Why Did Jacques Monod Not Become Ole Maaløe

by Elio
 

I was asked recently why Jacques Monod did not followup on his early work on bacterial growth. In­stead, he happily veered in a different direction and went on to become one of the fathers of Mo­le­cu­lar Biology. Together with François Jacob, he proposed the operon model and other key break­throughs on the regulation of gene expression. The Nobel prize followed.
 

Portrait of Jacques Monod. Source

Specifically, why did Monod not go on to study how bac­te­ria respond globally to changes in growth conditions? The questioner had in mind why Monod did not make the simple measurements that became the basis for the Copenhagen School of Growth Physiology (aka the Maa­løe School). Having lived through those times, I should be able to conjure up a response.
 

What's this about? Before and during WWII, Monod work­ed in Paris on basic aspects of bacterial growth. His doc­to­r­al thesis (1941) was entitled 'Recherches sur la Crois­sance des Cultures Bacteriénnes.' He was equipped with a sensitive apparatus for making rapid and precise mea­sure­ments of bacterial mass, a nephelometer. This device measures the turbidity of a suspension by having a light detector placed at, say, 90° from the source beam. This is a sensitive way to make such measurements because here the blank is set at zero, whereas in a colorimeter / spec­tro­pho­to­me­ter, it is set at 100%.
 

Among Monod’s contributions to the field of bacterial growth, two stand out. The first is that the rate of growth of a culture has a Michaelis-Menten-like dependence on substrate concentration, a topic masterfully reviewed here. The second is 'diauxie,' the discovery that when bacteria are fed two utilizable substrates, they reproducibly pause after exhausting the more utilizable one before resuming growth on the second. It is this discovery that led Monod and Jacob to postulate the ope­ron model and to other key breakthroughs on the regulation of gene expression.
 

Portrætfoto af Ole Maaløe. Portrættet hænger in­dram­met på Institut for Molekylær Cel­le­bio­logi, (tidligere Mi­krobiologisk Institut), Køben­havns Universitet, Øster Fa­ri­magsgade 2A (Kopi: Berthe Marie Willumsen). Source

Maaløe's Copenhagen School started out by carrying out measurements on how bacteria vary their basic cellular properties when grown in different media. The main con­clusions from this early work were that cell size and ma­cro­mo­le­cu­lar composition (the overall content of DNA, RNA, and proteins) change as a simple function of the growth rate. It is the growth rate, not the actual com­po­si­tion of the medium, that determines if a cell is to be large or small, replete with ribosomes or having relatively few, having multiple DNA replication forks or not. Out of such studies came the conclusion that at a given temperature, the rate of macromolecular synthesis is nearly constant, whether the bacteria are growing fast or slowly. When bacteria need to make more cell protein they adjust the content of ribosomes accordingly (as opposed to make the ribosomes work at faster speeds). These conclusions and others were elegantly articulated by Fred Neidhardt (see here). For a historical perspective on the studies of bacterial growth phy­si­o­lo­gy, see here and for a personal recollection of the Copenhagen school, here.
 

With a renewal of interest in understanding the mechanisms underlying bacterial growth phy­si­o­lo­gy (see for example papers from T. Hwa's lab, here and here), the question now surfaced: why did Monod not carry out such studies? Did Monod disdain growth physiology? In 1949 he did say that: 'The study of the growth of bacterial cultures does not constitute a specialized subject or a branch of research: it is the basic method of microbiology.' But, for all this ostensible disparagement of growth physiology as a science, Monod co-invented (along with Novick and Szilard) the chemostat, the continuous culture device effectively used to grow bacteria in the lab and in huge fer­men­ta­tion tanks.
 

In answer to the query, my guess is that Monod was focused on the molecular basis of regulatory mechanisms to the neglect of the cellular ones. He was far from alone in this. At that time, as the term 'Molecular Biology' became the vogue, reductionism reigned supreme – and deservedly so because mechanistic answers came along with stunning speed. Those were giddy times, with im­portant discoveries at the molecular level made with spectacular frequency. Cells were left behind – they just seemed too complicated to bother with and had to wait for the development of better tools, both experimental and computational. At the time, the work from Copenhagen was not per­ceived as mainstream, not by Monod, not by most of the people at the old CSH symposia (then the mecca for molecular biologists). I recounted (see here) that when I told Francis Crick of this work, he said: "Congratulations, you started a new field. But it's over!"  The topic, in his view, went from inception to oblivion in one step.
 

As John Ingraham pointed out to me, a personal factor also distinguished Monod and Maaløe. Broad­ly speaking, Monod dealt with yes or no answers, Maaløe with quantitation (digital vs. ana­log?). Did this matter? Quite possibly.
 

The old work of the Maaløe school is being resurrected and is now considered basic to what is called 'Systems Biology.' Interestingly, the current emphasis is in part about how cell size reflects the magic of the cell cycle (for some exciting examples, see here and here). To my personal satis­faction, mechanistic answers to the basic findings of the Copenhagen School are arising with some frequency. In his lugubrious assessment, Crick was, for a change, not quite right. The 'new field' of bacterial growth physiology was simply premature and had to wait for new tools and new insights. But cells are now finding their place in the sun. Time does tell…
 

I thank John Ingraham, Jon Beckwith, and Roberto Kolter for their help in finding the answer.
 

Front page: 1^er colloque international: "Le bactériophage", Royaumont, France, Juillet 1952. See source for where to spot Jacques Monod and Ole Maaløe. Source