The Dawn of Molecular Ecology

by Roberto
 

Almost exactly one year ago, I wrote a post on the key role played by a group of Spanish scientists in the early development of microbial mole­cular ecology. My main point was to drive home how the work they carried out in the early 1970s on species successions in the human gut, and their search for compounds mediating those successions, showed remarkable foresight. Their work led to the discovery of the microcins, and their overall thinking was literally decades ahead of the times.

 

What I wrote, though accurate, suffered from an enormous lacuna. I inadvertently omitted mentioning a key player of that influential group of scientists, the biochemist-ecologist Carlos Asensio. Now, two of the people I did mention, Fernando Baquero and Victor de Lorenzo, along with Alfredo Aguilar, provide us with a magnificent retelling of Asensio's cardinal role during the early days of molecular microbial ecology and in the development of Spanish science during that country's transition to democracy, after decades under Franco's dictatorship.

 

Why did I leave such a void in my prior post? Unfortunately, I never got a chance to meet Asensio in person. When I arrived at Harvard Medical School in mid-1983 I was aware of Asensio's role in the discovery of the microcins and was intent on working with him and his colleagues. By serendipity I learned that Felipe Moreno, who was starting to work on microcins in Madrid, had recently spent a few months at Harvard. I got Felipe's phone number and called him, hoping he would introduce me to Asensio. Then came the shock; Asencio had died tragically in an ex­plosion while on vacation the year before. Personally, the new paper comes to fill a large void; of its many important messages, here are my favorites.

 

Fig. 1. Working notes between the Asensio and Baquero groups on Microbial Ecology. Here, bacterial species (numbered squares) secrete a diversity of molecules constituting the molecular ecology of the intestinal microbiota. Source

Creativity emerges when individuals from different fields cross paths. The discovery of the microcins happened when Fernando Baquero, a microbiologist, and Carlos Asensio, a bio­chemist, began to exchange ideas on the mechanism of microbial successions in the guts of neonates. Just glancing at one of their working notes, where they sketched out their hypoth­e­sis that small, secreted molecules led to positive and negative interactions in multispecies mi­crobial communities, gives a sense of the synergy emerging from their working together (Fig. 1).

 

Intuition plays an important role in scientific discovery. The authors argue convincingly, based on Asensio's creative activity, on the value of intuition in the process of understanding. They call this the principle of there must be, something they consider a fusion of logical think­ing (reasoning) and intuition. In their words:

 

"Epistemologically, there must be implies a kind of anticipation of where and how to look for what we are after. In the case of microcins, Asensio became interested in the phenomena of microbial successions occurring during the normal colonization process of the intestinal tract in newborns. In this context, there must be some molecular mediators eliciting such replacements, but their action must have char­acteristics compatible with other circumstances operating in the intestine, i.e. they had to be resistant to degradation by intestinal proteases – as they indeed turned out to be."

 

Great science need not cost very much. Baquero's and Asensio's joint work during the mid-1970s was done when there were few funds for science in Spain. Their success is a clear example of what has come to be called frugal science. Experiments can be conceptually sophisticated yet be performed in simple and cost-effective ways. The assay that led to the discovery of microcins involved Petri plates, minimal growth medium, and cellophane membranes (to screen only low molecular weight compounds that would more likely be resistant to proteases). While readers might argue "that was fifty years ago, when such simple experiments could still be done," I'll argue back that there is still plenty of opportunity for sophisticated thoughts tested through simple platforms. The reality is that there are many countries today whose science budgets are minimal, yet great science is being done there. I am thrilled when I see efforts such as those done by Manu Prakash from Stanford to teach and promote frugal science.

 

Recognize the tension between elegant and brute-force experiments. Asensio had the natural talent to combine rigorous scientific inquiry with an aesthetic finesse in his experimental design. To him, experiments should be elegant rather than driven by brute force. The authors suggest that Asencio was disheartened when, after the discovery of the microcins through simple and elegant experiments, subsequent attempts at their purification were based on brute force. Here I beg to differ with the authors, at least in the case of our experiments purifying Microcin B17 in the mid-1980s. Somehow, we had the intuition that the protease-resistant peptide had to be resistant to high temperature. Unknowingly, we were applying the "there must be"  principle! This led to discover that we could rapidly and simply (dare I say elegantly?) obtain pure microcin by boiling cells. All proteins and other macromolecules, denatured and aggregated and were easily removed by centrifugation. Afterwards,  a single step of liquid chromatography yielded pure microcin. Brutal treatment yes, but not exactly a brute force approach! Still, if you ask me, I agree with the authors, given the choice between the elegance of a genetic experiment and a biochemical purification... you know what I would I choose. By way of warning, the authors send a directive to current-day scientists to never stop thinking, both logically and artistically. In today's science, which is often heavily driven by "data generation and its computational processing by automated learning platforms, scientists must envisage science in their minds, a task that is both logical and artistic." I completely agree!

 

 

 

 

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