bio innovations

Biology without a program: variation as a stability factor

A bio-economy that would preserve life and all its evolutionary potential cannot ignore what makes biological specificity. Biological is that level of organisation of matter where the random variation of entities is one of the conditions for the durability of their lineage. Hence the biological mechanisms of amplification of variation, from the mut genes of bacteria (which protect the population by the rapid acquisition of resistance) to the origins of sex. For biological lineage to have a future, entities ("individuals") must die. Fortuitous variation causes some individuals to die, but acts as genealogical "life insurance". What is good for the individual is not necessarily good for the lineage and vice versa. This is true at all levels of biological organization. The regularity of biological phenomena, wherever it can be documented, does not come from a "programme" but from selected random variations, on a time scale corresponding to the level of integration considered. Thus, a synthetic biology that speaks of "software" to designate interactions between genes, that abuses the metaphor of "program" and that looks at a cell like a car engine is doomed in the short term. Why is this?
Photo: The Three Monkeys of Wisdom-Sculpture by Hidari Jingoro at the Toshogu-a-nikko-Japan Sanctuary (Koshin belief)

Dn the issue of the newspaper Science of August 16, 2002 an article made a big splash. The same gene, in presumably identical cells, in an identical environment, does not express itself in the same way. This is the result of a fundamental variability that results from the random behaviour of the cellular machinery, behaviour that we now have the technical means to detect, and above all the intellectual predisposition to accept it. Indeed, we used to like to think that the apparent large-scale order (that of the "good functioning" of the organism) comes from a small-scale order, an order given by instructions, principals, a program.

Randomness of gene expression is a factor of regularity.

Random gene expression, followed by selective phenomena, now allows us to think of an order on a large scale (that of the population) from disordered variations among the multitude on a small scale. The stochastic, i.e. random, character of gene expression was demonstrated and has only since been confirmed. It has implications that are now considered crucial for the fate of cells.
In order to understand the functioning of cells, and more broadly the regularities of the organism, mechanistic, reductionist and ultra-deterministic models of the role of genes have gradually given way to probabilistic biology, where chance and natural selection enter into the very heart of cells. To force the line and measure the extent of the change in point of view, we could say that "DNA functions as a random generator of proteins subject to selective constraints imposed by its environment" (Pour La Science no. 385, November 2009, p. 90). French popular science journals will echo this new biology and its consequences (La Recherche, October 2009, Pour La Science, November 2009, Pour La Science special issue December 2013).

Natural selection as a source of stabilization

What is the use of natural selection? We learned at school that it explains the evolution of species. It explains change. Variation in populations of living things happens in all directions, not necessarily according to the future needs of the individuals who experience it. Individuals therefore have different abilities. The number of offspring they will have, and therefore the number of inheritable abilities they will pass on, depends on the local conditions of the environment in which they are. If one can use a metaphor, "variation proposes, the environment disposes". If the environment changes, in the long term, the populations, and therefore the species, will change. This is still true today, but it is not enough. In the twentieth century, we have (somewhat) forgotten that in the short term natural selection can be stabilizing. At least more precisely, we did not mobilize it as such as an explanation of the stabilities of one and the same biological body.

The species conceived in the depth of time

There's a reason for that oversight. In the twentieth century, Ernst Mayr, one of the main protagonists of the synthetic theory of evolution, practiced what is called "species realism". For him, the species is conceived here and now, broadly speaking, as populations in which and between which genes circulate. The species is real.
Yet, with Simpson, the species is conceived "in the depths of time", and it is only on this condition that its conventional, rather than real, character can appear. But what the synthetic theory of evolution will retain, roughly between 1937 and 1977, is that species exist in the material world. The role of natural selection will therefore consist mainly in explaining the change of species.
However, if we reread Charles Darwin carefully, natural selection is first and foremost a source of stabilization. It will only be a source of change if the environment changes significantly. It is remarkable to note that the subtitle of the famous book "The Origin of Species" does not include the word "evolution", "transformation" or "transmutation". It includes the word "preservation": "The Origin of Species by means of natural selection, or the preservation of races favoured in the struggle for existence".
To sum up, for Ernst Mayr, natural selection explains the change of species; for Darwin, natural selection explains the momentary preservation of an average organism, a resemblance to which we give a species name. For Mayr the species is real, for Darwin it is conventional. Mayr wonders why and how what is regular (the species) changes, Darwin wonders why what changes all the time (the variations of the individuals) still manages to offer to our eyes a regularity (a resemblance). Regularity from which we forge a species name for communication purposes.

Cells in a state of variability and heritability

This 20th century oversight will have considerable consequences. Indeed, biology will need a principle of change to explain the evolution of species, but a principle of stability to explain the regularity of the structure and functioning of the body and its organs. Since natural selection is not regarded as a principle of regularity, it will not be used in medicine, physiology, molecular biology or biochemistry at the scales concerned.
This principle of regularity will reside in a metaphor imported into biology from cybernetics, that of the genetic program. In the last third of the twentieth century, it will still be taught at the university that all the cells of a body have the same "program", and even the same "genetic information", with cell differentiation resulting only from the different activation of various parts of this same program. Occasionally, selection will be mobilized to solve difficult questions that cannot be solved under the dominant paradigm, but it will never be considered as the general theoretical framework for these disciplines. In other words, one could, in those years, defend a thesis in these disciplines without ever having heard of selection. Biology remained one-eyed.
Today, we know that within the same biological body, cells undergo and record genetic variations. These cells divide, and during mitosis, transmit these variations. So we are dealing with cells with variability and heritability, and from there, with selectable cells. The couple variation-natural selection entered massively in the body as a source of regularities at the hinge of the XXth-XXIst century.
Since the demonstration at the molecular level of the randomness of gene expression in 2002, today's biology is ripe to recognize that small-scale selective phenomena are a source of stability, of regularities in the organism on a larger scale, where once the notion of "programme" was mobilized, which has become less and less useful.
These phenomena began in immunology, before moving on to the neurosciences, embryonic development, and oncology. The upheavals can be considerable. Current events show us that evolution, and more precisely natural selection, is useful for conception at all levels of biology.

Good therapies should not be based on eradicating cancer cells...

Two recent articles show the topicality of the two pillars of the Darwinian theory of evolution for the interpretation of cancer tumours. These two pillars are the principle of natural selection, on the one hand, and genealogical filiation with modification, on the other hand.
With regard to the first pillar, Enriquez-Navas et al. have established Darwinian cancer therapies that make selection a source of stability.
To understand what this is all about, let's take a little step back. First of all, it is important to know that a cancerous tumour has considerable genetic variability, greater than any somatic diversity anywhere else in the body. In the past, we used to think that in order to cure a patient, proliferative tumour cells had to be eradicated. This led to aggressive anti-cancer treatments that, like the overuse of antibiotics on bacterial populations, inadvertently selected the few proliferative cells that were resistant to treatment (what oncologists refer to as "..."). competitive release "). Sometimes a flurry of metastases would follow, killing the patient.
The change we are witnessing is not only technological, it is also in our ideas: in reality, cells are proliferating by default. It's a selective balance and a cellular dialogue that channels and regulates the proliferative potential of each one, exactly like what happens with species in an ecosystem. What was thought to be the consequence - proliferation - is only a default state, and what was thought to be the cause - the presence of a "driver" mutation in a gene - is only a predisposition that can be channeled, but which is not channeled in the presence of selective instability or a lack of dialogue.
In seeking to eradicate tumour cells, neither dialogue nor selective balance is restored. You're dealing with the consequence, not the cause.
Enriquez-Navas et al. show that chemical therapies using adaptive reasoning are more effective than elimination therapies. Doses of anti-cancer substances using the fitness cost of the resistant phenotype are high at first, then randomized afterwards, to maintain a moderate natural selection that engages the tumor in a stable cohabitation between cell phenotypes, which then requires decreasing doses of substances. They thus show that good therapies should not be based on eradication but on evolutionary biology.

Characterize the order of appearance of mutations

Another paper (Zhao et al.) focuses on the other pillar, filiation with modification, showing that it is possible to reconstruct a phylogeny of cancer tumour cells with reconstruction of ancestral somatic mutations and inference of divergence times between metastatic cell lines.
One of the conclusions is that metastatic cells are not necessarily late in the tumour, but may appear early in the primary tumour, even before the diagnosis has had time to be made. Phylogeny makes it possible to establish the order of appearance of the signaling mutations in the cancer, making it possible to develop anti-cancer therapeutics specifically oriented towards these primitive "signaling" mutations, and therefore made more effective. Anti-cancer therapies are going to be profoundly revised, as a consequence of the introduction of natural selection as a principle for understanding the body's phenomena.

Epigenetics and Beyond, Extended Heritability

Over the past two decades, biology has become more flexible with respect to heritability. What a population passes on to the next generation is no longer just a matter of "genetic information" encoded in the so-called DNA. Anything that varies and is passed on is likely to be subject, at the population level, to the effects of natural selection, and thus to what is known as evolution.
Of course, the genes continue to transmit; only now they are no longer the only ones. Part of what happens to an individual leaves chemical marks on this DNA, "labels" that condition the "reading" of the genes. These are the epigenetic marks. Although a mother passes on some of her genes to her child, she also passes on her digestive tract flora after birth. And we now know how important this is for the health and phenotype of the individual.
The same goes for the skin flora. For example, a phylogeny of mites of the resident skin flora has been made, it corresponds perfectly to the genealogy of the families. This means that the transmission is fairly accurate.
Languages vary, and are passed on: in humans they even heavily condition the choice of sexual partners. The same is true of eating habits, which in turn tend to select certain genes involved in the assimilation of food components in the population. This is true at other scales of observation: it is now known that somatic cells (the cells of the same body) are subject to variation and selection.
These observations are common today in neuroscience, immunology and cancerology, for example. The heritability we are talking about therefore also concerns other levels of analysis of biological phenomena. The evolution of the 21st century is no longer focused solely on DNA. It is "at all levels" of an organism that characteristics are likely to vary and be transmitted. The gene is now a partner, not a notary.

Modern epigenetics is not "Lamarck's comeback."

Let us note in conclusion that it is customary to say that epigenetics announces Lamarck's return. This common idea is erroneous in several ways. Firstly, because it is based on the idea, in the background, that the difference between Lamarck and Darwin would lie in the heritability of characters acquired in the course of individual life, which would be admitted by Lamarck and not by Darwin. This is a historical error: Darwin also admitted it (he did not know the fine mechanisms of heredity).
The difference between these two authors lies mainly in two ideas. Lamarck is interested in the origin of variation in populations, Darwin takes it for granted, and is mainly interested in the consequences of variation.
For Lamarck, the variation appears according to the needs of the wearer, while for Darwin the variation appears randomly, independently of those needs. For Lamarck, the accumulated change in an individual lineage reflects the change in the whole population: there is no difference in level between ability and adaptation.
In Darwin, these two levels are decoupled: changes in an individual lineage do not necessarily reflect the average of stabilized changes in the population. Aptitude (of the individual) and adaptation (of the species) are two distinct qualities that correspond to two scales of observation. Modern epigenetics is Darwinian: indeed, epigenetic marks are not necessarily beneficial to the individuals who have them. Epigenetic heritability of behaviour and the effects of stress is an example.

The gene is not an absolute regulator.

Finally, and this is not new, the environment intervenes in gene expression, manifesting in organisms what is called plasticity. For example, in some species of butterflies, the colour of the wings will depend on the degree of humidity in the environment. In turn, many organisms modify their environment, so that what remains stable, or even evolves, are sometimes even loops of interactions. The gene depends on its surrounding proteins, it depends on the environment, it is therefore a partner, it is no longer conceived as an "absolute regulator", the holder of a program.
The biology of the 21st century is therefore able to recognize evolution by natural selection (or drift) at all levels of biological organization where variation and heritability of this variation can be found, and we now know that these phenomena do not only concern genes. This does not so much upset the theory of evolution as it does medicine and a certain conception of genetics (including the genetics of embryonic development) which, in the second half of the 20th century, were too focused on genes and all-DNA.

The end of genocentric biology

Therefore, there is no different mechanism to explain the development (ontogeny) or appearance and maintenance (the program) of an individual on the one hand, and the appearance and stability of a species on the other (phylogeny). It is natural selection that helps explain both relative stability, and changes as the environment changes, at both levels of observation. Hence the proposal of a new word, ontophylogenesis, to give coherence to biology.
The consequence of these upheavals is that biology in the 21st century is less centred on DNA and less inclined to speak of a "genetic programme". The metaphor has been revisited to such an extent that it is fading and fading away. This is the fraction of researchers who think about biology. In the public, in recent school curricula, among a certain synthetic biology that continues to lack an understanding of biological sustainability, and for a majority of non-biological researchers, 20th century biology, genocentric, DNA-centered, excessively reductionist and deterministic, remains in the minds.

The notion of genetic information is under debate

In emerging biology, the notion of the gene remains important, but its status and contribution are at the heart of the discussions. If the gene is only a partner, then the difference in status between "genotype" and "phenotype" becomes blurred. The notion of "blueprint" is only a mnemonic and utilitarian metaphor for learning one's anatomy compared to university, not an inscription in biological reality. The utilitarian metaphor of "map" should be preferred, and it has the merit of clarity. And in the field of what really is, we should speak not of a "map" but of a phylogenetic mosaic. Moreover, phylogenetic thinking alone is incompatible with this notion of "plan".
The notion of "genetic information" is under debate, and it could even be said that if it is to be retained it would have to be redefined. But that would be the subject of another colloquium.
In the meantime, it is highly likely that synthetic biology will not control living organisms as it intends to do, by hiding the spontaneous variation that is intrinsic to them, or by claiming to control it. Such is the view that modern natural history and its theoretical framework, that of evolution, can take on certain uses made of biological matter.
Guillaume LecointreNational Museum of Natural History
Intervention from 15 September 2016 to LIVELY FESTIVAL 

A few feature articles, mostly recent and in chronological order, attesting to these changes:
Elowitz, M.B. et al. Stochastic Gene expression in a single cell. Science 297 (5584) pp. 1183-1186 (August 16, 2002).
Laland, K. et al. Does Evolutionary theory need a rethink? Nature 514, pp. 161-164 (October 9, 2014).
Enriquez-Navas P.M. et al, Science Translational Medicine 8 (327) (February 24, 2016).
Zhao et al, PNAS, 113(8), pp. 2140-2145 (24 February 2016).
Kiberstis P.A., Science 352 (6282), pp. 163. (April 8, 2016).
Turajlic S. & Swanton, Science 352 (6282), pp. 169-175. (April 8, 2016).
Willyard C. Nature 532, pp. 166-168. (April 14, 2016).
A few books and articles to go further :
Dossier Pour La Science n°81 " L'hérédité sans gènes ", December 2013.
La Recherche, Le hasard au cœur de la Vie, n° 434, October 2009.
For La Science, Hasard et incertitude, n°385, November 2009.
Capp, Jean-Pascal. 2015. "New Perspectives on Stem Cells." Editions Matériologiques.
Heams, Thomas, Huneman, Philippe, Lecointre, Guillaume and Silberstein, Marc. 2011. The Darwinian Worlds. The Evolution of Evolution. Second Edition. Editions Matériologiques, Paris.
Kupiec, Jean-Jacques, Olivier Gandrillon, Michel Morange and Marc Silberstein (editors). 2009. Chance at the heart of the cell. Editions Matériologiques, Paris.
Lecointre, Guillaume, 2015. Are we descended from Darwin? Le Pommier.
Lecointre, Guillaume, 2013. Mauvais plan! pp. 58-59, in Espèces, revue d'histoire naturelle, n°9.
Théry, Frédérique, 2016. "The hidden face of cells." Editions Matériologiques.
Other books :
Deutsch, Jean. 2012. The gene. An evolving concept. Seuil, Paris.
Gage, Fred and Muotri, Alysson. 2013. Jumping genes in the brain. Dossier Pour La Science n°81 " L'hérédité sans gènes ", pp. 18-23.
Heams, Thomas. 2004. Molecular Biology: Facing the Midlife Crisis. Pp. 237-261 in Dubessy, Jean, Lecointre, Guillaume and Silberstein, Marc (eds.). Materialism (and its detractors). Syllepse, Paris.
Heams, Thomas. 2008. Towards a probabilistic theory of life. Prisme n°12, published by the Cournot Centre for Economic Research, Paris.
Heams, Thomas. 2009. Stochastic gene expression and cell differentiation. Pp. 31-62 in Kupiec, Jean-Jacques, Olivier Gandrillon, Michel Morange and Marc Silberstein (editors). Chance at the heart of the cell. Editions Matériologiques, Paris.
Heams, Thomas. 2013. Is there a genetic program? pp. 131-146 in Kupiec, Jean-Jacques. Life, so what? Belin, Paris.
Kupiec, Jean-Jacques. 2008. The origin of individuals. Fayard, Paris.
Kupiec, Jean-Jacques. 2013. Life, so what? Belin, Paris.
Kupiec, Jean-Jacques. 2012. Ontophylogenesis. Evolution of species and development of the individual. Collection Sciences en questions, Quae, Versailles.
Lewontin, Richard. 2003. The triple helix. Genes, organism, environment. Seuil, Paris.
Longo, Giuseppe, Miquel, Paul-Antoine, Sonnenshein, Carlos, Soto Ann. 2012. Is information a proper observable for Biological organization ? Progress in Biophysics and Molecular Biology, 109 (3): 108-114.
Mayr, Ernst. 1969. Principles of systematic zoology. McGraw-Hill. New York.
Mayr, Ernst. 1982. History of biology. Fayard, Paris.
       Théry, Frédérique. 2016. "The Hidden Face of Cells". Editions Matériologiques.
Wrong, Patrick. 2016. What is materialism? Belin, Paris.

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