A new sort of engineering: I. Of inner forces, programmes and duality in living systems

Biology is a young science and this is easy to forget. For all the hype and glamour of modern conferences and publications, we still are in the midst of empirical data gathering. A bit what astronomers and tinkerers were doing in the XVII century. We have changed collecting and classifying beetles and butterflies for genes and regulatory regions, but the method has not changed that much: systematics.

This aside, there are, let us say, three issue in Biology: how a system builds itself, how it works and how it evolves, We know a lot about the second, have a good hypothesis about the last one and think we know, though really we do not understand much, about the first one. Our knowledge about the functioning of biological systems is reflected in the way we use this knowledge in immunology, cancer biology and neurobiology. However, this praxis is a bit like the building of devices by engineers in the XVIII and XIX centuries, empirical, and it will improve once we understand the underpinning of the systems. In Biology this means to understand the connection between genotype and phenotype, how genes build organisms, which we don’t. If we agree (and you don’t really have to) that this is THE problem, you will see that something is changing though, and the roots of this change can be found in history. When something repeats itself in history it is that it has some deep roots and we should not ignore it. The seeds of the story I want to tell lie with C.F. Wolff , follow with H Driesch and reveal how for a while, perhaps necessarily, we had to forget the important questions, though we don’t have to any more. Wolff and Driesch saw the questions and those questions are, today, at the forefront of the agenda of biological research.

On forces: CF. Wolff and H. Driesch

In the midst of the XVIII century, guided by a curiosity about the development of embryos, C. F. Wolff carried out a number of dissections and reported findings that challenged the well established theory about the emergence of a living system; preformationism. The leader of this view was A. von Haller and Wolff entered into a lengthy and hard, though always polite, diatribe with him (for details see S Roe). In contrast with the at the time prevalent view that the embryo was preformed but not visible, Wolff favoured the notion that the organism emerged progressively from an informed mass which acquired shape and form progressively. The preformationist view may seem silly from the perspective of today but, it is not in the historical context, and I suspect that we also harbour many ideas that will look silly from the perspective of the future; the ‘power of the gene’ being a most interesting one. Wolff’s view was called epigenesis and its contrast with preformationism, took years to develop –such things always do-. Nonetheless, Wolff made his point and described how organs appear progressively from amorphous masses of tissue (cells were not yet the units of development), in two treatises (“Theoria Generationis” and “De Formatione Intestinorum”) and most clearly in the second. One question that Wolff was interested in was, naturally, what propelled this epigenesis.

Now, Physics had a good grip of human reasoning at the time. Since the time of Leibniz, natural philosophers (aka scientists) were aware of the existence of vis or forces and, in particular of a vis viva, which drove the motion of bodies and later became known as kinetic energy. What Wolff had described led him to speculate on the existence of a vis (force) of sorts driving the emergence of shape and form; he called this force ‘vis essentialis’, a formative force or energy. The notion has often been hijacked by vitalists but, if you thought about it, ‘vis essentialis’ is not, like potential energy was, some spooky spiritual notion but something which tried to account for some observations. Reams of philosophy have been written on vitalist interpretations of the vis essentialis but let us not digress from the simple point that Wolff had identified some internal inertia of a biological system that was precise and reproducible and which he claimed had a physical basis. History and some historians have a habit  of making a meal of what someone may or may not have said or thought but the fact is that Wolff only tried to encompass with words what his intuition told him lied behind what his eyes saw. The thought was laid to rest while the dust settled in the epigenesist/preformationism debate which would be won, as we now know, by force of observation on the side of epigenesis.

 

The XVIII and in particular the XIX century are rich in the description of the development of all sorts of organism and this descriptive phase takes over until towards the end W Roux in his very programmatic statements opening the journal that bears his name (“W Roux Archives of developmental biology”, nowadays “Development, genes and evolution“) ushers developmental biology as an experimental science, away from the mire of descriptive embryology.  It is in this context that H Driesch makes his formidable entrance into the story with a series of experiments which, unknowingly, set up the agenda of developmental biology for the XX century. In the first and most famous of experiments he separates the first two blastomeres of a sea urchin embryo which, under normal conditions each would have given rise to a half of the organism, and watches what happens. As he puts it in his famous paper: (Driesch, H. 1892 Zeitshrift für wissenshaftliche Zoologie 53, 160-178 Translated to English in Foundations of Experimental Embryology 1964 B. Willier and JM Oppenheimer eds Hafner Press)

“I awaited in excitement the picture which was to present itself in my dishes the next day. I must confess that the idea of a free swimming hemisphere or a half gastrula with its archenteron open lengthwise seemed rather extraordinary. I thought the formation would probably die. Instead the next morning I found in their respective dishes typical, actively swimming larvae of half the size”

Leaving aside the style (what a wonderful time when you were allowed to muse over your results with freedom!), there is nowhere to hide the result which contradicted a view, descended from preformationism and prevalent at the time, that embryos are mosaic…. But the result is surprising, the cells regulate, each gives rise to a whole organism. He repeats the experiment at the four cell stage and later in a series of variations, and finds very similar results. He ponders how can this be.

 

In 1911 he gave the Gifford lectures in Aberdeen where he looks back at his work. The book that comes from the lectures is, for the most part, an apology of vitalism. After all, Driesch did become an unrepentant vitalist in the second phase of his career, but the first part of the book is an excellent summary of his toilings with the experimental observations that led him to ‘despair’; in a mild manner. The section concerning his reasoning through his experiments in an attempt to find a rational explanation for what he was seeing, is remarkable reading and I suggest you look at it (see here some of it). An important point in this text is where he tries to reason what kind of a machine could behave like this and he reasons.

Much as Wolff earlier, he lived in a physics led intellectual environment in which engineering and machines were part of the daily life. More than Wolff, he lived in the hayday of engineering and machines. One guesses that both Physics and Engineering provide a guide to think rationally about the seemingly irrational principles that guide living systems. So, what he wondered in a mechanical analogy is whether one could describe a living system as a machine and if so and in the light of his experiments, what kind of a machine should this be. In his own words:

We shall understand the word ” machine ‘ in a most general sense. A machine is a typical configuration of physical and of chemical constituents, by the acting of which a typical effect is attained. We, in fact, lay much stress upon embracing in our definition of a machine the existence of chemical constituents also; we therefore understand by the word ” machine ” a configuration of a much higher degree of complication than for instance a steam-engine is.  (….). And we know, further, that this truly whole development sets in irrespective of the amount and direction of the separation. Let us first consider the second of these points. There may be a whole development out of each portion of the system ” above certain limits ” which is, say, of the volume V. Good! Then there ought to exist a machine, like that which exists in the whole undisturbed system, in this portion V also, only of smaller dimensions; but it also ought to exist in the portion V^ which is equal to V in amount, and also in V₂, in V₃, V₄ and so on.

Indeed, there do exist almost indefinitely many V_n, all of which can perform the whole morphogenesis, and all of which therefore ought to possess the machine.(…). A very strange sort of machine indeed, which is the same in all its parts (Fig. 14) ! But we have forgotten, I see, that in our operation the absolute amount of substance taken away from the system was also left to our choice.

 From this feature it follows that not only all the different V_n, all of the same size, must possess the hypothetic machine in its completeness, but that all amounts of the values  V_n – n, n being variable, must possess the totality of the machine also: and all values V_n – n, with their variable n, may again overlap each other. Here we are led to real absurdities !

He is absolutely right, what he is describing is, basically, a cell but, of course, at the time, cell biology is prehistoric, genetics does not exist and the functional structure of a cell is not even on the cards. So, he exclaims with despair “….no kind of causality based upon constellations of single physical and chemical acts can account for organic individual development; this development is not to be explained by any hypothesis of configuration of physical and chemical elements”. And,slowly, he turns towards vitalism for an answer. But before, just before, he leaves us a gem of his understanding of what needs to be explained. In trying to understand the development of an organism, he suggests that there must be a function of different variables that decides what we would call today the fate of a cell in development

pv (x) = f(x, l, E)

Where pv(x) is the prospective value of element x (which we could see as a cell), s is the absolute size of the system, l is the position of element x and E, the most interesting of all variables, is the prospective potency, what he called Entelechia. This notion had been used by Aristotle and Leibniz, but it is with Driesch that it lives up to its own etymology: Entelechia means ‘that which bears its end within itself’, and it is not difficult to see a connection between the vis essentialis of Wolff and the Entelechia of Driesch. Both are trying to grasp the observation (or intuition if you wished) of some internal material or measurable inertia that is reproducible and drives the generation of form in living systems. Unknowingly this is addressing the issue of the genetic programmes that drive development and that today we can see as the basis of both interchangeable notions. A. Garcia Bellido has been a modern bearer of these notions and the one who has placed Entelechia on a genetic footing, one where we can begin to try to think about the genetic programmes that drives the system (Wolff) and the system that drives its homeostasis (Driesch), developmental and adult.

More of this next time but before that, to wrap up this historical background a brief account of the last pre-genetics/cell biology ditch to search for a physical explanation of Biology.

On duality: N. Bohr and M. Delbruck in Copenhagen

In 1932 Max Delbruck arrived to Copenhagen to meet the members of the famed School of Copenhagen of quantum mechanics. The day he arrived, Bohr was giving a lecture entitled “Life and light” in which he would tackle the problem of the physical nature of the phenomenon of Life. This was taking place at the height of the development of Quantum Mechanics and the wave-particle duality exhibited by matter and light had been accepted, understood and interpreted. In his lecture, Bohr speculated that maybe there was a similar duality for Life, and that in this case, understanding would emerge from probing this dual nature which, in his opinion, would have a material and a vital element. In this context Bohr wondered whether the study of Life might not reveal new Physical principles, much as the deep study of matter and light had revealed to Physics at the beginning of the century. Life was, after all a physical phenomenon. Delbruck was in the audience and was very taken with this lecture; with encouragement from Bohr and Heisenberg, he turned his attention to Biology. Intriguingly, although he founded the Phage School which led to molecular Biology, he never found the new laws of Physics in Biology, that Bohr had made him think about in Copenhagen, though he continued to search for them all his life.

Almost a century later, Life, Biology, has not produced many dramatic new physical principles, certainly not in the physical sciences. Crick provides a reason for this state of affairs when he contrasts Delbruck, searching new laws of Physics, with Pauling on the trail that Life is just chemistry. As he puts it “so far history has proven that Pauling was right”. For the moment the triumph of Chemistry is clear: life is just chemistry in nonequilibrium conditions and Biology has not needed of any new physical concept in its main body of knowledge. However, Crick made the proviso of ‘so far’ and we might be on the verge of some surprises which could explain what Wolff and Driesch sensed in embryos and Delbruck searched in vain: the inner forces that shape embryos and endow them with the ability to control space and time (next: A new sort of engineering II. Genes, time and space. Supervising self organization ).