent paper “Intermediate stages in the origin of metabolism at a phosphorylating hydrothermal vent.” Natalia is a doctoral researcher at the Institute for Molecular Evolution at the Heinrich Heine University in Düsseldorf, Germany. She discusses the challenges early life faced in finding the building blocks it needed, and why serpentinizing hydrothermal vents may have provided a good source. (This interview has been edited for length and clarity.)

Your recent paper in Science Advances starts out with a fundamental question in origins of life research: How did metabolism begin? What led to your interest in life's origins and in this question in particular?

During my undergrad, I became fascinated by how enzymes work and I developed a passion for biochemistry and metabolism. I started reading up and thinking about how it all might have started. I found myself drawn to this question; it was exciting and stimulating. This eventually led me to a PhD in the field. I soon learned that the origin of life may be too broad a question to address in one sitting, and it is further complicated by the fact that there is no consensus on one definition of life. 

On the other hand, we know exactly what metabolism is, we can define it, so we can study it. Even though I am also interested in the emergence of other cellular processes and structures, such as genetic coding or compartmentalization, at the moment my research focuses on metabolism and bioenergetics. In order to fully describe the origin of cells, however, we will need to reconstruct the emergence of all essential cellular structures and life-sustaining processes.

You used enzyme sequences and structures to determine which metabolic pathways our last universal common ancestor (LUCA) had, which seems like a daunting task! What part of the project did you find the most challenging?

In our current study, the most challenging part was probably finding a reasonable way to quantify the gene distributions and trace those genes back to LUCA, bacteria, or archaea. In general, with computational studies that attempt to look so far back in time, there is a certain dependence on the method, the model, or the parameters we choose, so there is a dependence on the researchers’ decisions. I would say this part of the research process is often the most challenging because it might be where flaws in reasoning, personal bias, or subjectivity can influence the most. This is also why quality peer review is key for the advancement of science.

One theme that emerges from this work is that LUCA would have had to source metabolic intermediates from the environment, including some involved in autotrophy, or carbon metabolism based on CO2. Why do you think CO2 was the original carbon source, and are there other views?

CO2 is the carbon source for all modern ecosystems, whether they are based on photosynthesis or on chemosynthesis, and we think this is unlikely to have changed since life’s origin. In other words, I think it is reasonable to assume there would be continuity between the chemistry of life’s emergence and cellular biochemistry. This assumption could be wrong, but if prebiotic chemistry and biochemistry are disjunct, we would have little to go on when trying to reconstruct the origin of life. 

As with almost everything in the origin-of-life field, there are different views that envision a different primordial carbon source as well. However, the chemical space is vast, and with no constraints in terms of reactants, conditions, or chemistry, it seems extremely difficult to pinpoint the exact chemical route that would have led to life. Therefore, we are trying to develop our hypotheses under the premise that there was continuity between early Earth geochemistry and cellular biochemistry. So far, laboratory experiments show that non-enzymatic, metabolism-like reactions can generate a number of compounds relevant to life, which prompts us to look further for possible prebiotic reactions that are compatible with Earth’s geochemistry and resemble microbial metabolism. 

Another major barrier you identified is in phosphorus (P) availability. Why would P have been such a steep barrier to the evolution of metabolism?

In origin of life research, there is something called “the phosphorus problem,” which has been posited since the 1950s. In short, phosphorus is an essential chemical element for life. We find it in the structures of DNA and RNA, in cell membranes, and in the phosphate-bearing molecule ATP, which is key to driving many metabolic reactions that would otherwise not go forward due to unfavorable energetics. So, phosphorus and phosphate groups are non-negotiable components of cells. However, phosphate-bearing minerals in rocks, such as apatite, are poorly soluble in water, and phosphate is poorly reactive in water at mild temperatures and pressures. This leads to a conundrum: how did phosphorus become integrated into metabolism? 

In this work we present experiments showing that phosphite, which is a more reduced form of phosphorus than phosphate, might have been the early source of this element for emergent metabolism. Phosphite is more soluble and more reactive under mild aqueous conditions, and it has been reported in rocks from a special type of hydrothermal vents called serpentinizing vents. The reaction that we report is also very similar to a metabolic reaction carried out by some bacteria, which is in line with the continuity principle between geochemistry and the biochemistry that I previously mentioned.

You’ve suggested that these serpentinizing hydrothermal vents could have been the best place for metabolism to originate. Why is that?

There are a number of reasons why serpentinizing vents have been an appealing environment for origin of life hypotheses since their discovery. They harbour reducing conditions because the geochemical reaction we call serpentinization generates molecular hydrogen. Hydrogen is used as an electron donor and energy source by some bacteria and archaea, and it could have served as the reductant for prebiotic chemistry. These are out-of-equilibrium environments where serpentinization continuously provides new reactants and circulating fluids remove products, while pH and temperature gradients are generated. Minerals in these vents contain transition metals which can serve as catalysts for prebiotic chemistry. We also know that phosphite, a possible primordial source of phosphorus, has been reported from these environments. Today, abiotically generated simple organics such as methane and formate can be measured in vent effluents, and these environments harbour what we think are the most ancient lineages of bacteria and archaea.

What's next? Are you continuing to test these ideas with further analyses or experiments?

Yes, at the moment we are testing these results with other approaches, while at the same time working on new questions. We are continuing our laboratory experiments, looking for chemistry that aligns with both microbial metabolism and Earth’s geochemistry. In our computational studies, we are testing our protein families and the LUCA/bacteria/archaea assignments with other methods. I am also working on a project that involves looking more closely at the structurally most ancient part of each protein family.

Is there anything else you’d like to discuss that I haven’t asked you about?

I would like to point out that many achievements in science happen through collaborations that often encompass researchers from all over the world, which is one of the great aspects of science. The origin of life field is historically divided between different schools of thought, disciplines, and approaches. However, science is increasingly collaborative in our field as well. 

At the end of the day, even though not all hypotheses on the origin of life can be correct, all of us are working towards a common goal: finding out what actually happened on the early Earth roughly four billion years ago when life emerged. I hope we will have increasingly productive and evidence-based discussions about this outstanding scientific question in the years to come.