Complementarity, uncertainties and Stem Cell Biology in Copenhagen

Max Delbrück was a young german physicist visiting Copenhagen regularly in the early 30s drawn by the allure and charisma of Niels Bohr and the ongoing meetings on Quantum Mechanics that took place there. When he arrived in the summer of 1932 for one of these meetings, he was dragged from the train station by a friend to a lecture that was being delivered by Bohr under the title “Life and Light’ (published later in Nature 1933, 131, 421-423). This episode changed Delbrück ‘s life and, possibly, the path of discovery in Biology. The essence of the lecture was whether there was a duality to Life that would mirror that of Light (particle and wave) and whether the principle of complementarity, so important to some interpretations of Quantum Mechanics, had an equivalent in Biology. This has been read in a variety of manners, most commonly in the context of the relationship between the physical and the life sciences. It was the challenge of finding about this relationship, as inspired by Bohr, that set Delbrück in motion to explore biological systems. The rest, of course, is history: Delbrück founded the Phage School and thus made a significant and enduring contribution to Molecular Biology and, as has been recognized often, brought the Copenhagen spirit into Biology setting the form and content of discussions in Cold Spring Harbor and Caltech which would spread later to the rest of Biology.

Over the last few years strides are being made to apply physical methods and inspiration to biological systems and it is in this spirit that as part of an annual series organized by The Center for Models of Life, a meeting took place last week on Dynamics of Stem Cell Decisions (https://indico.nbi.ku.dk/conferenceDisplay.py?ovw=True&confId=582). The setting was the famed room at the Niels Bohr Institute in Copenhagen where the foundations of Quantum Mechanics were chiselled out in the 1920s. It is a small old fashioned place, with wooden benches and desks, antique looking lamps and a blackboard. It is lit by period lamps with low wattage and, although the old clock in the back has been retired and there are Power Point facilities, it has been kept as it was in the 1920s; the windows, the frames of the doors, the seats, the detail reminds one that this is no modern theatre of science, and the pictures on the walls give a hint of where you are. The small capacity of the place limits the number of participants but encourages discussions and enhances their intensity aided, one suspect, by the spirit of the place.

Complementarity can be defined as the need to link two descriptions of a reality which are both necessary but, in principle, incompatible with each other. The theme of the meeting, the ‘Dynamics of stem cell decisions’ bears this notion which, in some ways, is emerging as an important problem in developmental biology. In a nutshell, development is, largely, a macroscopic process in which chains of cell fate choices coordinated in space and time lead to morphogenetic processes that shape tissues and organs. While we can observe this and obtain (through Genetics) information about the molecular components that configure the hardware that drives these events, the link between the molecular interactions in which these agents are involved (let us call it the microscopic description of the system) and the actual processes (the macroscopic description) remains elusive. In a certain way the problem of complementarity is there: we can describe the system at either level but, for now, it is not obvious how to connect the two.

We do know, have known for a while, the macroscopic description of The System and as we begin to unravel the microscopic one, we sense that there is a problem. I shall explain. The use of Genetics on the system that we want to understand (take your favourite one: an organ, a cell type, an organism) has yielded genes which are the gateway to molecules.  You can fall prey to the mirage that we understand because using the rules of Genetics we can link the names of these genes with lines and arrows (Figure 9 of your average NCS paper).  However, those diagrams are very low level accounts of what is going on. We are beginning to be able to measure (concentrations, numbers of molecules, half lives), follow the kinetics of the processes of interest, follow molecules of interests and focus more on the processes, their time scales, the numbers and distributions of the molecules that drive the events: the microscopic description of the process. The important lesson for this is enshrined in Lord Kelvin’s statement:

“When you can measure what you are speaking about, and express it in numbers, you know something about it, when you cannot express it in numbers, your knowledge is of a meager and unsatisfactory kind; it may be the beginning of knowledge, but you have scarely, in your thoughts advanced to the stage of science”

And this is what is happening in Cell and Developmental Biology. The problem is that when we do measure, we run into problems because what we see is not what we expected. The picture does not fit Fig.9, and a gap emerges between our understanding and our knowledge. In an increasingly clear examples, gradients of signalling molecules are not read in a simple Wolpertian manner and Morphogens are closer to Turing’s original notion than to the visions of Positional Information. At the molecular level we find stochasticity and rules of numbers and dynamics which we need to make compatible with the deterministic and reproducible processes that we can observe.  Natural Selection has entangled (in the quantum mechanical sense) processes which are perceived as causally related and, as a consequence of all this, for the moment we are not yet able to flesh out a connection between the molecular events and the tissue and organs that they give rise to. These issue were much in evidence in Copenhagen in the discussions on stem cells, a fashionable system, but also a good system to ask some of these questions. Not only are they ubiquitous but they harbour the potential to generate many fates in a reproducible manner though themselves appear, in principle, to be ‘uncertain of their fate’ at the individual level.

The meeting run through a wide range of topics including epigenetics, oscillations, stochasticity, networks and morphogenesis. The leitmotif, quantitative approaches to the questions laid by these problems. The message that while God is, as Einstein put it, subtle rather than malicious, Natural selection is both. While living systems are evidence of subtlety, the second accolade challenges our efforts to understand them. These themes rumbled in the discussions in Copenhagen last week and it was much appreciated that the group gathered in Auditorium A of the Niels Bohr Institute emphasized much that we do not know YET, as well as the ways to move this forward. The spirit of Copenhagen was very much in the air.

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